Product Class 13: 1,2,3-Triazoles

13.13 Product Class 13: 

1,2,3-Triazoles 

A. C. TomØ 

General Introduction 

Previously published information regarding this product class can be found in Houben– 

Weyl, Vol. E 8d, pp 305–405 (1,2,3-triazoles) [1] and pp 406–478 (benzotriazoles). [2] Other important 

reviews on the chemistry of 1,2,3-triazoles and their benzo derivatives are also 

available. [3–9] 

1,2,3-Triazoles and benzotriazoles are important types of heterocyclic compounds. 

They find numerous applications in industry, namely as dyestuffs, fluorescent whiteners, 

photostabilizers of polymers, optical brightening agents, corrosion inhibitors and as photographic 

photoreceptors. [6,7] Also, due to their extensive biological activities, they find 

successful application in medicine and as agrochemicals. [6,7] Beyond this, these compounds 

are intensively studied by many research groups due to their theoretical interest 

and synthetic usefulness. 

The 1,2,3-triazoles can be divided in three main groups: monocyclic 1,2,3-triazoles, 

benzotriazoles, and 1,2,3-triazolium salts. As indicated in Scheme 1, for monocyclic 

1,2,3-triazoles three subclasses can be recognized, depending on the position of the substituents 

in the ring. While 1H- and 2H-1,2,3-triazoles are aromatic compounds their 4Hisomers 

are not. This fact is reflected in the abundance of examples of 1H- and 2H-1,2,3triazoles 

and the rarity of 4H-1,2,3-triazoles. [3] In the literature, the 1,2,3-triazole system is 

sometimes named as “v-triazole” in order to distinguish it from “s-triazole”, the 1,2,4-triazole 

system. 

Scheme 1 Classes of 1,2,3-Triazoles 

R 

N 

N 

N 

1 

R1 4 3 

5 

2 

1 

R1 1H-1,2,3-triazoles 

4 3 

5 N 

6 

7 

N 2 

1 N 

R 

1H-benzotriazoles 

1 

R 1 

R 1 

N 

NR 

N 

1 

2 

+ 

1 

R1 1,2,3-triazolium salts 

FOR PERSONAL USE ONLY 

N 

N 

NR1 R1 R1 4 3 

5 

1 

2 

2H-1,2,3-triazoles 

4 3 

5 

NR 

2 

N 

1 

2H-benzotriazoles 

1 

N 

6 

7 

N 

R 

N 

N 

1 

R 

4 3 

5 

1 

2 

1 

R1 4H-1,2,3-triazoles 

2 

NR 

N 

1 

1 

NR N 

1 

R 

N 

N 

1 

R1 R 

+ + 

N 2 

2 

1 

N 

1 

1 

N 

+ 

R1 R1 R1 benzotriazolium salts 

415 

for references see p 587 

A. C. TomØ, Section 13.13, Science of Synthesis, 2004 Georg Thieme Verlag KG

N-Unsubstituted 1,2,3-triazoles can be regarded either as 1H- oras2H-derivatives since 

these two tautomeric forms are in equilibrium, both in solution and in the gas phase 

(Scheme 2). In this article, for simplification, this type of compound will be represented 

as 1H-triazoles, independently of the predominant tautomer. 

Scheme 2 Tautomerism in 1,2,3-Triazoles 

N 

N 2 

1N 

H 

N 

2 

NH 

N 

1 

1H-1,2,3-triazole 2H-1,2,3-triazole 

N 

N 2 

N 

1 

H 


416 Science of Synthesis 13.13 1,2,3-Triazoles 

N 

2 

NH 

N 

1 

1H-benzotriazole 2H-benzotriazole 

The two tautomeric forms of 1,2,3-triazole and benzotriazole are in equilibrium, both in 

solution and in the gas phase (Scheme 2). However there is an extraordinary difference in 

stability between 1,2,3-triazole and benzotriazole tautomers. In the gas phase, the 2H-tautomer 

of 1,2,3-triazole represents more than 99.9% of the equilibrium mixture, whereas 

in benzotriazole the 1H-tautomer is the predominant one (more than 99.99% at equilibrium). 

[10] In solution, the much higher dipole moment of 1H-tautomers favor these structures 

and, as a consequence, mixtures of 1H- and 2H-1,2,3-triazole are observed in solution 

whereas the higher stability of 1H-benzotriazole is reinforced. [10] In the solid state, 

1,2,3-triazole exists as a 1:1 mixture of 1H- and 2H-tautomers, while 4-phenyl-1,2,3-triazole 

and 4-nitro-1,2,3-triazole are, respectively, in the 2H- and 1H- tautomeric forms. [11] 

The experimental dipole moment in benzene for the tautomeric mixture of 1H- and 2H- 

1,2,3-triazole is 1.85 D at 258C and 2.08 D at 458C. The experimental dipole moments are 

as follows: 1H-1,2,3-triazole 4.38 D, 2H-1,2,3-triazole 0.22 D, 1H-benzotriazole 4.15 D, and 

2-methyl-2H-benzotriazole 0.49 D. [7] 

1H-1,2,3-Triazole is both a weak base (pK a 1.17) and a weak acid (pK a 9.4) of comparable 

strength to phenol. 1H-1,2,3-Triazole-4,5-dicarbonitrile (pK a 2.53), 4,5-dibromo-1H- 

1,2,3-triazole (pK a 5.37), and 4-nitro-1H-1,2,3-triazole (pK a 4.80) are much more acidic compounds. 

1-Methyl-1H-1,2,3-triazole (pK a 1.25) shows a basicity comparable to 1H-1,2,3-triazole, 

but 2-methyl-2H-1,2,3-triazole is a much weaker base. [12–14] The basicity of N-unsubstituted 

and N-methyl-1,2,3-triazoles in the gas phase, in solution, and in the solid state 

has been determined. [11] The fused benzene ring in benzotriazole (pK a 8.2) is base-weakening 

and acid-strengthening. Substitution of hydrogen atoms by chlorine in the benzene 

ring results in increased acidity: 5-chlorobenzotriazole, pK a 7.7; 4,5,6,7-tetrachlorobenzotriazole, 

pK a 5.5. [15,16] 

The application of semi-empirical and ab initio methods in theoretical calculations 

for 1,2,3-triazoles and benzotriazoles and the description of a number of instrumental 

techniques used in the characterization of these systems have been reviewed. [7] 

1,2,3-Triazoles with a strong electron-withdrawing group at N1 (e.g., cyano, nitro, or 

arylsulfonyl groups) undergo ready and reversible ring opening to Æ-diazoimine tautomers 

(Scheme 3). This ring–chain tautomerism, also observed in some benzotriazole derivatives, 

is markedly temperature dependent. [17–20] 


Scheme 3 Ring–Chain Tautomerism in 1,2,3-Triazoles and Benzotriazoles 

R 1 

R 2 

N 

X 

N 

N 

X = CN, SO 2Ar 1 

N 

N 

N 

X 

X = CN, SO2Ar 1 , NO2 

R 2 N 2 

R 1 NX 

This type of tautomerism is also involved, for example, in the interconversion of 1-aryl- 

1,2,3-triazol-5-amines and 5-anilino-1,2,3-triazoles (R 1 = aryl) (Scheme 4). This isomerization 

is known as the Dimroth rearrangement. It is also observed in the interconversion 

of triazoles with other substituents at position 5 (or 4) and in the conversion of 1,2,3-triazoles 

into other ring systems. The equilibrium is established thermally, but its position 

is influenced by the basicity of the solvent. In pyridine, for example, the equilibrium position 

is shifted to the more acidic NH triazoles. It is also observed that electron-withdrawing 

groups and large, rigid groups tend to favor the exocyclic nitrogen while alkyl groups 

tend to favor the cyclic nitrogen. This subject has been reviewed. [21] 

N 2 

NX 

Scheme 4 Dimroth Rearrangement in 1,2,3-Triazoles 

H 2N 

R 2 

N 


General Introduction 417 

R 2 N 2 

R1 N 

N 

= Me 

R1 H2N NR1 R2 R 

N2 N 

2 

R 1 HN NH 

R 1 = aryl 

In terms of stability, monocyclic 1,2,3-triazoles and benzotriazoles are remarkably stable 

compounds. The triazole ring is not normally cleaved by hydrolysis or oxidation and reductive 

cleavage only occurs under forcing conditions. The presence of substituents that 

have a destabilizing effect on the ring system can facilitate the cleavage. When subjected 

to pyrolysis or photolysis, 1,2,3-triazoles and benzotriazoles extrude nitrogen and produce 

very reactive species which react further to form a range of stable compounds: nitriles, 

ketenimines, azirines, pyrazines, indoles, etc. The thermal or photochemical extrusion 

of nitrogen from 1-arylbenzotriazoles leads to the formation of carbazoles (Scheme 

5). 

R 1 HN 

N 

H 

N 



Scheme 5 Photolysis of 5-Chloro-1-(4-chlorophenyl)-1H-benzotriazole 

Cl 

N 

N 

N 

Cl 

MeCN, hν 

− N2 

Cl 

N 

• 

Cl 

Cl Cl 

Both monocyclic 1,2,3-triazoles and benzotriazoles are readily alkylated on nitrogen by 

alkyl halides, dimethyl sulfate, diazoalkanes, methyl sulfonates, and other alkylating 

agents; generally mixtures of all possible N-alkyl isomers are obtained. With more reactive 

reagents, or under forcing reaction conditions, triazolium salts are obtained. N-Arylation 

is also possible if activated aryl halides are used. 1,2,3-Triazoles and benzotriazoles 

also react with acyl halides and anhydrides to furnish the corresponding N-acyl derivatives. 

These compounds also react with sulfonyl chlorides, isocyanates, chlorotrimethylsilane, 

etc. to give the corresponding N-substituted derivatives. Electrophilic substitution 

at CH positions is also possible: halogenation and nitration are examples of such transformations. 

Lithiation of triazoles followed by addition of electrophilic reagents is another 

versatile approach to functionalization of these compounds at CH positions. Triazoles can 

also be activated toward electrophiles by introduction of an N-oxide group. 

All these types of reactions, and many others that produce new 1,2,3-triazole derivatives, 

are described in this section. Also, the synthetic methods available for the construction 

of the 1,2,3-triazole ring are reviewed. 

13.13.1 Product Subclass 1: 

Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 

13.13.1.1 Synthesis by Ring-Closure Reactions 

13.13.1.1.1 By Formation of One N-N and One N-C Bond 

13.13.1.1.1.1 Fragments C-C-N-N and N 



13.13.1.1.1.1.1 Method 1: 

From 2-Diazo-1,3-dicarbonyl Compounds and Amine Derivatives 

The cyclocondensation reaction of 2-diazo-1,3-dicarbonyl compounds with amine derivatives 

is an old but versatile, simple, and completely regioselective method for the preparation 

of 1H-1,2,3-triazoles. This method was developed by Wolff at the beginning of the 

20th century; he reported the synthesis of triazoles 3 by the reaction of ethyl 2-diazo-3oxobutanoate 

(1) with phenylhydrazine, semicarbazide, hydroxylamine, aniline, or ammonia 

(Scheme 6). [22,23,246] The mechanism of the reaction involves the in situ formation 

of Æ-diazoimines of type 2 followed by ring closure. Several variations of this method appeared 

since then and a range of 2-diazo-1,3-dicarbonyl compounds can be used: Æ-diazoâ-oxo 

esters, Æ-diazo-â-formyl esters, Æ-diazo-â-oxoaldehydes, diazomalonaldehyde, and 

diazomalonates. 

A. C. TomØ, Section 13.13, Science of Synthesis, 2004 Georg Thieme Verlag KG 

N 

H

Scheme 6 Reaction of Ethyl 2-Diazo-3-oxobutanoate with Amine Derivatives [22–24,246] 

EtO 

O 

N 2 

ZNH2 

O 

1 

Z = H, Ph, NHPh, OH, NHCONH2 EtO 

O 

NZ 

2 

N 2 

EtO 2C 

The 1H-1,2,3-triazol-1-ol 3 (Z = OH) is obtained in 53% yield by reaction of 1 with an excess 

of hydroxylamine (EtOH/H 2O 1:1, 808C, 5 h). [24] 

The method described by Wolff can be extended to Æ-diazo-â-oxo esters with bulky 

substituents. For example, the 5-(1-adamantyl)-1H-1,2,3-triazoles 5 are prepared by the reaction 

of the diazo compound 4 with aniline and methylamine, respectively (Scheme 

7). [25] In this case titanium(IV) chloride is used as catalyst to promote the formation of 

the intermediate imine and thus facilitate the formation of the triazole. 

Scheme 7 Reaction of Ethyl 3-(1-Adamantyl)-2-diazo-3-oxopropanoate with Amines [25] 

EtO 

4 

O 

O 

N 2 


13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 419 

+ R 1 NH 2 

TlCl4, Cl 

Cl 

reflux, 15 h 

R1 = Ph 74% 

R1 = Me 51% 

EtO2C 

Ethyl 5-(1-Adamantyl)-1-phenyl-1H-1,2,3-triazole-4-carboxylate (5,R 1 = Ph); 

Typical Procedure: [25] 

A soln of 4 (28 mg, 0.1 mmol), PhNH 2 (13 mg, 0.14 mmol), and TiCl 4 (19 mg, 0.1 mmol) in 

dry 1,2-dichloroethane (2 mL) was refluxed for 15 h, and the resulting mixture was basified 

with 1 M NaOH (1 mL). After adding Et 2O/H 2O (1:1, 10 mL) and shaking, the organic 

layer was separated, washed with H 2O and dried (Na 2SO 4). Evaporation of the solvent left 

a residue, which was chromatographed to give 5 (R 1 = Ph) as crystals; yield: 26 mg (74%); 

mp 134–138 8C. 

13.13.1.1.1.1.1.1 Variation 1: 

From 2-Diazo-3-oxopropanoates and Amine Derivatives 

Ethyl 2-diazo-3-oxopropanoate (6) reacts with a range of amine derivatives to give the corresponding 

triazoles 7 (R 1 = H, alkyl, aryl, OH, NHPh, NHCONH 2) (Scheme 8). [26–28] The 

yields of the reactions are highly dependent on the amine derivative used. The reaction 

of compound 6 with 2-aminoethanol gives triazole 7 (R 1 =CH 2CH 2OH), which is used as 

precursor to several 1,2,3-triazole-containing antibiotics. [29,30] 

5 

N 

N 

N 

R1 N 

Z 

3 

N 

N 




bScheme 8 Reaction of Ethyl 2-Diazo-3-oxopropanoate with Amine Derivatives [26–28] 

EtO 

H 

O 

O 

6 

N2 

+ R 1 NH 2 

EtO 2C 

7 

N 

N 

N 

R1 R 1 R 1 NH 2 Conditions Yield (%) Ref 

H NH3AcOH, 100 8C, 3–4 h 50 [27] 

H NH2OH H2O, rt, 48 h 7 [27] 

NHCONH2 H2NNHCONH2 H2O, rt, 48 h 35 [27] 

Ph PhNH2 EtOH, AcOH, rt, 30 min 74 [26] 

Ph PhNH2 EtOH, AcOH, rt, 16 h 70 [28] 

N 

H 

N 

Bu t 

H2N 

N 

H 

N 

Bu t 

EtOH, AcOH, rt, 16 h 81 [28] 

Ethyl 1-Phenyl-1H-1,2,3-triazole-4-carboxylate (7,R 1 = Ph); Typical Procedure: [28] 

Ethyl 2-diazo-3-oxopropanoate (6; 0.426 g, 3 mmol) was dissolved in EtOH (3 mL). A soln of 

PhNH 2 (0.27 g, 2.9 mmol) in EtOH (1.8 mL) and AcOH (0.6 mL) was added and the mixture 

was stirred at rt for 16 h. On removal of the solvent a solid was obtained, and crystallization 

(EtOH) gave white needles of the triazole 7 (R 1 = Ph); yield: 0.45 g (70%); mp 86–87 8C. 


From 2-Diazo-3-oxoaldehydes and Amine Derivatives 

2-Diazo-3-oxoaldehydes 8 react with anilines, hydroxylamine, or semicarbazide yielding 

4-acyl-1-substituted 1H-1,2,3-triazoles 9 in moderate to good yields (Scheme 9). [26,27] They 

also react with ammonia to give N-unsubstituted 1,2,3-triazoles in 20–26% yield. In the 

condensations with hydroxylamine and semicarbazide the reaction goes further and the 

ketone functions are converted into oximes and semicarbazones, respectively. [27] A newer 

method for the preparation of a wide range of the required 2-diazo-3-oxoaldehydes has 

been published. [31] Diazomalonaldehyde (8, R 1 = H) reacts with aniline hydrochloride, in 

water and at room temperature to yield 1-phenyl-1H-1,2,3-triazole-4-carbaldehyde (9, 

R 1 =H;R 2 = Ph) in 96% yield. [32] 

Scheme 9 Reaction of 2-Diazo-3-oxoaldehydes with Amine Derivatives [26–28] 

R 1 

H 

O 

N2 + R 

N 

N 

O 

N 

2NH2 R 

8 9 

2 

O 

R1 R 1 = H, alkyl, aryl; R 2 = H, aryl, OH, NHCONH2 



Condensation of 2-Diazo-3-oxoaldehydes with Aniline; General Procedure: [27] 

A soln of the 2-diazo-3-oxoaldehyde 8 (10 mmol) in EtOH (6 mL) and a mixture of PhNH 2 

(10.7 mmol) and AcOH (1.25 mL) were mixed. The mixture was stirred at rt for 30 min. In 

most cases during this time the triazoles precipitated and were obtained pure after recrystallization 

(EtOH). The yields were within the range of 26–87%. 


From Dimethyl Diazomalonate and Amines 

Dimethyl diazomalonate (10) undergoes reaction with primary alkylamines to generate 

the corresponding primary ammonium salts of methyl 1-alkyl-5-hydroxy-1H-1,2,3-triazole-4-carboxylates 

12 in 66–98% yield (Scheme 10). [33] The probable mechanism of this reaction 

involves the formation of the intermediate diazoamide 11, which then undergoes 

base-catalyzed cyclization to the 1,2,3-triazole salt 12. Acidification of an aqueous solution 

of 12 and extraction with dichloromethane gives the free triazolols. However, since 

triazol-5-ols undergo facile isomerization to the corresponding diazoamides, care must be 

taken during their formation and purification. The major limitation of this reaction is the 

fact that aromatic amines, e.g. aniline, fail to react. This is consistent with the reduced 

nucleophilicity of the nitrogen in aromatic amines. [33] 

Scheme 10 Reaction of Dimethyl Diazomalonate with Amines [33] 

MeO 

MeO 

O 

O 

N 2 



R 1 NH2 

MeO 

O 

O 

MeO 2C 

10 11 

12 

N 2 

NHR 1 

R 1 NH2 

R 1 Amine Time (d) Yield (%) mp (8C) Ref 

Bu BuNH2 3 82 111–113 [33] 

(CH2) 4Me Me(CH2) 4NH2 5 85 110–113 [33] 

(CH2) 5Me Me(CH2) 5NH2 3 70 120–122 [33] 

Cy CyNH2 3 66 154–157 [33] 

(CH2) 2OH HO(CH2) 2NH2 3 98 119–124 [33] 

Bn BnNH2 3 84 153–156 [33] 

2-thienyl 2-thienylamine 3 67 160–161 [33] 

3-thienyl 3-thienylamine 6 72 160–162 [33] 

1 + − 

R NH3 O 

1,2,3-Triazole Salts 12; General Procedure: [33] 

Dimethyl diazomalonate (10 mmol) was added to a large excess of the amine and the mixture 

was stirred at rt and monitored by IR spectroscopy until the diazo ester was completely 

consumed (3–6 d). At this point the resultant salt had crystallized from soln and 

was isolated by filtration and recrystallized. Alternatively, the reaction could be performed 

in toluene using 2–5 equiv of amine; yield: 66–98%. 

N 

N 

N 

R1 for references see p 587 



From Vinyldiazonium Salts and Amine Derivatives 

Vinyldiazonium salts 13 react with ammonia and amine derivatives (primary amines, hydrazines, 

hydroxylamine ethers) to give 1-substituted 1,2,3-triazoles 14 (Scheme 11). [34–36] 

A probable mechanism for this reaction is represented in Scheme 11. [36] The reaction of 

vinyldiazonium salts 13 with ø,ø¢-diaminoalkanes leads to ø,ø¢-bis(1H-1,2,3-triazol-1yl)alkanes. 

[37] 

Scheme 11 Reaction of Vinyldiazonium Salts with Amine Derivatives [36] 

N 

+ 

N 

R 1 

13 

R 5 = R 2 , R 3 

R 3 

R 2 

X − 



R 4 NH 2 

− HX 

N 

R1 NHR4 R2 R3 + N 

− 

− R 2 H or R 3 H 

N 

N 

N 

R4 R1 R2 R3 N 

N 

N 

R4 R1 R 

14 

5 

R 1 R 2 R 3 X R 4 R 5 Yield (%) Ref 

H OEt OEt SbCl6 H OEt 65 [36] 

H OEt OEt SbCl6 3-morpholinopropyl OEt 54 [36] 

H OEt OEt SbCl6 Cy OEt 62 [36] 

H OMe 4-MeOC6H4 SbCl6 furfuryl 4-MeOC6H4 63 [36] 

4-O2NC6H4 OEt piperidino SbCl6 H piperidino 48 [36] 

4-O2NC6H4 OEt piperidino SbCl6 furfuryl piperidino 80 [36] 

4-O2NC6H4 OEt piperidino SbCl6 3-morpholinopropyl piperidino 65 [36] 

4-O2NC6H4 OEt piperidino BF4 4-MeOC6H4 OEt 51 [36] 

4-O2NC6H4 OEt piperidino BF4 NH2 OEt 24 [36] 

2-(Benzoyloxy)alk-1-enediazonium trifluoromethanesulfonates 17 [generated in situ from 

the reaction of Æ-diazo ketones 15 and benzoyl trifluoromethanesulfonate (16)] react 

with isopropylamine to give the corresponding 1-isopropyl-1H-1,2,3-triazoles 18 in high 

yields (Scheme 12). [38] 


Scheme 12 Reaction of 2-(Benzoyloxy)alk-1-enediazonium Trifluoromethanesulfonates 

with Isopropylamine [38] 

N 2 

R 1 

O 

R 1 

+ BzOTf 

15 16 

A: 1. CH2Cl2, −70 to −50 oC, 2 h 

2. iPrNH2, −70 oC to rt, 2 h 

B: 1. CH2Cl2, −95 oC, 2 h 

2. iPrNH2, −95 oC, 0.5 h; −75 oC, 2 h 

N 

+ 

N 

R 1 

17 

OBz 

R1 OTf − 

N 

N 

N 

Pri R1 R 

18 

1 

A: R1 = Me 77% 

B: R1 = Ph 80% 

1-Isopropyl-4,5-dimethyl-1H-1,2,3-triazole (18, R 1 = Me); Typical Procedure: [38] 

A soln of benzoyl trifluoromethanesulfonate (5.20 g, 20.4 mmol) in CH 2Cl 2 (50 mL) was 

cooled to –708C and a soln of 15 (R 1 = Me; 2.00 g, 20.4 mmol) in CH 2Cl 2 (50 mL) was added 

dropwise. After the addition, the suspension was stirred at –708C for 1 h and at –508C for 

3 h. iPrNH 2 (6.00 g, 102 mmol) was gradually added after cooling to –708C. A homogeneous 

soln was formed and after 2 h at rt it was extracted with H 2O (4 ”). The organic layer 

was dried (MgSO 4) and the solvent was removed at 15 Torr. Distillation (908C/0.05 Torr, Kugelrohr 

apparatus) gave triazole 18 (R 1 = Me); yield: 2.19 g (77%). 


From Dichloro- or Trichloroacetaldehyde Sulfonylhydrazones and 

Primary Amines 

Tosyl and mesyl hydrazones of dichloroacetaldehyde and trichloroacetaldehyde react 

with ammonia and primary amines to produce 1H-1,2,3-triazoles 20 and 22, respectively, 

in good yields (Scheme 13). [39,40] This is a much more convenient and secure reaction system, 

especially for large-scale production of triazoles, than some alternative methods 

where thermally unstable, or explosive, starting materials are used, namely diazo and azido 

derivatives. For example, 1H-1,2,3-triazole itself can be prepared in 75% yield from the 

reaction of dichloroacetaldehyde tosylhydrazone (19, X = Ts) with ammonia. [40] The same 

hydrazone can be converted into 1-benzyl-1H-1,2,3-triazole, 1-phenyl-1H-1,2,3-triazole, or 

1H-1,2,3-triazol-1-amine in similar yields. These triazoles can also be prepared from the 

mesylhydrazone 19 (X = Ms) in almost the same yields (60–85%). When trichloroacetaldehyde 

tosylhydrazone (21) is treated with aqueous ammonia only unidentified materials 

are obtained, but the reaction with methylamine or benzylamine gives the 1,5-disubstituted 

triazoles 22. [39] 

Scheme 13 Reaction of Dichloro- and Trichloroacetaldehyde 

Sulfonylhydrazones with Ammonia and Primary Amines [39,40] 

Cl 

Cl 

H N 

19 

H 

NHX 

X = Ts, Ms; R 1 = H, Ph, Bn, NH2 



R1NH2, MeOH 

0−40 oC, 4 h 

70−83% 

N 

N 

N 

R1 20 



R 1 = Me: MeNH2, MeOH, 0 oC to rt, 19 h 

R1 = Bn: BnNH2, MeOH, 0 o Cl 

Cl 

C, 2.5 h 

Cl 

NHTs 

R 

H N 

1 = Me 25% 

R1 = Bn 30% 

21 

Æ,Æ-Dichloro ketone tosylhydrazones can also be used as precursors of 1H-1,2,3-triazoles. 

For example, 1,1-dichloroacetone tosylhydrazone (23) is converted into 1-benzyl- and 1-allyl-4-methyl-1H-1,2,3-triazoles 

24 in good yields (Scheme 14). [39] Also, an attempted synthesis 

of tosylhydrazone 26 from 2,2-dichloro-1-phenylethanone 25 gives the triazole directly 

27. [39] 

R 1 HN 

22 

N 

N 

N 

R1 Scheme 14 Reaction of Æ,Æ-Dichloro Ketone Tosylhydrazones with Primary Amines [39] 

Cl 

Cl 

Cl 

Cl 

H 

O 

Ph O 

25 

H 

TsNHNH2 

TsNHNH2 

Cl 

Cl 

Cl 

Cl 

H 

N 

23 

H 

Ph N 

26 

NHTs 

NHTs 

R 1 NH 2 

TsNHNH2 

24 

N 

N 

N 

R1 R1 = Bn 84% 

R1 = CH2CH CH2 83% 

Ph 

N 

N 

N 

NHTs 

27 20% 

1H-1,2,3-Triazole (20,R 1 = H); Typical Procedure: [40] 

To a soln of NH 3/H 2O (8.9 g, 523 mmol) in MeOH (40 mL) under ice-cooling was added slowly 

dichloroacetaldehyde tosylhydrazone (19, X = Ts; 4.4 g, 15.7 mmol) in MeOH (60 mL). 

The mixture was stirred at 228C for 9 h and then it was filtered to remove NH 4Cl. The filtrate 

was concentrated and chromatographed (silica gel, EtOAc/hexane 1:1) to give 1H- 

1,2,3-triazole as a colorless oil; yield: 0.81 g (75%); bp 208–2108C. 

13.13.1.1.1.2 Fragments C-C-N and N-N 




From Enaminones and Diazo Transfer Reagents 

Enaminones react with a range of diazo transfer reagents to give 1H-1,2,3-triazoles. 3-Diazo-1,3-dihydro-2H-indol-2-one 

derivatives and sulfonyl azides are particularly useful in 

these reactions. 


From Enaminones and 3-Diazo-1,3-dihydro-2H-indol-2-one Derivatives 

â-Amino-Æ,â-unsaturated ketones (enamino ketones) 28 (R 2 = Me) and â-amino-Æ,â-unsaturated 

esters (enamino esters) 28 (R 2 = OEt) react with 3-diazo-1,3-dihydro-2H-indol-2-one 

derivatives to give 1H-1,2,3-triazoles of type 30 in good to excellent yields (Scheme 

15). [41,42] Various 3-diazo-1,3-dihydro-2H-indol-2-ones can be used but the best results are 

obtained with the nitro derivatives 29 and 31. [41] When cyclic enaminones 33 or 34 are 

used, carbocyclic fused 1,2,3-triazoles of types 33 and 35 are obtained in good yields (49– 


83%). [42] The 3-diazobenzo[b]thiophen-2-one also reacts with enaminones to give 1,2,3-triazoles. 

[41] In these reactions, compounds 29, 31, and 3-diazobenzo[b]thiophen-2-one act as 

diazo transfer reagents; a probable mechanism has been described. [41] 

Scheme 15 Reaction of Enaminones with 3-Diazo-1,3-dihydro-2H-indol-2-ones [41,42] 

R 1 HN 

28 

O 

H 

R 2 

+ 

R 1 = Me, t-Bu; R 2 = Me, OEt 

R 1 HN 

28 

O 

H 

R 2 

+ 

R 1 = Me, t-Bu; R 2 = Me, OEt 

R 1 

R 1 

N 

H 

( ) n 

O 

n = 1, 2, 3 

32 

34 

H 

NHMe 

CO2Et 

+ 

+ 



O 2N 

O 2N 

O 2N 

O 2N 

NO2 29 

31 

NO 2 

NO 2 

29 

N 

H 

N2 

N2 

N 

Me 

29 

N 

H 

N 

H 

N2 

N2 

O 

O 

O 

O 

55−81% 

55−82% 

R1 = H 49% 

R1 = Me 50% 

73−83% 

R 2 

R 2 

( ) 

n 

O 

30 

O 

30 

N 

N 

N 

R1 N 

N 

N 

R1 R 1 

N 

N 

N 

35 

O 

N 

N 

N 

R1 Me 

CO2Et 

Reaction of Enaminones with 3-Diazo-1,3-dihydro-2H-indol-2-ones; General Procedure: [41] 

A mixture of the diazocarbonyl compound (1 mmol) and the enaminone (1 mmol) in dry 

toluene (30 mL) was refluxed until the disappearance of the N 2 absorption band at 

2100 cm –1 in the IR spectrum. The solvent was evaporated and the residue was submitted 

to column chromatography (Florisil, hexane/CH 2Cl 2/MeOH mixtures). The products were 

further purified by preparative TLC (silica gel, CHCl 3/MeOH 100:1). 

33 




From Enaminones and Sulfonyl Azides 

Mesyl and tosyl azides can act as diazo transfer reagents to enaminones yielding triazoles 

36 in good yields (Scheme 16). [43] For this purpose, mesyl azide is a much better reagent 

than tosyl azide (yields of 20–97% and 2–50%, respectively). The reaction works better 

with N-alkyl-substituted enaminones (72–97%) than N-aryl-substituted enaminones (20– 

37%). 

Scheme 16 Reaction of Enaminones with Sulfonyl Azides [43] 

R 1 HN 

O 

H 

R 2 

R 1 = alkyl, aryl; R 2 = Me, OEt 

TsN3 or MsN3, NaH 

R 2 

O 

N 

N 

N 

R1 36 

Reaction of Enaminones with Sulfonyl Azides; General Procedure: [43] 

To a stirred mixture of NaH (6.67 mmol; free of oil) in anhyd MeCN (4 mL), under N 2 at rt, 

was added a soln of the enaminone (1.85 mmol) in anhyd MeCN (4 mL). The stirring was 

continued for 30 min, followed by dropwise addition of mesyl azide (5 mmol) in anhyd 

MeCN (1 mL). Stirring was maintained for 24 h and the reaction was quenched with 

NaOH soln (10%). The separated organic layer was dried (MgSO 4) and the solvent was removed 

under reduced pressure to give a residue that was extracted with CH 2Cl 2 

(3 ” 10 mL). The crude 1,2,3-triazoles were purified by column chromatography (silica 

gel, hexane/EtOAc 9:1). 

13.13.1.1.2 By Formation of One N-N and One C-C Bond 

13.13.1.1.2.1 Fragments C-N-N and C-N 




From Diazoalkanes and Nitriles 

Diazoalkanes react with activated nitriles such as cyanogen, cyanogen halides, methyl cyanoformate, 

aryl cyanates, sulfonyl cyanides, and others to give 1,2,3-triazoles (Scheme 

17). These reactions can formally be regarded as 1,3-dipolar cycloadditions. [3] If an excess 

of diazoalkane is used the triazoles may be N-alkylated; generally mixtures of the three 

possible N-alkyl-1,2,3-triazoles are obtained. For example, cyanogen bromide reacts with 

excess diazomethane to give a mixture of the 4-bromo-2-methyl-2H-1,2,3-triazole (21%), 5bromo-1-methyl-1H-1,2,3-triazole 

(6.4%), and 4-bromo-1-methyl-1H-1,2,3-triazole (5.5%). [44] 

Tosyl cyanide reacts with 1 equivalent of diazomethane to afford 4-tosyl-1H-1,2,3-triazole 

(37, R 1 = H; X = Ts) in 68% yield. With excess diazomethane it gives a mixture (95%) of the 

three isomeric N-monomethylated triazoles 38 (R 1 = H; X = Ts). [45] Similarly, 4-oxo-4H-1benzopyran-2-carbonitriles 

react with diazomethane to yield mixtures of three isomeric 

N-methyl-1,2,3-triazoles. [46] 


Scheme 17 Reaction of Activated Nitriles with Excess Diazoalkanes [44,45] 

XCN 

R 1 CHN 2 

R 1 

X 

37 

N 

N 

N 

H 

R 1 CHN 2 

The importance of the nature of electron-withdrawing groups in nitriles with respect to 

their reactivity toward diazomethane is demonstrated by the relative yields of N-methyltriazoles 

39–41 given in Table 1. [47] For example, 1-methyl-1H-imidazole-4,5-dicarbonitrile 

reacts with diazomethane only at the 5-cyano group. 

Table 1 Examples of N-Methyltriazoles Obtained by Reaction of Diazomethane 

with Activated Nitriles [47] 

R 1 CN + CH 2N 2 

R 1 

N 

N 

NMe 

R1 Ratio Ref 

39 40 41 

CCl3 88.6 9.8 1.6 [47] 

CO2Et 23.6 74.8 1.6 [47] 

Bz 62.2 34.5 3.3 [47] 

NC 

O 

O 

N 

N 

Me 

+ 

R 1 

R 1 

X 

N 

38 

N 

N 

R 1 

N 

N 

N 

+ 

R 

N 

N 

N 

1 

Me Me 

39 40 

41 

91.5 3.1 5.4 [47] 

55.7 42.2 2.1 [47] 

Diazomethane also undergoes addition to the C”N bond of chloro(fluoroimino)acetonitrile 

(42) to yield triazole 43 (Scheme 18). Two equivalents of diazomethane are consumed 

in this reaction; the insertion of a methylene group is observed in the final product. [48] 

Scheme 18 Reaction of Diazomethane with 

Chloro(fluoroimino)acetonitrile [48] 

NF 

Cl CN 

42 



CH2N2 (2 equiv) 

Et2O, −78 oC 19.5% 

Cl 

43 

NF 

N 

H 

N 

N 



Reaction of Activated Nitriles with Diazomethane; General Procedure: [47] 

CAUTION: Diazomethane is explosive by shock, friction, or heat, and is highly toxic by inhalation. 

A soln of CH 2N 2 (0.13 mol) in Et 2O (600 mL) was added to the nitrile (0.02 mol). The reaction 

was monitored by TLC until the nitrile was completely consumed (several days). The 

solvent was evaporated and the residue was submitted to column chromatography (silica 

gel). The isomeric N-methyltriazoles were separated using appropriate eluents. 


From Diazoalkanes and Aryl Cyanates 

Aryl cyanates 44 react with diazoalkanes in a 2:1 proportion to yield the aryl 4-(aryloxy)- 

1H-1,2,3-triazole-1-carboximidates 45 (44–83%), which after hydrolysis give the corresponding 

N-unsubstituted triazoles 46 (Scheme 19). [49] 

Scheme 19 Reaction of Aryl Cyanates with Diazoalkanes [49] 

Ar 1 OCN 

44 



Ar 

N 

N 

H 

N 

1O R1 R1CHN2 Ar1OCN Ar 1 = Ph, 4-Tol, 4-MeOC 6H 4, 4-ClC 6H 4; R 1 = H, CO 2Et 


From Diazoalkanes and Unactivated Nitriles 

Ar 1 O 

R 1 

N 

N 

N 

HN OAr 1 

45 

H 2O 

Ar 1 O 

R 1 

N 

N 

H 

46 

Unactivated nitriles generally do not react with diazomethane or other diazoalkanes, 

however, reaction can occur in the presence of a catalyst. Aluminum trichloride, triethylaluminum, 

and other aluminum complexes can be used as catalysts in the reaction of diazomethane 

with benzonitrile. [50] Aryldiazomethanes also react with benzonitriles in the 

presence of potassium tert-butoxide (molar ratio 1:1:1), in toluene, to give 4,5-diaryl-1H- 

1,2,3-triazoles, mostly in good to satisfactory yields (26–75%). [51] A plausible mechanism 

for this reaction is shown in Scheme 20. The reaction can be carried out at room temperature 

or in refluxing toluene. 


N

Scheme 20 Synthesis of 4,5-Diaryl-1H-1,2,3-triazoles by Reaction of Aryldiazomethanes 

with Benzonitriles in the Presence of Potassium tert-Butoxide [51] 

Ar 1 CN + Ar 2 CHN 2 

Ar 1 

Ar 1 

Ar 2 

N 

N 

N 

N 

− 

N 

N K + 

t-BuOK 

Ar 1 Ar 2 Conditions Yield (%) Ref 

Ph Ph rt, 24 h 69 [51] 

Ph Ph 110 8C, 2 h 75 [51] 

4-ClC6H4 4-ClC6H4 1108C, 2 h 70 [51] 

4-ClC6H4 Ph 110 8C, 2 h 44 [51] 

4-BrC6H4 Ph rt, 24 h 66 [51] 

4-Tol Ph 110 8C, 2 h 26 [51] 


From [Diazo(trimethylsilyl)methyl]lithium and Nitriles 

[Diazo(trimethylsilyl)methyl]lithium (48) [generated in situ from the reaction of diazo(trimethylsilyl)methane 

and butyllithium] reacts smoothly with nitriles to give 4-substituted 

5-(trimethylsilyl)-1,2,3-triazoles 49 in excellent yields (Scheme 21). [52,53] Various nitriles, 

including aromatic, heteroaromatic, and aliphatic nitriles, react efficiently with 48 to 

give 4-(trimethylsilyl)triazoles 49. Since treatment of diazo(trimethylsilyl)methane with 

butyllithium followed by protonation gives 4,5-bis(trimethylsilyl)-1H-1,2,3-triazole, [54] 

the generation of 48 needs to be carefully controlled. 

Scheme 21 Reaction of Nitriles with [Diazo(trimethylsilyl)methyl]lithium [52,53] 

R 1 CN 

+ 

TMS 

48 

Li 

N 2 



H 

Ar 2 

Et 2O, 0 o C, 3 h N 

44−96% 

TMS 

R 1 

N 

H 

49 

R 1 = Pr, t-Bu, Bn, 3,7-dimethylocta-2,6-dienyl, Ph, 1-naphthyl, 2-pyridyl, 1-isoquinolyl, SEt, OPh, PO(OEt)2, TMS 

Triazoles 49; General Procedure: [52] 

15% BuLi in hexane (0.76 mL, 1.2 mmol) was added dropwise to a soln of TMSCHN 2 

(0.55 mL, 1.2 mmol) in Et 2O (10 mL) at 08C under argon and the mixture was stirred for 

20 min at 08C. To the resulting soln was added dropwise a soln of a nitrile (1 mmol) in 

Et 2O (3 mL) at 08C, then the mixture was stirred at 0 8C for 3 h. The mixture was treated 

with sat. aq NH 4Cl and extracted with Et 2O. The Et 2O extracts were washed with H 2O and 

dried (MgSO 4). Concentration of the solvent gave a residue, which was purified by preparative 

layer chromatography to give the triazole. 

N 

H 3O + 

Ar 1 

Ar 2 

47 

N 

H 

N 

N 




From Diazoalkanes and Imines, Oximes, or Diarylazines 

The 1,3-dipolar cycloaddition of diazoalkanes to C=N bonds is a general method for the 

synthesis of 4,5-dihydro-1H-1,2,3-triazoles and 1H-1,2,3-triazoles (Scheme 22). [4] It is an especially 

useful method for the regioselective preparation of 1H-1,2,3-triazoles with bulky 

substituents in positions 1 and 5. Imines are the most versatile C=N system to be used in 

this method, but oximes and diarylazines can also be used. 

Scheme 22 Addition of Diazoalkanes to Imines [55,56] 

R 1 

R 2 

50 

NR 3 

+ R 4 CHN 2 


From Diazoalkanes and Imines 

R 

N 

N 

N 

4 

R3 R2 R1 4,5-Dihydro-1H-1,2,3-triazoles 51 are the expected products from the cycloaddition reaction 

of imines 50 with diazoalkanes but in some cases they spontaneously aromatize to 

the corresponding triazoles. When the 4,5-dihydro-1H-1,2,3-triazoles are the isolated 

products they can be converted into triazoles by a large number of alternative procedures 

(see Section 13.13.1.3). 

The addition of diazoalkanes (especially diazomethane) to imines, to give 4,5-dihydro-1H-1,2,3-triazoles 

51, is very well studied. [4] In general it is favored by the presence of 

electron-withdrawing substituents in the imine, especially on an N-aryl moiety. [55,56] 

Though kinetic investigations of this reaction show that it follows essentially a concerted 

process and is not generally dependent on solvent polarity, a sizable increase in rate is 

noticed in the presence of protic solvents such as water or alcohols. [57] For example, while 

reaction of diazomethane with N-benzylideneaniline (52,Ar 1 =Ar 2 = Ph) does not occur in 

dry ether, it does occur in aqueous dioxane giving the 4,5-dihydro-1H-1,2,3-triazole 53 

(Ar 1 =Ar 2 = Ph) in 53% after eight days (Scheme 23). [55] This solvent system can be successfully 

used for the preparation of 5-hetaryl-substituted 4,5-dihydro-1H-1,2,3-triazoles of 

type 53 (Ar 1 = 2- or 3-pyridyl, 2-quinolyl). [58,59] Triethylaluminum and other aluminum 

complexes have been used as catalysts in the reaction of diazomethane with imines. [50] 

Scheme 23 Addition of Diazomethane to Diarylimines [58] 

Ar 1 

52 

N 

Ar 2 

+ CH2N 2 



dioxane, H2O (cat.) 

rt, 2−8 d 

51 

Ar 1 

53 

N 

N 

N 

Ar2 Diazomethane undergoes addition to hexafluoroacetone imines 54 to give 4,5-dihydro- 

1H-1,2,3-triazoles 55 as the sole product or to give mixtures of 4,5-dihydro-1H-1,2,3-triazoles 

55 and 56 (the latter produced as a result of the addition of diazomethane to the 

C=C bond) (Scheme 24). [60] 


Scheme 24 Addition of Diazomethane to Hexafluoroacetone Imines [60] 

F3C 

F 3C 

N 

54 

R 1 

R 2 

+ CH2N 2 

R1 R2 Yield (%) Ref 

55 56 

Me Me 91 – [60] 

Ph H 88 – [60] 

Me H 30 32 [60] 

iPr H 42 51 [60] 

Et 2O, rt 

N 

N 

N 

R1 R2 N 

N 

N 

R 

N 

N 

1 

R2 F3C F3C + 

F3C F3C 55 56 

Diazomethanes of the types 57, 58, and 59 react with formimidamides 60 to give directly 

the corresponding triazoles 61 in 11–62% yields (Scheme 25). [61] 

Scheme 25 Addition of Substituted Diazomethanes to Formimidamides [61] 

R 1 O 2C N 2 

R 1 

57 

O 

O 

58 

N 2 

(R 1 O) 2P N 2 

59 



R 1 = Me, Et, t-Bu 

R 1 = Me, t-Bu, Ph 

R 1 = Me, Et 


From Diazoalkanes and Oximes 

Me2N 60 

NBu t 

, MeCN, 81 o C, 24 h 

11−62% 

X 

N 

N 

N 

But Diazomethane undergoes addition to oximes to give 4,5-dihydro-1H-1,2,3-triazoles. The Omethyl 

oxime 62 reacts with diazomethane to yield the unstable 4,5-dihydro-1H-1,2,3-triazole 

63 (87%) that on treatment with piperidine gives the triazole 64 in 50% yield 

(Scheme 26). [62] 

61 



Scheme 26 Reaction of Diazomethane with Dimesylmethanone O-Methyloxime [62] 

Ms 

Ms 

N 

62 

OMe 

+ CH 2N 2 

dioxane, EtOAc 

0 oC, 30 min 

87% 


From Diazoalkanes and Diarylazines 

N 

Ms 

N 

Ms 

N 

OMe 

63 

piperidine, dioxane, EtOAc 

−10 to 50 oC, 3 h 

50% 

Ms 

N 

N 

N 

OMe 

64 

Aromatic aldehyde azines 65 react with aryldiazomethanes in the presence of potassium 

tert-butoxide to give N-unsubstituted 4,5-diaryl-1H-1,2,3-triazoles 66 (Scheme 27). [51] The 

scope of this method has yet to be demonstrated since only two symmetrical triazoles 

66 are prepared by this way. The mechanism of this reaction seems to involve one 1,3-dipolar 

cycloaddition followed by base elimination of an aromatic imide anion. However it 

should be noted that even in the absence of the aryldiazomethanes, the aromatic aldehyde 

azines (DMSO, rt) in the presence of potassium tert-butoxide (1 equiv), give the 

same 4,5-diaryl-1H-1,2,3-triazoles, although in much lower yields. [51] 

Scheme 27 Reaction of Aromatic Aldehyde Azines with Aryldiazomethanes in the Presence 

of Potassium tert-Butoxide [51] 

Ar 1 CH 

N 

N 

65 

CHAr 1 

N 

N 

N 

N Ar1 Ar1 Ar 

H 

1 

H 



+ Ar 1 CHN 2 

Ar 1 

DMSO, rt, 24 h 

Ar 1 

H 

N 

NH 

N 

N Ar1 13.13.1.1.2.1.3 Method 3: 

From Diazoalkanes and Heterocumulenes 

t-BuOK 

Ar 1 

Ar 1 

N 

H 

N 

N 

66 Ar 1 = Ph 92% 

Ar 1 = 4-ClC 6H 4 38% 

The reaction of diazoalkanes (or their organometallic derivatives) with heterocumulenes 

is a versatile method for the synthesis of 1H-1,2,3-triazoles. The reactions with ketenimines, 

carbodiimides, isocyanates, and isothiocyanates are performed under very mild 

conditions and generally they give the desired triazoles in moderate to excellent yields. 



From Diazoalkanes and Ketenimines 

Diazomethane reacts with ketenimines 67 (rt, 4 d) to give triazoles of type 68 in moderate 

yields (Scheme 28). [63,64] Other diazoalkanes fail to react with ketenimines 67 to give the 

corresponding 1,2,3-triazoles. [64] 

Scheme 28 Reaction of Ketenimines with Diazomethane [63,64] 

Ph 

Ph 

67 

NAr 1 

+ CH 2N 2 

Ar 1 = Ph, 4-Tol, 4-ClC6H4, 4-BrC6H4 

Et2O rt, 4 d 

31−43% 

Ph 

Ph 

N 

N 

N 

Ar1 N 

N 

N 

Ar1 Ph 

Ph 

68 

Better yields of triazoles are obtained if [diazo(trimethylsilyl)methyl]lithium (48) is used 

(Scheme 29). For example, alkyl and aryl ketenimines 69, (R 1 =R 2 = X = alkyl, aryl) react 

smoothly with 48 [prepared from diazo(trimethylsilyl)methane and butyllithium] to give 

4-(trimethylsilyl)-1,2,3-triazoles 71 in good yields. [65] Since desilylation of 71 is readily 

achieved in almost quantitative yields (10% aq KOH/MeOH, reflux, 6 h), [65] reagent 48 can 

be used, with better results, as a diazomethane equivalent. 

The reaction of 48 with ketenimines bearing electron-withdrawing groups (69, 

X = EWG) also gives 1,2,3-triazoles but in some cases only pyrazoles are obtained: it can 

give either 1H-1,2,3-triazoles 71 or pyrazoles 72 as the sole product or mixtures of these 

compounds (Scheme 29). [66] The nature and the yields of the products change with the solvent 

used in the reaction. The betaines 70 are likely to be intermediates in these reactions: 

the triazoles are formed by the attack of the nitrogen anion on the diazonium nitrogen. 

[66] 

Scheme 29 Reaction of Ketenimines with [Diazo(trimethylsilyl)methyl]lithium [65,66] 

Li 

TMS 

Z = X, H 

N 2 

+ 

R 1 

X 

48 69 



NR 2 

R 

X 

1 NR2 − 

+ 

Li 

N2 TMS 

70 

Et 2O, 0 o C, 2 h 

X = alkyl, aryl, EWG 

X = EWG 

X 

R 2 HN 

R 1 

TMS 

R 1 

71 

N 

Z 

72 

N 

N 

N 

R2 N 

TMS 



R 1 X R2Solvent Yield (%) Ref 

71 72 

Ph Ph 4-Tol Et2O 74 [65] 

Ph Ph Bu Et2O 67 [65] 

Me Me 4-Tol Et2O 82 [65] 

Et Bu Bu Et2O 82 [65] 

Me PO(OEt) 2 Et Et2O a 73 [66] 

a [66] 

Me PO(OEt) 2 Ph Et2O 68 2 

Me Ac Ph Et 2O 76 [66] 

Me Ac Ph THF 58 [66] 

b [66] 

Me Ac Ph hexane 46 14 

Me CN Et Et 2O 43 [66] 

a Z = PO(OEt)2. 

b Z=H. 

Reaction of Ketenimines with [Diazo(trimethylsilyl)methyl]lithium; 

General Procedure: [65] 

To 1.87 M TMSCHN 2 in hexane (0.64 mL, 1.2 mmol) in Et 2O (10 mL) was added, dropwise 

15% BuLi in hexane (0.76 mL, 1.2 mmol) at 08C under argon. The mixture was stirred at 

this temperature for 20 min. A soln of an alkyl or aryl ketenimine (1 mmol) in Et 2O 

(2 mL) was then added dropwise at 0 8C. The mixture was stirred at 0 8C for 2 h. After addition 

of cold H 2O, the mixture was extracted with benzene (CAUTION: carcinogen). The organic 

layer was washed with H 2O, dried (MgSO 4), and concentrated in vacuo. The residue 

was purified by column chromatography (silica gel) to give triazoles 71. 


From Diazoalkanes and Carbodiimides 

Carbodiimides 73 react with diazoalkanes to give 1H-1,2,3-triazoles 74 (Scheme 30). For 

example, reaction of diazomethane with di(1- or 2-naphthyl)carbodiimides [67] or with 

bis(4-X-phenyl)carbodiimides (X = H, NMe 2, OMe, Me, Cl, Br, Ac) gives triazoles 74 (R 1 =H) 

in low to moderate yields. [63,68,69] 

Scheme 30 Reaction of Carbodiimides with Diazoalkanes [63,67–69] 

Ar 1 N 

73 

NAr 1 



+ R 1 CHN2 

N 

Ar 

N 

N 

1 R 

N 

1 

Ar1 Et2O, rt, 4 d N 

Ar 

N 

N 

1 R 

HN 

1 

Ar1 Organometallic diazomethanes also react with carbodiimides to form 1,2,3-triazoles, for 

example diazo(trimethylsilyl)methane and diazobis(trimethylstannyl)methane give, respectively, 

compounds 75 (19%) and 76 (96%) by reaction with 73 (Ar 1 = 4-Tol) (Scheme 

31). [68] 


74

Scheme 31 Reaction of Organometallic Diazoalkanes with Carbodiimides [68] 

Ar 1 N NAr 1 

73 

Ar 1 = 4-Tol 

Et2O 35 oC, 2 h 

TMSCHN2 

19% 

(Me3Sn)2CN2 

96% 

N 

N 

Ar 

N 

1 TMS 

HN 

Ar1 75 

Me3Sn 

N 

Ar 

N 

N 

N 

1 

Me3Sn Ar1 Reaction of Carbodiimides with Diazomethane; General Procedure: [63] 


A freshly prepared ethereal soln of CH 2N 2 (12 mmol) was added to the carbodiimide 

(10 mmol) dissolved in a sufficient quantity of Et 2O. The mixture was allowed to stand at 

rt for 4 d. The separated crystals were collected by filtration and washed with Et 2O. The 

triazoles 74 were then recrystallized (MeOH or aq acetone). 


From Diazoalkanes and Isocyanates 

Alkyl and aryl isocyanates react with [diazo(trimethylsilyl)methyl]lithium (48) to give 1substituted 

1H-1,2,3-triazol-5-ols 77 in good yields (Scheme 32). [70] Experimental data indicate 

that these reactions proceed by a stepwise process, not by a concerted 1,3-dipolar cycloaddition 

process. [70] 

Scheme 32 Reaction of Isocyanates with [Diazo(trimethylsilyl)methyl]lithium [70] 

Li 

TMS 

48 

N2 

+ R 1 NCO 



Et2O 

R1N + 

N2 O − 

Li 

TMS 

76 

H2O − TMSOH 

TMS 

R 1 Conditions Yield (%) mp (8C) Ref 

Bu Et 2O, –788C, 1,5 h; rt, 3.5 h 63 132–133 [70] 

t-Bu Et 2O, 0 8C, 1 h; reflux, 6h 53 126–131 (dec) [70] 

Cy Et 2O, 0 8C, 1 h; rt, 1.7 h 71 148 [70] 

Ph Et 2O, 0 8C, 2 h 79 113–115 (dec) [70] 

4-ClC 6H 4 Et 2O, 0 8C, 2 h 83 111 (dec) [70] 

1-naphthyl Et 2O, 0 8C, 1 h 83 125 (dec) [70] 

LiO 

N 

N 

N 

R1 HO 

77 

N 

N 

N 



Benzoyl isocyanate reacts with ethyl diazoacetate, in refluxing xylene, to give ethyl 1-benzoyl-5-hydroxy-1H-1,2,3-triazole-4-carboxylate 

in 60% yield (Scheme 33). [71] 

Scheme 33 Reaction of Benzoyl Isocyanate with Ethyl Diazoacetate [71] 

BzNCO + EtO 2CCHN2 

xylene, reflux 

60% 

EtO2C 

N 

N 

HO 

N 

Bz 

1-(4-Chlorophenyl)-1H-1,2,3-triazole (77, R 1 = 4-ClC 6H 4); Typical Procedure for the Reaction 

of Isocyanates with [Diazo(trimethylsilyl)methyl]lithium: [70] 

To 2 M TMSCHN 2 in hexane (0.6 mL, 1.2 mmol) in Et 2O (10 mL) was added dropwise, 15% 

BuLi in hexane (0.76 mL, 1.2 mmol) at 08C under argon. The mixture was stirred at this 

temperature for 20 min. A soln of 4-chlorophenyl isocyanate (154 mg, 1 mmol) in Et 2O 

(3 mL) was then added dropwise at 0 8C. The mixture was stirred at 0 8C for 2 h and ice water 

was then added. The aqueous layer was separated and the organic phase was extracted 

with H 2O. The combined aqueous layer was acidified with 2 M HCl. The resulting white 

precipitates were collected by filtration, dried in vacuo, and purified by column chromatography 

(silica gel) to give 77 (R 1 = 4-ClC 6H 4); yield: 162 mg (83%). 


