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)
Cations)

N N N N
N N
N N N O S N
H H H H
pyrrole pyrazole imidazole oxazole thiazole triazole

-4 2.5 6.9 0.8 2.5 2.5

Azole Anions (Acidity of Neutral Azoles)

Azoles)

N N N N N
N N N N
N N N N N N
16.5 14,2 14,4 9,3 10 4.9

1
 Basicities of Six-Membered Heteroaromatics and Non-
Heteroaromatics
Basicities of Azines (pKa values)
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

NH3 N N N
H H H N
NH2 H
ammonia pyrrolidine piperidine aniline indoline tetrahydroquinoline
9.3 11.3 11.2 4.6 4.9 5.0

Pyrrole synthesis
„ synthesis: Condensation of α-Aminoketone and β-
Knorr pyrrole synthesis:
ketoester O
O O CH3
R O R O
AcOH R O
+ O CH3 O CH3
R' NH2 R' R''
O R'' R' N R'' N
H H
„ Paal- Pyrrole-Synthesis: condensation amine and 1,4-
Paal-Knorr Pyrrole- 1,4-ketone
„ Example: 1,2-
1,2-Diarylpyrroles as Inhibitors of Cyclooxygenase-
Cyclooxygenase-2 (J.
(J.
Med. Chem., 40 (11), 1619 -1633, 1997)
Med. Chem.,

NH2
O O OEt
TsOH N
+ OEt O
MeO2S
O
MeO2S
F
TsOH = Toluenesulphonic acid
F

2
 Pyrrole synthesis
„ Hantzsch pyrrole synthesis: from α-holomethyl ketones, β-keto
esters and ammonia or amines
OEt O O
OEt
O O EtO OEt
+ PhNH2 + Br
O O CH3
N
H CH3
Ph
A. Hantzsch, Ber. 23, 1474 (1890)

„ Piloty- Synthesis: by heating azines of

Piloty-Robinson Pyrrole Synthesis:
enolizable ketones with acid catalysts, ZnCl2 or HCl

R' R'
R' R' ∆
+ NH3
HCl R N R
R N N R
H

Thiophenes
„ Hinsberg Synthesis of Thiophene Derivatives
R R R
R S CO2R'
tBuOK
+
O R'O2C CO2R'
O R'O2C S
„ Paal Knorr
R' P2S3
O O R R' S CO2R'R

„ Gewald reaction
OR'' O
R'
O S8 R''O R'
O
+
R H2N R
N S

3
 Furans
„ Paal Knorr

R' H+ OH
R R' O R - H2O R' O R
O O

„ Feist-
Feist-Benary

CO2Et
O EtO2C Cl EtO2C
R'
+ - HCl
OH R OH
Cl O - H2O R O R'
R R'

Pyrazoles
„ Pyrazoles can be synthesized from 1,3-
1,3-dicarbonyls with
hydrazine CH
CH3 3
H2NNH2, NaOH
H3C O H3C N
H2O, 15°C N
O H

„ Pyrazoles are made also by 1,3-

1,3-dipolar cycloaddition of
diazomethane and acetylene.
acetylene.
O CH3
COOCH3
O N C
N C
+ N C H
N C
C
CH2 H H2

4
 Example of pyrazole synthesis:
Rimonabant
+
Li O
H3C H3C OEt
1. LiHMDS. ether -
Cl O Cl O
2. NH2
O EtO O
1. HN
OEt 2. AcOH
Cl
O

O
O
N H3C
H3C Cl OEt
N
H
N
N N
N Cl
Cl Cl
Cl

SR-141716A
Rimonabant (Acomplia)
Cl
Cl

Pyrazoles: The synthesis of sildenafil (Viagra)

Retrosynthesis
O CH3 O O
CH3 CH3

OEt HN
N N N
OEt HN H2N
N OEt N
N
N CO2H H2N
N

O CH3 CH3 CH3

S
N
O
N
CH3

O
O CH3 O CH3 O CH3 O
O
N N N O RO
H2N RO RO RO
N N N O OR
H2N O2N
O
H3C
CH3 CH3 CH3 CH3

CH3

5
 Pyrazoles: The synthesis of sildenafil (Viagra)
O O O CH3
O H
O N 1. (MeO)2SO2 N
H3C EtO EtO HO
(CO2Et)2 O H2N NH2 N N
base 2. NaOH/H2O
H2O
CH3
CH3 CH3 CH3

