5 lec heterocyclic.pdf

Synthesis of heterocyclic
compounds
Tapio Nevalainen
Drug synthesis II
2008
Basicities of Nitrogen in Heteroaromatic Five-
Membered Rings (pKa
values)
Azoles (Acidity
of Azole Cations)
N
H
N
N
N
H
pyrazole
N
N
N
H
N
pyrrole imidazole oxazole thiazole triazole
-4 2.5 6.9 0.8 2.5 2.5
Azole Anions (Acidity
of Neutral Azoles)
N
N
N
N
N
N
N
N
N N
N
N
16.5 14,2 14,4 9,3 10 4.9
O
N
S
N
N
N
H
N
1

Basicities of Six-Membered
Heteroaromatics and Non-
Heteroaromatics
Basicities of Azines (pKa
values)
N N N N
N
N
N
N
N N
N
N
N
pyridine pyridazine pyrimidine pyrazine 1,2,4-triazine 1,3,5-triazine
5.1 2.3 1.3 0.6 < 0 < 0
Basicities of Some Neutral Nitrogen Compounds
NH 3
N
H
N
H
NH 2
N
H
N
H
ammonia pyrrolidine piperidine aniline indoline tetrahydroquinoline
9.3 11.3 11.2 4.6 4.9 5.0
Pyrrole synthesis
R
R'
• Knorr pyrrole synthesis: Condensation of α-Aminoketone
and β-
ketoester
O
NH 2
+
O
O
O
O
R O
AcOH R O
O CH O 3
CH 3
R'
R''
R' N R''
N R''
H
H
• Paal-Knorr
Pyrrole-Synthesis
Synthesis: condensation amine and 1,4-ketone
• Example: 1,2-Diarylpyrroles as Inhibitors of Cyclooxygenase-2 2 (J.(
Med. Chem., 40 (11), 1619 -1633, 1997)
CH 3
NH 2
F
+
MeO 2
S
O
O
O
TsOH
OEt
MeO 2
S
TsOH = Toluenesulphonic acid
N
F
O
OEt
2

Pyrrole synthesis
• Hantzsch pyrrole synthesis: from α-holomethyl ketones, β-keto
esters and ammonia or amines
O
O
OEt
H
+ PhNH 2 +
O
O
OEt
O O
EtO
OEt
Br
N CH 3
CH 3
Ph
A. Hantzsch, Ber. 23, 1474 (1890)
• Piloty-Robinson
Pyrrole Synthesis: by heating azines of
enolizable ketones with acid catalysts, ZnCl 2 or HCl
R'
R
N N
R'
R
∆
HCl
R
R'
N
H
R'
R
+
NH 3
Thiophenes
• Hinsberg Synthesis of Thiophene Derivatives
R
R
O
O
• Paal Knorr
R'
R
S CO 2
R'
tBuOK
+
R'O 2
C
R'O 2
C
P 2
S 3
O R
R'
O
S
R
S CO 2
R'
CO 2
R'R
• Gewald reaction
OR''
O
+
O
R'
S 8
R''O
O
R'
N
R
N H 2
S
R
3

Furans
• Paal Knorr
R'
H +
O R
R'
O
O
OH
R
- H 2
O
R'
O
R
• Feist-Benary
CO 2
Et
O
+
OH
Cl
R
R'
EtO 2
C
R
O
Cl
R'
OH
- HCl
- H 2
O
EtO 2
C
R
O
R'
Pyrazoles
• Pyrazoles can be synthesized from 1,3-dicarbonyls
with
hydrazine
CH CH
3
3
H 2
NNH 2
, NaOH
H 3
C O
H N
H 2
O, 15°C
3
C
N
O
H
• Pyrazoles are made also by 1,3-dipolar
cycloaddition of
diazomethane and acetylene.
N
N + CH 2
O
O CH 3
COOCH 3
N C
C
C
N C
H CH2
H
4

