Aromatic Heterocyclic

Chemistry
D a v i d T . Babies
SmithKline Beecham Pharmaceuticals, Harlow, Essex

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© David T. Davies, 1992

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Library of Congress Cataloging-in-Publication Data

Davies, David T.
Aromatic heterocyclic chemistry/David T. Davies.
I. Heterocyclic chemistry. I. Title.
QD400.D38 1991 547'.S9-dc20 91-34831
ISBN 0 19 855660 8 (Pbk)

Printed in Great Britain by

The Bath Press, Avon
Series Editor's F o r e w o r d
A r o m a t i c h e t e r o c y c l i c c h e m i s t r y is an e n o r m o u s and c o m p l e x s u b j e c t of great
i n d u s t r i a l and a c a d e m i c s i g n i f i c a n c e . A n u m b e r of t h e m o l e c u l e s of l i f e a r e d e r i v e d
f r o m aromatic heterocycles and many important pharmaceutical and agrochemical
c o m p o u n d s are b a s e d o n a r o m a t i c h e t e r o c y c l e s . C o n s e q u e n t l y , the i m p o r t a n c e of
a r o m a t i c h e t e r o c y c l i c c h e m i s t r y h a s s t i m u l a t e d a vast a m o u n t of s y n t h e t i c a n d
theoretical w o r k in t h e area.
O x f o r d C h e m i s t r y P r i m e r s h a v e b e e n d e s i g n e d to p r o v i d e c o n c i s e i n t r o d u c t i o n s
r e l e v a n t to all s t u d e n t s of c h e m i s t r y , a n d c o n t a i n o n l y the essential m a t e r i a l that
w o u l d b e c o v e r e d in an 8 - 1 0 l e c t u r e c o u r s e . In this p r i m e r D a v i d D a v i e s h a s
p r o d u c e d an e x c e l l e n t i n t r o d u c t i o n to a r o m a t i c h e t e r o c y c l i c c h e m i s t r y that s h o u l d
s t i m u l a t e a n y r e a d e r to e x p l o r e f u r t h e r into this v a s t topic. T h i s p r i m e r will b e of
interest t o a p p r e n t i c e a n d m a s t e r c h e m i s t alike.

Stephen G. Davies
The Dyson Perrins Laboratory, University of Oxford

Preface
H e t e r o c y c l i c c h e m i s t r y is a vast discipline a n d at first sight i m p o s s i b l e to d o j u s t i c e
to in a text of this size. T h e a i m of this b o o k is to p r e s e n t o n l y t h e essential f e a t u r e s
of t h e m o r e i m p o r t a n t r i n g s y s t e m s . M a n y reaction m e c h a n i s m s are d i s c u s s e d in
detail and several c o m p l e t e s y n t h e s e s of h e t e r o c y c l e s a r e p r e s e n t e d . I h o p e that t h e
r e a d e r will f i n d this t e x t b o t h interesting a n d instructive, a n d t h a t it will p r o v i d e t h e
p l a t f o r m f o r f u r t h e r s t u d y of this f a s c i n a t i n g s u b j e c t .
I w o u l d like t o t h a n k m y f r i e n d s a n d c o l l e a g u e s at S m i t h K l i n e B e e c h a m
P h a r m a c e u t i c a l s f o r t h e i r h e l p f u l c o m m e n t s , including A n g e l a G a d r e , C l a r e
Hayward, Chris Johnson, H e l e n Morgan and vacation students Peter Ainsworth
a n d F r a n c i s M o n t g o m e r y . I a m similarly g r a t e f u l t o Prit S h a h a n d c o l l e a g u e s of
G l a x o G r o u p R e s e a r c h . I a m i n d e b t e d t o R o g e r M a r t i n of S m i t h K l i n e B e e c h a m
P h a r m a c e u t i c a l s f o r h e l p i n g m e with t h e c h e m i c a l s t r u c t u r e d r a w i n g p a c k a g e .
P r o f e s s o r G u r n o s J o n e s m a d e s e v e r a l h e l p f u l c o m m e n t s . Finally, I w o u l d like t o
t h a n k t h e Series E d i t o r , S t e v e D a v i e s , f o r his advice a n d e n c o u r a g e m e n t , as
well as his a c c e p t a n c e of an i n d u s t r i a l scientist t o w r i t e an a c a d e m i c t e x t .

Harlow D.T.D.
J u n e 1991
To Julie
Contents
1 Introduction 1

2 Pyrroles, thiophenes, and furans 10

3 Oxazoles, imidazoles, and thiazoles 20

4 Isoxazoles, pyrazoles, and isothiazoles 28

5 Pyridines 35

6 Quinolines and isoquinolines 46

7 Indoles 53

8 F i v e - m e m b e r e d ring heterocycles with three or four heteroatoms 61

9 Six-membered ring heterocycles containing one oxygen atom 67

10 Pyrimidines 73

1S A n s w e r s to problems 78

Index 87
 1. Introduction

1.1 Heterocyclic chemistry

H e t e r o c y c l i c c h e m i s t r y is a large and i m p o r t a n t b r a n c h of organic chemistry.
H e t e r o c y c l e s o c c u r in nature, f o r i n s t a n c e in n u c l e i c acids (see C h a p t e r 10)
and indole alkaloids (see C h a p t e r 7). Synthetic h e t e r o c y c l e s h a v e w i d e s p r e a d
uses as herbicides (e.g. 1.1), f u n g i c i d e s (e.g. 1.2), insecticides (e.g. 1.3), d y e s
(e.g. 1 . 4 ) , o r g a n i c c o n d u c t o r s (e.g. 1 . 5 ) , a n d , of c o u r s e , p h a r m a c e u t i c a l
products such as the anti-ulcer d r u g 1.6.

C1 N-N
1
A O / ^ C l n - S ^ W * *
r * „ / 7 fT t 1/ \ s
HA- X P h ^ o '
U
EtN^N NEt / ^ Y ^ O ^ ^
11 O 1.2 1.3

1.2 Aromaticity and heteroaromaticity

A n y r i n g s y s t e m c o n t a i n i n g at least o n e h e t e r o a t o m (i.e. an a t o m other t h a n T h e c o m p o u n d numbering s y s t e m
in this chapter is not as odd as it
c a r b o n - t y p i c a l l y n i t r o g e n , o x y g e n , o r s u l p h u r ) c a n b e d e s c r i b e d as
might seem. For more on
heterocyclic. This broad definition encompasses both aromatic heterocycles c o m p o u n d 5.1 s e e Chapter 5, etc.
(such as pyridine 5.1) and their n o n - a r o m a t i c counterparts (piperidine 1.7).

N N
H
5.1 1.7
A r o m a t i c heterocycles a r e d e s c r i b e d as b e i n g heteroaromatic, a n d w e shall
c o n c e n t r a t e o n t h e s e s y s t e m s in this b o o k at the e x p e n s e of m o r e saturated
s y s t e m s . L e t us n o w c o n s i d e r t h e c o n c e p t of a r o m a t i c i t y w i t h r e g a r d to
benzene.
 H
H, „H

H" ^H
H
1.8a

T h e c a r b o n a t o m s in b e n z e n e are sp2 hybridised, and the h y d r o g e n atoms

are in the s a m e p l a n e as the c a r b o n a t o m s . T h e r e m a i n i n g six p orbitals are at
right a n g l e s to t h e p l a n e of the ring a n d c o n t a i n six n e l e c t r o n s . B e n z e n e
f u l f i l s t h e H i i c k e l criteria f o r a r o m a t i c i t y as a p p l i e d to c y c l i c p o l y e n e s
c o n t a i n i n g 4 n + 2 e l e c t r o n s ( w h e r e n-1 in this c a s e ) in f i l l e d p o r b i t a l s
capable of overlap.
A l t h o u g h t w o m e s o m e r i c representations 1 . 8 a , b can be d r a w n f o r benzene,
this d o e s not i m p l y t w o r a p i d l y - i n t e r c o n v e r t i n g f o r m s . R a t h e r , t h e six 7t
electrons are delocalised in m o l e c u l a r orbitals resulting in an a n n u l a r electron
cloud a b o v e and b e l o w t h e p l a n e of the ring. B e n z e n e can also be represented
b y structure 1.9, w h i c h e m p h a s i s e s the cyclical a r r a n g e m e n t of electrons. In
a g r e e m e n t with this theory, the c a r b o n - c a r b o n b o n d lengths are all equivalent
(0.14 n m ) a n d i n t e r m e d i a t e b e t w e e n that of a single (0.154 n m ) and d o u b l e
(0.133 n m ) c a r b o n - c a r b o n bond. The extra thermodynamic stabilisation
i m p a r t e d to b e n z e n e b y this p h e n o m e n o n of electron delocalisation, called
' r e s o n a n c e ' , c a n b e d e t e r m i n e d i n d i r e c t l y . R e a l , d e l o c a l i s e d b e n z e n e is
t h e r m o d y n a m i c a l l y m o r e stable than a theoretical c y c l o h e x a t r i e n e m o l e c u l e
(i.e. n o n - d e l o c a l i s e d structure 1.8a) b y a r o u n d 150 kJ mol" 1 .
H o w d o e s this c o n c e p t of aromaticity apply to typical heterocycles such as
p y r i d i n e 5 . 1 and p y r r o l e 2.1? P y r i d i n e can f o r m a l l y be derived f r o m b e n z e n e
b y r e p l a c e m e n t of a C H u n i t b y an sp2 hybridised nitrogen atom.
C o n s e q u e n t l y , p y r i d i n e h a s a l o n e pair of e l e c t r o n s instead of a h y d r o g e n
atom. H o w e v e r t h e six 7t electrons are essentially u n c h a n g e d , and the pyridine
is a relatively aromatic heterocycle.

N
Q
H
S.l
2.1
A difficulty arises with f i v e - m e m b e r e d heterocycles such as pyrrole, w h i c h
at first sight w o u l d a p p e a r to h a v e only f o u r n electrons, t w o short of the 4 n
+ 2 Hiickel criteria f o r aromaticity. T h e n i t r o g e n a t o m is sp2 h y b r i d i s e d a n d
f o r m a l l y c o n t a i n s a l o n e p a i r of electrons in the r e m a i n i n g p orbital at right
angles to the ring. H o w e v e r , the s y s t e m is delocalised, as s h o w n b e l o w .

YW j ©N
© t>©N
o©N — o
H 2.1 H H H
 T h u s , d e l o c a l i s a t i o n of t h e n i t r o g e n l o n e p a i r c o m p l e t e s t h e sextet of
e l e c t r o n s r e q u i r e d f o r a r o m a t i c i t y . T h e s e t w o e x a m p l e s illustrate the p o i n t
that certain heterocycles (closely analogous to b e n z e n e and naphthalene) such
as p y r i d i n e 5 . 1 , p y r i m i d i n e 10.1, a n d q u i n o l i n e 6 . 1 a r e a r o m a t i c 'by right'
w h e r e a s o t h e r h e t e r o c y c l e s such as p y r r o l e 2.1, i m i d a z o l e 3 . 2 , a n d triazole
8 . 7 h a v e to 'earn' a r o m a t i c i t y b y d e l o c a l i s a t i o n of a l o n e p a i r of electrons
from the heteroatom.

5.1 10.1 6.1 2.1 3.2 8.7

W h a t are the c o n s e q u e n c e s of this c o n c e p t of lone pair delocalisation f o r a

related series of h e t e r o c y c l e s such as p y r r o l e 2 . 1 , t h i o p h e n e 2 . 2 , and f u r a n
2.3? A s delocalisation results in electron loss f r o m the h e t e r o a t o m concerned,
t h e e x t e n t of d e l o c a l i s a t i o n ( a n d h e n c e a r o m a t i c i t y ) will v a r y w i t h the
electronegativity of the h e t e r o a t o m . T h e h i g h l y electronegative o x y g e n a t o m
in f u r a n h o l d s on to e l e c t r o n d e n s i t y m o r e strongly than t h e h e t e r o a t o m in
t h i o p h e n e o r p y r r o l e . F u r a n is g e n e r a l l y c o n s i d e r e d to h a v e a n o n - a r o m a t i c
electron distribution fairly close to that depicted b y structure 2.3.

Q o o
H 2.2 2.3
2.1
In f a c t the thorny p r o b l e m as to h o w a r o m a t i c is a particular heterocycle or For a review on the concept of
heterocyclic aromaticity see
series of h e t e r o c y c l e s h a s b e e n a p r e o c c u p a t i o n of p h y s i c a l organic c h e m i s t s
Katritzky et a! (1991).
f o r s o m e time. B o n d l e n g t h s , heats of c o m b u s t i o n , s p e c t r o s c o p i c data, and
t h e o r e t i c a l l y - c a l c u l a t e d r e s o n a n c e e n e r g i e s h a v e all b e e n i n v o k e d , b u t an
a b s o l u t e m e a s u r e of a r o m a t i c i t y r e m a i n s e l u s i v e . N e v e r t h e l e s s , t r e n d s
r e g a r d i n g relative aromaticity will b e alluded to in this text as they arise.

1.3 Synthesis of heterocycles

T h e r e a r e m a n y s y n t h e s e s of t h e m a j o r h e t e r o c y c l e s a n d t h e y a r e o f t e n
c o m p l e m e n t a r y in that t h e y a f f o r d d i f f e r e n t substitution patterns on the ring.
M o s t of t h e synthetic m e t h o d s w e shall e x a m i n e are fairly classical (indeed
s o m e are decidedly ancient!) although m a n y of the specific e x a m p l e s are quite
m o d e r n . M a n y c l a s s i c a l s y n t h e s e s of h e t e r o c y c l e s r e v o l v e a r o u n d t h e
c o n d e n s a t i o n reaction in its v a r i o u s guises. L e t us consider the m e c h a n i s m of
a s i m p l e a c i d - c a t a l y s e d c o n d e n s a t i o n , that of g e n e r a l i s e d k e t o n e 1 . 1 0 and
a m i n e 1 . 1 1 to g i v e i m i n e 1.12.
P r o t o n a t i o n of the k e t o n e o x y g e n a t o m activates the k e t o n e to
n u c l e o p h i l i c a t t a c k b y t h e a m i n e . L o s s of a p r o t o n f r o m 1 . 1 3 p r o d u c e s
neutral intermediate 1.14. A second protonation, once again on the oxygen
a t o m a f f o r d s 1.15, w h i c h o n loss of a w a t e r m o l e c u l e a n d a p r o t o n gives the
 i m i n e 1 . 1 2 . A l l t h e s e s t e p s a r e r e v e r s i b l e , b u t in p r a c t i c e if w a t e r c a n b e
r e m o v e d f r o m the e q u i l i b r i u m (for instance by azeotropic distillation) then
s u c h r e a c t i o n s c a n b e f o r c e d t o c o m p l e t i o n . T h i s t y p e of r e a c t i o n o c c u r s
m a n y t i m e s i n this t e x t , b u t in f u t u r e w i l l n o t b e p r e s e n t e d in s u c h d e t a i l .
T h e s t u d e n t is s t r o n g l y a d v i s e d t o w o r k t h r o u g h , u s i n g p e n a n d p a p e r , t h e
m e c h a n i s m shown below and the m a n y subsequent mechanisms. Confidence
with reaction m e c h a n i s m s will facilitate u n d e r s t a n d i n g of heterocyclic
c h e m i s t r y a n d o r g a n i c c h e m i s t r y in g e n e r a l .

Ri catalytic H
+ H2N-R2 /=N-R 2 1.12
-H,0
1.10 R! 1.11
-H,0
j+H® -H

Rl r>„H -H V " +H®

K-l i Kj i
Rl
r2^h r2 R2
H,N - R,
1.13 1.14 1.15

The disconnection approach to synthesis essentially involves working

backwards from a target c o m p o u n d in a logical manner (so-called
r e t r o s y n t h e s i s ) , s o t h a t a n u m b e r of p o s s i b l e r o u t e s a n d s t a r t i n g m a t e r i a l s a r e
s u g g e s t e d . T h i s a p p r o a c h h a s b e e n a p p l i e d m a i n l y to a l i c y c l i c , c a r b o c y c l i c ,
a n d s a t u r a t e d h e t e r o c y c l i c s y s t e m s . R e t r o s y n t h e t i c a n a l y s e s a r e p r e s e n t e d in
this t e x t n o t as a n a l l - e m b r a c i n g a n s w e r t o s y n t h e t i c p r o b l e m s , b u t r a t h e r as
a n aid to u n d e r s t a n d i n g t h e a c t u a l c o n s t r u c t i o n of u n s a t u r a t e d h e t e r o c y c l e s .
R e t u r n i n g t o t h e c o n d e n s a t i o n p r e s e n t e d a b o v e , this l e a d s to a n i m p o r t a n t
d i s c o n n e c t i o n . T h e i m i n e - l i k e l i n k a g e p r e s e n t in s e v e r a l heterocycles
( g e n e r a l i s e d s t r u c t u r e 1 . 1 6 ) c a n a r i s e f r o m c y c l i s a t i o n of 1 . 1 7 , c o n t a i n i n g
amino and carbonyl functionalities.

T h e s y m b o l => d e n o t e s a
d i s c o n n e c t i o n , a n analytical
p r o c e s s in w h i c h a structure is
N' -NH,
t r a n s f o r m e d into a suitable
precursor 1.16 1.17

N o w c o n s i d e r c o n d e n s a t i o n of a m m o n i a w i t h k e t o e s t e r 1.18. T h e i s o l a t e d
p r o d u c t is n o t i m i n e 1 . 1 9 b u t t h e t h e r m o d y n a m i c a l l y m o r e s t a b l e e n a m i n e
tautomer 1.20 which has a conjugated double bond system and a strong
intramolecular hydrogen-bond. Although not a heterocyclic example, 1.20
i l l u s t r a t e s t h a t a n e n a m i n e - l i k e l i n k a g e , as in g e n e r a l i s e d h e t e r o c y c l e 1 . 2 1 , is
also accessible b y a condensation reaction.
 In a retrosynthetic sense, f o r m a l hydrolysis of the carbon-nitrogen b o n d of
1.21 reveals enol 1.22 w h i c h w o u l d exist as the m o r e stable ketone tautomer
1 . 2 3 . N o t e that in the h y d r o l y t i c d i s c o n n e c t i o n step the c a r b o n b e c o m e s
attached to a hydroxy g r o u p and the nitrogen to a hydrogen atom - there is n o
change in the oxidation levels of carbon or nitrogen.

H
1.21 1.22 1.23

U n l i k e o u r initial i m i n e d i s c o n n e c t i o n w h i c h is restricted to n i t r o g e n
h e t e r o c y c l e s (with o n e o r t w o specific e x c e p t i o n s such as p y r y l i u m salts, see
C h a p t e r 9), the h e t e r o a t o m in the e n a m i n e or e n a m i n e - l i k e d i s c o n n e c t i o n
could b e divalent. T h e r e f o r e this disconnection is also applicable to oxygen-
and sulphur-containing heterocycles, typified by 1.24 and 1.25.

1.25
Let us see h o w this disconnection approach can rationalize the synthesis of
pyrrole 2.16.

2.16 + NH3 1.26

Retrosynthetic analysis suggests a double c o n d e n s a t i o n b e t w e e n diketone

1.26 and a m m o n i a . P y r r o l e 2 . 1 6 can actually b e p r e p a r e d if this w a y - see
Chapter 2.2.
A n o t h e r aid to u n d e r s t a n d i n g heterocyclic synthesis in general is the fact
that a large n u m b e r of five- and six-membered heterocycles can be constructed
f r o m v a r i o u s c o m b i n a t i o n s of small acyclic m o l e c u l e s by c o m p l e m e n t a r y
m a t c h i n g of nucleophilic and electrophilic functionality.

C-C
©C C©
1.26 o o t - 2e 3
NH
NH,

Returning to the synthesis of pyrrole 2.16, diketone 1.26 can b e regarded as a

f o u r - c a r b o n bis-electrophilic f r a g m e n t and a m m o n i a , in this instance, as a
bis-nucleophilic nitrogen f r a g m e n t . A m m o n i a can f o r m up to three b o n d s in
a nucleophilic manner.
 In this particular i n s t a n c e the correct oxidation level automatically results
f r o m the c o n d e n s a t i o n reaction, g i v i n g p y r r o l e 2 . 1 6 directly. In other cases
c y c l i s a t i o n d o e s n o t a f f o r d the c o r r e c t o x i d a t i o n level and an u n s a t u r a t e d
s y s t e m has to be oxidised to a c h i e v e aromaticity. For instance, 1,5-diketones
1.27 react with a m m o n i a to give dihydropyridines 1.28 which can be oxidised
to p y r i d i n e s 1.29.

nh3^ [O] ^
-H,0 II 11 - 2H
•o O — R 2
R - S R „
H
1.27 1.28 1.29

E x a m p l e s of this c y c l i s a t i o n - o x i d a t i o n strategy i n c l u d e the s y n t h e s i s of

p y r i d o t r i a z i n e 5 . 3 2 ( p a g e 4 2 ) and s y n t h e s e s of quinolines and isoquinolines
( C h a p t e r 6). S o m e e x a m p l e s of nucleophilic and electrophilic f r a g m e n t s are
s h o w n in T a b l e 1.1. S e v e r a l points arise f r o m the table.
C o n s i d e r a c y l a t i n g species such as acid chlorides. A c y l a t i o n of d i a m i n e
1.30 initially gives a m i d e 1 . 3 1 w h i c h u n d e r g o e s a c o n d e n s a t i o n to p r o d u c e
b e n z i m i d a z o l e 1 . 3 2 . T h e c a r b o n y l m o i e t y is a c t i n g e x c l u s i v e l y as an
electrophilic centre.