From Diazoalkanes and Isothiocyanates 

Treatment of isothiocyanates with [diazo(trimethylsilyl)methyl]lithium (48) in tetrahydrofuran, 

followed by quenching with alkyl halides, gives 1-substituted 5-(alkylsulfanyl)- 

4-(trimethylsilyl)-1H-1,2,3-triazoles 78 in excellent yields (Scheme 34). [72] A dramatic solvent 

effect is observed in this reaction: changing tetrahydrofuran for diethyl ether leads 

to the exclusive formation of 1,3,4-thiadiazol-2-amines in good yields. [73] This is in contrast 

to the results observed with isocyanates (Scheme 32). Removal of the trimethylsilyl 

group from 78 is readily carried out with 10% aqueous potassium hydroxide in boiling 

methanol to give triazoles 79 in almost quantitative yields. [72] 

Scheme 34 Reaction of Isothiocyanates with [Diazo(trimethylsilyl)methyl]lithium [72] 

Li 

TMS 

48 

N 2 

+ R 1 NCS 



THF 

R 2 X 

R1 + 

N2 N 

TMS 

Li 

S − 

78 

N 

N 

N 

R1 OH − 

Li + − S 


TMS 

R 2 S 

TMS 

N 

N 

N 

R1 R 2 S 

79 

N 

N 

N 

R1



bR 1 R2X Yield (%) Ref 

78 79 

Ph MeI 98 94 [72] 

Ph BnBr 99 97 [72] 

Me MeI 96 100 [72] 

Me BnBr 90 98 [72] 

Bu BnBr 97 95 [72] 

Cy BnBr 98 96 [72] 

Bn BnBr 91 99 [72] 

CH2=CHCH2 BnBr 91 83 [72] 

Reaction of Isothiocyanates with [Diazo(trimethylsilyl)methyl]lithium; 


To a soln of 2 M TMSCHN 2 in hexane (0.6 mL, 1.2 mmol) in THF (10 mL) was added dropwise 

15% BuLi in hexane (0.76 mL, 1.2 mmol) at –788C under argon. The mixture was 

stirred at this temperature for 20 min. A soln of the isothiocyanate (1 mmol) in THF 

(3 mL) was then added dropwise at –788C. After 1 h at –78 8C, the alkyl halide (1.2 mmol) 

was added and the mixture was stirred at –788C for 1 h, then at 08C for 2 h. After addition 

of ice water, the mixture was extracted with benzene (CAUTION: carcinogen). The organic 

layer was washed with H 2O, dried (MgSO 4), and concentrated in vacuo. The residue was 

purified by column chromatography (silica gel) to give triazoles 78. 


From N-Alkyl-N-nitrosoamines and Nitriles 

Lithium salts of N-alkyl-N-nitrosoamines react with aryl cyanides to form triazoles 80 in 

40–70% yield (Scheme 35). [74] The main limitation of this method is the fact that enolizable 

nitriles cannot be used. 

Scheme 35 Reaction of Lithium Salts of N-Alkyl-N-nitrosoamines with 

Aryl Cyanides [74] 

THF, −78 

+ 

oC, 10 h 

Ar1CN N NO 

Li + 

R 

R1 40−72% 

2 

− 

Ar 1 = Ph, 4-Tol, 2-naphthyl; R 1 = Me, iPr, t-Bu; R 2 = H; R 1 ,R 2 = (CH 2) 3 

R 2 

Ar 1 

80 

N 

N 

N 

R1 1-Methyl-4-phenyl-1H-1,2,3-triazole (80,R 1 = Me; R 2 =H;Ar 1 = Ph); Typical Procedure: [74] 

CAUTION: N-Methyl-N-nitrosomethylamine (N,N-dimethylnitrosamine) is a probable human 

carcinogen and an eye and skin irritant. It is hepatotoxic and an exp. carcinogen and teratogen. 

All operations should be performed in a well-ventilated fume hood using appropriate safety precautions 

and procedures. 

Pure N-methyl-N-nitrosomethylamine (1.62 mL, 22 mmol) was added with stirring to a 

soln of LDA (23 mmol) in anhyd THF (70 mL) [from iPr 2NH (3.22 mL) and 1.6 M BuLi in hexane 

(14.2 mL)] at –788C and after 10 min the mixture was treated with PhCN (1.03 mL, 

10 mmol). The mixture was maintained at the temperature of dry ice for 10 h and the mixture 

was treated with a soln of glacial AcOH (1.32 mL, 23 mmol) in THF (5 mL). Working up 



with CH 2Cl 2 afforded a crystalline crude product that was recrystallized (CCl 4); yield: 

1.15 g (72%); mp 1228C. 

13.13.1.1.3 By Formation of Two N-C Bonds 

13.13.1.1.3.1 Fragments N-N-N and C-C 

The most important and general approach to the synthesis of the 1,2,3-triazole ring system 

involves azides. A wide variety of azides (organic or inorganic) can be used: alkyl, 

aryl, hetaryl, acyl, alkoxycarbonyl and sulfonyl azides, azidotrimethylsilane, hydrazoic 

acid, sodium azide, etc. All are suitable reagents for triazole synthesis. 

Azides react with various types of compounds to yield 1,2,3-triazoles or their immediate 

precursors. The most used are: (i) compounds with C”C bonds (here referred to as 

alkynes, irrespectively of other functional groups), (ii) compounds with C=C bonds (here 

referred to as alkenes, and including allenes, enamines, enol ethers, etc.), and (iii) activated 

methylene compounds. 

In spite of the great usefulness of the azides in the triazole synthesis, if the reaction 

conditions (especially the temperature) are not well controlled, the products obtained 

may be not the expected triazoles. This is because of the thermal instability of the azides 

and of some of the intermediates (dihydrotriazoles) formed during the triazole synthesis. 

[75] It is very important to always consider that most organic azides undergo thermal 

or photochemical decomposition to nitrenes. The decomposition temperature is dependent 

on the azide type (Table 2) and some azides, especially cyanogen azide and the lower 

alkyl azides, are unpredictably explosive. When the decomposition is carried out in the 

presence of an alkene the corresponding aziridine is usually obtained. [75] 

Table 2 Decomposition Temperature of Azides [76] 

Azide Type Decomposition Temp (8C) Ref 

alkyl azides 180–200 [76] 

aryl azides 140–170 [76] 

sulfonyl azides 120–150 [76] 

alkoxycarbonyl azides 100–130 

[76] 

acyl azides 25–80 [76] 

13.13.1.1.3.1.1 Addition of Azides to Alkynes 



The thermal 1,3-dipolar cycloaddition of azides to alkynes is often the method of choice 

for the synthesis of 1,2,3-triazoles since it gives directly the desired product. However, 

when unsymmetrical alkynes are used, mixtures of the two possible regioisomers are 

usually obtained. In general, addition to unsymmetrical alkynes tends to give mainly the 

isomers with the electron-withdrawing groups at the 4-position and the electron-releasing 

groups at 5-position. [3] The low regioselectivity of these reactions is the major disadvantage 

of this method as a preparative procedure. The accepted mechanism for these reactions 

is a concerted 1,3-dipolar cycloaddition. Kinetic data and the regio- and stereoselectivity 

of these reactions strongly support this mechanism. However, the reactions involving 

ionic azides (e.g., sodium azide) follow a nonconcerted ionic mechanism. These 

mechanisms have been discussed and documented in reviews. [76,77] 

N-Unsubstituted 1,2,3-triazoles are prepared by the direct addition of hydrazoic acid 

or an azide ion to alkynes but it is often more convenient to obtain these compounds by 

removal of a N-substituent from a 1H- or2H-triazole. 


13.13.1.1.3.1.1.1 Method 1: 

Addition of Hydrazoic Acid to Alkynes 

Hydrazoic acid reacts with alkynes to give the corresponding N-unsubstituted triazoles 81 

(Scheme 36). This method was originally performed by Dimroth and Fester who prepared 

the parent compound by heating an alcoholic solution of hydrazoic acid with an acetone 

solution of acetylene at 1008C for 70 hours. [78] With alk-1-ynes the reaction is generally 

carried out in benzene in a closed vessel at temperatures ranging from 90 to 1358C for 

30–48 hours. [79] The triazoles are obtained in low to moderate yields. Reactions involving 

alkynes with electron-withdrawing or donating groups are faster and the yields are higher. 

Scheme 36 Addition of Hydrazoic Acid to Alkynes [44,79–83] 

R2 R1 + HN3 FOR PERSONAL USE ONLY 


R 1 R 2 Yield (%) mp (8C) bp (8C)/Torr Ref 

H Me 14 35–36 108–109/25 [79] 

H Bu 56 – 103–105/1 [79] 

H (CH2) 5Me 63 27 120–122/2 [79] 

H (CH2) 9Me 29 59 148–149/0.6 [79] 

H Ph 48 148 – [79,80] 

H CHO 50 141–142 – [81] 

H CO2H71 222–224 – [44] 

Ph CHO 90 186–188 – [82] 

TMS CHO 83 171–183 – [83] 

TMS Ac 88 159–160 – [83] 

TMS CO-t-Bu 79 84–85 – [83] 

TMS Bz 85 102 – [83] 

4-Phenyl-1H-1,2,3-triazole (81,R 1 =H;R 2 = Ph): [79] 

CAUTION: Hydrazoic acid is highly toxic and explosive. Adequate protection and shielding are 

necessary during the preparation and handling of this reagent. 

A combustion tube containing phenylacetylene (14.7 g, 0.144 mol) and a soln of HN 3 in 

benzene (50 mL of 14.2% HN 3 in benzene, 0.165 mol) (CAUTION: carcinogen) was sealed 

and heated in a bath at 110–1158C for 40 h. After cooling to rt almost the entire contents 

crystallized. The solid was collected by filtration, washed with benzene, and recrystallized 

twice (benzene). Decolorizing charcoal was used during the first crystallization; 

yield: 10 g (48%); mp 148 8C. 

R 1 

R 2 

81 

N 

H 

N 

N 




Addition of the Azide Ion to Alkynes 

The azide ion undergoes addition to alkynes to give triazoles 82 in low to moderate yields 

(Scheme 37). Better yields are obtained with alkynes bearing electron-withdrawing 

groups. Almost quantitative yields (>98%) of 5-substituted 1H-1,2,3-triazole-4-carbaldehydes 

are obtained from the reaction of alk-2-ynals with sodium azide in dimethyl sulfoxide, 

at room temperature. [84] Generally the reaction is carried out in dimethyl sulfoxide or 

dimethylformamide; sodium azide [84–87] is frequently used as the azide ion source but lithium 

azide [88] and aluminum azide [89] have also been used. The mechanism of the reaction 

probably involves the nucleophilic addition of the azide ion to the triple bond followed by 

1,5-dipolar cyclization of the resulting vinyl anion. Addition of sodium azide to 1-aryl-5phenylpent-4-yne-1,3-diones 

in refluxing dimethylformamide gives the corresponding 4- 

(3-aryl-1,3-dioxopropyl)-5-phenyl-1H-1,2,3-triazoles 82 (R 1 = Ph; R 2 = COCH 2Bz, COCH 2CO- 

4-Tol, 4-MeOC 6H 4COCH 2CO) in good yields. [86] 

Scheme 37 Addition of Sodium Azide to Alkynes [84–86] 

R2 R1 + NaN3 FOR PERSONAL USE ONLY 


DMSO 

R 2 

R 1 

− 

+ 

N 

− 

N 

N 

R 1 R 2 Yield (%) mp (8C) Ref 

H H 11 – [85] 

H Ph 40 148 [85] 

Ph Ph 16 140 [85] 

H CO2Me 49 145 [85] 

CO2Me CO2Me 54 132 [85] 

Ph CHO >98 – [84] 

Bu CHO >98 – [84] 

Ph COCH2Bz 72 87 [86] 

Ph COCH2CO-4-Tol 72 122 [86] 

Ph 4-MeOC6H4COCH2CO 60 79 [86] 

H 3O + 

R 1 

R 2 

R 1 

N 

N 

N 

− 

The reaction of propynenitrile with aluminum azide (THF, reflux, 24 h) gives a mixture of 

the triazoles 83 (32%) and 84 (47%) (Scheme 38). [89] The formation of the tetrazole ring results 

from the addition of an azide ion to the cyano group. 


R 2 

82 

N 

H 

N 

N

Scheme 38 Addition of Aluminum Azide to Propynenitrile [89] 

H CN + Al(N3) 3 

THF, reflux 

24 h 

NC 

N 

H 

83 32% 

N 

N 

+ 

H 

N 

N 

N 

N 

84 47% 

Addition of sodium azide to (arylethynyl)triphenylphosphonium halides 85 gives 4-aryl-5triphenylphosphonio-1,2,3-triazolide 

ylides 86 in high yields (Scheme 39). [87] These ylides 

are readily hydrolyzed in aqueous basic solution to give quantitatively triazoles 87 and 

triphenylphosphine oxide. 

Scheme 39 Addition of Sodium Azide to (Arylethynyl)triphenylphosphonium Halides [87] 

Ar 1 

85 

PPh3 X − + 

NaN3, DMF 

60 oC, 3 h 

Ar1 = Ph 93% 

Ar1 = 4-ClC6H4 94% 

+ 

Ph3P Ar 1 

86 

N 

− 

N 

N 

NaOH 

EtOH/H2O (1:2) 

reflux, 2 h 

− Ph3PO 

100% 

Propargyl sulfonates 88 react with lithium azide/copper(I) chloride complex (THF/DMF, 

–60 8C) to give, after acidification, the 5-(1-azidoalkyl)-1H-1,2,3-triazoles 89 in low yields 

(4–24%); 50–70% of the starting material is recovered (Scheme 40). [88] 

Scheme 40 Addition of Lithium Azide to Propargyl Sulfonates [88] 

MsO 

R 1 R 2 

88 

R 3 

LiN3, CuCl 

THF/DMF (1:1) 

−60 oC, 10 h 

4−24% 

R 1 = t-Bu, Ph, 3-O 2NC 6H 4; R 2 = H, Ph; R 3 = t-Bu, Ph 



4-(3-Aryl-1,3-dioxopropyl)-5-phenyl-1H-1,2,3-triazoles 82 (R 1 = Ph; R 2 = COCH 2Bz, 

4-TolCOCH 2CO, 4-MeOC 6H 4COCH 2CO); General Procedure: [86] 

N3 

R2 CAUTION: Sodium azide can explode on heating and is highly toxic. 

A soln of 1-aryl-5-phenylpent-4-yne-1,3-dione (4 mmol) in DMF (20 mL) was refluxed with 

NaN 3 (4.6 mmol) for 3 h. The mixture was then poured into cold H 2O (200 mL), acidified 

with dil H 2SO 4, and the precipitated triazole 82 was collected by filtration, washed with 

H 2O several times, dried, and recrystallized [benzene/petroleum ether (bp 60–80 8C)] as 

yellow needles. 


Addition of Alkyl, Aryl, or Hetaryl Azides to Alkynes 

The addition of alkyl, aryl, and hetaryl azides to alkynes is the most popular method for 

the synthesis of 1,2,3-triazoles. The number of publications related to this method is so 

impressive that, although no substantial differences are found in the experimental procedures, 

for easier systematization of the information available, several variations of the 

method will be presented according to the type of alkyne used. Once again, it should be 

emphasized that azides are dangerous compounds, especially alkyl azides which are 

R 3 

R 1 

89 

N 

H 

N 

N 

N 

H 

N 

N 

Ar 1 

N 

H 

87 

N 

N 



treacherously explosive and should be treated with extreme caution. Wherever possible 

these compounds should only be handled as solutions. 

13.13.1.1.3.1.1.3.1 Variation 1: 

Addition of Azides to Acetylene and to Symmetrically Substituted Alkynes 

Azides undergo addition to acetylene and to symmetrically substituted alkynes 90 to give 

only one 1-substituted 1H-1,2,3-triazole 91, which simplifies the purification step 

(Scheme 41); this is a general method for the preparation of triazoles 91 and in some cases 

the yields are excellent. Addition of phenyl azide, [78] arylmethyl azides [90–92] or other alkyl 

azides [90] to acetylene yields the corresponding 4,5-unsubstituted triazoles 91 (R 2 = H). This 

method has also been used for the preparation of dendrimers containing various 1,2,3-triazole 

rings. [93] The addition of dimethyl acetylenedicarboxylate to per(6-azido-6-deoxy-2,3di-O-methyl)cyclodextrins 

yields the corresponding per(4,5-dicarboxy-1,2,3-triazol-1-yl) 

derivatives. [94] 1,4-Diazidobuta-1,3-dienes react with cyclooctyne at room temperature to 

give the corresponding bis(triazolyl) derivatives in high yields (86–99%). [95] 1,2-, 1,3-, and 

1,4-Bis(azidomethyl)benzenes react with dimethyl, diethyl, and di-tert-butyl acetylenedicarboxylates 

to afford the corresponding benzobis(triazoles) in good yields. [96] Other interesting 

bis(triazolyl) derivatives have been prepared by reacting dimethyl acetylenedicarboxylate 

and bis-azides (produced from the reaction of sodium azide and bis-epoxides). [97] 

Scheme 41 Addition of Azides to Symmetrically Substituted Alkynes [92,98–115] 

R 1 N 3 + 

R 2 

90 



R 2 

N 

N 

R 

N 

2 

R2 R1 R 1 R 2 Conditions Yield (%) Ref 

Me Ph benzene, 608C, 2 months 30 [98] 

CF2CHFCF3 Ph 1808C, 18 h 88 [99] 

(CF2) 2CO2Me CO2Me 1308C, 6 h 94 [99] 

Ph CH2OH benzene, 808C, 12 h 73 [100] 

Ph CH(OEt) 2 EtOH, 100 8C, 28 h 82 [101] 

Ph CO2Me EtOH, reflux, 20 h 92 [102] 

(CH2) 5Me CH(OEt) 2 EtOH, 100 8C, 43 h 90 [101] 

4-MeOC6H4 CO2Me benzene, reflux, 24 h 97 [103] 

4-O2NC6H4 CO2Me benzene, reflux, 24 h 87 [103] 

4-O2NC6H4 CO2Me benzene, reflux, 24 h 80 [104] 

2-AcOC6H4 Bz toluene, reflux, 2–30 h 82 [92] 

Bn CO2H acetone, rt to reflux, 1 h 93 [105] 

1-naphthyl Bz benzene, reflux, 48 h 70 [106] 

1-naphthyl CO2Me benzene, reflux, 5 h 95 [106] 

1-naphthyl TMS CHCl3, reflux, 96 h 37 [106] 

1-adamantyl CO2Me toluene, reflux, 24 h 77 [107] 

1-adamantyl CH2OH toluene, reflux, 90 h 32 [107] 

1-adamantyl Ph toluene, reflux, 500 h 17 [107] 


91

R 1 R 2 Conditions Yield (%) Ref 

(E)-CPH=CHMe CO 2Me rt 70 [108] 

cyclohepta-2,4,6-trienyl CO 2Me CCl 4, reflux, 1 h 73 [109] 

cyclohepta-2,4,6-trienyl Bz benzene, 100 8C, 2 h 58 [109] 

CH 2PO(OEt) 2 CO 2Me toluene, reflux, 30–40 h 92 [110] 

CH 2PO(OEt) 2 Bz toluene, reflux, 30–40 h 85 [110] 

AcO 

AcO 

AcO 

Pr i 

− + 

O N 

EtO 2C 

O 

S 

O 

O 

O O 

O O 

N 

H 

O 

OAc 

CO2Et 




Addition of Azides to Alk-1-ynes 

CH 2OH toluene/pyridine, reflux, 18 h 38 [111] 

CO 2Me benzene, reflux, 6 h 84 [112] 

CO 2Me toluene, 808C, 1.5 h 7 [113] 

Ph 808C, 120 h 51 [114] 

CH 2OH 808C, 30 h 66 [114] 

CO 2Me benzene, rt, 12 h 95 [115] 

Azides undergo addition to alk-1-ynes to give mixtures of 1,4- and 1,5-disubstituted 1H- 

1,2,3-triazoles (Scheme 42). The ratio of the two products is mainly dependent on the 

structure of alkyne: when R 2 is an electron-withdrawing group it goes preferentially to 

position 4 (triazoles 93), however isomers 94 are predominant when R 2 is an electron-releasing 

group. The mechanism and kinetics of the cycloaddition of phenyl azide to various 

4-substituted phenylacetylenes has been reported. [116] Phenyl azide reacts regioselectively 

with trifluoromethyl-substituted alkynyl Æ-amino acids to give the 1,4-disubstituted 

triazole. [117] It has been shown that cucurbituril substantially accelerates (ca. 10 5 -fold) 

the reaction of azide-substituted ammonium ions with alkyne-derived ammonium ions. 

The reaction is regioselective, affording only the 1,4-disubstituted triazole derivatives. [118] 

This method has been used for the preparation of oligo-1,2,3-triazoles and [n]rotax- 



anes. [119,120] A catalytic effect is also observed for zinc chloride doped natural phosphate 

for the cycloaddition of alkyl azides with alk-1-ynes. [121] With this catalyst a significant reduction 

in the reaction time is observed but the yields and the 1,4-/1,5-substitution ratio 

of the triazole are not improved. The enzyme acetylcholinesterase, which plays a key role 

in neurotransmitter hydrolysis in the central and peripheral nervous systems, has been 

used as a catalyst for the reaction of a tacrine-substituted alkyl azide with a phenanthridinium-substituted 

terminal alkyne. The 1,5-disubstituted triazole is the predominant isomer. 

[122] A high-yielding and simple copper(I)-catalyzed reaction sequence leading exclusively 

to 1,4-disubstituted 1,2,3-triazoles has been described. [123] It involves the reaction 

of organic azides with alk-1-ynes in the presence of the catalyst (0.25–2 mol%) prepared 

in situ by reduction of copper sulfate with ascorbic acid and/or sodium ascorbate. The reaction 

proceeds to completion in 6 to 36 hours at room temperature in a variety of solvents, 

including aqueous tert-butyl alcohol or ethanol and, very importantly, water with 

no organic cosolvent. The use of microwave-induced 1,3-dipolar cycloaddition of organic 

azides to alk-1-ynes under solvent-free conditions is also another important development. 

[124,125] It allows a substantial decrease in reaction times, reduced pollution, low 

cost, and simplicity in processing and handling. The addition of O-propargyl glycosides 

and propargyloxy-calixarenes to a calixarene diazide leads to the formation of interesting 

1,2,3-triazole derivatives having glycosyl and calixarene moieties. [126] 

Scheme 42 Addition of Azides to Alk-1-ynes [99,103,104,106–108,112,124,125,127–132] 

R 1 N 3 + 

H R 2 

92 

R 

N 

N 

N 

2 

R1 + 

93 

R 2 

94 

N 

N 

N 

R1 R1 R2 Conditions Yield (%) Ref 

93 94 

Ph Ph toluene, reflux, 17 h 43 52 [127] 

Ph (CH2) 3OH 1008C, 15 h 63 31 [128] 

Ph CO2Me rt, 12 d; 608C, 34 h 88 12 [103] 

Bn Ph toluene, reflux, 17 h 39 55 [127] 

Bn CONHBn microwave irradiation, 

558C, 30 min 

65 22 [125] 

(CH 2) 3Ph piperidinocarbonyl 



microwave irradiation, 

558C, 30 min 

65 22 [125] 

CH 2CO 2Et Ph toluene, reflux, 48 h 41 36 [129] 

1-adamantyl Ph toluene, reflux, 35 h 60 21 [107] 

1-adamantyl 1-adamantyl toluene, reflux, 30 h 67 0 [107] 

1-adamantyl CO 2Me toluene, reflux, 11 h 84 0 [107] 

CH 2PO(OEt) 2 Ph microwave irradiation, 

1208C, 30 min 

CH 2PO(OEt) 2 CH 2OH microwave irradiation, 

1008C, 30 min 

CH 2PO(OEt) 2 CO 2Et microwave irradiation, 

1008C, 5 min 

45 54 [124] 

30 69 [124] 

61 31 [124] 

CF 2CFHCF 3 Ph steel bomb, 130 8C, 6 h 32 62 [99] 

CF 2CFHCF 3 Bu steel bomb, 120 8C, 6 h 37 58 [99] 


R 1 R2 Conditions Yield (%) Ref 

93 94 

CF2CFHCF3 CO2Me steel bomb, 120 8C, 6 h 70 18 [99] 

CF2CFHCF3 TMS steel bomb, 90 8C, 6 h 50 – [99] 

CH2C(NO2) 2Me CO2H CHCl3, rt, 3 d a 89 [130] 

CH=CH-t-Bu CO 2Me rt 54 13 [108] 

4-O 2NC 6H 4 CO 2Et benzene, reflux, 48 h 60 25 [104] 

CH 2CH 2CO 2Et Bz benzene, reflux, 22 h 48 30 [131] 

Cy Bz benzene, reflux, 48 h 26 10 [131] 

4-Tol Bz benzene, reflux, 26 h 60 11 [131] 

1-naphthyl Bz benzene, reflux, 24 h 44 14 [131] 

1-naphthyl CO 2Et 1008C, 8 h 71 12 [106] 

Pr i 

Pr i 

Pr i 

O 

S 

O 

O 

O 

S 

O 

O 

O 

S 

O 

O 

N 

N 

N 

CO 2Me benzene, reflux, 18 h 66 23 [112] 

TMS 

a Combined yield of 93 and 94. 



benze 

ne, reflux, 7 d 

81 – [112] 

SO 2Ph benzene, reflux, 16 h 72 5 [112] 

Ph toluene, reflux, 2 h 40 60 [132] 

The 1,3-dipolar cycloaddition of aryl azides to (trimethylsilyl)acetylene is regioselective 

and gives, after several days at 258C, almost quantitative yields of the 1-aryl-4-(trimethylsilyl)-1,2,3-triazoles 

96 (Scheme 43). [133] A study has shown that the rate of these cycloadditions 

increases logarithmically with pressure. [134] For example, the reaction of 4methoxyphenyl 

azide with 95 takes 55 days, at atmospheric pressure, to complete consumption 

of the azide. The same reaction is complete in 1.5 hours if it is conducted at 

room temperature but under pressure (0.3 GPa). At pressures of about 1 GPa these reactions 

are almost instantaneous and quantitative. [134] 



Scheme 43 Addition of Aryl Azides to (Trimethylsilyl)acetylene [133] 

Ar 1 N 3 + 

H 

95 

TMS 

sealed tube 

25 oC Ar 1 Time (d) Yield (%) Ref 

Ph 35 96 [133] 

4-Tol 40 95 [133] 

4-MeOC6H4 55 95 [133] 

4-ClC6H4 25 95 [133] 

4-O2NC6H4 20 95 [133] 

4-NCC6H4 26 96 [133] 

benzo[b]thien-2-yl 9 93 [133] 

benzo[b]thien-3-yl 28 95 [133] 

TMS 

N 

N 

N 

Ar1 13.13.1.1.3.1.1.3.3 Variation 3: 

Addition of Azides to Unsymmetrical Disubstituted Alkynes 

Azides add to unsymmetrical disubstituted alkynes to give mixtures of isomeric triazoles 

97 and 98 (Scheme 44). The relative proportions of the two products are strongly dependent 

on the nature of R 2 and R 3 . 

Scheme 44 Addition of Azides to Unsymmetrical Disubstituted Alkynes [103,124,135–137] 

R 1 N 3 + 

R 2 



R 3 

R 

N 

N 

N 

2 

R1 R3 97 

96 

+ 

N 

N 

R 

N 

2 

R3 R1 R1 R2 R3 Conditions Yield (%) Ref 

97 98 

Ph CH2OH CO2Me toluene, 558C, 14 d 8 49 [135] 

4-MeOC6H4 CH2OH CO2Me benzene, rt, 60 d 31 59 [136] 

Ph Ph Bz benzene, 808C, 19 h 0 86 [103] 

1-naphthyl Me CO2Me 100 8C, 8 h 9 72 [106] 

CH2CO2-t-Bu CF3 PO(OiPr) 2 Et2O, rt, 20 h 68 22 [137] 

CH 2PO(OEt) 2 Me PO(OEt) 2 100 8C, 60 h 73 23 [124] 

CH 2PO(OEt) 2 Ph CO 2Et 160 8C, 10 min 58 42 [124] 

A recognition-mediated reaction between 4-(azidomethyl)benzo-15-crown-5 99 and the 

asymmetric alkyne 100 shows that the regioselectivity of the cycloaddition can be controlled. 

The mutual recognition between the ammonium cation and the crown ether 

leads to the formation of triazole 101 and its regioisomer in the ratio of 97:3 (Scheme 

45). [138] 


98

Scheme 45 Recognition-Mediated Reaction between Azides and Unsymmetrical 

Disubstituted Alkynes [138] 

O 

O 

O 

O 

O 

99 

+ 

N3 + 

H3N CF3CO 2 − 

O 

+ 

H3N CF 3CO 2 − 

Azido sugars have been extensively used to prepare carbohydrate-derived 1,2,3-triazoles. 

[139] For example, the â-D-galactopyranosyl azide 102 reacts with alkyne 103 to yield 

mixtures of the nucleoside triazole analogues 104/105 (30%/49%) (Scheme 46). [139] Analogously, 

the 5-azido-5-deoxy-Æ-D-xylofuranose 106 reacts with a range of alkynes to give 

mixtures of 5-(1H-1,2,3-triazol-1-yl)-Æ-D-xylofuranoses 107/108. [140,141] 2,3,5-Tri-O-benzoylâ-D-ribofuranosyl 

azide reacts with methyl 4-hydroxybut-2-ynoate to yield a mixture of 

the two expected isomeric triazoles in 75% yield. [142] 

Scheme 46 Addition of Azido Sugars to Alkynes [139–141] 

AcO 

AcO 

OAc 

102 

O 

OAc 

N 3 



+ Ph CF3 

103 

toluene 

reflux, 14 h 

AcO 

AcO 

100 

Ph 

F3C 

O 

AcO 

104 30% 

N 

N 

N 

OAc 

Bu t 

O 

+ 

O 

O 

Bu t 

101 

AcO 

AcO 

O 

O 

O 

F3C 

Ph 

O 

AcO 

105 49% 

N 

N 

N 

N 

N 

N 

OAc 



N 3 

OH 

O 

O 

O 

+ R 1 H 

toluene 

reflux 

N 

N 

N 

OH 

O 

b108 

106 

107 

R 1 = Ph, CH 2OH, CO 2Et 


Using Polymer-Supported Methods 

R 1 

O 

O 

+ 

R 1 

N 

N 

N 

OH 

O 

The use of polymer-supported methods to prepare carbohydrate-derived 1,2,3-triazoles is 

already established. Addition of azidodeoxy carbohydrate derivatives to the monomethyl 

ether derivative of polyethylene glycol 109 (a soluble polymer-supported alkyne) yields 

the polymer-supported triazoles 110/111 in a proportion of approximately 2:1 (Scheme 

47). Treatment of these polymers with sodium borohydride in hot ethanol gives the corresponding 

“free” triazoles 112/113 in greater than 75% yield. [143] In a variation of this procedure 

a succinate ester linkage (instead of an oxalyl ester) is also successfully used to prepare 

polymer-supported glycosyl triazoles. In this procedure, the “free” glycosyl triazoles 

can be obtained in high yields (>90%) and high purity by treatment of the polymer with an 

excess of ammonia in methanol solution, followed by precipitation of the polymer with 

ether and filtration. [141] 

Scheme 47 Addition of Azido Sugars to Soluble Polymer-Supported Alkynes [143] 

Me O 

sugar N3 = 

Me 

O 

n 

O 

O 

109 

O 

O 

O 



O 

O 

n 

O 

110 

O 

O 

sugar N 3 

N3 N3 

, 

OH 

O 

, AcO 

AcO 

O 

O 

O 

O 

+ 

N 

N 

N 

sugar 

+ 

NaBH4, EtOH 

heat, 3 h 

Me 

N 3 

O 

O 

AcO 

OMe 

toluene 

reflux, 12 h 

HO 

O 

n 

O 

O 

111 

O 

N 

N 

+ 

N 

sugar 

N 

HO 

N 

N 

sugar 

O 

O 

112 113 


N 

N 

N 

sugar

The complementary method, i.e. reaction of a polymer-supported azido sugar with alkynes, 

can also be used (Scheme 48). Azide 114 reacts with alkynes to give mixtures of 

the two regioisomers 115/116 in high yields (R 1 = Ph; R 2 = H, 50%; R 1 =CO 2Et; R 2 =H, 

>95%; R 1 =CH 2OH; R 2 = H, >95%). Treatment of these compounds with ammonia in methanol 

solution, followed by precipitation of the polymer with diethyl ether and filtration 

gives the corresponding “free” triazoles 117/118. [141] 

Scheme 48 Addition of Alkynes to Soluble Polymer-Supported Azido Sugars [141] 

Me 

Me 

O 

O 

n 

O 

n 

O 

O 

O 

114 

O 

O 

R 1 

N 3 

O 

O 

N 

O 

O 

O 

O 

R 2 

N 

N 

O 

O 

+ 

+ 

Me 

O 

R 1 

N 

N 

NH3, MeOH 

N 

OH 

rt, 10 h O 

n 

O 

O 

R 2 

O 

O 

toluene 

reflux, 2 d 

115 116 

R 1 

R 2 

O 

+ 

R 2 

N 

O 

O 

R 2 

R 1 

N 

N 

O 

O 

R 1 

N 

N 

N 

OH 

O 

O 

O 

117 118 

A solid-phase synthesis of functionalized 1,2,3-triazoles from the reaction of resin-bound 

azides 119 and terminal alkynes has been reported (Scheme 49). [144] The reaction with 

methyl propynoate occurs in dimethylacetamide at 608C and, after cleavage in trifluoroacetic 

acid, provides the free acids 120 (R 2 =CO 2Me), as single isomers, in moderate yields 

(17–27%). The reaction with phenylacetylene requires higher temperatures (120 8C) and 

provides 1:1 mixtures (22–25%) of the possible regioisomers 120 (R 2 = Ph) and 121 

(R 2 = Ph) after trifluoroacetic acid cleavage. 

Scheme 49 Solid-Phase Synthesis of 1H-1,2,3-Triazoles Using Resin-Bound Azides and 

Terminal Alkynes [144] 

O 

O 

R 1 

N3 

1. R 2 

H 

119 120 1:1 

R 1 = H, Me, Et, (CH2)5Me; R 2 = CO2Me, Ph 



DMA, 60 or 120 oC, 3 d 

2. TFA, CH2Cl2, rt, 18 h 

17−27% 

R 2 

N 

N 

N 

+ 

R 2 

R 1 CO 2H R 1 CO 2H 

N 

N 

121 

N 



A solid-phase, regioselective, copper(I)-catalyzed, 1,3-dipolar cycloaddition of terminal alkynes 

to azides has been used to prepare peptido-1,2,3-triazoles. [145] Copper(I) salts are 

used as catalysts in the reaction of resin-bound terminal alkynes to primary, secondary, 

and tertiary alkyl azides, aryl azides, and an azido sugar at 258C, affording selectively 1,4disubstituted 

1H-1,2,3-triazoles with quantitative conversions and purities ranging from 

75 to 99%. [145] 


Intramolecular 1,3-Dipolar Cycloadditions 

The intramolecular 1,3-dipolar cycloaddition of an azido group onto a C”C bond gives 

polycyclic triazoles. Azides 122 and 124, for example, give triazoles 123 (52%) and 125 

(59%), respectively, when heated in refluxing toluene (Scheme 50). [146] 

Scheme 50 Synthesis of 1,2,3-Triazoles via Intramolecular 

1,3-Dipolar Cycloadditions [146] 

N 3 

122 

OH 

toluene, reflux, 36 h 

52% 

N 

N 

N 

123 

HO OTBDMS 

HO 

N 3 

124 



toluene, reflux, 24 h 

59% 

OH 

N 

N 

N 

125 

OTBDMS 

Propargyl azides 127 undergo intramolecular cycloaddition reactions yielding N-unsubstituted 

1H-1,2,3-triazoles 130 (Scheme 51). The reaction must be carried out in nucleophilic 

solvents, such as methanol or ethanol, or in the presence of nucleophiles such as 

azide ion, amines, or thiols, if not, then only polymeric triazole products are obtained. 

The mechanism of this transformation involves the rearrangement of the propargyl azide 

to allenyl azide 128 that gives by rapid ring closure the triazafulvene 129. This short-lived 

intermediate is trapped by nucleophiles to give triazoles 130 in good yields. [147,148] Since 

propargyl azides can be prepared from propargyl halides or propargyl tosylates 126 

(X = halogen, OTs) and sodium azide, various substituted 1,2,3-triazoles can be synthesized 

in good yields in one-pot procedure from these precursors without the necessity to 

isolate the potentially hazardous propargyl azides. In the presence of sodium hydroxide 

the propargyl azides 127 undergo base-catalyzed (prototropic) rearrangement to allenyl 

azides 131. The immediate cyclization of this intermediate leads to the triazafulvene 

132, which can be trapped by nucleophiles to give triazoles 133 in good yields (Scheme 

51). [148] 


Scheme 51 Synthesis of 1H-1,2,3-Triazoles from Propargyl Azides or Their Precursors [148] 

R 2 

126 

R 1 

X 

20−70 o C 

NaOH 



N 3 

R 2 

R 2 

N3 

128 

131 

R 1 

R 1 

N 3 

R 2 

R 

127 

1 

R 1 R 2 X Conditions Nu Yield (%) 

of 130 

R 1 

Me H OTs NaN 3, MeOH, H 2O, 20–408C OMe 82 [148] 

Ph H Br NaN 3, MeOH, H 2O, reflux OMe 87 [148] 

H H Br 1. NaN 3, dioxane, H 2O, rt, 1 h S-iPr 31 [148] 

H H OTs 

2. iPrSH, 708C, 3 h 

1. NaN3, dioxane, H2O, rt 

2. NH3,H2O, 50–60 8C 

NH2 77 [148] 

H MOM OSO2Ph 1. NaN3, MeOH, H2O, rt, 24 h 

2. MeOH, reflux, 6 h 

OMe 88 [148] 

H Ph OTs 1. NaN3, MeOH, H2O, 358C 

2. MeOH, reflux, 45 h 

OMe 73 [148] 

Depending on the reaction conditions, propargyl azides 127 can be selectively converted 

into triazoles 130 or 133. For example, azide 134 can produce triazole 135 or triazole 136 

depending only on the presence or absence of sodium hydroxide (Scheme 52). [148] 

R 2 

N 3 

R 1 

R 2 

129 

N 


N 

N 

N 

N 

N 

NuH 

NuH 

Nu 

Nu 

R 1 

R 1 

R 2 


R 2 


N 

H 

N 

H 

N 

N 

N 

N 

Ref 



Scheme 52 Selective Synthesis of Isomeric 1H-1,2,3-Triazoles from Propargyl Azides [148] 

MeO 


N 3 

NH3 

62% 

NH3, NaOH 

75% 

The intramolecular 1,3-dipolar cycloaddition of an azide group with a C”C bond has been 

used extensively for the synthesis of nonclassical polycyclic â-lactams. [149–154] 


Addition of Azides to Alkoxyalkynes 

Nitrophenyl azides 138 undergo cycloaddition reactions with 1-methoxyalk-1-ynes 137 at 

room temperature to give 1H-1,2,3-triazoles 139 in low yields (R 1 = Et; X = H, 22%) or the 

corresponding ring-opened isomeric Æ-diazocarboximidates 140 (R 1 = Me, 52%; R 1 = Et, 

75%) (Scheme 53). [155] The reaction of ethoxyacetylene with 4-methxoyphenyl azide and 

4-nitrophenyl azide also gives the corresponding 1-aryl-5-ethoxy-1H-1,2,3-triazoles. [103] 

MeO 

H 2N 

H 2N 

MeO 



Scheme 53 Addition of Aryl Azides to 1-Methoxyalk-1-ynes [155] 

R 1 


OMe 

R 1 = Me, Et; X = H, NO 2 

+ 



O2N 

N 3 


NO 2 

X 

CHCl3, rt 

3−10 d 

N 

H 

N 

H 

N 

N 

N 

N 

MeO 

R 1 

N 


N 

N 

O 2N X 

X = NO 2 

NO 2 

R 1 N 2 

MeO 

N 

O2N X 

Similarly, 5-ethoxy-1H-1,2,3-triazoles 143 are obtained from the reaction of ethoxyacetylene 

(141) with phenyl azide, substituted phenyl azides [156] and hetaryl azides [114] 142 

(Scheme 54). The best yield is obtained with phenyl azide (87%). With 2-nitrophenyl azide, 

and 4-nitrophenyl azide the yields are very low (6–12%). 


140 

NO2

Scheme 54 Addition of Azides to Ethoxyacetylene [114,156] 

H OEt + R1N3 141 

R 1 = aryl, 

O O 

142 

6−87% 

5-Ethoxy-1-(6-methyl-2-oxo-2H-pyran-4-yl)-1H-1,2,3-triazole (143,R 1 = 6-methyl-2-oxo-2Hpyran-4-yl); 


A mixture of 4-azido-6-methyl-2H-pyran-2-one (0.77 g, 5.09 mmol), ethoxyacetylene 

(7.13 mmol, from a 50% soln in hexanes) and anhyd THF (18 mL) was left in a closed reactor 

for 7 d. The resulting precipitate of the product was collected by filtration and the filtrate 

was left 7 d more at 308C to give a second crop. The combined precipitates were 

washed with hexane to afford the pure product; yield: 24% (57% with respect to consumed 

azide 142); mp 159–1618C. 

EtO 

143 

N 

N 

N 

R1 13.13.1.1.3.1.1.4 Method 4: 

Addition of Ethyl Azidoformate and Cyanogen Azide to Alkynes 

Ethyl azidoformate (144) undergoes addition to phenylacetylene to give 1,2,3-triazoles. If 

the reaction is carried out at 508C (3 weeks) a mixture of the 1,4- and 1,5-disubstituted triazoles 

is obtained in a ratio of about 53:47 and an overall yield of 36% (Scheme 55). [157] If 

the reaction is performed at 1308C the two initially formed triazoles 145/146 isomerize to 

ethyl 4-phenyl-2H-1,2,3-triazole-2-carboxylate (147) and this is the isolated triazole product 

(16%). Under these reaction conditions, 2-ethoxy-4(or 5)-phenyloxazole 148 (16%) is 

also obtained. [157,158] The formation of this compound is due to the addition of (ethoxycarbonyl)nitrene 

(generated by thermal decomposition of the azide) to phenylacetylene. The 

reaction of ethyl azidoformate with dimethyl acetylenedicarboxylate and methyl propynoate 

also gives the corresponding triazoles (23 and 50% yield, respectively) and 2-ethoxyoxazoles 

(3%). [158] 

Scheme 55 Addition of Ethyl Azidoformate to Phenylacetylene [157,158] 

Ph H + N3CO2Et 144 



50 o C 

36% 

130 o C 

Ph 

N 

145 

N 

N 

CO 2Et 

+ 

53:47 

Ph 

N 

146 

N 

N 

CO 2Et 

Ph 

Ph 

N 

N 

N 

N 

CO2Et 

+ 

O 

OEt 

147 16% 148 or isomer 16% 



Ethyl azidoformate reacts with N,N-diethylprop-1-yn-1-amine (149,R 1 = Me) in carbon tetrachloride 

at room temperature to yield only triazole 150 (R 1 = Me) (Scheme 56). [159] However, 

if an excess of the ynamine is used, the initially formed triazole isomerizes to ethyl 

5-(diethylamino)-4-methyl-2H-1,2,3-triazole-2-carboxylate. [159] Ethyl azidoformate also 

adds to ynamines 149 (R 1 = Ac, CO 2Me) to give the corresponding triazoles 150 in good 

yields. [160] Benzoyl azide also adds readily to ynamines. [159,161] Addition of ethyl azidoformate 

to ethoxyacetylene (no solvent, rt, 35 d) gives a mixture of three isomeric triazoles: 

ethyl 5-ethoxy-1H-1,2,3-triazole-1-carboxylate, ethyl 4-ethoxy-1H-1,2,3-triazole-1carboxylate, 

and ethyl 4-ethoxy-2H-1,2,3-triazole-2-carboxylate in a ratio of 54.5:42:3.5 

(by NMR). Addition of 1,4-diazabicyclo[2.2.2]octane converts 1-ethoxycarbonyl isomers 

into the 2-ethoxycarbonyl derivative. [159] 

Scheme 56 Addition of Ethyl Azidoformate to Ynamines [159,160] 

N 3CO 2Et + 

144 

Me 2N 



149 

R 1 

CCl4, rt, 20 min, or 

THF, 65 oC, 3 h 

R1 = Me 100% 

R1 = Ac 82% 

R1 = CO2Me 70% 

Me2N 

R 1 

150 

N 

N 

N 

CO2Et 

Cyanogen azide (N 3CN) reacts with acetylene at 458C to give 77% of a 1:1 adduct that is 

colorless below its melting point (338C) but is yellow in the melt or in solution. The adduct 

is a tautomeric mixture of 1H-1,2,3-triazole-1-carbonitrile and N-cyano-Æ-diazoethylidenimine 

(see Scheme 3). [20] The cyanogen azide adducts of prop-1-yne, but-2-yne, and 

hex-1-yne are also tautomeric mixtures of the corresponding triazoles and N-cyano-Æ-diazoimines. 

[20] Cyanogen azide reacts with ethoxyacetylene [20] and N,N-diphenylacetylamine 

[162] to afford only the diazo derivatives, resulting from ring opening of the initially 

formed 1H-1,2,3-triazole-1-carbonitriles. 


Addition of Sulfonyl Azides to Alkynes 

Sulfonyl azides 151 undergo addition to electron-rich alkynes (ynamines and alkoxyalkynes 

152) to yield 1-sulfonyl-1H-1,2,3-triazoles 153 (Scheme 57). [103,155,163–167] However, 

these compounds are very labile and, in solution, exist in equilibrium with open-chain diazo 

tautomers. In many cases the diazo tautomer is the sole product. As an example, addition 

of arenesulfonyl azides 151 (R 1 = aryl) to ynamine 152 (R 2 = Me; Y = NEt 2) gives 

mainly 1,2,3-triazoles 153 while the reaction of this type of azides with ynamine 152 

(R 2 = Ph; Y = NMe 2) gives the Æ-diazoamidines 154 (Scheme 57). [166] 


Scheme 57 Addition of Sulfonyl Azides to Electron-Rich Alkynes [166] 

R 1 SO 2N 3 + 

151 

R 2 

152 

Y 

Y 

R 2 

N 

153 

N 

N 

SO 2R 1 

R1 R2 Y Yield (%) mp (8C) Ref 

153 154 

Ph Me NEt2 62 – 84–85 [166] 

4-MeOC6H4 Me NEt2 58 – 54–56 [166] 

4-Tol Me NEt2 65 – 49–52 [166] 

4-AcHNC6H4 Me NEt2 78 – 131–132 [166] 

4-O2NC6H4 Me NEt2 – 81 97–98 [166] 

2,4-Cl2C6H3 Me NEt2 – 62 87–88 [166] 

4-MeOC6H4 Ph NMe2 – 79 95–96 [166] 

4-O2NC6H4 Ph NMe2 – 70 106–107 [166] 

4-BrC6H4 Ph NMe2 – 65 102–103 [166] 

3-O2NC6H4 Ph NMe2 – 78 104–105 [166] 

2,5-Cl2C6H3 Ph NMe2 – 83 112–113 [166] 

R 2 N 2 

Y 

N 

SO2R1 Tosyl azide reacts with 3-aminoprop-2-ynimidamides 155 to yield 1H-1,2,3-triazole-4carboximidamide 

156 in good yields (Scheme 58). [168] 

Scheme 58 Addition of Tosyl Azide to 3-Aminoprop-2-ynimidamides [168] 

Ar 1 HN 

MeN Ph 

155 

Ar 1 = Ph, 4-Tol 

NAr 1 

+ TsN3 



CHCl 3 

rt, 20 d 

Ar 1 HN 

Ar 1 N 

MeN 

Ph 

N 

NTs 

N 

Ph 

MeN 

Ar 1 HN 

154 

NTs 

156 65−74% 

N 

N 

N 

Ar1 Reaction of Arenesulfonyl Azides 151 with Ynamines 152 (Y = Dialkylamino); 


A soln of the sulfonyl azide (0.01 mol) in THF (10 mL) was added to a soln of the ynamine 

(0.01 mol) in THF (5 mL) at –788C (cooled in dry ice/acetone bath) over 1 h. The soln was 

then allowed to warm to rt, filtered through anhyd alumina, and the solvent was removed 

by evaporation under reduced pressure. The resulting solid (or oil) was crystallized (Et 2O/ 

petroleum ether) to afford the appropriate triazole or Æ-diazoamidine. 




Addition of Azidotrimethylsilane and Azidotributylstannane to Alkynes 

Azidotrimethylsilane can be successfully used as a safe synthetic equivalent of the highly 

explosive hydrazoic acid. [169,170] It undergoes addition to alkynes to give the corresponding 

2-(trimethylsilyl)-2H-1,2,3-triazoles 158 [via the 1-(trimethylsilyl)-1H-isomers 157] in good 

yields (Scheme 59). For example, the reaction of azidotrimethylsilane with but-2-yne gives 

4,5-dimethyl-2-(trimethylsilyl)-2H-1,2,3-triazole (158, R 1 =R 2 = Me) in 78–87% yield. Similar 

results are obtained with other alkynes. [171] The trimethylsilyl group can be subsequently 

replaced by a proton under very mild conditions. [171–173] In some cases, the N-unsubstituted 

triazole 159 is the isolated product of the cycloaddition reaction. [174,175] A related 

silyl azide, (trimethylsilyl)methyl azide (TMSCH 2N 3), also reacts with alkynes to give 

quantitative yields of the corresponding 1-[(trimethylsilyl)methyl]-1H-1,2,3-triazoles. [176] 

Scheme 59 Addition of Azidotrimethylsilane to Alkynes 

TMSN 3 + 

R 1 

R 2 

120−150 oC 10−20 h 

R 1 

R 2 

R 

N 

N 

N 

2 

R1 TMS 

N 

N 

NTMS 

158 50−90% 

H2O or 

R 

EtOH N 

2 

Azidotributylstannane (160) is another synthetic equivalent of hydrazoic acid. It gives 2substituted 

triazoles 162 by reaction with mono- and disubstituted alkynes by a 1,3-dipolar 

cycloaddition to give initially the 1-substituted triazoles 161 (Scheme 60). [177–179] 

Triazoles 162 can be converted into the N-unsubstituted derivatives by treatment with hydrogen 

chloride. As an example, phenylacetylene reacts with 160 (neat, 1408C, 12 h) to 

give triazole 162 (R 1 =H;R 2 = Ph) in 61% yield. On treatment with hydrogen chloride this 

compound is converted into triazole 163 (R 1 =H;R 2 = Ph) in 75% yield. 

157 

Scheme 60 Addition of Azidotributylstannane to Alkynes [177–179] 

Bu3SnN3 + 

160 

R 1 



R 2 

140−180 oC 12−70 h 

R 1 

R 2 

N 

N 

N 

162 

R 1 

R 2 

SnBu 3 

N 

161 

N 

N 

SnBu3 

100% 

HCl, Et 2O 


R 1 

R 1 

159 

R 2 

163 

N 

H 

N 

H 

N 

N 

N


Addition of Azides to Metal Acetylides 

Alkyl, [180,427] aryl, [180,181,425,427] and sulfonyl [182–184] azides form triazole derivatives with lithium, 

magnesium, and sodium derivatives of terminal alkynes. The mildness of the conditions 

required for the additions (0 8C or below) suggests that the mechanism of the reaction 

may be different from that of normal azide addition to alkynes. A plausible mechanism 

(Scheme 61) involves nucleophilic attack of the acetylenic anion 164 on the terminal 

nitrogen of the azide, followed by 1,5-anionic cyclization to give the triazolyl anion 

165. [3] The total regioselectivity of the reaction supports this interpretation. The triazolyl 

anion so formed can be protonated (to give 166), carboxylated (to give 167) or can react 

with more azide to give a linear triazene 168 which, in turn, can be hydrolyzed to the triazolamine 

169. [182] 

Scheme 61 Addition of Azides to Metal Acetylides [182] 

R1 − + 

164 

R 1 

165 

N N NR2 + − 

N 

N 

N 

R2 − 



H 3O + 

CO 2 

R 2 N 3 

R 1 

R 1 

HO 2C 

R 1 

166 

N 

N 

N 

−N R2 N 

N 

N 

R2 167 

R1 R2N − 

N 

N 

N 

R2 N 

168 

N 

N 

N 

R2 H3O + N 

R 

N 

N 

1 

R2 H2N Sodium phenylacetylide reacts with tosyl azide (1 equiv) to yield, after acidification, triazole 

170. If an excess of tosyl azide is used, the 4-azidotriazole 171 is obtained (Scheme 

62). In both cases the yields are very low. [184] A copper(I)-catalyzed reaction of resin-bound 

terminal alkynes (probably involving the corresponding copper acetylides) with a range 

of organic azides has been reported. [145] 

169 



Scheme 62 Addition of Sodium Phenylacetylide to Tosyl Azide [184] 

Ph Na + − 



1. TsN 3 (1 equiv) 

2. H 3O + 

9% 

1. TsN3 (excess) 

2. H3O + 

16% 

Ph 

170 

N 

N 

N 

Ts 

N3 

N 

N 

Ph 

N 

Ts 

4-Azido-5-phenyl-1-tosyl-1H-1,2,3-triazole (171); Typical Procedure: [184] 

A slurry of sodium phenylacetylide [prepared from PhC”CH (0.05 mol) and Na (0.05 mol)] 

in dry Et 2O (25 mL) was added slowly to a stirred soln of tosyl azide (19.7 g, 0.10 mol) in dry 

Et 2O (50 mL) at a rate which maintained the solvent at reflux. As the mixture was stirred 

for 24 h a brown solid separated (15.2 g, 58%), which corresponds to a sodium salt of an 

intermediate compound. Part of this compound (5.0 g) was treated with hot glacial AcOH 

(10 mL) and a light yellow solid was obtained upon cooling. Two recrystallizations (glacial 

AcOH) afforded pure triazole 171; yield: 0.52 g (16%); mp 170–1718C (dec). 

13.13.1.1.3.1.2 Addition of Azides to C=C Bonds 

The thermal cycloaddition of azides to alkenes is an important route to 1H-1,2,3-triazoles. 

Azides undergo addition to a wide range of angle strained, unstrained, and unactivated 

double bonds; to electron-rich double bonds such as enamines, enamides, enol ethers, 

and ketene acetals; and to alkenes bearing one or two electron-withdrawing groups. [7] In 

these reactions, 4,5-dihydro-1H-1,2,3-triazoles (D 2 -1,2,3-triazolines) are the addition products 

but they can be aromatized to the corresponding triazoles by elimination of suitable 

groups or by oxidation. In some cases the dihydrotriazoles aromatize spontaneously. Unlike 

the case of alkynes, the reaction of azides with alkenes is highly regioselective. Because 

of this, it may be convenient to prepare a triazole via the dihydrotriazole since at 

the end the separation of regioisomers is not needed. 

The synthesis of 1,2,3-triazoles via 1,3-dipolar cycloaddition of azides to alkenes requires 

patience. It may take weeks to months to obtain reasonable yields of the desired 

compound, especially if the C=C bond is not activated by electron-withdrawing or electron-donating 

substituents. Increasing the reaction temperature is not always a solution 

since it is restricted by the thermal lability of most dihydrotriazoles (they readily extrude 

N 2). 