Example of pyrazole synthesis:
Rimonabant
Cl
C H 3
O
1. LiHMDS. ether
2. O
EtO
OEt
O
Cl
H 3
Li +
O
C
-
OEt
O
NH
O
2
1. HN
Cl
2. AcOH
Cl
H 3
C
O
N
N
N
N
H
Cl
Cl
Cl
H 3
C
O
N
N
Cl
OEt
Cl
SR-141716A
Rimonabant (Acomplia)
Cl
Pyrazoles: : The synthesis of sildenafil (Viagra)
Retrosynthesis
O
O
O
CH 3
CH 3
CH 3
CH 3
OEt HN
N
O
S
O
N
N
N
CH3
N
OEt HN
N
N
N
OEt
CO 2 H
N H 2
N H 2
CH 3
N
N
CH 3
N H 2
O
H 2 N
CH 3
N
N
CH 3
RO
O
O 2 N
CH 3
N
N
CH 3
RO
O
CH 3
N
N
CH 3
RO
O
O
O
RO
O
OR
O
O
H 3 C
CH 3
CH 3
5

Pyrazoles: : The synthesis of sildenafil (Viagra)
O
H 3 C
CH 3
(CO 2 Et) 2
base
EtO
O
O
O
O
O
H
H 2 N
EtO
NH 2
N 1. (MeO) 2 SO 2 HO
N
N
N
H 2 O
2. NaOH/H 2 O
CH 3
CH 3
CH 3
CH 3
O
O
O
CH 3
CH 3
N
HNO
HO
3
1. SOCl
N
2
H
O 2 N
2 SO 4 2. NH 4 OH
N H 2
O 2 N
CH 3
CH 3
N
N
H 2
Pd/C
N H 2
H 2 N
CH 3
CH 3
N
N
OEt
O
Cl
+
N H 2
O
H 2 N
N
N
pyridine
N H 2
O
HN
N
N
NaOH
O
OEt HN
N
CH 3
CH 3
N
N
CH 3
CH 3
O
ClSO 2 OH
O
OEt HN
N
CH 3
CH 3
CH 3
CH 3
N
N
HN
OEt
O
OEt HN
N
CH 3
CH 3
N
N
N
CH3
N
O S O
Cl
Bioorg. . Med. Chem. Lett. . 6, pp. 1819, 1996
O S
O
N
CH3
Isooxazoles
• Oximation of 1,3-Dicarbonyl
Compounds
HO
NH 2
O O
NaOH
OMe H 2
O/MeOH
O N
OH
Brehm, L.; Johansen, J.S.; Krogsgaard-Larsen, P.; J.
Chem. Soc., Perkin Trans I, 1992, 16, 2059-2063.
• Cycloaddition of Nitrile Oxides to Unsaturated
Compounds
R
N +
O
+
O
OMe
benzene
Chimichi, S.; Cosimelli, B.; Synth. Commun., 1992, 22, 2909-2920
O
N
• Nitrile oxides can be prepared by the γ-elimination
of chlorooximes
or the dehydration of nitroalkanes
R
O
R
OH
N
Cl 2
Cl
OH
R N
Et 3
N
N +
O
R
nitrile oxide
PhNCO
or Ph 3
P, DEAD
R NO 2
6

Azoles
• 1,3-azoles
are made in general from 1,4-dicarbonyls
by Paar-Knorr
cyclization.
R
O
H
N
O
R'
H 2
SO 4
∆
R
N
O
R'
R
O
H
N
R'
O
R''
NH 4+
OAc -
HOAc, 120°C
R
H
N
N
R''
R'
R
O
H
N
O
R'
+ P 2
S 5
120°C
R
N
S
R'
N
H
N
Histamine
NH 2
Cl
Cl
N
N
H
Clonidine
Imidazoles
N
H
HN
CH 3
N
S
Cimetidine
H
N
H
N
CH 3
N
CN
CH 3
H 3
C
CH 3
CH 3
CH 3
Xylometazoline
H
N
N
• Synthesis of 1,2,5-Trisubstituted
Imidazoles from
N-monosubstituted
amidines and 2-halo2
halo-3-alkoxy-
2-propenals
R
R'
NH
NH
Br X
R'
K X
2
CO 3 N
+ X = CHO, CN
R
O CHCl 3
/H 2
O N
O
OH
J. Org Chem. 1997, 62, 8449 N
N
Eprosartan
O
S
OH
7