1.32

H o w e v e r , delocalisation of the n i t r o g e n l o n e pair in the a m i d e l i n k a g e (see

mesomeric representations 1.33a,b) produces a nucleophilic oxygen atom
which can react with electrophiles as s h o w n .

o
R
K®A
N'
I I
H
H 1.33a 1.33b .

O J

vj I
H
Nucleophilic fragments Table 1.1
No. of ring atoms
1 NH3,H20,H2S (see Chapters 2 and 5)

2 H2N— NH 2 , H2N— OH (see pyrazole and isoxazole synthesis, Chapter4)

(see quinoline synthesis, Chapter 6)

(see benzimidazole synthesis, Chapter 1)

(see isoquinoline synthesis, Chapter 6)

) NH 2
J V
Electrophilic fragments
No. of ring atoms
O
(X = leaving group, eg. CI- see benzimidazole synthesis, Chapter 1
R
A x and isoquinoline synthesis, Chapter 6)

2 (see thiazole synthesis, Chapter 3)

^ i f ^See 4u'n°l'ne synthesis, Chapter 6)

Rj,k2 = aiKyi or u-aiKyi

(see pyrazole and isoxazole synthesis, Chapter 4, and pyrimidine synthesis, Chapter 10)

^ ^ \\ U ^ (see pyrrole, thiophene, and furan syntheses, Chapter 2)

O O

Nucleophilic / Electrophilic fragments

No. of ring at

2 (see Chapter 1 and oxazole synthesis, Chapter 3)

(see Chapter 1 and coumarin synthesis, Chapter 9)

(see oxazole synthesis, Chapter 3, and Knorr pyrrole

synthesis, Chapter 2)
The reaction of an acylating species A m i d e s c a n c y c l i z e in this m a n n e r as, f o r e x a m p l e , in the acylation of a m i n o
with a nucleophile is shown below. acids 1.34 to a f f o r d o x a z o l i d i n o n e s 1.35.

o
c° excess
O
0"O
O
R, a
R, -> N^/
OH
r Nuc
NH2 1.34 1.35

R Nuc Acylating species are thus included in both electrophilic and

e n u c l e o p h i l i c / e l e c t r o p h i l i c c a t e g o r i e s in T a b l e 1.1. F o r a r e l a t e d e x a m p l e see
the s y n t h e s i s of o x a z o l e s in C h a p t e r 3.
o 1,3-Dicarbonyl c o m p o u n d s , such as malonate derivatives, can also b e
c l a s s i f i e d u n d e r t w o c a t e g o r i e s . A s w e l l as r e a c t i n g s i m p l y as a t h r e e - a t o m
R Nuc b i s - e l e c t r o p h i l i c f r a g m e n t (as in t h e s y n t h e s i s of b a r b i t u r a t e 1 0 . 2 5 ( p a g e 7 7 ) ,
a n alternative reactivity is aivailable. C o n d e n s a t i o n (by n u c l e o p h i l i c attack)
of t h e a c t i v e m e t h y l e n e c a r b o n a n d e l e c t r o p h i l i c r e a c t i o n at j u s t o n e of t h e
c a r b o n y l g r o u p s is a t w o - a t o m n u c l e o p h i l i c / e l e c t r o p h i l i c p r o f i l e , as s e e n in
the p r e p a r a t i o n of c o u m a r i n 9.16.

For the spke of simplicity in this text

the two-stage process is abbreviated H
thus: Br. r' OEt Br. C0 2 Et
O

0 H EtO ' ^ O - H20

- EtOH
(T0 9.16
O
| Nuc
OEt
©
Nuc"
EtO ^O
o

R^Nuc T h e s e c o n c e p t s of retrosynthesis a n d h e t e r o c y c l e construction will h e l p p u t

the syntheses encountered in t h e f o l l o w i n g c h a p t e r s i n t o a broader
perspective.

1.4 References

Textbooks
Acheson, R.M. (1967). An introduction to the chemistry of heterocyclic
compounds, ( 2 n d edn). W i l e y , N e w Y o r k .
Paquette, L.A. (1966). Principles of modern heterocyclic chemistry.
Benjamin, N e w York.
Joule, J.A. and Smith, G.F. (1979). Heterocyclic chemistry, (2nd edn).
Van Nostrand Reinhold, New York.
Gilchrist, T.L. (1985). Heterocyclic chemistry. Longman, Harlow.
T h e first t w o ( A c h e s o n and P a q u e t t e ) are still very g o o d texts e v e n today. Of
the m o r e r e c e n t pair, b o t h are w a r m l y r e c o m m e n d e d . J o u l e a n d S m i t h is
p o s s i b l y a m o r e i n t r o d u c t o r y text t h a n G i l c h r i s t , w h i c h c o n t a i n s m a n y
j o u r n a l r e f e r e n c e s and is pitched at the a d v a n c e d u n d e r g r a d u a t e / p o s t g r a d u a t e
l e v e l . S e e G i l c h r i s t f o r a d i s c u s s i o n of t h e n u c l e o p h i l i c / e l e c t r o p h i l i c
f r a g m e n t a p p r o a c h to heterocyclic synthesis.

W a r r e n , S. ( 1 9 7 8 ) . Designing organic syntheses, p.150-172. Wiley,

Chichester.
W a r r e n S. ( 1 9 8 2 ) . Organic synthesis - the disconnection approach, p.
3 2 6 0 - 3 4 5 . W i l e y , Chichester.

Reference books and series

C o f f e y , S. (ed.) ( 1 9 7 3 - 1986). Heterocyclic compounds (Vols. 4 A - 4 K of
Rodd's chemistry of carbon compounds). Elsevier, A m s t e r d a m .
E l d e r f i e l d , R . C . (ed.) ( 1 9 5 0 - 1967). Heterocyclic chemistry, V o l s . 1 - 9.
Wiley, N e w York.
K a t r i t z k y , A . R . a n d B o u l t o n , A . J . (ed.) ( 1 9 6 3 - 1989). Advances in
heterocyclic chemistry, V o l s . 1 - 4 5 . A c a d e m i c Press, O r l a n d o .
Katritzky, A . R . and R e e s , C . W . (ed.) (1984). Comprehensive heterocyclic
chemistry, Vols. 1 - 8. P e r g a m o n Press, O x f o r d .
K a t r i t z k y , A . R . et al, (1991). Heterocycles, 32, 1 2 7 - 1 6 1 .
S a m m e s , P.G. (ed.) (1979). Heterocyclic chemistry ( V o l . 4 of
Comprehensive organic chemistry, ed. D . B a r t o n and W . D . Ollis).
P e r g a m o n Press, O x f o r d .
W e i s s b u r g e r , A . and T a y l o r , E . C . (ed.) ( 1 9 5 0 - 1990). The chemistry of
heterocyclic compounds. W i l e y Interscience, N e w Y o r k .

All of these sources c o n t a i n e x c e l l e n t r e v i e w s o n virtually e v e r y aspect of

h e t e r o c y c l i c c h e m i s t r y . In p a r t i c u l a r , K a t r i t z k y and R e e s is a t h o r o u g h l y
c o m p r e h e n s i v e w o r k . F o r t h o s e p a r t i c u l a r l y interested in t h e s y n t h e s i s of
heterocycles as pharmaceutical agents see:

L e d n i c e r , D . a n d M i t s c h e r , L . A . ( 1 9 7 7 , 1980, 1984, a n d 1990). Organic

chemistry of drug synthesis, V o l s . 1 - 4 . W i l e y , N e w Y o r k .

Experimental references
In this i n t r o d u c t o r y t e x t t h e r e is little d e t a i l r e g a r d i n g s o l v e n t s , y i e l d s ,
w o r k u p p r o c e d u r e s , etc. H o w e v e r , s e v e r a l c h a p t e r s r e f e r e n c e a r e l e v a n t
e x p e r i m e n t a l p r o c e d u r e (taken f r o m Organic syntheses or Vogel) which the
s t u d e n t is s t r o n g l y e n c o u r a g e d to r e a d . F o r an e x c e l l e n t s e l e c t i o n of
experimental procedures f o r the synthesis of heterocycles see:

F u r n i s s , B.S., H a n n a f o r d , A.J., S m i t h , P . W . G . , and Tatchell, A . R . (1989).

Vogel's textbook of practical organic chemistry (5th edn),
pp. 1127 - 1194. L o n g m a n , H a r l o w .
 2. Pyrroles, thiophenes, and
furans

2.1 Introduction
Pyrrole 2.1, thiophene 2.2, and furan 2.3, are five-membered ring
heteroaromatic c o m p o u n d s containing one heteroatom. T h e y derive their
aromaticity from delocalisation of a lone pair of e l e c t r o n s f r o m the
h e t e r o a t o m . C o n s e q u e n t l y t h e l o n e p a i r is n o t a v a i l a b l e f o r p r o t o n a t i o n a n d
hence these heterocycles are not basic.
T h e n u m b e r i n g of h e t e r o c y c l e s
generally starts at the h e t e r o a t o m 4/

H N
' a
H
N© H 2.1 2.2 2.3

H T h e b a s i s a n d e x t e n t of t h e i r a r o m a t i c i t y is d i s c u s s e d in C h a p t e r 1. I n
U n d e r e x t r e m e c o n d i t i o n s of s u m m a r y , the capacity for the lone pair on a particular heteroatom to be
acidity p y r r o l e is p r o t o n a t e d , but d e l o c a l i s e d is i n v e r s e l y r e l a t e d to t h e e l e c t r o n e g a t i v i t y of t h e h e t e r o a t o m . F o r
at the C2 position. i n s t a n c e , f u r a n is t h e l e a s t a r o m a t i c of t h e t r i o b e c a u s e o x y g e n h a s t h e
greatest electronegativity and hence mesomeric representations 2.4b-e m a k e
r e l a t i v e l y l e s s of a c o n t r i b u t i o n to t h e e l e c t r o n i c s t r u c t u r e of f u r a n t h a n t h e y
d o in t h e c a s e s of p y r r o l e a n d t h i o p h e n e . T h e o r d e r of a r o m a t i c i t y is f u r a n <
p y r r o l e < t h i o p h e n e . W e s h a l l s e e l a t e r h o w this v a r i a t i o n in a r o m a t i c i t y
a f f e c t s t h e reactivities of t h e s e three related h e t e r o c y c l e s .

QNFFI e
1 e Q — t > - C I
h/\H P yv
N o t e that protonation of the 2.4e
2.4a 2.4b 2.4c 2.4d
p y r r o l e nitrogen w o u l d l e a d to a
X = NH,S,O
n o n - a r o m a t i c cation.
A s m a l l n u m b e r of s i m p l e p y r r o l e s s u c h as 2 . 5 a n d 2 . 6 o c c u r n a t u r a l l y .
Far more important are the tetramic pyrrole derivatives (porphyrins) such as
chlorophyll-a 2.7 and h a e m 2.8.

\-o o.

\J
2.5
 C h l o r o p h y l l - a is a plant p i g m e n t
i n v o l v e d in the c r u c i a l
p h o t o s y n t h e t i c p r o c e s s in w h i c h
the e n e r g y of sunlight is
h a r n e s s e d to i n c o r p o r a t e c a r b o n
d i o x i d e into plant m e t a b o l i s m .
C20H34O H a e m , h o w e v e r , is f u n d a m e n t a l to
m a m m a l i a n biology, b e i n g the
o x y g e n - b i n d i n g c o m p o n e n t of
haemoglobin. Oxygen absorbed
f r o m the air is t r a n s p o r t e d a r o u n d
the b o d y w h i l e t e m p o r a r i l y co-
o r d i n a t e d to the iron a t o m of
h a e m o g l o b i n , w h i c h o c c u r s in t h e
A c e t y l e n i c t h i o p h e n e 2 . 9 , f o u n d in s o m e s p e c i e s of h i g h e r p l a n t s , is o n e red b l o o d cells.
of t h e f e w n a t u r a l l y - o c c u r r i n g t h i o p h e n e s . H o w e v e r , t h e t h i o p h e n e r i n g is
u s e d in s e v e r a l i m p o r t a n t p h a r m a c e u t i c a l p r o d u c t s , s u c h as t h e p e n i c i l l i n
antibiotic 2.10.

CO,H

CO,H
2.10

In c o n t r a s t to t h e p y r r o l e a n d t h i o p h e n e series, t h e f u r a n n u c l e u s o c c u r s in Terpenes are plant-derived

natural p r o d u c t s c o n s t r u c t e d of
m a n y p l a n t - d e r i v e d t e r p e n e s s u c h as 2 . 1 1 . T h e m o s t i m p o r t a n t f u r a n -
multiples of the f i v e - c a r b o n
c o n t a i n i n g d r u g is 2 . 1 2 , w h i c h r e d u c e s g a s t r i c acid s e c r e t i o n a n d is i m p o r t a n t hydrocarbon isoprene.
in t h e t r e a t m e n t of ulcers.

/y 9

H„/ NHMe
O
u , NMe,

2.12
2.11

2.2. Synthesis of pyrroles, thiophenes, and furans

We shall first examine a general synthesis applicable to all three
h e t e r o c y c l e s , then c o n s i d e r t w o s p e c i f i c s y n t h e s e s of p y r r o l e s .
R e t r o s y n t h e t i c c l e a v a g e of a c a r b o n - h e t e r o a t o m b o n d in 2 . 1 3 g i v e s e n o l
2 . 1 4 w h i c h is e q u i v a l e n t t o k e t o n e 2 . 1 5 . R e p e a t i n g t h e p r o c e s s g i v e s u s a
1 , 4 - d i c a r b o n y l c o m p o u n d a n d t h e h e t e r o a t o m - c o n t a i n i n g f r a g m e n t s u c h as a
primary amine or hydrogen sulphide.
 T h e f o r w a r d p r o c e s s is k n o w n as the P a a l - K n o r r synthesis. T h i s is a very
s t r a i g h t f o r w a r d s y n t h e s i s l i m i t e d o n l y b y t h e a c c e s s i b i l i t y • of t h e 1,4-
dicarbonyl precursors.

The mechanism is illustrated by

the preparation of 2,5-dimethyl
pyrrole 2.16 and is simply two
consecutive condensations.

T h e P a a l - K n o r r s y n t h e s i s c a n s i m i l a r l y be a p p l i e d to t h i o p h e n e s , e.g.
c o m p o u n d s 2 . 1 7 - 2.20.

W h e n h y d r o g e n s u l p h i d e is t h e h e t e r o a t o m s o u r c e t h e m e c h a n i s m is
similar to the p y r r o l e case.

H o w e v e r , t h e s i t u a t i o n is slightly d i f f e r e n t w h e n p h o s p h o r u s ( V )
s u l p h i d e is used. T h i s r e a g e n t c o n v e r t s k e t o n e s to thioketones, b y e x c h a n g e
of a p h o s p h o r u s - s u l p h u r d o u b l e b o n d with a c a r b o n - o x y g e n d o u b l e b o n d .
 F o r i n s t a n c e , in t h e s y n t h e s i s of 2 . 1 9 , t h e 1 , 4 - d i k e t o n e is c o n v e r t e d i n t o
the c o r r e s p o n d i n g 1 , 4 - d i t h i o k e t o n e f o l l o w e d b y loss of h y d r o g e n s u l p h i d e .

p2s5 H,S T h e m e c h a n i s m of the cyclisation

Ph ^ ^ P h Ph Ph Ph step is similar to that of t h i o p h e n e
Ph S
O O S S 2.17.
2.19
O u r r e t r o s y n t h e t i c a n a l y s i s of t h e P a a l - K n o r r s y n t h e s i s l e a d s to a p r o b l e m
w h e n a p p l i e d to f u r a n , as it i m p l i e s a d d i t i o n of a w a t e r m o l e c u l e , f o l l o w e d b y
e l i m i n a t i o n of t w o w a t e r m o l e c u l e s . In p r a c t i c e , s i m p l e d e h y d r a t i o n of a 1,4-
d i c a r b o n y l c o m p o u n d l e a d s to f u r a n s as in t h e p r e p a r a t i o n of 2.21.

Ph oO Ph
2.21

R e t u r n i n g again to pyrroles, p r o b a b l y the m o s t widely-used m e t h o d f o r

their p r e p a r a t i o n is t h e K n o r r p y r r o l e s y n t h e s i s , w h i c h is t h e c o n d e n s a t i o n o f
a k e t o n e 2 . 2 2 w i t h a n a - a m i n o k e t o n e 2 . 2 3 to g i v e p y r r o l e 2 . 1 3 , v i a e n a m i n e
2 . 2 4 . A r e a s o n a b l e m e c h a n i s m is s h o w n b e l o w , a l t h o u g h n o n e o f t h e
i n t e r m e d i a t e s is isolated.

K s k
1 V ^ i v
R

2.22 2.23
R2 R3 OH

1
N
H
2.13
T h e a - a m i n o k e t o n e s a r e o f t e n p r e p a r e d b y n i t r o s a t i o n of a n active
m e t h y l e n e g r o u p f o l l o w e d b y r e d u c t i o n of t h e o x i m e to t h e a m i n e (e.g. 2 . 2 5
t o 2 . 2 6 to 2 . 2 7 ) .

O
W? °
C0 2 Et , C0 2 Et - C 5 H h OH Jl,C0 Et C0 2 Et CO,Et
2 Zn
2.25 V H
U N : 0 « ^ N AcOH
AcOH NH 2

O c - 2.26 2.27

A s a - a m i n o k e t o n e s are p r o n e to self-condensation (see p a g e 2 2 for a

d i s c u s s i o n of a - a m i n o k e t o n e s ) , t h e initial c o n d e n s a t i o n s t e p is f a c i l i t a t e d b y
R-2 in 2 . 2 2 being an electron-withdrawing group. This enhances the
e l e c t r o p h i l i c n a t u r e of t h e k e t o n e c a r b o n y l g r o u p t h e r e b y i n c r e a s i n g t h e r a t e
of t h e d e s i r e d r e a c t i o n , a n d f a v o u r s e n a m i n e t a u t o m e r 2 . 2 4 o v e r t h e i m i n o
 t a u t o m e r b e c a u s e of c o n j u g a t i o n w i t h t h e e l e c t r o n - w i t h d r a w i n g g r o u p . A
s e l e c t i o n of K n o r r p y r r o l e s y n t h e s e s , s h o w i n g t h e k e y i n t e r m e d i a t e e n a m i n e s ,
is s h o w n b e l o w .