Addition of Sodium Azide to Activated Alkenes 

Sodium azide undergoes addition to alkenes with strongly electron-withdrawing substituents 

to give N-unsubstituted 1,2,3-triazoles in good yields (Scheme 63). The mechanism 

seems to involve the conjugate addition of the azide ion to the double bond, cyclization 

of the resulting anion, and aromatization. The synthesis of triazoles 173 by the reaction 

of sodium azide with Æ-nitroacrylic ester 172 (Y = CO 2Et) and Æ-nitro ketone 172 (Y = Bz) 

are examples of this method. [185] Other nitroalkenes are converted into 1,2,3-triazoles in 

the same way. [186] Similarly, triazole 175 is obtained, along with two minor dihydrotriazoles, 

from the reaction of diethyl (4-nitrobenzylidene)malonate (174) with sodium 


171

azide. [187] Ethyl 3-(4-nitrophenyl)acrylate reacts with sodium azide, in aprotic solvents, to 

give triazole 175 in moderate yields. [188] The reaction of â-aryl-Æ-(phenylsulfinyl)acrylates 

176 with sodium azide gives triazoles 177 in good yields. [189] 5-Tosyl-1H-1,2,3-triazole 

(179) is prepared in 50% yield from the reaction of 1,2-ditoylacetylene (178) with sodium 

azide. [190,191] It has been shown that (E)-2-azidovinyl 4-methylphenyl sulfone is an intermediate 

in this transformation. Another example of synthesis of 1,2,3-triazoles from the 

addition of sodium azide to activated alkenes is found in the preparation of (4-oxo-4H-1benzopyran-2-yl)-1,2,3-triazoles 

181 from 2-(2-arylvinyl)-4H-1-benzopyran-4-ones 180. [192] 

Using 180 (X = H) as starting compounds, triazoles 181 are the only isolated products; 

the yields are in the range of 48–59%. When 2-(2-aryl-1-bromovinyl)-4H-1-benzopyran-4ones 

180 (X = Br) are used the triazoles 181 (38–40%) are obtained together with unexpected 

1-aryl-5-[(4-oxo-4H-1-benzopyran-2-yl)methyl]tetrazoles (10–12%). 

Scheme 63 Addition of Sodium Azide to Activated Alkenes 

H 

N 

172 

4-O 2NC 6H 4 

174 

Y 

NO 2 

H 

EtO 2C CO 2Et 

Ar 1 H 

EtO 2C SOPh 

176 

Ar 1 = Ph, 1-naphthyl, 2-furyl 

Ts 

178 

O 

O 

Ts 

180 

+ NaN3 

X 

+ NaN3 

+ NaN3 

Ar 1 



+ NaN3 

+ NaN3 

DMF, rt, 120 h 

Y = CO2Et 70% 

Y = Bz 54% 

DMSO, 25 oC, 2 h 

41% 

DMF, AcOH, rt, 24 h 

57−73% 

DMSO, rt, 24 h 

50% Ts 

DMF, reflux 

X = H 48−59% 

X = Br 38−40% 

N 

H 

179 

Y 

173 

4-O2NC 6H 4 

EtO 2C 

175 

H 

N 

N 

H 

N 

H 

Ar 

177 

N 

H 

N 

N 

1 

EtO2C N 

N 

O 

O 

Ar 1 

181 

N 

N 

N 

N 

N 

N 

NH 



Sodium azide also adds to Æ-chloroenamines 182 (NR 2 R 3 = NMe 2, pyrrolidinyl, morpholino) 

to give 1,2,3-triazoles 184 (via the Æ-azidoenamines 183) in good yields (Scheme 

64). [193,194] However, with less basic Æ-chloroenamines (NR 2 R 3 = NMePh), azirines 185 are 

the sole reaction products. 

Scheme 64 Addition of Sodium Azide to Æ-Chloroenamines [193,194] 

R 1 

Cl 

182 

NR 2 R 3 

R 1 

R 1 = Me, t-Bu, Ph 

183 

N3 

+ NaN 3 

NR 2 R 3 

MeCN, CCl 4 

R 1 

R 3 R 2 N 

R 1 

N 

185 

N 

N 

N 

NR 2 R 3 

R 3 R 2 N 

R 1 

N 

H 

N 

N 

184 58−84% 

The addition of sodium azide to (1- and 2-acylvinyl)triphenylphosphonium salts 186 and 

189 gives, respectively, acyl or alkoxycarbonyl-1,2,3-triazoles 188 and 191 (via the ylides 

187 and 190) (Scheme 65). [195,196] 

Scheme 65 Addition of Sodium Azide to (1- and 2-Acylvinyl)triphenylphosphonium 

Salts [195,196] 

Cl − 

R 1 

Ph3P + 

186 

O 

R 2 

NaN3, MeOH 

H2O R 1 = iPr, t-Bu, Cy, cyclopropyl; R 2 = H, Et 

X 

Ph3P 

+ 

− 

189 

R 1 

Ph3P + 

O 

− 

187 

R 

NaN3, H2O 1 h 

− 

1 

O O 

R 1 = Me, Et, Pr, iPr, Ph, OMe 



Ethyl 5-(4-Nitrophenyl)-1H-1,2,3-triazole-4-carboxylate (175); Typical Procedure: [187] 

Ph3P + 

CAUTION: Sodium azide can explode on heating and is highly toxic. 

190 

N3 

R 2 

N3 

R 1 

− PPh 3 

− PPh 3 

R 

N 

N 

N 

H 

2 

R 

188 15−50% 

1 

O 

N 

R 

N 

N 

H 

191 30−95% 

1 

O 

Diethyl (4-nitrobenzylidene)malonate (174; 2.0 g, 6.82 mmol) was added in one portion to 

a soln of NaN 3 (443 mg, 6.82 mmol) in dry DMSO (10 mL) at 258C. The mixture immediately 

became deep orange-brown in color and heat was evolved. After stirring for 2 h, the 

mixture was poured onto an ice/water slurry (40 g). The resultant mixture was extracted 


with Et 2O (two minor dihydrotriazoles could be obtained from this fraction), the aqueous 

layer was acidified with dil HCl to pH 1 and extracted with Et 2O. These ethereal extracts 

were dried (MgSO 4) and evaporated to give a yellow amorphous solid (800 mg) which was 

recrystallized (CH 2Cl 2) to give pale yellow crystals; yield: 730 mg (41%); mp 174–1768C. 


Addition of Azides to Activated Alkenes 

Azides undergo addition to alkenes with strongly electron-withdrawing substituents to 

give 4,5-dihydro-1H-1,2,3-triazoles. Frequently these 4,5-dihydro-1H-triazoles are unstable 

and, by elimination of a stable fragment, aromatize to 1,2,3-triazoles [197–199] or are converted 

into aziridines by elimination of nitrogen. [200] Generally the addition of azides to these 

alkenes is regioselective and only one triazole is obtained. However, in some cases mixtures 

of triazoles are formed. For example, 1-nitroalk-1-enes 192 react with phenyl or 

methyl azide to give mixtures of the triazoles 193, 194, and 195 (Scheme 66). [197] The relative 

proportions of these compounds are dependent of the experimental conditions. 

Nitrotriazoles 195 are obtained by air oxidation of the corresponding 4,5-dihydro-1H-triazoles. 

The formation of the two regioisomeric triazoles 193 and 194 is explained by the 

isomerization of the 1-nitroalk-1-enes to 2-nitroalk-1-enes. [197] 

Scheme 66 Reaction of Azides with 1-Nitroalk-1-enes [197] 

R 1 N 3 + 

R 2 

H 

192 

NO2 

H 

R 1 = Me, Ph; R 2 = Me, Ph, CO 2Me 

benzene 

30−70 oC 4−15 d 

R 2 

193 

N 

N 

N 

R1 N 

N 

N 

R1 R2 R2 O2N + + 

Phenyl azide adds to 1-bromoethenesulfonyl chloride (196), in refluxing chloroform, to 

yield 4-bromo-1-phenyl-1H-1,2,3-triazole (198) in 45% yield (Scheme 67). [198] The unstable 

4,5-dihydro-1H-triazole 197 aromatizes promptly by losing sulfur dioxide and hydrogen 

chloride. 

Scheme 67 Addition of Phenyl Azide to 1-Bromoethenesulfonyl Chloride [198] 

PhN 3 + 

H 

H 

Br 

196 

SO2Cl 



CHCl 3 

reflux, 1 h 

ClO2S 

N 

H 

N 

H N 

Ph 

Br 

197 

194 

− SO 2 

− HCl 

195 

N 

N 

N 

R1 Br 

N 

N 

N 

Ph 

198 45% 

Several perfluoroalkyl-substituted 1,2,3-triazoles linked to C6 of D-galactose and D-altrose 

are synthesized by this method. [199] For example, addition of the monosaccharide azide 

199 to the perfluoroalkyl-substituted phenyl vinyl sulfones 200 yields the reversed nucleosides 

201 in good yields (Scheme 68). Only a single 1,2,3-triazole derivative is formed 

in each of these reactions. 



Scheme 68 Addition of Monosaccharide Azides to Perfluoroalkyl-Substituted 

Phenyl Vinyl Sulfones [199] 

O 

O 

N3 

199 

O 

O O 

R 1 = CF3, (CF2)3CF3, (CF2)5CF3 



+ 

R 1 

SO 2Ph 

toluene, reflux 

17−21 h 

72−75% 

200 201 

O 

O 

N 

N 

N 

Other sugar-derived 1,2,3-triazoles are prepared by a one-pot substitution–cyclization–oxidation 

procedure starting from D-arabinose and L-fucose. The key step in this process is 

an intramolecular 1,3-dipolar cycloaddition of an azide to the C=C bond of an Æ,â-unsaturated 

carboxylic ester. The resulting 4,5-dihydro-1H-triazole is readily aromatized by air 

oxidation. [201] Analogous sugar-derived 4,5-dihydro-1H-1,2,3-triazoles (related to D-glucose 

and D-galactose) are stable but can be aromatized in good yields to the corresponding triazoles 

by oxidation with bromine. [202] 

Maleimides and quinones have also been used as dipolarophiles in reactions with 

aryl azides, [203–206] silyl azides, [207] (azidoalkyl)indoles, [208] glycosyl azides, [209] (1-azidoalkyl)phosphonates 

[210] and Æ-azidocarboxylic esters. [210] 

6-Deoxy-1,2:3,4-di-O-isopropylidene-6-[4-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]-Æ-Dgalactopyranose, 

(201,R 1 =CF 3); Typical Procedure: [199] 

A soln of azide 199 (0.85 g, 3.0 mmol) and sulfone 200 (R 1 =CF 3; 0.57 g, 2.40 mmol) in toluene 

(15 mL) was refluxed under argon for 17 h (TLC control). Then the solvent was evaporated 

under reduced pressure and the residue was purified by column chromatography 

(toluene/EtOAc 20:1); yield: 0.64 g (72%); mp 128–1308C; [Æ] D –49.2 (CHCl 3). 


Addition of Azides to Strained Alkenes 

Azides react with alkenes to yield 4,5-dihydro-1H-1,2,3-triazoles. Whereas unactivated alkenes 

are sluggish in their reaction with aryl azides, in contrast strained bicyclic alkenes 

are particularly reactive. [76] For example, the reaction of 4-bromophenyl azide with hex-1ene 

(in excess) affords the corresponding 4,5-dihydro-1H-1,2,3-triazole in 89% yield after 

5.5 months at room temperature. At elevated temperatures (>808C), extensive decomposition 

of the 4,5-dihydro-1H-1,2,3-triazole is observed. [211] No detectable addition product 

is observed when the same azide and cyclohexene are left for three months at room temperature. 

Conjugated dienes are, however, much more reactive than the corresponding 

mono-unsaturated alkenes. For example, the adduct from the reaction of cyclohexa-1,3diene 

and 4-bromophenyl azide begins to crystallize after three days at room temperature 

and, after 18 days, a 77% yield of the corresponding 4,5-dihydro-1H-1,2,3-triazole is obtained. 

[211] On the other hand, phenyl azide and substituted phenyl azides react with norbornene, 

in refluxing petroleum ether (60–90 8C) for three to four hours, to give the corresponding 

1-aryl-4,5-dihydro-1H-1,2,3-triazoles in 51–93% yield. [212,213] Norbornene and 

other strained alkenes also react with azidotrimethylsilane to give the corresponding 1- 

(trimethylsilyl)-4,5-dihydro-1H-1,2,3-triazole adducts in high yields. [214] The reaction of 

norbornene and dicyclopentadiene with several heterarylmethyl azides has been studied. 

[132] 


O 

O O 

R 1

The reaction of azides with norbornadiene is particularly interesting since it allows 

the synthesis of 4,5-unsubstituted triazoles 204 (Scheme 69). The thermolysis of the intermediate 

4,5-dihydro-1H-1,2,3-triazole 203 gives the triazole and cyclopentadiene (via a 

retro-Diels–Alder reaction). For example, the reaction of norbornadiene with diethyl (azidomethyl)phosphonate 

[202, X = PO(OEt) 2] in tetrahydrofuran at room temperature gives 

the 4,5-dihydro-1H-1,2,3-triazole [203, X = PO(OEt) 2] in 92% yield. Thermolysis of this compound 

at 608C yields the corresponding triazole in 74% yield. [249] Similarly, Æ-alkoxy- and 

Æ-alkylsulfanyl-substituted azides, on reaction with norbornadiene in refluxing 1,4-dioxane, 

also give the corresponding triazoles in high yields. [215] Phenyl azide and substituted 

phenyl azides also react with norbornadiene to give the corresponding 4,5-dihydro-1H- 

1,2,3-triazoles which, by thermolysis, yield the corresponding 1-aryl-1H-1,2,3-triazoles. 

[213,216,217] In the reaction of norbornadiene with azidotrimethylsilane the initially 

formed 4,5-dihydro-1H-1,2,3-triazole is converted, spontaneously, into 2-(trimethylsilyl)- 

2H-1,2,3-triazole. [214] Addition of a range of hetaroyl azides to the strained 5-methylenebicyclo[2.2.1]hept-2-ene, 

at room temperature, afforded carbonyl aziridines as the major 

product. These compounds are formed by loss of molecular nitrogen from the 4,5-dihydro-1H-1,2,3-triazole 

adducts. [218] 

Scheme 69 Reaction of Azides with Norbornadiene [215,249] 

+ 

X = PO(OEt) 2, OR 1 , SR 1 

X N 3 

202 

THF, rt 

N 

203 

N 

N 

X 60 o C 

− 

N 

N 

N 

X 

204 

The oxa and aza analogues of norbornadiene 205 (X = O, NCO 2Et) also react with phenyl 

azide to give 1,2,3-triazoles (Scheme 70). While triazole 207 is obtained in quantitative 

yield from 205 (X = O), the reaction with 205 (X = NCO 2Et) gives two triazoles: 207 (64%) 

and 1-phenyl-1H-1,2,3-triazole (36%). [219,220] 

Scheme 70 Reaction of Phenyl Azide with 7-Oxa- and 7-Azabicyclo[2.2.1]hepta- 

2,5-dienes [219,220] 

X X 

CO2Me X = O, NCO 2Et 

CO 2Me 



PhN 3 

MeO 2C 

205 206 

CO2Me NPh 

N 

N 

− 

X 

MeO2C 

MeO2C 

207 

N 

N N 

Ph 

Methylenecyclopropane is another interesting strained system that reacts readily with 

phenyl azide to give stable 4,5-dihydro-1H-1,2,3-triazoles. [221] However, the equivalent reaction 

with alkyl 2-methylenecyclopropane-1-carboxylates 208 yields 1,2,3-triazoles 210 

(Scheme 71). [128] A probable mechanism for the rearrangement of the intermediate 4,5-dihydro-1H-1,2,3-triazoles 

209 is shown in Scheme 71. 



Scheme 71 Reaction of Phenyl Azide with Alkyl 2-Methylenecyclopropane- 

1-carboxylates [128] 

R1O2C R2 208 

R 3 

+ PhN3 

100 oC 12−24 h 

R 1 O 

R 2 

O H 

209 

R 3 

N 

N 

N 

Ph 

R 2 

R 1 O 2C 

R 3 

N N 

N 

Ph 

210 R1 = Me; R2 = H; R3 = CO2Me 91% 

R1 = Et; R2 = R3 = H 50% 

R1 = Et; R2 = Me; R3 = H 

Dimethyl 2-(1-Phenyl-1H-triazol-4-yl)butanedioate (210,R 1 = Me; R 2 =H;R 3 =CO 2Me); 


A mixture of 208 (R 1 = Me; R 2 =H;R 3 =CO 2Me; 2 g) and phenyl azide (10 mL) was heated on 

a steam bath for 12 h. The mixture was cooled and hexane was added to dissolve the remaining 

phenyl azide. The supernatant layer was decanted and the resulting brown solid 

was recrystallized (acetone/cyclohexane) to give triazole 210 (R 1 = Me; R 2 =H;R 3 =CO 2Me); 

yield: 3.1 g (91%). A pure sample was obtained by recrystallization (EtOAc); mp 114–1158C. 


Addition of Azides to Allenes 

Aryl azides undergo addition to allenes to give 4-alkylidene-4,5-dihydro-1H-1,2,3-triazoles 

in reasonable yields. 4,5-Dihydro-1H-1,2,3-triazoles 212, for example, are obtained in 29– 

73% yield from the reaction of 2,4-dimethylpenta-2,3-diene (211) (tetramethylallene) with 

phenyl azide and nitrophenyl azides (Scheme 72). [222] 

Scheme 72 Addition of Aryl Azides to Tetramethylallene [222] 

211 

+ Ar 1 N 3 



Ar1 = Ph 29% 

Ar1 = 4-O2NC6H4 73% 

Ar1 = 2,4,6-(O2N) 3C6H2 72% 

N N 

Ar1 When it is possible, the 4-alkylidene-4,5-dihydro-1H-1,2,3-triazoles aromatize spontaneously 

to 1,2,3-triazoles, as observed in the reaction of propa-1,2-diene with phenyl azide. 

In this case a mixture of 5-methyl-1-phenyl-1H-1,2,3-triazole (0.6%), 4-methyl-1-phenyl-1H- 

1,2,3-triazole (1%), and a diamine (18%) is obtained. [223] Similarly, addition of phenyl azide 

to methyl buta-2,3-dienoate (213) gives a mixture of the triazoles 214 and 215 (9:1) in 67% 

yield (Scheme 73); [224] the addition occurs exclusively at the Æ,â-double bond. 


212 

N

Scheme 73 Addition of Phenyl Azide to Methyl Buta-2,3-dienoate [224] 

213 

CO2Me 

+ PhN 3 

74 o C, 24 h 

67% 

N N 

MeO2C 

N 

Ph 

214 

+ 

9:1 

MeO 2C 

215 

N 

N N 

Ph 

Phenyl azide adds to cyclonona-1,2-diene (216) to give selectively the 4,5-dihydro-1H- 

1,2,3-triazole 217 (Scheme 74). This stable compound can be isomerized to the corresponding 

triazole 218 by treatment with a strong base. [223] When optically active (+)-(R)-cyclonona-1,2-diene 

is used the (+)-(S)-4,5-dihydro-1H-1,2,3-triazole 217 is obtained, suggesting 

a concerted cycloaddition mechanism. 

Scheme 74 Addition of Phenyl Azide to Cyclonona-1,2-diene [223] 

216 

+ PhN 3 

toluene 

reflux, 10 h 

21% 

217 

N 

N 

N 

Ph 

NaOEt, EtOH 

reflux, 3 d 

70% 

N 

N 

N 

Ph 

218 

2,4,6-Trinitrophenyl azide (220) (picryl azide) adds to (aryloxy)allenes 219 to give triazoles 

222 or 223, depending on the substituents R 1 and R 5 (Scheme 75). The reactions proceed 

via the unisolated 4,5-dihydro-1H-1,2,3-triazoles 221, which undergo an exceptionally facile 

Claisen rearrangement to triazoles 222. [225] These compounds, unless blocked by a substituent 

at R 1 , rapidly tautomerize to the isomeric compounds 223. When R 1 and R 5 are 

chloro or methyl the cyclohexadienone derivatives 222 are isolated in 66–85% yield. 

When R 1 or R 5 is hydrogen, triazoles 223 are isolated in 67–79% yield. 

Scheme 75 Addition of 2,4,6-Trinitrophenyl Azide to (Aryloxy)allenes [225] 

R 3 

R 4 

R 2 

R 5 

219 

R 1 

O 

Ar 1 = 2,4,6-(O 2N) 3C 6H 2 



+ Ar 1 N3 

220 

R 3 

R 4 

CHCl3, rt 

24 h to 3 weeks 

R2 R1 R 5 

O 

N 

N 

N 

Ar1 R 3 

R 4 

R 2 

R 5 

R 1 

O 

221 

N 

N N 

Ar1 222 R 1 = R 5 = Cl, Me 66−85% 223 R 1 or R 5 = H 67−79% 

R 3 

R 4 

R 2 

R 5 

OH 

N 

N 

N 

Ar1 for references see p 587 




bAn interesting one-pot procedure for the conversion of allenyl derivatives into 4,5-unsubstituted 

1,2,3-triazoles has been described. [226,227] The method involves a sequential and 

cascade palladium-catalyzed azide formation (from aryl/hetaryl/vinyl iodides, allene, and 

sodium azide) followed by a 1,3-dipolar cycloaddition to norbornadiene and finally a retro-Diels–Alder 

reaction. 

1-Phenyl-1,4,5,6,7,8,9,10-octahydrocyclonona[d][1,2,3]triazole (218); Typical Procedure: [223] 

A soln of cyclonona-1,2-diene (216; 1.22 g, 0.01 mol) and phenyl azide (1.19 g, 0.01 mol) in 

toluene (15 mL) was refluxed for 10 h. The viscous yellow oil, obtained upon solvent evaporation, 

crystallized when stored at rt for several days. Recrystallization [petroleum ether 

(bp 60–1108C)] gave 4,5-dihydro-1H-1,2,3-triazole 217; yield: 0.51 g (21%). A soln of the 4,5dihydro-1H-triazole 

(1.00 g, 4.14 mmol) in 0.75 M NaOEt in EtOH (40 mL) was refluxed for 

3 d. After solvent evaporation, the residue was extracted with Et 2O and the ether extract 

was washed with H 2O until the aqueous washes were neutral. The Et 2O layer was dried 

(MgSO 4) and evaporated to give 0.81 g of crude product. Crystallization (petroleum 

ether/benzene 3:1) afforded white crystalline triazole 218; yield: 0.70 g (70%); mp 77– 

788C. 


Addition of Azides to Æ-Acylphosphorus Ylides 

The addition of azides to Æ-acylphosphorus ylides is a versatile method for the synthesis 

of 1,2,3-triazoles. Combining different Æ-acyl- or Æ-alkoxycarbonyl phosphorus ylides 224 

with azides of various types gives a range of substituted triazoles 226 (Scheme 76). The 

reaction is regioselective, it requires mild conditions (room temperature or refluxing benzene) 

and generally the triazoles are obtained in good to very good yields. 

Æ-Acylphosphorus ylides are commonly represented in the three resonance forms 

224A, 224B, and 224C. However, it has been demonstrated that they exist essentially or 

exclusively in the cis-enolate configuration 224C. The reaction of these ylides with azides 

is accelerated by electron-releasing substituents on the ylide and electron-withdrawing 

substituents on the azide. The polarity of the solvent has only a small effect on the reaction 

rate. Low entropies of activation are obtained for these reactions. All these kinetic 

data indicate that the mechanism of these reactions involves a concerted 1,3-dipolar cycloaddition 

of the azide to the C=C bond in 224C. [228] The resulting 4,5-dihydro-1H-1,2,3triazoles 

225 are converted into triazoles 226 by spontaneous elimination of triphenylphosphine 

oxide. When acyl or alkoxycarbonyl azides are used, the initially formed 1-substituted 

triazoles 226 (R 1 = COX) isomerize to the corresponding 2-substituted triazoles 

227. [229,231] This synthetic method is, however, not general; with some phosphorus ylides, 

especially Æ-ethoxycarbonyl phosphorus ylides (224,R 2 = OEt), diazo compounds and other 

products are obtained rather than triazoles. [230–232] With these compounds, in the cases 

where 1,2,3-triazoles are formed the yields are moderate (when R 3 = Me) or very low 

(when R 3 = Ph). 


Scheme 76 Addition of Azides to Æ-Acylphosphorus Ylides [228–230,233,234]a 

R 2 O 

R 3 PPh 3 

224A 

R 

N 

N 

N 

3 

Ph3P − 

O 

R2 + 

R1 R 1 = alkyl, aryl, COR 4 , CO2Et, SO2Ar 1 

R 2 O 

R3 − + 

PPh3 R 2 O − 

R3 + 

PPh3 224B 224C 

− Ph 3PO 

R 2 

R 3 

N N 

R1 R 1 = COX 

+ R 1 N 3 

225 226 227 

N 

R 2 

R 3 

N 

N NR1 


226 227 

O 

O 

O 

O 

(MeO) 3C 6H 2 

O 



O 

O 

Me 

Ph 

benzene, reflux, 

14–16 h 

benzene, reflux, 

14–16 h 

63 – [233] 

52 – [233] 

(MeO) 3C6H2 O 

acridin-9-yl CH2NMe2 benzene, reflux, 2 h 49 – [234] 

acridin9-yl N benzene, reflux, 2 h 73 – [234] 

Ph Ph benzene, reflux, 48 h 80 – [228] 

Ph 4-O 2NC 6H 4 benzene, reflux, 6 d 67 – [228] 

4-O 2NC 6H 4 Me benzene, reflux, 0.5 h 73 – [228] 

4-O 2NC 6H 4 4-O 2NC 6H 4 benzene, reflux, 48 h 98 – [228] 

4-MeOC 6H 4 Ph benzene, reflux, 72 h 54 – [228] 

4-MeOC 6H 4 4-O 2NC 6H 4 benzene, reflux, 10 d 70 – [228] 

Ts Me CH 2Cl 2, rt, 0.25 h 98 – [230] 

Ts Ph CH 2Cl 2, rt, 1 h 98 – [230] 

Ts 4-O 2NC 6H 4 CH 2Cl 2, rt, 10 h 87 – [230] 

Bz Me CH 2Cl 2, rt, 48 h – 50 [229] 

4-O 2NC 6H 4CO Me CH 2Cl 2, rt, 24 h – 65 [229] 

4-O 2NC 6H 4CO Ph CH 2Cl 2, rt, 24 h – 68 [229] 

4-MeOC 6H 4CO Me CH 2Cl 2, rt, 7 d – 24 [229] 

4-MeOC 6H 4CO Ph CH 2Cl 2, rt, 14 d – 75 [229] 

3-O 2NC 6H 4CO 4-O 2NC 6H 4 CH 2Cl 2, rt, 20 d – 43 [229] 

CO 2Et Ph CH 2Cl 2, rt, 48 h – 46 [229] 

CO 2Et 4-O 2NC 6H 4 CH 2Cl 2, rt, 14 d – 76 [229] 

a Note: R 3 = H for all examples in the table. 



The reaction of a quinuclidin-3-yl Æ-acylphosphorus ylide with 3-nitrobenzoyl azide in refluxing 

acetonitrile, followed by column chromatography on basic alumina, affords the 

corresponding N-unsubstituted 1,2,3-triazole in 52%. [235] The reaction of vinyl azides with 

Æ-acylphosphorus ylides is a convenient method for the synthesis of 1-vinyl-1H-1,2,3-triazoles. 

[236] The reaction of Æ-acylphosphorus ylides with azides has been used to prepare a 

range of 1-[(diethoxyphosphoryl)methyl]-1H-1,2,3-triazoles 230 [237] and 1,2,3-triazole nucleosides 

231 [238] and 232 [239] (Scheme 77). Addition of acetyl azide to Æ-acyl-Æ-alkylphosphorus 

ylides or acetylation of those phosphorus ylides and subsequent treatment with 

sodium azide gives the same 1,2,3-triazoles. [240] 

Scheme 77 Addition of (Diethoxyphosphoryl)methyl Azides and Glycosyl Azides to 

Æ-Acylphosphorus Ylides [237–239] 

R 1 

(EtO)2P N 3 

O 

228 

+ 

R 1 = H, Ph; R 2 = Me, Ph, CO2Et 

BzO 

BzO 

O 

N 3 

OBz 

R 2 O − 

+ 

Br 

+ 

PPh3 

toluene 

110 oC, 5−27 h 

61−83% 

R 2 

N N 

229 230 

O − 

+ 

PPh3 

toluene 

110 oC, 45 min 

38% 

N 

R1 P(OEt) 2 

O 

BzO 

R2 O − 

AcO 

N3 

O 

OAc 

+ 

+ 

PPh3 

toluene 

80 o BzO 

C, 60 h 

59−82% 

BzO 

AcO 

N 

N 

O 

OAc 

R 2 = Me, Et, iPr, CO 2Et 



N 

232 

BzO 

N 

N 

N 

O 

1-[1-(Diethoxyphosphoryl)alkyl]-1H-1,2,3,-triazoles 230; General Procedure: [237] 

A soln of diethyl (azidomethyl)phosphonate 228 (2 mmol) and Æ-acylphosphorus ylide 

229 (2–2.3 mmol) in dry toluene (15 mL) was refluxed for 5–27 h. The solvent was then 

evaporated in vacuo. The product was separated from the Ph 3PO by flash chromatography 

to give analytically pure triazole 230. 


Addition of Azides to Enamines or Enol Ethers 

Azides undergo addition to enamines 233 (R 1 = amino) [241] and to enol ethers 233 (R 1 = alkoxy) 

[242,243] under mild conditions, frequently at room temperature, to yield 4,5-dihydro- 

1H-1,2,3-triazoles 234 (Scheme 78). These reactions are completely regioselective; the 

amino or alkoxy group in the resulting 4,5-dihydro-1H-1,2,3-triazoles is in the 5-position. 

In some cases the 4,5-dihydro-1H-1,2,3-triazoles aromatize spontaneously to 1,2,3-triazoles 

235, in others the aromatization is effected by heating the compound alone (for 

enol ether adducts) or by treatment with acid or base (Scheme 78). 


OBz 

231 

R 2 

Br

Scheme 78 Addition of Azides to Enamines or Enol Ethers [241–243] 

R 1 N 3 + 

Y = NR 4 2, OR 4 

R 3 H 

R 2 

233 

Y 

N 

N 

N 

R 

234 

1 

Y 

R2 H 

R3 H + or OH − 

− HY 

N 

N 

N 

R1 R3 R2 The thermal elimination of nitrogen from the 4,5-dihydro-1H-1,2,3-triazoles is a possible 

competing reaction. Some dihydrotriazoles derived from cyclic enol ethers and enamines 

fail to give triazoles for this reason. [242,244,245] In general, however, yields are very good. The 

reaction is most effective with azides bearing electron-withdrawing groups such as nitrophenyl, 

phenylsulfonyl, or ethoxycarbonyl. Sulfonyl azide adducts give N-unsubstituted 

triazoles, the substituent being lost on aromatization. [13] 


Addition of Azides to Enamines 

There are substantial differences in the products obtained from the reactions of enamines 

with aryl azides or sulfonyl azides. Nitroenamine 236 (X = NO 2), for example, reacts with 

aryl azides to yield the expected triazoles 237 while with tosyl azide it gives the N-unsubstituted 

triazole 238 (X = NO 2) (Scheme 79). [13] With sulfonylenamines 236 (X = SO 2Ph, 4- 

O 2NC 6H 4SO 2) the corresponding triazoles 238 are also obtained. Similar results are observed 

in the reaction of methyl (E)-3-pyrrolidin-1-ylprop-2-enoate (239) with hetaroyl 

azides 240 (Scheme 79). In all cases methyl 1H-1,2,3-triazole-4-carboxylate is formed in approximately 

90% yield. [218] Dienamines also react with 4-nitrophenyl azide to give 1,2,3-triazoles 

but with tosyl azide only amidines are obtained (formed by decomposition of the 

intermediate 4,5-dihydro-1H-1,2,3-triazoles). [247] 

Scheme 79 Addition of Aryl, Sulfonyl, and Hetaroyl Azides to Enamines [13,218] 

O N 

X = NO2, SO2Ph, 4-O2NC6H4SO2; Ar 1 = Ph, 4-O2NC6H4 

MeO 2C 

236 

239 

N 

R 1 = 2-furyl, 2-thienyl, 2-selanylphenyl, 

X 



Ar 1 N3 

X = NO 2 

TsN3, EtOH 

reflux, 12−24 h 

O 

50−80% 

+ R 1 N 3 

240 

S 

S 

N 

N 

N 

Ar1 O2N 

X 

CHCl3 

rt, 20−25 d 

90% 

237 

N 

H 

238 

N 

N 

+ 

MeO2C 

O NTs 

N 

H 

N 

N 

+ 

235 

O 

R 1 N 



An interesting difference in chemical behavior is observed with the two isomeric cyanoenamines 

241 and 244 (Scheme 80). Both react with aryl azides to give 4,5-dihydro-1H- 

1,2,3-triazoles (242 and 245, respectively), which spontaneously aromatize to 1,2,3-triazoles 

243 and 246. [248] However, under identical experimental conditions, in one case 

the elimination of hydrogen cyanide is the favorable process while in the other only 

amine is eliminated. Both reactions are completely regioselective. The elimination of hydrogen 

cyanide or amine is independent of the structure of the amine; the process depends 

only on the relative positions of the amino and cyano groups. These reactions can 

be done without solvent, at 62–65 8C, and the yields, in both cases, are very good (75–95%). 

Scheme 80 Addition of Aryl Azides to Cyanoenamines [248] 

R 1 R 2 N 

NC 

R 1 R 2 N 

241 

H 

244 

H 

H 

H 

CN 

+ Ar 1 N 3 

+ Ar 1 N 3 

NC 

R 1 R 2 N 

242 

N 

N 

N 

Ar1 N 

N 

N 

Ar1 R1R2 H 

NC 

N 

H 

245 

− HCN 

− HNR 1 R 2 

R 1 R 2 N 

243 

246 

N 

N 

N 

Ar1 N 

N 

N 

Ar1 NC 

The synthetic versatility of this method is exemplified in Scheme 81: a range of 1,2,3-triazoles 

249 are obtained in good yields from the reaction of (azidomethyl)phosphonates 

247 with enamines 248. [124,249,250] 

Scheme 81 Reaction of (Azidomethyl)phosphonates with Enamines 

(EtO) 2P N3 O 

247 

R 1 

+ 



R 3 R 2 N 

R 4 

248 

H 

R 5 

56−77% 

N 

N N 

R5 toluene, reflux 

48 h R4 R1 P(OEt) 2 

O 

R 1 = H, Me, Ph; NR 2 R 3 = piperidino, morpholino; R 4 ,R 5 = (CH2)4; R 4 = H, Me; R 5 = CO2Me, CO2Et, POPh2, PO(OEt)2 

The synthesis of 4-(aminomethyl)-1H-1,2,3-triazoles (Scheme 82) is another interesting application 

of this method. Enamines 250 (resulting from the reaction of propenal with 2 

equivalents of secondary amines) react with aryl azides to give 4,5-dihydro-1H-1,2,3-triazoles 

251 [251,252] which, upon treatment with base, [251] are converted into triazoles 252.Ina 

similar process, reaction of propenal with benzenethiol, followed by the addition of a secondary 

amine and an aryl azide gives 4-[(phenylsulfanyl)methyl]-4,5-dihydro-1H-1,2,3-triazoles 

which, after treatment with base, give mixtures of three triazoles, resulting from 

the elimination of the amine or the phenylsulfanyl group. [253] Thiopyrano[3,4-d]-1,2,3-triazoles 

can also be prepared in moderate yields from the reaction of enamines, derived 

from tetrahydrothiopyran-4-one, and aryl azides. [254] 


249

Scheme 82 Synthesis of 4-(Aminomethyl)-1H-1,2,3-triazoles [251,252] 

O 

H 

R 1 2NH 

R 1 2N NR 1 2 

250 

R1 R 

2N 

H 

1 2N 

251 

NR 1 2 = NMe 2, morpholino, piperidino, pyrrolidin-1-yl; X = H, Cl, CN, NO 2 

H 

N 

X 

N 

N 

X N 3 

NaOH or 

NaOMe 

R 1 2N 

N 

X 

252 

The reactions of azides with enamines in which tautomerism is possible give mixtures of 

triazoles (Scheme 83). [255] 

Scheme 83 Addition of Azides to Enamines in Which Tautomerism Is Possible [255] 

R 2 

R 1 2N 

R 2 

R 1 2N 

H 

H 

H 

+ R 3 N 3 

+ R 3 N 3 



− R 1 2NH 

− R 1 2NH 

R 2 

N 

N 

N 

R3 R2 Imines with an Æ-methylene group can also react with azides via their enamine tautomers. 

[256] This method has been extended to the solid-phase synthesis of 1,2,3-triazoles. 

The resin-bound 3-oxobutanamide 253 reacts with primary aliphatic amines yielding 3aminobut-2-enamides 

which react with tosyl azide to give the polymer supported triazoles 

254 (Scheme 84). Upon treatment with trifluoroacetic acid, the “free” triazoles (as 

trifluoroacetates) 255 are obtained in purities of up to 82% ( 1 H NMR, HPLC). [257] 

N 

N 

N 

R3 N 

N 



Scheme 84 Solid-Phase Synthesis of Triazoles via Enamines [257] 

O 

O N 

253 

N 

O O 

O 

TsN3, DMF 

iPr2NEt O N 

N 

R1 O 

NH2, DMF 

HC(OEt) 3 O N 

O 

NR 1 

N 

N 

TFA H2N 

+ 

254 255 

N 

N 

O 

O NHR 1 

NR 1 

N 

N 

CF3CO 2 − 

Enamides 256, despite being less reactive than enamines, also react with aryl azides at 

room temperature (3 days to 10 months) to give 4,5-dihydro-1H-1,2,3-triazoles 257 as stable 

crystalline products (Scheme 85). In refluxing ethanol, however, the reaction yields 

the corresponding triazoles as the major product. The reaction of the 4,5-dihydro-1H- 

1,2,3-triazoles 257 with potassium hydroxide in refluxing methanol yields triazoles 

258. [258] 

Scheme 85 Reaction of Aryl Azides with Enamides [258] 

Y 

256 

+ 

N3 

Y = 2-oxopyrrolidin-1-yl, NMeAc 



X 

rt, 3 d to 10 months 

44−91% 

EtOH, reflux 

24−90 h 

17−66% 

Y 

N 

257 

N 

258 

N 

N 

N 

X 

N 

X 

KOH, MeOH 

70−84% 

reflux, 30 min 

1-[1-(Diethoxyphosphoryl)alkyl]-1H-1,2,3-triazoles 249; General Procedure: [249] 

To the (azidomethyl)phosphonate 247 (5 mmol) dissolved in toluene (20 mL) was added 

the enamine 248 (5 mmol). The resulting mixture was refluxed for 48 h, with stirring. 

The soln was concentrated and the residue was then purified by flash chromatography 

(silica gel, hexane/Et 2O 1:1). 



Addition of Azides to Enol Ethers 

As indicated in Section 13.13.1.1.3.1.2.6, azides react very readily with enol ethers to afford 

4,5-dihydro-1H-1,2,3-triazoles in good yields; [242,243] these reactions are completely 

regioselective. As an example, 2-ethoxypropene reacts with 4-nitrophenyl azide to give 

the 4,5-dihydro-1H-1,2,3-triazole 259 in 99% yield; when heated at 1508C it eliminates ethanol 

and the corresponding 1,2,3-triazole 260 is formed in quantitative yield (Scheme 

86). [242] Cyclic enol ethers, like 2,3-dihydrofuran or 3,4-dihydro-2H-pyran, also react with 

azides to give the corresponding 4,5-dihydro-1H-1,2,3-triazoles 261. However, when these 

compounds are heated, nitrogen is evolved and the imino ethers 262 are formed. [242,259] 

The reaction of enol ethers with heterocyclic azides gives similar results. [114] 

Scheme 86 Reaction of Aryl Azides with Enol Ethers [242] 

N 3 

NO 2 

Ar 1 N 3 + 

n = 1, 2 

+ 

( ) n 

O 

OEt 



50 oC, 90 h 

99% 

20 oC 72−98% 

EtO 

261 

259 

N 

N 

N 

NO2 

150 oC 100% 

( ) 

n 

N 

N 

100−130 oC O N 

Ar1 N 

N 

N 

NO2 260 

( ) 

n O 

Aryl azides containing no electron-withdrawing groups add to the enolate ion of acetaldehyde 

(formed by cycloreversion of tetrahydrofuran in the presence of butyllithium) to 

give 1-aryl-4,5-dihydro-1H-1,2,3-triazol-5-ols 263 in very good yields (Scheme 87). [260] These 

compounds are converted into the corresponding 1-aryl-1H-1,2,3-triazoles 264 in good to 

nearly quantitative yields by treatment with sodium methoxide in methanol or with 

potassium tert-butoxide in tert-butyl alcohol. [260] In a similar process, benzyl azide and 

phenyl azide react with the enolate ions of methyl ketones to give mixtures of triazole 

derivatives. [261,262] For example, benzyl azide reacts with acetone, in the presence of potassium 

tert-butoxide, to give a mixture (ca. 1:1) of 1-benzyl-5-methyl-1H-1,2,3-triazole (265) 

and 1-benzyl-4-isopropenyl-5-methyl-1H-1,2,3-triazole (266) (Scheme 87). When phenyl 

azide is used, triazole 267 is the main product. [262] Under similar reaction conditions, 

phenylacetone reacts with organic azides to give triazoles 268 in high yields. [263] 

262 

NAr 1 



Scheme 87 Reaction of Azides with Enolates [260] 

O − 

+ 

N 3 

X 

THF 

rt, 1−24 h 

70−99% 

X = H, 2-SMe, 2-SEt, 4-Me, 2-OMe, 3-OMe, 4-OMe 

BnN 3 + 

PhN 3 + 

R 1 N 3 + 

R 1 = Me, Bn, Ph 

Ph 

O 

O 

O 



t-BuOK, t-BuOH 

rt, 3.5 h 

77% 


rt, 40 min 

74% 

HO 


rt, 0.5−4 h 

79−92% 

263 

O 

N 

N 

N 

X 

N 

N 

N 

Bn 

265 

N 

267 

+ 

NaOR1 , R1OH rt, 0.5−60 h 

NH 

N 

N 

N 

Ph 

N 

N 

N 

R1 268 

65−100% 

N 

N 

N 

Bn 

1-Benzyl-5-methyl-4-phenyl-1H-1,2,3-triazole (268,R 1 = Bn); Typical Procedure: [263] 

Benzyl azide (2.48 mL, 0.02 mol) and phenylacetone (2.67 mL, 0.02 mol) were added to t- 

BuOK stock soln (20 mL). The mixture turned red and heat evolution was observed after 

a few min. After 2 h, the mixture was poured into ice water (150 mL). The crystalline product 

was washed with H 2O and pentane; crude product yield: 4.22 g (85%). Recrystallization 

(EtOAc/pentane) gave the pure product; mp 93–94 8C. 


Addition of Azides to Vinyl Acetate 

Azides undergo addition to vinyl esters of lower (C 1–C 4) carboxylic acids to yield 1-substituted 

1,2,3-triazoles 269 in good yields (Scheme 88). Vinyl acetate is the most readily available 

and is the preferred vinyl ester substrate. Generally vinyl acetate is also used as solvent 

and the reaction takes place at 50–1508C. This method has been frequently used for 

the preparation of 1-aryl- and 1-benzyl-1H-1,2,3-triazoles with biological activities. [264–268] 

Heteraryl azides also add to vinyl acetate to give the corresponding triazoles. [114] Similar 

reaction with isopropenyl acetate yields the 5-methyl-1-substituted 1H-1,2,3-triazoles. [114] 


Ph 

266 

N 

264 

N 

N 

X

Scheme 88 Reaction of Azides with Vinyl Acetate [114,264–268] 

R 1 N 3 + 

AcO 

50−150 o C 

1-(4-Acetylphenyl)-1H-1,2,3-triazole (269,R 1 = 4-AcC 6H 4); Typical Procedure: [267] 

A soln of 4-azidoacetophenone (4.0 g, 24.8 mmol) and vinyl acetate (6 mL) in a closed tube 

was heated at 808C for 24 h. After evaporation of the solvent, the residue was dissolved in 

CHCl 3 and the soln was washed with 2 M NaOH and 2 M HCl. The CHCl 3 layer was evaporated 

in vacuo and the crude residue was recrystallized [benzene (CAUTION: carcinogen)]; 

yield: 2.86 g (61%); mp 169–1718C. 


Addition of Azides to Ketene Acetals 

Ketene N,N-, S,S-, S,N-, O,O-, and O,N-acetals react with organic azides or sodium azide to 

yield 1,2,3-triazoles. These reactions are completely regioselective but the yields are 

strongly dependent on the structure of the ketene acetal. 

Aryl azides undergo 1,3-dipolar cycloaddition to 1,1-dimorpholinoethenes 270 to 

give 4,5-dihydro-1H-1,2,3-triazoles 271 (Scheme 89). When R 1 = Me the 4,5-dihydro-1H- 

1,2,3-triazoles 271 are stable and can be isolated. [253] These compounds are deaminated 

in almost quantitative yields (95–98%) to the corresponding triazoles 272 by treatment 

with acetic acid (608C, 30 min). [253] When R 1 is an electron-withdrawing group (COR 2 , 

CO 2R 2 ,SO 2R 2 ,NO 2) the 4,5-dihydro-1H-1,2,3-triazoles 271 cannot be isolated or detected; 

the deamination process to 272 proceeds so rapidly that NMR monitoring of the reaction 

mixture does not allow detection of signals unequivocally associated with the structure 

271. [269] 

N 

N 

N 

R1 Scheme 89 Reaction of Aryl Azides with 1,1-Dimorpholinoethenes [253] 

R 1 H 

N N 

O O 

270 



Ar1N3, toluene 

rt or reflux, 4−50 h 

16−73% 

269 

O 

N 

N 

N 

Ar1 R 

N 

N 

1 

O 

271 

− O NH 

O 

N 

N 

N 

Ar1 R1 N 

Cyclic ethene-1,1-diamines 273 react readily with 4-nitrophenyl azide to yield exclusively 

1,2,3-triazoles 274 in excellent yields (Scheme 90). However, when phenyl azide or other 

substituted phenyl azides are used the reaction proceeds much more slowly and mixtures 

of triazoles 274 and 275 are obtained. [270] The formation of triazoles 274 can be explained 

by a mechanism where the ethene-1,1-diamines act as nucleophiles and attack the terminal 

nitrogen of the azide. Cyclization and elimination of one molecule of water yields the 

272 



triazoles. The formation of triazoles 275 can be explained by a 1,3-dipolar cycloaddition 

of the azide to the ethene-1,1-diamine, followed by Dimroth rearrangement of the intermediate 

dihydrotriazole and finally aromatization by deamination. [270] 

Scheme 90 Reaction of Aryl Azides with Cyclic Ethene-1,1-diamines [270] 

( ) 

n 

HN NH 

O 

273 

X 

n = 1, 2; Y = H, Cl, Me, OMe, NO 2 

+ 

N3 

Y 

1,4-dioxane 

rt to 80 oC, 5 h to 5 d 

X 

( ) 

n NH 

N 

274 

N 

Y 

N 

N 

+ 

( ) 

n N 

N 

H 

2-Nitroethene-1,1-diamines of types 276 or 280, with at least one free NH group, react 

with 4-chlorobenzenesulfonyl azide to give 4-nitro-1,2,3-triazoles 279 and 281, respectively, 

in low to moderate yields (Scheme 91). The mechanism of formation of these compounds 

is likely to involve Dimroth rearrangement of the 4,5-dihydro-1H-triazoles 277, 

resulting from 1,3-dipolar cycloaddition, to 278 followed by elimination of the arylsulfonamide 

as show in Scheme 91. [271] 

Scheme 91 Reaction of 4-Chlorobenzenesulfonyl Azide with 

2-Nitroethene-1,1-diamines [271] 

( ) 

n 

HN NH 

H 

276 

n = 1, 2 

NO 2 

N 

280 

4-ClC 6H 4SO 2N 3 

MeCN, rt, 7 d 

H 

35−65% 

NO2 

NHMe 



N 

( ) N 

n 

N 

SO2Ar1 NO2 H 

N 

NH 

277 

4-ClC6H4SO2N3 

dioxane, 80 o C, 15 h 

12% 

+ 

( ) 

n N 

N 

N 

N 

H 

Ar 

NH 

1O2S NO2 281 

278 

N 

Me 

N 

N 

N 


O 2N 

X 

275 

( ) 

n N 

N 

H 

279 

N 

N 

N 

N 

O 

NO2

Aroylketene dithioacetals 282 react with sodium azide via intermediates 283 to afford Nunsubstituted 

1,2,3-triazoles 284 in good yields (Scheme 92). [272] Under similar conditions, 

the reaction with 4,4-bis(methylsulfanyl)but-3-en-2-one does not yield the corresponding 

triazole. 

Scheme 92 Reaction of Aroylketene Dithioacetals with Sodium Azide [272] 

NaN3, DMSO 

110 o Ar 

C, 12−25 h 

65−75% 

O 

1 

MeS SMe 

H 

Na 

− 

N 

N 

N 

+ 

− NaSMe 

MeS 

Ar1 Ar 

O 

O 

282 283 284 

1 

MeS 

MeS 

Ar 1 = Ph, 4-Tol, 4-MeOC6H4, 4-ClC6H4, 3,4-Cl2C6H3 

Tosyl azide reacts smoothly with acylketene S,N-acetals 285 in ethanolic sodium hydroxide 

solutions to give 1,2,3-triazoles 286 in good yields (Scheme 93). [273] Under similar conditions, 

the reaction of tosyl azide with cyclic ketene S,N-acetals 288 results in intractable 

tar, however, in dioxane, at higher temperature, the fused thiazolo[3,2-c][1,2,3]triazole derivatives 

289 are obtained in good yields. [273] Detosylation of compounds 286 with concentrated 

sulfuric acid leads to the corresponding 4-acyl-1,2,3-triazol-5-amines 287. 

Scheme 93 Reaction of Acylketene S,N-Acetals with Tosyl Azide [273] 

R 1 

O 

H 

MeS NHR 2 

285 

+ TsN 3 

NaOH, EtOH 

0 oC to rt, 10 h 

44−75% 

R 1 = Me, Ph, 4-ClC 6H 4, 4-Tol; R 2 = Me, Et, Pr, iPr, Bu, Cy, CH 2CH(OEt) 2, Bn, Ph 

R 1 

O 

H 

S NH 

288 

+ TsN 3 

R 1 = Ph, 4-ClC 6H 4, 4-MeOC 6H 4 



dioxane 

95−100 oC, 15 h 

60−69% 

O 

R 

N 

N 

TsHN 

N 

1 

R2 286 

N 

N 

N 

concd H2SO4 rt, 25 min 

75−95% 

Ketene O,O-acetals (1,1-bis-enol ethers) 290 react with aryl azides to give triazoles 291 in 

varying yields (Scheme 94). [6,156,274] With temperature control and in the presence of an excess 

of the ketene acetal, the intermediate 4,5-dihydro-1H-1,2,3-triazole is obtained. [275,276] 

The intermediate 4,5-dihydro-1H-1,2,3-triazole obtained from the reaction of ethyl azidoformate 

and ketene acetals decomposes readily at room temperature, the reaction path- 

S 

R 1 

289 

O 

R 1 

H 2N 

287 

O 

N 

H 

N 

N 

N 

N 

N 



way depending on the presence of the substituents on the 4-position. [276] With benzoyl 

azide the main products are oxazole derivatives. [275] 

Scheme 94 Reaction of Ketene O,O-Acetals with Azides [156,274] 

R 1 H 

EtO OEt 

290 

+ Ar 1 N 3 



N 

N 

N 

Ar1 R1 EtO 

EtO 

− EtOH 

N 

N 

N 

Ar1 R1 EtO 

4-Acyl-5-(tosylamino)-1H-1,2,3-triazoles 286; General Procedure for Reaction of 

Acylketene S,N-Acetals with Tosyl Azide: [273] 

A soln of NaOH (4.80 g, 0.12 mol) in EtOH (10 mL) was added slowly (5 min) to an ice-cooled 

and stirred suspension of the ketene S,N-acetal 285 (0.01 mol) and tosyl azide (2.36 g, 

0.012 mol) in EtOH (10 mL), and the mixture was further stirred at rt for 10 h. It was then 

poured over crushed ice (150 g), acidified with 20% AcOH (30 mL), and extracted with 

CHCl 3 (3 ” 50 mL). The organic extract was washed with H 2O (3 ” 50 mL), dried (Na 2SO 4), 

and evaporated to give crude triazoles 286, which were further purified by recrystallization 

(EtOH). 

13.13.1.1.3.1.3 Reaction of Azides with Active Methylene Compounds 

The base-catalyzed condensation of azides with active methylene compounds (the Dimroth 

reaction) is a versatile method for the preparation of 1H-1,2,3-triazoles. It was first 

described by Dimroth in 1902. [277,426] Depending on the functional groups present in the 

active methylene compound used, the substituent in the 5-position of the triazole can be 

an alkyl or aryl group, a hydroxy group, an alkoxycarbonyl group, or an amino group. Although 

the reactions are stepwise, [278] they are completely regioselective. The mechanism 

of the Dimroth reaction can be envisaged as a nucleophilic attack by the carbanion on the 

terminal nitrogen of the azide, followed by cyclization to a dihydrotriazole and aromatization. 

In accord with this mechanism, the reaction goes least readily with azides bearing 

electron-releasing groups. The reactions are generally carried out with alkoxides in alcohols 

at room temperature or under reflux. However, in some cases better results are obtained 

using potassium tert-butoxide in tetrahydrofuran, [279] sodium amide in diisopropyl 

ether, [280] or potassium carbonate in dimethyl sulfoxide. [281] 


Reaction of Azides with 1,3-Diketones, 3-Oxo Esters, or 3-Oxoamides 

Organic azides react with 1,3-diketones, 3-oxo esters, or 3-oxoamides to yield, generally in 

good yields, 1H-1,2,3-triazoles with a carbonyl group in position 4 (Scheme 95). The reaction 

with aryl or hetaryl azides gives better yields. With simple vinyl azides [282] and 2-azidovinyl 

ketones [283] the expected 1-vinyl-1,2,3-triazoles are obtained. However, when 1azidovinyl 

ketones are reacted with 3-oxo esters in the presence of triethylamine the initially 

formed 1-vinyl-1,2,3-triazoles undergo further reaction with another molecule of 

the oxo ester. [284] In hexamethylphosphoric triamide, 4-nitrophenyl azide reacts smoothly 

with acyclic 1,3-diketones and 3-oxo esters to afford the corresponding triazoles 293 in 

almost quantitative yields. [285] However, with five- and six-membered cyclic 1,3-diones it 

gives mainly the corresponding diazo derivatives. 1,3-Dicarbonyl compounds react with 

tosyl azide in hexamethylphosphoric triamide to give only the corresponding diazo compounds, 

usually in high yields. [285] 


291

Scheme 95 Reaction of Azides with 1,3-Diketones, 3-Oxo Esters, or 3-Oxoamides 

[135,267,281,286–295] 

R 1 N3 + 

O O 

R 2 R 3 

R 2 = alkyl, aryl; R 3 = alkyl, aryl, OR 4 , NR 4 R 5 

base 

N 

N 

− 

N 

R1 O 

R2 O 

R3 R 

− 

O 

3 

R 2 

O 

N 

N 

N 

R1 R 3 

R 2 

O 

293 

N 

N 

N 

R1 R 1 R 2 R 3 Conditions Yield a (%) Ref 

4-O2NC6H4 Me Me NaOEt, EtOH, rt, 5 h 83 [267] 

3-HO-4-MeO2CC6H3 Ph Ph Et3N, MeOH, reflux, 15 h 60 [286] 

2-O2NC6H4 Me OEt NaOEt, EtOH, 08C, 2 h 56 [287] 

Ph Me OMe Et3N, MeOH, 70 8C, 10 d 68 [135] 

3,5-Cl2C6H3CH2 Me OEt K2CO3, DMSO, 358C, 18 h 89 [281] 

2-O2N-4-ClC6H3 Me NHPh NaOEt, EtOH, rt, 18 h 80 [287] 

4-(HO2CCH2O)C6H4 Me NEt2 NaOEt, EtOH, reflux, 16 h 65 [288] 

4-pyridyl 4-O2NC6H4 OEt NaOEt, EtOH, rt, 24 h 86 [289] 

MeO 

Cl 

N N 

N N Ph 

N 

N 



Me Me NaOEt, EtOH, rt, 4 h 90 [290] 

Ph OEt NaOEt, EtOH, rt, 4 h 71 [291] 

4-O 2NC 6H 4 OEt NaOEt, EtOH, 0–38C, 6 h n.r. [292] 

Me NHPh NaOEt, EtOH, 08C to rt, 6 h n.r. [293] 

acridin-9-yl Me Me NaOMe, MeOH, rt, 24 h 62 [294] 

acridin-9-yl Me OMe KOH, MeOH, rt, 12 h 75 [294] 



R 1 R 2 R 3 Conditions Yield a (%) Ref 

MeO2C 

MeO 2C 

HO 

HO 

S 

S 

a n.r. = not reported. 