Imidazoles
• Cimetidine
O
Cl
O
O
2
N H 2
O
H
Bredereck-reaktio*
O +
H
N
HN
H
O
H
O
O
H
N
O +
H
N
O
H
O
O
HN
N
O
O
LiAlH 4
HN
N
HS
OH
NH 2
HN
N
S
NH 2
S
H
N
N
CN
* Bredereck, H.; Theilig, G., Chemische Berichte-Recueil 1953, 86, 88-96.
http://www.chem.yale.edu/~wood/Theses/thesisstu.pdf
HN
N
S
cimetidine
H
N
H
N
N
CN
Imidazoles
• 2-butyl-4(5)
4(5)-chloro-5(4)
5(4)-hydroxymethyl-1H-
imidazole
HO
Cl
H
N
N
CH 3
HO
Cl
O
OH
N H 2
NH
CH 3
HO
O
+
OH
H 2
N
NH
CH 3
NH 3
, MeOH
HO
N H N
CH 3
HN
N N
N
1. Me 3
SiCl,
2.Chlorosuccinimide
3. Zn, AcOH
HO
Cl
H
N
N
CH 3
Synthetic Communications (1993), 23(18), 2623-30.
N
HO N
Cl
Losartan
CH 3
8

Dihydroimidazoles
Clonidine (anti-hypertensive
agen)
Cl
Cl
NH 2
+
NH 4 S
N
Cl
Cl
N
H
S
C
NH 2
CH 3 I
Oxymetazoline (topical
decongestant)
Cl
Cl
N
H
Cl
CH 3 H N
S
2
N H
C
N
NH 2 H
NH . N
HI
Cl
Clonidine
HO
CH 3
CH 3
CH 2 O/HCl
HO
CH 3
Cl
CH 3
KCN
HO
CH 3
CN
CH 3
H 2 N
H 2 N
235°C, N 2
HO
CH 3
CH 3
H
N
N
Oxymetazoline
Imidazoles
• The reaction of aldehydes, primary amines and
toluenesulphonylmethyl isocyanide (TOSMIC) yield 1,4,5-
trisubstituted imidazoles (A. M. van Leusen, , J. Wildeman, , O.
H. Oldenziel, J. Org. Chem. 1977, 42, , 1153. A. M. van
Leusen, Heterocycl. Chem. 1980, 5, , S-111) S
NH 2
CHO - H R 1
R 1
+
2
O
R 2
N H C
R 3 2
N
R3
Tos
R 1
N R 2
B
N
R3
R 1
N R 2
O
S
O
C H 3
R3
NC
TOSMIC
O
S
OH
http://www.organic-chemistry.org/Highlights/2005/05May.shtm
+
B
CN
R3
Tos
R 1
N R 2
9

R
C H 3
S
H 3 C
N
NH 2
S
+
N
Br
S
O
H 3 C
R'
H
N
N
H
Nizatidine (H 2 -antihistamine)
NO 2
Thiazoles
• Most important method for syntesis of thiazoles is
from thioamides and α-halocarbonyl
compounds
C H 3
R'
H
S
S
- HBr O
R' - H 2
O
R NH R N OH
• Example: synthesis of Nizatidine
N
NH 2
N
R
Cl
S
N
CH 3
N + S
OH
Thiamine (vitamin B 1 )
R'
+
Br
O
CO 2 Et
NaOEt
S
Me
N NH 2
Me
2-dimethylaminothioasetamide
Me
S
CO 2 Et
N N
Me
2-dimethylaminomethylthiazol-4-carboxylic
acid
ethylester
MeS
1. LiAlH 4
2. PBr 3
Me
N
Me
HS
S
NH 2
N
Br
Me
N
Me
S
N
S
Nizatidine
Me
H
N
N
H
NO 2
HN
NO 2
Me
Me
N
Me
S
N
S
NH 2
Oxazoles
• The oxazole ring is constructed by heating an α-haloketone
with amide
O
R NH 2
+
R'
Br
O
R'
H
100 °C O
O
- HBr O
R' - H 2 O R
R NH R N OH
O
O
R'
N
• Oxazole ring can be formed also from amide and vinylene carbonate or acid
chloride and 1,2,3-triazole
O NH 2
O
O
vinylene
carbonate
PPA
Br
H
N
N /K
O Cl 2 CO 3
N
Br
O
N
+
HO
OH
B
R
(Ph 3 P) 4 Pd,
aq Na 2 CO 3 ,
EtOH/toluene
O
N
R
Br
S
O O
Sulfolane
J. Med. Chem., 43 (16), 3111 -3117, 2000
10