COjEt CO,Et /
CO,Et 0

X H2N ^ C0 2 Et N
H
C0 22Et N-

H
C0 2 Et

X
The Knorr pyrrole synthesis COzEt o

y -
:o 2 Et
consists of a k e t o n e a n d a m i n e
c o n d e n s i n g to give an e n a m i n e , J ' H W
f o l l o w e d by i n t r a m o l e c u l a r
H,N V
H
cyclisation of this e n a m i n e onto
the remaining ketone. C(
C0 2 Et C5Hn
COjEt \Et 0^,C5H n

- r i
N
COjEt C0 2 Et H C0 22Et
H
Ph Ph

%
Ph O^-Ph
Ph
l H,N
° I Ph -N^^ph
//
H

2.3 Electrophilic substitution of pyrrole, thiophene,

and furan

Note that pyrrole reacts w i t h

e l e c t r o p h i l e s o n c a r b o n , like a n
enamine.
All t h r e e h e t e r o c y c l e s u n d e r g o a r o m a t i c s u b s t i t u t i o n r e a c t i o n s , t h o u g h t h e i r
reactivities vary considerably. Let us consider a generalised m e c h a n i s m and
h o w t h e s t a b i l i t y of t h e t w o p o s s i b l e i n t e r m e d i a t e s a f f e c t s t h e p o s i t i o n of
substitution.

v >
CY_ -CX—
X H X H "X
(&'H
2.28a 2.28b 2.28c

>
H H
E 1

o X
<—1>
-H // w
v
x'

X=NH,S,0 2.29a 2.29b

T h e i n t e r m e d i a t e d e r i v e d f r o m a t t a c k at t h e C 2 p o s i t i o n h a s g r e a t e r
d e l o c a l i s a t i o n of t h e p o s i t i v e c h a r g e ( m e s o m e r i c f o r m s 2 . 2 8 a , b , c ) t h a n that
d e r i v e d f r o m a t t a c k at t h e C 3 p o s i t i o n ( m e s o m e r i c f o r m s 2 . 2 9 a , b ) . A s t h e
c h a r g e is m o r e e x t e n s i v e l y d e l o c a l i s e d in t h e f o r m e r , this i n t e r m e d i a t e is at
l o w e r e n e r g y . T h i s in t u r n is r e f l e c t e d in a l o w e r a c t i v a t i o n e n e r g y f o r this
p a t h w a y a n d m a n i f e s t e d in a s e l e c t i v i t y f o r e l e c t r o p h i l i c s u b s t i t u t i o n at t h e
C 2 position over the C 3 position. T h e actual isomer ratio depends on the
h e t e r o c y c l e , t h e e l e c t r o p h i l e , a n d t h e p r e c i s e c o n d i t i o n s , a l t h o u g h in m a n y
cases such reactions are virtually regiospecific, and only the C 2 substitution
p r o d u c t s a r e i s o l a t e d . V e r y r e a c t i v e e l e c t r o p h i l e s ( s u c h as t h e n i t r o n i u m ion
N 0 2 + ) exhibit lower selectivity b e c a u s e they tend to b e less discriminating
as t o w h e r e t h e y a t t a c k t h e h e t e r o a r o m a t i c n u c l e u s .
T h e e a s e of e l e c t r o p h i l i c s u b s t i t u t i o n is p y r r o l e > f u r a n > t h i o p h e n e >
benzene.
P y r r o l e is e x t r e m e l y r e a c t i v e t o w a r d s e l e c t r o p h i l e s w h i l e t h i o p h e n e , t h e T o give a quantitative feel for
t h e s e d i f f e r e n c e s in reactivity,
most aromatic o f t h e t r i o , is m u c h less reactive. At a very rough
d a t a for the b r o m i n a t i o n of three
a p p r o x i m a t i o n , t h e r e a c t i v i t y of t h i o p h e n e is of t h e o r d e r of a h e t e r o a t o m - r e p r e s e n t a t i v e d e r i v a t i v e s are
s u b s t i t u t e d b e n z e n e d e r i v a t i v e s u c h as p h e n o l . D e s p i t e l a r g e d i f f e r e n c e s in shown below.
t h e r a t e s of e l e c t r o p h i l i c s u b s t i t u t i o n s t h e r e a r e s o m e i m p o r t a n t a r o m a t i c
s u b s t i t u t i o n r e a c t i o n s c o m m o n to all t h r e e h e t e r o c y c l e s .
CO,Me
T h e V i l s m e i e r r e a c t i o n is t h e f o r m y l a t i o n of r e a c t i v e a r o m a t i c c o m p o u n d s
by using a combination of phosphorus oxychloride and N,N-
Br,
dimethylformamide, followed by a hydrolytic workup.

o X
X=NH,S,0
1. Me2NCHO / POCI3
2. H , 0
//
"X
CO,Me
H

T h e r e a c t i o n p r o c e e d s b y f o r m a t i o n of t h e e l e c t r o p h i l i c V i l s m e i e r c o m p l e x X Relative Rate
2 . 3 0 , f o l l o w e d b y e l e c t r o p h i l i c s u b s t i t u t i o n of t h e h e t e r o c y c l e . T h e f o r m y l
g r o u p is g e n e r a t e d in t h e h y d r o l y t i c w o r k u p . P y r r o l e , t h i o p h e n e , a n d f u r a n all
s 1

u n d e r g o this f o r m y l a t i o n w h i c h is h i g h l y s e l e c t i v e f o r t h e C 2 p o s i t i o n . o 1.2 x 102

NH 5.6 x 108

a
Cl- P - CI
Cl-P.O
O
11 Cl°
\
v ©
CI
e
CP H"^NMe2 ci 2.30
C l ^
V-NMe2 H i ^ J
H k j
NMe,
o -H e
H,0
// V // V
NMe2 CI
o Q
</ X F NMe, •HNMe 2 ^X
H H

All three heterocycles u n d e r g o sulphonation with the p y r i d i n e - s u l p h u r

trioxide c o m p l e x . This b e h a v e s like a mild source of sulphur trioxide,
enabling the sulphonation to be carried out under essentially neutral
conditions.
O
II e
N- s-

o
II
o
X
( X SO,H
X=NH,S,0
F u r a n a n d p y r r o l e a r e n o t s t a b l e to m i n e r a l a c i d s , b u t a c e t y l n i t r a t e c a n b e
u s e d f o r t h e n i t r a t i o n of all t h r e e h e t e r o c y c l e s .

NO,

—H
cx NO,
T h e f o r m a t i o n of 2 . 3 2 raises a n
i m p o r t a n t theoretical point:
b e c a u s e f u r a n is not very a r o m a t i c
a n d the driving f o r c e to 're-
aromatise' by loss of a proton is
not v e r y s t r o n g , cation 2 . 3 1 c a n
be i n t e r c e p t e d to give 2 . 3 2 . T h i s
b e h a v i o u r is not o b s e r v e d w i t h
pyrrole and thiophene.
W h i l s t t h e m e c h a n i s m s h o w n a b o v e a p p l i e s to p y r r o l e a n d t h i o p h e n e , t h e
n i t r a t i o n of f u r a n w i t h a c e t y l n i t r a t e g i v e s t h e 2 , 5 - a d d i t i o n p r o d u c t 2 . 3 2 ,
a r i s i n g f r o m a t t a c k of a c e t a t e i o n o n t h e i n t e r m e d i a t e c a t i o n 2 . 3 1 . T r e a t m e n t
of 2 . 3 2 w i t h p y r i d i n e e l i m i n a t e s t h e e l e m e n t s of a c e t i c a c i d p r o d u c i n g
nitrofuran 2.33.
o o

N0! Xr NO,

Q C
CV
f o ffi H
-AcOH
NO,

2.3 AcO © v
m d
2.31 2.32 2.33

Thiophene, alkyl-substituted furans, and especially pyrrole, undergo

Mannich reactions.

CH 2 0/HNEt 2

Q
NEt,
AcOH N
H H
CH20/HNMe2 • NMe,
HC1

CH20/HNMe2 •
/ M
J J AcOH
NMe,

T h i s i n v o l v e s c o n d e n s a t i o n of t h e h e t e r o c y c l e , f o r m a l d e h y d e , a n d a n a m i n e
( u s u a l l y a s e c o n d a r y a m i n e ) to g i v e a n a m i n o m e t h y l d e r i v a t i v e .

AcOH
CH-p= NMe,
eOAc
Me,NH + C H , 0
• H,0

O r (h NMe, NMe,
CH7—— NMe, r X H X

T h e F r i e d e l - C r a f t s acylation and alkylation reactions are f u n d a m e n t a l

p r o c e s s e s in a r o m a t i c c h e m i s t r y . P y r r o l e s a n d f u r a n s a r e n o t s t a b l e t o t h e
L e w i s a c i d s n e c e s s a r y f o r t h e s e r e a c t i o n s , b u t t h i o p h e n e s a r e s t a b l e to L e w i s
acids, a n d d o u n d e r g o F r i e d e l - C r a f t s acylation and alkylation.

V
PhCOCl O
Q
o
A1C1,
Ph

/ / \ ,0
SnCL

O b s e r v e that electrophilic
EtBr // V
substitution o c c u r s at the C 3
s A1C1,
position w h e n both t h e C 2 a n d C5
p o s i t i o n s are b l o c k e d .
 T h e r e a c t i v i t y o f all t h r e e h e t e r o c y l e s is c o n s i d e r a b l y r e d u c e d when
e l e c t r o n - w i t h d r a w i n g g r o u p s a r e p r e s e n t o n t h e r i n g . T h i s is i m p o r t a n t in t h e
s y n t h e s i s of p y r r o l e d e r i v a t i v e s as it a d d s c h e m i c a l s t a b i l i t y t o t h e r i n g ,
e n a b l i n g r e a c t i o n s to b e p e r f o r m e d in the p r e s e n c e of L e w i s acids.

T h e r e g i o c h e m i s t r y of t h e s e
r e a c t i o n s is easily e x p l a i n e d by
rationalisations f r o m classical
b e n z e n e c h e m i s t r y , i.e. e l e c t r o n -
w i t h d r a w i n g g r o u p s direct meta.

jtC
AcONO,

NO2 O

2.4 Anion chemistry of pyrroles, thiophenes, and

furans
P y r r o l e h a s a w e a k l y a c i d i c h y d r o g e n a t o m a t t a c h e d to t h e n i t r o g e n ( p ^ a =
17.5) a n d c a n b e d e p r o t o n a t e d b y s t r o n g b a s e s . T h e s o d i u m a n d p o t a s s i u m
salts a r e i o n i c in c h a r a c t e r a n d t h e n a k e d a n i o n t e n d s to r e a c t o n n i t r o g e n as in
t h e p r e p a r a t i o n of N - m e t h y l p y r r o l e 2 . 3 4 . T h e c o r r e s p o n d i n g m a g n e s i u m
d e r i v a t i v e 2 . 3 5 h a s m o r e c o v a l e n t c h a r a c t e r a n d t e n d s to r e a c t m o r e o n c a r b o n
t h a n n i t r o g e n , as in t h e p r e p a r a t i o n of p y r r o l e a l d e h y d e 2 . 3 6

f \ NaNH^ f \ Mel > f \

2.34
N N e N
H © Na Me
2.1

O
( f—TV H ' V ^ O E t r=\
o
N f N N H N
H H
MgBr «
2.1 2.35 2.36

N - m e t h y l p y r r o l e 2 . 3 4 , t h i o p h e n e , a n d f u r a n c a n b e m e t a l l a t e d at t h e C 2
p o s i t i o n w i t h a l k y l l i t h i u m r e a g e n t s . T h i s p o s i t i o n is m o r e a c t i v a t e d t o
deprotonation than the C 3 position b e c a u s e of the e l e c t r o n - w i t h d r a w i n g
i n d u c t i v e e f f e c t of t h e h e t e r o a t o m . T h e n u c l e o p h i l i c 2 - l i t h i o s p e c i e s c a n t h e n
b e r e a c t e d w i t h v a r i o u s e l e c t r o p h i l e s , a s in t h e p r e p a r a t i o n of 2 . 3 7 , 2 . 3 8 ,
 a n d 2 . 3 9 . L e t u s s e e h o w this m e t h o d o l o g y c a n b e a p p l i e d t o t h e s y n t h e s i s o f
2 . 4 2 , a f u r a n - c o n t a i n i n g m i m i c of a l o n g - c h a i n f a t t y a c i d . D e p r o t o n a t i o n o f
f u r a n a n d a l k y l a t i o n p r o d u c e s 2 . 3 9 . A s e c o n d d e p r o t o n a t i o n at t h e C 5
p o s i t i o n a n d a l k y l a t i o n g i v e s b r o m i d e 2 . 4 0 . D i s p l a c e m e n t of t h e b r o m i d e
a f f o r d s nitrile 2 . 4 1 , a n d a c i d i c h y d r o l y s i s y i e l d s the target f u r a n 2 . 4 2 .

n-BuLi
o N
e Li
as ClC0 2 Me
• cx N
Me
CO,Me
Me Me 2.37
T h e precise n a t u r e of the c a r b o n -
lithium b o n d is b e y o n d t h e s c o p e
of this b o o k . O r g a n o l i t h i u m
i n t e r m e d i a t e s are here ClP(0)(0Et) 2
r e p r e s e n t e d as c a r b a n i o n a n d / r y " - B u L i » / r \
© Li
c a t i o n to e m p h a s i s e d i f f e r e n c e s in S -OEt
properties a n d reactivities as OEt
2.2 2.38
c o m p a r e d w i t h full c o v a l e n t b o n d s .

T h e alkyl g r o u p at the C 2 position n-BuLi / CH 3 (CH 2 ) 6 Br n-BuLi / Br(CH2)6Br

is not d e p r o t o n a t e d in the s e c o n d r \ +jr\
alkylation. 'O' CH 3 (CH 2 ) 6 C H 3 ( C H 2 ) 6 ^ 0 - / ^ (CH2)6Br

2.3 2.39 2.40

NaCN

Note the u s e of " C N as a s y n t h o n

HCI/H 2 O J T \
for - C O 2 H .
CH3(CH2)6-^O (CH 2 ) 6 C0 2 H <3 CH^CHJs'^-o (CH2)6CN
2.42 2.41

2.5 Problems
l.

MeN

2.43

T r i c y c l i c p y r r o l e d e r i v a t i v e 2 . 4 3 is a d r u g c u r r e n t l y u n d e r d e v e l o p m e n t f o r
t h e t r e a t m e n t of s c h i z o p h r e n i a . It is p r e p a r e d b y a K n o r r p y r r o l e s y n t h e s i s .
W h a t a r e t h e s t r u c t u r e s o f t h e t w o s t a r t i n g m a t e r i a l s r e q u i r e d , a n d that of t h e
intermediate enamine?

2. W h y is p y r r o l e a l d e h y d e 2 . 4 4 l e s s r e a c t i v e to n u c l e o p h i l e s t h a n , s a y ,
b e n z a l d e h y d e ? W h y is p y r r o l e a l c o h o l 2 . 4 5 r e a d i l y p o l y m e r i s e d o n e x p o s u r e
to acid?

H H H
2.44 2.45
3. N i t r a t i o n of f u r a n w i t h n i t r o n i u m t e t r a f l u o r o b o r a t e p r o d u c e s n i t r o f u r a n
2 . 3 3 d i r e c t l y . C o n t r a s t this r e s u l t to t h e t w o stage r e a c t i o n n e c e s s a r y w i t h
acetyl nitrate, p a g e 16. E x p l a i n t h e s e o b s e r v a t i o n s .

©
Q JO*^ ^
2.2 2.33

4. W h a t is the m e c h a n i s m of this r e a c t i o n ?

o S'
phC0C1

AlClj
, Ph

o
ti y

2.2

2.6 References
Dean, F.M. (1982). Adv. heterocyclic chem., 30, 167; 3 1 , 231
(furans).
G r o n o w i t z , S. (ed.) (1985). In Thiophene and its derivatives (The
chemistry of heterocyclic compounds [ed. A. W e i s s b u r g e r a n d E . C . T a y l o r ] ,
V o l . 44). W i l e y I n t e r s c i e n c e , N e w Y o r k .
Furniss, B.S., Hannaford, A.J., Smith, P.W.G, and Tatchell, A.R. (1989).
Vogel's textbook of practical organic chemistry (5th e d n ) , p . 1 1 4 8
(preparation of p y r r o l e 2.16). L o n g m a n , H a r l o w .
Jackson, A.H. (1979). I n Heterocyclic chemistry (ed. P.G. Sammes)
( V o l . 4 of Comprehensive organic chemistry, ed. D. Barton and W . D .
Ollis) (pyrroles). P e r g a m o n Press, O x f o r d .
J o n e s , R . A . ( e d . ) ( 1 9 9 0 ) . In Pyrroles (The chemistry of heterocyclic
compounds [ed. A . W e i s s b u r g e r a n d E . C . T a y l o r ] , V o l 48, Part 1). W i l e y
Interscience, N e w Y o r k .
J o n e s , R . A . a n d B e a n , G . P . ( 1 9 7 7 ) . The chemistry of pyrroles. Academic
Press, L o n d o n .
J o n e s , E . a n d M o o d i e , I . M . ( 1 9 7 0 ) . Org. syn., 5 0 , 104 ( C 2 m e t a l l a t i o n of
thiophene).
K a t r i t z k y , A . R . a n d R e e s , C . W . (ed.) ( 1 9 8 4 ) . Comprehensive heterocyclic
chemistry, Vol. 4, Part 3 (five-membered rings with one heteroatom).
P e r g a m o n Press, O x f o r d .
M e t h - C o h n , O. ( 1 9 7 9 ) . I n Heterocyclic chemistry (ed. P . G . Sammes)
( V o l . 4 of Comprehensive organic chemistry, ed. D. Barton and W . D .
Ollis), p . 7 3 7 ( t h i o p h e n e s ) . P e r g a m o n P r e s s , O x f o r d .
Sargent, M.V. (1979). I n Heterocyclic chemistry (ed. P.G. Sammes)
( V o l . 4 of Comprehensive organic chemistry, ed. D. Barton and
W . D . Ollis), p . 6 9 3 ( f u r a n s ) . P e r g a m o n P r e s s , O x f o r d .
Silverstein, R.M., Ryskiewicz, E.E., and Willard, C. (1963). Organic
syntheses, Coll. V o l . I V , 8 3 1 ( V i l s m e i e r f o r m y l a t i o n of p y r r o l e ) .
 3. Oxazoles, imidazoles, and
thiazoles

3.1 Introduction
O x a z o l e 3 . 1 , i m i d a z o l e 3 . 2 , a n d t h i a z o l e 3 . 3 a r e t h e p a r e n t s t r u c t u r e s of a
related series of 1,3-azoles containing a nitrogen atom plus a second
h e t e r o a t o m in a f i v e - m e m b e r e d ring.

3.1 3.2 3.3

T h e y are isomeric with the 1,2-azoles isoxazole, pyrazole, and isothiazole

( s e e C h a p t e r 4 ) . T h e i r a r o m a t i c i t y d e r i v e s f r o m d e l o c a l i s a t i o n of a l o n e p a i r
f r o m the second heteroatom, 3.4a-e.

X=0,NH,S

T h e b i o s y n t h e s i s of h i s t a m i n e T h e i m i d a z o l e r i n g o c c u r s n a t u r a l l y in h i s t a m i n e 3 . 5 , a n important
i n v o l v e s d e c a r b o x y l a t i o n of t h e
m e d i a t o r of i n f l a m m a t i o n a n d g a s t r i c a c i d s e c r e t i o n . A q u a t e r n i s e d t h i a z o l e
a m i n o acid histidine.
r i n g is f o u n d in t h e e s s e n t i a l v i t a m i n t h i a m i n 3 . 6 . T h e r e a r e f e w n a t u r a l l y
occurring oxazoles, apart f r o m some secondary metabolites f r o m plant and
fungal sources.

H
3.5 3.6
Oxazole, imidazole, and thiazole can be formally derived f r o m furan,
pyrrole, and t h i o p h e n e respectively by r e p l a c e m e n t of a C H g r o u p b y a
n i t r o g e n a t o m at t h e 3 p o s i t i o n . T h e p r e s e n c e of this p y r i d i n e - l i k e n i t r o g e n
deactivates the 1,3-azoles towards electrophilic attack and increases their
s u s c e p t i b i l i t y t o w a r d s n u c l e o p h i l i c a t t a c k (see later). T h e s e 1 , 3 - a z o l e s c a n b e
v i e w e d as h y b r i d s b e t w e e n f u r a n , p y r r o l e , o r t h i o p h e n e , a n d p y r i d i n e .
 I m i d a z o l e (p/T a =7.0) is m o r e b a s i c t h a n o x a z o l e ( p / f a = 0 . 8 ) o r t h i a z o l e T h e statement that oxazole has a
(p/sT a =2.5). T h i s increased basicity arises f r o m the greater electron-releasing p K a of 0.8 means that the
protonated form of oxazole is a
c a p a c i t y of t w o n i t r o g e n a t o m s r e l a t i v e to a c o m b i n a t i o n of n i t r o g e n and a
very strong acid.
h e t e r o a t o m of h i g h e r e l e c t r o n e g a t i v i t y . A l s o n o t e that a s y m m e t r i c a l Therefore oxazole (as the free
resonance-stabilised cation 3 . 7 a , b is f o r m e d . base) is a very w e a k base indeed.

^ H
© H

o -
N'

0 N
1
0 .
H H
H
3.7b
3.7a
F u r t h e r m o r e , certain s u b s t i t u t e d i m i d a z o l e s can exist in t w o t a u t o m e r i c
forms.

H
N

>3 N
H
3.8

F o r i n s t a n c e , t h e i m i d a z o l e s h o w n a b o v e e x i s t s as a r a p i d l y e q u i l i b r a t i n g
m i x t u r e of 4 - m e t h y l 3 . 8 a n d 5 - m e t h y l 3 . 9 t a u t o m e r s , and is r e f e r r e d to as
4 ( 5 ) - m e t h y l i m i d a z o l e . It m u s t a g a i n b e s t r e s s e d that t a u t o m e r i s a t i o n a n d
r e s o n a n c e are totally d i f f e r e n t . M e s o m e r i c r e p r e s e n t a t i o n s 3 . 7 a , b are n o t
interconverting like t a u t o m e r s 3.8 and 3.9; this is simply a m e a n s to describe
an intermediate hybrid structure.