Me Me MeOH, Et 3N, rt, 2 d 67 [295] 

Me OEt MeOH, Et 3N, rt, 2 d 62 [295] 

Aryl azides react with 2-substituted 1H-indane-1,3(2H)-diones to give fairly stable tricyclic 

4-acyl-4,5-dihydro-1H-triazol-5-ols in good yields. [296] With tosyl azide the isolated products 

are isoquinolinediones. [296] Ethyl 2-oxocyclododecanecarboxylate (294) reacts with 

phenyl azide, in the presence of 1 equivalent of sodium ethoxide, to give the 1H-1,2,3-triazol-5-ol 

295 in 48% yield (Scheme 96). [297] 

Scheme 96 Reaction of Ethyl 2-Oxocyclododecanecarboxylate with Phenyl Azides [297] 

O 

294 

CO 2Et 

+ PhN 3 

NaOEt, EtOH, THF 

rt, 3 d 

48% 

EtO2C ( ) 10 

HO 

N 

N 

N 

Ph 

3-Oxoamides react with sulfonyl azides in a different way than with alkyl or aryl azides. In 

this case, the sulfonyl azide acts as a diazo transfer agent and the nitrogen of the amide 

function is involved in the formation of the 1,2,3-triazole ring. As indicated in Scheme 97, 

in the presence of sodium ethoxide, tosyl azide reacts with 3-oxoamides 296 to give the 

sodium salts of 4-acyl-1H-1,2,3-triazol-5-ols in almost quantitative yields. However, attempts 

to convert salts 297 into the corresponding hydroxy derivatives leads to the formation 

of diazoamides 298. [298] 

Scheme 97 Reaction of Tosyl Azide with 3-Oxoamides [298] 

O O 

R 1 NHPh 

R 1 = Me, Ph 

296 



+ TsN 3 

NaOEt 

EtOH 

97−100% 

R 

N 

N 

N 

1OC Na − 

O 

+ 

Ph 

297 

295 

H + 

NaOEt 

O O 

R 1 NHPh 

Dimethyl 3-oxopentanedioate (299) reacts with aryl [299] and glycosyl azides [300] to yield selectively 

triazoles 300 (Scheme 98). 


N2 

298

Scheme 98 Reaction of Dimethyl 3-Oxopentanedioate with Azides 

MeO 

O O 

299 

O 

OMe 

+ R 1 N 3 

base 

MeO 2C 

MeO 2C 

R 1 Conditions Yield (%) Ref 

Ph Et3N, MeOH, reflux, 4 d 62 [299] 

4-ClC6H4 Et3N, MeOH, reflux, 1 d 76 [299] 

4-O2NC6H4 Et3N, MeOH, reflux, 1 d 94 [299] 

4-AcC6H4 Et3N, MeOH, reflux, 1 d 82 [299] 

BzO 

O 

BzO OBz 

BzO 

OBz 

O 

BnO 

OBn 

OBz 

OBn 

O 

300 

K 2CO 3, DMSO, rt, 15 h 95 [300] 

K 2CO 3, DMSO, rt, 24 h 93 [300] 

K 2CO 3, DMSO, 45 8C, 24 h 80 [300] 

Diethyl 2-oxobutanedioate, ethyl 2,4-dioxo-4-phenylbutanoate, and ethyl 4-(2-furyl)-2,4dioxobutanoate, 

all as sodium salts 301, react with aryl azides to afford triazoles 302 in 

low yields (Scheme 99). [301] 

N 

N 

N 

R1 Scheme 99 Reaction of 2-Oxobutanedioate and 2,4-Dioxobutanoate Derivatives 

with Azides [301] 

Na + 

X 

− 

O O 

X = OEt, Ph, 2-furyl 

301 

O 



OEt 

+ 

Ar 1 N 3 

THF, 50 o C, 7 h 

17−26% 

X 

EtO 2C 

302 

O 

N 

N 

N 

Ar1 13.13.1.1.3.1.3.2 Method 2: 

Reaction of Azides with Malonic Esters, Malonamides, or Acetamides 

The base-catalyzed reaction of organic azides with malonic acid derivatives is one of the 

best methods for the synthesis of 1H-1,2,3-triazol-5-ols 303 with an alkyloxy (or aryloxy) 

carbonyl or carbamoyl functions in the 4-position (Scheme 100). As observed with other 

active methylene compounds, these reactions are stepwise and completely regioselective. 



Scheme 100 Reaction of Azides with Diethyl Malonate [281,302–304] 

R1N3 + EtO2C CO2Et base 

EtO 2C 

H 

N 

O OEt 

N NR1 

− 


Bn K2CO3, DMSO, 358C, 44 h 77 [281] 

Bn NaOMe, MeOH, reflux, 15 h 88 [302] 

3,5-Cl2C6H3CH2 K2CO3, DMSO, 408C, 72 h 96 [281] 

4-MeOC6H4CH2 K2CO3, DMSO, 358C, 72 h 92 [281] 

4-MeOC6H4CH2 NaOEt, EtOH, reflux, 18 h 67 [303] 

4-pyridyl NaOMe, MeOH, rt, 24 h 75 [304] 

EtO 2C 

Malonamides 304 (X = CONHR 1 ) give an unusual reaction with phenyl azide from which 

1H-1,2,3-triazol-5-ols 306 are isolated; aniline is also formed (Scheme 101). [305] A mechanism 

has been suggested involving cyclization of the triazene intermediate 305 with displacement 

of aniline. Similar behavior is observed in the reaction of N-methylphenylacetamide 

(304, X = Ph; R 1 = Me) with phenyl azide. [305] However, with phenylacetamide (304, 

X = Ph; R 1 = H) a mixture of two triazoles is obtained: the corresponding triazole 306 

(R 1 = H; X = Ph) and 1,4-diphenyl-1H-1,2,3-triazol-5-ol. With malonic esters and amides substituted 

at the central carbon, triazole formation is accompanied by decarboxylation and 

4-alkyl- or 4-aryl-1H-1,2,3-triazol-5-ols are obtained. [305,306] 

Scheme 101 Reaction of Phenyl Azide with Malonamides and Phenylacetamide [305] 

PhN3 

+ 

X 

O 

304 

R 1 = H, Me; X = CONHR 1 , Ph 

NHR 1 



NaOEt 

N 

O NHR 1 

305 

N NHPh 

− PhNH2 

N-Arylsulfonylmalonamide derivatives 307 and malonohydrazides 309 react with tosyl 

azide to give selectively 1-(arylsulfonyl)- and 1-(arylmethyleneamino)-1H-1,2,3-triazol-5ols 

308 and 310, respectively, in moderate to good yields (Scheme 102). [307] The mechanism 

of the reaction involves a diazo group transfer followed by subsequent cyclization 

of the intermediate diazomalonate derivative. 


X 

HO 

HO 

303 

X 

306 

N 

N 

N 

R1 N 

N 

N 

R1

Scheme 102 Reaction of Tosyl Azide with Malonohydrazides and N-Tosylmalonamides [307] 

O 

O 

R 1 R 2 N N H 

307 

SO 2Ar 1 

R 1 = H, Me; R 2 = Ts, 4-O2NC6H4; Ar 1 = 4-Tol, Ph 

O 

O 

BnHN N H 

309 

N 

Ar 1 

TsN3, NaOEt, EtOH 

62−68% 

TsN3, NaOEt, EtOH 

0−5 oC to rt, 2 h 

Ar1 = 4-MeOC6H4 52% 

Ar1 = 4-FC6H4 82% 

N 

N 

Na 

N 

+ − O 

SO2Ar 

308 

1 

O 

R1R2N BnHN 

Na + − O 

The reaction of phosphonyl and phosphinyl acetamides 311 with tosyl azide, in the presence 

of potassium tert-butoxide, yields 1H-1,2,3-triazolols 313, presumably via diazo derivatives 

312 (Scheme 103). [308,309] 

Scheme 103 Reaction of Tosyl Azide with Phosphonyl and Phosphinyl Acetamides [308,309] 

O 

R 1 2P CONH 2 

311 



TsN 3, t-BuOK 

O 

R 1 2P CONH 2 

O 

310 

N 

N 

N 

N 

Ar 1 

R 1 2P 

N 2 O 

312 

HO 

N 

H 

N 

N 

R1 = OEt 56% 

R1 313 

= Ph 70% 

1-(Arylmethyleneamino)-1H-1,2,3-triazol-5-ol Sodium Salts 310; General Procedure: [307] 

The malonohydrazide 309 (2 mmol) was suspended in a soln of NaOEt (0.136 g, 2 mmol) in 

EtOH (12 mL) and tosyl azide (0.40 g, 2 mmol) was added dropwise at 0–5 8C. The mixture 

was stirred for 2 h after which the precipitate 310 was collected by filtration and dried. 


Reaction of Azides with Acetonitrile Derivatives 

Organic azides react with acetonitrile derivatives 314 to give 1-substituted 1H-1,2,3-triazol-5-amines 

315 in good yields (Scheme 104). However, to avoid Dimroth rearrangement 

of the products, the reactions must be carried out at low temperatures (0–208C). [304] 

In the reactions of acetonitrile derivatives with 2-substituted aryl azides (e.g., 2-nitrophenyl 

azide, 2-azidobenzoic acid, or 2-azidobenzonitrile), the 1H-1,2,3-triazol-5-amine can react 

further by condensation of the amino group with the ortho substituent on the 1-phenyl 

group, resulting in the formation of fused 1,2,3-triazoles. [310–313,317] Best yields are obtained 

with aryl, hetaryl, and benzyl azides but some good results have also been obtained with 

alkyl azides. [279,314] 



Scheme 104 Reaction of Azides with Acetonitrile Derivatives [279–282,291,294,304,315–324] 

R 1 N 3 + 

R 2 CN 

314 

base 

R 2 = aryl, CN, CO2R 3 , CONR 3 R 4 , PO(OEt)2 

R 2 

N 

H 

N 

N 

NR1 − 

R 2 

HN 

N 

N 

N 

R1 H 

R 

N 

N 

N 

2 

H2N R1 R 1 R 2 Conditions Yield (%) Ref 

(CH 2) 5Me Ph t-BuOK, THF, rt, 12 h 98 [279] 

Me t-Bu LDA, Et 2O, –78 to 08 C, 1 d 35 [315] 

Bn Bn NaNH 2, iPr 2O, reflux, 7 d 24 [280] 

CH 2SPh 2-FC 6H 4 K 2CO 3, DMSO, rt, 16 h 29 [316] 

Ph Ph NaOMe, MeOH, 08C to rt, 24 h 99 [317,318] 

4-pyridyl Ph NaOMe, MeOH, rt, 24 h 82 [304] 

4-O 2NC 6H 4 CO 2Me NaOMe, MeOH, rt, 24 h 89 [304] 

Bn Ph K 2CO 3, DMSO, rt to 408C, 24 h 84 [281] 

Bn Ph t-BuOK, THF, rt, 12 h 78 [279] 

Bn CN K 2CO 3, DMSO, rt to 408C, 18 h 48 [281] 

Bn CONH 2 K 2CO 3, DMSO, rt to 408C, 5 h 84 [281] 

Bn CONH 2 NaOEt, EtOH, reflux, 1 h 81 [319] 

Bn CO 2Et NaOEt, EtOH, reflux, 3 h 25 [319] 

Bn CO 2H NaOEt, EtOH, reflux, 4 h 20 [319] 

Ph CONH 2 NaOMe, MeOH, rt, 24 h 88 [320] 

Ph CONMe 2 Et 2O, NaOMe, MeOH, 0 8C, 24 h 74 [321] 

4-HO 2CC 6H 4 CONH 2 NaOMe, MeOH, rt, 7 d 61 [320] 

2-O 2NC 6H 4 CONH 2 NaOEt, EtOH, 08C to rt, 23 h 55 [322] 

3,3-dimethylbut-1-enyl CONH 2 NaOMe, MeOH, reflux, 30 min 62 [282] 

1-naphthyl CO 2Et NaOEt, EtOH, 08Ctort,6h 94 [323] 

4-pyridyl CO 2Et NaOEt, EtOH, 08C to rt, 16 h 86 [323] 

4-quinolyl CONH 2 NaOEt, EtOH, 08C to rt, 21 h 91 [323] 

4-quinolyl CO 2Et NaOEt, EtOH, 08C to rt, 21 h 79 [323] 

N N Ph 



315 

CN NaOEt, EtOH, rt, 4 h 69 [291] 



N N Ph 

Ph NaOEt, EtOH, rt, 4 h 81 [291] 

acridin-9-yl 2-pyridyl NaOMe, MeOH, rt, 24 h 70 [294] 

acridin-9-yl piperidinocarbonyl 

NaOMe, MeOH, rt, 24 h 26 [294] 

acridin-9-yl 4-ClC 6H 4NHCO NaOMe, MeOH, rt, 24 h 15 [294] 

Ph PO(OEt) 2 NaOEt, EtOH, rt, 3 h 76 [324] 

The reaction of cyanoacetamide with glycosyl azides, in aqueous dimethylformamide 

with potassium hydroxide and at room temperature gives 5-amino-1-glycosyl-1H-1,2,3-triazole-4-carboxamide 

shows that this type of cycloaddition has a two-step mechanism. [278] 

Also using cyanoacetamide and gycosyl azides, a study of the influence of the reaction 

conditions (the nature of the solvent and base) on the retention or inversion of the configuration 

of the anomeric carbon has been described. [325] A range of 1-(substituted benzyl)-5amino-1H-1,2,3-triazole-4-carboxamides 

has been prepared from the reaction of cyanoacetamide 

with benzyl azides. [326] 

Treatment of 2-oxocyclododecanecarbonitrile (316) with phenyl azide in the presence 

of a catalytic amount of sodium ethoxide for four days at room temperature leads 

to the formation of 1H-1,2,3-triazol-5-amine 317 and lactam 318 in 60 and 10% yield, respectively 

(Scheme 105). [297] A mechanism for the formation of these two compounds has 

been proposed. 

Scheme 105 Reaction of 2-Oxocyclododecanecarbonitrile with Phenyl Azide [297] 

O 

316 

CN 

+ 

PhN3 



NaOEt 

EtOH, THF 

rt, 4 d 

EtO2C 

( )10 

N 

H2N N 

N 

Ph 

317 60% 

+ 

HN 

318 10% 

N 

N 

N 

Ph 

O 

Sulfonyl azides do not generally give triazoles with activated methylene compounds. 

However, in aqueous alkaline solutions, sulfonyl azides, and also azidoformates and 

N,N-dimethylcarbamoyl azide, react with malononitrile to yield N-unsubstituted 1,2,3-triazoles 

319, 320, and 321, respectively, in good to excellent yields, as indicated in Scheme 

106. [327] 



Scheme 106 Reaction of Malononitrile with Sulfonyl and Carbonyl Azides [327] 

CN 

CN 

OH − , H2O 5 oC, 1 h 

− 

CN 

CN 

R 1 = Me, Ph, 4-Tol, 4-MeOC 6H 4, 4-O 2NC 6H 4; R 2 = Et, t-Bu 


Reaction of Aryl Azides with Alkoxides 

R1SO2N3 71−96% 

O 

R 2 O N3 

58−60% 

O 

Me 2N N 3 

NC 

S 

R 

N 

H 

1 

O 

O 

H 2N 

NC 

Me2N 

320 

N 

H 

319 

N 

N 

N 

H 

NC 

O 

Aryl azides react with sodium ethoxide or propoxide to afford 1-aryl-1H-1,2,3-triazoles 

322 in moderate yields (Scheme 107). [328] Two equivalents of azide are required, the second 

being reduced to aniline. The mechanism [3] of this reaction probably involves the formation 

of an aldehyde by hydride transfer from the alkoxide to one mole of aryl azide. 

The attack of the carbanion of the aldehyde so produced on a second mole of the azide 

leads to the triazole. The reaction of tosyl azide with sodium butoxide yields only butyl 

toluenesulfonate. [184] 

63% 

Scheme 107 Reaction of Aryl Azides with Alkoxides [328] 

2 X N3 + NaO 

R 1 = H, Me; X = H, Cl, Br, Me, NO 2 



R 1 

reflux, 1−5 d 

− 4-XC 6H 4NH 2 

30−70% 

1-Aryl-4-methyl-1H-1,2,3-triazoles 322 (R 1 = H); Typical Procedure for Condensation of 

Aryl Azides with Sodium Propoxide: [328] 

The appropriate aryl azide (0.03 mol) was added to a cold soln of NaOPr (0.04 mol) and the 

mixture was refluxed on a water bath for 24 h. The brownish product was acidified with 

concd HCl, steam-distilled, made alkaline, and steam-distilled again. The residual soln 

was extracted with Et 2O; when the extract was evaporated, the 1-aryl-4-methyl-1H-1,2,3triazole 

322 (R 1 = Me) separated and was crystallized (petroleum ether or EtOH/H 2O). 


R 1 

N 

X 

322 

N 

N 

H 

321 

N 

N 

N 

N 

H 

N 

N

13.13.1.1.4 By Formation of One N-N Bond 

13.13.1.1.4.1 Fragment N-N-C-C-N 


Cyclization of Æ-Diazoamides 

Æ-Diazoamides can be cyclized to 1H-1,2,3-triazoles by treatment with base [298,308,309,329] or 

by other methods. Some reactive Æ-diazoamides cyclize spontaneously to the corresponding 

triazoles; one example is indicated in Scheme 108. The intermediate Æ-diazoamides 

324, generated in situ from the reaction of ethyl N-(diazoacetyl)glycinate (323) with benzoyl 

bromides, cyclize spontaneously to triazoles 325. [330] 

Scheme 108 Cyclization of Ethyl N-(3-Aryl-2-diazo-3-oxopropanoyl)glycinates [330] 

R 1 

O 

Br 

R 1 

+ 

H 

O 

N 2 

N 2 

O 

O 

324 

N 

H 

323 

N 

H 

CO 2Et 

CO 2Et 

CH 2Cl 2 

rt, 76−91 h 

R 1 

325 

O 

HO 

N 

N 

N 

R1 = H 50% 

R1 = Br 15% 

CO 2Et 

Reaction of Æ-diazoamide 326 with phosphorus pentachloride gives methyl 1-benzyl-5chloro-1H-1,2,3-triazole-4-carboxylate 

(328) through the intermediate imidoyl chloride 

327 (Scheme 109). [331] N-Unsubstituted 5-halo-1H-1,2,3-triazoles are also obtained in good 

to excellent yields by treatment of diazomalononitrile derivatives with hydrogen halides. 

[1] 

Scheme 109 Cyclization of a Diazomalonamide [331] 

MeO 2C N 2 

O NHBn 

326 



PCl 5 

80 o C, 3 h 

MeO2C N2 MeO2C N 

Cl NBn 

Cl 

N 

N 

Bn 

327 328 


Thermolysis of Æ-Azidoacetophenone (Phenylsulfonyl)hydrazones 

Æ-Azidoacetophenone (phenylsulfonyl)hydrazones 330, prepared by the reaction of the 

corresponding Æ-bromoacetophenone (phenylsulfonyl)hydrazones with sodium azide, 

are converted into 4-aryl-1H-1,2,3-triazoles 332, in good yields on heating in refluxing 

benzene (Scheme 110). The reaction proceeds probably via the elimination of benzenesulfinic 

acid from the intermediate 2-(phenylsulfonyl)-2,5-dihydro-1H-1,2,3-triazoles 

331. [332] The Æ-bromoacetophenone (phenylsulfonyl)hydrazones 329 react with benzyl- 



ideneaniline to yield 4-aryl-1-phenyl-1H-1,2,3-triazoles (19–25%) and substituted 2,3,4,5tetrahydro-1,2,4-triazines 

(20–45%). [333] 

Scheme 110 Thermolysis of Æ-Azidoacetophenone (Phenylsulfonyl)hydrazones [332,333] 

Br 

Ar 1 N 

H 

N 

329 

N 

Ar 1 N 

NaN3, DMF 

82−94% 

Ar1 SO2Ph N3 N 

H 

N 

SO2Ph H 

N 

SO2Ph 

Ar 1 = 4-XC6H4; X = H, Br, Cl, NO2, Me, Ph, N NPh 

330 

Ar 

N 

NH 

N 

1 SO2Ph 13.13.1.1.4.1.3 Method 3: 

Cyclization of Æ-Hydroxyimino Hydrazones 

331 

benzene 

reflux, 2 h 

− N2 

− PhSO2H 

71−96% 

Cyclic Æ-hydroxyimino hydrazones 334 and 337 (prepared from Æ-hydroxyimino ketones 

333 and 336, respectively) on heating at 170–1908C for three hours in diethylene glycol 

containing potassium hydroxide yield the N-unsubstituted 1,2,3-triazoles 335 and 338 

(Scheme 111). The yield of triazole significantly decreases as the size of the ketone ring 

increases from five- to six- to seven-membered, that is as the rings become more flexible 

and the hydrazone and oxime groups less coplanar. [334,335] Under the same conditions, acyclic 

Æ-hydroxyimino hydrazones do not give triazoles; in this case, the normal Wolff–Kishner 

reduction products are obtained. 

Scheme 111 Cyclization of Æ-Hydroxyimino Hydrazones [334,335] 

n = 1−3 

( )n 

O 

333 

O 

336 



OH ( )n OH 

H2NNH2 N 

N 

334 

N 

NH 2 

N 

H2NNH2 N 

OH OH 

KOH 

diethylene glycol 

170−190 oC, 3 h 

15−52% 

KOH 

diethylene glycol 

170−190 oC, 3 h 

Glyoxal O-benzyloxime hydrazone 340, generated in situ by addition of glyoxal O-benzyloxime 

339 to a 10-fold excess of hydrazine, gives 1-(benzyloxy)-1H-1,2,3-triazole 341 by 

oxidative cyclization (Scheme 112). Copper(II) sulfate is the best oxidant but manganese 

dioxide and nickel peroxide can also be used. [336] 


N 

337 

NH 2 

32% 

Ar 1 

332 

335 

338 

( ) n 

N 

H 

N 

H 

N 

N N 

N 

N 

N 

NH

Scheme 112 Cyclization of Æ-Hydroxyimino Hydrazone Derivatives [336] 

O 

N 

OBn 

339 

H2NNH2, MeOH 

0 oC, 45 min 

NH 2 

N 

N 

OBn 

340 

CuSO4 5H2O, py 

100 oC, 30 min 

52−63% 

3,8-Dihydroindeno[1,2-d][1,2,3]triazole (335, n = 1); Typical Procedure: [335] 

1H-Indene-1,2(3H)-dione 1-hydrazone 2-oxime (334, n = 1; 930 mg, 5.3 mmol) and KOH 

(1.23 g, 22 mmol) in purified diethylene glycol (50 mL) was heated, with a stream of N 2 

bubbling through it, until the temperature reached 170–1908C (ca. 30 min). Heating was 

maintained at this temperature for 3 h and N 2 was bubbled through the soln for the entire 

time. The mixture was then cooled, diluted with 1 M aq KOH (400 mL), and extracted with 

CH 2Cl 2 (4 ” 200 mL). The alkaline soln was acidified with HCl and the pH was adjusted to 7 

with NaHCO 3. The soln was again extracted with CH 2Cl 2 (4 ” 200 mL). Each extract was 

back-washed with sat. aq NaCl (2 ” 100 mL). These organic extracts were combined, dried 

(Na 2SO 4), filtered, and evaporated in vacuo to yield a weakly acidic fraction (584 mg) 

which was sublimed (1008C/0.2 Torr) to yield triazole 335 (n = 1); yield: 432 mg (52%); mp 

1448C. 


Cyclization of Æ-Hydroxyimino Aroyl- or Arylsulfonylhydrazones 

Oxidation of Æ-hydroxyimino aroylhydrazones 342 with lead(IV) acetate in acetic acid 

gives 1-(aroyloxy)-4,5-dimethyl-1H-1,2,3-triazoles 344 in moderate yields (Scheme 113). 

This transformation probably involves an intramolecular [1,3]-aroyl migration in the intermediate 

343. [337] 

Scheme 113 Oxidation of Æ-Hydroxyimino Aroylhydrazones with Lead(IV) Acetate [337] 

N 

N 

OH 

N 

H 

342 

O 

Ar 1 

Ar 1 = 4-XC 6H 4; X = H, Me, OMe, Cl, NO 2 



Pb(OAc) 4, AcOH 

CH2Cl2 0 oC, 30 min 

35−48% 

N 

N 

N 

O − 

+ 

343 

O 

Ar 1 

N 

N 

341 

N 

OBn 

N 

O 

N 

N 

Ar 

344 

1 

Æ-Hydroxyimino tosylhydrazones 345 are converted into 4-aryl-5-methyl-1H-1,2,3-triazol- 

1-ols 347 in good yields by thermal cyclization of salts 346 (Scheme 114). [24] The Æ-diazo 

oximes 348 are probable intermediates in this transformation. Attempts to prepare 4,5dimethyl-1H-1,2,3-triazol-1-ol 

by this method failed. [24] 

O 



Scheme 114 Cyclization of Æ-Hydroxyimino Tosylhydrazones [24] 

Ar 1 

N 

N 

345 

NHTs 

OH 

Ar 1 = Ph, 4-MeOC6H4 



NaOEt, EtOH 

DME 

rt, 30 min 

Ar 1 

Ar 1 

N 

N 

346 

N 

N 

NHTs 

O − Na + 

N Ts 

− 

Na + 

OH 

diglyme 

reflux, 45−90 min 

348 

75−77% 

Ar 1 

Ar 

N 

N 

N 

OH 

347 

1 

N 

N − 

+ 

1-(Aryloxy)-4,5-dimethyl-1H-1,2,3-triazole 344 by Oxidation of Æ-Hydroxyimino Aroylhydrazones; 


A soln of 342 (1 mmol) in AcOH/CH 2Cl 2 (1:5, 30 mL) was added over 20 min to a stirred soln 

of Pb(OAc) 4 (4 mmol) in dry CH 2Cl 2 (30 mL). The soln was stirred at 08C for 30 min and then 

10% aq Na 2S 2O 3 was added. The organic layer was separated, washed with brine, dried, and 

evaporated. The resulting residue was either chromatographed or recrystallized from the 

appropriate solvent. 


Cyclization of 1,2-Diketone Bis(hydrazone) Derivatives 

1,2-Diketone bis(hydrazones) and some of their derivatives such as bis(semicarbazones), 

bis(arylsulfonylhydrazones), and bis(acylhydrazones) are converted into 1H-1,2,3-triazol- 

1-amines. The cyclization of these compounds is carried out by oxidation or by treatment 

with acids or bases. 


Cyclization of 1,2-Diketone Bis(hydrazones) 

Oxidation of bis(hydrazones) 349 with manganese dioxide or mercury(II) oxide gives 1H- 

1,2,3-triazol-1-amines 350 (Scheme 115). Although two isomeric triazoles would be expected 

from unsymmetrical bis(hydrazones), compounds 349 give only the 4-aryl-1,2,3triazol-1-amines. 

[338] Other vicinal bis(hydrazones) have been converted into 1H-1,2,3-triazol-1-amines. 

[339–342] The major disadvantage of this method is that unless the conditions 

are carefully controlled, complete oxidation of the bis(hydrazones) occurs and the isolated 

products are alkynes. Pyrolysis of cyclooctane-1,2-dione bis(hydrazone) yields the corresponding 

N-unsubstituted 1H-1,2,3-triazole. [342] 


NOH

Scheme 115 Cyclization of 1,2-Diketone Bis(hydrazones) [338] 

Ar 1 

H 

349 

N 

N 

NH2 

NH 2 

MnO 2 or HgO 

Ar 1 = Ph, 4-ClC 6H 4, 4-BrC 6H 4, 4-MeOC 6H 4, 2-naphthyl 

H 

Ar 1 

350 

N 

N 

N 

NH2 13.13.1.1.4.1.5.2 Variation 2: 

Cyclization of 1,2-Diketone Bis(arylsulfonylhydrazones) 

Vicinal bis(arylsulfonylhydrazones) 351 can be cyclized using either acid or base to give 1- 

(arylsulfonylamino)-1H-1,2,3-triazoles. [343,344] When unsymmetrical 1,2-diketones are 

used, the two possible triazoles 352 and 353 are obtained (Scheme 116). [345,346] Benzil bis- 

(tosylhydrazone) cyclizes to 4,5-diphenyl-1-(tosylamino)-1H-1,2,3-triazole by oxidation 

with either mercury(II) or lead(IV) acetates in acetic acid. [347] This type of triazole is also 

obtained by thermal [348] or photochemical [349] decomposition of the dianions of the 

bis(tosylhydrazones) of 1,2-diketones. The 1-(arylsulfonylamino)-1H-1,2,3-triazoles are 

converted into 1H-1,2,3-triazol-1-amines by treatment with sulfuric acid. 

Scheme 116 Cyclization of 1,2-Diketone Bis(arylsulfonylhydrazones) [345,346] 

R 1 

R 2 

SO2Ar 

N N 

H 

H 

N N 

1 

SO2Ar1 351 



H + or OH − 

heat 

N 

R 

N 

N 

HN 

2 

R1 N 

R 

N 

N 

HN 

1 

R2 + 

SO2Ar1 SO2Ar1 4,5-Diphenyl-1-(tosylamino)-1H-1,2,3-triazole (352,R 1 =R 2 = Ph; Ar 1 = 4-Tol); 


Benzil bis(tosylhydrazone) (74 g, 0.14 mol) was added rapidly to a stirred soln of KOH (9 g, 

0.16 mol) in ethylene glycol (400 mL) at 120 8C. After 10 min the soln was cooled to 408C 

and H 2O was added slowly, with rapid stirring, until a precipitate began to appear. The 

mixture was then acidified with 2 M HCl and more H 2O was added until the total volume 

was 1 L. The precipitate was then collected by filtration, dried, and washed well with 

petroleum ether to leave the triazole; yield: 43 g (81%); mp 232–2338C (EtOH). 


Cyclization of 1,2-Diketone Bis(semicarbazones) 

The 1,2-diketone bis(semicarbazones) 354 undergo cyclization on treatment with lead(IV) 

acetate to give 1-ureido-1H-1,2,3-triazoles 355 (Scheme 117). These compounds are hydrolyzed 

with concentrated hydrochloric acid to give the corresponding 1H-1,2,3-triazol- 

1-amines 356. [350] 

352 

353 



Scheme 117 Cyclization of 1,2-Diketone Bis(semicarbazones) [350] 

R 1 

R 2 

CONH2 

N N 

H 

H 

N N 

CONH2 354 



Pb(OAc)4 

CH2Cl2 

rt, 3 h 

30−40% 

R 2 

R 1 

N 

N 

N 

HN 

CONH2 355 

HCl, reflux, 2 h 

50−65% 

R 

N 

N 

N 

NH2 

2 

R1 R1 R2 1-Ureido-1H-1,2,3-triazole 355 1H-1,2,3-Triazol-1-amine 356 Ref 

Yield (%) mp (8C) Yield (%) mp (8C) [350] 

Me Me 30 225–226 65 89–91 [350] 

Ph Ph 40 209–211 55 126–128 [350] 

Ph Me 34 207–208 55 142–144 [350] 

4-Tol Me 40 203–204 58 164–165 [350] 

4-BrC6H4 Me 38 204–205 50 169–171 [350] 

4-Tol H 32 224–226 52 123–124 [350] 

1-Ureido-1H-1,2,3-triazoles 355; General Procedure: [350] 

Pb(OAc) 4 (0.021 mol) was added to a suspension of bis(semicarbazone) 354 (0.02 mol) in 

CH 2Cl 2 (100 mL) and the mixture was stirred at rt for 3 h. The mixture was filtered and 

the precipitate was treated with MeOH. The methanolic soln upon evaporation gave the 

1-ureido-triazole which was recrystallized (MeOH or EtOH). 


Cyclization of 1,2-Diketone Bis(acylhydrazones) 

1,2-Diketone Bis(acylhydrazones) undergo oxidative cyclization to 1H-1,2,3-triazol-1amine 

derivatives 360–362 (via intermediate 358/359) (Scheme 118). Lead(IV) acetate is 

the oxidant most used for this transformation. With bis(aroylhydrazones) 357 (R 2 = aryl) 

the principal products are imides 360 and amides 361. [351–355] On the other hand, oxidation 

of bis(arylacetylhydrazones) 357 (R 2 = arylmethyl) yields mainly 1-(arylacetylamino)- 

1,2,3-triazoles 362 (R 2 = arylmethyl) in moderate yields. [356] Oxidation of bis(acetylhydrazones) 

357 (R 2 = Me) with lead(IV) acetate gives amides 361 (R 2 = Me) as the primary products 

but partial hydrolysis to monoacetylamino derivatives 362 may occur in some cases 

during the workup. [357] Lead(IV) acetate oxidation of mixed aroylhydrazones of biacetyl affords 

pairs of isomeric triazoles (of the imide 360 type) in different proportions. [358] 


356

Scheme 118 Cyclization of 1,2-Diketone Bis(acylhydrazones) [357] 

R 1 

R 1 

COR 

N N 

H 

H 

N N 

2 

COR2 357 

Pb(OAc)4 

CH 2Cl 2 

rt, 1−2 h 

R 1 

R 1 

R 1 

N 

360 

R 1 

N 

N 

N 

COR 

− 

N 

2 

COR2 + 

358 

N 

N 

N OCOR2 R 2 

R 1 

R 1 

N 

N 

N 

COR 

N 

2 

+ 

O − 

359 

R 2 

N 

R 

N 

N 

HN 

1 

R1 N 

R 

N 

N 

N 

1 

R1 + + 

R2OC COR2 COR2 361 362 

Lead(IV) Acetate Oxidation of Bis(acylhydrazones) 357; General Procedure: [357] 

To a stirred suspension of the bis(acylhydrazone) (2 mmol) in CH 2Cl 2 (20 mL) was added 

Pb(OAc) 4 (2.4 mmol) dissolved in CH 2Cl 2 (20 mL). The slight excess of the oxidant was 

checked throughout the experiment by the use of KI/starch paper and maintained, if necessary, 

by the addition of extra amounts of Pb(OAc) 4. When all the starting material was 

consumed the mixture was filtered and the filtrate was extracted successively with aq 

Na 2S 2O 3 and Na 2CO 3. The dried soln was evaporated under reduced pressure and the residue 

was chromatographed (medium pressure, silica gel, petroleum ether/EtOAc, gradient 

elution). The isolated products were further purified by recrystallization. 


Cyclization of (1,2-Diphenylethene-1,2-diyl)bis(trityldiazene) 

(1,2-Diphenylethene-1,2-diyl)bis(trityldiazene) (363) cyclizes readily to the 1H-1,2,3-triazol-1-amine 

derivative 365 when treated with acetic acid or left in suspension in ordinary 

unpurified chloroform for several days (Scheme 119). [359] The dipolar compound 364 is 

a probable intermediate in this transformation. Treatment of compound 365 with benzoyl 

chloride yields 1-benzoylamino)-4,5-diphenyl-1H-1,2,3-triazole. The synthetic usefulness 

of this method is still to be demonstrated. See also Section 13.13.2.1.3.1.2 for the cyclization 

of 1,2-diketone bis(arylhydrazones) to 2H-triazoles. 

Scheme 119 Cyclization of (1,2-Diphenylethene-1,2-diyl)bis(trityldiazene) [359] 

Ph 

Ph 

N 

N 

363 

NTr 

NTr 



AcOH 

Ph 

Ph 

N 

N 

N 

+ 

Tr 

− 

N 

Tr 

364 

90% 

Ph 

Ph 

365 

N 

N 

N 

NHTr 

4,5-Diphenyl-N-trityl-1H-1,2,3-triazol-1-amine (365): [359] 

A suspension of (1,2-diphenylethene-1,2-diyl)bis(trityldiazene) (363; 0.5 g, 0.69 mmol) in 

90% AcOH (10 mL) was evaporated to one half of the original volume on a hot plate. The 

solid dissolved with disappearance of the red color in a few minutes. Upon cooling, the 



white crystalline triazolamine 365 was separated; yield: 0.30 g (90%). Recrystallization 

(petroleum ether/benzene) gave crystals; mp 265–2678C. 

13.13.1.1.5 By Formation of One N-C Bond 

13.13.1.1.5.1 Fragment N-N-N-C-C 


Cyclization of Linear Triazenes and Tetrazenes 

Triazenes are a recognized intermediate in the synthesis of 1,2,3-triazoles starting from 

an azide and an activated methylene compound (see Section 13.13.1.1.3.1.3, Scheme 95). 

Stable triazene compounds can also be cyclized to 1,2,3-triazoles. [360–364] For example, 1aryl-3-(cyanomethyl)triazenes 

366 cyclize in aprotic media with Lewis base catalysis to 

give 1-aryl-1H-1,2,3-triazol-5-amines 367 (Scheme 120). If the reaction is carried out in 

protic media the cyclization is followed by Dimroth rearrangement and the isolated products 

are the isomeric N-aryl-1H-1,2,3-triazol-5-amines 368. [363] Treatment of chloroform solutions 

of triazenes 366 with suspended basic alumina for several days yields the 1H-1,2,3triazol-5-amines 

367 essentially free from isomers 368. However, refluxing the triazenes 

(X = 4-NO 2 or 4-CN) in absolute ethanol for 1–2 hours gives triazoles 368 with no trace of 

the isomeric triazoles 367. In a similar process, 1-aryl-1H-1,2,3-triazol-5-ols are prepared 

by cyclization of 1-aryl-3-(ethoxycarbonylmethyl)triazenes. [364] 

Scheme 120 Cyclization of Linear Triazenes [363] 

X 

N 

N NH 

366 

X = NO2, CN, CO2Me, CONH2 



CN 

alumina, CHCl3 

rt, 7 d 

36−92% 

H 2N 

N 

367 

N 

N 

X 

Dimroth 

rearrangement 

The 1,2,3-triazole system can also be formed by the isomerization of 1-(arylazo)aziridines 

369 (Scheme 121). This isomerization is catalyzed by iodide ions and the product is a 1aryl-4,5-dihydro-1H-1,2,3-triazole 

371. [365] The isomerizations probably occur by a nucleophilic 

attack of iodide ion on the aziridinyl carbon to yield the ion 370, which subsequently 

displaces an iodide ion by the negatively charged nitrogen. Although the 4,5-dihydro-1H-1,2,3-triazoles 

371 are obtained in high yields, this is a dangerous method since 

some 1-(arylazo)aziridines 369 explode violently on standing at room temperature for 

20–30 minutes. [365] 


HN 

X 

368 

N 

H 

N 

N

Scheme 121 Isomerization of 1-(Arylazo)aziridines [365] 

N 

N 

Ar1N 369 

NaI, acetone 

rt, 30 min 

or reflux, 1 h 

− 

N 

N 

Ar1N I 

370 

N 

N 

Ar1N − 

64−98% 

I 

N 

N 

N 

Ar1 Anodic oxidation of 1-aryl-3,3-dimethyltriazenes in acetonitrile gives 2-aryl-5-methyl-2H- 

1,2,3-triazole-4-carbonitriles in low yields. [366] Methyl 1-benzyl-1H-1,2,3-triazole-4-carboxylate 

is obtained in 2% yield, together with several other products, by photolysis of a tetraz-2-ene; 

[367] this method has very limited synthetic interest. 

1-Aryl-1H-1,2,3-triazol-5-amines 367 by Cyclization of 1-Aryl-3-(cyanomethyl)triazenes; 


The triazene 366 (250 mg) was dissolved in the minimum volume of CHCl 3 (25–50 mL) and 

basic alumina (2.5 g) was added. The suspension was stirred at rt for 7 d. The mixture was 

filtered to remove alumina and the filtrate evaporated to dryness in vacuo. The residue 

was the 1H-1,2,3-triazol-5-amine 367. 


Cyclization of Vinyl Azides 

In the presence of a base, vinyl azides (e.g., 372) cyclize to 1H-1,2,3-triazoles, such as 374 

(Scheme 122). [85,190] A probable mechanism for such transformation involves the formation 

of the anion of the vinyl azide, which then cyclizes to the aromatic triazole anion 

(e.g., 373). Protonation affords the final product. 

Scheme 122 Cyclization of 2-Tosylvinyl Azides [85,190] 

Ts H NaTs, DMSO 

Ts 

>24 h 

H N 3 

372 



N N 

+ 

− 

Methyl 3,3-diazido-2-cyanoacrylate (375) reacts with amines to give vinyl azides 376, 

which undergo 1,5-cyclization to form triazoles 378 (via 4H-1,2,3-triazoles 377) in good 

yields (Scheme 123). [368] Under controlled reaction conditions (catalytic amount of the 

amine and absence of moisture) vinyl azides 376 are converted into methyl 1,2,3-triazole-2-carboxylates 

379. [369] 

− 

N 

Ts 

H2O 

N 

− 

N 

N 

373 

Ts 

371 

N 

H 

374 

N 

N 



Scheme 123 Reaction of Methyl 3,3-Diazido-2-cyanoacrylate with Amines [368,369] 

N 3 

N 3 

NC CO 2Me 

375 

R 1 R 2 NH, CH 2Cl 2 

0 o C to rt, 12 h 

− HN3 

R 1 R 2 N 

NC 

MeO 2C 

377 

N 

N 

N 

R 1 R 2 N N 3 

NC CO 2Me 

376 

61−84% 

R 1 R 2 N 

NC 

378 

N 

H 

N 

N 

R 

N 

N 

N 

379 

1R2N NC CO2Me NR1R2 = pyrrolidin-1-yl 90% 

NR1R2 = piperidino 68% 

NR 1 R 2 = NEt 2, pyrrolidin-1-yl, piperidino, morpholino, thiomorpholino, 4-methylpiperazin-1-yl, 4-benzylpiperazin-1-yl 


Cyclization of 2-(Formyloxy)vinyl Azides 

(Z)-2-(Formyloxy)vinyl azides are converted into 1H-1,2,3-triazoles by using triethyl phosphite 

(Scheme 124). [370] Addition of triethyl phosphite to formate 380 immediately initiates 

an exothermic reaction producing a deep orange solution. Evaporation of the solvent 

and purification by silica gel chromatography gives triazole 382. It has been shown by 

NMR that N-formyltriazole 381 (which can be isolated) is the initial product of cyclization. 

4-Phenyl-1H-1,2,3-triazole is prepared by cyclization of formate 383 following the same 

methodology. [370] 

Scheme 124 Cyclization of (Z)-2-(Formyloxy)vinyl Azides [370] 

380 

H 

Ph O O 

H 

H N3 383 

O 

N 3 

O 



P(OEt) 3 

CHCl3 rt, 24 h 

N 

silica gel 

1. P(OEt) 3, CHCl3, 10 min 

2. silica gel 

62% 

Ph 

381 

N 

H 

N 

N 

N 

N 

CHO 

382 46% 


N 

N 

N 

H

13.13.1.2 Synthesis by Ring Transformation 

There are several heterocyclic compounds that, by chemical modification or just by isomerization, 

are converted into 1H-1,2,3-triazoles or 2H-1,2,3-triazoles (see also Section 

13.13.2.2). Despite some synthetically interesting exceptions, in most cases the starting 

heterocycles are not readily available and the routes are unlikely to be general. The 

following are examples of transformations of this type that lead to 1H-1,2,3-triazole derivatives: 

(a) diazotization of isoxazol-4-amines to give triazol-1-ols, [371,372] (b) diazotization of 

5-aminothiazol-2-ols to give triazol-4-ols, [373] (c) diazotization of 3-aminopyridinium salts 

to give 4-(3-oxoprop-1-enyl)-1,2,3-triazole derivatives, [374,375] (d) base-induced rearrangement 

of sydnoneimines to give triazol-4-ols, [376] (e) reaction of ethyl 2-amino-4,5-dihydrofuran-3-carboxylates 

with phenyl azide to give 1H-1,2,3-triazol-5-amines, [377] (f) thermolysis 

of 5-diazo-6-methoxyuracils results in the formation of 4-acyl-1,2,3-triazole derivatives, 

[378–380] (g) reaction of 1,2,4-triazin-3-ones with N-chlorinating agents, [381] (h) treatment 

of 1,2,4-triazin-3-one 2-oxides with acetic anhydride, [382] (i) reduction or oxidation 

of triazolotriazoles, [383,384] (j) diazotization of 7â-amino cephalosporin sulfones, [385] (k) 

thermolysis of mesoionic oxatriazolones in the presence of alkynes, [386] (l) reaction of 

1,3,3-trimethyl-2-methylene-2,3-dihydro-1H-indole with aryl azides, [387] (m) reaction of 

isothiazole dioxides with sodium azide, [388] (n) reaction of triazolo[1,5-a]pyridines with 

aniline, [389] (o) permanganate oxidation of substituted benzotriazoles, [390–392] (p) hydrolytic 

cleavage of 1,2,3-triazolo[4,5-d]pyrimidines, [393–395] and (q) reaction of 4-oxo-4H-pyridino[1,2-a]pyrimidine-3-diazonium 

salts with primary alcohols. [396] 

The chemical transformation of 1,2,3-thiadiazoles into 1H-1,2,3-triazoles is a synthetically 

useful method. For example, base-catalyzed isomerization of 1,2,3-thiadiazol-5amine 

derivatives affords 1H-1,2,3-triazole-5-thiols in high yields. [397–401] Also, thermolysis 

of 5-[alkyl- or 5-[allyl(alkoxycarbonyl)amino]-1,2,3-thiadiazoles 384 in a sealed glass tube 

in the absence of solvent gives 5-(alkylsulfanyl)-1H-1,2,3-triazoles 385 (Scheme 125). [402] 

Scheme 125 Thermolysis of 5-(Alkoxycarbonylamino)-1,2,3-thiadiazoles [402] 

− CO2 43−92% 

R 

N 

N 

N 

2S R1 220 o R 

N 

N 

N 

S 

C, 15 min 

2O2C R1 384 385 

R 1 = Me, Et, CH 2CH CH 2; R 2 = Me, Et 



Another example of this approach is the conversion of 5-chloro-1,2,3-thiadiazole-4-carbaldehyde 

386 into 1H-1,2,3-triazole-4-carbothioamides 390 (Scheme 126). [403] A wide variety 

of amine derivatives can be used in this method. A probable mechanism for this transformation 

involves intermediates 387–389 and is indicated in Scheme 126. Other examples 

of conversion of 5-chloro-1,2,3-thiadiazole derivatives into 1H-1,2,3-triazoles are reported. 

[404,405] 



Scheme 126 Reaction of 5-Chloro-1,2,3-thiadiazole-4-carbaldehyde with Amines [403] 

OHC 

N 

Cl 

S 

N 

386 

R 1 N 

Cl 

H 

387 

S 

N 

N 



R1NH2, MeOH 

rt, 30 min to 8 h 

50−93% 

R 1 = Me, Et, Bn, Ph, 4-MeOC6H4, 4-ClC6H4, NH2, NHPh, morpholino, OH 

Cl 

S 

388 

The reaction of diazoalkanes with 3,5-dichloro-2H-1,4-oxazin-2-ones 391 and 3-chloro-2H- 

1,4-benzoxazin-2-ones 395 is another interesting method for the synthesis of 1H-1,2,3-triazole 

derivatives (Schemes 127 and 128). [406,407] The intermediate bicyclic or tricyclic triazolo-fused 

compounds 393 and 396 are converted into the monocyclic 1H-1,2,3-triazoles 

394 or 397 by reaction with nucleophiles (amines, methanol, water). The first step of this 

procedure involves the selective attack of the diazoalkane to the imidoyl chloride function 

(e.g., giving 392) followed by ring closure. Reactions with diazomethane give higher 

yields (68–91%) of the fused triazoles than reactions with diazoethane or diazopropane 

(41–52%). The reaction conditions required for the ring cleavage of the lactone function 

in compounds 393 are dependent on the nucleophile: with propylamine or diethylamine 

it takes one hour at room temperature, with aniline it requires three hours at reflux and 

with methanol or water it takes 12 hours at reflux. The triazoles 394 obtained from this 

two-step procedure have the interesting Æ-chloro ketone substituent at N1, which may be 

used for the elaboration of other heterocycles. 

N2 

NR 1 

Cl 

389 

R 1 NH 2 

S 

N 

N 

N 

R1 R 1 HN 


390 

S 

N 

N 

N 

R1

Scheme 127 Reaction of Diazoalkanes with 3,5-Dichloro-2H-1,4-oxazin-2-ones [406,407] 

R 1 

Cl 

O O 

N 

391 

Cl 

+ R 2 CHN 2 

Et2O 

0 oC, 3 d 

O 

393 

R 1 

Cl 

N 

N 

N 

O O 

N 

+ N 

Compound R 1 R 2 Nu Yield a,b (%) Ref 

393 Me H – 91 [407] 

393 Ph H – 81 [407] 

393 2,6-Cl 2C 6H 3 H – 72 [407] 

393 2,6-Cl 2C 6H 3 Me – n.r. [407] 

393 Me Et – n.r. [407] 

394 Me H OMe 95 [407] 

394 Ph H OMe 80 [407] 

394 Me H NEt 2 87 [407] 

c [407] 

394 Me Et OMe 28 

c [407] 

394 2,6-Cl2C6H3 Me OMe 25 

394 2,6-Cl 2C 6H 3 H NHPh 84 [407] 

394 Me H OH 55 [407] 

R 1 

O 

Cl 

R 2 

392 

a n.r. = not reported. 

b Yield of 394 from 393 or 393 from 391 unless otherwise stated. 

c Yield of 394 from 391. 

Scheme 128 Reaction of Diazoalkanes with 3-Chloro-2H-1,4-benzoxazin-2-ones [406,407] 

R 1 

O O 

N 

Cl 



+ R 2 CHN2 

Et2O 

0 oC, 3 d 

− 

N 

NuH 

395 396 

O 

R 1 

O 

NuH 

R 2 

R 2 

N 

N 

N 

Nu 

Nu 

O 

O 

R 1 

R 2 

Cl 

R 2 

394 

397 

N 

N 

N 

N 

N 

N 

O 

R 1 

OH 



Compound R 1 R 2 Nu Yield a (%) Ref 

396 H H – 75 [407] 

396 Me H – 71 [407] 

396 Cl H – 68 [407] 

396 H Me – 52 [407] 

396 Cl Et – 41 [407] 

397 Cl H OMe 75 [407] 

397 Cl Et OMe 60 [407] 

397 Cl Et NHPr 76 [407] 

397 Me H NHPh 59 [407] 

397 H H NEt 2 60 [407] 

397 H H OH 58 [407] 

a Yield of 397 from 396 or 396 from 395. 

Methyl 1H-1,2,3-Triazole-5-carboxylates 394 and 397 (Nu = OMe); General Procedure: [407] 


Compound 391 or 395 (10 mmol) was slowly added to a Et 2O soln of CH 2N 2 (40 mmol) at 

08C. In the cases of MeCHN 2 and EtCHN 2, iPr 2O was used as solvent and, to avoid violent 

reactions, the initial temperature was –788C. Afterwards the temperature was brought to 

48C and, after stirring for 3 d, the excess of diazo compound and the solvent was evaporated. 

Then the residue was recrystallized (CHCl 3/hexane) yielding 393 or 395. This compound 

(10 mmol) was dissolved in MeOH (50 mL), the soln was brought to reflux temperature, 

and the solvent was evaporated after 15 min (for 393) or 12 h (for 396). The residue 

was recrystallized (CHCl 3/hexane) yielding 394 or 397. 

13.13.1.3 Aromatization 

4,5-Dihydro-1H-1,2,3-triazoles (triazolines) are intermediates of 1,2,3-triazoles in many 

synthetic methods, especially those involving the addition of azides to C=C bonds. In 

most cases 4,5-dihydro-1H-1,2,3-triazoles aromatize spontaneously to the corresponding 

triazoles but when they are stable compounds they can be aromatized by oxidation, elimination, 

or isomerization reactions. This subject is discussed in a review. [4] Some illustrative 

examples are described below. 

13.13.1.3.1 Method 1: 

By Oxidation Reactions 



The oxidative dehydrogenation of 4,5-dihydro-1H-1,2,3-triazoles 398 to triazoles 399 is 

carried out mainly with potassium permanganate or nickel peroxide (Scheme 129). Very 

good results are obtained when the reaction is carried out with potassium permanganate 

in a two-phase system (benzene/water) using tetrabutylammonium chloride as a phasetransfer 

catalyst. [59,408,409] If the reaction is run in a single phase in anhydrous benzene 

alone, the products are not triazoles but imines. [410] The oxidation of 4,5-dihydro-1H- 

1,2,3-triazoles bearing sterically crowded ortho-substituted phenyl groups in the 5-position 

with potassium permanganate gives low yields of the corresponding triazoles. In 

these cases much better results are obtained with nickel peroxide. [58,411] 


Scheme 129 Oxidative Dehydrogenation of 4,5-Dihydro-1H-1,2,3-triazoles [58,408] 

R 1 

398 

N 

N 

N 

R2 A: KMnO4, TBACl, benzene, H2O, reflux, 2−8 h 

B: NiO2, benzene, reflux, 3−4 h 

R 1 

399 

N 

N 

N 

R2 R 1 R 2 Method Time (h) Yield (%) Ref 

4-pyridyl Ph A 2 65 [408] 

4-pyridyl 4-Tol A 2 73 [408] 

4-pyridyl 4-ClC6H4 A 3 72 [408] 

3-pyridyl 3-O2NC6H4 A 8 58 [408] 

2-quinolyl Ph A 7 40 [408] 

2-quinolyl 4-ClC6H4 A 5.5 57 [408] 

4-O2NC6H4 4-O2NC6H4 A 8 38 [408] 

2-ClC6H4 4-MeOC6H4 B 4 63 [58] 

2-ClC6H4 3,4-Cl2C6H3 B 3 63 [58] 

2,4-Cl2C6H3 Ph B 4 65 [58] 

2,4-Cl2C6H3 4-F3CC6H4 B 4 70 [58] 

2,6-Cl2C6H3 Ph B 4 50 [58] 

2,6-Cl2C6H3 3-ClC6H4 B 3 52 [58] 

2,6-Cl2C6H3 4-BrC6H4 B 3 74 [58] 

The oxidation of 1-aryl-4-methylene-5-morpholino-4,5-dihydro-1H-1,2,3-triazoles 400 

with 3-chloroperoxybenzoic acid affords 1-aryl-1H-1,2,3-triazole-4-carbaldehydes 401 

(Scheme 130). The corresponding carboxylic acids are also produced as byproducts. [412] 

4,5-Dihydro-1H-1,2,3-triazoles 400 also react with halomethyl radicals to yield 1,2,3-triazole 

derivatives. [413] Oxidation of 4,5-dihydro-1H-triazole 402 with bromine gives triazole 

403 in 83% yield (Scheme 130). [202] 

Scheme 130 Oxidation of 4,5-Dihydro-1H-1,2,3-triazoles with 

3-Chloroperoxybenzoic Acid [412] or Bromine [202] 

O 

N 

400 

N 

R 1 

N 

N 

R 2 

R 1 = CO2Et, Me, NO2, Cl, H; R 2 = H, CF3 

TBDMSO 

TBDMSO 

MeO 2C 

N 

N N 

402 

OH 



OTBDMS 

MCPBA, CHCl 3 

rt, 30 min 

38−70% 

Br2, NaOAc 

MeCCl3 rt, 8 h 

83% 

OHC 

N 

R 1 

401 

N 

N 

R 2 

TBDMSO 

TBDMSO 

MeO 2C 

N 

N N 

403 

OH 

OTBDMS 



1,5-Disubstituted 1H-1,2,3-Triazoles 399 by Nickel Peroxide Oxidation; 


To a soln of the 4,5-dihydro-1H-1,2,3-triazole 398 (5 mmol) in benzene (100 mL) (CAU- 

TION: carcinogen) was added dried, finely powdered NiO 2 (0.06 mol) and the mixture was 

refluxed with vigorous magnetic stirring for 3–4 h. The mixture was then allowed to cool 

to rt and filtered under gravity. The residual NiO 2 was washed with hot CHCl 3, and the 

combined filtrates were subjected to rotary evaporation. The resulting oily residue was 

cooled and triturated with petroleum ether, or an Et 2O/petroleum ether mixture, when 

it solidified to a clean, crystalline mass, and the colored impurities remained in soln. 