O CH3 O CH3 O CH3

HO N H2N N H2N N
HNO3 1. SOCl2 H2
N N N

H2SO4 O2 N 2. NH4OH O2 N Pd/C H2N

CH3 CH3 CH3

O CH3
O CH3 O CH3
N
OEt O N H2N N
H2N N OEt HN
N pyridine NaOH N
Cl + H2N
HN
N
O
CH3
CH3 CH3
OEt
O CH3
O CH3
N
N OEt HN
OEt HN N
N
ClSO2OH HN N
N
N
CH3
CH3
CH3 O S
O S O
O N
Cl
N
CH3

Bioorg.
Bioorg. Med. Chem. Lett.
Lett. 6, pp. 1819, 1996

Isooxazoles
„ Oximation of 1,3-
1,3-Dicarbonyl Compounds
HO NH2 O N
O O NaOH
OH
OMe H2O/MeOH

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 OMe N
O
+O benzene
N + O
R R
O
Chimichi, S.; Cosimelli, B.; Synth. Commun., 1992, 22, 2909-2920

ƒ Nitrile oxides can be prepared by the γ-elimination of chlorooximes

or the dehydration of nitroalkanes

Cl2 Cl Et3N +O
OH N PhNCO
R N OH R NO2
R N R or Ph3P, DEAD
nitrile oxide

6
 Azoles
„ 1,3-azoles are made in general from 1,4-dicarbonyls
by Paar-Knorr cyclization.

O N
H H2SO4
R N R'
R
R' ∆ O
O

O R''
H NH4+OAc- H
R N N
R''
HOAc, 120°C R R'
O R' N

O
H N
R N 120°C
+ P2S5
R' R R'
S
O

Imidazoles
Cl CH3 CH3
N N H H CH3
NH2 N N
HN S CH3 H3C H
N N N N
H H H N N CH3
Cl CN
CH3 N
Histamine Clonidine Cimetidine Xylometazoline

„ Synthesis of 1,2,5-
1,2,5-Trisubstituted Imidazoles from
N-monosubstituted amidines and 2- 2-halo-
halo-3-alkoxy-
alkoxy-
2-propenals
R' Br X R'
NH K2CO3 X
N
R + X = CHO, CN
R O
NH O CHCl3/H2O N OH

O
J. Org Chem. 1997, 62, 8449 N
OH
N
Eprosartan S

7
 Imidazoles
„ Cimetidine
O O
O O
2 H2N H O
O O N O N
Bredereck-reaktio* N O
Cl + HN O +
O H H O
H
H H H

H
NH2 S N
O HS
LiAlH4 NH2 N
HN O HN OH HN S CN
N N N

* Bredereck, H.; Theilig, G., Chemische Berichte-Recueil 1953, 86, 88-96. H H

http://www.chem.yale.edu/~wood/Theses/thesisstu.pdf N N
HN S
N N
CN
cimetidine

Imidazoles
„ 2-butyl-
butyl-4(5)-
4(5)-chloro-
chloro-5(4)-
5(4)-hydroxymethyl-
hydroxymethyl-1H-
1H-
imidazole
H O H2N
N CH3
CH3 HO
HO OH NH
N Cl
Cl

O NH3, MeOH H
H2N N
+ CH3 CH3
HO N
OH NH HO N HN N
N

1. Me3SiCl,
2.Chlorosuccinimide H
N
3. Zn, AcOH CH3 N
CH3
HO N HO N
Cl
Cl
Losartan
Synthetic Communications (1993), 23(18), 2623-30.

8
 Dihydroimidazoles

Clonidine (anti-
anti-hypertensive agen)
agen)
Cl Cl Cl Cl
+ CH3 H2N H
NH4 S S S N
N CH3I
NH2 N C NH2 N C N
H H NH2 H
NH .HI N
Cl Cl Cl Cl
Clonidine

Oxymetazoline (topical decongestant)

decongestant)
H2N
HO CH3 HO CH3 HO CH3 HO CH3

CH2O/HCl Cl KCN CN
H2N H
235°C, N2 N
CH3 CH3 CH3 CH3 N

Oxymetazoline

Imidazoles
„ The reaction of aldehydes,
aldehydes, primary amines and
toluenesulphonylmethyl isocyanide (TOSMIC) yield 1,4,5-
1,4,5-
trisubstituted imidazoles (A. M. van Leusen,
Leusen, J. Wildeman,
Wildeman, O.
H. Oldenziel,
Oldenziel, J. Org.
Org. Chem. 1977, 42,
Chem. 1977, 42, 1153. A. M. van
Leusen,
Leusen, Heterocycl.
Heterocycl. Chem. 1980, 5, S-
Chem. 1980, S-111)
R3
O
S NC R3
O CN Tos
NH2 CHO - H2O R1
R1 + R2 N R2 H 3C TOSMIC
R1
B N R2
R3 R3
Tos
N N O
B S

