Product Class 13: 1,2,3-Triazoles

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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%). 13.13.1.1.2.1.3.4 Variation 4: 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 FOR PERSONAL USE ONLY 436 Science of Synthesis 13.13 1,2,3-Triazoles THF R 2 X R1 + N2 N TMS Li S − 78 N N N R1 OH − Li + − S A. C. TomØ, Section 13.13, Science of Synthesis, 2004 Georg Thieme Verlag KG TMS R 2 S TMS N N N R1 R 2 S 79 N N N R1
FOR PERSONAL USE ONLY 13.13.1 Monocyclic N-Unsubstituted and 1-Substituted 1,2,3-Triazoles 437 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; General Procedure: [72] 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. 13.13.1.1.2.1.4 Method 4: 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 for references see p 587 A. C. TomØ, Section 13.13, Science of Synthesis, 2004 Georg Thieme Verlag KG
Page 1 and 2: 13.13 Product Class 13: 1,2,3-Triaz
Page 3 and 4: Scheme 3 Ring-Chain Tautomerism in
Page 5 and 6: Scheme 6 Reaction of Ethyl 2-Diazo-
Page 7 and 8: Condensation of 2-Diazo-3-oxoaldehy
Page 9 and 10: Scheme 12 Reaction of 2-(Benzoyloxy
Page 11 and 12: 83%). [42] The 3-diazobenzo[b]thiop
Page 13 and 14: Scheme 17 Reaction of Activated Nit
Page 15 and 16: Scheme 20 Synthesis of 4,5-Diaryl-1
Page 17 and 18: Scheme 24 Addition of Diazomethane
Page 19 and 20: 13.13.1.1.2.1.3.1 Variation 1: From
Page 21: Scheme 31 Reaction of Organometalli
Page 25 and 26: 13.13.1.1.3.1.1.1 Method 1: Additio
Page 27 and 28: Scheme 38 Addition of Aluminum Azid
Page 29 and 30: R 1 R 2 Conditions Yield (%) Ref (E
Page 31 and 32: R 1 R2 Conditions Yield (%) Ref 93
Page 33 and 34: Scheme 45 Recognition-Mediated Reac
Page 35 and 36: The complementary method, i.e. reac
Page 37 and 38: Scheme 51 Synthesis of 1H-1,2,3-Tri
Page 39 and 40: Scheme 54 Addition of Azides to Eth
Page 41 and 42: Scheme 57 Addition of Sulfonyl Azid
Page 43 and 44: 13.13.1.1.3.1.1.7 Method 7: Additio
Page 45 and 46: azide. [187] Ethyl 3-(4-nitrophenyl
Page 47 and 48: with Et 2O (two minor dihydrotriazo
Page 49 and 50: The reaction of azides with norborn
Page 51 and 52: Scheme 73 Addition of Phenyl Azide
Page 53 and 54: Scheme 76 Addition of Azides to Æ-
Page 55 and 56: Scheme 78 Addition of Azides to Ena
Page 57 and 58: Scheme 82 Synthesis of 4-(Aminometh
Page 59 and 60: 13.13.1.1.3.1.2.6.2 Variation 2: Ad
Page 61 and 62: Scheme 88 Reaction of Azides with V
Page 63 and 64: Aroylketene dithioacetals 282 react
Page 65 and 66: Scheme 95 Reaction of Azides with 1
Page 67 and 68: Scheme 98 Reaction of Dimethyl 3-Ox
Page 69 and 70: Scheme 102 Reaction of Tosyl Azide
Page 71 and 72: R 1 R 2 Conditions Yield (%) Ref N
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13.13.1.1.4 By Formation of One N-N
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Scheme 112 Cyclization of Æ-Hydrox
Page 77 and 78:
Scheme 115 Cyclization of 1,2-Diket
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Scheme 118 Cyclization of 1,2-Diket
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Scheme 121 Isomerization of 1-(Aryl
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13.13.1.2 Synthesis by Ring Transfo
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Scheme 127 Reaction of Diazoalkanes
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Scheme 129 Oxidative Dehydrogenatio
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13.13.1.4 Synthesis by Substituent
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13.13.1.4.1.1.2 Method 2: N-Trimeth
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08C). [434] Reaction of 1,2,3-triaz
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Scheme 141 Arylation of 1-Benzyloxy
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Scheme 144 Reaction of Triazoles wi
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Scheme 148 Halogenation of 1,2,3-Tr
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Scheme 153 N-Hydroxylation of 1H-1,
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13.13.1.4.1.3 Of Carbon Functionali
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Scheme 161 Hydrolysis of O-Aryl-1H-
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Scheme 166 Catalytic Hydrogenation
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Scheme 170 Substitution of Diazoniu
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Scheme 174 Preparation of 1-Substit
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Scheme 178 Isomerization of 1-Alkyl
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Scheme 181 2-Allyl-2H-1,2,3-triazol
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Scheme 186 Cyclization of N-Unsubst
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with nitrous acid gives the corresp
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13.13.2.1.3.1.4 Method 4: Cyclizati
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Scheme 201 Synthesis of 2-Alkyl-5-n
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Scheme 207 Synthesis of 2H-1,2,3-Tr
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Scheme 209 Proposed Structures for
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5,6-Dinitro-1H-benzotriazole [601,R
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Scheme 215 Synthesis of Benzotriazo
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(15 mL) and the mixture was refluxe
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AlCl3, PhNO2 70 oC, 3 d H + Cl HO 6
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13.13.3.2.3 Method 3: Transformatio
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13.13.3.3.1.1.3 Method 3: Acylation
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o-3-nitropyridine in dimethyl sulfo
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13.13.3.3.1.1.8 Method 8: Alkylatio
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Scheme 242 Alkylation of 1H-Benzotr
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1H-benzotriazole derivatives are pr
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Scheme 250 Sulfonylation of Benzotr
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Scheme 253 Nitration of 1H-Benzotri
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13.13.3.3.2 Of Carbon Functionaliti
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Scheme 261 Deoxygenation of 1-Alkyl
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13.13.4.1.2 By Formation of One N-N
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Scheme 270 Synthesis of 2-Azidoazob
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13.13.4.1.2.1.3 Method 3: Cyclizati
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2-Methyl-6-nitro-2H-benzotriazole 1
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Scheme 282 Transformation of 1,3,3-
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Synthesis of 2H-Triazol-1-ium Salts
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Scheme 289 Alkylation of 1- and 2-S
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Scheme 294 Synthesis of Symmetrical
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References FOR PERSONAL USE ONLY Re
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FOR PERSONAL USE ONLY References 58
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Product Class 13: 1,2,3-Triazoles

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