Many of the triazoles at this point were quite pure, giving reasonably sharp melting 

points. Recrystallization (acetone/petroleum ether) gave analytically pure samples. 


By Elimination Reactions 

Several methods for the synthesis of 1,2,3-triazoles involve spontaneous or induced elimination 

reactions. Typical examples are the reactions of azides with enamines, enol 

ethers, or enolates, and the thermal elimination of stable molecules from 4,5-dihydro- 

1H-1,2,3-triazoles via retro-Diels–Alder reactions (see, for example, Schemes 69 and 

70). [213,214,217,220,414] The elimination of morpholine from compound 404 on heating in formic 

acid (Scheme 131) is another example. In this process the piperidine ring is cleaved 

reductively, with carbon dioxide evolution, and the triazole 405 is obtained. [415] In some 

cases the elimination reaction corresponds to an isomerization, as exemplified in the 

conversion of 4,5-dihydro-1H-triazole 406 into triazole 407 (Scheme 131). [387] The base-catalyzed 

dehydration of 4,5-dihydro-1H-1,2,3-triazol-5-ols (by treatment with hot methanolic 

potassium hydroxide) also gives high yields of the corresponding triazoles. [263] In a 

related method, 1-benzyl-4,5-difluoro-4,5-bis(trifluoromethyl)-4,5-dihydro-1H-1,2,3-triazole 

is converted into 1-benzyl-4,5-bis(trifluoromethyl)-1H-1,2,3-triazole in 69% yield by 

defluorination with tetrakis(dimethylamino)ethene. [416] 

Scheme 131 Aromatization of 4,5-Dihydro-1H-1,2,3-triazoles by 

Elimination Reactions [387,415] 

MeN 

N 

O 

404 

Me 

N 

O 2N 

406 

N 

N 

N 

Ph 

N 

N 

N 



HCO 2H 

− CO2 

KOH, EtOH 

67% 

Me 2N 

405 

407 

N 

N 

N 

Ph 

NHMe 

N 


N 

N 

NO 2 

+ 

H 

N 

O

13.13.1.4 Synthesis by Substituent Modification 

13.13.1.4.1 Substitution of Existing Substituents 

13.13.1.4.1.1 Of Hydrogen 


Lithiation 

1-Substituted 1,2,3-triazoles undergo lithiation with butyllithium or lithium diisopropylamide 

preferentially at the 5-position at –20 to –788C. The resulting lithiated species react 

with carbon, silicon, halogen, and sulfur electrophiles to yield a range of 1,5-disubstituted 

1,2,3-triazoles. This subject has been reviewed comprehensively. [417] At room temperature, 

the lithiated species rapidly undergo fragmentation to nitrogen and lithium ketenimines. 

[418,424] 

The lithiation of 1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-1,2,3-triazole (408, R 1 = SEM) 

followed by addition of an electrophile, gives moderate yields of 1,5-disubstituted 1,2,3triazoles 

410 (R 1 = SEM) (Scheme 132). [419] The 2-(trimethylsilyl)ethoxymethyl (SEM) group 

is a particularly interesting N1 protecting group for lithiation: it is readily attached to the 

triazole, it helps the stabilization of the intermediate triazol-5-yllithium species by intramolecular 

coordination, and it is removed under very mild conditions (by heating with 

dilute hydrochloric acid or by treatment with tetrabutylammonium fluoride in refluxing 

tetrahydrofuran). In a similar way, 5-substituted 1-benzyloxy-1H-1,2,3-triazoles 410 

(R 1 = OBn) are obtained in excellent yields from lithiation of 1-(benzyloxy)-1H-1,2,3-triazole 

(408, R 1 = OBn), followed by reaction with an electrophile. [336] Removal of the benzyl 

group by catalytic hydrogenation affords the corresponding 1H-1,2,3-triazol-1-ols in 98– 

100% yield. Compound 408 (R 1 = OBn) is also converted into 5-acyl- and 5-aryl-1,2,3-triazoles 

through a lithiation–transmetalation strategy. [420] Lithiation of 1-methyl-1H-1,2,3-triazole 

with butyllithium or lithium 2,2,6,6-tetramethylpiperidide, followed by addition of 

an electrophile gives moderate yields of 5-alkyl- or 5-acyl-1-methyl-1,2,3-triazoles. [421] Lithiation 

of 1-methyl-5-(phenylsulfanyl)-1H-1,2,3-triazole with lithium 2,2,6,6-tetramethylpiperidide 

occurs at the 4-position and after quenching with aldehydes and carboxylic 

amides the corresponding 4-(1-hydroxyalkyl) and 4-acyl derivatives are obtained 

in good yields (71–86%). [421] 

Scheme 132 Lithiation of 1H-1,2,3-Triazoles and Quenching with Electrophiles [336,419] 

N 

N 

N 

R1 408 

BuLi, THF 

−78 oC, 5−30 min 



Li 

409 

N 

N 

N 

R1 R 1 R 2 Electrophile Yield (%) Ref 

SEM CH(OH)Ph PhCHO 45 [419] 

SEM Bz EtOBz 21 [419] 

SEM Me MeI 30 [419] 

SEM SPh PhSSPh 80 [419] 

SEM Cl Cl3CCCl3 50 [419] 

SEM TMS TMSCl 37 [419] 

OBn D D2O 90 [336] 

OBn Me MeI 93 [336] 

electrophile, THF 

−78 o C to rt, 1−4 h N 

R 2 

410 

N 

N 



R 1 R 2 Electrophile Yield (%) Ref 

OBn CHO DMF 87 [336] 

OBn CO2Me ClCO2Me 76 [336] 

OBn CONMe2 ClCONMe2 97 [336] 

OBn Cl Cl3CCCl3 88 [336] 

OBn Br Br2 86 [336] 

OBn I I2 96 [336] 

OBn SMe MeSSMe 67 [336] 

OBn TMS TMSCl 93 [336] 

OBn SnBu3 Bu3SnCl 91 [336] 

The lithiation of 1,2,3-triazoles is also carried out with 4,5-dibromotriazoles (both 1H- and 

2H-) via a bromine–lithium exchange reaction. [462] For example, 4,5-dibromo-1-(methoxymethyl)-1H-1,2,3-triazole 

(411) reacts with butyllithium, in diethyl ether or tetrahydrofuran 

at –80 to –70 8C, at position 5 and the resulting lithiated derivative 412 is quenched 

with aqueous ammonium chloride, carbon dioxide, methyl chloroformate, benzophenone, 

or dimethyl or diphenyl disulfide to give high yields of the corresponding 5-substituted 

1,2,3-triazoles 413 (Scheme 133). 

Scheme 133 Lithiation of 4,5-Dibromo-1-(methoxymethyl)-1H-1,2,3-triazole [462] 

Br 

Br 

N 

411 

N 

N 

OMe 



BuLi, Et2O −80 oC, 20 min 

Li 

Br 

N 

412 

R 1 Electrophile Yield (%) Ref 

H NH4Cl 84 [462] 

CO2H CO272 [462] 

C(OH)Ph2 Ph2CO 93 [462] 

SMe MeSSMe 87 [462] 

SPh PhSSPh 71 [462] 

N 

N 

OMe 

electrophile 

−80 to −70 oC 20−60 min 

5-Substituted 1-Benzyloxy-1H-1,2,3-triazoles 410 (R 1 = OBn) by Lithiation Followed by 

Reaction with an Electrophile; General Procedure: [336] 

Under N 2 at –788C, a 0.1 M soln of 408 (R 1 = OBn) in dry THF was treated dropwise with 

1.6 M BuLi in hexane (1.2 equiv). After 5 min the electrophile was added (neat or dissolved 

in THF) and stirring was continued at –788C for 1 h and at rt 1 h. The mixture was then 

quenched with sat. NH 4Cl and the product was extracted with CH 2Cl 2. The organic phase 

was washed with H 2O, dried (MgSO 4), concentrated, and purified by flash chromatography 

(EtOAc/heptane 1:2). 


R 1 

Br 

N 


N 

N 

OMe


N-Trimethylsilylation 

1H-1,2,3-Triazole (414, R 1 =H) [421,430] and 4-methyl-1H-1,2,3-triazole (414, R 1 = Me) [430] react 

with chlorotrimethylsilane to give selectively 2-trimethylsilyl derivatives 415 (Scheme 

134). Refluxing a mixture of 1H-1,2,3-triazole and hexamethyldisilazane for six hours 

gives an 81% yield of 1-(trimethylsilyl)-1H-1,2,3-triazole (416) and 2-(trimethylsilyl)-2H- 

1,2,3-triazole (417) in a 1:5 ratio. [422] 1,2,3-Triazole N-oxides are C-silylated at ring and exocyclic 

Æ-positions in high yields in a one-pot procedure involving treatment with trimethylsilyl 

trifluoromethanesulfonate, iodotrimethylsilane, or tert-butyldimethylsilyl trifluoromethanesulfonate 

in the presence of 1,2,2,6,6-pentamethylpiperidine, diisopropylethylamine, 

or lithium tetramethylpiperidide. [423] 

Scheme 134 N-Trimethylsilylation of 1H-1,2,3-Triazoles [421,430] 

R 1 

N 

H 

414 

N 

N 

TMSCl, benzene, Et3N 0 oC, 30 min, then reflux, 2 h 

81−96% 

(TMS) 2NH, reflux, 6 h 

R 1 = H 81% 

R 1 

N 

N 

NTMS 

415 R 1 = H, Me 

N 

N 

N 

TMS 

416 

+ 

1:5 

N 

N 

417 

NTMS 

2-(Trimethylsilyl)-2H-1,2,3-triazole (415, R 1 = H): [421] 

TMSCl (10.7 mL, 84 mmol) was added to a soln of 1H-1,2,3-triazole (4.7 mL, 80 mmol) and 

Et 3N (12.1 mL, 87 mmol) in benzene (80 mL) (CAUTION: carcinogen) under N 2 with ice cooling, 

and the mixture was stirred for 30 min and then refluxed at 808C for 2 h. After filtration, 

the filtrate was evaporated to afford a residue, which was distilled under atmospheric 

pressure to give a colorless oil; yield: 9.72 g (86%); bp 1488C; 1 H NMR (CDCl 3, ä): 7.73 (s, 

2H, hetaryl), 0.51 (s, 9H, TMS). 


Carboxylation 



Carboxylation of C-lithio [424,425] or Grignard [180,181] derivatives of triazoles gives the corresponding 

carboxylic acids (Scheme 135). The lithiated species 412 (Scheme 133) is 

quenched with carbon dioxide to give 4-bromo-1-(methoxymethyl)-1H-1,2,3-triazole-5-carboxylic 

acid in 72% yield. [462] The 2-methoxymethyl analogue of 412 yields methyl 4-bromo-2-(methoxymethyl)-2H-1,2,3-triazole-3-carboxylate 

in 71% when quenched with methyl 

chloroformate. [462] Similarly, lithiation of 1-benzyloxy-1H-1,2,3-triazole and quenching 

the resulting 5-lithiated species with methyl chloroformate or dimethylcarbamoyl chloride 

yields the corresponding 5-carboxylate (76%) or N,N-dimethyl carboxamide (97%) 

(see Scheme 132). [336] 

5-Amino-1H-1,2,3-triazole-4-carboxylic acid is obtained in low yield (14%) by heating 

1H-1,2,3-triazol-4-amine with aqueous potassium hydrogen carbonate for 16 hours at 

1008C. [428] 



Scheme 135 Carboxylation of 1,4-Diphenyl-1H-1,2,3-triazole [424] 

Ph 

N 

N 

N 

Ph 

418 

1. BuLi 

2. CO2 62% 

HO2C 

Ph 

419 

N 

N 

N 

Ph 

1,4-Diphenyl-1H-1,2,3-triazole-5-carboxylic Acid (419); Typical Procedure: [424] 

To a stirred soln of 1,4-diphenyl-1H-1,2,3-triazole (418; 0.04 mol) in anhyd THF (80 mL) was 

added dropwise over 15 min, 1.6 M BuLi in hexane (26 mL) at –20 to –608C under N 2. When 

the addition was completed the mixture was stirred and cooled for an additional 0.5–1 h 

and then the mixture was poured onto solid CO 2. Acidification of an aqueous soln of the 

salt yielded the carboxylic acid 419; yield: 62%; mp 169–1708C (dec). 


Acylation 

N-Unsubstituted 1,2,3-triazoles can be N-acylated by acyl halides and anhydrides with dry 

benzene or pyridine as the solvent. Substitution takes place at the 1-position but the acyl 

group may migrate to the 2-position on heating or on treatment with base. [173,429,430] Thus, 

acetylation with acetyl chloride gives 1-acetyl derivatives that rearrange to the 2-isomers 

above 1208C; acetylation by heating the triazoles with acetic anhydride gives the 2-acetyl 

derivatives directly. An alternative route to 1-acetyl-1H-1,2,3-triazoles is the reaction of 2trimethylsilyl 

derivatives (e.g., 420) with acetyl chloride, giving products such as 421 

(R 1 = Me) (Scheme 136). [173,430] This method can be used to prepare a range of 1-acyl-1H- 

1,2,3-triazoles, intermediates in the synthesis of oxazoles. [431] 

Scheme 136 Acylation of 2-(Trimethylsilyl)-2H-1,2,3-triazole [173,430] 

N 

N 

NTMS 

420 

R 1 = Me, aryl 

+ R 1 COCl 

benzene, rt 

N 

N 

421 

N 

O R 1 

+ TMSCl 

Reaction of 4,5-diphenyl-1H-1,2,3-triazole with benzoyl chloride in pyridine gives the corresponding 

1-benzoyl derivative. [432] The 1H-1,2,3-triazol-4-ols 422 react with benzoyl 

chloride in pyridine to yield the dibenzoyl derivatives 423 in high yields (Scheme 137). [433] 

Scheme 137 Benzoylation of 1H-1,2,3-Triazol-4-ols [433] 

R 1 

HO 

422 

N 

H 

N 

N 



BzCl, py, 5 o C, 1 d 

R1 = H 80% 

R1 = Ph 92% 

The reaction of 1,2,3-triazole with thiobenzoyl chloride (CCl 4,Et 3N, rt) yields a mixture of 

1- and 2-thiobenzoyl-1,2,3-triazoles (22:78). [434] Similar results are obtained if the sodium 

salt of 1,2,3-triazole is used. However, only 1-(thiobenzoyl)-1,2,3-triazole is formed in 40% 

yield in the reaction of thiobenzoyl chloride with 2-(trimethylsilyl)-2H-1,2,3-triazole (CCl 4, 


BzO 

R 1 

N 

423 

N 

NBz

08C). [434] Reaction of 1,2,3-triazole with isocyanates affords the corresponding urea derivatives. 

[435] 

1,2,3-Triazoles are also C-acylated. In this case, the corresponding lithiated species 

are reacted with appropriate electrophiles (acyl halides, esters, amides) (see Section 

13.13.1.4.1.1.1). 


Formylation 

As shown in Scheme 132, C-lithiated 1,2,3-triazole species are quenched with dimethylformamide 

to afford the corresponding formyl derivatives in excellent yields; [336] however 

other attempts to quench 1,2,3-triazolyllithium compounds with dimethylformamide 

have failed. [419,462] The Vilsmeier–Haack formylation of 1H-1,2,3-triazol-5-amines 424 gives 

the corresponding 1H-1,2,3-triazole-4-carbaldehydes 425 in good yields (Scheme 138). 

These compounds are hydrolyzed by dilute hydrochloric acid to the corresponding 5-amino 

derivatives 426. [436] The Vilsmeier–Haack formylation of 1-benzyl-1,2,3-triazol-5-ols affords 

the corresponding 5-chloro-1H-1,2,3-triazole-4-carbaldehydes in 60–94% yields. [302] 

1H-1,2,3-Triazole-4-carbaldehydes are also prepared from the corresponding carbonitriles 

by catalytic hydrogenation (10% Pd/C, aq 0.1 M HCl) [437] or by Raney nickel/formic acid reduction. 

[438] 

Scheme 138 Vilsmeier–Haack Formylation of 1H-1,2,3-Triazol-5-amines [436] 

H 2N 

424 

R 1 = Me, Bn 

N 

N 

N 

R1 DMF, POCl3 85 oC, 1 h 

75−85% 

Me 2N 

OHC 

N 

425 

N 

N 

N 

R1 1 M HCl 

reflux, 20 min 

65% 

5-Amino-1-methyl-1H-1,2,3-triazole-4-carbaldehyde (426,R 1 = Me); Typical Procedure: [436] 

POCl 3 (0.16 g, 1 mmol) was added to 1-methyl-1H-1,2,3-triazol-5-amine (424, R 1 = Me; 

0.05 g, 0.5 mmol) in DMF (1 mL) at 08C. The mixture was then heated at 858C for 1 h, 

cooled, and poured onto ice (15 g). The mixture was adjusted to pH 7 and extracted with 

CHCl 3 (3 ” 20 mL). The extract was dried (K 2CO 3) and the solvent was removed in vacuo. 

The residue was recrystallized (benzene/cyclohexane 1:4) (CAUTION: carcinogen) to give 

5-{[(dimethylamino)methylene]amino}-1-methyl-1H-1,2,3-triazole-4-carbaldehyde (425, 

R 1 = Me); yield: 75%; mp 1368C. This compound was refluxed for 20 min with 1 M HCl (16 

equiv). The soln was neutralized and extracted with CHCl 3. Evaporation of the dried 

(K 2CO 3) extract gave 426 (R 1 = Me); yield: 65%. 


Arylation 



1,2,3-Triazoles can be N-arylated by reaction with activated aryl halides. Reaction of 1H- 

1,2,3-triazole with 1-fluoro-2-nitrobenzene [439] or 1-fluoro-4-nitrobenzene [440] gives mixtures 

of the corresponding 1- and 2-nitrophenyl-1,2,3-triazoles. However, with 1-fluoro- 

2,4-dinitrobenzene and 2-chloro-1,3,5-trinitrobenzene only the 1-substituted derivatives 

are obtained (Scheme 139). [440] Reaction of 1H-1,2,3-triazole with 2-chloro-1,3,5-trinitrobenzene 

(427, X = Cl), 2-fluoro-1,3,5-trinitrobenzene (427, X = F) or 1,2,3,5-tetranitrobenzene 

(427, X=NO 2) in dioxane, dimethylformamide, or dimethyl sulfoxide for two days 

at room temperature gives 1-(2,4,6-trinitrophenyl)-1H-1,2,3-triazole (428) exclusively, except 

in one case. [471] When the reaction is carried out with 2-fluoro-1,3,5-trinitrobenzene 

OHC 

H2N 

426 

N 

N 

N 



(427, X = F) in dimethyl sulfoxide, the 2-(2,4,6-trinitrophenyl)-2H-1,2,3-triazole is also 

formed; the final product composition depends on the way in which the reagents are 

mixed. 

Scheme 139 Arylation of 1H-1,2,3-Triazole with 2,4,6-Trinitrophenyl Derivatives [440] 

N 

H 

N 

N 

X = Cl, F, NO2 

O2N 

+ X NO 2 

O2N 

427 

dioxane 

DMF or DMSO 

rt, 2 d 

58−96% 

1-(4-Tolyl)-1H-1,2,3-triazole is obtained in 11% yield from the reaction of 1H-1,2,3-triazole 

and 4-tolylboronic acid in the presence of anhydrous copper(II) acetate and pyridine. [441] A 

mixture of 9-(1H-1,2,3-triazol-1-yl)acridine (429) (49%) and 9-(2H-1,2,3-triazol-2-yl)acridine 

(430) (26%) is obtained from the reaction of the anion of 1H-1,2,3-triazole, generated using 

sodium hydride in dry dimethylformamide, with 9-chloroacridine (Scheme 140). [442] Deprotonation 

of triazole 431 with potassium hexamethyldisilazanide followed by the addition 

of pentafluoropyridine gives the 2-(4-pyridyl)-substituted triazole 432 in 49% yield 

(Scheme 140). [174] 

O 2N 

N 

N 

N 

NO2 

428 

NO 2 

Scheme 140 Arylation of 1H-1,2,3-Triazoles with 9-Chloroacridine [442] and 

Pentafluoropyridine [174] 

N 

N 

H 

N 

N 

431 

NaH, DMF 

9-chloroacridine 

60 oC, 2 h 

N 

H 

N 

N 



F F 

KHDMS 

pentafluoropyridine, THF 

0 oC to rt, 20 min 

49% 

N 

N 

N 

N 

+ 

429 49% 430 26% 

N 

N 

N 

F 

F 

N 

N 

N 

1,2,3-Triazoles are also C-arylated. The palladium-catalyzed reaction of the 1,2,3-triazol-5ylzinc 

iodide species 433 with appropriate aryl and hetaryl iodides gives the 5-aryl-1- or 5hetaryl-1H-1,2,3-triazoles 

434 (Scheme 141). [420] 


432 

N 

N 

F 

N 

F

Scheme 141 Arylation of 1-Benzyloxy-1H-1,2,3-triazol-5-ylzinc Iodide [420] 

N 

N 

N 

OBn 

BuLi, THF 

−78 oC, 5 min 

Li 

N 

N 

N 

OBn 

ZnI2 

−78 o C, 30 min 

Ar1I, DMF 

Pd(PPh3) 4 

−78 oC to rt 

then 80 oC, 1 h 

IZn 

433 

Ar 1 

N 

N 

N 

OBn 

N 

N 

N 

OBn 

434 Ar1 = aryl 30−87% 

Ar1 = 2-pyridyl 80% 

Ar1 = 2-thienyl 63% 

Ar1 = N 

49% 

N 

OBn 

1-(2,4,6-Trinitrophenyl)-1H-1,2,3-triazole (428): [471] 

A soln of 1H-1,2,3-triazole (4.20 g, 60 mmol), 2-fluoro-1,3,5-trinitrobenzene (427, X=F; 

13.40 g, 60 mmol) and dry DMF (100 mL), protected from atmospheric moisture, was 

stirred at rt for 3 d. This soln was then poured with stirring into H 2O (2 L). The precipitated 

product was collected by filtration, washed with H 2O, and dried. The product was then 

dissolved in a minimal amount of acetone (~400 mL), and to this stirred soln was added 

H 2O (1.5 L), dropwise at first, until crystallization was induced, at which time the flow 

was increased to a slow, steady stream. The precipitated product was again collected by 

filtration, washed with H 2O, and dried to give white crystals; yield: 14.6 g (90%); mp 

2148C (dec). 


Alkylation 



1,2,3-Triazoles can be N- and C-alkylated. N-alkylation is readily achieved by one of the 

following methods: (i) reaction with alkyl halides, [443] dimethyl sulfate, [50,444–446,460] diazomethane, 

[44,46,47,50,447] methyl tosylate, [448,449] or methyl fluorosulfonate [450] (ii) by reaction 

with alcohols in acidic media, [451] (iii) by addition to aziridines, [90] (iv) by conjugate addition 

to activated alkenes [90,198,445,452] and alkynes, [87,443] and (v) by the Mannich reaction. [453] 

Alkylation with alkyl halides requires the use of a base; generally a sodium alkoxide, sodium 

hydride, or sodium hydroxide are employed. 

Alkylation of N-unsubstituted 1,2,3-triazoles under basic, neutral or weakly acidic 

conditions generally affords mixtures of the N-alkyl derivatives. The 1,2,3-triazole itself 

and the symmetrical 4,5-disubstituted triazoles give mixtures of 1- and 2-alkyl isomers 

while unsymmetrical 4,5-substituted triazoles frequently give all the three possible 

monoalkyl derivatives. Some selectivity for 1-alkylation is observed when silver or thallium 

salts of the triazoles are reacted with iodoalkanes. [454] Selective alkylation at N1 is obtained 

by reaction of a 2-(trimethylsilyl)-2H-1,2,3-triazole with primary alkyl halides in 

the presence of tetrabutylammonium fluoride. [421] 

It has been shown that 1H-1,2,3-triazole reacts with propan-2-ol in concentrated sulfuric 

acid to yield 1-isopropyl-1H-1,2,3-triazole (80%) as the sole reaction product. [451] The 

scope of this method is still to be demonstrated. 



Alkylation of 1-methyl- and 1-benzyl-1H-1,2,3-triazole gives only the 1,3-disubstituted 

triazolium salts. [455] The 2-alkyl-2H-1,2,3-triazole 1-oxides are quantitatively methylated at 

the N-oxygen by trimethyloxonium tetrafluoroborate to yield the corresponding 1-methoxytriazolium 

tetrafluoroborates. [456] 1-Alkyl-1H-1,2,3-triazol-5-ols on reaction with diazomethane 

or iodomethane are alkylated at the alcohol oxygen, N2, and N3. [306,331] 1H-1,2,3- 

Triazole-4-thiol is converted selectively into the 4-(methylsulfanyl) derivative by reaction 

with a small excess iodomethane, in the presence of an equimolar amount of ethanolic 

potassium hydroxide (1.8 M). [447] Addition of diazomethane to the 4-(methylsulfanyl)triazole 

gives a mixture of the three possible N-methylated 4-(methylsulfanyl)triazoles. [447] 

The alkylation of ethyl 4-(4-hydroxyphenoxy)-1H-1,2,3-triazole-5-carboxylate (435) 

under alkaline conditions exclusively yields the N2 and N3 alkylation products (Scheme 

142). Alkylation at N1 or at the hydroxy group is not observed. [457] While alkylation of 435 

with benzyl or 4-methoxybenzyl chlorides gives a 1:1 mixture of the two isomers, with 4bromophenacyl 

bromide preferential substitution at N2 is observed (14% and 65% respectively 

to 436 and 437). Alkylation with trityl chloride shows a marked steric preference 

for the less hindered N2 position, with isomer 437 (R 1 = Tr) being formed almost exclusively. 

Scheme 142 Alkylation of Ethyl 4-(4-Hydroxyphenoxy)-1H-1,2,3-triazole-5-carboxylate [457] 

HO 

EtO2C 

435 

O 

N 

H 

N 

N 

R 1 = CH2Ar 1 , CH2COAr 1 , Tr; X = Cl, Br 

1. K2CO3, DMF 

2. R1X, 20−40 oC HO 

EtO 2C 

436 

O 

HO 

N 

N 

N 

R1 EtO2C 

N-Unsubstituted triazoles also react with compounds of other types to yield N-substituted 

derivatives. For example, they react with nitrilimines (gererated in situ) to yield a mixture 

of 1- and 2-(benzohydrazonoyl)-1,2,3-triazoles, as illustrated in Scheme 143, [458] and react 

with 1-O-acetyl ribofuranose derivatives (by an acid-catalyzed fusion procedure) to afford 

mixtures of triazole nucleosides 438 and 439 (Scheme 144). [459] 

Scheme 143 Reaction of Triazoles with Nitrilimines [458] 

N 

H 

N 

N 

+ 



+ − 

PhC N NPh 

benzene 

reflux, 10 h 

N 

N 

N 

Ph N 

+ 

NHPh 

+ 

N 

437 

N 

N 

41% 33% 


O 

Ph 

N 

N 

N 

NR 1 

NHPh

Scheme 144 Reaction of Triazoles with 1-O-Acetyl Ribofuranose Derivatives [459] 

R 1 O 

O 

OR 1 

OAc 

OR 1 

+ 

X 

R 1 = Bz, Ac; X = H, CO2Me, CN, NO2 

N 

H 

N 

N 

heat 

R 1 O 

X 

O 

OR 1 

N 

OR 1 

N 

N 

+ 

R 1 O 

X 

O 

OR 1 

438 439 

C-Alkylation of triazoles is achieved by lithiation followed by addition of an alkyl halide. 

For example, reaction of 1-phenyl-1H-1,2,3-triazole with butyllithium and addition of 

iodomethane gives 5-methyl-1-phenyl-1H-1,2,3-triazole (440,R 1 = H) in 94% yield (Scheme 

145). [424] It is interesting to note that under similar reaction conditions, 4-methyl-1-phenyl- 

1H-1,2,3-triazole yields 4,5-dimethyl-1-phenyl-1H-1,2,3-triazole (440, R 1 = Me), while its 

isomer 5-methyl-1-phenyl-1H-1,2,3-triazole gives only the 5-ethyl derivative 441. Lithiation 

of 1,4-diphenyl- and 1,5-diphenyl-1H-1,2,3-triazole, followed by iodomethane 

quench, gives the corresponding derivatives 440 (R 1 = Ph) and 442 in 78 and 99% yield, respectively, 

reflecting the higher steric hindrance in the 1,4-diphenyl isomer. For other examples 

of C-alkylation of triazoles see Section 13.13.1.4.1.1.1. 

Scheme 145 C-Methylation of 1-Phenyl-1H-1,2,3-triazoles [424] 

R 

N 

N 

N 

1 

Ph 

R 1 = H, Me, Ph 

R 1 

R 1 = Me, Ph 

N 

N 

N 

Ph 


Halogenation 

BuLi, THF, MeΙ 

−60 to −20 oC 78−94% 



BuLi, THF, MeΙ 

−20 to −60 oC R 

N 

N 

N 

1 

Ph 

440 

R 1 = Me 42% 

R 1 = Ph 99% 

Et 

Ph 

441 

N 

N 

N 

Ph 

442 

N 

N 

N 

Ph 

The reaction of 1,2,3-triazole, 1-methyl-, 2-methyl-, 4-methyl-, and 4,5-dimethyl-1,2,3-triazole 

with chlorine, bromine, iodine, hypochlorite, hypobromite, and hypoiodite has 

been studied. [460] 1H-1,2,3-Triazole reacts with bromine to afford 4,5-dibromo-1H-1,2,3-triazole 

(443) in almost quantitative yield (Scheme 146). [461,462] The intermediate monobro- 

N 

N 

OR 1 

N 



motriazole cannot be trapped; apparently it is brominated faster than the starting material. 

The 4,5-dibromo-1H-1,2,3-triazole is also obtained in 90–95% yield by bromodecarboxylation 

of 1,2,3-triazole-4-carboxylic acid. [462] 

Scheme 146 Bromination of 1H-1,2,3-Triazole [461,462] 

N 

H 

N 

N 

+ Br 2 

H2O, 40−45 o C, 1 h N 

97% 

1-Methyl- and 4-methyl-1H-1,2,3-triazole react with bromine to give, respectively, the 4bromo-1-methyl- 

and 5-bromo-4-methyl-1H-1,2,3-triazole in good yields. The isomeric 2methyl-2H-1,2,3-triazole, 

less reactive toward halogenation, reacts with bromine only in 

the presence of a catalyst (iron filings) and yields 4,5-dibromo-2-methyl-2H-1,2,3-triazole; 

the monobrominated product is not obtained. [460] 4-Bromo- and 5-bromo-1H-1,2,3-triazoles 

are obtained indirectly by bromination of a triazole with a removable group at N1, 

as shown in Scheme 147. [463] 

Scheme 147 Bromination of 1H-1,2,3-Triazoles with a Removable Substituent at N1 [463] 

N 

N 

N 

OMe 



MeX 

concd H2SO4 

120 o C, 1 h 

Br 2, Na 2CO 3 

20 o C 

Br 

Br 

N 

N 

H 

Br 

Br 

+ 

NMe 

N 

N 

N 

N 

Br 

N 

443 

N 

X − 

N 

H 

Br 

N 

OMe 

Br 

OMe 

concd H 2SO 4 

120 o C, 1 h 

Br 

N 

N 

N 

Me 

2- and 3-Substituted 1,2,3-triazole 1-oxides 444 and 447 are halogenated selectively in position 

5 in excellent yields (Scheme 148). [456,464,465] Since compounds 445 and 448 are deoxygenated 

almost quantitatively (see Section 13.13.1.4.1.4.4), this is a useful route for the 

synthesis of 1- and 2-substituted 4-halo-1,2,3-triazoles. The chlorination/deoxygenation of 

2-(4-tolyl)-2H-1,2,3-triazole 1-oxides to give 446 is carried out in one step by reaction with 

gaseous hydrogen chloride. [466] 


Scheme 148 Halogenation of 1,2,3-Triazole 1-Oxides [456,464–466] 

R 2 

N 

N+ 

O − 

NR1 NaOCl, Cl2, or Br2 rt 

72−100% 

444 445 

R 1 = Me, Bn, Ph; R 2 = H, Me; X = Cl, Br 

N + 

O − 

R 

N 

N 

1 

R 1 = Ph, OMe 

N+ 

O − 

N 

447 

NR 1 

4-Tol 

NaOCl or Br2 rt 

78−100% 

R 1 = Me, Bn, Ph; X = Cl, Br 

HCl, dioxane 

68% 

X 

X 

Cl 

448 

R 2 

R 1 

NR 1 

N+ 

O − 

N 

N 

N+ 

O − 

NR1 1-Methoxy-2-phenyl-2H-1,2,3-triazol-1-ium tetrafluoroborates 449 react with potassium 

hydrogen fluoride to yield 4-fluoro-2-phenyl-2H-1,2,3-triazoles 450 (Scheme 149). [465] 

N N 

446 

N 

4-Tol 

Scheme 149 Fluorination of 1-Methoxy-2-phenyl-2H- 

1,2,3-triazol-1-ium Tetrafluoroborates [465] 

R 1 

N 

NPh 

N+ 

OMe 

449 

R 1 = H, Me 

BF 4 − 

KHF2, MeCN, rt, 3 d 

61−64% 

F 

R 1 

N 

N NPh 

Mesoionic compound 451 reacts with bromine in acetic acid to give the 5-bromo derivative 

452 (Scheme 150). [362] 

450 

Scheme 150 Bromination of Mesoionic Triazole Compounds [362] 

− 

O 4 -Tol 

N 

N 

N+ 

Me 

451 


13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 513 

Br2, AcOH, rt, 2 h 

68% 

− 

O 4 -Tol 

N 

N 

Br 

N+ 

Me 

452 

C-Lithiated 1,2,3-triazole species are quenched with bromine or iodine to afford the corresponding 

halogenated derivatives in excellent yields. [336] Using hexachloroethane as the 

electrophile, the chlorinated derivatives are obtained. [336,419] 



Reaction of 1H-1,2,3-triazole with iodine monochloride yields 1-iodo-1H-1,2,3-triazole 

(453). Melting a mixture of this compound with 3,5-dimethyl-2H-1,2,4-triazole for 

5–10 minutes gives 4,5-diiodo-1H-1,2,3-triazole (454) (Scheme 151). [467] 1H-1,2,3-Triazole 

gives 1,4,5-tribromo-1H-1,2,3-triazole when treated with an excess of sodium hypobromite. 

[460] 

Scheme 151 Iodination of 1H-1,2,3-Triazole [467] 

N 

H 

N 

N 

ICl, NaOEt 

EtOH, rt 

60−80% 

N 

N 

N 

I 

453 

110 o N 

N 

N 

H 

C, 5−10 min 

75% 

I 

I 

N 

N 

N 

H 

454 

2-Phenyl-2H-1,2,3-triazol-4-ol reacts with bromine to give the corresponding 5-bromo derivative 

in high yield. [474] A method for the selective conversion of 2,4,5-triphenyl-2H- 

1,2,3-triazole into 2-(2-chlorophenyl)-4,5-diphenyl-2H-1,2,3-triazole has been reported. [468] 

4,5-Dibromo-1H-1,2,3-triazole (443); Typical Procedure: [462] 

Br 2 (15 mL, an excess) was added dropwise to a stirred soln of 1H-1,2,3-triazole (15.0 g, 

217 mmol) in H 2O (100 mL) warmed to 40–458C and the resulting soln was stirred for a 

further 1 h. The precipitate was collected by filtration and further Br 2 (10 mL) was added 

to the filtrate, then it was kept at rt overnight, after which a second crop of product had 

precipitated. The combined amounts of product were washed with H 2O (3 ” 50 mL), dried, 

and recrystallized (aq MeOH) to give the product; yield: 47.8 g (97%); mp 192–1948C. 


N-Amination 

4,5-Diphenyl-1H-1,2,3-triazole is aminated by reaction with hydroxylamine-O-sulfonic 

acid yielding the corresponding triazol-1-amines and triazol-2-amines in approximately 

equal amounts (Scheme 152). [3] 

Scheme 152 N-Amination of 4,5-Diphenyl-1H-1,2,3-triazole [3] 

Ph 

Ph 

N 

H 


N-Hydroxylation 

N 

N 



Ph 

Ph 

H2NOSO3H Ph 

N 

N 

N 

NH2 

+ 

Ph 

N 

N 

N 

NH2 

1H-1,2,3-Triazole is oxidized by peracids to 1H-1,2,3-triazol-1-ol (Scheme 153). Best yields 

are obtained with 3-chloroperoxybenzoic acid or hydrogen peroxide plus formic 

acid. [336,469] Yields of 65% are obtained by adding the oxidant (hydrogen peroxide/formic 

acid) portionwise over 30 days followed by continuous extraction of the triazolol with diethyl 

ether over three weeks. [336] The autoxidation of an N-unsubstituted 1,2,3-triazole to 

the corresponding triazol-2-ol has been reported. [342] 


Scheme 153 N-Hydroxylation of 1H-1,2,3-Triazole [336,469] 

N 

H 


Nitration 

N 

N 

A: HCO2H, H2O2, 20 oC, 30 d 

B: MCPBA, EtOAc, rt, 7 d 

A: 65% 

Direct nitration of 1H-1,2,3-triazole to give 4-nitro-1H-1,2,3-triazole is not possible. [470] 

However, this compound is obtained in moderate yield from the reaction of 1-morpholino-2-nitroethene 

and tosyl azide. [471] Attempts to introduce a nitro group in the triazole 

ring of 1-phenyl- and 4-phenyl-1H-1,2,3-triazole are unsuccessful since nitration occurs 

only in the phenyl ring. For example, the reaction of 4-phenyl-1H-1,2,3-triazole with a 

mixture of nitric acid and sulfuric acid at 0 8C gives the 4-(4-nitrophenyl) derivative in 

50% yield; at 908C the 4-(2,4-dinitrophenyl) derivative is obtained in 35% yield. [471] Similarly, 

the 3-phenyl-1,2,3-triazole 1-oxide is nitrated with fuming nitric acid, at room temperature, 

at the para phenyl position. [464] 

The nitration of 2-phenyl-2H-1,2,3-triazole with a mixture of fuming nitric acid and 

concentrated sulfuric acid at 208C gives a mixture of 2-(4-nitrophenyl)-2H-1,2,3-triazole 

(454) and 4-nitro-2-(4-nitrophenyl)-2H-1,2,3-triazole (455) (Scheme 154). [472,473] However, 

if the nitration is carried out with nitric acid in acetic anhydride at 158C, only triazole 

454 is obtained. [473] 

N 

N 

N 

OH 

Scheme 154 Nitration of 2-Phenyl-2H-1,2,3-triazole [472,473] 

N 

N 

N 



A: HNO3, H2SO4 20 oC, 1 h 

B: HNO3, Ac2O 15 oC N 

A: 69%; (454/455) 20:3 

B: 81% (454 only) 

N 

N 

NO 2 

+ 

O 2N 

454 455 

While 2-(2,4,6-trinitrophenyl)-2H-1,2,3-triazole is nitrated at C4 of the triazole ring, the 

isomeric 1-(2,4,6-trinitrophenyl)-1H-1,2,3-triazole is resistant to nitration, even under 

forcing conditions. [471] Nitration of 2-phenyl-2H-1,2,3-triazol-4-ol with nitric acid in glacial 

acetic acid affords 5-nitro-2-phenyl-2H-1,2,3-triazol-4-ol in 60% yield. [474] Under similar 

conditions, 2-phenyl-2H-1,2,3-triazol-4-ol 1-oxide also gives the corresponding 5-nitro derivative. 

[474] Nitration of 4-(2,4,6-trinitroanilino)-1H-1,2,3-triazole with a mixture of nitric 

acid and sulfuric acid, at 20–258C, affords the corresponding 5-nitro derivative in 30% 

yield. [475] 

Nitration of 2-methyl-2H-1,2,3-triazole with a mixture of fuming nitric acid and concentrated 

sulfuric acid, at room temperature, affords 2-methyl-4-nitro-2H-1,2,3-triazole 

(456) in 98% yield (Scheme 155). Under more vigorous conditions (10 h at 1008C) this compound 

is further nitrated to 2-methyl-4,5-dinitro-2H-1,2,3-triazole (457) (97%). [456] Nitration 

of 2-methyl-2H-1,2,3-triazole 1-oxide at room temperature gives a mixture of the 4and 

5-nitro derivatives. At 1008C both compounds are further nitrated to 2-methyl-4,5-dinitro-2H-1,2,3-triazole 

1-oxide. [456] Nitration of 2-phenyl-2H-1,2,3-triazole 1-oxide at room 

temperature gives initially (detectable after 1 min of reaction time) a mixture of 2-(4-nitrophenyl)-2H-1,2,3-triazole 

1-oxide, 5-nitro-2-phenyl-2H-1,2,3-triazole 1-oxide, and 5-nitro-2- 

N 

N 

N 

NO 2 



(4-nitrophenyl)-2H-1,2,3-triazole 1-oxide. The final product, 2-(2,4-dinitrophenyl)-5-nitro- 

2H-1,2,3-triazole 1-oxide, is formed after approximately two hours. [465] 

Scheme 155 Nitration of 2-Methyl-2H-1,2,3-triazole [456] 

N 

N 

NMe 

O2N HNO 3, H 2SO 4 

HNO3, H2SO4 rt, 3 h 

N 

100 

N 

NMe 

oC, 10 h 

98% 97% 

2-Methyl-4-nitro-2H-1,2,3-triazole (456); Typical Procedure: [456] 

2-Methyl-2H-1,2,3-triazole (1 mmol), concd H 2SO 4 (1.02 mL), and fuming HNO 3 (d 1.55; 

0.51 mL) were stirred at rt for 3 h. H 2O (5 mL) was added. Extraction with CH 2Cl 2 (5 mL, 

2 ” 3 mL), drying (K 2CO 3), and removal of the solvent gave the crude product (98%). Recrystallization 

(ligroin) gave crystals; mp 99–1018C. 

13.13.1.4.1.2 Of Metals 


Desilylation 

N-Trimethylsilyl substituents are readily removed under very mild conditions: treatment 

with aqueous methanol, ethanol, or aqueous acid. [172,173,476] Triazole derivatives containing 

both N- and C-trimethylsilyl substituents, such as 458, are selectively desilylated: 

methanol cleaves N-Si bonds (e.g., to give 459), while methanol/hydrochloric acid 

cleaves Si-C bonds as well, both with protonation (Scheme 156). [172] 

456 

Scheme 156 Selective Desilylation of 4-Phenyl-2,5-bis(trimethylsilyl)-2H-1,2,3-triazole [172] 

Ph 

TMS 

N 

N 

N 

TMS 

458 

MeOH 

TMS 

Ph 

459 

N 

H 

N 

N 

MeOH, HCl 

Removal of the trimethylsilyl group from 460 is readily carried out with 10% aqueous potassium 

hydroxide in boiling methanol to give triazoles 461 in almost quantitative yields 

(Scheme 157). [72] Heating 4-substituted 5-(trimethylsilyl)-1H-1,2,3-triazoles with potassium 

fluoride and concentrated hydrochloric acid (2 drops) in refluxing ethanol gives the 4-substituted 

1H-1,2,3-triazoles in high yields. [52] 

Scheme 157 Desilylation of 5-(Alkylsulfanyl)-5-(trimethylsilyl)-1,2,3-triazoles [72] 

TMS 

R 2 S 

460 

N 

N 

N 

R1 FOR PERSONAL USE ONLY 


KOH, H 2O, MeOH, reflux 

~100% 

R 1 = Me, Bu, Cy, CH 2CH CH 2, Bn, Ph; R 2 = Me, Bn 

461 

N 

N 

N 

R1 A. C. TomØ, Section 13.13, Science of Synthesis, 2004 Georg Thieme Verlag KG 

R 2 S 

O 2N 

O2N 

Ph 

N 

457 

N 

N 

H 

NMe 

N 

N

13.13.1.4.1.3 Of Carbon Functionalities 


Decarboxylation 

Most 1,2,3-triazolecarboxylic acids lose carbon dioxide when heated above their melting 

point. This reaction has been known since the 19th century. [477–479] A reasonable number 

of examples of this transformation are found in the literature. [23,105,282,331,430,480] 1H-1,2,3- 

Triazole (464, R 1 = H) is obtained in 93% by heating 1H-1,2,3-triazole-4-carboxylic acid 

(462, R 1 = H) in an oil bath at 220 8C for a few minutes (Scheme 158). [44] 1,5-Disubstituted 

1,2,3-triazole-4-carboxylic acids decarboxylate slowly in boiling benzene [481] or toluene. [482] 

5-Amino-1-benzyl-1H-1,2,3-triazole-4-carboxylic acid is decarboxylated to the corresponding 

triazolamine, in 60–84% yield, by refluxing in N,N-dimethylaniline for 15 minutes. 

[319,428] 5-Amino-1-methyl-1H-1,2,3-triazole-4-carboxylic acid decarboxylates in refluxing 

butan-1-ol (3 h, 65% yield) [393] while 5-amino-1H-1,2,3-triazole-4-carboxylic acid and 5amino-1-cyclohexyl-1H-1,2,3-triazole-4-carboxylic 

acid are decarboxylated to the corresponding 

triazolamines, in 57 and 63% yield, respectively, by heating in 1 M hydrochloric 

acid for one hour. [428] 1H-1,2,3-Triazole-4,5-dicarboxylic acids 463 generally lose two moles 

of carbon dioxide on heating above their melting point (Scheme 158). [105,478] For example, 

1-benzyl-1H-1,2,3-triazole is obtained in essentially quantitative yield by thermal decarboxylation 

of 1-benzyl-1H-1,2,3-triazole-4,5-dicarboxylic acid. [105] However 1-phenyl-1H- 

1,2,3-triazole-4,5-dicarboxylic acid preferentially decarboxylates at the 5-position, giving 

the corresponding 4-carboxylic acid. [479] 1-(1-Naphthyl)-1H-1,2,3-triazole-4,5-dicarboxylic 

acid decarboxylates in refluxing toluene (24 h) to give 1-(1-naphthyl)-1H-1,2,3-triazole in 

90% yield. [106] 

Scheme 158 Decarboxylation of 1H-Triazolecarboxylic Acids [44,105,478] 

HO2C 

462 

N 

N 

N 

R1 N 

N 

HO2C 

N 

R 

463 

1 

HO2C R 1 = H, alkyl, aryl 

210−240 o C 

− CO2 

200 oC − 2CO2 1H-1,2,3-Triazole (464, R 1 = H); Typical Procedure: [44] 

1H-1,2,3-Triazole-4-carboxylic acid (462, R 1 = H; 40 g, 0.35 mol) was heated in an oil bath. 

At a bath temperature of 2208C a vigorous evolution of CO 2 took place. The reaction was 

over in a few min and the 1,2,3-triazole was distilled; yield: 22.8 g (93%); bp 205–2068C/ 

760 Torr. 


Deformylation 



1,4-Diphenyl-1H-1,2,3-triazole-5-carbaldehyde (465) is deformylated in almost quantitative 

yield by treatment with sodium methoxide in refluxing methanol (Scheme 159). Under 

the same conditions, the isomer 1,5-diphenyl-1H-1,2,3-triazole-4-carbaldehyde is re- 

N 

N 

N 

R1 464 



covered quantitatively. [438] Alternatively, quantitative deformylation of 465 is accomplished, 

on treatment with a large excess of hydrazine (100-fold) in refluxing ethanol to 

give 1,4-diphenyl-1H-1,2,3-triazole (466) via hydrazone 467 (Scheme 159). [438] 

Scheme 159 Deformylation of 1,4-Diphenyl-1H-1,2,3-triazole-4-carbaldehyde [438] 

Ph 

N 

N 

OHC 

N 

Ph 

465 

NaOMe, MeOH, reflux, 12 h 

93% 

467 

Ph 

N 

N 

N 

Ph 

H2NNH2, EtOH 

Ph 

reflux, 4 h N H2NNH2 H2NN 

N 100% 

N 

Ph 

1,4-Diphenyl-1H-1,2,3-triazole (466); Typical Procedure: [438] 

A soln of freshly cut Na (0.23 g, 10 mmol) and 1,4-diphenyl-1H-1,2,3-triazole-5-carbaldehyde 

(465; 1.00 g, 4 mmol) in anhyd MeOH (50 mL) was refluxed for 12 h in a vessel provided 

with a dry ice condenser, after which time 25–30 mL of liquid was distilled. On cooling 

the soln remaining in the reaction vessel the product was obtained; yield: 0.83 g (93%). 


Deacylation 

1- and 2-Acyltriazoles are readily hydrolyzed in water or dilute acid; the rate constants for 

hydrolysis and aminolysis of several N-acetyl-1,2,3-triazoles have been measured. [429] 2- 

Benzoyl-4-(benzoyloxy)-2H-1,2,3-triazoles 468 are hydrolyzed selectively to the corresponding 

4-benzoyloxy derivatives 469 (Scheme 160). [433] 

Scheme 160 Selective Hydrolysis of 2-Benzoyl- 

4-(benzoyloxy)-2H-1,2,3-triazoles [433] 

BzO 

R 1 

N 

468 

N 

NBz 



H2O, acetone 


R1 = H 89% 

R1 = Ph 89% 

O-Aryl-1H-1,2,3-triazole-1-carboximidates 470 are hydrolyzed to the corresponding N-unsubstituted 

derivatives 471 by reaction with concentrated hydrochloric acid at room temperature 

(Scheme 161); [49] they are also hydrolyzed in aqueous sodium hydroxide (1008C, 

15 min). 


BzO 

R 1 

469 

N 

H 

N 

N 

466

Scheme 161 Hydrolysis of O-Aryl-1H-1,2,3-triazole- 

1-carboximidates [49] 

Ar 1 O 

R 1 

N 

470 

N 

N 

HN OAr 1 


Dearylation 

HCl, 20 o C, 5 h 

43−91% 

R 1 = H, CO2Et; Ar 1 = Ph, 4-Tol, 4-MeOC6H4, 4-ClC6H4 

N-Aryl substituents that are activated by nitro groups are removed by nucleophilic displacement 

by hydrazine [483] or by potassium hydroxide. [484] Oxidative removal of a 4-aminophenyl 

substituent at N1 by potassium permanganate has also been reported. [485] Oxidation 

of 2,4-bis(2,4-diaminophenyl)-2H-1,2,3-triazole (472) gives 1H-1,2,3-triazole-4-carboxylic 

acid (Scheme 162). [486] 

Ar 1 O 

R 1 

Scheme 162 Oxidative Dearylation of 2,4-Bis(2,4-diaminophenyl)-2H-1,2,3-triazole [486] 

H 2N 

N 

NH 2 

N 

472 

N 

H 2N 


Dealkylation 



NH 2 

471 

N 

H 

KMnO4, NaOH 

100 oC N-Benzyl-1,2,3-triazoles are frequently used as precursors of N-unsubstituted triazoles. 

The benzyl group is removed by reduction with sodium in liquid ammonia, [105,319,432,487] 

catalytic hydrogenation, [90,105,457,488] or chromic acid oxidation. [280] The 4-methoxybenzyl 

group is readily removed by solvolysis in trifluoroacetic acid [303] at 658C or with 47% hydrobromic 

acid [336] at 1208C (Scheme 163). The related 3-bromo-4-methoxybenzyl group 

is removed by treatment with concentrated sulfuric acid at 1208C. [463] Triazoles having a 

2-acetoxybenzyl group in N1 are dealkylated, in low yield, simply by refluxing in piperidine 

or in diethanolamine. [92] 2-Benzyl-2H-1,2,3-triazole and 1-benzyl-1H-1,2,3-triazole 3oxides 

are N-debenzylated by treatment with iodotrimethylsilane, concentrated hydrobromic 

acid, or concentrated sulfuric acid. [489] 

80% 

N 

N 

HO2C 

N 

H 

N 

N 



Scheme 163 Removal of a 4-Methoxybenzyl Group from 

1-(4-Methoxybenzyl)-1H-1,2,3-triazoles [303,336] 

R 1 

R 2 

N 

N 

N 

473 

OMe 

TFA, 60−65 oC, 1−7 h 

or 47% HBr, 120 oC, 3 h 

52−100% 

R 1 = H, CO 2Et; R 2 = H, OH, Cl, CN, Ph, OPh, 4-MeOC 6H 4 

Triazoles having a 2-(trimethylsilyl)ethoxymethyl group at N1 (e.g., 474) are dealkylated 

in good yields under mild conditions, namely by action of dilute aqueous hydrochloric 

acid or by treatment with tetrabutylammonium fluoride in tetrahydrofuran (Scheme 

164). [419] The cleavage of 1-cycloheptatrienyltriazoles 475 is carried out by passing hydrogen 

chloride through a solution of the triazole in diethyl ether (Scheme 165). [109] The 

cleavage is probably facilitated by the stability of the tropylium ion. 

Scheme 164 N-Dealkylation of 1-{[(2-Trimethylsilyl)ethoxy]methyl}-1H-1,2,3-triazoles [419] 

R 1 

N 

N 

N 

O 

R 1 = H, Bz, SPh 

474 

TMS 

2 M HCl, EtOH, reflux, 2 h 

or 1 M TBAF/THF, reflux, 4 h 

71−89% 

Scheme 165 Cleavage of 1-Cycloheptatrienyl-1H-1,2,3-triazoles [109] 

R 1 

R 1 

475 

N 

N 

N 



HCl, EtOH 

rt, 30 min to 1 h 

R 

N 

NH 

N 

1 

R1 + 

R 1 

R 2 

R 1 

R 1 

N 

H 

R 1 

N 

N 

N 

H 

N 

N 

H 

N 

N 

N 

R1 = CO2Me 34% 

R1 = Bz 100% 

1-Benzyloxy-1H-1,2,3-triazoles (e.g., 476) are debenzylated in almost quantitative yields to 

the corresponding 1,2,3-triazol-1-ols by catalytic hydrogenation (Scheme 166). [490] 


+ 

Cl

Scheme 166 Catalytic Hydrogenation of 1-Benzyloxy-1,2,3-triazoles [490] 

R 1 

N 

N 

R 1 = MOM, Ac 

N 

OBn 

476 

H2, Pd/C, 0 o C, 30 min 

93−99% 

1H-1,2,3-Triazoles by Removal of the 4-Methoxybenzyl Group from Triazoles 473; 


A soln of the N-protected triazole (ca. 1 g) in TFA (15–30 mL) was stirred at 60–65 8C for 1– 

7 h; the course of the reaction was monitored by RP–HPLC. The TFA was removed in vacuo 

and H 2O was added to the residue. The product was isolated from the water-insoluble material 

by column chromatography (CHCl 3). In the case of compounds 473 (R 1 =CO 2Et; 

R 2 = OH, CN) the product was obtained by evaporation of the filtered aqueous phase. 