N R2
+ OH
N R2
H3 C
R1 R1

http://www.organic-chemistry.org/Highlights/2005/05May.shtm

9
 S H
H3C S N NH2 Cl CH3
N N +
NO2 N N

Thiazoles
H3C H3C N
H
H3C N S
Nizatidine (H2-antihistamine) OH
Thiamine (vitamin B1)

„ Most important method for syntesis of thiazoles is

from thioamides and α-halocarbonyl compounds
R' H
S R' S S
Br S
+ R'
R NH2 O - HBr O R' - H2O R N
R NH R N OH
„ Example: synthesis of Nizatidine

S Br
Me Br NaOEt Me S 1. LiAlH4 S
CO2Et CO2Et Me
N NH2 + N N 2. PBr3
O N N
Me Me Me
2-dimethylamino- 2-dimethylaminomethyl-
thioasetamide thiazol-4-carboxylic acid
ethylester HS
NH2
MeS

S HN NO2
S H S
Me N Me Me S NH2
N N N N
Me Me N NO2
H Me
Nizatidine

Oxazoles
„ The oxazole ring is constructed by heating an α-haloketone with amide

R' H
O R' 100 °C O O
Br O
+ R'
R NH2 O - HBr O R' - H2 O R N
R NH R N OH

„ Oxazole ring can be formed also from amide and vinylene carbonate or acid
chloride and 1,2,3-
1,2,3-triazole
O

O O
O NH2
vinylene O N
(Ph3P)4Pd,
carbonate O N HO OH aq Na2CO3,
B
PPA EtOH/toluene
+ R
Br
H
N R
N /K2CO3
O Cl Br
N

S
O O
Sulfolane J. Med. Chem., 43 (16), 3111 -3117, 2000
Br

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.
CO2Me

CO2Me
NH3 H2N Me NO2
+
NO2 NO2 MeO2C CO2Me
O Me
CHO CO2Me
Me N Me
O Me H
Nifedipine
CO2Me NH3
NO2

O Me MeO2C CO2Me

Me Me
O O

Glutarimides
„ Thalidomide O
NH2
O
O O
H2N O NH2
Ac2O
OH
O N O
O N
N
OH H
O O O
O O
Thalidomide
O
O CO H O
2 CF3
CO2H NH2 HOBt = N-hydroxybenzotriazole
N N O N
HOBt N N
N
O EDCCI O O H OH
2-phthalimido-D-glutaric acid (R)-Thalidomide
EDCCl = N-(3-dimethylamino)propyl-
N'-ethylcarbodiimide hydrochloride
Tetrahedron Letters (1999), 40(19), 3697-3698.
CH3
N +
Cl
H3C N
N H CH3

„ Aminoglutethimide
O2N O E tO O2N H2N
O2N O H2SO4
OE t Ac OH H2
CN O O
Bu 4N+OH- N Ni N
C H H
N O O

Aminoglutethimide
(Aromatase Inhibitor,
breast cancer)

11
 Pyrimidines
„ From 1,3-dicarbonyl compounds and amidines
„ Example: trimethoprim (bacteriostatic antibiotic)
NH2 NH2
guanidine O O O O
N N H2N NH
EtO OEt EtO OEt
NH2 O O FGI MeO Br
MeO
MeO
H NH2
MeO
MeO
MeO OMe MeO
OMe
OMe
MeO
OMe

O O
O

O O 1. NaH EtO OEt

OEt
MeO NaCl HCO2Et
EtO OEt 2. ArCH2Br MeO
DMSO EtO
MeO
MeO
OMe
OMe
NH2 NH2
OH O NH2
N N N N
OEt H2N NH 1. POCl3
MeO OH NH2
MeO 2. NH3 MeO

