Synthesis of heterocyclic compounds

Tapio Nevalainen
Drug synthesis II
2010

http://www.scripps.edu/chem/baran/heterocycles/

Heterocyclic compounds

• Heterocycles contain one or more hereroatoms in a ring

X X
X Z Y
Y
X,Y,Z are usually N,O,S

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Heterocycles
• Aromatic five‐membered heterocycles

Heterocycles

• Aromatic six‐membered heterocycles

5 4 5 4 5 4 5 4
6 3 6 3 6
N3 6 N 3

7 2 7 N2 7 2 7 2
N N N
8 8 1 8 8
1 1 1
isoquinoline
quinoline quinazoline quinoxaline

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Heterocycles

• Aliphatic heterocycles

Heterocycles
• Tautomerism

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Reactions of heterocycles
Five‐membered heterocycles are good nucleophiles
• Reaction with bromine requires no Lewis acid and leads to 
substitution at all four free positions.

In Friedel–Crafts reactions the 2

the 2‐‐position is more reactive than 
the 3‐position
the 3‐ p

Reactions of heterocycles
Vilsmeier reaction (Vilsmeier‐Haack  O
reaction) allows the formylation of  CH3
H N
heterocyclic and electron‐rich 
CH3 O
arenes. The formylating agent, 
y g g , N N
chloroiminium ion, is formed in situ  H 1. POCl3 H H
from N,N‐dimethylamide and POCl3 2. H2O

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 Reactions of heterocycles
• Aromatic heterocycles undergoes aminoalkylation (Mannich reaction)
• For example N‐methylpyrrole reacts at the 2‐position . Reaction is 
used in the manufacture of the nonsteroidal anti‐inflammatory 
compound, tolmetin.
compound, tolmetin.
CH3
HN H3C
H3C
CH3 H3C
N CH
N 3 N CH
CH2=O N 3
H3C N
Mannich H3C O CH3
reaction
Tolmetin
 Five
Five‐‐membered heterocycles act as dienes
act as dienes in Diels–
in Diels–Alder reactions

Common building‐blocks for 
heterocyclic compounds

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 General strategies for heterocycle synthesis
• ”1+4” strategy

 ”1+5” strategy

General strategies
General strategies for 
for heterocycle
heterocycle synthesis
 ”2+3” strategy
”2+3” strategy  ”3+3” strategy
”3+3” strategy

 Examples
O

X H2N H2N O H2N O X H2N

H

O HO O
O

X O
X = Cl, Br, I

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Reactions used in heterocyclic ring synthesis
 Aldol‐‐type reactions of 
Aldol of enols
enols or enolate anions with
electrophiles. 
electrophiles. 

 Imine/enamine formation

Reactions used in heterocyclic ring 
synthesis
•Enamine is tautomeric form of imine. If dialkylamine is 
used, enamine is formed
used, enamine is formed

 Enamines can function as 

as enolates
enolates
H H H H
H H N H H
O N N N
H H + R1
N R1 -H R1
R3 R2 R1 R2
R1 R2 R2
R2 OH + H+ R3 H - H2O - H+
R4 O R3
R3 H R3
enamine
R4 R4 R4 R4

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 Reactions used in heterocyclic ring 
synthesis
•When the process leads to C‐heteroatom bond formation, 
then the nucleophile is an appropriate heteroatom.
then the nucleophile is an appropriate heteroatom.

Furans

 Paal Knorr

 Feist--Benary
Feist

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Thiophenes 
 Paal Knorr

•Hinsberg Synthesis of Thiophene Derivatives 

 Gewald reaction

Pyrroles

•Knorr pyrrole synthesis: Condensation of ‐aminoketone 


and ‐ketoester

 Pyrrole-Synthesis: condensation amine and 1,4

Paal--Knorr Pyrrole-
Paal 1,4--ketone
 Example:: Synthesis of atorvastatin (Lipitor
Example Lipitor))

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 Pyrroles
• Hantzsch pyrrole synthesis: from α‐halomethyl ketones, β‐keto esters and 
ammonia or amines