13.13.1.4.1.4 Of Heteroatoms 


Substitution of Halogens by Nucleophiles 

Heating 5-bromo-1-methyl-1H-1,2,3-triazole with ethanolic ammonia for 10 hours at 

1008C in a sealed tube affords the corresponding 5-amino derivative in low yield (22% of 

the hydrochloride). The 4-bromo-1-methyl-1H- and 4-bromo-2-methyl-2H-1,2,3-triazoles 

do not react with ammonia under the same conditions. [44] 5-Bromo-1-methyl-1H-1,2,3-triazole 

also reacts with aniline to yield the corresponding 5-anilino derivative in 54%. [44] The 

displacement of the chloro group in triazoles 477 (R 1 = Bn) [457,491,756] and 477 (R 1 =4- 

MeOC 6H 4CH 2) [303,491,756] by nucleophiles, such as cyanide, aryloxide, and arenethiolate, 

gives good yields of the corresponding derivatives 478 (Scheme 167). Similarly, 1,4-diphenyl-1H-1,2,3-triazole-5-carbonitrile 

is prepared in 75% yield from the reaction of the 

corresponding 5-chloro derivative with sodium cyanide in dimethyl sulfoxide (1408C, 

4 h). [438] 

Scheme 167 Displacement of a Chlorine by Nucleophiles [303,457,491,756] 

EtO 2C 

Cl 

477 

N 

N 

N 

R1 FOR PERSONAL USE ONLY 


Nu − , DMF, 70−80 o C, 18−24 h 

66−82% 

R 1 

N 

N 

OH 

R 1 = Bn, 4-MeOC 6H 4CH 2; Nu = CN, OPh, 4-MeOC 6H 4S, 2-thienylsulfanyl 

Nu 

N 

EtO2C 

Heating 1-aryl-5-chloro-1H-1,2,3-triazoles 479 with hydrazine gives directly 5-(substituted 

amino) 1H-1,2,3-triazol-1,5-diamines 481 (Scheme 168). The 5-hydrazinotriazoles 480 are 

presumably formed first but rearrange spontaneously under the reaction conditions. [492] 

Heating 5-chloro-1-phenyl-1H-1,2,3-triazole with an aqueous solution of sodium hydrosulfide 

at 1008C in a sealed tube produces a bis(1-phenyl-1H-1,2,3-triazol-5-yl) sulfide. [404] Curiously, 

when the same reaction is carried out at room temperature the product is N-phenyl-1,2,3-thiadiazol-5-amine. 

[404] 

478 

N 

N 

N 



Scheme 168 Reaction of 1-Aryl-5-chloro-1H-1,2,3-triazoles with Hydrazine [492] 

R 

N 

N 

Cl 

N 

1 

Ar1 479 

H2NNH2 

60−130 o C, 2−24 h 

R 1 = H, Ph; Ar 1 = Ph, 4-ClC6H4, 4-BrC6H4, 4-pyridyl 

R 

N 

N 

H2NHN N 

1 

Ar1 480 

47−80% 

Ar 1 HN 

Attempted displacement of bromine from 4,5-dibromo-1H-1,2,3-triazole by dimethylamine 

under vigorous conditions (sealed tube, 260 8C, 140 h) yields only the dimethylamine 

salt of the dibromotriazole. [445] The halo group in 4-chloro- and 4-bromo-3-substituted 

1H-1,2,3-triazole 1-oxides is readily displaced by methoxide ions at 208C while the 5chloro 

analogues require heating at 1408C. [464] The displacement of bromine from bromoand 

dibromo-1,3-disubstituted 1,2,3-triazolium salts by methoxide, hydroxide, and sulfide 

has been studied extensively. [449,493–495] The 5-bromo-1,2-disubstituted 1,2,3-triazolium 

fluorosulfonates react with hydroxide or methoxide ions to form 1,2-disubstituted 

1,2,3-triazol-5-ones. [450] Intramolecular displacement of chlorine in 4-acyl-5-chloro-1H- 

1,2,3-triazoles gives access to interesting polycyclic triazole derivatives. [496,497] 


Substitution of Hydroxy Groups by Halogens 

Reaction of the 1H-1,2,3-triazol-5-ol 482 with phosphorus pentachloride in toluene at 

408C gives the 5-chloro derivative 483 in 65% yield (Scheme 169). [303] 

Scheme 169 Reaction of a 1H-1,2,3-Triazol-5-ol with Phosphorus Pentachloride [303] 

EtO2C 

HO 

N 

N 

N 

482 



OMe 

PCl5, toluene 

40 oC, 90 min 

65% 

EtO2C 


Substitution of Diazonium Groups by Nucleophiles 

Displacement of nitrogen from diazonium salts derived from 1,2,3-triazol-4-amines and 

1,2,3-triazol-5-amines is achieved in the same manner as for other aromatic diazonium 

salts. For example, a range of 4-substituted 5-azido-1-phenyl-1H-1,2,3-triazoles 486 is prepared 

in high yield by diazotization of the corresponding 5-amino derivatives 484 followed 

by addition of excess sodium azide to the diazonium ions 485 (Scheme 170). [498,499] 

In a similar process, 5-amino-1H-1,2,3-triazole-4-carboxamide is converted into the 5-iodo 

derivative in 33%. [500] Diazotization of 1-methyl-1H-1,2,3-triazol-4-amine with sodium nitrite/hydrobromic 

acid gives directly the 4-bromo derivative in 41% yield. [44] 


Cl 

N 

N 

N 

483 

OMe 

R 1 

481 

N 

N 

N 

NH 2

Scheme 170 Substitution of Diazonium Groups by Nucleophiles [498,499] 

R 

N 

N 

H2N N 

1 

Ph 

484 

NaNO2, H2O, HCl 

−5 to 0 oC R 1 = Ph, XC6H4, CHO, CONH2, CN, PO(OEt)2, SO2Ph 

R 

N 

+ N 

N2 

N 

1 

Ph 

485 

NaN3, H2O 

−30 or 0 oC R 

N 

N 

N3 N 

1 

Ph 

486 

5-Azido-1-phenyl-1H-1,2,3-triazole-4-carbaldehyde (486,R 1 = CHO); Typical Procedure: [499] 

CAUTION: Sodium azide can explode on heating and is highly toxic. 

An aqueous soln of NaNO 2 (0.76 g, 11 mmol) was added slowly to a well stirred soln of 5amino-1-phenyl-1H-1,2,3-triazole-4-carbaldehyde 

(484, R 1 = CHO; 1.88 g, 10 mmol) in 

concd HCl (120 mL) at –5to08C. Then, a 10-fold excess of NaN 3 in H 2O was added dropwise 

at about –308C. After dilution with H 2O, the mixture was extracted with Et 2O and the 

combined extracts were dried (MgSO 4). The solvent was evaporated and the residue was 

chromatographed (silica gel, CH 2Cl 2). Crystallization (CHCl 3/Et 2O) gave pure compound; 

yield: 62%; mp 978C (dec). 


Deoxygenation 

Triazole N-oxides, such as 487, 489, and 491, are deoxygenated to triazoles (e.g., 488, 490, 

and 492) in almost quantitative yield by refluxing in phosphorus trichloride (Scheme 

171) [456,464,465] or by reduction with zinc in acidic media (Scheme 172). [466,501] 2-Aryl-2H- 

1,2,3-triazole 1-oxides are converted directly into 2-aryl-4-chloro-2H-1,2,3-triazoles by reaction 

with gaseous hydrogen chloride [466] or by heating with concentrated hydrochloric 

acid in a sealed tube. [465] 

Scheme 171 Deoxygenation of Triazole N-Oxides 

with Phosphorus Trichloride [456,464,465] 

X 

X = Cl, Br 

X 

N 

NR 

N 

1 

O − 

+ 

487 

X = Cl, Br 

NR 1 

N 

N 

O − 

+ 

489 

PCl3 reflux, 1 h 

83−99% 



PCl3 reflux, 1 h 

90−97% 

X 

X 

N 

488 

N 

N 

490 

NR 1 

NR 1 

N 



Scheme 172 Reductive Deoxygenation of 2H-1,2,3-Triazole 1-Oxides [466,501] 

N 

NAr 

N 

1 

Zn, AcOH 


O 

80−95% 

− 

HO HO 

+ 

491 

Ar 1 = Ph, 3-ClC6H4, 4-ClC6H4, 4-EtO2CC6H4 


Dehalogenation 

1-Substituted 5-bromo-1H-1,2,3-triazole 3-oxides 493 are debrominated in virtually quantitative 

yield when heated at 100 8C for 1 hour with sodium sulfite (Scheme 173). [464] 

Scheme 173 Debromination of 5-Bromo- 

1H-1,2,3-triazole 3-Oxides [464] 

Br 

493 

NR 1 

N+ 

O − 

N 

R 1 = Me, Ph, Bn 

Na2SO3, H2O reflux, 1 h 

97−100% 

1-Methyl-1H-1,2,3-triazole 3-Oxide (494,R 1 = Me); Typical Procedure: [464] 

5-Bromo-1-methyl-1H-1,2,3-triazole 3-oxide (493, R 1 = Me; 0.56 g, 3.1 mmol), Na 2SO 3 

(1.19 g, 9.4 mmol), and H 2O (5.6 mL) were refluxed for 1 h. The H 2O was removed and the 

residue was extracted with boiling MeCN (3 ” 10 mL). Removal of the MeCN afforded 494 

(R 1 = Me); yield: ~100%; mp 123–1248C. 

13.13.1.4.2 Addition Reactions 

13.13.1.4.2.1 Method 1: 

Conversion into N-Oxides 



1-Substituted 1,2,3-triazole 3-oxides 496 are prepared by oxidation of 1-substituted triazoles 

495 with 3-chloroperoxybenzoic acid (Scheme 174). The yields are good but decrease 

when electron-withdrawing substituents are present, particularly if situated adjacent 

to the nitrogen to be oxidized. Phenyl groups at this position also lead to decreased 

yields. The low yield in these cases is not a serious drawback since unchanged starting 

material is readily recovered. [464,489] Oxidation of 1-(arylmethyl)-1H-1,2,3-triazoles with 

peracetic acid does not give the expected N-oxides but 1-arylmethyloxy derivatives. [91] Attempts 

to obtain 2-phenyl-2H-1,2,3-triazole 1-oxide by oxidation of 2-phenyl-2H-1,2,3-triazole 

with a range of oxygen donators are unsuccessful. [465] 

N+ 

O − 

N 


494 

N 

N 

492 

NR 1 

NAr 1

Scheme 174 Preparation of 1-Substituted 1H-1,2,3-Triazole 3-Oxides [464,489] 

R 3 

R 2 

N N 

495 

NR 1 

MCPBA, EtOAc 

rt, 5 d 

6−85% 

N+ 

O − 

N 

496 

NR 1 

R 1 = Me, Ph, Bn, 4-MeOC6H4CH2; R 2 = H, Me, Cl; R 3 = H, Me, Ph, Cl, Br, OMe 

1-Substituted 1H-1,2,3-Triazole 3-Oxides 496; General Procedure: [464] 

The 1-substituted triazole 495 (1.0 g) was dissolved with heating in EtOAc (1 mL). After 

cooling to 208C, MCPBA (1.2 molar equiv) was added. The mixture was stirred for 120 h, 

diluted with CH 2Cl 2 (10 mL) and washed with aq 1 M NaOH (8 mL). The aqueous soln was 

extracted with CH 2Cl 2 (2 ” 8 mL). The combined organic phase was dried, the CH 2Cl 2 was 

removed, EtOAc (10 mL) was added, and the suspension was filtered through silica gel 

(2 g). Washing with further EtOAc (2 ” 10 mL) and removal of the solvent gave unchanged 

starting material. Subsequent extraction of the silica gel (EtOAc/MeOH 1:1; 5 ” 10 mL) and 

removal of the solvents gave the crude product. 

13.13.1.4.3 Rearrangement of Substituents 

Appropriately substituted 1,2,3-triazoles may undergo thermal, photochemical, acid-catalyzed, 

or base-catalyzed isomerizations. As shown in many of the previous methods, frequently 

these isomerizations occur spontaneously during the synthesis of the triazole 

ring. Isomerizations are also observed during reactions involving substitution or modification 

of substituents on a 1,2,3-triazole (see, for example, Scheme 168). The most important 

isomerization reaction in 1,2,3-triazoles is the Dimroth rearrangement, illustrated in 

Scheme 175 for 1H-1,2,3-triazol-5-amines. This type of isomerization is also observed in 

other heterocyclic systems. The interconversion of compounds 497 and 498 is mainly 

controlled by the nature of R 1 , but it is also influenced by the basicity of the solvent 

used. Isomers 498 are favored when R 1 is an aryl group, a large rigid group, or an electron-withdrawing 

group. Isomers 497 are favored when R 1 is an alkyl group. [21] 

Scheme 175 Dimroth Rearrangement in 1H-1,2,3-Triazol-5-amines 

N 

N 

H2N N 

R1 R2 FOR PERSONAL USE ONLY 


R 2 N 2 

H 2N NR 1 

R 3 

R 2 

R 2 N 2 

R 1 HN NH 

R 1 HN 

497 498 

This type of isomerization is also observed in 1-substituted 4-(iminomethyl)-1H-1,2,3-triazoles 

(Scheme 176). For example, imines 500 and 501 (R 1 = H) are interconvertible when 

heated in dimethyl sulfoxide at 808C. The equilibrium position depends on the electronic 

properties of the R 2 substituent, favoring 501 when R 2 is alkyl, benzyl, and 4-methoxyphenyl, 

and 500 when R 2 is 4-chlorophenyl and 4-nitrophenyl. [502] An interesting application 

of this isomerization is the synthesis of 1-alkyl-1H-1,2,3-triazole-4-carbaldehydes 502 

from 1-phenyl-1H-1,2,3-triazole-4-carbaldehyde (499, R 1 = H). [502] This type of isomerization 

is also applied to the conversion of 1-phenyl-1H-1,2,3-triazole-4-carbaldehydes 499 

(R 1 = Me, Ph) into 4-oxo-substituted 1-alkyl-1H-1,2,3-triazoles 502 (R 1 = Me, Ph). [503] 

R 2 

N 

H 

N 

N 



Scheme 176 Isomerization of 1-Substituted 4-(Iminomethyl)-1H-1,2,3-triazoles [502,503] 

R 2 N 

R 1 

O 

R 1 

H 

N 

N 

N 

Ph 

80−130 o C R 2 N 

H 

500 501 

H 

499 

R 2 NH 2 

N 

N 

N 

Ph 

N 2 

R 1 NPh 

R 1 = H, Me, Ph; R 2 = Me, Et, iPr, t-Bu, Bn, 4-MeOC 6H 4, 4-ClC 6H 4, 4-O 2NC 6H 4 

PhN 

O 

R 1 

R 1 

N 

N 

N 

R2 H2O 

HCO2H or silica gel 

N 

N 

N 

R 

502 

2 

Despite the failure of hydrazone and oxime derivatives 500 (R 1 =H;R 2 =NH 2, NHPh, OH) 

to isomerize to 501, [502] phenylhydrazone 504 (prepared from aldehyde 503) are converted 

into derivative 505 (Scheme 177). Similarly, phenylhydrazone 507 (R 1 = NHPh) and oxime 

507 (R 1 = OH) are converted into amides 508. [504] Triazole 506 [and 1-benzyl, 1-(4-chlorobenzyl), 

and 1-(4-methoxybenzyl) analogues] are converted into carboxamides of type 

508 (R 1 = Me, Et) by reaction with methylamine or ethylamine followed by rearrangement 

of the resulting imines on heating above their melting points. [302] 

Scheme 177 Isomerization of 1-Phenyl-1H-1,2,3-triazoles Bearing a Hydrazone or 

Oxime Function at the 4-Position [504] 

O 

H 2N 

O 

Cl 

H 

N 

N 

N 

Ph 

PhNHNH2 EtOH 

86% 

PhHN 

N 

H 2N 

N 

N 

N 

Ph 

503 504 

505 

H 

N 

N 

N 

Ph 



R 1 NH 2 

R1 = NHPh 53% 

R1 = OH 56% 

R 1 N 

Cl 

H 

H 

N 

N 

N 

Ph 

CHCl3 reflux, 2 d 

52% 

DMSO 

70 oC, 2−3 d 

R1 = NHPh 69% 

R1 = OH 59% 

506 507 

508 

PhN 

O 

NH 2 

N 

N 

N 

NHPh 

Another interesting type of isomerization in 1,2,3-triazoles corresponds to the migration 

of alkyl groups between nitrogens. This is not a very common transformation, but some 

examples have been reported. [505,506,757] Triazole 509, for example, isomerizes to 510 when 

treated with boron trifluoride (Scheme 178). [506,757] 


NHPh 

N 

N 

N 

R1

Scheme 178 Isomerization of 1-Alkyl-1H-1,2,3-triazoles to 

2-Alkyl-2H-1,2,3-triazoles [506,757] 

MeO2C 

MeO 2C 

509 

N 

N 

BOM 

N 

BF3 OEt2, Et2O 20 oC, 36 h 

82% 

MeO2C 

MeO 2C 

Migration of alkyl groups is also observed in 1,3-disubstituted 1,2,3-triazolium-4-thiolates 

511. Heating these compounds in an organic solvent at 1808C results in transfer of alkyl 

groups with the formation of (alkylsulfanyl)-1,2,3-triazoles (Scheme 179). [495,507] When R 1 

and R 2 are different alkyl groups, four compounds 512–515 are obtained. The formation 

of compounds 514 and 515 clearly indicates that this is an intermolecular reaction. If 511 

has only one alkyl group, only one product is formed. For example, 1-methyl-3-phenyl- 

1,2,3-triazolium-4-thiolate (511,R 1 = Me; R 2 = Ph) is quantitatively converted into 5-(methylsulfanyl)-1-phenyl-1H-1,2,3-triazole 

(513, R 1 = Me; R 2 = Ph). [495] 

N 

510 

N 

N 

BOM 

Scheme 179 Migration of Alkyl Groups in 1,3-Disubstituted 1,2,3-Triazolium- 

4-thiolates [495,507] 

− S 

NR2 N 

N 

R1 + 

511 

180 o C 



R 2 S 

N 

N 

N 

R1 512 

1-Ethyl-1H-1,2,3-triazole-4-carbaldehyde (502,R 1 =H;R 2 = Et); Typical Procedure: [502] 

To a soln of 499 (R 1 = H; 1 g, 5.8 mmol) in MeOH (20 mL), was added 70% aq EtNH 2 (0.57 mL, 

1.5 equiv), and the whole was stirred overnight at rt. The soln was concentrated and the 

resulting precipitate 500 (R 1 =H;R 2 = Et) was collected by filtration and dried; yield: 0.6 g 

(52%); mp 358C. This compound (0.6 g, 3 mmol) was heated overnight in DMSO (2 mL) at 

808C. The soln was poured into ice water and the precipitate 501 (R 1 =H;R 2 = Et) was collected; 

yield: 0.5 g (83%); mp 838C. Compound 501 (0.5 g, 2.5 mmol) was dissolved in a 

mixture of H 2O/MeOH (1:1; 20 mL) containing 10% of HCO 2H and the soln was heated overnight 

at 808C. After addition of H 2O (20 mL), the soln was extracted with CHCl 3, and the 

extracts were washed with H 2O and dried (MgSO 4). The solvent was removed and the resulting 

oil (0.3 g) was chromatographed (silica gel, CH 2Cl 2/Et 2O 9:1) to give 502 (R 1 =H; 

R 2 = Et); yield: 0.15 g (48%). 

+ 

R 1 S 

N 


NR 2 

N 

+ 

R 1 S 

N 

N 

N 

R1 514 

+ 

R 2 S 

N 

515 

NR 2 

N 




Monocyclic 2-Substituted 1,2,3-Triazoles 





From N-Aminophthalimide and Conjugated Azoalkenes 

2-(Phenylazo)propene (517, R 1 = Me; R 2 = H) and 1-(phenylazo)cyclopentene [517, 

R 1 ,R 2 = (CH 2) 3] react with N-aminophthalimide (516), in the presence of lead(IV) acetate, 

to give 2-phenyl-2H-1,2,3-triazoles 520 in moderate yields (Scheme 180). [508] A probable 

mechanism for this reaction involves the initial formation of the azimine intermediate 

518, 1,5-electrocyclization to the 2,5-dihydro-1H-triazole 519, and, finally, 1,2-elimination 

of phthalimide. 

Scheme 180 2H-1,2,3-Triazoles from N-Aminophthalimide and Conjugated Azoalkenes [508] 

O 

N 

NH2 + 

Ph 

N 

N 

O 

R1 516 517 

O Ph 

+ 

N N 

N 

O 

N 

− 

R1 518 





H 

R 2 

H 

R 2 

Pb(OAc) 4 

K 2CO 3, CH 2Cl 2 

−10 o C, 40 min 

R 2 

520 

R 1 

N 

N 

R 

N 

N 

NPh 

1 

O 

R N 2 

NPh 

+ 

R1 = Me; R2 = H 41% 

R1 ,R2 = (CH2) 3 70% 


Addition of Azidotrimethylsilane and Azidotributylstannane to Alkynes 

Azidotrimethylsilane and azidotributylstannane undergo addition to alkynes to give 2- 

(trimethylsilyl)- or 2-(tributylstannyl)-2H-1,2,3-triazoles, resulting from the isomerization 

of the initially formed 1-substituted derivatives These reactions are discussed in Section 

13.13.1.1.3.1.1.6 (Schemes 59 and 60). A palladium-catalyzed three-component coupling 

reaction of azidotrimethylsilane, alkynes, and allyl methyl carbonate has been described. 

[509] It affords selectively 2-allyl-2H-1,2,3-triazoles 521 in low to moderate yields 

(Scheme 181). A ð-allylpalladium azide complex, which undergoes the 1,3-dipolar cycloaddition 

with the alkyne, has been proposed as a key intermediate in this reaction. 


519 

O 

O 

O 

NH

Scheme 181 2-Allyl-2H-1,2,3-triazoles from Azidotrimethylsilane, Alkynes, and 

Allyl Methyl Carbonate [509] 

TMSN 3 + 

R 1 

R 2 

+ 

OCO 2Me 

R1 = H, Et, t-Bu, cyclohex-1-enyl; R2 = Ac 

R1 = H, (CH2)5Me, CO2Me; R2 = CO2Me 

R1 = (CH2)4Me; R2 = CHO 

R1 = Ph; R2 = CN, CHO, Ac, CO2Me, PO(OEt)2, SO2Ph, NEt2 

2.5 mol% Pd2(dba) 3, CHCl3 10 mol% dppp, EtOAc 

100 oC, 2−24 h 

15−66% 


Addition of Acyl or Alkoxycarbonyl Azides to Æ-Acylphosphorus Ylides 

Acyl and alkoxycarbonyl azides undergo addition to Æ-acylphosphorus ylides 522 to yield 

2-substituted 2H-1,2,3-triazoles, which result from the spontaneous isomerization of the 

initially formed 1-substituted triazoles (Scheme 182). For the discussion of this type of reaction 

and examples see Section 13.13.1.1.3.1.2.5 (Scheme 76). 

Scheme 182 2H-1,2,3-Triazoles from Acyl or Alkoxycarbonyl Azides and 

Æ-Acylphosphorus Ylides [229,231] 

R 1 N 3 + 

R 1 = acyl, CO2Et 

R3 + 

PPh3 R 2 O − 

522 

− Ph 3PO 



R 

N 

N 

N 

3 

R2 R1 13.13.2.1.3.1.1 Method 1: 

Cyclization of Æ-Hydroxyimino Hydrazones 

The intramolecular elimination of water from Æ-hydroxyimino hydrazones is a general 

method for the synthesis of 2H-1,2,3-triazoles (Scheme 183). Generally acetic anhydride 

[510–514] is the reagent of choice, but other reagents are also used, namely phosphorus 

pentachloride, [515] urea, [516] or bromine. [513] As an example, 2H-1,2,3-triazole 524 

(R 1 =R 2 = Ph; R 3 = 4-O 2NC 6H 4) is obtained in 57% yield by refluxing the corresponding hydroxyimino 

hydrazone 523 with acetic anhydride for 40 minutes. [289] 

Scheme 183 Cyclization of Æ-Hydroxyimino Hydrazones [289] 

R 2 N 

R 1 NOH 

523 

NHR 3 


13.13.2 Monocyclic 2-Substituted 1,2,3-Triazoles 529 

Ac2O, heat or PCl5, heat 

or urea, heat or Br2, heat 

This method has been applied to the synthesis of a range of 2,2¢-diaryl-5,5¢-dimethyl-4,4¢bi-2H-1,2,3-triazoles 

526 from Æ-hydroxyimino hydrazones 525 (Scheme 184). [517] 

R 1 

R 2 

N 

524 

N 

NR 3 

R 2 

R 1 

R 2 

N 

N 

N 

521 

R 3 

N 

N 

NR 1 



Scheme 184 Synthesis of 4,4¢-Bi-2H-1,2,3-triazoles [517] 

N 

PhN 

N 

N 

NOH 

525 

N 

H 

X = H, 2-Cl, 3-Cl, 4-Cl, 4-NO2, 2-Br, 3-Br, 4-Br 

X 

PCl 5, CHCl 3 

rt, 1 h 

55−68% 

N 

PhN 

N 

Another interesting example of the application of this method is the synthesis of 2-aryl- 

2H-1,2,3-triazoles starting from dehydro-ascorbic acid 527 (Scheme 185). On boiling with 

acetic anhydride, the dehydro-ascorbic acid 3-(hydroxyimino)-2-arylhydrazones 528 are 

converted into the acetylated triazole derivatives 529, whereas the unacetylated triazole 

derivatives 530 are obtained upon reaction with bromine in water. [512] Treatment of triazole 

529 (Ar 1 = Ph) with ammonia gives the 2H-1,2,3-triazole-4-carboxamide 531 in quantitative 

yield. [512] Compound 529 (Ar 1 = 3-BrC 6H 4) is obtained in 85% yield by treating the 

corresponding 3-(hydroxyimino)-2-arylhydrazone 528 with acetic anhydride in pyridine 

overnight at room temperature. [514] 

N 

N 

N 

Scheme 185 Cyclization of Dehydro-ascorbic Acid 3-(Hydroxyimino)- 

2-arylhydrazones [512,514] 

HO 

HO 

O 

527 

O 

O 

O 

Ac2O reflux, 1 h 

Br2, H2O rt, 3 h 

2 steps 

AcO 

AcO 

Ar 1 = Ph, 4-ClC 6H 4, 3-BrC 6H 4, 4-Tol, 4-MeOC 6H 4 



HO 

HO 

HO 

O 

HO 

HON 

O 

528 

O 

Ar 1 HN 

N 

O 

526 

N N 

N 

Ar1 Ar 

N N 

N 

Ph 

529 531 

1 = Ph 

100% 

N N 

N 

Ar1 530 

O 

O 

NH3, MeOH 

rt, overnight 

HO 

HO 

X 

OH 

CONH 2 

If the Æ-hydroxyimino hydrazone is N-unsubstituted, dehydration with acetic anhydride 

gives a 2-acetyl-2H-1,2,3-triazole, which is readily hydrolyzed to the corresponding N-unsubstituted 

triazole (Scheme 186) (see also Section 13.13.1.1.4.1.3). [510] 


Scheme 186 Cyclization of N-Unsubstituted Æ-Hydroxyimino Hydrazones [510] 

R 1 N 

R 2 NOH 

R 

N 

1 

R 

NH2 Ac2O N 

1 

H2O 

R 2 

Dehydration of amide derivatives 532 in refluxing thionyl chloride gives 2-phenyl-2H- 

1,2,3-triazole-4-carboxamides 533 in good yields (Scheme 187). [518] 

N 

Scheme 187 Cyclization of Æ-Hydroxyimino Hydrazones with Thionyl Chloride [518] 

Ar 1 HN 

Ar 2 N 

O 

532 

NOH 

NHPh 



SOCl2 

reflux, 3 h 

60−80% 

NAc 

Ar 1 HN 

Ar 2 

O 

533 

N 

N 

NPh 

Ar 1 = Ph, 4-Tol, 2-MeOC6H4, 2-ClC6H4, 4-ClC6H4, 2,4-Me2C6H3; Ar 2 = Ph, 4-ClC6H4, 4-O2NC6H4 

In acetic acid, the nitro(arylhydrazono)acetaldehyde oximes 534 are converted into the 2aryl-2H-1,2,3-triazol-4-ol 

1-oxides 536, probably via the intermediate 535 (Scheme 

188). [466,501] 

Scheme 188 Cyclization of Nitro(arylhydrazono)acetaldehyde Oximes [466,501] 

O2N N 

N 

NOH 

NAr 

N 

1 

NHAr1 AcOH 

rt, 12 h 

50−62% 

O 

534 536 

− 

O N 

NAr1 HO 

N + 

O 

535 

Ar 1 = Ph, 4-Tol, 4-MeOC 6H 4, 2-ClC 6H 4, 3-ClC 6H 4, 4-ClC 6H 4, 4-EtO 2CC 6H 4 

Oxidation of (arylhydrazono)acetaldehyde oximes 537 with copper(II) sulfate [465,466,519] in 

aqueous pyridine, with mercury(II) oxide, [520] or with N-iodosuccinimide [521] leads to the 

formation of 2-aryl-2H-1,2,3-triazole 1-oxides 538 (Scheme 189). 

Scheme 189 Oxidation of (Arylhydrazono)acetaldehyde Oximes with Copper(II) Sulfate [519] 

R 

NOH 

1 N 

N 

NAr 

N 

1 

NHAr1 CuSO4, py, H2O reflux, 30 min or rt, overnight 

O 

537 538 

− 

R 

+ 

1 

R1 = H; Ar1 = Ph 80% 

R1 = Me; Ar1 = Ph 90% 

R1 = Me; Ar1 = 2,6-Cl2-4-F3CC6H2 90% 

Cyclization of the oxomalonaldehyde derivatives 540 and 541 [produced from bis(oxyimino) 

hydrazone 539] with cesium carbonate in tetrahydrofuran affords 2-aryl-2H-1,2,3-triazoles 

542 and 543 in moderate to excellent yields (Scheme 190). [519,522,523] These triazoles 

are hydrolyzed to the 4-formyl derivative or converted into a range of other interesting 4substituted 

2-aryltriazoles. 

R 2 

N 

H 

N 



Scheme 190 Oxidation of Æ-Acetyloxyimino Arylhydrazones with 

Cesium Carbonate [519,522,523] 

H 

NOH 

H 

539 

N NHAr 1 

NOH 

Ac2O, rt 

30 min 

H 

Ac2O, heat 

5−10 min H 

NOAc 

N 

1 NHAr 

H 

540 

NOH 

NOAc 

N 

NHAr1 H 

NOAc 

541 

Cs2CO3 THF 

rt, 1 h 

26−82% 

Cs 2CO 3 

THF, rt 

72−95% 

HON 

AcON 

Ar 1 = Ph, 2-FC6H4, 2-ClC6H4, 4-ClC6H4, 2-BrC6H4, 2,6-Cl2C6H3, 3,4-Cl2C6H3, 2,4,6-Cl3C6H2, 2,6-Cl2-4-F3CC6H2 

Oxidation of both hydroxyimino arylhydrazones 544 and 545 with lead(IV) acetate yields 

2-aryl-2H-1,2,3-triazole 1-oxides 546 in moderate to excellent yields (Scheme 191). [524] 

Scheme 191 Oxidation of Æ-Hydroxyimino Arylhydrazones with Lead(IV) Acetate [524] 

R 2 

N 

R 1 

NHAr 1 

544 

NOH 

O 



Ar1NHNH2, MeOH, H2O AcOH (cat.), 0 oC, 20−30 min 

Pb(OAc)4 

CH2Cl2, rt 

45−72% 

R 1 = R 2 = Me, Ph; Ar 1 = Ph, 4-Tol, 4-ClC6H4, 4-O2NC6H4 


Cyclization of 1,2-Diketone Bis(arylhydrazones) 

R 2 

N 

R 1 

23−98% 

NHAr 1 

546 

NOH 

N 

545 

NHAr 1 

Pb(OAc) 4 

CH 2Cl 2, rt 

N 

NAr 

N 

1 

O − 

R 

+ 

2 

R1 O 

The oxidation of 1,2-diketone bis(arylhydrazones) to 2-aryl-2H-1,2,3-triazoles (Scheme 

192) is a very general reaction and it has been used extensively for the preparation of sugar 

“osotriazoles” from osazones. This subject has been reviewed. [525] The nitrogen eliminated 

is that attached to the 1-position for sugar osazones; a possible mechanism for the 

reaction is shown in Scheme 192. [3] Many oxidizing agents have been used, especially copper 

sulfate and other copper(II) salts, [526–529] and nitrous acid. [530,531] As an example, oxidation 

of the phenyl-D-glucosazone [547, R 1 =H;R 2 = (CHOH) 3CH 2OH] with copper(II) sulfate 

gives the corresponding triazole 550 in 59% yield. [526–528] In a similar way, glyoxal is converted 

into 2-phenyl-2H-1,2,3-triazole in 59% overall yield via osazone 547 (R 1 =R 2 = H). [472] 

Oxidation of the tetra-O-acetylphenylosazones from D-glucose, D-galactose, and L-sorbose 


542 

543 

N 

N 

N 

N 

NAr 1 

NAr 1

with nitrous acid gives the corresponding 2-phenyl-2H-1,2,3-triazole tetraacetates in approximately 

80% yield. [530] 

Scheme 192 Oxidation of 1,2-Diketone Bis(phenylhydrazones) [525] 

R 

N 

2 N 

NHPh oxidant 

R 

N 

NPh 

N+ 

NPh 

547 549 

2 

R2 N 

NPh 

N NPh 

R 

548 

1 

NHPh 

R1 R1 − 

R 1 = R 2 = H, alkyl, aryl 



R 1 

R 2 

N 

NPh 

N 

550 

This type of reaction can be extended to 1,2-diketone bis(phenylhydrazones) 547 

(R 1 =R 2 = alkyl or aryl). Oxidation of these compounds with potassium dichromate in acetic 

acid, [532] nickel peroxide, [533] manganese(IV) oxide, [534] or with other oxidants yields a 

variety of products; the products formed depend upon the reaction conditions. In some 

cases, 2-substituted 2H-1,2,3-triazoles are obtained in low to moderate yields. As indicated 

in Scheme 192, a probable mechanism for the formation of triazoles involves the oxidation 

of the bis(phenylhydrazones) to bis(phenylazo)ethene derivatives 548, which can exist 

in the mesoionic form 549. [535,536] Loss of phenylnitrene from this species yields triazoles 

550. The bis(phenylazo)ethene derivatives 548 are isolated in high yields, [533] and 

can be converted into 2-phenyl-2H-1,2,3-triazoles by acid treatment [537] or by irradiation 

with UV light. [538] Mesoionic species 549 have been trapped by dipolarophiles in 1,3-dipolar 

cycloadditions to yield new interesting 1,2,3-triazole derivatives. [535,539,540] N-Benzoyl 

analogues of mesoionic species 549 are isolated in good yields as stable crystalline compounds. 

[541] 1,2-Bis(arylazo)cycloalkenes (548,R 1 ,R 2 = ring with six or more carbons) when 

heated or treated with acid undergo intramolecular rearrangements, via 1,2,3-triazolium 

imide 1,3-dipoles of type 549, to yield 2-aryl-2H-1,2,3-triazoles bearing a 2-aminoaryl 

group in the cycloalkene ring. [542] 

1,2-Diketone bis(hydrazones) also cyclize to 1,2,3-triazoles solely by thermolysis: 

heating biacetyl bis(hydrazone) at 1708C gives 4,5-dimethyl-1H-1,2,3-triazole (25%) and 

heating biacetyl bis(phenylhydrazone) at 300 8C yields 2-phenyl-4,5-dimethyl-2H-1,2,3-triazole 

in 51% yield. [543] 

Oxidation of phenylhydrazones of aromatic aldehydes 551 with manganese(IV) oxide 

in refluxing benzene also affords triazoles 553 and other isolated products (Scheme 

193). [534] The dimerization of the phenylhydrazones to 552 appears to be the key step in 

this transformation. Triazoles 553 are obtained in low to moderate yields. The oxidation 

of arylhydrazones derived from 2-acetylpyridine and 2-benzoylpyridine with lead(IV) acetate 

leads to the formation of fused 1,2,3-triazolium systems. [544] 



Scheme 193 Oxidation of Phenylhydrazones of Aromatic Aldehydes [534] 

Ar 1 

N NHPh 

H 

551 

Ar 1 

Ar 1 

N 

N 

552 

MnO2, benzene 


7−44% 

NPh 

NPh 


Cyclization of Æ-Imino Hydrazones 

Ar 1 

Ar 1 

Ar 1 

N NPh 

H 

N 

N 

NHPh 

NHPh 

Ar 1 

Ar 1 

Ar 1 

N NPh 

H 

N 

N 

NPh 

553 Ar1 = Ph 44% 

Ar1 = 4-Tol 15% 

Ar1 = 4-MeOC6H4 7% 

The oxidative cyclization of 1,2-diketone imine hydrazones 554 with ammoniacal copper 

sulfate yields 2H-1,2,3-triazoles 555. [545] N-Substituted imines 556 give 1,2-disubstituted 

triazolium salts 557 when N-bromosuccinimide is used as the oxidant (Scheme 194). [546] 

Scheme 194 Oxidative Cyclization of Æ-Imino Hydrazones [545,546] 

R 2 

R 1 

N 

554 

NH 

NHR 3 

CuSO 4, NH 3 

R 1 = R 3 = alkyl, aryl; R 2 = Ac, aroyl, CO 2Et, CN 

R 2 

R 1 

N 

NPh 

556 

NHAr 1 

R 1 = alkyl, aryl; R 2 = alkyl, CN 

NBS 

R 1 

R 2 

N 

555 

N 

NR 3 

N 

NAr 

N 

1 

R2 R1 Ph + 

A related reaction is the oxidative cyclization of (carbamimidoyl)(phenylazo)acetamide 

558 (X = O) and (phenylazo)malonimidamide 558 (X = NH) to triazoles 559 (Scheme 

195). [547] 

Scheme 195 Oxidative Cyclization of (Carbamimidoyl)(phenylazo)acetamide and 

(Phenylazo)malonimidamide [547] 

H2N 

X 

N 

HN NH 2 

558 

NPh 



557 

Br − 

CuSO4, NH4OH, rt, 24 h, then 100 oC, 3 h 

or CuSO4, py, 100 oC, 18 h 

X = O 64% 

X = NH 24% 


H2N 

H 2N 

X 

559 

N 

N 

NPh


Cyclization of 1,2-Bis(N-alkoxy-N-nitrosoamines) 

1,2-Bis(N-alkoxy-N-nitrosoamines) 560 are smoothly converted into 1-alkoxy-4,5-dihydro- 

1H-1,2,3-triazole 2-oxides 561, in high yields, under reflux in methanol. Reaction of these 

compounds with sodium methoxide affords 4H-1,2,3-triazole 2-oxides 562 or 2H-1,2,3-triazol-2-ols 

563 (Scheme 196). [548,549] 

Scheme 196 Cyclization of 1,2-Bis(N-alkoxy-N-nitrosoamines) [548,549] 

R 1 

R 2 

R 3 

R 4 

OR 5 

N 

560 

NO 

N NO 

OR 5 

MeOH, reflux 

0.5−5.5 h 

78−98% 


R 3 

R 2 

R 4 

R 1 

N 

N 

N 

O − 

+ 

561 

OR 5 

NaOMe 

MeOH 

rt, 48 h 

R1 = H 

13−35% 

NaOMe 

MeOH 

rt, 3 h 

R1 = R4 = H 

65−86% 

R 3 

R 4 

R 2 

N 

N 

N 

O − 

+ 

562 

R 

N 

N 

NOH 

563 

2 

R3 Thermal or basic treatment of arylhydrazones 565 of 3-acylisoxazoles 564 affords 4-acyl- 

2-aryl-2H-1,2,3-triazoles 566 (Scheme 197). For example, hydrazone 565 (R 1 =R 2 = Me; 

Ar 1 = 2-ClC 6H 4) is converted into the corresponding triazole 566 by warming it to fusion 

in a test tube plunged in a silicone oil bath at ca. 2408C. [517] Hydrazone 565 (R 1 =R 2 = Ph; 

Ar 1 = 4-O 2NC 6H 4) is converted quantitatively into the corresponding triazole 566 when it 

is melted in the presence of copper powder or by treatment with ammonia. [550] Copper(II) 

acetate can also be used as catalyst for this transformation. [551] The kinetics of the transformation 

of hydrazones 565 into triazoles 566 catalyzed by amines [552] or in the presence 

of borate buffers, [553] has been studied. 

Scheme 197 Synthesis of 2-Aryl-2H-1,2,3-triazoles from Arylhydrazones of 

3-Acylisoxazoles [517,550] 

R 1 

564 

O 

N 

O 

R 2 



Ar 1 NHNH2 

R 1 

R 2 

N 

O 

N 

NHAr 1 

4-(Arylazo)isoxazol-5-ones 568 (produced from 4-arylisoxazol-5-ones 567) are converted 

into 2-aryl-2H-1,2,3-triazoles 569 when refluxed in propan-2-ol, in the presence of a tertiary 

amine, or in 1-(dimethylamino)propan-2-ol (Scheme 198). [554] 

565 

R 1 

O 

R 2 

566 

N 

N 

NAr 1 



Scheme 198 Synthesis of 2-Aryl-2H-1,2,3-triazoles from 4-(Arylazo)isoxazol-5(4H)-ones [554] 

R 1 R 2 

N 

O 

567 

O 

Ar1N2 Cl − + 

R 1 

R 2 

N 

O 

568 

N 

NAr 

O 

1 

R 1 = Me, Ph, XC 6H 4; R 2 = Me, Bn; Ar 1 = XC 6H 4, naphthyl, heteroaryl 

Et3N, iPrOH 

reflux, 3 h 

Arylhydrazones of 3-acyl-1,2,4-oxadiazoles yield 4-(acylamino)-2-aryl-2H-1,2,3-triazoles 

571 by thermal or basic rearrangement (Scheme 199). For example, hydrazone 570 

(R 1 = 3-O 2NC 6H 4;Ar 1 = 4-O 2NC 6H 4) is converted into the corresponding triazole in 60% yield 

when it is melted in the presence of copper powder. [550] The same triazole is obtained in 

90% yield by treatment of hydrazone 570 (R 1 = 3-O 2NC 6H 4;Ar 1 = 4-O 2NC 6H 4) with ammonia. 

[550] Phenylhydrazone 570 (R 1 =Ar 1 = Ph) gives the corresponding triazole 571 in almost 

quantitative yield when treated with either equimolar or catalytic amounts of copper(II) 

acetate monohydrate in methanol at room temperature for two hours. [551] A kinetic study 

of the rearrangement of arylhydrazones 570 (R 1 = Ph; Ar 1 =XC 6H 4) into triazoles 571 has 

been reported. [555] The effect of â-cyclodextrin on the mononuclear rearrangement of 570 

(R 1 =Ar 1 = Ph) into 571 (R 1 =Ar 1 = Ph), in aqueous borate buffer at pH = 9.6, at temperatures 

ranging from 293.15 to 313.15 K, has also been reported. [556] The 2,4-dinitrophenylhydrazone 

of 3-benzoyl-1,2,4-oxadiazol-5-amine 570 [R 1 =NH 2;Ar 1 = 2,4-(O 2N) 2C 6H 3] is converted 

rapidly into the 4-ureido-2H-1,2,3-triazole 571 [R 1 =NH 2;Ar 1 = 2,4-(O 2N) 2C 6H 3], in dimethyl 

sulfoxide at room temperature or by heating above its melting point. [557] 

Scheme 199 Synthesis of 4-(Acylamino)-2-aryl-1,2,3-triazoles from 

Arylhydrazones of 3-Acyl-1,2,4-oxadiazoles [550,551] 

R 1 

Ph 

N 

N 

O 

570 

N 

NHAr1 R 1 = NH 2, Ph, 3-O 2NC 6H 4; Ar 1 = Ph, 4-O 2NC 6H 4, 2,4-(O 2N) 2C 6H 3 

When refluxed in ethanol, in the presence of sodium ethoxide, the 1,2,5-oxadiazole phenylhydrazone 

572 rearranges to triazoles 573 and 574 (Scheme 200). The two isomeric oximes 

573 (E, 80%) and 574 (Z, 10%) can be separated by column chromatography. [551] 

R 1 

O 

N 

H 

Ph 

571 

N 

N 

NAr 1 

Scheme 200 Synthesis of 2H-1,2,3-Triazoles from the Phenylhydrazone of 

3-Benzoyl-4-methyl-1,2,5-oxadiazole [551] 

Ph 

N N 

O 

572 

N 

NHPh 



NaOEt, EtOH 

reflux, 6 h 

HO 

N 

Ph 

N 

573 80% 

N 

NPh 

+ 

Ph 

R 1 

N 

N 

OH 

N 

574 10% 

4-(Alkylamino)-3-nitro-1,2,5-oxadiazole 2-oxides 575 react with primary aliphatic amines 

to afford 2-alkyl-4-(alkylamino)-5-nitro-2H-1,2,3-triazole 1-oxides 577, via intermediates 

576, in low to moderate yields (Scheme 201). Compounds 577 are also prepared in a 

one-pot procedure from 3,4-dinitro-1,2,5-oxadiazole 2-oxide. [558–560] 


R 2 

NPh 

N 

569 

N 

NAr 1

Scheme 201 Synthesis of 2-Alkyl-5-nitro-2H-1,2,3-triazole 1-Oxides from 4-(Alkylamino)- 

3-nitro-1,2,5-oxadiazole 2-Oxides [558–560] 

R 

N 

O2N 

O 

N 

1HN R2NH2 CH2Cl2, rt 

O − 

+ 

575 

R 1 HN NOH 

O2N N NHR2 

O −+ 

576 

− H 2O 

R 1 HN 

O 2N 

N 

NR 

N 

2 

O −+ 

577 30−40% 

Oxidation of 4-(arylhydrazono)-4H-pyrazole-3,5-diamines 578 with lead(IV) acetate (2 

equiv) provides 2-aryl-2H-1,2,3-triazole-4-carbonitriles 579 in moderate yields (Scheme 

202). Plausible mechanisms for this transformation have been proposed. [561] 

Scheme 202 Synthesis of 2-Aryl-2H-1,2,3-Triazoles from 

4-(Arylhydrazono)-4H-pyrazole-3,5-diamines [561] 

N 

N 

NH 2 

NHAr 

N 

1 

NH2 Pb(OAc) 4, DMF, MeCN 

0−5 oC, 1.5−2 h 

41−58% 

578 

NC 

Ar 1 = Ph, 4-Tol, 4-BrC 6H 4, 4-O 2NC 6H 4, 4-MeOC 6H 4, 3-O 2NC 6H 4, 3-MeOC 6H 4 

2-Methyl-4-nitro-1-phenyl-1H-imidazole (580) reacts with hydroxylamine, in the presence 

of potassium hydroxide, to yield 4-(acetylamino)-2-phenyl-2H-1,2,3-triazole 1-oxide (581) 

(Scheme 203). A mechanism for this transformation was suggested. [562] 

N 

579 

Scheme 203 Synthesis of 2H-1,2,3-Triazole 1-Oxides from 

2-Methyl-4-nitro-1-phenyl-1H-imidazole [562] 

O2N 

N 

N 

Ph 

580 

+ NH 2OH 

KOH, MeOH 

−5 oC, 3 h 

57% 

N 

NAr 1 

AcHN 

N 

NPh 

N 

O 

581 

− 

+ 

Photolysis of 2-methyl-5-phenyl-2H-tetrazole (582) produces, among other minor products, 

2-methyl-4,5-diphenyl-2H-1,2,3-triazole (583) in low yield (Scheme 204). [563] 

Scheme 204 Synthesis of 2H-1,2,3-Triazoles from 2-Methyl-5-phenyl-2H-tetrazole [563] 

Ph 

N 

N 

582 

N 

NMe 



benzene, hν, 3 h 

Ph 

Ph 

N 

N 

583 27% 

NMe 

+ other products 

4,6-Disubstituted 2-methyl-2,5-dihydro-1,2,3-triazines 584 are oxidized by 3-chloroperoxybenzoic 

acid (2 equiv) to give 4-substituted 2-methyl-2H-1,2,3-triazoles 585 in good 

yields if at least one of the substituents is a phenyl group (Scheme 205). [564,565] 



Scheme 205 Synthesis of 2H-1,2,3-Triazoles from 

2-Methyl-2,5-dihydro-1,2,3-triazines [564,565] 

R 1 

R 2 

N 

NMe 

N 

584 

MCPBA (2 equiv) 

CH2Cl2, 0 oC, 12 h 

R1 = R2 = Me trace 

R1 = R2 = Ph 69% 

R1 = Ph; R2 = Me 68% 

R 1 

N 

N 

585 

NMe 

+ R 2 CO 2H 

The 1,2,3,4-tetrazine 587, generated from the reaction of an (alkylazo)alkene 586 and dimethyl 

azodicarboxylate, is unstable and on workup yields 2,5-dihydro-1H-1,2,3-triazole 

588 (Scheme 206). This isomerization is probably acid catalyzed since by addition of trifluoroacetic 

acid 587 is converted in near quantitative yield into triazole 589. [566] The 

same triazole is also obtained cleanly when 588 alone is treated with trifluoroacetic acid 

under the same conditions. 

Scheme 206 Synthesis of 2H-1,2,3-Triazoles from 1,2,3,4-Tetrazines [566] 

O 

N 

NMe N 

N CO 

+ 

2Me 

CO2Me NHPh 

586 



PhHN 

O 

N 

benzene 

rt, 12 h 

NMe 

N N 

CO2Me 

CO2Me 587 

75% 

TFA 

PhHN 

MeO2C PhHN 

O 

O 

N 

NMe 

NH 

N 

CO2Me 588 

589 

TFA, CH 2Cl2 

rt, 6 h 

[1,2,3]Triazolo[1,5-b]pyridazinium salts 590, when treated with morpholine, undergo 

opening of the pyridazine ring to yield mixtures of the triazoles 591 and 592 (Scheme 

207). [567] The ratio of these products varies significantly depending on whether R 1 is an 

alkyl or an aryl group. Reaction of triazolopyridazinium salts 590 with alkoxides or thiolates 

affords the 4-vinyl-2H-1,2,3-triazoles 593 and 594, respectively, as the sole products. 

[567] 


80% 

N 

N 

NMe

Scheme 207 Synthesis of 2H-1,2,3-Triazoles from Triazolopyridazinium Salts [567] 

R 1 

N 

N 

N + N 

Ar1 BF4 − 

590 

R 1 = Me, 4-ClC6H4; Ar 1 = 4-BrC6H4 

N 

N 

N + N 

1 Ar BF4 − 

590 

R 1 

N 

N 

N + N 

Ar1 BF4 − 

590 

R 1 



O 

morpholine 

MeCN, rt 

84% 

R1 = Me (591/592) 3:2 

R1 = 4-ClC6H4 (591/592) 1:10 

N 

NaOMe, MeOH, rt 

R1 = Me 72% 

R1 = 4-ClC6H4 82% 

R1 CN 

591 

BnSH, KOH, EtOH, 5−10 o C 

R1 = Me 95% 

R1 = 4-ClC6H4 90% 

Irradiation of 2-aryl-2H-benzotriazoles 595 with UV light, in an aerated solvent, results in 

the oxidation of the benzo ring and formation of 2-aryl-2H-1,2,3-triazole-4,5-dicarboxylic 

acids 597 (Scheme 208). [568] The 2-aryl-2H-benzotriazole-4,7-diones 596 are plausible intermediates 

since photooxidation of compound 596 (R 1 =R 2 = H), obtained by oxidation of 

595 (R 1 =R 2 = H) with potassium dichromate, also leads to 597 (R 1 =R 2 = H). Oxidation of 

2-phenyl-2H-benzotriazole (595, R 1 =R 2 = H) with potassium permanganate also gives the 

dicarboxylic acid 597 (R 1 =R 2 = H) (in 50% yield) but oxidation of 595 (R 1 = OMe; R 2 = Me) 

under similar conditions, results in the formation of a tricarboxylic acid 597 (R 1 = OMe; 

R 2 =CO 2H) in 48% yield. [568] 

N 

N 

MeO 

NAr 1 

BnS 

+ 

593 

O 

R 1 

N 

N 

R 1 

594 

N 

NAr 1 

N 

N 

592 

NAr 1 

R 1 

N 

N 

NAr 1 



Scheme 208 Photooxidation of 2-Aryl-2H-benzotriazoles [568] 

N 

N 

N 

595 

R 1 

R 1 = H, OMe; R 2 = H, Me 

O2, EtOH 

hν, rt, 12.5 d 


R 2 

O 

O 

oxidation 

N 

N 

N 

596 

R 1 

HO2C 

HO2C 

R 2 

N 

N 

N 

R 1 

597 R 1 = R 2 = H 93% 

Since substituent modification reactions in 1H- and 2H-1,2,3-triazoles are, in many cases, 

very similar, the synthesis of new 2H-1,2,3-triazoles by substituent modification of monocyclic 

2-substituted 2H-1,2,3-triazoles is covered in Section 13.13.1.4. 


N-Unsubstituted and 1-Substituted Benzotriazoles 


13.13.3.1.1 By Formation of Two N-N Bonds 

13.13.3.1.1.1 Fragments N-C-C-N and N 




From Benzene-1,2-diamines and Nitrous Acid 

The diazotization of benzene-1,2-diamine derivatives is the most common synthetic route 

to benzotriazoles. This is a very general method, which can also be applied to the cyclization 

of other 1,2-diaminocarbocycles [569] and 1,2-diaminoheterocycles. [570–574] In almost all 

the cases the diazotization is carried out with nitrous acid (generated in situ from sodium 

nitrite and a mineral acid) but other reagents can also be used. Esters of nitrous acid with 

primary or secondary alcohols, preferentially methyl nitrite [575] or diphenylnitrosamine, 

[576] also react with benzene-1,2-diamine derivatives to afford benzotriazoles in 

high yields. Molecules consisting of a benzene-1,2-diamine group linked to a fluorophore 

moiety are used as probes for nitric oxide (NO) detection; fluorescent benzotriazoles are 

formed in this reaction. [577–579] 

The structure of the products obtained from the action of nitrous acid on an aromatic 

1,2-diamine, or on one of its alkyl, aryl, or acyl derivatives, was the subject of a very interesting 

scientific dispute, which occurred between the 1870s and 1910. The symmetrical 

structure 598 (Scheme 209), proposed by Griess, [580,581] was shown to be incorrect and 

structure 599, suggested by KekulØ, was confirmed as the correct one. [582,583] 


R 2

Scheme 209 Proposed Structures for the Product of 

the Reaction of Nitrous Acid on Benzene-1,2-diamine 

598 

N NR 1 

N 

599 

N 

N 

N 

R1 A range of diversely substituted benzotriazole derivatives 601 is prepared by diazotization 

of the corresponding benzene-1,2-diamine derivatives 600, a few examples are 

shown in Scheme 210. 