3.2 Synthesis of oxazoles

R e t r o s y n t h e t i c c l e a v a g e of t h e c a r b o n - o x y g e n b o n d in g e n e r a l i s e d o x a z o l e
3.10 p r o d u c e s iminoalcohol 3 . 1 1 (better represented in the a m i d e f o r m

3 . 1 2 ) . S i m i l a r t a u t o m e r i s a t i o n o f t h e e n o l g r o u p g i v e s an a c t u a l
i n t e r m e d i a t e 3 . 1 3 , a n d d i s c o n n e c t i o n of t h e a m i d e l i n k a g e r e v e a l s
a m i n o k e t o n e 3 . 1 5 a n d an acylating species 3 . 1 4 such as an acid chloride. T h e
f o r w a r d p r o c e s s , c y c l o c o n d e n s a t i o n of a m i d e s 3 . 1 3 to yield oxazoles 3.10, is
k n o w n as the R o b i n s o n - G a b r i e l synthesis.
 O
NH, A, H
"T
N

Base
H,0
fV\
R
1 O O r3

3.15 3.13 3.10

In p r a c t i c e t h e d e h y d r a t i o n c a n b e a c h i e v e d w i t h a b r o a d r a n g e of a c i d s o r
acid a n h y d r i d e s , s u c h as p h o s p h o r i c acid, p h o s p h o r u s o x y c h l o r i d e , p h o s g e n e
( C O C I 2 ) , a n d t h i o n y l c h l o r i d e . A n e x a m p l e of t h e m e c h a n i s m is s h o w n
b e l o w f o r t h i o n y l c h l o r i d e a n d i n v o l v e s a c t i v a t i o n of t h e a m i d e to i m i d o l y l
h a l i d e 3 . 1 6 t h e n i n t r a m o l e c u l a r a t t a c k b y t h e e n o l i c f o r m of t h e k e t o n e .

3 .R, - HC1
R^V 1 Y -
R.X o
ou C1
R, so-'2 R .I
Cl ^
D ^ O H Ri' *o"

3.13 <0 3.16 3.10

T h e a m i n o k e t o n e s t h e m s e l v e s c a n b e p r e p a r e d b y a n u m b e r of m e t h o d s . A
t y p i c a l r o u t e is i l l u s t r a t e d b y t h e s y n t h e s i s of a n t i - i n f l a m m a t o r y d r u g 3 . 2 3 .

Ph, Ph Br Ph N3 Ph. . NH,.HC1

Br, NaN, H2/Pd

P h X 0 P t A o Ph^O HC1 Ph^O

3.19 3.20
3.17 3.18
O
Et3N (2 eq.)
Cl' CO,Et

Ph Ph
^ l.NaOH POC1, CO,Et
2 HC1
Ph" u CO,H Ph-^Q CO,Et

3.23 3.22 3.21

Drugs which reduce inflammation B r o m i n a t i o n of k e t o n e 3 . 1 7 g i v e s 3 . 1 8 w h i c h c a n b e c o n v e r t e d to a z i d e 3 . 1 9 .

are often u s e d to treat the
Hydrogenation of 3 . 1 9 in the p r e s e n c e of h y d r o c h l o r i c acid a f f o r d s
s y m p t o m s of arthritis.
a m i n o k e t o n e h y d r o c h l o r i d e salt 3 . 2 0 . S u c h a m i n o k e t o n e s a r e o f t e n i s o l a t e d as
the corresponding salts b e c a u s e the f r e e a m i n o k e t o n e s are prone to
dimerisation, having both nucleophilic and electrophilic centres. (For a
c o m m o n alternative p r e pa r a t i o n of a m i n o k e t o n e s , see the K n o r r pyrrole
s y n t h e s i s , C h a p t e r 2 . ) L i b e r a t i o n of t h e f r e e b a s e of 3 . 2 0 in t h e p r e s e n c e of
t h e a c i d c h l o r i d e a f f o r d s a m i d e 3 . 2 1 w h i c h is c y c l i s e d to o x a z o l e 3 . 2 2 . E s t e r
hydrolysis then affords the biologically-active carboxylic acid 3.23.

3.3 Synthesis of imidazoles

A l t h o u g h t h e r e a r e s e v e r a l w a y s o f p r e p a r i n g i m i d a z o l e s , t h e r e is n o o n e
o u t s t a n d i n g m e t h o d . O n e u s e f u l synthesis is the c o n d e n s a t i o n of a 1,2-
 d i c a r b o n y l c o m p o u n d w i t h a m m o n i u m a c e t a t e a n d a n a l d e h y d e , as in t h e
p r e p a r a t i o n of i m i d a z o l e 3 . 2 5 .

MeO

A r e a s o n a b l e r a t i o n a l i s a t i o n is a c y c l o c o n d e n s a t i o n t y p e of p r o c e s s to g i v e
3.24 followed by irreversible tautomerisation to 3.25.

® ^^ ®
. H
o / ^ H

/ 2
R
K D,
R
H H
1
l 1 w NH,

R
X x . — V f v
i N R2 RI N ^ H r - ^ N H
H *
3.25 3.24

3.4 Synthesis of thiazoSes

R e t r o s y n t h e t i c d i s c o n n e c t i o n of t h e n i t r o g e n - c a r b o n b o n d i n t h i a z o l e 3 . 2 6
l e a d s f o r m a l l y t o e n o l 3 . 2 7 w h i c h is e q u i v a l e n t to k e t o n e 3 . 2 8 . T h i s c a n b e
d e r i v e d f r o m h a l o k e t o n e 3 . 2 9 a n d t h i o a m i d e 3.30.

3.26 3.27 3.28 3.29 3.30

X=Cl,Br,I

T h e f o r w a r d p r o c e s s is t h e H a n t z s c h s y n t h e s i s of t h i a z o l e s w h i c h , d e s p i t e
its a n t i q u i t y (it is a r o u n d 1 0 0 y e a r s old), is still v e r y w i d e l y u s e d .

y° r Y l Thiocarbonyl compounds are

much more nucleophilic than
CI Heat
3.31 carbonyl compounds because
T h e m e c h a n i s m f o r t h e f o r m a t i o n of thiazole 3 . 3 1 i n v o l v e s initial of the lower electronegativity
of sulphur as compared to
nucleophilic attack by sulphur followed by a cyclocondensation.
oxygen.
 T h e thioamides themselves are conveniently prepared f r o m the corresponding
amides by treatment with phosphorus (V) sulphide (see the P a a l — K n o r r
s y n t h e s i s o f t h i o p h e n e s , C h a p t e r 2 , f o r t h i s t y p e of c o n v e r s i o n ) . A v a r i a t i o n
o f t h e H a n t z s c h r e a c t i o n u t i l i s e s t h i o u r e a s , w h e r e R 3 in 3 . 3 0 i s a n i t r o g e n
a n d n o t a c a r b o n s u b s t i t u e n t . F o r i n s t a n c e , t h i o u r e a i t s e l f is u s e d i n t h e
p r e p a r a t i o n o f 2 - a m i n o t h i a z o l e s s u c h as 3 . 3 2 .

HEAT
c f S ^ N H 2 %^NH 2 .HCI S - NH 2
3.32

3.5 EOectrophiNc substitution reactions of oxazoles,

imidazoles, and thiazoles
A s w i t h pyridine, not o n l y d o e s T h e 1,3-azoles are not very reactive towards electrophilic attack due to the
the electronegative nitrogen atom
deactivating effect of the pyridine-like nitrogen. However, electron-donating
withdraw electron density from
t h e ring, but u n d e r t h e acidic g r o u p s c a n f a c i l i t a t e e l e c t r o p h i l i c a t t a c k , as in t h e p r e p a r a t i o n o f o x a z o l e s
c o n d i t i o n s of m a n y electrophilic 3.34 and 3.35. D i m e t h y l a m i n o o x a z o l e 3 . 3 3 is e s s e n t i a l l y f u n c t i o n i n g l i k e
reactions the a z o l e n i t r o g e n is a n e n a m i n e i n this r e a c t i o n .
p r o t o n a t e d . T h e a z o l i u m c a t i o n is
relatively inert to further attack by fo o^
a positively charged electrophile.
CF 3 ^O ^ cf3

MejNji O ph Me 2 N. A .o K Ph

3.33 3.34

N02 % ' ^ O M E
Me ~ H
> I kOMe
3.35
Imidazole can be nitrated under forcing conditions, nitration remarkably
occurring on the imidazolium cation 3.7a,b, giving nitroimidazole 3.36 after
l o s s of t w o p r o t o n s .

N02

E /T%> HNO3/h2so4 C // A 3.36

H, N Heat N _H
© P H H \
NO-2
N02 © H © H N02 © H
N'

Hi —
H V N '
i N/>
- H

C1^
'
XJf 3.7ab H
H
3.6 Anion chemistry of oxazoies, imidazoles, and
thiazoles
T h e C 2 p o s i t i o n of 1 , 3 - a z o l e s is p a r t i c u l a r l y e l e c t r o n - d e f i c i e n t b e c a u s e of t h e
e l e c t r o n - w i t h d r a w i n g e f f e c t of t h e a d j a c e n t h e t e r o a t o m s . T h e a c i d i t y of t h e
p r o t o n s at t h i s p o s i t i o n is s u c h t h a t d e p r o t o n a t i o n c a n b e a c h i e v e d w i t h
s t r o n g b a s e s to g i v e n u c l e o p h i l i c c a r b a n i o n s 3 . 3 7 w h i c h c a n b e q u e n c h e d
w i t h e l e c t r o p h i l e s p r o d u c i n g s u b s t i t u t e d 1,3-azoles 3 . 3 8 .

_I\\ " - B u L i t> Li© / f x 3'38

X 3.37 x E

S i m i l a r l y , a l k y l g r o u p s at t h e C 2 p o s i t i o n s ( b u t n o t t h e C 4 o r C 5 p o s i t i o n s ) T h e r e is a useful a n a l o g y
between resonance-stabilised
can be deprotonated giving carbanions 3.39a,b which can also be quenched
a n i o n 3.39a,b a n d an ester
w i t h e l e c t r o p h i l e s to a f f o r d 1 , 3 - a z o l e s 3 . 4 0 . enolate anion. Note that in both
c a s e s the negative c h a r g e c a n be
N© d e l o c a l i s e d onto a h e t e r o a t o m .
^ n-BuLi -N
Li
w 0
X X
RO A . ©
X=0,NR,S 3.39a 3.39b

S o m e e x a m p l e s of b o t h t h e a b o v e t y p e s of r e a c t i v i t y are g i v e n b e l o w
1
o®

Cv>
1. n-BuLi RO A ,

CPh, H

1. n-BuLi
2.CH3CHO
3.HC1 / H 2 0
> . vO H
Ph
OH
1. n-BuLi ^ f t Ph
2.Ph2CO Ph Ph
3.HC1/H 2 0

v\ »-B"Li„ r a 0H
S
N ^ 2.PhCHO ^Ph
Me 3.HC1/H 2 0 Me

V N \ - N
// \\ 1. »-BuLi ^ / / \\
2.Mel " S ^ ^
 3.7 Nucleophilic aromatic substitution of oxazoles,
imidazoles, and thiazoles
W e h a v e p r e v i o u s l y d i s c u s s e d t h e r e d u c e d r e a c t i v i t y t o e l e c t r o p h i l e s of
o x a z o l e , i m i d a z o l e , and thiazole, as c o m p a r e d to f u r a n , p y r r o l e , and
t h i o p h e n e , w h i c h r e s u l t s f r o m t h e p r e s e n c e of t h e p y r i d i n e - l i k e n i t r o g e n
a t o m . T h i s b e h a v i o u r is p a r a l l e l e d b y i n c r e a s e d r e a c t i v i t y to n u c l e o p h i l e s .
Nucleophilic attack on furan, pyrrole, and thiophene derivatives only occurs
w h e n a n a d d i t i o n a l a c t i v a t i n g g r o u p is p r e s e n t , as in t h e displacement
reaction giving thiophene 3.41.

H
^ R N
Br
N ^N

>
©N ^S
• HBr
I ^
e, I NO 2 S'
©O 3.41

O n c e a g a i n this reactivity parallels
c e r t a i n f e a t u r e s of c a r b o n y l
c h e m i s t r y . C o m p a r e t h e reaction of
aniline w i t h c h l o r o f o r m a t e s , b e l o w .
T h e n i t r o g r o u p p l a y s a k e y r o l e as a n e l e c t r o n - a c c e p t o r in t h i s r e a c t i o n ,
w h i c h a l s o illustrates t h e f a c t that i m i d a z o l e is a g o o d n u c l e o p h i l e . H o w e v e r ,
n o a c t i v a t i o n is n e c e s s a r y w i t h 2 - h a l o - 1 , 3 - a z o l e s , w h i c h c a n r e a c t w i t h
n u c l e o p h i l e s , as s h o w n b y t h e p r e p a r a t i o n s of 3 . 4 2 a n d 3 . 4 3 .

Ph Ph Ph
Heat N J. ©
• CI
RO^Cl 1 1
P h ^ o ^ C l Ph O
-3s
NHPh Ph NHPh 3.42
I H 2 NPh
H 2 NPh

O
f \ ^L -Br
C x OMe
S^j Br 3.43
A
OMe
RO OMe
NPh
H 3.8 Problems
1. S u g g e s t a s y n t h e s i s o f o x a z o l e 3 . 3 3 .

Me2N'^o
A Ph
3.33

2. A l e s s g e n e r a l s y n t h e s i s of o x a z o l e s is t h e c o n d e n s a t i o n of b r o m o k e t o n e s
w i t h a m i d e s . W h a t is t h e m e c h a n i s m f o r t h e f o r m a t i o n of o x a z o l e 3 . 4 4 ? H o w
does 3.44 relate to the oxazole w h i c h might b e prepared f r o m the s a m e
bromoketone by conversion to the corresponding aminoketone, N-
formylation, and cyclocondensation?

O
3. C a r b o x y l i c acid 3 . 4 6 h a s b e e n e x t e n s i v e l y u s e d in t h e p r e p a r a t i o n of
s e m i - s y n t h e t i c p e n i c i l l i n s a n d c e p h a l o s p o r i n s . D e v i s e a s y n t h e s i s of 3 . 4 6
f r o m ester 3 . 4 5 .

3.45 3.46

3.9 References
C a m p b e l l , M . M . ( 1 9 7 9 ) . In Heterocyclic chemistry (ed. P . G . Sammes)
(Vol. 4 of Comprehensive organic chemistry, ed. D. Barton and W . D .
Ollis), p. 9 6 2 (oxazoles) and p. 9 6 7 (thiazoles). P e r g a m o n Press, O x f o r d .
Furniss, B . S . , H a n n a f o r d , A.J., S m i t h , P . W . G . , a n d T a t c h e l l , A . R . (1989).
Vogel's textbook of practical organic chemistry ( 5 t h e d n ) , p. 1 1 5 3
(preparation of a m i n o t h i a z o l e 3.32). L o n g m a n , H a r l o w .
G r i m m e t t , M . R . ( 1 9 7 0 ) . Adv. heterocyclic chem., 1 2 , 103 ( i m i d a z o l e s ) .
G r i m m e t t , M . R . ( 1 9 7 9 ) . In Heterocyclic chemistry (ed. P . G . S a m m e s )
(Vol. 4 of Comprehensive organic chemistry, ed. D . B a r t o n a n d W . D .
Ollis), p . 3 5 7 (imidazoles). P e r g a m o n Press, O x f o r d .
G r i m m e t t , M . R . ( 1 9 8 0 ) . Adv. heterocyclic chem., 2 7 , 2 4 1 ( i m i d a z o l e s ) .
L a k h a n , R . a n d T e r n a i , B . ( 1 9 7 4 ) . Adv. heterocyclic chem., 1 7 , 9 9
(oxazoles).
M e t z g e r , J . V . ( 1 9 7 9 ) . In Thiazole and its derivatives (The chemistry of
heterocyclic compounds [ed. A . W e i s s b u r g e r and E.C. T a y l o r ] , V o l . 34).
W i l e y Interscience, N e w York.
Turchi, I.J. (1986). In Oxazoles {The chemistry of heterocyclic compounds
[ed. A . W e i s s b u r g e r and E . C . Taylor], V o l . 45). W i l e y Interscience, N e w
York.
T u r c h i , I.J. a n d D e w a r , M . J . S . ( 1 9 7 5 ) . Chem. rev. , 7 5 , 3 8 9 ( o x a z o l e s ) .
 4. Isoxazoles, pyrazoles, and
isothiazoles

I s o x a z o l e 4.1, p y r a z o l e 4.2, and isothiazole 4 . 3 are the parent structures of

t h e 1 , 2 - a z o l e f a m i l y of h e t e r o c y c l e s , h a v i n g a n i t r o g e n a t o m p l u s o n e o t h e r
h e t e r o a t o m in a 1 , 2 - r e l a t i o n s h i p in a f i v e - m e m b e r e d r i n g .

4 3 4 3 4 3

5 ft )N 2 5 FT VL 2 5 ft V 2
o N x
s ;
1
1 H
4.1 4.2 4.3

T h e a r o m a t i c s e x t e t is c o m p l e t e d b y d e l o c a l i s a t i o n of t h e l o n e p a i r f r o m t h e
s e c o n d h e t e r o a t o m , 4 . 4 a - e . C o n s e q u e n t l y , as in p y r i d i n e , t h e n i t r o g e n a t o m s
of t h e 1 , 2 - a z o l e s h a v e a l o n e p a i r a v a i l a b l e f o r p r o t o n a t i o n . H o w e v e r t h e 1,2-
a z o l e s a r e s i g n i f i c a n t l y l e s s b a s i c t h a n t h e 1 , 3 - a z o l e s b e c a u s e of t h e e l e c t r o n -
w i t h d r a w i n g e f f e c t of t h e a d j a c e n t h e t e r o a t o m . I s o x a z o l e a n d i s o t h i a z o l e a r e
e s s e n t i a l l y n o n - b a s i c h e t e r o c y c l e s (pA" a s < 0 ) , a n d e v e n p y r a z o l e (pAT a =2.5) is
a m u c h w e a k e r b a s e than t h e c o r r e s p o n d i n g 1,3-azole i m i d a z o l e (pA' a =7).

—> ?n — — C ? n 0 —> e G
X X X X x
ffi © ffi ©
4.4a 4.4b 4.4c 4.4d 4.4e

X = 0,NH,S

A s w i t h s u b s t i t u t e d i m i d a z o l e s , s u b s t i t u t e d p y r a z o l e s m a y e x i s t as a
m i x t u r e of t a u t o m e r s . 5 - M e t h y l p y r a z o l e 4 . 5 a n d 3 - m e t h y l p y r a z o l e 4 . 6 e x i s t
as a r a p i d l y e q u i l i b r a t i n g m i x t u r e in s o l u t i o n .

A 3 4 5

5// v ^ 34
N N
H1 2

4.5 4.6

A l t h o u g h t h e r e a r e a f e w e x a m p l e s of n a t u r a l l y - o c c u r r i n g 1,2-azoles, m a n y
totally s y n t h e t i c d e r i v a t i v e s h a v e f o u n d p h a r m a c e u t i c a l a p p l i c a t i o n .
4.1 Synthesis of isoxazoles and pyrazoles
R e t r o s y n t h e t i c d i s c o n n e c t i o n of g e n e r a l i s e d 1 , 2 - a z o l e 4 . 7 g i v e s initially 4 . 8
w h i c h w o u l d e x i s t as k e t o n e 4 . 9 . T h i s in t u r n is c l e a r l y d e r i v e d f r o m 1,3-
diketone 4.10.
r *
R2 R3
R, *3 k2 / 4.11 H 2 NOH

RI
x "OH XH
N
O XH Ri O
O 4.12
4.13
H 2 NNH 2
H 2 NSH
4.9 4.10
4.7 4.8

X=0,NH,S In practice h y d r o x y l a m i n e a n d
h y d r a z i n e are v e r y reactive
nucleophiles, far m o r e so t h a n
might be e x p e c t e d f r o m
c o n s i d e r a t i o n of s i m p l e p h y s i c a l
T h i s a n a l y s i s s u g g e s t s t h a t c o n d e n s a t i o n of 4 . 1 0 w i t h h y d r o x y l a m i n e 4 . 1 1 , parameters. The inceased
hydrazine 4.12, or thiohydroxylamine 4 . 1 3 should give the corresponding nucleophilicity of a h e t e r o a t o m
1,2-azole. . This a p p r o a c h represents an important route to isoxazoles and w h e n b o n d e d to a s e c o n d
p y r a z o l e s , b u t t h i o h y d r o x y l a m i n e 4 . 1 3 , a l t h o u g h k n o w n , is f a r t o o u n s t a b l e h e r e o a t o m is k n o w n as t h e a
effect. For a theoretical
f o r s y n t h e t i c p u r p o s e s . T h e s y n t h e s i s of i s o t h i a z o l e s will b e m e n t i o n e d later.
rationalisation of the a effect in
T h e m e c h a n i s m of t h e f o r w a r d p r o c e s s is i l l u s t r a t e d b y t h e p r e p a r a t i o n of t e r m s of frontier obitals s e e
i s o x a z o l e 4 . 1 4 a n d is s i m p l y t w o c o n s e c u t i v e c o n d e n s a t i o n s . Fleming, 1976.