MeO
OMe MeO MeO
OMe OMe

Pyrimidines
„ Biginelli Reaction:
Reaction: acid-
acid-catalyzed,
catalyzed, reaction between an aldehyde,
a,ß-
a,ß-ketoester and urea constitutes a rapid and facile synthesis of
tetrahydropyrimidones.
tetrahydropyrimidones.
Ph
Ph
H O
H+ EtO2C
EtO2C NH Biginelli, P. Gazz.
+ NH2 Chim. Ital. 1893, 23, 360.
EtOH, ∆ R N O
R O H 2N O H

„ Synthesis of rac-Monastrol (Mitosis blocker by kinase Eg5

inhibition)
OH
OH

Yb(OTf)3
H O
EtO2C Dondoni, A., et. al.
EtO2C THF, reflux NH Tet. Lett. 2001, 43, 5913
+ NH2 12h
H3C N S
H3C O H2N S H
(+/-) Monastrol

12
 Tetrazoles
N N N N
„ Carboxylic acid isostere N NH N N +
+ H
„ Synthesis R R
pKa = 5
NaN3, NH4Cl R N R R
+
N H N
R N
LiCl, DMF + N N N NH
100 °C N N N N N

„ Synthesis of Losartan (antihypertensive)

antihypertensive)
Br Br N N N
CN NaN3, ZnBr2 N HN N
N
H N
(Ph3P)4Pd

H
N N
CH3 CH3
HO N (HO)2B HO N
Br Cl
N Cl
CH3
(HO)2B DMA HO Losartan
N
Cl

Indoles
ƒ Fischer Indole Synthesis:
The conversion of aryl hydrazones to R
R

indoles;
indoles; requires elevated R' ZnCl2, ∆
R'
temperatures and the addition of N NH
H
N
H
Brønsted or Lewis acids

ƒ Synthesis of Sumatriptan
CN
O O CN
O O
S S
HN HNO2 HN S S
O O Sn Cl 2 HN O HN
CH3 NH2 O H O
CH3 N NO
H CH3 N NH2 CH3 N N
H H
I

CN
CN
O O H CN
O
S S H+
HN HN S +
O O NH HN NH3
CH3 N NH CH3 NH O
H CH3 N
H

Me
N Me
CN NH2
O H2 CH2O/ Na BH4 O
S O S
HN Pd - C S HN
O O
CH3 N HN N
O CH3 H
CH3 N
H Sumatriptan

13
 Quinolines
„ Quinoline nucleus is usually formed in one of
two ways
H3C
C
+ CH3
Skraup. Döbner von Miller and
N NH2 Conrad-Limpach syntheses

CH3
CH3
+ CH3 Friedländer and Pfitzinger synthesis
N NH2

„ Skraup-
Skraup-reaction
OH
H2SO4
+ HO OH
NH2 As2O5, ∆
N

CHO
„ Mechanism: OH H+ H2C
O NH2

HO OH
H N
H

[O]

N N
H

Quinolines
„ α,β-unsaturated ketone or aldehyde can be used instead of glycerol
CH3

FeCl3
+ H2C
CH3
ZnCl2
NH2 N
O

„ Saturated aldehyde can aldolcondensate to α,β-

α,β-unsaturated aldehyde to form
a quinoline (Doebner-
Doebner-Miller -reaction)
reaction)

R'
conc. HCl NH2
R' CH2 CH C CHO
R' CH2 CHO
100 °C R'
N CH2R'

14
 Quinolines
„ Conrad-Limpach reaction: Synthesis of 4-
oxyquinolines by condensation of esters of beta-keto
acids with aromatic amines Skraup-
Skraup-reaction

CH3 CH3
< 100 °C O H+
- H2O
EtO2C - H2O
N O N O
+ H H
NH2 O CH3
O
EtO2C
∆
260 °C
- EtOH
N CH3 - EtOH
N CH3
H

Quinolines
„ Friedländer-quinoline synthesis
CHO O
pH 12
+
NH2 H3C CH3
N CH3

Mechanism:
O O
CHO O
CH2
+
NH2 H3C CH3 +
N CH3 N CH3
H H
OH
-H2O

N CH3
N CH3

15
 Isoquinolines
„ The general synthetic routes to
isoquinolines involve the following skeletal
types:
types:

N NH2
+ C Pictet-Spengler and
Bischler-Napieralski syntheses

C
C
N
+ NH2
Pomeranz-Fritsch synthesis
C

C
N NH2
+ C Schlittler-Müller synthesis

Isoquinolines
„ Bischler-
Bischler-Napieralski Reaction:
Reaction:
„ β-Phenylethylamine is
P2O5, ∆
acylated then HN O N
cyclodehydrated using CH3 CH3
phosphoryl chloride,
phosphorous pentoxide or
other lewis acids. This gives MeO
CN
H2, Raney-Ni MeO NH2