1,4-Dihydropyridines
Hantzsch Dihydropyridine (Pyridine) Synthesis
• 4-Aryl-1,4-dihydropyridines (e.g. nifedipine) are calcium channel
modulators for the treatment of cardiovascular diseases such as
hypertension, cardiac arrhythmias, or angina.
CO 2
Me
CHO
NO 2
+
O
CO 2
Me
Me
CO 2 Me
O
NO 2
CO 2
Me
Me
H 2
N
Me
MeO 2
C
Me
N
H
Nifedipine
NO 2
CO 2
Me
Me
NH 3
NH 3
O
Me
MeO 2
C
NO 2
CO 2
Me
Me
O
O
Me
• Thalidomide
O
N
O
O
O
CO 2 H
N H 2
O
CO 2 H
O
2-phthalimido-D-glutaric acid
Glutarimides
O
OH
NH 2
CF 3
O
NH 2
HOBt
EDCCI
O
N
O
O
O
OH
O
NH 2
N
O O
N
H
(R)-Thalidomide
Tetrahedron Letters (1999), 40(19), 3697-3698.
• Aminoglutethimide
Ac 2 O
O
O
N
O
O O
N
H
Thalidomide
HOBt = N-hydroxybenzotriazole
N
N
N
OH
EDCCl = N-(3-dimethylamino)propyl-
N'-ethylcarbodiimide hydrochloride
CH 3
N
+
H 3 C
N Cl
N
H CH 3
O 2 N
CN
O
EtO
O 2 N
O
H 2 SO 4
OE t
Ac OH
Bu 4 N + OH - C
N
O 2 N
O
N
H
O
H 2
Ni
H 2 N
O
N
H
O
Aminoglutethimide
(Aromatase Inhibitor,
breast cancer)
11

Pyrimidines
• From 1,3-dicarbonyl compounds and amidines
• Example: trimethoprim (bacteriostatic antibiotic)
MeO
NH 2
N N
NH 2
NH 2
H
guanidine
2 N NH
O O FGI
MeO
H
NH 2
MeO
EtO
O
O
OEt
O
EtO
MeO
O
OEt
Br
MeO
OMe
MeO
MeO
OMe
MeO
OMe
OMe
O
O
O
O
EtO
MeO
O
OH
OEt
O
1. NaH
2. ArCH 2 Br
OEt
N H 2
MeO
NH 2
MeO
NH
EtO
MeO
OMe
N
OEt
NaCl
DMSO
NH 2
N
OH
MeO
MeO
1. POCl 3
2. NH 3
OMe
MeO
OEt
HCO 2 Et
EtO
NH 2
N N
NH 2
MeO
OMe
MeO
OMe
MeO
OMe
Pyrimidines
• Biginelli Reaction: acid-catalyzed
catalyzed, reaction between an aldehyde,
a,ß-ketoester
and urea constitutes a rapid and facile synthesis of
tetrahydropyrimidones.
EtO 2
C
R
Ph
H O
O
+
N H 2
NH 2
O
• Synthesis of rac-Monastrol (Mitosis blocker by kinase Eg5
inhibition)
OH
H +
EtOH, ∆
EtO 2
C
R
Ph
N
H
NH
O
OH
Biginelli, P. Gazz.
Chim. Ital. 1893, 23, 360.
EtO 2
C
C H 3
O
H
+
O
N H 2
NH 2
S
Yb(OTf)3
THF, reflux
12h
EtO 2
C
C H 3
N
H
NH
S
(+/-) Monastrol
Dondoni, A., et. al.
Tet. Lett. 2001, 43, 5913
12