O O V O (OH
-H,o •H,0
- M s -
H'NVOH
V'
H,N-OH 4.14
H

N o t e that if h y d r o x y l a m i n e o r a s u b s t i t u t e d h y d r a z i n e is c o n d e n s e d w i t h a n
unsymmetrical diketone ( 4 . 1 0 , w h e r e R] a n d R 3 a r e d i f f e r e n t ) t h e n a
r e g i o i s o m e r i c m i x t u r e of i s o x a z o l e s o r p y r a z o l e s m a y r e s u l t . H o w e v e r a
s i n g l e r e g i o i s o m e r m a y p r e d o m i n a t e w h e r e t h e r e is an i n h e r e n t bias,
o o
R2 R3 R, r„
H,NOH
r, Y
H N o
Rl T h e g e n e r a l reactions of H 2 N O H
R2
O R, N'
o o a n d H 2 N N H R with u n s y m m e t r i c a l
R2
d i k e t o n e s a r e s h o w n here.
H,NNHR
f/ vN +
l S
N'
^
N
,NR
R
F o r i n s t a n c e , t h e p r e p a r a t i o n of i s o x a z o l e 4 . 1 7 is v i r t u a l l y r e g i o s p e c i f i c
b e c a u s e t h e r e a c t i o n c o m m e n c e s w i t h t h e m o r e n u c l e o p h i l i c h e t e r o a t o m (i.e.
nitrogen) attacking the m o r e electrophilic ketone (activated by the electron-
w i t h d r a w i n g i n d u c t i v e e f f e c t of t h e a d j a c e n t e s t e r g r o u p ) . T h e r e a d e r is
e n c o u r a g e d to c o n s i d e r t h e r e g i o c h e m i c a l b i a s in t h e p r e p a r a t i o n of i s o x a z o l e
4.15 and pyrazole 4.16.
 4.16

HO. CO,Et
N
H,NOH
h7 VN
C0 2 Et -H20 C0 2 Et -H20 o'
4.17

The other important isoxazole synthesis involves the concerted [3+2]

cycloaddition reaction of nitrile oxides 4 . 1 8 with either alkynes 4 . 1 9 or
alkyne equivalents 4.20.

X=0Ac,NMe 2 ,N0 2
A w i d e r a n g e of n i t r i l e o x i d e s is k n o w n ( R 3 = H , aryl, a l k y l , e s t e r , h a l i d e ,
etc). T h e m e t h o d of c h o i c e f o r t h e p r e p a r a t i o n of s i m p l e n i t r i l e o x i d e s ( R 3 =
a l k y l , aryl) is o x i d a t i o n of t h e c o r r e s p o n d i n g o x i m e :

o N - o h
11 H2NOH © e
A • X R3—= N - O 4.18
R3-^H H20 R 3^H (-2H)
 Several oxidising agents can be used (lead tetraacetate, N-
b r o m o s u c c i n i m i d e , c h l o r i n e , e t c ) . A m e c h a n i s m is i l l u s t r a t e d b e l o w f o r
alkaline sodium hypochlorite.

N'
ft N' N
OH f © ©
Wn
3 -EEN - O
CI-OH CI *3 ^
4.18
L e t us n o w c o n s i d e r the synthesis of isoxazole 4 . 2 8 , a drug f o r the
t r e a t m e n t of b r o n c h i a l a s t h m a . T h e m o s t d i r e c t p r e p a r a t i o n of i s o x a z o l y l
ketone 4.24 is t h e c y c l o a d d i t i o n of u n s t a b l e b r o m o n i t r i l e o x i d e 4.22
( p r e p a r e d in situ b y d e h y d r o b r o m i n a t i o n of 4 . 2 1 ) w i t h a c e t y l e n i c k e t o n e 4 . 2 3 .
O b s e r v e the regioselectivity of this reaction. Both electron-donating and
electron-withdrawing groups on the acetylenic components in such
c y c l o a d d i t i o n s t e n d to o c c u r at t h e C 5 p o s i t i o n in t h e f i n a l i s o x a z o l e a n d n o t
at C 4 . B r o m i n a t i o n of k e t o n e 4 . 2 4 a f f o r d s b r o m o k e t o n e 4 . 2 5 w h i c h is
4.23 n
Br Br Br Br
Br.
Y K2C°3
ill // Br, //
N OH NFFI
N
O Br
4.21 Oft
©
4.24 4.25
4.22 NaBH4 .

Br.
HjN-f-Bu // NaH
< N
s
NH-«-Bu O

4.28 4.27
r e d u c e d w i t h s o d i u m b o r o h y d r i d e to g i v e b r o m o h y d r i n 4.26. T r e a t m e n t w i t h a
strong base p r o d u c e s e p o x i d e 4 . 2 7 via the intermediate alkoxide, and
n u c l e o p h i l i c o p e n i n g of this e p o x i d e at t h e least s t e r i c a l l y h i n d e r e d p o s i t i o n
a f f o r d s t h e t a r g e t d r u g 4.28.

4.2 Synthesis of isothiazoles

Isothiazoles are usually p r e p a r e d by routes involving f o r m a t i o n of the
n i t r o g e n - s u l p h u r b o n d in t h e c y c l i s a t i o n s t e p . T h i s is o f t e n s e t u p b y
o x i d a t i o n of t h e s u l p h u r a t o m , as in t h e c o n v e r s i o n of t h i o a m i d e 4 . 2 9 t o
isothiazole 4.30.
NH, C1NH,
'/ \\ 4.30
4.29 N
N NH 2
I Cl-NH,

. H \
€1. H N,
Q -H — HC1 N
N
®s~c> ^N S NH

tS
 4.3 Electrophilic substitution of isoxazoles,
pyrazoles, and isothiazoles
T h e p r e s e n c e of a p y r i d i n e - l i k e nitrogen in the 1,2-azoles m a k e s t h e m
markedly less reactive towards electrophilic substitution than f u r a n , pyrrole,
and thiophene. (The same effect was noted for the 1,3-azoles in Chapter 3.)
Nevertheless, electrophilic substitution is k n o w n in 1,2-azoles, occurring
principally at the C 4 position. This selectivity is reminiscent of p y r i d i n e
chemistry w h e r e the position meta to the electronegative nitrogen a t o m is
the 'least deactivated' (see Chapter 5).

B^-Br ®r Br
H
-J^ PN I O'W N

i j > ' Cy© Br

^Br^-Br Br

If ^ —" V
Nitration and sulphonation of 1,2-azoles under vigorous conditions are
also k n o w n , as in the preparation of 4-nitropyrazole 4 . 3 1 .
NO2 J ° 2 NO 2

H
o n ^ cv ^ rv T\
N N' NR -H ©N' V 431
H H H H H
- 3-36 A s w e h a v e s e e n with o t h e r e l e c t r o n - d e f i c i e n t h e t e r o c y c l e s , the
See the related preparation of i n t r o d u c t i o n of an e l e c t r o n - d o n a t i n g g r o u p p r o m o t e s e l e c t r o p h i l i c
nitroimidazole 3.36. substitution, as in the facile bromination of aminoisothiazole 4 . 3 2 .

Br—B
5 Ph ?r Ph Br Ph

NH 2 S'
^ ,*M ^
H Z N
V S
' NH
2
H
s'
4.32

4.4 Anion chemistry of isoxazoles, pyrazoles, and

isothiazoles
Isothiazoles and nitrogen-blocked pyrazoles can be deprotonated at the C5
position with alkyl lithium reagents, and the resultant carbanions q u e n c h e d
with a wide range of electrophiles, as in the preparation of 4.33 and 4.34.
 \\ n-BuLi ffi // \\ (C0 2 Et) 2
N • Li e(* N 1
s' 4,3
O
H-BuLi © Mel
N • Li eti. N
N 'N' N' 4.34
Ph Ph Ph

This useful m e t h o d o l o g y (complementary to the C 4 selectivity of normal

e l e c t r o p h i l i c s u b s t i t u t i o n ) is n o t a p p l i c a b l e t o i s o x a z o l e c h e m i s t r y b e c a u s e
the i n t e r m e d i a t e a n i o n s ( s u c h as 4 . 3 5 ) a r e r a t h e r u n s t a b l e a n d d e c o m p o s e via
oxygen-nitrogen cleavage.

Ph Ph Ph Ph Ph

V \N »- B "Li » Li y / vN + PhCN
o
Li
°©
4.35

H o w e v e r , a l k y l g r o u p s at the C 5 p o s i t i o n of i s o x a z o l e s c a n b e d e p r o t o n a t e d
a n d r e a c t e d w i t h electrophiles.

Note the analogy to the anions

'/ VN n-BuLi
derived f r o m crotonate esters.
Li ©
OR
D i m e t h y l i s o x a z o l e 4 . 1 4 c a n b e s e l e c t i v e l y d e p r o t o n a t e d at t h e C 5 m e t h y l
group, nearer the more electronegative oxygen atom. Although simple
©
d e p r o t o n a t i o n c a n n o t a f f o r d a n e n t r y i n t o C 4 s u b s t i t u t i o n in this s y s t e m , it is
p o s s i b l e t o g e n e r a t e a c a r b a n i o n at t h e C 4 p o s i t i o n in a r o u n d a b o u t f a s h i o n .
B r o m i n a t i o n of 4 . 1 4 a f f o r d s t h e C 4 - f u n c t i o n a l i s e d i s o x a z o l e 4 . 3 6 . M e t a l - OR
h a l o g e n e x c h a n g e \fcith n - b u t y l l i t h i u m at l o w t e m p e r a t u r e ( - 7 8 ° C ) g e n e r a t e s
c a r b a n i o n 4 . 3 7 w h i c h c a n b e q u e n c h e d w i t h e l e c t r o p h i l e s to g i v e i s o x a z o l e s N©
©
O
s u c h as 4 . 3 8 .
Interestingly, 1, 3, 5 - t r i m e t h y l
p y r a z o l e is d e p r o t o n a t e d o n the
N - m e t h y l g r o u p , facilitating
ICO, reaction w i t h electrophiles at this
position.
2.HC1

// WN
N
4.5 Problems Me
— 78°C
n-BuLi
1. W h a t is t h e m e c h a n i s m f o r t h e f o r m a t i o n of i s o t h i a z o l o n e 4 . 3 9 ?

o ,0 N"
NEC — S K» Mel
I © a
EtOH / H 2 0 NH CH 2 Li
NH,
S
4.39 N
N'
Et
 2. W h a t g e n e r a l strategy m i g h t b e e m p l o y e d to c o n v e r t p y r a z o l e to a l c o h o l
4 . 4 0 , a p o t e n t i n h i b i t o r of steroid b i o s y n t h e s i s .

Q ^ H O ^ - 1 4 4 ( ^

H Ar Ar H

3. W h a t is the p r o d u c t resulting f r o m oxidation of 4.41?

NaOCl 9
NaOH

4.41
4. A s y n t h e s i s of 2 - c y a n o c y c l o h e x a n o n e 4 . 4 5 f r o m c y c l o h e x a n o n e is s h o w n
b e l o w . F o r m y l a t i o n of c y c l o h e x a n o n e p r o d u c e s a m i x t u r e of k e t o / e n o l
t a u t o m e r s 4 . 4 2 a n d 4 . 4 3 , the e q u i l i b r i u m lying to the side of the e n o l 4 . 4 2 .
T r e a t m e n t with h y d r o x y l a m i n e affords isoxazole 4.44, and base-induced
f r a g m e n t a t i o n of t h e i s o x a z o l e ring a f f o r d s 4.45. E x p l a i n the regioselectivity
of t h e i s o x a z o l e f o r m a t i o n , and the m e c h a n i s m of the f r a g m e n t a t i o n p r o c e s s .

° o

n r 0 " ^ cx^'^o* — • rr"

NaOEt V A > 2.NH4Q / H 2 0
4.42 4.43 4.44 ° 4.45
4.6 References
Campbell, M.M. (1979). In Heterocyclic chemistry (ed. P . G . S a m m e s )
( V o l . 4 of Comprehensive organic chemistry, ed. D. Barton and W . D .
O l l i s ) , p . 9 9 3 ( i s o x a z o l e s ) a n d p. 1 0 0 9 ( i s o t h i a z o l e s ) . Pergamon Press,
Oxford.
F l e m i n g , I. ( 1 9 7 6 ) . Frontier orbitals and organic chemical reactions,
p.77. Wiley, Chichester.
Furniss, B.S., Hannaford, A.J., Smith, P.W.G., and Tatchell, A.R.
(1989). In Vogel's textbook of practical organic chemistry (5th e d n ) ,
p. 1149 ( p r e p a r a t i o n of 3 , 5 - d i m e t h y l p y r a z o l e ) . Longman, Harlow.
G r i m m e t t , M . R . ( 1 9 7 9 ) . In Heterocyclic chemistry (ed. P . G . Sammes)
( V o l . 4 of Comprehensive organic chemistry, e d . D. B a r t o n a n d W . D .
Ollis), p . 3 5 7 ( p y r a z o l e s ) . P e r g a m o n P r e s s , O x f o r d .
Kochetkov, N . K . and Sokolov, S.D. (1963). Adv. heterocyclic chem., 2,
3 6 5 (isoxazoles).
Kost, A.N. a n d G r a n d b e r g , I.I. (1966). Adv. heterocyclic chem., 6, 3 4 7
(pyrazoles).
Slack, R. and Wooldrige, K.R.H. ( 1 9 6 5 ) . Adv. heterocyclic chem., 4, 107
(isothiazoles).
W a k e f i e l d , B.J. a n d W r i g h t , D . J . (1979). Adv. heterocyclic chem., 25,
147 (isoxazoles).
5. Pyridines

5.1 Introduction
P y r i d i n e 5 . 1 is a p o l a r liquid (b.p. 1 1 5 ° C ) w h i c h is m i s c i b l e w i t h b o t h
o r g a n i c s o l v e n t s a n d w a t e r . It c a n f o r m a l l y b e d e r i v e d f r o m b e n z e n e b y
r e p l a c e m e n t of a C H g r o u p b y a nitrogen atom. P y r i d i n e is a highly aromatic
h e t e r o c y c l e , b u t t h e e f f e c t of t h e h e t e r o a t o m m a k e s its c h e m i s t r y q u i t e
distinct f r o m that of b e n z e n e . T h e a r o m a t i c sextet of six n e l e c t r o n s is
c o m p l e t e w i t h o u t i n v o k i n g p a r t i c i p a t i o n of the l o n e pair o n the nitrogen.
T h i s is in direct contrast with the situation in p y r r o l e ( C h a p t e r 2) w h e r e the
a r o m a t i c sextet includes the lone p a i r on the nitrogen. H e n c e the lone pair of
p y r i d i n e is a v a i l a b l e f o r b o n d i n g w i t h o u t d i s t u r b i n g the a r o m a t i c i t y of the
ring. P y r i d i n e is m o d e r a t e l y b a s i c (p/T a =5.2) and can be q u a t e r n i s e d with
a l k y l a t i n g a g e n t s to f o r m p y r i d i n i u m s a l t s 5 . 2 . P y r i d i n e a l s o f o r m s
c o m p l e x e s with L e w i s acids such as s u l p h u r trioxide. T h i s c o m p l e x 5 . 3 is a
mild source of sulphur trioxide f o r sulphonation reactions (see C h a p t e r 2).

R-X
e
x
©N
I
H
SO,
•T 5.2
R

N'
5.3
SO©
T h e e f f e c t of the h e t e r o a t o m is to m a k e t h e p y r i d i n e ring very u n r e a c t i v e
to n o r m a l e l e c t r o p h i l i c a r o m a t i c s u b s t i t u t i o n . C o n v e r s e l y , p y r i d i n e s are
susceptible to nucleophilic attack. T h e s e topics are discussed later.

5.2 Synthesis of pyridines

O u r r e t r o s y n t h e t i c analysis of g e n e r a l i s e d p y r i d i n e 5 . 4 c o m m e n c e s with an
a d j u s t m e n t of t h e o x i d a t i o n l e v e l to p r o d u c e d i h y d r o p y r i d i n e 5 . 5 . T h i s
m o l e c u l e c a n n o w b e d i s c o n n e c t e d very r e a d i l y . C l e a v a g e of t h e c a r b o n -
h e t e r o a t o m b o n d s in the usual w a y leaves dienol 5.6 w h i c h exists as diketone
5.7. T h e 1,5-dicarbonyl relationship can be d e r i v e d f r o m a M i c h a e l reaction
of k e t o n e 5 . 8 a n d e n o n e 5 . 9 , w h i c h in turn can arise f r o m c o n d e n s a t i o n of
aldehyde 5 . 1 0 and ketone 5.11.
 T h e s e p r o c e s s e s are facilitated w h e n R 2 and R 4 are e l e c t r o n - w i t h d r a w i n g
g r o u p s such as esters. F u r t h e r m o r e , w h e n k e t o n e s 5.11 and 5 . 8 are the s a m e ,
w e h a v e the basis f o r the classical H a n t z s c h pyridine svnthesis.

5.12 S.13
F o r i n s t a n c e , c o n d e n s a t i o n of ethyl a c e t o a c e t a t e , f o r m a l d e h y d e , a n d
a m m o n i a gives dihydropyridine 5 . 1 2 which is readily oxidised with nitric acid
to g i v e p y r i d i n e 5 . 1 3 . A l t h o u g h t h e p r e c i s e details of this m u l t i c o m p o n e n t
c o n d e n s a t i o n are not k n o w n , a reasonable p a t h w a y is s h o w n below,
o

Note that in this example R 2 and

R4 are ethyl esters, so the
adjacent carbon is actually an
active methylene group. T h e
higher acidity a n d hence
nucleophilicity of these cent
facilitates the reaction sequence.

N
H HO.
5.12 HS
 S o m e e x a m p l e s of dihydropyridines p r e p a r e d in this w a y are s h o w n b e l o w .
(The student is encouraged to work out the aldehydes used in each case.)

N ^ N

A s well as b e i n g i n t e r m e d i a t e s f o r t h e s y n t h e s i s of p y r i d i n e s , t h e s e A consequence of the asymmetry

of 5.14 is that C 4 is a stereogenic
d i h y d r o p y r i d i n e s are t h e m s e l v e s an i m p o r t a n t class of h e t e r o c y c l e s . F o r
centre. Hence the product is formed
instance, d i h y d r o p y r i d i n e 5 . 1 4 is a d r u g f o r l o w e r i n g b l o o d pressure. In the as a racemic mixture.
s y n t h e s i s of 5 . 1 4 n o t e that c a r r y i n g o u t t h e H a n t z s c h s y n t h e s i s s t e p w i s e
allows f o r the preparation of an u n s y m m e t r i c a l d i h y d r o p y r i d i n e , h a v i n g both
a m e t h y l and an ethyl ester.

piperidine gtQ
H ^O
-H,0
N
H 5.14
5.3 Electrophilic substitution of pyridines
P y r i d i n e is virtually inert t o a r o m a t i c e l e c t r o p h i l i c s u b s t i t u t i o n . C o n s i d e r
nitration of p y r i d i n e b y nitric acid. First, as p y r i d i n e is a m o d e r a t e b a s e , it
will b e a l m o s t c o m p l e t e l y p r o t o n a t e d b y t h e acid, m a k i n g it m u c h less
susceptible to electrophilic attack. S e c o n d , addition of the electrophile to the
s m a l l a m o u n t of u n p r o t o n a t e d p y r i d i n e p r e s e n t in s o l u t i o n is n o t a f a c i l e
process.
A t t a c k o f t h e e l e c t r o p h i l e at t h e C 2 o r C 4 p o s i t i o n r e s u l t s in an
intermediate cation with partial positive charge on the electronegative
n i t r o g e n a t o m . T h i s is clearly n o t energetically f a v o u r a b l e w h e n c o m p a r e d to
C 3 substitution, w h e r e n o partial positive c h a r g e resides o n nitrogen. In f a c t
t h e p r o d u c t of C 3 substitution, n i t r o p y r i d i n e 5 . 1 5 , can b e isolated f r o m the
e x h a u s t i v e nitration of pyridine, but only in p o o r yield.
 NO, NO,
< > < • NO,
N H H "N X
H C2-attack

N02 NO, N02

H H
C3-attack
N N

H ,N°2 H ,N02

< >- C4-attack

C-alkylation of a sterically- A l t h o u g h b e t t e r r e s u l t s h a v e b e e n a c h i e v e d w i t h t h e s u l p h o n a t i o n of
hindered phenolate anion.
p y r i d i n e to g i v e t h e s u l p h o n i c a c i d 5 . 1 6 , e l e c t r o p h i l i c s u b s t i t u t i o n s o n an
i n a c t i v a t e d p y r i d i n e r i n g a r e in g e n e r a l n o t p r e p a r a t i v e l y u s e f u l .