the dihydroisoquinoline,
dihydroisoquinoline,
which can be aromatised by
MeO MeO

H2SO4
dehydrogenation with
palladium. E.g. in the
MeO MeO Cl
CO2H SOCl 2

synthesis of papaverine MeO MeO

O

MeO
MeO MeO

N N NH
MeO
MeO MeO POCl
Pd , 250 3
O
- H2O

OMe OMe
Papaverine OMe
OMe OMe MeO
Bischler-Napieralski

16
 Isoquinolines
„ Pictet-
Pictet-Spengler synthesis: β-Arylethylamine is heated in the presence
of an aldehyde and acid.
acid.
„ A special case of the Mannich reaction.
reaction.

O H HCl
+ N N
NH2 R
R R
A. Pictet and T. Spengler, Ber. 44, 2030 (1951)

Synthesis of Tadalafil O CH3

N
CO2Me
CO2Me N
CHO NH O
NH2 CF3CO2H,
+ N
N H
N CH2Cl2 H
O O
H O
O O
D-(-)-tryptophan
O Tadalafil (Cialis)
methyl ester
J. Med. Chem. 2003; 46(21); 4525-4532

Isoquinolines
„ Pomeranz-
Pomeranz- EtO OEt
- H2O
OEt
H3O+
O

Fritsch O +
H2N N
OEt
N
Reaction R
R R
C. Pomeranz, Monatsh. 14, 116 (1893)
P. Fritsch, Ber. 26, 419 (1893)
OH
- H2O
N
N
R
R

EtO OEt
„ Schlittler-
Schlittler- OEt

Müller O
NH2OH
NOH NH2
O
N
OEt

Reaction R R R
R
H3O+
E. Schlittler and J. Muller, Helv. Chim. Acta 31,914,1119(1948)

EtO OEt EtO OEt EtO OEt

KMnO4 Pb(OAc)4
HO N
H2C OH O
R

17
 O

Quinolones F CO2H

N N
N O
„ Retrosynthesis H3C CH3
ofloxacin (antibiotic)

O O O
CO2H O OH
EtO OEt
EtO OEt
N NH2 O H
H
EtO OEt
OEt
„ Synthesis - EtOH

ethyl orthoformate O O O O
O O HC(OEt)3 Ph NH2 EtO H OEt
EtO OEt
EtO OEt Ac2O EtO OEt
EtO
- EtOH
O O O
CO2H O O
EtO OEt 1. Heat
EtO OEt
2.NaOH,
N 3. H+ N EtO
H H

Thiadiazoles
CH3

Synthesis of Timolol (β-

O HO H
N
„ CH3
CH3
N O
blocker N N
timolol
S
O
Cl
N
O Cl O Cl O
cyanamide NH2
+ N
Cl N S N NH N NH
H S
S S Cl S
Cl Cl
sulfur chloride
CH3
O OH H2N OH
Cl O CH3 H
Cl O Cl Cl O
Cl CH3 N CH3
N NH CH3
S N N N N H3C
S S

O
O
OH
N H
H N O N CH3
CH3
N N H3C
S

18
 Benzodiazepines
ƒ The retrosynthesis of diazepam
O
N Cl
O O
Cl
NH
Cl N + +

Diazepam H2N
Cl

ƒ The synthesis of diazepam (Sternbach et al, 1961).

O CH3
N
CH3 O N H
O CH3
Ac2O NaOH, H2O
NH N Ph C Cl O
O Cl
CH3 Cl
AlCl3
Cl Cl
O
CH3 CH3
O O Cl
Cl
N N
NH3 Cl
O
Cl N Cl

Diazepam

Benzodiazepines
„ Ugi Reaction (Ugi, I., et. al. Angew. Chem.
1959, 71, 386)
O R
O NH2 R CN H
N
+ + + R3 N R4
R3 OH R2 H O R4
R2 O

„ Concise synthesis of benzodiazepines with Ugi

Reaction (Hulme, C., et. al. J. Org. Chem.
1998, 63, 8021)
O R O
R R2
O H
N N
N AcCl/MeOH
H O R4
OH R4 R
R4 R2 O
Boc NH2 NC N ∆
N N
N Boc O
R2 R3 R3
R3

19