• Carboxylic acid isostere
• Synthesis
R
N
NaN 3
, NH 4
Cl
LiCl, DMF
100 °C
Tetrazoles
N
N
R
N
NH
• Synthesis of Losartan (antihypertensive)
R
N
N N + N
R
pKa = 5
N
N
N
N
N
N
R
H +
N
N
+
H +
R
N
N NH
N
Br
CN
NaN 3 , ZnBr 2
Br
N N
N
N
H
(Ph 3 P) 4 Pd
HN
N N
N
(HO) 2
B
Br
HO
Cl
H
N
N
DMA
CH 3
(HO) 2
B
HO
Cl
N
N
CH 3
N
HO N
Cl
Losartan
CH 3
Indoles
• Fischer Indole Synthesis:
The conversion of aryl hydrazones to
indoles; requires elevated
temperatures and the addition of
Brønsted or Lewis acids
N
H
R
NH
R'
ZnCl 2 , ∆
R
N
H
R'
• Synthesis of Sumatriptan
O
S
HN
O
CH 3
I
NH 2
HNO 2
O
S
HN
O
SnCl 2
CH 3
N
H
NO
O
S
HN
O
CH 3
N
H
NH 2
O
CN
O
S
H
HN
O
CH 3
N
H
N
CN
O
S
HN
O
CH 3
O
S
HN
O
CH 3
N
CN
N
H
NH
CN
O
S
HN
O
CH 3
H
CN
NH
NH
O
S
HN
O
CH 3
NH 2
H 2 CH 2 O/ Na BH 4
O
O
S
Pd- C
S
HN
O
HN
O
CH N
CH N
3
H
3
H
Sumatriptan
H +
N
H
CN
NH 3
+
Me
N Me
13

Quinolines
• Quinoline nucleus is usually formed in one of
two ways
N NH 2
H 3
C C
+
CH 3
Skraup. Döbner von Miller and
Conrad-Limpach syntheses
• Skraup-reaction
reaction
N NH 2
CH 3
CH 3
+
CH 3
Friedländer and Pfitzinger synthesis
NH 2
+
HO
OH
OH
H 2
SO 4
As 2
O 5
, ∆
N
• Mechanism:
HO
OH
OH
H +
C H 2
H
O
NH 2
N
H
CHO
[O]
N
H
N
Quinolines
• α,β-unsaturated
ketone or aldehyde can be used instead of glycerol
CH 3
+
CH
H 3
2
C
NH 2
O
FeCl 3
ZnCl 2
N
• Saturated aldehyde can aldolcondensate to α,β-unsaturated
aldehyde to form
a quinoline (Doebner-Miller
-reaction)
conc. HCl R' CH
R' CH 2
CHO
2
CH C CHO
100 °C
R'
NH 2
N
R'
CH 2
R'
14

Quinolines
• Conrad-Limpach
reaction
reaction: Synthesis of 4-
oxyquinolines by condensation of esters of beta-keto
acids with aromatic amines Skraup-reaction
reaction
EtO 2
C
+
NH 2
O CH 3
< 100 °C
- H 2 O
∆
- EtOH
O
N
H
EtO 2
C
CH 3
O
N CH 3
H +
- H 2 O
260 °C
- EtOH
O
N
H
CH 3
N
H
O
CH 3
Quinolines
• Friedländer-quinoline
synthesis
CHO
NH2
+
H 3
C
O
CH 3
pH 12
N CH 3
Mechanism:
CHO
NH2
+
H 3
C
O
OH
CH 3
O
CH 2
N CH 3
H
O
N + CH 3
H
-H 2
O
N CH 3
N CH 3
15

Isoquinolines
• The general synthetic routes to
isoquinolines involve the following skeletal
types:
N NH 2
+
C
Pictet-Spengler and
Bischler-Napieralski syntheses
N
C
+
C C
NH 2
Pomeranz-Fritsch synthesis
N
NH 2
+
C C
Schlittler-Müller synthesis
Isoquinolines
• Bischler-Napieralski
Reaction:
• β-Phenylethylamine
is
acylated then
cyclodehydrated using
phosphoryl chloride,
phosphorous pentoxide or
other lewis acids. This gives
the dihydroisoquinoline,
which can be aromatised by
dehydrogenation with
palladium. E.g. in the
synthesis of papaverine
MeO
N
MeO
Pd, 250
-H 2 O
P
HN O 2
O 5
, ∆
CH 3
MeO
H 2
, Raney-Ni
CN
MeO
MeO
MeO
H 2 SO 4
MeO
MeO
CO 2 H SOCl 2
MeO
MeO
MeO
N
MeO
POCl 3
Cl
O
MeO
MeO
CH 3
N
NH 2
NH
O
Papaverine
OMe
OMe
OMe
OMe
MeO
Bischler-Napieralski
OMe
16