Scheme 210 Diazotization of Benzene-1,2-diamine Derivatives [322,579,584–594] 

R 2 

600 

NH 2 

NHR 1 

R 1 = H, alkyl, aryl, acyl, sulfonyl 

NaNO2, H3O + 

R 2 

601 

N 

N 

N 

R1 R 1 R 2 Conditions Yield (%) Ref 

H H NaNO2, AcOH, H2O, 5–808C, 1 h 75–81 [584] 

H 5,6-Cl2 NaNO2, HCl, H2O, 0 8C 50 [585] 

H 5,6-(NO2) 2 NaNO2, HCl, H2O, 5–25 8C, 1 h 83 [586] 

Me 6-Cl NaNO2, HCl, H2O, 108C 29 [585] 

2,4,6-(O2N) 3C6H2 4,6-(NO2) 2 NaNO2,H2SO4,H2O, 5–258C, 1 h 63 [586] 

Ac 5,6-Me2 NaNO2, AcOH, H2O, 10–508C 63 [587] 

Ac 5-NHAc-6-OMe NaNO2, HCl, H2O, 5 8C, 2 h 97 [588] 

CSCHMeNHBoc 6-NO2 NaNO2, AcOH, H2O, 08C, 30 min 79 [589] 

S 

H NaNO 2, AcOH, H 2O >90 [590] 

CO2Et 7-Cl-4-OEt-5-CO2Me NaNO2,H2SO4,H2O, 58C, 15 min 68 [591] 

SO2Ph 5-Me NaNO2, HCl, H2O, rt 100 [592] 

N 

HN 

N 

O 

NH 2 


13.13.3 N-Unsubstituted and 1-Substituted Benzotriazoles 541 

H NaNO 2, HCl, H 2O, 0 8C to rt, 2 h 96 [322] 

benzotriazol-2-yl H NaNO 2, HCl, H 2O, 0 8C 63 [593] 

6-methyl-3-pyridyl H NaNO 2, HCl, H 2O, 0 8C, 1 h 84 [594] 

acridin-9-yl 5,6-Me 2 NaNO 2, HCl, H 2O, 0 8C, 1 h 85 [579] 

Benzo[1,2-d:4,5-d¢]bistriazoles are synthesized, in one step, by diazotization of benzene- 

1,2,4,5-tetraamine derivatives (Scheme 211). 1,7-Bis(2,4,6-trinitrophenyl)benzobistriazole 

603 is obtained in 60% yield from the bis(acetylamino) derivative 602, [595] while the 1,7-diacetyl 

analogue 605 is prepared in 93% from 1,5-bis(acetylamino)-2,4-dinitrobenzene 

(604). [596,597] 



Scheme 211 Diazotization of Benzene-1,2,4,5-tetraamine Derivatives [595–597] 

AcHN NHAc 

Ar 1 HN 

602 

Ar 1 = 2,4,6-(O2N)3C6H2 

O2N NO 2 

AcHN 

604 

H2SO4, H2O 

100 oC, 20 min 

NHAr 1 Ar 1 HN 

H2, Pd/C, EtOH 

rt, 3100 Torr, 3 h 

NHAc AcHN 

H2N NH 2 

NHAr 1 

H2N NH 2 

NHAc 

N 

N 

N 

NaNO2 

5−10 o C 

603 60% 

N 

N 

N 

Ar 1 Ar 1 

N 

N 

N 

NaNO2, HCl 

0 oC, 30 min 

605 93% 

N 

N 

N 

Ac Ac 

An alternative method for the conversion of benzene-1,2-diamine derivatives into benzotriazoles 

consists of their reaction with benzonitrile oxide, followed by diazotization of 

the resulting N-substituted benzamide oximes 607 to 1-benzohydroximoyl-1H-benzotriazoles 

608 (Scheme 212). These compounds are hydrolyzed in refluxing concentrated hydrochloric 

acid to afford benzotriazoles 609 in quantitative yields. [598,758] There is no obvious 

advantage of this method over direct diazotization of diamines 606, except the fact 

that compounds 607 can also be converted into benzimidazoles by treatment with hydrochloric 

acid. 

Scheme 212 Synthesis of Benzotriazoles via N-Substituted Benzamide Oximes [598,758] 

R 2 NH 2 

R 1 

606 

NH 2 

NaNO2, H2O, HCl 


100% 

R 1 = H, Me, CO2Me; R 1 ,R 2 = (CH 

+ 



Ph N O − + 

R 2 

R 1 

CH)2; R 2 = H, Me, Cl 

benzene 

reflux, 1 h 

Ph 

608 

70−82% 

N 

N 

N 

NOH 

R 2 NH 2 

R 1 

concd HCl 

reflux, 2 h 


100% 

Ph 

607 

NH 

NOH 

R 2 

R 1 

609 

N 

N 

N 

H

5,6-Dinitro-1H-benzotriazole [601,R 1 =H;R 2 = 5,6-(NO 2) 2]; Typical Procedure: [586] 

A slurry of 4,5-dinitrobenzene-1,2-diamine (7.0 g, 35 mmol) in concd HCl (300 mL) was 

treated dropwise with a 10% aq NaNO 2 (90 mL) at 5–10 8C. After the resulting mixture 

had stirred at 258C for 1 h it was chilled to 08C and the product was collected by filtration, 

washed with H 2O, and air-dried to provide analytically pure crystals of the monohydrate 

of 5,6-dinitrobenzotriazole; yield: 6.6 g (83%); mp 1448C. Anhyd product was obtained 

when the monohydrate was dried in an oven at 808C overnight. 


13.13.3.1.2.1 Fragments C-C-N and N-N 


From Arylamines and 2-Azido-3-ethyl-1,3-benzothiazolium 

Tetrafluoroborate 

The benzothiazolium tetrafluoroborate 610 reacts with 2-naphthylamine to afford naphtho[1,2-d]triazole 

612 in 70% yield (Scheme 213). [599] Since salt 610 is a good diazo-transfer 

reagent, [600] diazoamino derivative 611 is a probable intermediate in this reaction. Compound 

610 also reacts with amino-heterocycles to yield heterocycle-fused 1,2,3-triazoles 

in good yields. [599] 

Scheme 213 Synthesis of 1H-Naphtho[1,2-d][1,2,3]triazole from 2-Naphthylamine [599] 

610 

BF 

− 

Et 4 

N+ 

N3 S 

+ 



NH 2 

0.4 M HCl, EtOH 

rt, 1 h 

+ 

N2 611 

NH2 

612 70% 

1H-Naphtho[1,2-d][1,2,3]triazole (612); Typical Procedure: [599] 

To a soln of 2-naphthylamine (0.615 g, 5 mmol) in 0.4 M HCl in EtOH (40 mL) at rt was 

added 2-azido-3-ethyl-1,3-benzothiazolium tetrafluoroborate (610; 1.5 g, 5.1 mmol) in 

one portion and the mixture was stirred for 1 h. The solvent was evaporated and aq 2 M 

NH 3 (20 mL) was added to the residue. The mixture was stirred, filtered, and extracted 

with CHCl 3 (2 ” 5 mL). The organic phase was discharged. The aqueous phase was neutralized 

and the resulting solid was filtered, washed with H 2O, and dried; yield: 0.60 g (70%); 

mp 175–180 8C. 

N 

N 

N 

H 





From Æ-Diazo Ketones and Amines 

Benzoyl trifluoromethanesulfonate (614) smoothly transforms 10-diazophenanthren- 

9(10H)-one (613) into diazonium salt 615, which reacts with isopropylamine to give the 

phenanthrotriazole 616 in 86% overall yield (Scheme 214). [38] 

Scheme 214 Synthesis of Phenanthro[9,10-d][1,2,3]triazole from 

a Æ-Diazo Phenanthrenone [38] 


O 

N 2 

+ 

O 

Ph OTf 

614 






From Azides and Dehydrobenzene 

CH 2Cl 2 

−70 to −40 o C, 3 h 

615 

iPrNH 2, CH 2Cl 2 

−70 o C, 5 h 

OBz 

+ 

N 2 OTf − 

616 86% 

Pr 

N 

N 

N 

i 

Dehydrobenzene (benzyne) reacts with alkyl, aryl, glycosyl, acyl, or sulfonyl azides to 

yield 1-substituted benzotriazoles 617 (Scheme 215). The benzyne is generated in situ by 

slow addition of 2-aminobenzoic acid to a solution of the azide and an alkyl nitrite (generally 

butyl, pentyl, or isopentyl nitrite). [601] 


Scheme 215 Synthesis of Benzotriazoles from Azides and Dehydrobenzene [601–604] 

CO 2H 

NH 2 

BuONO 

R 1 = alkyl, aryl, glycosyl, acyl, sulfonyl 

R 1 N3 


(CH2) 5Me CH2Cl2, acetone, reflux, 2 h 70 [601] 

Ph CH2Cl2, acetone, reflux, 2 h 52 [601] 

4-OHCC6H4 CH2Cl2, acetone, reflux, 2 h 50 [601] 

4-AcC6H4 CH2Cl2, acetone, reflux, 2 h 50 [601] 

4-O2NC6H4 CH2Cl2, reflux, 1.5 h 62 [602] 

1-napthyla CH2Cl2, acetone, reflux, 3 h 75 [603] 

acridin-9-yl CH2Cl2, acetone, reflux, 2 h 47 [601] 

AcO 

AcO 

H 

OAc 

H 

O 

H 

H AcO 

H 

CH 2Cl 2, acetone, reflux, 2.5 h 73 [604] 

Bz CH 2Cl 2, reflux, 1.5 h 63 [602] 

4-MeOC 6H 4CO CH 2Cl 2, reflux, 1.5 h 60 [602] 

SO 2Ph CH 2Cl 2, reflux, 1.5 h 52 [602] 

4-ClC 6H 4SO 2 CH 2Cl 2, reflux, 1.5 h 78 [602] 

a Isopentyl nitrite was used. 

N 

N 

N 

R1 617 50−78% 

The synthesis of 1-(2-methyl-1-naphthyl)-1H-naphtho[2,3-d][1,2,3]triazole (620) from the 

reaction of a naphthyl azide with 2,3-dehydronaphthalene (619), produced from 3-amino-2-naphthoic 

acid (618), is an interesting extension of this method (Scheme 216). [603] 

Scheme 216 Synthesis of Naphthotriazoles from Azides and 2,3-Dehydronaphthalene [603] 

R 1 = 

CO 2H 

NH 2 



Me(CH2) 4ONO 

DME, reflux, 1.5 h R1N3 618 619 

620 21% 

N 

N 

N 



1-(1-Naphthyl)-1H-benzotriazole (617,R 1 = 1-naphthyl); Typical Procedure: [603] 

A stirred soln of 1-naphthylazide (8.45 g, 50 mmol) and isopentyl nitrite (13.5 mL, 

100 mmol) in CH 2Cl 2 (400 mL) was refluxed and treated with a soln of 2-aminobenzoic 

acid (13.7 g, 100 mmol) in acetone (100 mL) over 2 h. Heating was continued for a further 

1 h, after which the mixture was cooled and evaporated under reduced pressure to leave a 

brown oil. Chromatography (silica gel) afforded the benzotriazole as a white crystalline 

solid; yield: 9.15 g (75%); mp 114–1158C. 


From Azides and Quinones 

As described in Section 13.13.1.1.3.1.2.3, organic azides undergo addition to alkenes with 

electron-withdrawing groups to yield dihydrotriazoles or triazoles. When benzoquinones 

or naphthoquinones are used, benzotriazole derivatives are obtained. From the reaction 

of benzo-1,4-quinone and phenyl azide, mono- or bis-addition products 621, and 622 and 

623, respectively, are formed, depending on the number of equivalents of azide used 

(Scheme 217). [203,605,759] Phenyl azide adds to 2-methylbenzo-1,4-quinone to give only one 

monoadduct. [204] 

Scheme 217 Reaction of Benzo-1,4-quinone with Phenyl Azide [203,605,759] 

O 

O 

O 

O 

PhN 3 (1 equiv) 

PhN 3 (2 equiv) 

O 

O 

N 

N 

N 

Ph 

621 

N 

N 

N 

Ph 

O 

O 

622 

N 

N 

N 

Ph 

+ 

Ph 

N 

N 

N 

O 

O 

623 

N 

N 

N 

Ph 

Naphtho-1,4-quinone reacts with methyl azide (sealed tube, 1058C, 20 h) to afford triazole 

624 (R 1 = Me) in 48% yield. [205,605,759] Similar reactions of naphtho-1,2-quinone and 6-bromonaphtho-1,2-quinone 

with methyl azide or phenyl azide do not give any triazole derivatives. 

[205] Naphtho-1,4-quinone reacts with (azidoalkyl)phosphonates and with ethyl azidoacetate 

to afford triazole derivatives 624 in good yields (Scheme 218). [210] 

Scheme 218 Reaction of Naphtho-1,4-quinone with Alkyl Azides [210] 

O 

O 



R1N3, THF 

reflux, 20 h 

R1 = CH2PO(OEt)2 75% 

R1 = CHMePO(OEt)2 70% 

R1 = CHPhPO(OEt) 2 76% 

R1 = CH2CO2Et 80% 

O 

O 

624 

N 

N 

N 

R1 1-Substituted 1H-Naphtho[2,3-d][1,2,3]triazole-4,9-diones 624; General Procedure: [210] 

A soln of naphtho-1,4-quinone (0.47 g, 3 mmol) in THF was added dropwise, with stirring, 

to a soln of diethyl (1-azidoalkyl)phosphonate or ethyl azidoacetate (3 mmol) in THF 


(15 mL) and the mixture was refluxed for 20 h. The solvent was evaporated and the residue 

was purified by flash chromatography (silica gel, Et 2O/hexane) to give the triazole. 




Cyclization of 2-Nitrophenylhydrazines 

When treated with a base, 2-nitrophenylhydrazines cyclize to benzotriazol-1-ols (Scheme 

219). [606–610] Benzotriazol-1-ol exists in tautomeric equilibrium with 1H-benzotriazole 3-oxide. 

The position of the equilibrium depends on the solvent; e.g. in water the N-oxide form 

predominates. [611–613] In some circumstances, the use of 2,4-dinitrophenylhydrazine to 

prepare 2,4-dinitrophenylhydrazones may lead to the formation of 6-nitrobenzotriazol- 

1-ol. [614] The cyclization of 2-nitrophenylhydrazines can also be carried out with polyphosphoric 

acid (e.g., conversion of 625 into 626, Scheme 220). [615] Benzotriazol-1-ols are powerful 

explosives [617] and decompose violently at 200–2108C to carbonaceous material. [619] 

A large variety of benzotriazol-1-ol derivatives are used extensively as coupling reagents. 

[616,621] 

Scheme 219 Cyclization of 2-Nitrophenylhydrazines in Alkaline Media 

R 1 

NHNH2 

NO2 

NaOH 

− H2O R 1 

N 

N 

N 

OH 

Scheme 220 Cyclization of 2-Nitrophenylhydrazines with Polyphosphoric Acid [615] 

NO2 Me 

NHNH 2 

NO 2 



PPA, 10 min 

− H2O 

41% 

NO2 

625 626 

N 

N 

N + 

O − 

Me 

R 1 

H 

N 

N 

N+ 

O − 

1-Methyl-7-nitro-1H-benzotriazole 3-Oxide (626); Typical Procedure: [615] 

A mixture of 1-(2,6-dinitrophenyl)-1-methylhydrazine (0.4 g, 1.9 mmol) and PPA (15 g) was 

gently warmed and stirred for 10 min. The resulting brown soln was cooled and poured 

into H 2O (100 mL). The soln was extracted with CHCl 3 (3 ” 30 mL) and the yellow organic 

extract was chromatographed (basic alumina, 100–200 mesh, 100 g). The unchanged hydrazine 

was eluted with CHCl 3. A second fraction was collected, concentrated under reduced 

pressure, and recrystallized (EtOH) to give 626 as yellow plates; yield: 0.15 g (41%); 

mp 242–243 8C. 


Reaction of 1-Chloro-2-nitrobenzenes or 

1,2-Dinitrobenzenes with Hydrazine 

1,2-Dinitrobenzenes 627 (X = NO 2) [609,617] and 1-chloro-2-nitrobenzenes 627 (X = Cl) [618–621] 

react with hydrazine to yield benzotriazol-1-ols 629 via the 2-nitrophenylhydrazines 628 

(Scheme 221). The yields of the reactions are highly dependent on the substituents on the 



starting material. In some cases the substitution of the nitro group is the most favorable 

process, the corresponding arylhydrazines are then the main products. [619] The synthesis 

of benzotriazol-1-ols from 1-methoxy-2-nitrobenzenes (627, X = OMe) has also been described. 

[609,617] 

Scheme 221 Benzotriazol-1-ols from 1,2-Dinitrobenzenes or 1-Chloro-2-nitrobenzenes 

and Aqueous Hydrazine [617,619–621] 

R 

X 

NO2 1 R1 R1 aq H2NNH2 

EtOH 


NHNH2 NO2 − H2O 627 628 629 

X R 1 Yield (%) Ref 

NO2 4,6-Cl2 60 [617] 

NO2 4,6-Br2 a – [617] 

Cl H 90 [619] 

Cl 4,5-Cl 2 85 [619] 

Cl 4,5,6-Cl 3 67 [619] 

Cl 4,5,6,7-Cl 4 40 [619] 

Cl 6-CF 3 90 [620] 

Cl 6-OMe 6 [620] 

Cl 6-CONH 2 39 [620] 

Cl 6-SO 2NHMe 79 [620] 

Cl 6-SO 2NHBn 96 [621] 

a Yield not reported. 

N 

N 

N 

OH 

Polymer-supported benzotriazol-1-ol derivatives 633 [621] and 637 [622] are prepared, respectively, 

from the reaction of polymer-supported 1-chloro-2-nitrobenzenes 632 and 636 and 

hydrazine (Scheme 222). Precursor 632 is obtained from the reaction of the aminomethylated 

polystyrene 630 and the benzenesulfonyl chloride 631 while 636 is prepared by 

Friedel–Crafts alkylation of polystyrene 634, using 4-chloro-3-nitrobenzyl alcohol (635). 

The polymeric reagent 633 is highly efficient for the synthesis of amides. [621,623] 

Scheme 222 Polymer-Supported Benzotriazol-1-ol Derivatives [621,622] 

630 

NH2 + ClO 2S 



631 

NO2 

Cl 

Et 3N, CH 2Cl 2 

rt, 5 h 

100% 

1. aq H2NNH2, EtOH, reflux, 5 h 

2. HCl, dioxane 

70−80% 

NH 

O 

S 

O 

632 

H 

N 

S 

O O 


633 

NO2 

Cl 

N 

N 

N 

OH

AlCl3, PhNO2 70 oC, 3 d 

H + 

Cl 

HO 

634 

635 

NO 2 

1. H2NNH OH 

2, , reflux, 20 h 

MeO 

2. concd HCl, dioxane, reflux, 20 h 

636 

NO 2 

Cl 

637 

N 

N 

N 

OH 

Benzotriazol-1-ols 629; General Procedure: [619] 

The appropriate 1-chloro-2-nitrobenzene (5 g) was dissolved in hot EtOH (15–20 mL) and 

85% aq hydrazine (5 g) was added. The mixture was refluxed for 3 h and cooled. The precipitate 

was collected by filtration, dissolved in hot H 2O, and the benzotriazol-1-ol derivative 

was precipitated with aq HCl. The crude product was decolorized with charcoal and 

recrystallized (EtOH/MeOH 1:1). 


Cyclization of (2-Aminophenyl)hydrazine Derivatives 

Oxidative cyclization of 1-(acetylamino)-2-hydrazino-3-nitrobenzene with chlorine affords 

4-nitro-1H-benzotriazole in 80% yield (Scheme 223). [624] 

Scheme 223 Cyclization of 1-(Acetylamino)-2-hydrazino-3-nitrobenzene [624] 

NO 2 

NHNH 2 

NHAc 

Cl2, EtOH 

80% 

NO2 

N 

N 

N 

H 


Cyclization of (2-Aminophenyl)triazene Derivatives 

Polymer-bound 1-(2-aminophenyl)triazenes 638 are cleaved smoothly with trifluoroacetic 

acid in dichloromethane at room temperature within minutes to give 1-substituted benzotriazoles 

639 in excellent yields (Scheme 224). [625] 

Scheme 224 Benzotriazoles from Polymer-Bound 1-(2-Aminophenyl)triazenes [625] 

O 2N 

R 1 = CH 2CH 

638 

N 

NHR 1 

N NBn 



TFA, CH2Cl2, rt 

up to 95% 

CH 2, cyclopropyl, cyclopentyl, 4-MeOC 6H 4CH 2 

O 2N 

639 

N 

N 

N 



13.13.3.2 Synthesis by RIng Transformation 


From 4,5-Dimethylene-4,5-dihydro-1H-triazoles 

4,5-Dimethyl-4,5-dihydro-1H-triazoles 641, generated from 640 by 1,4-elimination of bromine, 

are trapped in low to moderate yields by dienophiles in Diels–Alder reactions 

(Scheme 225). [626] Benzotriazole 642 is obtained when 641 is generated in the presence 

of dimethyl acetylenedicarboxylate; adduct 643 is formed when N-methylmaleimide is 

used as the dienophile. This adduct is converted into the benzotriazole derivative 644 by 

treatment with N-bromosuccinimide. 

Scheme 225 Benzotriazoles from 4,5-Dimethyl-4,5-dihydro-1H-triazoles [626] 

Br 

640 

Br 

N 

N 

N 

Ph 

DMAD 

− 2H 

27% 

NMM 

38% 

NaI, DMF 

115 oC MeO 2C 

MeO 2C 

MeN 

O 

O 

642 

N 

N 

N 

Ph 

641 

643 

N 

N 

N 

Ph 

N 

N 

N 

Ph 

NBS, CCl4 

heat 

50% 


Transformation of 1,3-Dihydro-2H-benzimidazol-2-ones 

MeN 

O 

O 

644 

N 

N 

N 

Ph 

The reaction of 1,3-dihydro-2H-benzimidazol-2-one (645) with sodium nitrite and water, 

in a autoclave at high temperature, gives the sodium salt of benzotriazole, which, by acidification 

gives 1H-benzotriazole in high yield (Scheme 226). [627] This reaction can be extended 

to 1,3-dihydro-2H-benzimidazol-2-ones with substituents on positions 4–7. 

Scheme 226 Benzotriazoles from 1,3-Dihydro-2H-benzimidazol-2-ones [627] 

H 

N 

N 

H 

645 

O 



NaNO2, H2O 190−300 oC pressure 

15−75 min 

N 

N 

H3O N 

N 

N − + 

Na N 

H 

+ 


61−93%


Transformation of 1,2,4-Benzotriazin-3(2H)-ones 

1,2,4-Benzotriazin-3(2H)-one (646) and phenanthrotriazin-3-one 647 are converted into 

1H-benzotriazole and phenanthrotriazole 648, respectively, on treatment with ethereal 

chloramine at room temperature (Scheme 227). [381] Treatment of benzotriazin-3-one 646 

with lead(IV) acetate in refluxing benzene affords 1-acetyl-1H-benzotriazole in good 

yield. [381] 

Scheme 227 Benzotriazoles from 1,2,4-Benzotriazin-3(2H)-ones [381] 

N O 

N 

646 

NH 

647 

N O 

N NH 

NH2Cl, CH2Cl2, DMF 

rt, 14 h 

65% 

Pb(OAc)4, benzene 

reflux, 2 h 

92% 

86% 

NH2Cl, Et2O, DMF 

rt, 48 h 

648 

N 

N 

N 

H 

N 

N 

N 

Ac 

N 

N 

N 

H 


Transformation of 1,2,3,4-Benzotetrazine 1,3-Dioxides 

The reduction of 1,2,3,4-benzotetrazine 1,3-dioxides 649 with sodium hydrosulfite or 

tin(II) chloride affords benzotriazoles 651 in almost quantitative yields (Scheme 228). [628] 

It has been suggested that this transformation proceeds via the intermediate N-nitrosobenzotriazoles 

650. 

Scheme 228 Benzotriazoles from 1,2,3,4-Benzotetrazine 1,3-Dioxides [628] 

R 2 

R 1 

649 

N O 

N 

− 

+ 

N N 

O − 

+ 

R 1 = H, Br; R 2 = H, Br, NO2 



Na2S2O4 (4 equiv) or 

SnCl2 2H2O (4 equiv) 

EtOAc, H2O rt, 3 min 

R 2 

R 1 

650 

H 2O 

− HNO 2 

N 

N 

N 

N O 

R 2 

R 1 

651 95−98% 

N 

N 

N 

H 




13.13.3.3.1 Substitution of Existing Substituents 

13.13.3.3.1.1 Of Hydrogen 


N-Trimethylsilylation 

Benzotriazole reacts with hexamethyldisilazane to give 1-(trimethylsilyl)-1H-benzotriazole 

(652) in 95% yield (Scheme 229). [169,434,629,630] 

Scheme 229 N-Trimethylsilylation of 1H-Benzotriazole [169] 

N 

N 

N 

H 


Carboxylation 

+ (TMS)2NH 

heat 

95% 

Heating an intimate mixture of 1H-benzotriazol-5-ol with a large excess of anhydrous potassium 

carbonate in a nickel-lined steel autoclave, with carbon dioxide under pressure, 

affords 5-hydroxy-1H-1,2,3-benzotriazole-4-carboxylic acid (653) in 49% yield (Scheme 

230). [631,632] 

652 

N 

N 

N 

Scheme 230 Carboxylation of 1H-Benzotriazol-5-ol [631,632] 

K2CO3, CO2 

180−190 

49% 

o HO N 

HO 

C, 16 h 

N 

N 

H 

Benzotriazole reacts with chloroformates 654, in alkaline solutions, to afford selectively 

the corresponding alkyl 1H-benzotriazole-1-carboxylates 655 (Scheme 231). [633–635] 

CO2H 

653 

TMS 

N 

N 

N 

H 

Scheme 231 N-Alkoxycarbonylation of 1H-Benzotriazole [633–635] 

N 

N 

N 

H 

R 1 = Me, Et, Ph, Bn 

+ ClCO 2R 1 



654 

aq NaOH 

58−100% 

655 

N 

N 

N 

CO 2R 1 

Ethyl 1H-1,2,3-Benzotriazole-1-carboxylate (655,R 1 = Et); Typical Procedure: [634] 

Ethyl chloroformate (6.0 g, 0.056 mol) was slowly added to a stirred and cooled aqueous 

soln of 1H-benzotriazole (6.0 g, 0.05 mol) and NaOH (2.0 g, 0.05 mol). After completion of 

the addition, the mixture was stirred for an additional 15 min, and the precipitated white 

solid was then collected by filtration, washed with H 2O, dried, and recrystallized (Et 2O); 

yield: 9.1 g (95%); mp 70–71 8C. 



Acylation 

Benzotriazoles react with acyl chlorides and anhydrides to afford the 1-acyl derivatives 

656 (Scheme 232). [587] 

Scheme 232 Acylation of 1H-Benzotriazole [587] 

N 

N 

N 

H 

R 1 COCl or (R 1 CO)2O 

1-Acyl-1H-benzotriazoles 656 (R 1 = aryl, 2-arylvinyl) are prepared in moderate to good 

yields from the reaction of 1H-benzotriazole and acyl chlorides in pyridine or in aqueous 

sodium hydroxide. [634] Other benzotriazole derivatives 656 (R 1 = alkyl, aryl) are obtained 

in high yields (87–99%) from the reaction of 1H-benzotriazole and acyl chlorides in anhydrous 

dichloromethane and triethylamine at 0 8C. [636,637] 1-Acyl-1H-benzotriazoles 656 

(R 1 = Me, Et, Bu, Ph) are prepared in good yields by fusion of 1H-benzotriazole and acyl 

chlorides at 80–1008C. [630] When the acyl chlorides are not available, 1-acyl-1H-benzotriazoles 

are also conveniently prepared from 1-mesyl-1H-benzotriazole and the respective 

carboxylic acids in yields of 80–95%. [630] 1-Acyl-1H-benzotriazoles are also prepared in excellent 

yields (94–95%) from the reaction of 1-(trimethylsilyl)-1H-benzotriazole and acyl 

chlorides. [629] 

5,6-Dimethyl-1H-benzotriazole reacts with acetic anhydride (reflux for 30 min) to 

give the 1-acetyl derivative in 93% yield. [587] The same compound also reacts with benzoyl 

chloride and 4-nitrobenzoyl chloride, in the presence of aqueous sodium hydroxide, to 

yield the 1-acyl derivatives in 82 and 50% yield, respectively. [587] 

1H-Benzotriazole reacts with trifluoroacetic anhydride in tetrahydrofuran, at room 

temperature, to give 1-(trifluoroacetyl)-1H-benzotriazole (656, R 1 =CF 3) in almost quantitative 

yield. [638] This compound is a convenient trifluoroacetylating reagent for amines 

and alcohols. 1H-Benzotriazol-5-amine reacts with trifluoroacetic anhydride in dimethylformamide, 

at room temperature, to give selectively 5-[(trifluoroacetyl)amino]benzotriazole 

in 85% yield. [639] 

Thiobenzoyl chloride reacts with benzotriazole or 1-(trimethylsilyl)-1H-benzotriazole 

to yield 1-(thiobenzoyl)-1H-benzotriazole in 64 and 44% yield, respectively. [434] 

1H-Benzotriazole reacts with aryl isocyanates to yield 1-(arylaminocarbonyl)-1H-benzotriazoles. 

[640] 


N-Formylation 



1H-1,2,3-Benzotriazole-1-carbaldehyde (657) is conveniently prepared from 1H-benzotriazole 

and formic acid in the presence of dicyclohexylcarbodiimide (Scheme 233). [641] This 

compound is a stable N- and O-formylating agent for a variety of amines and alcohols. The 

diethyl acetal of compound 657 is prepared directly in 90% yield from the reaction of 1Hbenzotriazole 

and triethyl orthoformate. [642] 

656 

N 

N 

N 

COR 1 



Scheme 233 N-Formylation of 1H-Benzotriazole [641] 

N 

N 

N 

H 

+ HCO 2H 

DCC, CH2Cl2, rt, 15 h 

71% 

1H-1,2,3-Benzotriazole-1-carbaldehyde (657); Typical Procedure: [641] 

To a mixture of 1H-benzotriazole (14.85 g, 0.125 mol) and HCO 2H (6.9 g, 0.15 mol) in anhyd 

CH 2Cl 2 (250 mL) was added DCC (36.05 g, 0.175 mol). The mixture was stirred at rt for 15 h, 

the precipitate filtered and the solvent removed in vacuo. Recrystallization of the residue 

gave pure 657 as white needles; yield: 13 g (71%); mp 94–96 8C. 


Arylation 

1H-Benzotriazole reacts with activated aryl halides and hetaryl halides to yield the 1-arylor 

1-hetaryl-1H-benzotriazole derivatives as the main (or sole) products. With 1-chloro-2nitrobenzene 

(658, R 1 =R 2 = H) it gives a mixture of 659 (R 1 =R 2 = H; 39%) and 660 

(R 1 =R 2 = H; 16%), which can be separated by column chromatography (Scheme 234). [643] 

The reaction with 1-chloro-2,4-dinitrobenzene (658,R 1 =NO 2;R 2 = H) in refluxing toluene, 

in the absence of any added base, affords exclusively the 1H-isomer 659 (R 1 =NO 2;R 2 =H) 

in 96% yield [644] but if it is carried out in refluxing ethanol, in the presence of anhydrous 

sodium acetate, it gives a mixture of 659 (R 1 =NO 2;R 2 = H) and 660 (R 1 =NO 2;R 2 = H) in the 

ratio of approximately 23:10. [645] With 2-chloro-1,3,5-trinitrobenzene (658, R 1 =R 2 =NO 2) 

or 2-fluoro-1,3,5-trinitrobenzene the 1H-isomer 659 (R 1 =R 2 =NO 2) is the sole product. [586] 

2-Fluoro-1,3,5-trinitrobenzene reacts with mono- and dinitrobenzotriazoles [586] to afford 

the corresponding 1-(2,4,6-trinitrophenyl) derivatives; with benzo[1,2-d:4,5-d¢]bistriazole 

it gives a mixture of 1,5- and 1,7-bis(2,4,6-trinitrophenyl)benzo[1,2-d:4,5-d¢]bistriazoles. 

[595] 

Scheme 234 N-Arylation of 1H-Benzotriazole [643,644] 

N 

N 

N 

H 

R 1 = R 2 = H, NO2 

+ Cl 



O 2N 

R 2 

658 

R 1 

657 

O 2N 

+ 

N 

N 

N 

CHO 

N 

N 

N 

659 

R 1 

R 2 

N 

N 

N 

O 2N 

R2 660 

1H-Benzotriazole reacts with 2-bromopyridine and 2-bromopyrimidine, in the absence of 

added base, to give the corresponding 1-substituted benzotriazole derivatives in high 

yields. [642,644] The reaction of 1H-benzotriazole with 2-chloro-3-nitropyridine and 4-chlo- 


R 1

o-3-nitropyridine in dimethyl sulfoxide at 808C, in the presence of sodium carbonate, 

also affords the corresponding 1-substituted benzotriazole derivatives. [646] Under microwave 

irradiation, benzo- and naphthotriazoles 661 react with 4-chloropyridine and 4chloroquinoline 

derivatives 662 to give the 1-substituted derivatives 663 in good yields 

(Scheme 235). [647] 

Scheme 235 N-Arylation of Benzotriazoles under Microwave Irradiation [647] 

R 3 

R 3 

661 

N 

N 

N 

H 

+ 

R 2 

R 2 

Cl 

N 

662 

R 1 

R 1 = R 3 = H, Me; R 2 = H; R 2 ,R 2 = R 3 ,R 3 = (CH CH) 2 

microwave irradiation 

no solvent, 7−10 min 

A palladium(0)-catalyzed N-arylation of benzotriazole with aryl iodides with both electron-donating 

and electron-withdrawing groups and hetaryl halides has been reported. 

[648] The reaction is carried out in dimethylformamide at 1508C, under phase-transfer 

conditions, in the presence of potassium carbonate and copper salts. The 1-aryl-1H-benzotriazole 

derivatives are obtained in excellent yields (75–98%). 1H-Benzotriazole is also Narylated 

in water by diaryliodonium salts (Ar 1 2IBF 4) yielding the 1-aryl derivatives in almost 

quantitative yields. [649] This is also a palladium- and copper-catalyzed reaction. 

The benzotriazole anion reacts with triacetoxy(4-tolyl)lead [4-TolPb(OAc) 3] in the 

presence of copper(II) acetate to afford a mixture of 1-(4-tolyl)- and 2-(4-tolyl)benzotriazoles 

in 23 and 6% yield, respectively. [650] 

The polymer-supported benzotriazole 664 reacts with 4-tolylboronic acid in the presence 

of copper(II) acetate and pyridine, under microwave irradiation, to yield the corresponding 

N-tolyl derivatives. Cleavage of these products with trifluoroacetic acid gives 

the two regioisomeric benzotriazoles 665 and 666 (1:1) in 55% yield (Scheme 236). [651] 

Scheme 236 N-Arylation of a Polymer-Supported Benzotriazole [651] 

H 

N 

O 

664 



N 

N 

N 

H 

+ 4-TolB(OH)2 

H 2N 

1. Cu(OAc) 2, py 

2. TFA 

55% 

1-(2,4-Dinitrophenyl)-1H-benzotriazole (659,R 1 =NO 2;R 2 = H); Typical Procedure: [644] 

A mixture of 1-chloro-2,4-dinitrobenzene (658, R 1 =NO 2;R 2 = H; 6.08 g, 30 mmol), 1H-benzotriazole 

(21.44 g, 180 mmol), and toluene (30 mL) was refluxed for 9 d. The mixture was 

treated with 20% KOH (200 mL), extracted with CHCl 3 (5 ” 500 mL), dried (MgSO 4), and 

evaporated to afford a yellow solid; yield: 8.20 g (96%); mp 182–1848C. 

O 

665 

N 

N 

N 

4-Tol 

+ 

1:1 

R 3 

R 3 

H2N 

O 

R 2 

R 2 

663 

666 

N 

N 

N 

N 

N 

N 

N 

R 1 

4-Tol 




Alkynylation 

Potassium benzotriazol-1-ide, prepared from 1H-benzotriazole and potassium tert-butoxide, 

reacts with alkynyl(phenyl)iodonium tosylates 667 to give 1-(2-arylethynyl)-1H-benzotriazoles 

668 in good yields (Scheme 237). [652,653] The reaction with oct-1-ynyl(phenyl)iodonium 

tosylate [667,R 1 = (CH 2) 5Me] affords a mixture of two 1-(alk-1-enyl)-1H-benzotriazole 

derivatives. An alternative one-pot synthesis of 1-(substituted ethynyl)-1H-benzotriazoles 

668 (R 1 = alkyl or aryl) has been published. [654,655] 

Scheme 237 N-Alkynylation of Potassium Benzotriazol-1-ide with Alkynyl(phenyl)iodonium 

Tosylates [652,653] 

N 

K N + 

N − 

+ OTs − I + 

R 

Ph 

1 

R 1 = Ph, 4-ClC6H4, 4-Tol, 4-MeOC6H4 


Alkenylation 

667 

THF, t-BuOH, CH2Cl2 rt, 24 h 

45−62% 

A simple and convenient method for the stereoselective synthesis of 1-(alk-1-enyl)-1H-benzotriazole 

derivatives, directly from benzotriazole, has been reported. [656] It involves the 

reaction of alkenyl(phenyl)iodonium salts with 1H-benzotriazole in the presence of a 

base (Scheme 238). In the reaction with alkenyl(phenyl)iodonium salts 669 (R 1 = Ph) and 

671, retention of configuration is observed in the products 670 and 672, but with 669 

(R 1 = Bu) complete inversion of configuration occurs. This method is particularly efficient 

for the preparation of 1-(alk-1-enyl)-1H-benzotriazoles with amino-, acyl-, and alkoxycarbonyl 

substituents, which are difficult to prepare by other methods. Other nonselective 

or less convenient methods for the synthesis of 1-(alk-1-enyl)-1H-benzotriazoles are also 

known. [656] 

668 

N 

N 

N 

Scheme 238 N-Alkenylation of 1H-Benzotriazole with Alkenyl(phenyl)iodonium Salts [656] 

N 

N 

N 

H 

N 

N 

N 

H 

+ 

+ 

H 

+ 

Ph I 

R 

+ 

I 

2OC Ph 

H 

669 

R 1 

671 

R 1 = Me, Bn, 4-ClC6H4; R 2 = Me, Ph, OEt 



BF4 − 

NHR 1 

OTs − 

t-BuOK, t-BuOH, DMF, rt 

R1 = Ph 64% (E-isomer) 

R1 = Bu 59% (Z-isomer) 

K2CO3, DMF, H2O 

rt, 6 h 

67−94% 

N 

N 

N 

670 

R 2 OC 


N 

N 

N 

672 

R 1 

R 1 

NHR 1


Alkylation 

1H-Benzotriazole reacts with dimethyl sulfate, [657,658] diazomethane, [657] and iodomethane 

[658] to give mixtures of 1- and 2-methylbenzotriazole. The 1-methyl isomer is always 

the main product, except in the reaction with diazomethane where the 1-methyl/2-methyl 

ratio is 5:17. [657] Methylation of 4-nitrobenzotriazole and 5-methylbenzotriazole with diazomethane 

leads to the formation of the 2-methyl derivatives. [585] Methylation of 5,6- and 

4,7-dichlorobenzotriazole with dimethyl sulfate gives the 1-methyl isomer as the main 

product. [585] 

The alkylation of 1H-benzotriazole is frequently carried out with alkyl halides in the 

presence of a base; the 1-alkyl isomer 673 is generally the main product and, in some 

cases, 1,3-dialkyl-1H-benzotriazolium salts 675 are also formed (Scheme 239). Sodium hydride 

[659] and sodium alkoxides [660,661] are frequently used as the base but higher yields may 

be obtained using sodium hydroxide in dimethylformamide. [662] Alkylations with alkyl halides 

using phase-transfer catalysis with 18-crown-6, [663] polyethylene glycols or their dialkyl 

ethers, [664] or quaternary ammonium salts [665–667] also give excellent yields. Many other 

reaction conditions have also been used, namely aqueous sodium hydroxide, [668] triethylamine 

in toluene, [669] potassium carbonate in tetrahydrofuran, [670] potassium fluoride and 

alumina in acetonitrile, [661] or just by refluxing the benzotriazole and the alkyl halide in 

benzene or toluene in the absence of any added base. [644,671] 1H-Benzotriazole can also be 

alkylated with alkyl halides in the absence of solvent, either in basic media under solventfree 

phase-transfer catalysis conditions or in the absence of base by conventional or microwave 

heating. [672] 

Scheme 239 Alkylation of 1H-Benzotriazole with Alkyl Halides [659–662] 

X = halo 

N 

N 

N 

H 



R 1 X, base 

673 

N 

N 

N 

R1 NR 

N 

1 

N 

+ + 

The alkylation of 1H-benzotriazole with ethyl bromoacetate, in the presence of sodium 

hydride, gives different ratios of the 1-alkyl/2-alkylbenzotriazole depending on the solvent 

used: 85:15 in acetonitrile and 95:5 in toluene. [659] Mixtures of the two isomers are 

also obtained by alkylation of the sodium salt of 1H-benzotriazole with other Æ-halogenated 

esters or ketones. [644,671] However, in refluxing benzene or toluene, and in the absence 

of any added base, 1H-benzotriazole reacts with these Æ-halogenated carbonyl compounds 

to yield only the 1-alkyl isomer in good yield. [644,671] 

Addition of bromocyclopentane and bromocycloheptane to the anion of benzotriazole 

(generated with sodium ethoxide in ethanol) yields the expected mixtures of 1- and 

2-cycloalkylbenzotriazoles. However, under the same conditions, bromocyclohexane 

gives only cyclohexene and benzotriazole, cyclohexyl tosylate affords only the 2-cyclohexyl-2H-benzotriazole 

674 (R 1 = Cy), while with tricyclohexyl phosphate the 1-cyclohexyl-1H-benzotriazole 

is formed with the complete absence of the N2 isomer. [673] 

A high-yielding route to produce selectively 1-ethyl-1H-benzotriazole involves the 

carbonylation of 1H-benzotriazole with ethyl chloroformate (see Section 13.13.3.3.1.1.2) 

followed by alkylation or the resulting compound with triethyloxonium tetrafluoroborate 

and then methanolysis (Scheme 240). [634] This gives pure 1-ethyl-1H-benzotriazole 

in 89% overall yield from 1H-benzotriazole. Another method for the selective synthesis of 

674 

675 

N 

N 

N 

R1 R1 + 

X − 



1-alkyl-1H-benzotriazoles involves the reaction of 1-(trimethylsilyl)-1H-benzotriazole with 

alkyl halides. [629] 

Scheme 240 A Selective Route to 1-Ethyl-1H-benzotriazole [634] 

N 

N 

N 

H 

EtOCOCl 

aq NaOH 

95% 

N 

N 

N 

CO2Et 

Et3O + BF4 − 

CH2Cl2 

MeOH 

Et 

N+ 

N BF 

− 

4 

N 

CO2Et 

94% 

N 

N 

N 

Et 

The reaction of 1H-benzotriazole with dibromoalkanes may give the two monosubstituted 

derivatives or the three possible disubstituted isomers, depending on the molar ratio 

of the dibromoalkane to 1H-benzotriazole. [661,668] 1H-Benzotriazole reacts with 1 equivalent 

of bis(bromomethyl)benzene (1,2-, 1,3-, or 1,4-), 4,4¢-bis(bromomethyl)biphenyl and 

4¢,4¢¢-bis(bromomethyl)-1,3-terphenyl, [674] and 2,6-bis(bromomethyl)pyridine [675] to yield, 

in each case, only the bis(benzotriazol-1-yl) isomer. Addition of another equivalent of 

the bis(bromomethyl) derivative affords, in each case, only one dicationic benzotriazolophane 

(see schemes in Section 13.13.5.2.2). 1H-Benzotriazole also reacts with dichloromethane 

and chloroform, in the presence of a phase-transfer catalyst, to yield mixtures of 

all possible isomers of di- and tri(benzotriazol-1-yl and -2-yl)methane. [676,677] 

1H-Benzotriazole reacts with diarylmethanols, in the presence of a catalytic amount 

of 4-toluenesulfonic acid and azeotropic removal of water, to give mixtures of the corresponding 

1- and 2-diarylmethylbenzotriazole derivatives (Scheme 241). [669,678] 

Scheme 241 Alkylation of 1H-Benzotriazole with Diarylmethanols [669,678] 

N 

N 

N 

H 

+ HO 



Ar 1 

Ar 2 

TsOH, benzene 

reflux 

− H2O 66−90% 

Ar 1 = Ar 2 = Ph, 4-Me 2NC 6H 4, 4-MeOC 6H 4, 4-ClC 6H 4, 4-Tol 

1H-Benzotriazole reacts with 2-(chloromethyl)oxirane (epichlorohydrin) in benzene to 

yield the two compounds resulting from oxirane ring opening. [679] Using 2 equivalents of 

benzotriazole (and triethylamine) or sodium benzotriazolide the reaction gives a complex 

mixture of products resulting from the oxirane ring opening and simultaneous substitution 

of chlorine by a benzotriazolyl group (Scheme 242). [680] 


Ar 1 

N 

N 

N 

Ar 2 

+ 

N 

N 

N 

Ar 2 

Ar 1

Scheme 242 Alkylation of 1H-Benzotriazole with 2-(Chloromethyl)oxirane [680] 

Bt 1 = 

N 

N 

N 

H 

+ 

Cl 

N 

N ; Bt 

N 

2 = 

O 

+ 

N 

N 

N 

Et3N, toluene 

reflux, 7 h 

Cl 

OH 

Bt 2 

OH 

Bt1 Bt + + 

1 

OH 

Bt1 Bt2 + 

Bt 2 

O 

OH 

Bt2 Bt2 1H-Benzotriazole gives conjugate addition reactions with Æ,â-unsaturated carbonyl compounds 

to yield only 1-alkyl derivatives (reactions carried out without solvent and in the 

presence of a few drops of pyridine or benzyltrimethylammonium hydroxide solution). 

[452] Under similar conditions, and in striking contrast, 4,5,6,7-tetrahalogenated benzotriazoles 

afford only the 2-alkyl derivatives. [16,585] This difference is due mainly to the 

steric effect of the 4,7-substituents, which direct this type of addition to the 2-position. 

This was confirmed by using 4,7-dichloro-1H-benzotriazole and 5,6-dichloro-1H-benzotriazole, 

which give only 2- and 1-substituted derivatives, respectively. [585] Heating a mixture 

of 1H-benzotriazole and N,2-dimethylpropenamide at 1508C for six days gives only the N1 

Michael addition product in 45% yield. [681] 1H-Benzotriazole reacts with acrylamide in basic 

medium (pyridine–sodium methoxide) to afford only the N1 Michael addition product 

in 96% yield. [682] However, it was shown by NMR analysis that the crude product of this 

reaction is a 35:65 mixture of the N1 and N2 addition products, but after 24 hours only 

the signals of the N1 isomer are observed. [682] This means that the Michael addition yields 

a kinetic mixture which slowly equilibrates to the most stable isomer (the thermodynamic 

product). In an aqueous micellar medium, mixtures of N1 and N2 addition products are 

obtained from the reaction of benzotriazole with 1,3-diphenylprop-2-en-1-one (chalcone) 

(Scheme 243), acrylonitrile, and diethyl maleate. [667] 

Scheme 243 Reaction of 1H-Benzotriazole with 1,3-Diphenylprop-2-en-1-one [667] 

N 

N 

N 

H 

+ Ph 

CTAB = cetyltrimethylammonium bromide 



O 

Ph 

NaOH, H2O, CTAB 

rt, 1 d 

1H-Benzotriazole reacts with aliphatic aldehydes to yield isolable crystalline 1-hydroxyalkyl 

benzotriazole derivatives (Scheme 244). [683] In solution these condensation products 

dissociate into their components and equilibrate between the 1- and 2-positions of the 

benzotriazole ring. [8] The reaction with aromatic aldehydes or ketones does not afford 

the corresponding condensation products. 

79% 

+ 

Ph 

N 

N 

N 

O 

N 

N 

N 

Ph 

Ph 

O 

Ph 



Scheme 244 Hydroxymethylation of 1H-Benzotriazole [683] 

N 

N 

N 

H 

+ 

R 1 

O 

H 

R 1 

N 

N 

N 

OH 

H 

1H-Benzotriazole reacts with an aldehyde or ketone and an amine to yield the condensation 

products 676 generally in very high yields (Scheme 245). [684] The aminomethylation 

of 1H-benzotriazole by the Mannich reaction [453,685] is an example of this very general reaction: 

both aliphatic and aromatic aldehydes can be used, ketones (particularly cyclic 

ones), ammonia, and primary and secondary amines (aliphatic, aromatic, and heteroaromatic) 

all give the expected products. [8] 

Scheme 245 Aminomethylation of 1H-Benzotriazole [684] 

N 

N 

N 

H 

+ 

R 1 

O 

R 2 

+ 

R 3 

HN 

R 4 

N 

N 

N 

NR3R4 R2 R1 676 

1-Chloro- and 1-bromo-1H-benzotriazoles 677 (X = Cl, Br) undergo electrophilic addition 

to alkenes to afford 1- and 2-(2-haloalkyl)benzotriazoles, with trans configuration, in 

good yields. [686,687] 1-Bromo-1H-benzotriazole is much more reactive than the chloro derivative. 

For example, the addition of 677 (X = Br) to cyclohexene (giving products 678 and 

679) is essentially instantaneous in dichloromethane at room temperature compared 

with a reaction time of approximately 4 hours for 677 (X = Cl), despite the low solubility 

of 677 (X = Br) (Scheme 246). N,4,5,6,7-Pentachlorobenzotriazole, although extremely insoluble 

in organic solvents, also undergoes rapid addition to alkenes. [687] 1-Chloro-1H-benzotriazole 

also gives addition products with enamines and enol ethers. [642] 

Scheme 246 Addition of 1-Halo-1H-benzotriazoles to Alkenes [686,687] 

677 

X = Cl, Br 

N 

N 

N 

X 

+ 



CH 2Cl 2, rt 

The reaction of 1H-benzotriazol-1-ol derivatives with alkyl halides in the presence of a 

base affords mainly the 1-alkoxy derivatives 680, but the N-alkyl derivatives 681 can also 

be formed (Scheme 247). For example, methylation of 1H-benzotriazol-1-ol with iodomethane, 

in methanol/sodium methoxide, affords a mixture of the O- and N-methyl derivatives. 

[609,615,688] However, using the same conditions, 4-nitro-1H-benzotriazol-1-ol and 6-nitro-1H-benzotriazol-1-ol 

give only the 1-methoxy compounds. [615,689] Reaction of 1H-benzotriazol-1-ol 

with 1-acetoxy-4-iodobutane in acetonitrile, with potassium carbonate as 

base, gives only the O-alkyl derivative in 95% yield. [670] A range of 1-alkoxy-4,5-dichloro- 

1H-benzotriazole derivatives is prepared by reaction of the sodium salt of 4,5-dichloro- 

1H-benzotriazol-1-ol with the appropriate alkyl halides. [690] Several 1-alkoxy-4-nitro- 


678 

N 

N 

N 

X 

+ 

N 

N 

N 

679 

X

1H-benzotriazole derivatives are prepared by alkylation of the 1-hydroxy derivative with 

alkyl halides under phase-transfer conditions. [691] 

Scheme 247 Alkylation of 1H-Benzotriazol-1-ols with Alkyl Halides [688–691] 

R 1 

N 

N 

N 

OH 

R 2 X, base 

R 1 

680 

N 

N 

N 

OR2 Alkylation of 1H-Benzotriazole with Alkyl Halides; General Procedure: [662] 

To a flask provided with a CaCl 2 guard tube and magnetic stirrer was introduced finely 

ground NaOH (40 mmol), DMF (8–10 mL), 1H-benzotriazole (10 mmol), and the alkyl halide 

(10 mmol). After stirring for 15–60 min, the mixture was poured into H 2O (50–70 mL) 

to give a solid or oily product. Solids were collected by filtration, washed with H 2O 

(25 mL), and dried, while the oily products were extracted with CHCl 3 (3 ” 10 mL), washed 

with H 2O (5 ” 10 mL), dried (MgSO 4), and the solvent evaporated under reduced pressure. 

1-Alkyl- and 2-alkylbenzotriazole isomers were separated by column chromatography 

(hexane/CHCl 3 2:1). 


Halogenation 

Benzotriazole is rapidly converted into crystalline 1-chloro-1H-1,2,3-benzotriazole (682, 

X = Cl) by treatment with sodium hypochlorite in aqueous acetic acid (Scheme 248). [692] 

Similar reaction with sodium hypoiodite in aqueous sodium hydroxide gives 1-iodo- 

1H-benzotriazole in 43% yield. [687] Alternatively 1-iodo-1H-benzotriazole is obtained in 

94% yield by treatment of 1-chloro-1H-benzotriazole in dichloromethane with 1 equivalent 

of iodine. [687] Similarly, 1-bromo-1H-benzotriazole is prepared in 80% yield by the addition 

of 1-chloro-1H-benzotriazole to a solution of bromine in dichloromethane. [687] Addition 

of sodium hypochlorite to a solution of 4,5,6,7-tetrachloro-1H-benzotriazole in glacial 

acetic acid, at room temperature, rapidly affords N,4,5,6,7-pentachloro-1H-benzotriazole 

(because of the extreme insolubility of this compound, the position of the fifth chlorine 

at N1 or N2 was not assigned unambiguously). [687] 

Scheme 248 Synthesis of 1-Chloro- and 1-Iodo-1H-benzotriazole [687,692] 

N 

N 

N 

H 

+ NaOX 



AcOH, H 2O, rt 

X = Cl 100% 

X = I 43% 

1H-Benzotriazole is chlorinated to 4,5,6,7-tetrachloro-1H-benzotriazole (683, X = Cl) in 

87% yield by refluxing with aqua regia (a mixture of concentrated hydrochloric acid and 

concentrated nitric acid) for three hours (Scheme 249). [16] Under similar conditions, 2methyl-2H-benzotriazole 

gives 4,5,6,7-tetrachloro-2-methyl-2H-benzotriazole in 50% 

yield [16] but chlorination of 1-methyl-1H-benzotriazole with aqua regia requires three 

days to give 4,5,6,7-tetrachloro-1-methyl-1H-benzotriazole in 57% yield. [585] Refluxing 4-nitro-1H-benzotriazole 

with aqua regia for three days affords 4,5,6,7-tetrachloro-1H-benzotriazole 

(62%), and 2,5-dimethyl-2H-benzotriazole gives 4,5,6,7-tetrachloro-2-methyl- 

2H-benzotriazole (yield not reported); in these systems the substituents on the benzenic 

ring are replaced by chlorine. [585] 

682 

+ 

N 

N 

N 

X 

R 1 

681 

R 2 

N 

N 

N 

O − 

+ 



Scheme 249 Synthesis of 4,5,6,7-Tetrachloro- and 

4,5,6,7-Tetrabromo-1H-benzotriazole [16,585] 

N 

N 

N 

H 

A: HCl, HNO3, reflux, 3 h 

B: Br2, HNO3, reflux, 30 h 

A: X = Cl 87% 

B: X = Br 54% 

Reaction of 1H-benzotriazole with bromine in concentrated nitric acid under reflux affords 

4,5,6,7-tetrabromo-1H-benzotriazole in 54% yield (Scheme 249). [585] 1-Methyl- and 2methyl-1H-benzotriazoles 

are brominated in the same way affording, respectively, 

4,5,6,7-tetrabromo-1-methyl-1H-benzotriazole (48% yield) and 4,5,6,7-tetrabromo-2-methyl-2H-benzotriazole 

(67% yield). [585] 

1-Chloro-1H-benzotriazole (682, X = Cl); Typical Procedure: [692] 

CAUTION: 1-Chloro-1H-benzotriazole reacts violently with DMSO. 