NO, ^ / S 0 3 H

N
N
5.16
5.15

P y r i d i n e c a n b e a c t i v a t e d t o e l e c t r o p h i l i c s u b s t i t u t i o n b y c o n v e r s i o n to
p y r i d i n e N - o x i d e 5 . 1 7 . A t f i r s t s i g h t it is c u r i o u s to c o n s i d e r o x i d a t i o n (i.e.
e l e c t r o n l o s s ) as a m e a n s of a c t i v a t i n g a s y s t e m to e l e c t r o p h i l i c s u b s t i t u t i o n ,
b u t 5 . 1 7 c a n act r a t h e r l i k e a s t e r i c a l l y - h i n d e r e d p h e n o l a t e a n i o n t o w a r d s
electrophiles, producing i n t e r m e d i a t e 5.18 which then loses a p r o t o n to
give s u b s t i t u t e d N - o x i d e 5 . 1 9 . F o r t h i s m e t h o d o l o g y t o b e u s e f u l it is of
course necessary to r e m o v e the activating oxygen atom. This can b e d o n e
with phosphorus trichloride, which becomes oxidised to phosphorus
oxychloride.

N
[O]
o 5.17

OH e

-H
5.17 5.19
5.18

- POCl,
5.19

PCI,
F o r i n s t a n c e , 4 - n i t r o p y r i d i n e 5 . 2 0 can be p r e p a r e d f r o m p y r i d i n e in three
steps b y this m e t h o d o l o g y .

5.17 oe oe 5.20
P y r i d i n e N - o x i d e s c a n a l s o b e c o n v e r t e d into s y n t h e t i c a l l y u s e f u l 2 -
chloropyridines 5.21 (see later).

A n o t h e r a p p r o a c h to electrophilic substitution i n v o l v e s t h e c h e m i s t r y of
2 - p y r i d o n e 5 . 2 2 and 4 - p y r i d o n e 5.23. T h e s e are the t a u t o m e r i c f o r m s of 2 -
<3y\ t j
and 4 - h y d r o x y p y r i d i n e r e s p e c t i v e l y . T h e y exist exclusively in the p y r i d o n e
f o r m , the h y d r o g e n a t o m b e i n g a t t a c h e d to the n i t r o g e n a t o m , n o t the
o x y g e n . T h e i r electronic structures are not a d e q u a t e l y described b y a single
v a l e n c e representation, the l o n e pair f r o m the nitrogen a t o m being delocalised
t o a c o n s i d e r a b l e e x t e n t o n t o t h e o x y g e n a t o m , as in m e s o m e r i c
representations 5.22a and 5.23a.
OH o

B o t h p y r i d o n e s can react with electrophiles at positions ortho a n d para to

the activating oxygen atom. For instance, 4-pyridone reacts with
e l e c t r o p h i l e s at t h e C 3 p o s i t i o n (the m e c h a n i s m can b e f o r m u l a t e d f r o m
either m e s o m e r i c representation) to g i v e intermediate 5.24. A s with pyridine
N-oxides, reaction with phosphorus oxychloride gives useful
c h l o r o p y r i d i n e s 5.25. W e shall see the utility of 2- and 4 - c h l o r o p y r i d i n e s in
the n e x t section.
 5.23a

5.4 Nucleophilic substitution of pyridines

P y r i d i n e c a n b e a t t a c k e d b y n u c l e o p h i l e s at t h e C 2 / C 6 a n d C 4 p o s i t i o n s in a
m a n n e r a n a l o g o u s t o t h e a d d i t i o n o f n u c l e o p h i l e s to a c a r b o n y l g r o u p in a
1,2 o r 1,4 f a s h i o n . A t t a c k at t h e C 3 / C 5 p o s i t i o n s is n o t f a v o u r e d b e c a u s e t h e
negative charge on the intermediate cannot be delocalised onto the
electronegative nitrogen atom.

l C
O H
X = Nucleophile

T h e actual m e c h a n i s m is rather
c o m p l i c a t e d . H y d r o g e n g a s is
e v o l v e d , but in reality free s o d i u m
h y d r i d e is n e v e r g e n e r a t e d . S e e
McGill a n d R a p p a (1988).
U n d e r conditions of high temperatures the intermediate anion can re-
a r o m a t i s e b y l o s s of a h y d r i d e i o n , e v e n t h o u g h it is a v e r y p o o r l e a v i n g
g r o u p . T h i s is i l l u s t r a t e d b y t h e C h i c h i b a b i n r e a c t i o n o f p y r i d i n e and
s o d a m i d e to p r o d u c e 2-aminopyridine 5.26. T h e immediate product of the
r e a c t i o n is 5 . 2 7 , t h e s o d i u m salt of 5 . 2 6 , as t h e e l i m i n a t e d h y d r i d e ion is
v e r y b a s i c . P r o t o n a t i o n of this s o d i u m salt d u r i n g t h e a q u e o u s w o r k u p t h e n
r e g e n e r a t e s 5 . 2 6 . A s i m p l i s t i c r a t i o n a l e is s h o w n b e l o w .

NaH (—H
—2) •
NH 2 •
N'VhV - N a H
N
Aq. workup
N
e ©
NH, NH Na

5.26 5.27
These nucleophilic substitution reactions are m u c h more facile w h e n better
l e a v i n g g r o u p s (e.g. h a l i d e i o n s i n s t e a d of h y d r i d e i o n s ) are e m p l o y e d .

e
x ^ x -a!
o
©
e -- 7

x
e
-ci •.
• ( h
3
X = Nucleophile

N u c l e o p h i l i c s u b s t i t u t i o n s a r e w i d e l y u s e d in p y r i d i n e c h e m i s t r y . S o m e
e x a m p l e s are s h o w n below.

NH3 I (| ^ HN(CH 2 CHCH 2 ) 2

CI

CI SEt

H 2 NNH 2 Na® 0 SEt

"N' ^ci "~N-NH2 "N ^n'

H

CI HNPh

H,NMe 1 rf H,NPhs>
N CI N NMe N N'
H

CI HN-™2
© ©
Na OMe
i>
N
N ci OMe N' "N

F i n a l l y , b e f o r e l e a v i n g t h i s s e c t i o n , w e s h a l l c o n s i d e r t h e s y n t h e s i s of
pyridotriazine 5 . 3 2 , a potential anti-fungal drug. This synthesis illustrates
f e a t u r e s of b o t h e l e c t r o p h i l i c a n d n u c l e o p h i l i c p y r i d i n e c h e m i s t r y .
N i t r a t i o n of 4 - p y r i d o n e 5 . 2 3 gives 5 . 2 8 , a n d r e a c t i o n w i t h p h o s p h o r u s
oxychloride affords chloropyridine 5.29. This pyridone-chloropyridine
conversion activates the system to nucleophilic attack by hydrazine, affording
5 . 3 0 . T h e n i t r o g r o u p a l s o f a c i l i t a t e s n u c l e o p h i l i c a t t a c k b y d e l o c a l i s a t i o n of
n e g a t i v e c h a r g e in t h e i n t e r m e d i a t e .
 H,N H,N
H 2 N - N H 2 CI 1
.NH,
n HN

&
CI NH /P
•CX, NO, N. e © NO-
© o -CI

N N
5.29 5.30
N-Acylation, reduction of nitro to a m i n o , and c o n d e n s a t i o n produce
d i h y d r o t r i a z i n e 5 . 3 1 . T h i s s y s t e m is r e a d i l y d e h y d r o g e n a t e d w i t h m a n g a n e s e
dioxide to afford the fully aromatic heterocycle 5.32. N o t e h o w relatively
s i m p l e c h e m i s t r y c a n b e u s e d to f o r m a q u i t e c o m p l e x h e t e r o c y c l e .

CI.
O
.NH,
CI HN HN'

fir
NO, NO, NO, NO,
HN03 POC1, H 2 NNH 2
1
H 2 SO 4
N N N
H H
5.29 5.30
5.23 5.28
H2 Pd/C
11
H
.N.
HN' HN'
O
MnO, Heat ( - H 2 0 ) NH 2

N N N
5.32 5.31

5.5 Anion chemistry of pyridines

W e earlier drew a parallel between nucleophilic attack on the C 2 / C 6 and C 4
p o s i t i o n s of p y r i d i n e a n d 1,2 a n d 1,4 a d d i t i o n of n u c l e o p h i l e s to a c a r b o n y l
g r o u p . T h i s a n a l o g y c a n b e e x t e n d e d to d e p r o t o n a t i o n of a l k y l s u b s t i t u e n t s at
the C 2 / C 6 and C 4 positions.

J u s t as a c a r b o n y l g r o u p s t a b i l i s e s a n a d j a c e n t n e g a t i v e c h a r g e as a n
e n o l a t e a n i o n , s o t h e a n i o n d e r i v e d f r o m 2 - m e t h y l p y r i d i n e is s t a b i l i s e d by
d e l o c a l i s a t i o n of t h e n e g a t i v e c h a r g e o n t o t h e e l e c t r o n e g a t i v e n i t r o g e n a t o m .
A similar a r g u m e n t h o l d s f o r 4 - m e t h y l pyridine. T h e s e stabilised anions can
then react with the usual r a n g e of electrophiles.

T h e negative c h a r g e resulting
from deprotonation of the ethyl
methylene group of 5.33 c a n n o t
be delocalised onto the nitrogen
atom.

D i a l k y l p y r i d i n e 5 . 3 3 is selectively d e p r o t o n a t e d at the C 4 alkyl g r o u p ,

illustrating t h e g r e a t e r acidity of this p o s i t i o n o v e r the C 3 p o s i t i o n . W i t h
r e g a r d to ring d e p r o t o n a t i o n , h o w e v e r , t h e r e are relatively f e w e x a m p l e s
k n o w n f o r s i m p l e pyridines, in contrast to the extensive c h e m i s t r y d e v e l o p e d
f o r t h e f i v e - m e m b e r e d r i n g h e t e r o c y c l e s . T h i s is b e c a u s e t h e r e s u l t a n t
o r g a n o m e t a l l i c species are g o o d n u c l e o p h i l e s , and b e c a u s e pyridines are also
m o d e r a t e electrophiles, p o l y m e r i s a t i o n p r o b l e m s are often encountered. M o r e
s u c c e s s h a s b e e n a c h i e v e d w i t h s u b s t i t u t e d p y r i d i n e s h a v i n g an ortho
activating substituent (e.g. -CONHR, -NHCOR, -OMe,
- C H 2 N R 2 etc). T h e s e substituents increase the rate of kinetic d e p r o t o n a t i o n
and stabilise the intermediate o r g a n o l i t h i u m species by coordination.
F o r instance, 4 - a m i n o p y r i d i n e 5 . 3 4 can b e c o n v e r t e d to a m i d e 5.35 which,
o n t r e a t m e n t w i t h t w o e q u i v a l e n t s of b u t y l l i t h i u m , g i v e s o r g a n o m e t a l l i c
species 5.36. F o r m y l a t i o n of the m o r e reactive anion (the c a r b a n i o n ) then re-
p r o t o n a t i o n of the a m i d e a n i o n g i v e s 5 . 3 7 . A c i d i c h y d r o l y s i s r e m o v e s the
activating g r o u p to release pyridine aldehyde 5.38.
T h e m e t a l a t i o n p r o c e e d s by initial
d e p r o t o n a t i o n of the a m i d e
f o l l o w e d by o r f f r o - d i r e c t e d
d e p r o t o n a t i o n at the C3 position to
p r o d u c e the p s e u d o six-
m e m b e r e d ring o r g a n o l i t h i u m
species 5.36.
f-BuCOCl
1 n-BuLi
Et,N . ( 2 equivalents) „ ,
4
N N 5.36
5.35 O
11
1.H NMe 2
2.HC1 / H 2 0

NH 2 O HN'^O
O
H HC1 (conc.)
Heat
N IN
5.38 5.37

5.6 Problems
1. W h a t is t h e m e c h a n i s m of this r e a c t i o n ?

C0 2 Et
r
CO z Et
C0 2 Et
N NaOEt/EtOH N
C0 2 Et

Hint. Start by acetylating the 2. T h e c o n d e n s a t i o n of a c t i v e m e t h y l g r o u p s w i t h a l d e h y d e s c a n b e c a t a l y s e d

pyridine to give a quaternary w j t h a c e t i c a n h y d r i d e as w e l l as b a s e . S u g g e s t a p o s s i b l e m e c h a n i s m ,
cationic species. How can
deprotonation afford a Ph
nucleophilic enamine-like system?

PhCHO
Ac20/Ac0H

3. R a t i o n a l i s e t h e f o r m a t i o n of l a c t o n e 5 . 4 0 f r o m p y r i d y l a m i d e 5 . 3 9 .

OMe
DMP
1. 2 eq. n-BuLi
2.p-MeOC 6 H 4 CHO
3.H2S04/H20

4. S o m e p y r i d i n e N - o x i d e s a r e n o t j u s t s y n t h e t i c i n t e r m e d i a t e s , b u t a r e of
i n t e r e s t in t h e i r o w n r i g h t . F o r i n s t a n c e , p y r i d i n e N - o x i d e 5 . 4 1 is a n e w d r u g
c l a i m e d to b e u s e f u l f o r the t r e a t m e n t of senile d e m e n t i a . W h a t a r e t h e
m e c h a n i s m s of the p y r i d o n e - f o r m i n g step and the final displacement?

5
"1 oe o©

5.7 References
A b r a m o v i t c h , R . A . (1974). In Pyridine and its derivatives (The chemistry
of heterocyclic compounds [ed. A . W e i s s b u r g e r a n d E . C . T a y l o r ] , Vol.
14, S u p p l e m e n t Parts 1 - 4). W i l e y Interscience, N e w York.
E i s n e r , V . a n d K u t h u m , J. ( 1 9 7 2 ) . Chem. rev., 7 2 , 1 ( d i h y d r o p y r i d i n e s ) .
Furniss, B . S . , H a n n a f o r d , A.J., S m i t h , P . W . G . , and Tatchell, A . R . (1989).
Vogel's textbook of practical organic chemistry ( 5 t h e d n ) , p. 1168
(preparation of pyridine 5.13). L o n g m a n , H a r l o w .
K l i n s b e r g , E. ( 1 9 7 4 ) . In Pyridine and its derivatives (The chemistry of
heterocyclic compounds [ed. A . W e i s s b u r g e r a n d E . C . T a y l o r ] , Vol. 14,
Parts 1 - 4). W i l e y Interscience, N e w Y o r k .
M c G i l l , C . K . and R a p p a , A . ( 1 9 8 8 ) . Adv. heterocyclic chem., 4 4 , 3.
S m i t h , D . M . (1979). In Heterocyclic chemistry (ed. P . G . S a m m e s ) (Vol.
4of Comprehensive organic chemistry, ed. D . B a r t o n and W . D . Ollis), p.3.
P e r g a m o n Press, O x f o r d .

Quinoline and isoquinoline can
also be viewed as being formally
derived from naphthalene
Note the numbering system for
isoquinoline
6= Quinolines and isoquinolsnes
6.1 Introduction
Q u i n o l i n e 6 . 1 and i s o q u i n o l i n e 6 . 2 are t w o i s o m e r i c h e t e r o c y c l i c s y s t e m s ,
w h i c h can b e e n v i s a g e d as b e i n g c o n s t r u c t e d f r o m the f u s i o n of a b e n z e n e
ring at t h e C 2 / C 3 and C 3 / C 4 p o s i t i o n s of p y r i d i n e r e s p e c t i v e l y . T h e y are
both ten 7t-electron a r o m a t i c heterocycles. L i k e pyridine, they are m o d e r a t e l y
b a s i c ( p ^ a q u i n o l i n e = 4.9, p K a i s o q u i n o l i n e = 5.1). I n d e e d q u i n o l i n e is
s o m e t i m e s used as a high boiling-point ( 2 3 7 ° C ) basic solvent.
A s w i t h p y r i d i n e , the n i t r o g e n a t o m s of quinoline and i s o q u i n o l i n e e a c h
b e a r a l o n e p a i r of electrons n o t i n v o l v e d in aromatic b o n d i n g w h i c h can be
p r o t o n a t e d , alkylated, or c o m p l e x e d to L e w i s acids. This c h a p t e r s h o u l d b e
read in c o n j u n c t i o n with the c h a p t e r o n pyridines as several points discussed
at l e n g t h t h e r e a r e a l s o r e l e v a n t to t h e c h e m i s t r y of q u i n o l i n e a n d
isoquinoline.
6.2 Synthesis of quinolines and isoquinolines
T h e classical S k r a u p synthesis of quinolines is e x e m p l i f i e d by the reaction of
aniline 6 . 3 with g l y c e r o l 6 . 4 u n d e r a c i d i c / o x i d a t i v e c o n d i t i o n s to p r o d u c e
quinoline 6.1.
At f i r s t sight this r e a c t i o n a p p e a r s to b e a n o t h e r o n e of t h o s e a n c i e n t
h e t e r o c y c l i c s y n t h e s e s that o w e m o r e to a l c h e m y than to logic, b u t in f a c t
the processes involved are relatively straightforward.
 H H
HO' H OH -H,0
OH
HO^^OH
OH
6.4
H
-H,0
/ 6.5

H
6.7
Protonation of glycerol 6.4 catalyses dehydration via secondary c a r b o n i u m
i o n 6 . 5 to g i v e enol 6 . 6 . A c i d c a t a l y s e d e l i m i n a t i o n of a s e c o n d w a t e r
m o l e c u l e a f f o r d s acrolein 6.7. T h u s glycerol acts essentially as a p r o t e c t e d
f o r m of acrolein, slowly releasing this unstable a , p - u n s a t u r a t e d aldehyde into Acrolein is a highly reactive olefin
t h e r e a c t i o n m e d i u m . B e t t e r yields are r e a l i s e d w i t h this a p p r o a c h than if that is prone to polymerisation.
acrolein itself is p r e s e n t f r o m the start. T h e reaction p r o c e e d s with a M i c h a e l
addition of aniline 6 . 3 to acrolein, p r o d u c i n g saturated a l d e h y d e 6 . 8 w h i c h
cyclises via an a r o m a t i c substitution reaction to alcohol 6.9. A c i d - c a t a l y s e d
dehydration to 6 . 1 0 then oxidation yields quinoline 6.1. N i t r o b e n z e n e can b e
used as a m i l d oxidant, as can iodine and ferric salts.

S o m e e x a m p l e s of the S k r a u p synthesis are s h o w n b e l o w .

OMe OMe

T h e k e y i n t e r m e d i a t e s in t h e s y n t h e s i s of i s o q u i n o l i n e s a r e P -
a r y l e t h y l a m i n e s . F o r instance, a c y l a t i o n of P - p h e n y l e t h y l a m i n e 6 . 1 1 gives
a m i d e s of g e n e r a l s t r u c t u r e s 6.12 w h i c h c a n b e cyclised w i t h p h o s p h o r u s
o x y c h l o r i d e to p r o d u c e d i h y d r o i s o q u i n o l i n e 6.13. Better yields are o b t a i n e d
 w i t h e l e c t r o n - d o n a t i n g g r o u p s o n t h e a r o m a t i c ring f a c i l i t a t i n g this a r o m a t i c
substitution cyclisation.
x. X\
RCOC1
NH, Base
6.11
X = Electron-donating POC1
substituent

Pdu
-2H

6.14 6.13
T h i s d e h y d r o g e n a t i o n is A s in t h e S k r a u p q u i n o l i n e s y n t h e s i s , l o s s of t w o h y d r o g e n a t o m s is
the reverse of a n o r m a l
n e c e s s a r y t o r e a c h t h e f u l l y a r o m a t i c s y s t e m . H o w e v e r , t h i s is u s u a l l y
hydrogenation reaction. T h e
d e h y d r o g e n a t i o n c a n be c a r r i e d a c c o m p l i s h e d in a s e p a r a t e s t e p , u t i l i s i n g p a l l a d i u m c a t a l y s i s t o give
out u n d e r milder c o n d i t i o n s w h e n g e n e r a l i s e d i s o q u i n o l i n e 6 . 1 4 . T h i s is k n o w n as t h e B i s c h l e r - N a p i e r a l s k i
a h y d r o g e n a c c e p t o r ( s u c h as s y n t h e s i s . T h e m e c h a n i s m p r o b a b l y i n v o l v e s c o n v e r s i o n o f a m i d e 6 . 1 2 to
c y c l o h e x e n e ) is p r e s e n t . protonated imidoyl chloride 6.15 followed by electrophilic aromatic
s u b s t i t u t i o n t o g i v e 6 . 1 3 . ( F o r a s i m i l a r a c t i v a t i o n of a n a m i d e t o a n
e l e c t r o p h i l i c s p e c i e s s e e t h e V i l s m e i e r r e a c t i o n , C h a p t e r 2.)