Isoquinolines
• Pictet-Spengler
synthesis: β-Arylethylamine
is heated in the presence
of an aldehyde and acid.
• A special case of the Mannich reaction.
NH 2
O H
HCl
N
R
R
A. Pictet and T. Spengler, Ber. 44, 2030 (1951)
+
R
N
Synthesis of Tadalafil
N
H
CO 2 Me
NH 2
D-(-)-tryptophan
methyl ester
+
CHO
O
O
CF 3 CO 2 H,
CH 2 Cl 2
N
H
CO 2 Me
NH
O
J. Med. Chem. 2003; 46(21); 4525-4532
O
N
H
O
N
CH 3
N
O
O
O
Tadalafil (Cialis)
• Pomeranz-
Fritsch
Reaction
Isoquinolines
R
EtO
O +
H 2
N
C. Pomeranz, Monatsh. 14, 116 (1893)
P. Fritsch, Ber. 26, 419 (1893)
OEt
OEt
- H 2
O H 3
O +
OEt
R
N
R
N
- H 2
O
O
N
R
OH
N
R
• Schlittler-
Müller
Reaction
NH 2 OH
O
NOH
NH 2
R
R
R
E. Schlittler and J. Muller, Helv. Chim. Acta 31,914,1119(1948)
EtO
O
OEt
OEt
OEt
N
R
H 3 O +
EtO OEt
KMnO 4
EtO OEt
EtO
Pb(OAc) 4
H 2 C
HO
OH
O
OEt
R
N
17

Quinolones
F
O
CO 2 H
• Retrosynthesis
C H 3
N
N
N
O
CH 3
ofloxacin (antibiotic)
• Synthesis
O
N
H
CO 2
H
NH 2
EtO
O
O
O
H
OEt
EtO
O
EtO
OH
OEt
OEt
OEt
- EtOH
EtO
O
O
ethyl orthoformate O
HC(OEt) 3
EtO
OEt Ac 2
O
EtO
O
OEt
Ph NH 2
O
EtO
H
EtO
O
OEt
OEt
EtO
O
N
H
O
OEt
1. Heat
2.NaOH,
3. H +
O
N
H
CO 2
H
O
EtO
EtO
- EtOH
O
OEt
• Synthesis of Timolol (β-
blocker
O
N
cyanamide NH 2
+
Cl
S S
Cl
sulfur chloride
Thiadiazoles
Cl
N
O
N
H
S
Cl
O
Cl
N
N
O
N N
S
O
NH
S
Cl
HO
N H CH 3
timolol
Cl
N
CH 3
CH 3
S
O
NH
Cl
O
O
Cl
Cl
O
OH
CH 3
H 2 N
OH
CH
Cl
3
CH Cl O
3
N H CH 3
N
S
NH
N
S
N
N
S
N
CH
H 3 C 3
O
N
H
O
N
O
OH
H
N
CH 3
N
S
N
CH
H 3 C 3
18

Benzodiazepines
• The retrosynthesis of diazepam
Cl
N
N
O
NH
Cl
O
+ +
Cl
O
Diazepam
Cl
N H 2
• The synthesis of diazepam (Sternbach et al, 1961).
O
CH 3
CH 3
NH
Ac 2 O
O
O
N Ph
CH 3
C
AlCl 3
Cl
Cl
N
CH 3 NaOH, H 2 O
O
Cl
N
H
O
Cl
Cl
O
CH 3
N
O
CH 3
N
O
Cl
Cl
Cl
N
NH 3
Cl
O
Cl
Diazepam
Benzodiazepines
• Ugi Reaction (Ugi, I., et. al. Angew. Chem.
1959, 71, 386)
R3
O
NH
R
2
+ + +
OH
R2
H O
CN
R4
R3
O
N
R2
R
O
H
N
R4
• Concise synthesis of benzodiazepines with Ugi
Reaction (Hulme, C., et. al. J. Org. Chem.
1998, 63, 8021)
R4
O
OH
Boc
N
R3
R
H O
NH 2 NC
R2
R4
O R
N
R2
N
Boc
R3
O
H
N
AcCl/MeOH
∆
R4
O
R3
N
R2
N
R
N
O
19