2 M NaOCl (50 mL, 0.1 mol) was added dropwise at rt to a stirred soln of 1H-benzotriazole 

(10 g, 0.08 mol) in aq AcOH (1:1). After dilution with H 2O the resulting solid was collected 

and recrystallized once (CH 2Cl 2/petroleum ether) to give pure (682, X = Cl) as colorless 

needles; yield: 13 g (~100%); mp 104–1088C. 

4,5,6,7-Tetrachloro-1H-benzotriazole (683, X = Cl); Typical Procedure: [16] 

A soln of 1H-benzotriazole (4.76 g, 0.040 mol) in a mixture of concd HCl (525 mL) and 

concd HNO 3 (175 mL) was refluxed for 3 h, cooled, and diluted to precipitate the product; 

yield: 9.0 g, (87%). Recrystallization (MeNO 2) gave a white crystalline solid; mp 256–2608C. 


Sulfonylation 



1H-Benzotriazole reacts with trifluoromethanesulfonic anhydride, in dry dichloromethane 

and dry pyridine at –788C, to afford 1-(trifluoromethylsulfanyl)-1H-benzotriazole in 

87% yield. [642] 

5,6-Dimethyl-1H-benzotriazole reacts with benzenesulfonyl chloride, in the presence 

of 10% aqueous sodium hydroxide solution, to yield the 1-phenylsulfonyl derivative in 

72% yield; [587] naphthotriazoles also give only the 1-phenylsulfonyl derivatives. [582] 

1H-Benzotriazol-4-amine reacts with an equimolar amount of 4-toluenesulfonyl chloride 

in pyridine at room temperature to give 4-(tosylamino)-1H-benzotriazole (684,Ar 1 =4- 

Tol) (Scheme 250). [699] Under similar experimental conditions, 5-methyl-1H-benzotriazol-4amine 

gives the 1-tosyl-1H-benzotriazole derivative 685 as the only isolated product. With 

an excess of arenesulfonyl chloride both starting benzotriazol-4-amines afford the bis-sulfonylated 

derivatives 686. [699] The reaction of benzotriazol-5-amines with arenesulfonyl 

chlorides has also been reported. [639] 1-Mesyl- and 1-(phenylsulfonyl)-1H-benzotriazole are 

prepared in good yields from the reaction of the corresponding sulfonyl chlorides and 1- 

(trimethylsilyl)-1H-benzotriazole [630] or 1-(tributylstannyl)-1H-benzotriazole. [693] 


X 

X 

X 

X 

683 

N 

N 

N 

H

Scheme 250 Sulfonylation of Benzotriazol-4-amines [699] 

R 1 

R 1 

NH 2 

N 

N 

N 

H 

Ar1SO2Cl (4 equiv) 

py, rt 

NHSO2Ar 1 

686 

N 

N 

N 

R 1 = H, Me; Ar 1 = Ph, 4-Tol 


N-Amination 

SO 2Ar 1 

TsCl (1 equiv) 

py, rt 

R 1 = H 

R 1 = Me 

NHTs 

684 

NH 2 

685 

N 

N 

N 

H 

N 

N 

N 

Ts 

1H-Benzotriazol-1-amines are valuable precursors to didehydrobenzenes under notably 

mild conditions, using either lead(IV) acetate [694] or N-bromosuccinimide. [695] Treatment 

of 1H-benzotriazole with hydroxylamine-O-sulfonic acid in hot (70–75 8C) aqueous potassium 

hydroxide solution gives a mixture of 1H-benzotriazol-1-amine (687) and 2H-benzotriazol-2-amine 

in an approximately 3:1 ratio (Scheme 251). [694] The formation of the 2amino 

isomer is avoided by changing the reaction conditions (temperature and solvent). 

The 1-amino isomer is obtained selectively in 62% yield when the reaction is carried out in 

dioxane containing 5% water and the reaction mixture is maintained below 508C. Better 

yields (69%) of the 1-isomer, uncontaminated by the 2-isomer, are obtained in dimethylformamide 

containing 5% water. [696] In ethanol the conversion is nearly quantitative, but a 

2:1 mixture of the two isomers is formed, the 2-amino derivative being the main product. 

[696] 

Scheme 251 N-Amination of 1H-Benzotriazole [694,696] 

N 

N 

N 

H 



H2NOSO3H, aq KOH, DMF 

tion of a 1,2,3-triazolo[4,5-d][1,2,3]triazole with O-(mesitylsulfonyl)hydroxylamine affords 

the 1-amino and 2-amino derivatives in 22 and 46% yield, respectively. [698] N-Amination of 

4-cyanoazuleno[1,2-d]-1,2,3-triazole with 1-(aminooxy)-2,4-dinitrobenzene gives a 3:2 mixture 

of two isomeric N-amino derivatives in 54% yield. [569] 

Scheme 252 N-Amination of Benzo[1,2-d:4,5-d¢]bistriazole [596] 

H 

N 

N 

N 

688 

+ 

N 

N 

N 

H 

H 2N 

N 

N 

N 

1. 10% KOH, 60 oC 2. H2NOSO3H 

66−68 oC, 2 h 

N 

N 

N 

NH 2 

+ 

1H-Benzotriazol-1-amine (687): [696] 

Hydroxylamine-O-sulfonic acid (94.9 g, 0.84 mol) was added portionwise to a stirred soln 

of 1H-benzotriazole (50.0 g, 0.42 mol) and KOH (117.6 g, 2.1 mol) in DMF (250 mL) and H 2O 

(12 mL) such that the temperature of the mixture remained below 508C (ca. 1.0 g •min –1 ). 

After the addition was complete, the mixture was cooled to rt and stirring continued for a 

further 1 h. The resulting precipitate was removed by vacuum filtration and washed thoroughly 

with Et 2O. The filtrate was evaporated to dryness using a rotary evaporator attached 

to a rotary pump. The temperature of the water bath was kept below 508C; above 

this, rearrangement to the corresponding 2-amino isomer became significant. The residue 

was dissolved in a minimum of 2 M HCl and the resulting soln kept at –28C overnight 

during which time 1H-benzotriazol-1-amine hydrochloride crystallized and was removed 

by filtration. The solid was dried under vacuum and showed mp 131–1348C and was >95% 

pure according to 1 H NMR data. The free amine was obtained by direct basification of the 

solid salt using aq 2 M NaOH followed by extraction with Et 2O (3 ” 100 mL). The combined 

extracts were dried and evaporated to leave 687 as a colorless solid; yield: 38.8 g (69%); mp 

848C. 


Nitration 



Nitration of 1H-benzotriazole with a mixture of concentrated nitric and sulfuric acids, at 

room temperature, gives 4-nitro-1H-benzotriazole in 50% yield while 5-methyl-1H-benzotriazole 

gives the 4-nitro derivative 689 (R 1 = Me) in 90% yield under similar experimental 

conditions (Scheme 253). [699] Nitration of 5-chloro-1H-benzotriazole (at 608C) affords derivative 

689 (R 1 = Cl) in 83% yield. [700] Nitration of 1H-benzotriazole-5-carboxylic acid at 

908C gives derivative 690 (R 1 =CO 2H) while 5-nitro-1H-benzotriazole at 1158C affords a 

mixture of 690 (R 1 =NO 2, 30%) and 691 (67%). [700] 


H 

N 

N 

N 

N 

N 

N 

H 2N 

N 

N 

N 

N 

N 

N 

NH 2 

NH 2 

+ 

+ 

N 

N 

N 

H 

H 2N 

N 

N 

N 

N 

N 

N 

NH2 

N 

N 

N 

NH 2

Scheme 253 Nitration of 1H-Benzotriazoles [699,700] 

R 1 

N 

N 

N 

H 

A: HNO3, H2SO4, rt, overnight 

B: HNO3, H2SO4, 0−60 oC, 2 h 

A: R1 = H 50% 

A: R1 = Me 90% 

B: R1 = Cl 83% 

A: HNO3, H2SO4, 0−90 oC, 2.5 h 

B: HNO3, H2SO4, 0−115 oC, 12.5 h 

A: R1 = CO2H 48% (690 only) 

B: R1 = NO2 97%; (690/691) 30:67 

Nitration of 1-methyl-1H-benzotriazole affords 1-methyl-7-nitro-1H-benzotriazole [701] 

while 2-methyl-2H-benzotriazole gives 2-methyl-5-nitro-2H-benzotriazole. [585] Nitration of 

1-(1,2,3-triazolyl)-1H-benzotriazole derivatives with potassium nitrate in concentrated 

sulfuric acid at 60 8C affords the corresponding 5-nitro derivatives in high yields (ca. 

80%). If the 5-position is occupied, nitration occurs at the 4-position. [322] 1-Phenyl- and 2phenylbenzotriazoles 

give the corresponding 4-nitrophenyl derivatives by nitration with 

potassium nitrate in concentrated sulfuric acid at 608C. [702,703] Nitration of 1-(2,4,6-trinitrophenyl)-1H-benzotriazole 

with a mixture of concentrated nitric and sulfuric acids, at 

reflux for 2 hours, gives the 5,7-dinitro derivative in 73% yield. [586] Nitration of 2-(2-hydroxy-5-methylphenyl)-2H-benzotriazole 

with a mixture of concentrated nitric and acetic 

acids, at 708C for 10 minutes, gives the 2-(2-hydroxy-5-methyl-3-nitrophenyl) derivative in 

84% yield. [704] Nitration of 1,5-bis(2,4,6-trinitrophenyl)benzo[1,2-d:4,5-d¢]bistriazole with a 

mixture of nitric acid and sulfuric acid gives the 4-nitro derivative in 21% yield. [595] 

5-Methyl-4-nitro-1H-benzotriazole (689,R 1 = Me); Typical Procedure: [699] 

To 5-methyl-1H-benzotriazole (5 g, 37.5 mmol) in concd H 2SO 4 (20 mL) was added a mixture 

of HNO 3 (70%, 5 mL) and concd H 2SO 4 (5 mL) at below 208C, and the resulting mixture 

was allowed to stand overnight. The soln was poured onto ice, and the resulting precipitate 

was collected by filtration, washed with H 2O, and recrystallized (EtOH) to give microcrystals; 

yield: 6.0 g (90%); mp 254–2558C. 

13.13.3.3.1.1.13 Method 13: 

Azo Coupling 



N-Unsubstituted, 1- and 2-substituted activated benzotriazoles (with a hydroxy or amino 

group) all react with arenediazonium salts to yield (arylazo)benzotriazoles. [631,701,705] A 

range of benzo[1,2-d:3,4-d¢]bistriazoles 695 are prepared by oxidation of the 4-(arylazo)benzotriazol-5-amines 

694 (see Section 13.13.4.1.2.1.1) obtained from the reaction of 2aryl-2H-benzotriazol-5-amines 

692 with diazonium salt 693 (Scheme 254). [706] 

R 1 

R 1 

NO 2 

689 

NO 2 

690 

N 

N 

N 

H 

N 

N 

N 

H 

+ 

O 2N 

O 2N 

691 

N 

N 

N 

H 



Scheme 254 Azo Coupling to 2-Aryl-2H-benzotriazol-5-amines [706] 

R 1 

H 2N 

692 

N 

NAr 1 

N 

Ar2N2 Cl − 

+ 

693 

R 1 = H, Me, Et, OMe, Cl, Br, CO2H, SO3H; Ar 1 = Ph, aryl, naphthyl 

Ar 2 = 

SO 3H 

HO3S 

NO2 

R 1 

H 2N 

Ar 2 N 

N 

694 

N 

NAr 1 

N 

CuSO 4, NH 4OH 

R 1 

N 

Ar2N N 

695 

N 

NAr1 N 

Both 1H-benzotriazol-5-ol and 5-hydroxy-1H-benzotriazole-4-carboxylic acid afford the 

same azo dye 696 when reacted with diazonium salts (Scheme 255). [631] The complementary 

synthetic route to (arylazo)benzotriazoles, i.e. diazotization of benzotriazol-5-amine 

followed by reaction with an activated aromatic compound can also be used successfully. 

[707] 

Scheme 255 Azo Coupling with Activated Benzotriazoles [631] 

HO 

HO 

CO 2H 

Ar 1 = 4-ClC 6H 4 

N 

N 

N 

H 

N 

N 

N 

H 



Ar1N2 Cl − 

+ 

693 

85% 

Ar1N2 Cl − 

+ 

693 

− CO2 

93% 

HO 

N NAr1 

4-(4-Chlorophenylazo)-1H-benzotriazol-5-ol (696); Typical Procedure: [631] 

4-Chloroaniline (6.38 g, 0.05 mol) was dissolved in 2.5 M HCl (100 mL) and diazotized by 

the addition of 5 M NaNO 2 (10 mL) at 108C. This soln was filtered and diluted to 200 mL 

to make a 0.25 M soln. Part of this soln (8 mL, 2 mmol) was added with stirring to a soln 

of 1H-benzotriazol-5-ol (0.286 g, 2.12 mmol) dissolved in a mixture of H 2O (40 mL), 1 M 

NaOH (4 mL) and 1 M Na 2CO 3 (2 mL). A deep orange soln was formed immediately. After 

15 min stirring, the soln was acidified by the addition of 5 M HCl (1 mL). The reddish-orange 

precipitate formed was collected by filtration, washed, and dried at 1008C; yield: 

0.47 g (85%); mp 247–2498C. 


696 

N 

N 

N 

H

13.13.3.3.2 Of Carbon Functionalities 


Decarboxylation 

When refluxed in water, 5-hydroxy-1H-benzotriazole-4-carboxylic acid decarboxylates to 

afford 1H-benzotriazol-5-ol in 76% yield (Scheme 256). [631] Its isomer, 5-hydroxy-1H-benzotriazole-6-carboxylic 

acid does not decarboxylate under the same conditions. [631] 

Scheme 256 Decarboxylation of Benzotriazoles [631] 

HO 

CO2H 

N 

N 

N 

H 


Deacylation 

H2O reflux, 20 h 

76% 

HO N 

H2O reflux HO 

N 

N 

N 

N 

H 

HO2C N 

H 

1-Acetyl-5-methyl-1H-benzotriazole and 1-acetyl-6-methyl-1H-benzotriazole are deacetylated 

in boiling acetic acid/water (1:1) for eight to nine hours. [583] 1-Acetyl-6-(acetylamino)- 

5-methyl-1H-1,2,3-benzotriazole is selectively hydrolyzed to 6-(acetylamino)-5-methyl-1H- 

1,2,3-benzotriazole which then is hydrolyzed to 5-methyl-1H-benzotriazol-6-amine. [708] 

1-Substituted benzotriazol-5-amines are obtained in 85% yield by deacylation of the corresponding 

5-[(trifluoroacetyl)amino]-1H-benzotriazoles in methanol/potassium carbonate. 

[639] 1-Acetyl-5,6-dimethyl-1H-benzotriazole (697) is slowly deacetylated when dissolved 

in ethanol/water (3:1) at room temperature (Scheme 257). [587] Compound 698 is 

hydrolyzed in 6 M hydrochloric acid to the propanoic acid derivative 699. [709] 

Scheme 257 Deacetylation of 1-Acetyl-1H-benzotriazoles [587,709] 

EtO 2C 

697 

AcO 

N 

N 

N 

Ac 

698 

EtOH, H 2O, rt 

N 

N 

N 

Ac 

HCl, H 2O, rt, 17 h 

1,7-Diacetylbenzobistriazole 700, dissolved in ethanol/water (1:1), is deacetylated in almost 

quantitative yield by acid treatment (Scheme 258). [596] 

90% 

N 

N 

N 

H 

HO 2C 

HO 

699 

N 

N 

N 

H 

Scheme 258 Deacetylation of 1,7-Diacetyl-1,7-dihydrobenzo[1,2-d:4,5-d¢]bistriazole [596] 

N 

N 

N 

Ac 

700 

N 

N 

N 

Ac 



H2SO4, H2O, EtOH 

reflux, 1 h 

96% 

N 

N 

N 

H 

688 

H 

N 

N 

N 



1,5-Dihydrobenzo[1,2-d:4,5-d¢]bistriazole (688); Typical Procedure: [596] 

A mixture of 1,7-diacetyl-1,7-dihydrobenzo[1,2-d:4,5-d¢]bistriazole (700; 0.73 g, 3 mmol), 

50% aq EtOH (100 mL), and concd H 2SO 4 (1 mL) was refluxed for 1 h, then the reflux condenser 

was removed and most of the EtOH was allowed to evaporate. The resultant mixture 

was chilled and filtered to remove the product, which was washed with H 2O and 

dried at 1008C to give pure 688; yield: 0.46 g (96%); explosion temperature 3708C when 

heated at 208C • min –1 . 

13.13.3.3.3 Of Heteroatoms 


Deoxygenation 

2H-Benzotriazole 1-oxides of type 701 are readily deoxygenated to 2H-benzotriazoles 702 

or 703 by reduction with zinc dust in alkaline ethanolic solutions, [710] zinc powder and 

sulfuric acid, [711] hydrazine hydrate in a high-boiling ether, [712] or by using baker s yeast 

in sodium hydroxide solution [713] (Scheme 259). If the reduction with zinc is carried out 

with heating, the 5-chloro-2H-benzotriazole 1-oxides 701 (R 1 = Cl) are simultaneously deoxygenated 

and dechlorinated (see Section 13.13.3.3.3.2). [710] 

Scheme 259 Deoxygenation of 2-Aryl-2H-benzotriazole 1-Oxides [710,713] 

R 1 

N 

N 

N 

O − HO R2 + 

701 

R 3 

R 1 = H, Cl; R 2 = H, t-Bu, CH 2t-Bu; R 3 = Me, t-Bu, CH 2t-Bu 

Zn, NaOH, EtOH 

rt, 1 h 

68−88% 

baker's yeast 

NaOH 

85 oC, 24−30 h 

86−90% 

R 1 

R 1 

N 

N 

N 

702 

N 

N 

N 

703 

R 3 

HO Bu t 

R 3 

HO R 2 

2-Alkyl-2H-benzotriazole 704 is deoxygenated to 705 by reduction with tin(II) chloride 

(Scheme 260). [714] 

Scheme 260 Deoxygenation of 2-Alkyl-2H-benzotriazole 1-Oxides [714] 

N 

N 

N 

O − 

+ 

704 

OHC 



SnCl2, HCl 

72% 

Refluxing 1-nonyl-1H-benzotriazole 3-oxide (706) in neat acetic anhydride gives the deoxygenated 

1-nonyl-1H-benzotriazole (707; yield not reported) (Scheme 261). [715] 


N 

N 

N 

705 

OHC

Scheme 261 Deoxygenation of 1-Alkyl-1H-benzotriazole 3-Oxides [715] 

706 

O − 

N+ 

N 

N 

( ) 8 

Ac 2O, reflux, 48 h 

Polymer-supported 1H-benzotriazol-1-ol 708 is readily converted into the corresponding 

NH derivative 709 by reductive cleavage of the 1-hydroxy moiety with either phosphorus 

trichloride or samarium(II) iodide (Scheme 262). [622] 

707 

N 

N 

N 

Scheme 262 Reductive Cleavage of the 1-Hydroxy Moiety in a Polymer-Supported 

1H-Benzotriazol-1-ol [622] 

708 

N 

N 

N 


Dehalogenation 

OH 

PCl3, CHCl3, reflux, 20 h 

or SmI2, THF, reflux, overnight 

A simultaneous deoxygenation and dehalogenation, to give products 711, is observed 

during the reduction of 5-chloro-2H-benzotriazole 1-oxides 710 with zinc dust in alkaline 

ethanolic solution and heating on a steam bath for five hours (Scheme 263). [710] 

Scheme 263 Dehalogenation of 5-Chloro-2H-benzotriazole 1-Oxides [710] 

Cl 

O HO But − 

N+ 

N 

N 

710 

13.13.3.3.4 Addition Reactions 



R 1 

Zn, NaOH, EtOH, H2O 100 oC, 5 h 

R1 = Me 73% 

R1 = t-Bu 80% 


Conversion into N-Oxides or Epoxides 

( ) 8 

709 

N 

N 

N 

711 

N 

N 

N 

H 

HO Bu t 

1-Alkyl-1H-benzotriazoles react with dimethyldioxirane to give the corresponding 1-alkyl- 

1H-benzotriazole 3-oxides 712. In contrast, under similar conditions, 2-alkyl-2H-benzotriazoles 

713 are converted into the corresponding trans-4,5,6,7-diepoxy-4,5,6,7-tetrahydro- 

2H-benzotriazoles 714 (Scheme 264). [715] 

R 1 



Scheme 264 Oxidation of Benzotriazoles with Dimethyldioxirane [715] 

N 

N 

N 

O (2−3 equiv) 

O 

CH2Cl2, rt, 24−36 h 

35−92% 

N 

N 

N 

O − 

R 

+ 

1 R1 R 1 = Me, Et, Pr, (CH 2) 5Me, (CH 2) 8Me, Bn, CH 2CH 2Ph, CHPhMe, CH 2CO 2Et, CH 2OPh, CH 2C CH, CH 2CN 

N 

N 

N 


Ar 1 

O (4 equiv) 

O 

CH2Cl2, rt, 3 d 

Ar1 = Ph 50% 

Ar1 = 4-O2NC6H4 77% 

2-Methyl-2H-benzotriazole is converted into its 1-oxide derivative, in very low yield, by oxidation 

with 3-chloroperoxybenzoic acid (Scheme 265). [615] Most of the starting benzotriazole 

is recovered unchanged. 

712 

O 

O 

N 

N 

N 

Scheme 265 Oxidation of Benzotriazoles with 3-Chloroperoxybenzoic Acid [615] 

N 

NMe 

N 

MCPBA (4 equiv) 

CH2Cl2, 0 oC to rt, 12 d 

0.8% 


2-Substituted Benzotriazoles 


13.13.4.1.1 By Formation of Two N-N Bonds 

13.13.4.1.1.1 Fragments N-C-C-N and N 


From Benzene-1,2-diamine and Nitrobenzenes 

O 

N 

NMe 

N 

− 

+ 

Benzene-1,2-diamine reacts with nitrobenzenes to yield 2-aryl-2H-benzotriazoles and 2aminoazobenzenes 

(Scheme 266). [716] The latter compounds can be converted into 2-aryl- 

2H-benzotriazoles (see Scheme 267). 

Scheme 266 2-Aryl-2H-benzotriazoles from Benzene-1,2-diamine and Nitrobenzenes [716] 

NH 2 

NH 2 


+ Ar 1 NO2 



NAr 

N 

1 

N 

+ 

714 

Ar 1 

N NAr 1 


NH2




Cyclization of 2-Aminoazobenzenes 

2-Aminoazobenzenes are converted into 2-aryl-2H-benzotriazoles by oxidation with copper 

sulfate in ammonia or pyridine solution (Scheme 267). Using ammoniacal copper sulfate, 

2,4-diaminoazobenzene (715, R 1 = 4-NH 2;R 2 = H) is converted quantitatively into 2phenyl-2H-benzotriazole-5-amine, 

[717] and 2,2¢-diaminoazobenzene (715, R 1 =H; R 2 =2- 

NH 2) is oxidized to 2-(2-aminophenyl)-2H-benzotriazole (716; R 1 =H,R 2 = 2-NH 2) with copper 

sulfate in pyridine in 65% yield. [643] 

Scheme 267 Oxidative Cyclization of 2-Aminoazobenzenes [643,717] 

R 1 

N N 

NH 2 

715 

R 2 

CuSO4, H2O NH3 or py 

rt to reflux, 2 h 

Similarly, 1-(2-nitrophenylazo)-2-naphthylamine 717 is converted into the naphthotriazole 

718 by oxidative cyclization with copper sulfate in pyridine (Scheme 268). [643] The 

same naphthotriazole is obtained in 70% yield by refluxing the azo compound in thionyl 

chloride. [643] 

R 1 

N 

N 

N 

Scheme 268 Oxidative Cyclization of 1-(2-Nitrophenylazo)-2-naphthylamine [643] 

O 2N 

N N 

NH 2 

717 


13.13.4 2-Substituted Benzotriazoles 571 

A: CuSO4, py, reflux, 4 h 

B: SOCl2, benzene, reflux, 18 h 

A: 83% 

B: 70% 

2-(Arylazo)anilines 719 and 1-(arylazo)-2-naphthylamines 721 are converted into the corresponding 

2H-benzotriazoles 720 and 2H-naphthotriazoles 722, respectively, by refluxing 

in dimethylformamide, with a current of bubbling air, in the presence of copper(II) 

acetate (Scheme 269). [718] This procedure [718,719] and the one using copper sulfate as oxidant, 

[547,720,721] can also be applied to the synthesis of heterocycle-fused 1,2,3-triazoles. 

716 

R 2 

N 

N 

N 

718 

O 2N 



Scheme 269 Air Oxidation of 2-(2-Thienylazo)aniline and 1-(2-Thienylazo)- 

2-naphthylamine Derivatives [718] 

R 1 

N N 

NH2 

719 

S 

R 1 = Me, OMe; R 2 = CN, CO 2Et 

R 1 = CN, CO2Et 

N N 

NH2 

R 2 

R 1 

721 



S 

Cu(OAc)2, air 

DMF, reflux, 4 h 

61−69% 

Cu(OAc)2, air 

DMF, reflux, 4 h 

71−74% 

A range of benzo[1,2-d:3,4-d¢]bistriazoles is prepared by oxidation of 4-(arylazo)benzotriazol-5-amines 

(see Scheme 254 in Section 13.13.3.3.1.1.13). [706] 

2-(2-Aminophenyl)-2H-benzotriazole (716,R 1 =H;R 2 = 2-NH 2); Typical Procedure: [643] 

2,2¢-Diaminoazobenzene (4.4 g, 0.02 mol) was dissolved in pyridine (50 mL) and treated 

with anhyd CuSO 4 (12.8 g, 0.08 mol) added in portions with stirring. After 30 min at rt, 

the mixture was refluxed for 2 h, cooled, and poured into cold H 2O (200–250 mL) with stirring. 

The dark solid which separated was collected by filtration and washed with H 2O. 

Three recrystallizations (2 ” EtOH and 1 ” hexane), with concomitant treatment with 

activated carbon, yielded well-defined, yellow crystals; yield: 65%; mp 97–98 8C. 


Cyclization of 2-Azidoazobenzenes 

The synthesis of 2H-benzotriazoles by thermal extrusion of nitrogen from 2-azidoazobenzenes 

has been known since the 19th century. [722,723] This is a very convenient method 

since a range of 2-azidoazobenzenes can be prepared from simple precursors (Scheme 

270). [724,725] The kinetics of the thermal decomposition of 2-azidoazobenzenes 723 to 2aryl-2H-benzotriazoles 

724 has been investigated. [726] The reaction of 723 with boron trichloride 

or trifluoride in benzene at room temperature also gives benzotriazoles 724 in 

high yields (90–94%). [727] 


R 1 

N 

N 

N 

720 

N 

N 

N 

722 

R 1 

R 2 

S 

S

Scheme 270 Synthesis of 2-Azidoazobenzenes and Their Conversion into 

2-Aryl-2H-benzotriazoles [724,725] 

NH 2 

N 3 

NaNO2, H + 

+ 

N2 N3 

X = NR 1 R 2 , OH 

+ Ar 1 NO 

+ Ar 1 X 

− H 2O 

723 

N NAr 1 

N 3 

heat 

− N2 

724 

NAr 

N 

1 

N 

The benzotriazolo[2,1-a]benzotriazole 727 is prepared in good yield by the thermal or 

photochemical decomposition of 2,2¢-diazidoazobenzene (725). This transformation requires 

the elimination of 2 equivalents of nitrogen and this can be performed at 1758C 

(Scheme 271). However, since the nitrogen is liberated in two distinct stages, 1 equivalent 

at approximately 608C and the second equivalent at approximately 1708C, it is possible to 

convert 725 into 2-(2-azidophenyl)-2H-benzotriazole (726) in good yield. [643,728] Benzotriazole 

726 is also formed when a benzene solution of 725 is exposed to sunlight for three 

days. Similarly, 726 is converted into 727 when exposed to sunlight for ten days. [643] 

Scheme 271 Thermolysis of 2,2¢-Diazidoazobenzene [643,728] 

N 3 

N N 

725 

N 3 

− 2N 2 

93% 



Decalin 

175 oC, 2−3 h 

acetone or benzene 

reflux, 2 h 

− N 2 

70% 

N 

N 

N 

+ N 

− 

727 

− N 2 

95% 

N 

N 

N 

726 

N 3 

Decalin 

175−185 oC, 2−3 h 

2,4-Bis(arylazo)-1-azido- and 1-(arylazo)-2-azidonaphthalene derivatives 728 and 730 are 

converted into 2H-naphtho[1,2-d][1,2,3]triazoles 729 by thermal decomposition (Scheme 

272). [729] 



Scheme 272 Thermolysis of (Arylazo)azidonaphthalenes [729] 

R 1 

R 1 

728 

730 

N NAr 1 

N 3 

N3 

N 

NAr 1 

heat 

− N 2 

R 1 = N2Ar 1 78−81% 

heat 

− N2 

R 1 = H 60−85% 

R 1 

729 

NAr 

N 

1 

N 

1-(2-Azidophenyl)-3-methyl-3-phenyltriazene (731) is converted into 2-[methyl(phenyl)amino]-2H-benzotriazole 

(732) when refluxed in m-xylene (Scheme 273). [725] 

Scheme 273 Thermolysis of a (2-Azidophenyl)triazene Derivative [725] 

N3 

m-xylene, reflux, 1 h 

N 

N 

N 

N N Ph 

N 

Me 

− N2 63% 

731 732 

Ph 

N 

Me 

2-Azidoazobenzenes 734 are intermediates in the conversion of 2-nitro-, 2-chloro-, and 2bromoazobenzenes 

733 into 2-aryl-2H-benzotriazoles 735 (Scheme 274). This transformation 

is accelerated by the addition of a suitable metal catalyst (e.g., CuBr). [730] 

Scheme 274 Synthesis of 2-Aryl-2H-benzotriazoles from 2-Nitro-, or 2-Haloazobenzenes 

and Sodium Azide [730] 

R 1 

733 

X = NO 2, Cl, Br 

X 

N NAr1 



NaN3, DMSO 

or DMF 

125 oC, 4−10 h 

R 1 

734 

N 3 

N NAr1 

− N 2 

R 1 

735 

NAr 

N 

1 

N 

2-(2-Azidophenyl)-2H-benzotriazole (726); Typical Procedure: [643] 

A soln of 725 (5 g, 18.9 mmol) in acetone or benzene (CAUTION: carcinogen) was refluxed 

for 2 h. N 2 was evolved, and the orange color was discharged. The solvent was removed by 

distillation, and the crystalline residue was recrystallized (petroleum ether or aq acetone) 

to afford light yellow needles; yield: 70%; mp 78–79 8C. 



Cyclization of 2-Nitroazobenzenes 

2-Nitroazobenzenes 736 give reductive cyclization reactions to afford 2-aryl-2H-benzotriazole 

1-oxides 737 or 2-aryl-2H-benzotriazoles 738, depending on the reducing agent and 

the reaction conditions (Scheme 275). For example, reduction of azo compounds 736 with 

glucose [710] or with hydroxylamine [731] in ethanolic sodium hydroxide solution, at reflux, 

affords 2H-benzotriazole 1-oxides 737 in good yields. 2-Nitroazobenzenes react with thiourea 

S,S-dioxide in ethanolic sodium hydroxide to give, depending on the reaction conditions, 

either the corresponding 2-aryl-2H-benzotriazoles 738 or their 1-oxides 737. [732] Several 

other reducing agents can be used for the conversion of 2-nitroazobenzenes into 2aryl-2H-benzotriazoles 

or their 1-oxides, namely sodium sulfide, sodium hydrosulfide, [733] 

ammonium sulfide, [734] sodium dithionite, [735] hydrazine hydrate, [711,712] zinc dust with sodium 

hydroxide, [710] molybdenum-promoted Raney nickel, [736] hydrogen in the presence 

of a catalyst, [737,738] and carbon monoxide in an alkaline medium in the presence of a copper–amine 

complex catalyst. [739] 

Scheme 275 Reductive Cyclization of 2-Nitroazobenzenes [710] 

R 1 

736 

NO2 

N NAr1 



reduction 

R 1 

737 

NAr 

N 

1 

N 

O − 

+ 

reduction 

R 1 

738 

NAr 

N 

1 

N 

2-Nitroazobenzenes 739 cyclize selectively to give 2-aryl-2H-benzotriazole 1-oxides 740 

by reduction with baker s yeast (Saccharomyces cerevisiae) in sodium hydroxide solution 

(Scheme 276). Using twice the amount of baker s yeast, a larger amount of sodium hydroxide, 

and a longer reaction time, gives 2-aryl-2H-benzotriazoles 741 as the sole product 

in good yields. [713] 



Scheme 276 Reductive Cyclization of 2-Nitroazobenzenes Using Baker s Yeast [713] 

R 1 

NO 2 

N N 

HO 

739 

R 2 

R 3 

R 1 = H, Cl; R 2 = H, t-Bu, CMe 2Et; R 3 = Me, t-Bu, CMe 2Et 

baker's yeast 

NaOH, H2O 

85 oC, 3.5−4 h 

84−87% 

baker's yeast 

NaOH, H2O 

85 oC, 36−40 h 

80−87% 


Cyclization of 1-Substituted 2-(2-Nitroaryl)hydrazines 

R 1 

R 1 

O − 

N+ 

N 

N 

740 

N 

N 

N 

741 

OH 

HO 

R 3 

R 2 

baker's yeast 

NaOH, H2O 

85 o 86−90% 

C, 24−30 h 

Under reductive conditions, 1-aryl-2-(2-nitroaryl)hydrazines 743 cyclize to 2-aryl-2H-benzotriazoles 

744 (Scheme 277). [740] Frequently benzotriazoles 744 are prepared directly 

from the reaction of 1-halo-2-nitrobenzene derivative 742 (X = Cl, Br), or a 1,2-dinitrobenzene 

derivative 743 (X = NO 2), and an excess of an arylhydrazine. [609,645] Under acidic conditions, 

hydrazines 743 are dehydrated to 2-aryl-2H-benzotriazole 1-oxides 745 (Scheme 

277). [741] Most 1-aryl-2-(2,4,6-trinitrophenyl)hydrazines 743 [R 1 = 4,6-(NO 2) 2;Ar 1 = Ph, 4-Tol, 

C 6F 5] are readily cyclized by refluxing in anhydrous ethanolic hydrogen chloride. [742] However, 

cyclization of 1,2-bis(2,4,6-trinitrophenyl)hydrazine to 4,6-dinitro-2-(2,4,6-trinitrophenyl)-2H-benzotriazole 

1-oxide requires more vigorous conditions. Cyclization proceeds 

smoothly and nearly quantitatively by gentle heating a suspension of that hydrazine 

derivative in concentrated sulfuric acid for 30–60 minutes. [742] 

Scheme 277 Cyclization of 1-Aryl-2-(2-nitroaryl)hydrazines [609,445,741] 

R 1 

742 

X = Cl, Br, NO2 

X 

NO2 

R 1 



Ar 1 NHNH 2 

743 

H 

N 

NO 2 

NHAr 1 

KI, AcOH, heat 

or Ar1NHNH2, heat 


H + 

− H2O 

R 1 

R 1 

744 

745 

R 3 

R 2 

NAr 

N 

1 

N 

NAr 

N 

1 

N 

O − 

+

2-Methyl-6-nitro-2H-benzotriazole 1-oxide (747) is prepared by acid-catalyzed dehydration 

of 1-methyl-2-(2,4-dinitrophenyl)hydrazine (746) or by addition of iodomethane to a solution 

of 2,4-dinitrophenylhydrazine (Scheme 278). [743] 

Scheme 278 Acid-Catalyzed Dehydration of 1-Methyl-2-(2,4-dinitrophenyl)hydrazine [743] 

O2N 

O 2N 

746 

H 

N 

NO 2 

H 

N 

NO 2 

NHMe 

NH2 

HCl, MeOH 

rt, 7 h 

86% 

MeΙ, DMSO 

rt, 42 h 

60% 

O 2N 

747 

N 

NMe 

N 

O − 

+ 

The 2-nitrophenylhydrazine derivative 748 gives the 2-alkyl-2H-benzotriazole 1-oxide 749 

when treated with pyridine (Scheme 279). [714] 

Scheme 279 Base-Catalyzed Conversion of a 2-Nitrophenylhydrazine 

Derivative into a 2-Alkyl-2H-benzotriazole 1-Oxide [714] 

H 

N 

NO 2 

748 

N + 

Br − 


Cyclization of Vicinal Diazides 



py 

N 

N 

N 

O − 

+ 

2,3-Diazidonaphtho-1,4-quinone (750) reacts with triphenylphosphine to form almost 

quantitatively the phosphorane 751 (Scheme 280). This compound undergoes an aza-Wittig 

reaction with aldehydes (e.g., to give 753) and is readily hydrolyzed to the triazol-2amine 

752, which is a stable and high-melting compound. [744] 

749 

OHC 



Scheme 280 Synthesis of Naphthotriazol-2-amine Derivatives from Vicinal Diazides [744] 

O 

O 

750 

N3 

N 3 

O 

O 

751 

Ph3P, MeOH 

rt, 3 h 

N 

N 

N 

− N 2 

96% 

PPh3 N 


1 M HCl 

reflux, 4 h 

PhCHO, CH2Cl2 

rt, overnight 


Isomerization of 4-(Arylazo)-2,1,3-benzoxadiazoles 

Addition of a diazonium salt to 5-(dimethylamino)-2,1,3-benzoxadiazole 1-oxide (754) 

gives the 4-arylazo derivative 755, which isomerizes to the 2-aryl-2H-benzotriazole 756 

(Scheme 281). [745] 

43% 

36% 

O 

O 

O 

O 

752 

753 

N 

N 

N 

N 

N 

N 

Scheme 281 2-Aryl-2H-benzotriazoles from 4-(Arylazo)-2,1,3-benzoxadiazoles [745] 

Me 2N 

754 

Ar 1 = 2,4-(O2N)2C6H3 

N 

O 

N 

O − 

+ 



Ar1 + 

N2 Me2N 

N NAr1 

755 

N 

O 

N 

O − 

+ 


Transformation of 1,3,3-Trialkyl-2-(2,4-dinitrophenyl)diaziridines 

NMe 2 

NO 2 

NH 2 

N 

756 

Ph 

NAr 

N 

1 

N 

1-(2,4-Dinitrophenyl)diaziridines bearing an NH group 757 (R 1 = H), upon heating in toluene 

for ca. 3 hours, rearrange to the corresponding 2,4-dinitrophenylhydrazones. However, 

heating 1,3,3-trialkyl-2-(2,4-dinitrophenyl)diaziridines or 1,3-dialkyl-2-(2,4-dinitrophenyl)diaziridines 

757 (R 3 = H) does not give hydrazones but affords instead 2-alkyl-6-nitro-2H-benzotriazole 

1-oxides 759 (via intermediates 758) in almost quantitative yields 

(Scheme 282). [743] 


Scheme 282 Transformation of 1,3,3-Dialkyl-2-(2,4-dinitrophenyl)diaziridines [743] 

O 2N 

757 

N 

R 

N 

2 

R3 R1 NO 2 

toluene, reflux 

3−14 h 

− R 2 COR 3 

R 1 = Me, iPr, Cy; R 2 ,R 3 = (CH2)5; R 2 = Me, Et; R 3 = H, Me 


Transformation of 1-(2-Nitrophenyl)-1H-tetrazoles 

O 2N 

758 

N NR 1 

N 

O 

O2N 

759 97−100% 

NR 

N 

1 

N 

O − 

+ 

5-Aryl-1-(2-nitrophenyl)-1H-tetrazoles [746,747] and 1-aryl-5-(2-nitrophenyl)-1H-tetrazoles [748] 

decompose when heated to give nitrogen, carbon dioxide, and 2-aryl-2H-benzotriazoles; 

the former react much faster than the latter. For example, decomposition of 1-(2-nitrophenyl)-5-phenyl-1H-tetrazole 

(760) in refluxing nitrobenzene is complete after one hour 

while decomposition of 5-(2-nitrophenyl)-1-phenyl-1H-tetrazole (763) requires 19 hours 

(Scheme 283). [748] It has been shown that the thermal decomposition of these tetrazoles 

to 2-aryl-2H-benzotriazoles (e.g., 762) proceeds via 2-nitrophenyl(phenyl)carbodiimides 

(e.g., 761; Ph may be replaced by a substituted-phenyl ring). A sequence of electrocyclic 

ring closing and opening reactions is proposed as the mechanism of the conversion of 

carbodiimides 761 to 2-aryl-2H-benzotriazoles. [746,747] There are several other precursors 

(both cyclic and acyclic) of diarylcarbodiimides with an ortho nitro group and, consequently, 

they can be used in the synthesis of 2-aryl-2H-benzotriazoles. [746,747] 

Scheme 283 Transformation of 1(5)-(2-Nitrophenyl-5(1)-phenyltetrazoles into 

2-Phenyl-2H-benzotriazole [748] 

N 

N 

760 

763 

N 

N 

Ph 

NO2 N N 

N 

N 

Ph 

NO2 



PhNO2, reflux 

1 h 

− N2 70% 

PhNO2, reflux 

19 h 

− N2 

60% 

N 

NO2 

761 

NPh 

− CO 2 

762 

N 

NPh 

N 

The carbodiimides 765 are suggested as probable intermediates in the reaction of the 

phosphoramidate 764 with aryl isocyanates to yield the 2-aryl-2,4-dihydroimidazo[4,5d][1,2,3]triazoles 

766 (Scheme 284). [749] 



Scheme 284 Synthesis of 2-Aryl-2,4-dihydroimidazo[4,5-d][1,2,3]triazoles via 

Carbodiimides [749] 

EtN 

N 

N 

764 

P(OEt)3 

NO2 

Ar1NCO MeCN, 60 oC 13.13.4.3 Synthesis by Substituent Modification 

EtN 

N 

N 

765 

NO 2 

NAr 1 

Et 

N 

N 

766 57−79% 

NAr 

N 

1 

N 

Since substituent modification reactions in 1H- and 2H-benzotriazoles are, in many cases, 

very similar, the synthesis of new 2H-benzotriazoles by substituent modification is covered 

in Section 13.13.3.3. 


1,2,3-Triazolium Salts 



13.13.5.1.1.1 Fragments C-N-N and C-N 


From Diarylnitrilimines and Alkyl Isocyanides 

Diarylnitrilimines 768 (generated in situ from 767 and triethylamine) react with alkyl isocyanides 

to form the triazolium salts 769 (Scheme 285). [444,750] Depending on the reaction 

conditions, other heterocyclic compounds are obtained, namely 1,2,4-triazolium salts, 

pyrazole derivatives, and quinoxaline derivatives. Experiments with tert-butyl isocyanide 

and phenyl isocyanide failed to give the respective triazolium salts 769. 

Scheme 285 Reaction of Diarylnitrilimines with Alkyl Isocyanides [444,750] 

Ar 1 

Cl 

NHAr 

N 

2 

767 

Et3N MeCN, rt 

R 1 = Me, iPr, Cy; Ar 1 = Ph, 4-Tol; Ar 2 = Ph, 4-Tol 



Ar N 

1 NAr2 + − 

768 

1. R1NC, MeCN, rt, 24 h 

2. HClO4, H2O N 

NAr 

N 

2 

Ar1 R1 + 

769 57−73% 


ClO 4 −

Synthesis of 2H-Triazol-1-ium Salts 769; General Procedure: [444] 

CAUTION: Perchlorate salts are potential explosives. 

Et 3N (2 mmol) was added at rt to a soln of the N-arylbenzohydrazonoyl chloride 767 

(2 mmol) and the alkyl isocyanide (2 mmol) in dry MeCN (50 mL); the mixture was allowed 

to stand for 24 h. Removal of the solvent gave a crystalline residue which was washed 

with Et 2O and dissolved in the minimum amount of H 2O (some insoluble material was filtered 

off). Then 10% aq HClO 4 was added to cause precipitation of crude 769 as a greenishwhite 

solid. Chromatography (acidic alumina, acetone), followed by addition of Et 2Oto 

the concentrated eluate, afforded colorless plates. 

13.13.5.1.2 By Formation of One N-C Bond 

13.13.5.1.2.1 Fragment N-N-N-C-C 


Cyclization of Æ-Imino Hydrazones 

The oxidation of substituted Æ-imino hydrazones 770 with N-bromosuccinimide affords 

1,2-disubstituted 2H-triazol-1-ium salts 771 (Scheme 286). [751] 

Scheme 286 Oxidative Ring Closure of Substituted Æ-Imino Hydrazones [751] 

R 2 N NH 

R 1 NPh 

770 

R 3 

NBS 

R 1 = alkyl, aryl; R 2 = alkyl, CN; R 3 = H, halo, alkyl 

R 

N 

N 

N 

2 

R 

+ 

Ph 

771 

1 


Cyclization of (3-Aryl-1-methyltriaz-2-enyl)acetic Acid Derivatives 

Cyclization of ethyl (1-methyl-3-phenyltriaz-2-enyl)acetate 772 (Ar 1 = Ph; X = OEt) with 

thionyl chloride/pyridine gives the mesoionic compound 773 (Ar 1 = Ph) together with a 

small amount of the sulfide 774 (Scheme 287). [362] Under similar reaction conditions, cyclization 

of amide 772 (Ar 1 = Ph; X = NH 2) gives only sulfide 774. Similar results are obtained 

when Ar 1 = 4-tolyl. Treatment of acetonitrile derivatives 775 with dry hydrogen 

chloride affords 4-amino-3-aryl-1-methyl-3H-1,2,3-triazol-1-ium chlorides 776. Cyclization 

of 775 with acetyl chloride gives the acetamido derivatives 777. The yields from all these 

transformations are low. 

Scheme 287 Cyclization of (3-Aryl-1-methyltriaz-2-enyl)acetic Acid Derivatives [362] 

O 

X 

Ar1N N 

NMe 

772 

Ar 1 = Ph, 4-Tol; X = OEt, NH2 


13.13.5 1,2,3-Triazolium Salts 581 

SOCl2, py 

− O 

NAr 1 

N 

N+ 

Me 

773 

+ 

R 3 

NAr1 − 

O 

N 

S 

N+ 

Me 

2 

774 



NAr1 H2N N 

N+ 

Me 

776 


Cl − 

HCl 

Ar 1 N 

N 

NC NMe 

775 

AcCl 

AcHN 

NAr 1 

N 

N+ 

Me 

This type of chemistry has been applied to the synthesis of the mesoionic 1,3-diaryl-1,2,3triazoles 

778 (Scheme 288). [752] 

Scheme 288 Cyclization of (3-Aryl-1-methyltriaz-2-enyl)acetic Acid Derivatives [752] 

O 

OH 

H 

N 

R 1 

R 1 = CO 2Me, NHAc, NHCOEt 



Ar1 + 

N2 Ar 

HO N 

1N 13.13.5.2 Synthesis by Introduction of Substituents 


Alkylation of N-Alkyl-1,2,3-triazoles 

O 

N 

R 1 

777 

Ac 2O, py, rt 

R 1 

− O 

Cl − 

NAr 1 

N 

N+ 

778 20−55% 

Alkylation of 1-alkyl-1H-1,2,3-triazoles 779 gives 1,3-disubstituted 3H-1,2,3-triazol-1-ium 

salts 780 [455] while alkylation of 2-substituted 2H-1,2,3-triazoles 781 affords 1,2-disubstituted 

2H-1,2,3-triazol-1-ium salts 782 (Scheme 289). [450] 2-Substituted 2H-triazoles are 

much more difficult to alkylate than the isomeric 1-substituted 1H-triazoles; this difference 

in reactivity agrees with the fact that 1-substituted triazoles are much more basic 

than the isomeric 2-substituted compounds. [450] While 1-substituted 1,2,3-triazoles react 

readily with methyl 4-toluenesulfonate, [448,449] producing 1,3-disubstituted 1,2,3-triazolium 

4-toluenesulfonates in high yields, 2-substituted 1,2,3-triazoles, when treated with 

methyl 4-toluenesulfonate, iodomethane, or dimethyl sulfate do not react, or they give 

the triazolium salts in low yield only. [450] 2,4-Diphenyl-2H-1,2,3-triazole is, however, converted 

into the triazolium salt, in 80% yield, by methylation with dimethyl sulfate. [444] Methyl 

fluorosulfonate is a successful methylating reagent for 2-substituted 1,2,3-triazoles 

(Scheme 289). [450] The reaction is carried out in the absence of a solvent and the required 

temperature is dependent on the substituents R 1 and R 2 in triazole 781. For example, 2methyl-2H-1,2,3-triazole 

reacts with methyl fluorosulfonate at 0 8C, 2-phenyl-2H-1,2,3-triazole 

reacts at room temperature, and the reaction with 4,5-dibromo-2-methyl-2H-1,2,3triazole 

only occurs at 608C. [450] 


Scheme 289 Alkylation of 1- and 2-Substituted 1,2,3-Triazoles [450,455] 

N 

N 

N 

R1 779 

+ R 2 I 

N 

N 

NR2 R1 R1 F S O O 

+ 

OMe 

781 

acetone, Et2O 

rt, 5−8 d 

R1 = Me; R2 = Bn 83% 

R1 = Bn; R2 = Me 74% 

NR 2 

N 

+ N 

R 

780 

1 

0 oC, rt, or 60 oC R1 = H; R2 = Me 79% 

R1 = H; R2 = Ph 99% 

R1 = Br; R2 = Me 99% 

I − 

N 

NR 

N 

2 

R 

+ 

1 

R1 Me 

782 

FSO3 − 

1-Phenyl-1H-1,2,3-triazole adds fairly rapidly to vinylsulfonyl chloride, in the absence of a 

base, to yield quantitatively the sulfonate 783 (Scheme 290). [198] 

Scheme 290 Addition of 1-Phenyl-1H-1,2,3-triazole to Vinylsulfonyl Chloride [198] 

N 

N 

N 

Ph 

SO2Cl 

benzene 

reflux, 6 h 

N 

N 

N+ 

Ph 

SO2Cl 

− 

H2O 

N 

N 

N+ 

Ph 

783 99% 

1-Ethyl-1H-1,2,3-triazole reacts with tetracyanoethene oxide, at 0 8C, to yield 3-ethyl-3H- 

1,2,3-triazol-1-ium-1-dicyanomethanide (784) in 73% yield (Scheme 291). [753] 

Scheme 291 Reaction of 1-Ethyl-1H-1,2,3-triazole with Tetracyanoethene Oxide [753] 

N 

N 

N 

Et 

+ 

NC 

CN 

NC CN 

O 



EtOAc 

0 oC, 2−5 min 

73% 


Alkylation of N-Alkylbenzotriazoles 

NC 

− 

CN 

N+ 

N 

N 

Et 

784 

As discussed in Section 13.13.3.3.1.1.8, during the alkylation of benzotriazole with alkyl 

halides, in some cases, [672] the 1,3-dialkylbenzotriazolium salts are also formed (Scheme 

239). 1-Substituted 3-methyl-3H-benzotriazol-1-ium iodides 785 are prepared in low to 

good yields by the reaction of 1-substituted 1H-benzotriazoles with iodomethane (Scheme 

292). [754] 

+ O 

CN 

CN 

SO3 − 



Scheme 292 Methylation of 1-Substituted 1H-Benzotriazoles [754] 

N 

N 

N 

R1 MeI, toluene, sealed tube 

80 oC, 16−72 h 

R1 = CH2SPh 65% 

R1 = CH2SOPh 82% 

R1 = CH2SO2Ph 35% 

N 

N 

N 

R1 Me 

+ 

Alkylation of 1-[(dialkylamino)methyl]-1H-benzotriazoles 786 leads to the formation of 

(1H-benzotriazol-1-ylmethyl)ammonium salts 787 (Scheme 293). [755] This reaction is limited 

to iodomethane, iodoethane, and 1-(chloromethyl)-1H-benzotriazole. Methyl 4-toluenesulfonate 

can also be used but reacts only with 1-(pyrrolidin-1-ylmethyl)-1H-benzotriazole 

[786, R 1 ,R 2 = (CH 2) 4]. In some cases, the 1,3-dialkylbenzotriazolium salts 790 are obtained. 

Indeed, when 1-(pyrrolidin-1-ylmethyl)-1H-benzotriazole [786, R 1 ,R 2 = (CH 2) 4] is 

heated with benzyl bromide in a sealed tube at 60–808C, 1,3-dibenzyl-3H-benzotriazol-1ium 

bromide (790,R 3 = Bn; X = Br) is obtained in 65% yield. [755] The explanation for the formation 

of salts 790 depends on the fact that compounds 786, in solution, are in equilibrium 

with the ion pair 788, which reacts with the alkylating agent to form successively 1alkyl-1H-benzotriazole 

789 and then 790. 

Scheme 293 Alkylation of 1-[(Dialkylamino)methyl]-1H-benzotriazoles [755] 

N 

N 

N 

786 

NR 1 R 2 

R 1 ,R 2 = (CH2)4 

N 

N 

N 

− 

788 

H 2C 



N 

R1 R2 + 

R3X 40−60% 

R 3 X 

785 

N 

N 

N R2 787 

+ N 

R1 R3 X − 

I − 

N 

N 

N 

R3 R3X N 

N 

N 

R3 R3 X − 

+ 

789 790 R3 = Bn; X = Br 65% 

Ethyl 1H-benzotriazole-1-carboxylate reacts with triethyloxonium tetrafluoroborate to 

yield the corresponding 3-(ethoxycarbonyl)-1-ethyl-3H-benzotriazol-1-ium salt (see 

Scheme 240). [634] 

Alkylation of benzotriazole with bis(bromomethyl)benzenes (1,2-, 1,3- or 1,4-) in two 

steps affords the benzotriazolophanes 791 (Scheme 294). [674] The symmetrical benzotriazolophanes 

792, 793, and 794 are prepared in a similar manner. [674,675] 


Scheme 294 Synthesis of Symmetrical Benzotriazolophanes [674] 

N 

N 

N 

H 

N 

N 

N+ 

N 

N 

N+ 



Br 

Br 

NaOH, MeCN, rt, 2 d 

1,2-xylenyl 65% 



792 

794 

Br 

Br 

MeCN, reflux, 5 d 




N 

N 

N+ 

N 

N 

+N 

2Br − 

2Br − 

N 

N 

N 

N 

N 

N+ 

N 

N 

N+ 

N 

N 

791 

N 

N 

N 

793 

N 

N 

+ N 

The unsymmetrical benzotriazolophanes 796 and 797 are obtained by alkylation of the 

precyclophane 795 with the corresponding bis(bromomethyl)benzene derivatives 

(Scheme 295). [675] 

N 

N 

+N 

2Br − 

2Br − 



Scheme 295 Synthesis of Unsymmetrical Benzotriazolophanes [675] 

N 

N 

N 

N 

N 

N 

N 

795 

N 

795 

N 

N 

N 

N 

N 

N 

Br 

OMe 

Br 


59% 

NO 2 

Br OH Br 


52% 

N 

N 

N+ 

N 

N 

N+ 

OMe 

N 

796 

NO 2 

N 

N 

+N 

OH N 

N 

+N 

N 

1-Ethyl-1H-benzotriazole reacts with tetracyanoethene oxide, at room temperature, to 

yield 3-ethyl-3H-benzotriazol-1-ium-1-dicyanomethanide 798 (Scheme 296). [753] 

Scheme 296 Reaction of 1-Ethyl-1H-benzotriazole with Tetracyanoethene Oxide [753] 

N 

N + 

N 

Et 



NC 

CN 

NC CN 

O 

Et2O rt, 24 h 

− 

+ 

Et 

N 

NC 

CN 

N 

N 

798 21% 

797 

+ O 


CN 

CN 

2Br − 

2Br −

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