©
H N-_
ci-
0 =PTClR a
R R
r O = PR- C I a
6.15 6.13

f a X = Electron-donating substituent

T h e P i c t e t - S p e n g l e r s y n t h e s i s is C l o s e l y r e l a t e d t o t h e B i s c h l e r - N a p i e r a l s k i s y n t h e s i s is t h e Pictet-
usually u s e d w h e n t h e
Spengler synthesis, which utilises aldehydes rather than acylating species.
tetrahydroisoquinoline oxidation
level is r e q u i r e d . C o n d e n s a t i o n of P - a r y l e t h y l a m i n e s w i t h a l d e h y d e s p r o d u c e s i m i n e s s u c h as
6.16 which can be cyclised with acid to give tetrahydroisoquinoline 6.17. As
with the Bischler-Napieralski synthesis, electron-donating groups (typically
m e t h o x y g r o u p s ) f a c i l i t a t e t h e c y c l i s a t i o n step. T h e l o w e r o x i d a t i o n s t a t e of
6 . 1 7 as c o m p a r e d to 6 . 1 3 is a d i r e c t c o n s e q u e n c e of u s i n g a c a r b o n y l g r o u p at
t h e a l d e h y d e r a t h e r than c a r b o x y l i c a c i d o x i d a t i o n level. F o u r h y d r o g e n a t o m s
h a v e t o b e r e m o v e d f r o m t e t r a h y d r o i s o q u i n o l i n e s b y o x i d a t i o n to p r o d u c e the
fully aromatic isoquinoline.
O.
CH,0 < 6.16
NH, HC1
H

O
NH
O O O ' V j s I ,
H
6.17
 6.3 Electrophilic substitution of quinoline and
isoquinoline
Quinoline and isoquinoline undergo electrophilic substitution reactions m o r e
easily than pyridine, though not surprisingly the i n c o m i n g electrophile
a t t a c k s t h e b e n z e n o i d r i n g . A s w i t h p y r i d i n e , t h e n i t r o g e n a t o m s of q u i n o l i n e
a n d i s o q u i n o l i n e a r e p r o t o n a t e d u n d e r t h e t y p i c a l l y a c i d i c c o n d i t i o n s of
nitration or sulphonation, m a k i n g the heterocyclic ring resistant to attack.
T h e C 5 a n d C 8 p o s i t i o n s a r e m o s t s u s c e p t i b l e to e l e c t r o p h i l i c a t t a c k .

6.18a H 6.18b H
H ©
E p S

N;
r
6.19 H

A t t a c k of an e l e c t r o p h i l e at C 5 of p r o t o n a t e d q u i n o l i n e g i v e s c a t i o n
6 . 1 8 a , b w h i c h is s t a b i l i s e d b y r e s o n a n c e as s h o w n w i t h o u t d i s t u r b i n g t h e
aromaticity of t h e a d j a c e n t p y r i d i n i u m ring. However, attack of an
e l e c t r o p h i l e at C 6 p r o d u c e s c a t i o n 6 . 1 9 w h i c h d o e s n o t p o s s e s s t h e s a m e
resonance stabilisation of cation 6.18a,b. (The student should p e r f o r m the
s a m e exercise f o r the C 7 and C 8 positions and c o n f i r m that the s a m e
a r g u m e n t s c a n b e applied.)
NO 2

HNO,
+
6.1 6.20 NO, 6.21

F o r i n s t a n c e , n i t r a t i o n of q u i n o l i n e g i v e s an e q u a l m i x t u r e of r e g i o i s o m e r s
6 . 2 0 a n d 6 . 2 1 . H o w e v e r , n i t r a t i o n of i s o q u i n o l i n e is r e a s o n a b l y s e l e c t i v e
(10:1) f o r the C 5 position over the C8, a f f o r d i n g mainly 6.22.

NO.

HNO,
H 2 SO„

6.22

6.4 Nucleophilic substitution of quinoline and

isoquinoline
Q u i n o l i n e a n d i s o q u i n o l i n e u n d e r g o n u c l e o p h i l i c s u b s t i t u t i o n r e a c t i o n s , like
pyridine.
1.KNH,/Heat
1
2. Aq. Workup
OEt
6.25

1. KNH 2 /Heat NaOEt

6
2. Aq. Workup

6.24 NH, CI 6.26 OEt

For instance, both quinoline and isoquinoline undergo the Chichibabin

reaction (with f o r m a l h y d r i d e e l i m i n a t i o n , see C h a p t e r 5) to give 2-
aminoquinoline 6.23 and 1-aminoisoquinoline 6.24 respectively. Halogen
s u b s t i t u e n t s ortho t o t h e n i t r o g e n a t o m s a r e e a s i l y d i s p l a c e d , as in t h e
preparations of 6.25 and 6.26.

X = Nucleophile

J CI

N o t e t h a t n u c l e o p h i l i c d i s p l a c e m e n t in i s o q u i n o l i n e s o c c u r s m o r e e a s i l y at
t h e C I p o s i t i o n t h a n at t h e C 3 p o s i t i o n ( e v e n t h o u g h t h e y a r e b o t h ortho to
n i t r o g e n ) b e c a u s e d i s p l a c e m e n t at C 3 i n v o l v e s t e m p o r a r y d i s r u p t i o n of t h e
benzenoid ring.

6.5 Anion chemistry of quinoline and isoquinoline

A l k y l g r o u p s at t h e C 2 a n d C 4 p o s i t i o n s of q u i n o l i n e c a n b e d e p r o t o n a t e d b y
s t r o n g b a s e s . T h i s is b e c a u s e (as w i t h p y r i d i n e ) t h e n e g a t i v e c h a r g e o n t h e
resultant carbanions c a n b e delocalised onto the electronegative nitrogen
a t o m , as in c a r b a n i o n 6 . 2 7 a , b .

N ^ ^ N
6.27a 6.27b ®
S u c h c a r b a n i o n s c a n b e alkylated, acylated, or c o n d e n s e d w i t h a l d e h y d e s :

l.KNH,
2. EtBr

l.KNH 2 O

2. PhC0 2 Et N Ph
 1. NH4OH
Ar = />MeOC 6 H 4
2. ARCHO

T h i s t y p e of c h e m i s t r y is a l s o o b s e r v e d w i t h 1 - m e t h y l i s o q u i n o l i n e 6 . 2 8 .
H o w e v e r 3 - m e t h y l i s o q u i n o l i n e is m u c h less a c t i v a t e d b e c a u s e d e l o c a l i s a t i o n
of c h a r g e in 6 . 2 9 a , b i n v o l v e s d i s r u p t i o n of a r o m a t i c i t y of t h e b e n z e n o i d r i n g .
T h i s p h e n o m e n o n is c l o s e l y r e l a t e d to t h e r e l u c t a n c e of 3 - h a l o i s o q u i n o l i n e s
to undergo nucleophilic substitution.

6.29a 6.29b

As with pyridine, activated alkyl groups can be condensed with aldehydes

u n d e r a c i d i c as w e l l as b a s i c c o n d i t i o n s , as in t h e p r e p a r a t i o n o f 6 . 3 0 a n d
6.31.

PhCHO
ZnCl, / Heat T h e r e a d e r is referred to t h e
p r e v i o u s c h a p t e r ( P r o b l e m 2) for a
m e c h a n i s t i c e x p l a n a t i o n of s u c h
condensations.

PhCHO
Ac,0/Heat
6.31

6.6 Problems
1. T h e s y n t h e s i s of t h e i m p o r t a n t q u i n o l o n e a n t i b i o t i c 6 . 3 3 is s h o w n . T h e
k e y s t a g e s a r e t h e G o u l d - J a c o b s o n q u i n o l o n e s y n t h e s i s to g i v e 6 . 3 2 , a n d t h e
d i s p l a c e m e n t r e a c t i o n t o a f f o r d 6 . 3 3 . W h a t a r e t h e m e c h a n i s m s of t h e s e
reactions?
O o

EtO OEt O o
CO,Et CO,Et
F
OEt
l.NaH
NH, Heat cr N
2. EtI
cr
6.32 H

1. NaOH 2. HC1

NH O
CO,H CO,H
1.HN
2. HC1

HC1.HN 6.33
 2. A s y n t h e s i s of the n a t u r a l l y - o c c u r r i n g i s o q u i n o l i n e alkaloid 6 . 3 4 is s h o w n
b e l o w . W h a t r e a g e n t s m i g h t b e u s e d to a c c o m p l i s h each t r a n s f o r m a t i o n ?

R = CH2Ph

6.7 References
Adams, R. and Sloan, A . W . (1941). Organic syntheses, Coll. V o l . I, 4 7 8
(a real b l o o d - a n d - t h u n d e r preparation of quinoline).
Claret, P.A. ( 1 9 7 9 ) . In Heterocyclic chemistry (ed. P . G . S a m m e s ) ( V o l . 4
of Comprehensive organic chemistry, ed. D. Barton and W . D . Ollis),
p. 155 (quinolines) a n d p . 2 0 5 (isoquinolines). P e r g a m o n Press, O x f o r d .
F u r n i s s , B . S . , H a n n a f o r d , A.J., S m i t h , P . W . G . , a n d T a t c h e l l , A . R . (1989).
Vogel 's textbook of practical organic chemistry (5th e d n ) , p . 1 1 8 5 (a
rather m o r e s a f e t y - c o n s c i o u s preparation of quinoline). L o n g m a n , H a r l o w .
G r e t h e , G . (ed.) ( 1 9 8 1 ) . In Isoquinolines (The chemistry of heterocyclic
compounds [ed. A . W e i s s b u r g e r a n d E . C . T a y l o r ] , V o l . 3, Part 1). W i l e y
Interscience, N e w Y o r k .
Jones, G. ( 1 9 7 7 , 1990). In Quinolines (The chemistry of heterocyclic
compounds [ed. A . W e i s s b u r g e r a n d E . C . T a y l o r ] , V o l . 3 2 , P a r t s 1, 2,
a n d 3). W i l e y Interscience, New*York.
K a t h a w a l a , G . F . , C o p p o l a , G . M . , a n d S c h u s t e r , H . F . ( e d . ) ( 1 9 8 9 ) . In
Isoquinolines (The chemistry of heterocyclic compounds [ed. A .
W e i s s b u r g e r a n d E . C . T a y l o r ] , V o l . 3, P a r t 2). W i l e y I n t e r s c i e n c e , N e w
York.
Manske, R.H.F. and Kalka, M. ( 1 9 5 3 ) . Organic reactions, 7, 59 (Skraup
synthesis).
W h a l e y , W . M . a n d G o v i n d a c h a r i , T . R . ( 1 9 5 1 ) . Organic reactions, 6, p.151
( P i c t e t - S p e n g l e r synthesis).
 7. Indoles

7.1 Introduction
F u s i o n of a b e n z e n e r i n g o n t o t h e C 2 / C 3 p o s i t i o n s of p y r r o l e f o r m a l l y
p r o d u c e s the c o r r e s p o n d i n g b e n z o p y r r o l e 7.1 k n o w n as indole. A n a n a l o g o u s
t h e o r e t i c a l t r a n s f o r m a t i o n c a n b e e n v i s a g e d to f o r m b e n z o f u r a n 7 . 2 a n d
b e n z o t h i o p h e n e 7.3. T h i s c h a p t e r will c o n c e n t r a t e e x c l u s i v e l y o n indole, b y
f a r the m o s t i m p o r t a n t m e m b e r of this series.

7 H 1
Ou Cm

Indole is a ten-7t electron a r o m a t i c system. A s with pyrrole, delocalisation

of t h e l o n e p a i r of e l e c t r o n s f r o m t h e n i t r o g e n a t o m is n e c e s s a r y f o r
a r o m a t i c i t y . T h e s i n g l e o v e r a l l e l e c t r o n i c s t r u c t u r e of i n d o l e is n o t
c o m p l e t e l y described by structure 7.1, b e c a u s e this implies localisation of t h e
l o n e pair o n the n i t r o g e n a t o m . M e s o m e r i c r e p r e s e n t a t i o n 7 . 1 a m a k e s a
c o n t r i b u t i o n to t h e e l e c t r o n i c s t r u c t u r e of indole, as to a l e s s e r e x t e n t d o
m e s o m e r i c representations w h e r e the negative charge occurs o n the b e n z e n o i d
ring.

[cu -
L I
a?] I® J
H H
7.1 7.1a

A c o n s e q u e n c e of this delocalisation is that t h e l o n e pair is n o t a v a i l a b l e

f o r p r o t o n a t i o n u n d e r m o d e r a t e l y acidic c o n d i t i o n s so, like p y r r o l e , indole is
a n o t h e r w e a k l y basic heterocycle. A n o t h e r similarity to p y r r o l e is that b e i n g
an 'electron-rich' h e t e r o c y c l e i n d o l e easily u n d e r g o e s a r o m a t i c electrophilic
s u b s t i t u t i o n , a n d is a l s o r a t h e r u n s t a b l e to o x i d a t i v e ( e l e c t r o n - l o s s )
c o n d i t i o n s . H o w e v e r , an i m p o r t a n t d i f f e r e n c e e m e r g e s here, in that w h e r e a s
p y r r o l e preferentially reacts with electrophiles at the C 2 / C 5 positions, indole
s u b s t i t u t e s s e l e c t i v e l y at t h e C 3 p o s i t i o n . T h e r e a s o n s f o r this w i l l b e
discussed later.
 Historically, interest in indoles arose with the isolation and
c h a r a c t e r i s a t i o n o f m e m b e r s of t h e e n o r m o u s f a m i l y of i n d o l e a l k a l o i d s , s u c h
as l y s e r g i c a c i d 7.4. M a n y i n d o l e a l k a l o i d s p o s s e s s i n t e r e s t i n g a n d s o m e t i m e s
u s e f u l b i o l o g i c a l a c t i v i t i e s . A l t h o u g h n a t u r a l p r o d u c t c h e m i s t r y is still a n
a c t i v e a r e a of p r i m a r i l y a c a d e m i c r e s e a r c h , c o n s i d e r a b l y m o r e e f f o r t is
N e u r o t r a n s m i t t e r s are naturally- e x p e n d e d n o w a d a y s i n t h e p r e p a r a t i o n of i n d o l e d e r i v a t i v e s as p o t e n t i a l
o c c u r r i n g s u b s t a n c e s w h i c h effect drag candidates. Following on f r o m the observations that certain indole
chemical communication between
alkaloids or their semi-synthetic derivatives (e.g. lysergic acid d i e t h y l a m i d e ,
n e r v e cells by b i n d i n g at specific
sites o n the cell s u r f a c e called L S D 7 . 5 ) h a v e p o t e n t c e n t r a l n e r v o u s s y s t e m a c t i v i t y , it w a s e s t a b l i s h e d t h a t
receptors. t h e s i m p l e i n d o l e 5 - h y d r o x y t r y p t a m i n e 7 . 6 is a m a j o r neurotransmitter.
Many indole derivatives which mimic or block the binding of this
n e u r o t r a n s m i t t e r t o its r e c e p t o r s h a v e b e e n s y n t h e s i s e d a n d a r e b e g i n n i n g
t o f i n d u s e i n t h e t r e a t m e n t of v a r i o u s p s y c h o l o g i c a l d i s o r d e r s .

NH,

7.4 x = OH
7.5 X = NEt 2
7.6

7.2 Synthesis of indoles

A s m i g h t b e e x p e c t e d f o r a l a r g e b r a n c h of h e t e r o c y c l i c c h e m i s t r y , m a n y
s y n t h e s e s of i n d o l e s h a v e b e e n d e v e l o p e d . W e shall restrict o u r d i s c u s s i o n to
two, c o m m e n c i n g with the widely-used Fischer synthesis.
T h e F i s c h e r s y n t h e s i s is t h e c o n d e n s a t i o n of a n a r y l h y d r a z i n e w i t h a
k e t o n e f o l l o w e d b y c y c l i s a t i o n of t h e r e s u l t a n t h y d r a z o n e u n d e r a c i d i c
c o n d i t i o n s to g i v e t h e c o r r e s p o n d i n g i n d o l e , as i l l u s t r a t e d b y t h e p r e p a r a t i o n
of 2 - p h e n y l i n d o l e 7.9.
O
Ph'.A AcOH or
Ph - N - NH 2
H -H20
Ph - N - N = <
H Ph ZnCl2 JLPh
7.7 7.8 7.9

T h e a c t u a l c y c l i s a t i o n s t a g e is n o t as i m p o n d e r a b l e as it a p p e a r s . T h e f i r s t
s t e p is t h e a c i d - c a t a l y s e d e q u i l i b r a t i o n b e t w e e n h y d r a z o n e 7 . 8 a n d e n e
hydrazine 7 . 1 ® . T h e n e x t s t e p , w h i c h i s i r r e v e r s i b l e , is a concerted
electrocyclic reaction, f o r m i n g a strong c a r b o n - c a r b o n bond, and breaking a
weak nitrogen-nitrogen bond. T h e resulting imine 7 . 1 1 immediately re-
a r o m a t i s e s by t a u t o m e r i s a t i o n to aniline 7 . 1 2 . Finally, acid-catalysed
e l i m i n a t i o n of a m m o n i a f o r m s i n d o l e 7.9, r e m i n i s c e n t of t h e last s t e p of t h e
K n o r r p y r r o l e s y n t h e s i s ( C h a p t e r 2).
 T h e e l e c t r o c y c l i c r e a c t i o n is v e r y s i m i l a r to t h e C l a i s e n r e a r r a n g e m e n t of Co
Pe rearrangement
p h e n y l allyl e t h e r 7 . 1 2 to g i v e p h e n o l 7 . 1 3

^ ^ LJ
H

J
J 0 OH

7.12 7.13

S o m e e x a m p l e s of t h e F i s c h e r i n d o l e s y n t h e s i s a r e s h o w n b e l o w .

,OMe OMe

Ph - N - NH 2 41 -
H

OMe

Ph - N - NH 2 -f-

Ph-N-NH, J

MeO NMe2

Y l +
H
F

+
F - "N-NH2 o
H
F

An interesting regioselectivity question arises with the use of

unsymmetrical ketone 7.14 to prepare indole 7.15. T w o ene hydrazines 7.16
and 7 . 1 7 can f o r m , w h i c h w o u l d give rise to indoles 7 . 1 5 and 7 . 1 8
respectively.

SPh
SPh

NH
N' 7.15
H 7.16 (major)
Ph - N - NH 2
H
jr
7.7 SPh
SPh
NH
N
H 7.18
7.17 ( minor)

In s u c h c a s e s t h e m o s t t h e r m o d y n a m i c a l l y s t a b l e e n e h y d r a z i n e , i.e. t h e o n e
w i t h t h e m o r e h i g h l y s u b s t i t u t e d d o u b l e b o n d , f o r m s p r e f e r e n t i a l l y . In t h i s
p a r t i c u l a r e x a m p l e t h e r e is a l s o e x t r a s t a b i l i s a t i o n d e r i v e d f r o m c o n j u g a t i o n
of t h e l o n e p a i r s of e l e c t r o n s o n t h e s u l p h u r a t o m w i t h t h e d o u b l e b o n d . T h i s
regioselectivity in e n e hydrazine f o r m a t i o n is t h e n r e f l e c t e d in the
r e g i o s e l e c t i v i t y of i n d o l e f o r m a t i o n .
The more recent Leimgruber synthesis is illustrated by the
aminomethylenation of nitrotoluene 7 . 1 9 to give 7 . 2 0 , followed by
h y d r o g e n a t i o n to p r o d u c e i n d o l e 7.1.

MeO. , O M e 7.21
h ^ N ^
N

NO,
Heat
NO, Pd/C 1
7.19 7.20 7.1

T h e c o m b i n a t i o n of f o r m y l p y r r o l i d i n e a c e t a l 7 . 2 1 a n d n i t r o t o l u e n e 7 . 1 9
produces electrophilic cation 7.22 and nucleophilic carbanion 7.23a,b which
r e a c t t o g e t h e r a f f o r d i n g e n a m i n e 7.20.

MeO)°Me
h ^ N , 7_21

5
©
— OMe - c e
7.20
 H y d r o g e n a t i o n of e n a m i n e 7 . 2 0 r e d u c e s t h e n i t r o g r o u p g i v i n g a n i l i n e
7 . 2 4 , t h e n e l i m i n a t i o n of p y r r o l i d i n e p r o d u c e s i n d o l e 7 . 1 . N o t e t h e s i m i l a r i t y
of this r i n g c l o s u r e s t e p t o t h e last s t e p of t h e F i s c h e r s y n t h e s i s . I n b o t h
c a s e s t h e e v e n t u a l C 2 c a r b o n a t o m is f o r m a l l y at t h e c a r b o n y l o x i d a t i o n
l e v e l , e v e n t h o u g h it o c c u r s as e i t h e r a n i m i n e ( F i s c h e r s y n t h e s i s ) o r a n
e n a m i n e ( L e i m g r u b e r s y n t h e s i s ) . E l i m i n a t i o n of a m m o n i a o r p y r r o l i d i n e
r e s p e c t i v e l y is a n a l o g o u s to a c o n d e n s a t i o n p r o c e s s i n v o l v i n g e l i m i n a t i o n of
w a t e r (as in t h e K n o r r p y r r o l e s y n t h e s i s ) .