A. Hantzsch, Ber. 23, 1474 (1890)

 Huisgen Pyrrole Synthesis

From Amino acids and

alkynes. Example:
atorvastatin

1,2‐Azoles
 Pyrazoles can be synthesized from 1,3
1,3‐‐dicarbonyls 
with hydrazine

 Isoxazoles can be made from 1,3-

1,3-dicarbonyl compounds or β-
ketoesters with hydroxylamine

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 1,2‐Azoles 
Example of pyrazole synthesis: Rimonabant

1,2‐Azoles
The synthesis of sildenafil (Viagra)

Retrosynthesis

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1,2‐Azoles
The synthesis of sildenafil (Viagra)

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

1,2‐Azoles
The synthesis of sildenafil (Viagra)

O CH3
O C 3
CH O CH3
H2N N
OEt O N N
H2N N EtO HN
N pyridine NaOH N
Cl + EtO HN
H2N N
O
CH3
CH3 CH3
OEt O
O CH3 CH3
N EtO HN N
EtO HN N
N
ClSO2OH HN N
N
N
CH3
CH3 CH3
O S O O S
O N
Cl
N
CH3

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

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1,2‐Azoles
synthesis of isoxazoles

 By 1,3
1,3--cycloaddition from nitrile oxides and
unsaturated compounds

 Nitrile oxides can be prepared by the -elimination of chlorooximes

or the dehydration of nitroalkanes

1,3‐Azoles
•Oxazoles  and thiazoles can be obtained by the 
Robinson‐Gabriel synthesis from 2‐acylamino‐ketones.

 2‐acylamino
acylamino‐‐ketones reacts  with phosphorus 
pentasulfide to form thiazoles
pentasulfide to form  thiazoles

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1,3‐Azoles

• Oxazoles  can be made by Blümlein‐Lewy Synthesis: heating an 
haloketone with amide

 Most important method for thiazoles

for thiazoles is 
is Hantzsch
Hantzsch thiazole synthesis
from thioamides and a
and a‐halocarbonyl compounds

1,3‐Azoles 

 Example:: synthesis of nizatidine

Example

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 1,3‐Azoles:  Synthesis of imidazoles

•From amidines and hydroxy or halocarbonyl compounds 

 Debus‐Radziszewski imidazole synthesis

Debus‐ synthesis:: diketone
and ammonia form an diimine, which condenses with 
the aldehyde
the  aldehyde

For more imidazole syntheses, look:

http://www.scripps.edu/chem/baran/images/grpmtgpdf/Zografos_Feb_04.pdf

1,3‐Azoles: Imidazoles from isocyanides
• The reaction of aldehydes, primary amines and 
toluenesulphonylmethyl isocyanide (TOSMIC) yield 1,4,5‐
trisubstituted imidazoles (van Leusen et al. J. Org. Chem. 1977, 42, 1153). 
R3 O
S
O N CH3 R3
O C N
- H2O R1 C
NH2 Ts
R1 + H R2 N R2 TOSMIC
Base N R
H 2
R3 R3 R1
Ts O
N N
Base S
H + OH
N N R2
R2 H3C
R1 R1

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

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1,3‐Azoles: Imidazoles from isocyanides
• Substituted tosylmethyl isocyanides (TosMICs) are synthesized from 
tosylmethyl formamides and p‐methylphenylsulphinic acid.

• Synthesis of the GSK p38 kinase inhibitor 

1,3‐Azoles
 Synthesis of 2-Butyl-4-chloro-5-hydroxymethyl-1H-
imidazole
H O H2N
N CH3
CH3 HO
HO OH HN
N Cl
Cl

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

1. Me3SiCl,
2.Chlorosuccinimide H
3. Zn, AcOH N
CH3 N
CH3
HO N HO N
Cl
Cl
2-Butyl-4-chloro-5-hydroxy-
methyl-1H-imidazole Losartan

Synthetic Communications (1993), 23(18), 2623-30.

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 Dihydroimidazoles

Clonidine (anti-hypertensive agent)

Oxymetazoline (topical 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

1,4‐Dihydropyridines

• Hantzsch Dihydropyridine (Pyridine) Synthesis

 4-Aryl-1,4-dihydropyridines (e.g.
nifedipine)
p ) are calcium channel
modulators for the treatment of
cardiovascular diseases such as
hypertension, cardiac
arrhythmias, or angina.

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 Pyridines
•Pyridoxine, vitamin B6, has been synthesised by 
Guareschi ring synthesis

Glutarimides
 Thalidomide O
NH2
O
O O
H2N O NH2
Ac2O
OH
O N O
O N
NH
OH
O O O
O O
Thalidomide
O
O CO H O
2 F3C
CO2H NH2 HOBt = N-hydroxybenzotriazole
N N O N
HOBt NH N
EDCCI N
O O O
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 -
H3C N C NH+ Cl
CH3

 A i
Aminoglutethimide
l t thi id

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Pyrimidines 
• Pinner pyrimidine sythesis: from 1,3-dicarbonyl compounds and amidines

Instead of amidines, pyrimidines are obtained also by using guanidine,

urea and thiourea
R4 O
R4
N N O N NH
H2N NH
R1 R3 H2N NH2 R1 R3
R2 O O R2

R1 R3
R2
NH2 NH2 S S

N N H2N NH H2N NH2 N NH

R1 R3 R1 R3
R2 R2

Pyrimidines
•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

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Pyrimidines 
•Biginelli Reaction: acid‐catalyzed, reaction between an 
aldehyde, a,ß‐ketoester and urea constitutes a rapid and facile 
synthesis of tetrahydropyrimidones.

•Synthesis of rac‐Monastrol (Mitosis blocker by kinase Eg5 
inhibition)

Tetrazoles
 Carboxylic acid isostere
 Synthesis

 Synthesis of Losartan (antihypertensive

antihypertensive))

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 Indoles
 Fischer Indole Synthesis:
The conversion of aryl hydrazones to
indoles;; requires elevated temperatures
indoles
and the addition of Brønsted or Lewis acids

 Synthesis
y of Sumatriptan
p

(Daniel Lednicer
Lednicer:: Strategies for Organic Drug Synthesis and Design)

Quinolines
 Quinoline nucleus is usually
is usually formed in 
in one
one of 
of two
two
ways

•Skraup‐reaction

O
 Mechanism: OH + O NH2
H H2C
HO OH
- 2 H2O H N
H
H
H
O OH
[O]
- H2O N N
N N H
H H

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Quinolines
• Doebner‐Miller –reaction: ‐unsaturated ketone or aldehyde can be
used instead of glycerol to form a quinoline

 Conrad‐‐Limpach reaction: Synthesis of 4
Conrad Limpach reaction: Synthesis of 4‐‐oxyquinolines by 
condensation of esters of beta‐
condensation of esters of beta‐keto acids with aromatic amines 

Quinolines

•Friedländer‐quinoline synthesis

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 Isoquinolines

 The general synthetic routes to isoquinolines

involve the following
g skeletal types:
yp

Isoquinolines
•Bischler‐Napieralski Reaction:
 -Phenylethylamine is acylated
then cyclodehydrated using
phosphoryl chloride, phosphorous
pentoxide or other lewis acids. This
gives the dihydroisoquinoline,
dihydroisoquinoline,
which can be aromatised by
dehydrogenation with palladium.
E.g. in the synthesis of papaverine

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

Synthesis of Tadalafil

Isoquinolines
OEt O
• Pomeranz‐ EtO OEt
H3O+
- H2O
Fritsch O + OEt
H2N N N
Reaction R
R R
C. Pomeranz
C Pomeranz, Monatsh
Monatsh. 1414, 116 (1893)
P. Fritsch, Ber. 26, 419 (1893)
OH
- H2O
N
N
R
R

 Schlittler-
Schlittler-
Müller
ü e
Reaction

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Quinolones
•Retrosynthesis

 Synthesis

Thiadiazoles
•Synthesis of Timolol (‐blocker)

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Benzodiazepines
 The retrosynthesis of diazepam

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

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

Diazepam

Benzodiazepines
 Ugi Reaction (Ugi, I., et. al. Angew. Chem. 1959,
71, 386)

 Concise synthesis of benzodiazepines with Ugi

Reaction (Hulme, C., et. al. J. Org. Chem. 1998,
63, 8021)

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