D H, D N
H

'^CcT Pd/C
^ o7.24 c Hen - O u
7.1
7.20
S o m e e x a m p l e s of t h e L e i m g r u b e r s y n t h e s i s a r e s h o w n b e l o w .

XX
MeO MeO

NO,
J O
H2N- ^ -no2 H,N'

C0 2 Et C0 2 Et

c o c NO, o- J NO,

7.3 Electrophilic substitution of indoles

A s an electron-rich heterocycle, indole easily undergoes electrophilic
s u b s t i t u t i o n . H o w e v e r w h e r e a s p y r r o l e r e a c t s p r e f e r e n t i a l l y at t h e C 2 / C 5
p o s i t i o n s ( s e e C h a p t e r 2), i n d o l e r e a c t s p r e f e r e n t i a l l y at the C 3 p o s i t i o n .

J
1
H "H

N
©V E I
H E®
7.25 H H

O n e e x p l a n a t i o n is t h a t a t t a c k at C 2 r e s u l t s in d i s r u p t i o n of t h e a r o m a t i c i t y
of t h e b e n z e n o i d r i n g , as in i n t e r m e d i a t e 7 . 2 5 . T h i s is t h e r e f o r e a h i g h - e n e r g y
i n t e r m e d i a t e , a n d this r e a c t i o n p a t h w a y is s l o w e r b e c a u s e t h e first s t e p is r a t e -
d e t e r m i n i n g . A l s o t h e C 3 s e l e c t i v i t y is i n a c c o r d w i t h t h e e l e c t r o p h i l e
a t t a c k i n g t h e site of h i g h e s t e l e c t r o n d e n s i t y o n t h e r i n g . In e s s e n c e , i n d o l e
tends to react like an e n a m i n e t o w a r d s electrophiles, with substitution
 occurring at the C 3 position, although substitution occurs at the C 2 position
w h e n t h e C 3 p o s i t i o n is b l o c k e d .
I n d o l e i t s e l f is u n s t a b l e t o t h e m i n e r a l a c i d c o n d i t i o n s f o r n i t r a t i o n . T h e
n i t r a t i o n of s u b s t i t u t e d i n d o l e s is q u i t e c o m p l e x a n d t h e o u t c o m e is d e p e n d e n t
on the precise reaction conditions.
L i k e pyrrole, indole readily undergoes the M a n n i c h reaction a f f o r d i n g the
a m i n o m e t h y l d e r i v a t i v e 7 . 2 6 . A v a r i e t y of n u c l e o p h i l e s c a n d i s p l a c e t h e
a m i n e via a n e l i m i n a t i o n f o l l o w e d b y a 1 , 4 - a d d i t i o n r e a c t i o n , as i n t h e
p r e p a r a t i o n of a c e t a t e 7 . 2 7 .

CH 2 0 NMe2
HNMe 2
H AcOH H
T h i s is t h e r e a c t i v e electrophilic 7.1 7.26
s p e c i e s of t h e M a n n i c h reaction.
© r e , OAc
CH 2 = NMe 2 f^jl |f^>-NMe2 NaOAc OAc

v
AcOH

H 7.27

T h e Vilsmeier reaction proceeds extremely well with indoles giving

T h i s is t h e reactive electrophilic a l d e h y d e s s u c h as 7 . 2 8 .
s p e c i e s of the V i l s m e i e r reaction.
H
^>=NMe2 1. P0C13 / HCONMe2
CI •
J 2. H 2 0
7.1 7.28

A l d e h y d e 7 . 2 8 is a n o t h e r u s e f u l s y n t h e t i c i n t e r m e d i a t e , r e a d i l y u n d e r g o i n g
condensation reactions with active methylene c o m p o u n d s such as malonic
acid and nitromethane to p r o d u c e 7.29 and 7.30.

^C02H

CO 2 H ,C02H
•

H 7.30
Pyridine Oc?
7.29 H

A c y l a t i o n of t h e C 3 p o s i t i o n c a n a l s o b e a c c o m p l i s h e d w i t h a c i d c h l o r i d e s ,
as i l l u s t r a t e d i n t h e s y n t h e s i s o f i n d o l e 7 . 3 4 , a d r u g f o r t h e t r e a t m e n t o f
d e p r e s s i o n . R e a c t i o n of i n d o l e 7 . 3 1 with oxalyl c h l o r i d e a f f o r d s C 3 -
s u b s t i t u t e d p r o d u c t 7 . 3 2 e v e n t h o u g h t h e b e n z e n e r i n g is v e r y e l e c t r o n - r i c h .
C o n v e r s i o n t o a m i d e 7 . 3 3 is f o l l o w e d b y r e d u c t i o n w i t h l i t h i u m a l u m i n i u m
hydride which removes both carbonyl groups, affording the target indole
7.34.
 ci
cr
MeO MeO CI

H 1 U
MeO MeO 7.32

o
H H
7.31
N.

N
Ph

O r^^NPh
MeO MeO

MeO 1.LiAlH 4 MeO N'

2. H 2 0 H
7.34 7.33

7.4 Anion chemistry of indole

T r e a t m e n t o f i n d o l e ( p K a = 1 7 ) w i t h s t r o n g b a s e s s u c h as b u t y l l i t h i u m ,
Grignard reagents, or metal hydrides produces the corresponding indolyl
a n i o n , w h i c h r e a c t s w i t h e l e c t r o p h i l e s e i t h e r o n n i t r o g e n o r at t h e C 3
p o s i t i o n . W i t h l i t h i u m , s o d i u m , o r p o t a s s i u m as c o u n t e r i o n t h e i n d o l y l
a n i o n t e n d s to r e a c t o n n i t r o g e n , as in t h e p r e p a r a t i o n of 7 . 3 5 . H o w e v e r , w i t h
m a g n e s i u m as t h e c o u n t e r i o n t h e i n t e r m e d i a t e h a s a n e s s e n t i a l l y c o v a l e n t
r a t h e r t h a n i o n i c s t r u c t u r e , a n d r e a c t i o n t e n d s to o c c u r at t h e C 3 p o s i t i o n , as
in t h e p r e p a r a t i o n of 7 . 3 6 .

u
NaH Mel
a N
1
7.1 e Me
Na' 7.35
EtMgBr

cx?
H

a NJ- — MgBr2
H
7.36
MgBr

W h e n t h e n i t r o g e n is b l o c k e d , d e p r o t o n a t i o n c a n o c c u r at t h e C 2 p o s i t i o n ,
a d j a c e n t to t h e e l e c t r o n e g a t i v e h e t e r o a t o m . T h i s o f f e r s a m e a n s of i n t r o d u c i n g
e l e c t r o p h i l e s at this p o s i t i o n , c o m p l e m e n t i n g t h e C 3 s e l e c t i v i t y s h o w n b y
classical electrophilic substitution. For instance, alcohol 7.37 can be prepared
in t h i s w a y u s i n g e t h y l e n e o x i d e as t h e e l e c t r o p h i l e .

n - BuLi

N
J N
J8 Li 2. HC1 / H 2 0
Me Me
7.35 7.37
 7.5 Problems
1. D e v i s e a s y n t h e s i s of the a n t i d e p r e s s a n t d r u g 7.38.

7.38

2. T h e s y n t h e s i s of a m i n o e s t e r 7 . 4 1 is s h o w n b e l o w . W h a t is t h e
m e c h a n i s m of the c o n v e r s i o n of 7 . 3 9 to 7.40.
C0 2 Et
R 0 C E t
fto / ° 2 „ •, , C0 22Et
^ ^ NMe2 2 || jy Raney nickel ^ ^ ^
N0
Heat ^ ^ N ^ 2 ^ ^ N
H H
7.39 7-40 H 7.41
R = PhCH2

3. It w a s i n t e n d e d to p r e p a r e i m i n e 7 . 4 3 f r o m indole 7 . 4 2 b y d e p r o t o n a t i o n
at the C 2 p o s i t i o n then q u e n c h i n g w i t h b e n z o n i t r i l e f o l l o w e d by an a q u e o u s
w o r k u p . H o w e v e r , the isolated p r o d u c t s w e r e k e t o n e 7 . 4 4 a n d s u l p h o n a m i d e
7.45. A c c o u n t f o r this o b s e r v a t i o n .

i- 11 ~n i. n-BuLi \ / r ?r i
7.42 | l| II - -V-+- I II I Ph 7.43
N 2. P h — C E N / N ^ - ^ N
l 3. HCl / H 2 0 I
0 = S =0
o = sI = o ^ _ Ii _
Ph Ph

NH2
7.44
Ph
N 0 = S=0 7.4 5
H M Ph
O
7.6 References
Brown, R.T. and Joule, J.A. (1979). In Heterocyclic chemistry (ed. P . G .
' S a m m e s ) (Vol. 4 of Comprehensive organic chemistry, e d . D. B a r t o n a n d
W . D . Ollis), p.411 (indoles and related systems). Pergamon Press,
Oxford.
F u r n i s s , B . S . , H a n n a f o r d , A.J., S m i t h , P . W . G . , a n d T a t c h e l l , A . R . (1989).
Vogel's textbook of practical organic chemistry ( 5 t h e d n ) , p . 1161
( p r e p a r a t i o n of indole 7.9). L o n g m a n , H a r l o w .
H o u l i h a n , W . J . ( e d . ) ( 1 9 7 2 ) . Indoles (The chemistry of heterocyclic
compounds [ed. A . W e i s s b u r g e r a n d E . C . T a y l o r ] , V o l . 2 5 , P a r t s 1 - 3).
W i l e y Interscience, N e w York.
Leimgruber, W. (1985). Organic syntheses, 63, 214 (indole synthesis).
Robinson, B. (1969). Chem. rev., 69, 227 (Fischer indole synthesis).
Saxton, J.E. (ed.) ( 1 9 7 9 ) . Indoles (The chemistry of heterocyclic
compounds
[ed. A . W e i s s b u r g e r a n d E . C . T a y l o r ] , V o l . 25, Part 4). W i l e y I n t e r s c i e n c e ,
N e w York.
Sundberg, R.J. (1970). The chemistry of indoles. Academic Press,
8. Five-membered ring
heterocycles with three or four
heteroatonris

8.1 Introduction

T h e b r o a d c a t e g o r y of f i v e - m e m b e r e d r i n g h e t e r o c y c l e s c o n t a i n i n g t h r e e o r
four heteroatoms encompasses m a n y heterocyclic systems. Obviously there
Note the parallel w i t h f u r a n b e i n g
is c o n s i d e r a b l e v a r i a t i o n in t h e p h y s i c a l a n d c h e m i c a l p r o p e r t i e s of s u c h a
less a r o m a t i c t h a n pyrrole,
l a r g e g r o u p of h e t e r o c y c l e s . F o r i n s t a n c e , w i t h r e g a r d t o aromaticity, C h a p t e r 2.
o x a d i a z o l e 8 . 3 is c o n s i d e r e d to b e l e s s a r o m a t i c than t r i a z o l e 8 . 8 or t e t r a z o l e
8.9.

n
N-N

V U N oxadiazoles 4., 3

8.1 8.2 8.3 c N

5 V
N J
N 2
N N-N H '
H

0 N
V
U N thiadiazoles 8.7 triazoles 8.8

8.4 8.5 8.6

3
4 N-N N-N N-N
5^ >2 o i >
N, tetrazole O oxatriazole S thiatriazole
H
8.9 8.10 8.11

N e v e r t h e l e s s , this c o l l e c t i o n of h e t e r o c y c l e s d o e s s h a r e c e r t a i n c h a r a c t e r i s t i c s .
T h e trend w e h a v e seen of d e c r e a s i n g t e n d e n c y t o w a r d s electrophilic
s u b s t i t u t i o n o n g o i n g f r o m f u r a n , p y r r o l e , a n d t h i o p h e n e t o t h e a z o l e s is
c o n t i n u e d i n t o t h e s e series. T h e p r e s e n c e of a d d i t i o n a l ' p y r i d i n e - l i k e ' n i t r o g e n
atoms renders these systems particularly 'electron-deficient', and electrophilic
s u b s t i t u t i o n is of little i m p o r t a n c e .
C o n v e r s e l y , n u c l e o p h i l i c s u b s t i t u t i o n ( w h i c h w e h a v e s e e n in e a r l i e r
c h a p t e r s o n 1 , 3 - a z o l e s a n d p y r i d i n e s ) d o e s o c c u r in t h e s e s y s t e m s , e s p e c i a l l y
w h e n t h e c a r b o n a t o m c o n c e r n e d is b e t w e e n t w o h e t e r o a t o m s , as in t h e
d i s p l a c e m e n t r e a c t i o n s of o x a d i a z o l e 8 . 1 2 a n d t e t r a z o l e 8.13.
O n c e a g a i n note the a n a l o g y w i t h
stand

l 11IUU1V1 1111111 Lll 11J V» 1111 AO 11 'Ul U1V1V IUV/ W\ [11I 1J11VI V.' 1 Ut/piuiuijdtion
of a l k y l s u b s t i t u e n t s b e t w e e n t w o h e t e r o a t o m s f o l l o w e d b y q u e n c h i n g t h e
r e s u l t a n t c a r b a n i o n s w i t h e l e c t r o p h i l e s , as in t h e p r e p a r a t i o n of o x a d i a z o l e
8.14.

R i n g d e p r o t o n a t i o n is a l s o k n o w n w i t h c e r t a i n m e m b e r s of t h e s e s e r i e s .
C a r b a n i o n 8 . 1 5 is s t a b l e at l o w t e m p e r a t u r e ( - 7 0 ° C ) a n d c a n b e t r a p p e d w i t h
e l e c t r o p h i l e s , b u t o n w a r m i n g t o r o o m t e m p e r a t u r e it d e c o m p o s e s w i t h r i n g
f r a g m e n t a t i o n a n d e x t r u s i o n o f n i t r o g e n . T h i s f r a g m e n t a t i o n p r o c e s s is
r e m i n i s c e n t of t h e b a s e - c a t a l y s e d c l e a v a g e of i s o x a z o l e s ( C h a p t e r 4).

F o r s i m p l i c i t y w e shall n o w c o n s i d e r t h e s y n t h e s i s of j u s t t h r e e m e m b e r s
of t h e s e s e r i e s , 1 , 2 , 4 - o x a d i a z o l e 8.3, 1,2,3-triazole 8.7, a n d t e t r a z o l e 8.9.

8.2 Synthesis of 1,2,4-oxadiazoles

D i s c o n n e c t i o n o f t h e C 5 - o x y g e n b o n d in 8 . 1 6 l e a d s to i m i n o a l c o h o l 8 . 1 7
w h i c h o c c u r s a s a m i d e 8 . 1 8 . C l e a v a g e of t h e a m i d e l i n k a g e l e a d s t o a n
activated carboxylic acid 8.20 plus the heteroatom-containing amidoxime
8.19.
 R R
2 2 R2 R2

R A ' * R,^ O H OH ^ N-OH N.OH + R A X

8 1 8 8 1 9 8 2 0
8.16 8.17
X = Leaving group

A m i d o x i m e s can b e p r e p a r e d b y a c i d - c a t a l y s e d additon of h y d r o x y l a m i n e to
nitriles.

H 2 NOH R~V
0 H
R2-CEN • R 2 — C E N —H »• D A K T ^
2
HCL A ® N
H
V .
H 2 N— OH

A n e x a m p l e of this a p p r o a c h to o x a d i a z o l e s is s h o w n b y t h e c o n v e r s i o n of
e s t e r 8 . 2 1 t o o x a d i a z o l e 8 . 2 2 , p r e p a r e d as a p o t e n t i a l c a n d i d a t e f o r t h e
t r e a t m e n t of s e n i l e d e m e n t i a . S i m p l e e s t e r s a r e m e t a b o l i c a l l y u n s t a b l e in m a n
b e c a u s e of the high activity of esterases. T h e s e e n z y m e s catalyse the
h y d r o l y s i s of e s t e r s to c a r b o x y l i c a c i d s . A c o m m o n t a c t i c in d r u g r e s e a r c h
w h e n c o n f r o n t e d w i t h t h e p r o b l e m o f m e t a b o l i c i n s t a b i l i t y of a b i o l o g i c a l l y
a c t i v e e s t e r is t o r e p l a c e t h e e s t e r g r o u p w i t h a s m a l l h e t e r o c y c l e ( o f t e n
o x a d i a z o l e ) , to try to p r o d u c e a b i o l o g i c a l l y - a c t i v e m o l e c u l e w i t h i m p r o v e d
m e t a b o l i c s t a b i l i t y . T h i s c o n c e p t o f r e p l a c i n g f r a g m e n t s of a m o l e c u l e b y
g r o u p s w i t h b r o a d l y s i m i l a r p h y s i c o c h e m i c a l p a r a m e t e r s in a s y s t e m a t i c
m a n n e r is k n o w n as b i o i s o s t e r i c r e p l a c e m e n t . In this i n s t a n c e o x a d i a z o l e
8 . 2 2 c a n m i m i c b o t h t h e p h y s i c a l a n d b i o l o g i c a l p r o p e r t i e s of 8 . 2 1 , b u t it is
obviously not a substrate for esterases.

NH
M J^ 0® 0
M
OMe £ __ r C r ^ o -
EtOH, heat

8.21 8.22

8.3 Synthesis of 1,2,3-triazoles

T h e s e a r e b e s t p r e p a r e d b y a 1 , 3 - d i p o l a r c y c l o a d d i t i o n of an a z i d e a n d a n
acetylene.
NaNj r— N 8 8
H-CEC-H • // N -
H 2 SO 4
H

F o r instance, triazole 8 . 8 itself h a s b e e n p r e p a r e d b y c y c l o a d d i t i o n of

h y d r a z o i c acid to acetylene.
 A l t h o u g h a s i m p l e m e c h a n i s m c a n b e d r a w n f o r t h i s t r a n s f o r m a t i o n , it is
o n l y u s e f u l as a ' b o o k - k e e p i n g e x e r c i s e ' to e n s u r e t h a t t h e c o r r e c t s t r u c t u r e is
d r a w n f o r t h e p r o d u c t . In r e a l i t y t h e r e a c t i o n is a c o n c e r t e d p r o c e s s a n d t h e
u s u a l c o n s i d e r a t i o n s of n u c l e o p h i l i c a n d e l e c t r o p h i l i c attack d o n o t a p p l y .
E x c e l l e n t y i e l d s a r e a c h i e v e d in t h e s e c y c l o a d d i t i o n s w h e n electron-
w i t h d r a w i n g g r o u p s a r e p r e s e n t o n t h e a c e t y l e n e , as in t h e p r e p a r a t i o n of
triazol

8.23

m
8.4 Synthesis of tetrazoles
T e t r a z o l e itself e x p l o d e s o n T e t r a z o l e s of g e n e r a l s t r u c t u r e 8 . 2 4 c a n b e p r e p a r e d in a v e r y s i m i l a r m a n n e r
heating with loss of t w o m o l e c u l e s tQ t r i a z o l e S ) eXcept that nitriles are used rather than acetylenes. O n c e again
of N 2
' t h e r e a c t i o n w i t h a z i d e s is a c o n c e r t e d c y c l o a d d i t i o n p r o c e s s .

N N N-N
III Jn© heat
• X N 8.24
C V . / J N'
K
I | 2
R I R2
L e t u s n o w c o n s i d e r t h e s y n t h e s i s o f t e t r a z o l e 8 . 2 7 , a n i n h i b i t o r of t h e
e n z y m e o r n i t h i n e d e c a r b o x y l a s e , w h i c h c a t a l y s e s t h e c o n v e r s i o n of o r n i t h i n e
8.25 to diamine 8.26.
N-N
„ _ COM ^ ,NM2 M N
— • H2N^ ^ ^ ^ H2N
NH2 " C ° 2 8.26 NH2 "
8.25 8.27
T h e t e t r a z o l e m o i e t y is a n e x c e l l e n t b i o i s o s t e r i c r e p l a c e m e n t f o r a
c a r b o x y l i c a c i d , b e i n g a s m a l l , p o l a r , acidic h e t e r o c y c l e .

N " N , v N-N
L > ^ 1 N +
N- \ -^N pKa = 5 6 3
H 0

O O

Aoh ^ + h p k a = 4 7 6
 T e t r a z o l e 8 . 2 7 is s u f f i c i e n t l y s i m i l a r to o r n i t h i n e 8 . 2 5 in its p h y s i c a l
p r o p e r t i e s to b i n d to t h e a c t i v e site of t h e e n z y m e . H o w e v e r , as it o b v i o u s l y
c a n n o t u n d e r g o t h e d e c a r b o x y l a t i o n p r o c e s s , it a c t s as a n i n h i b i t o r of t h e
enzyme.
T h e s y n t h e s i s c o m m e n c e s w i t h a l k y l a t i o n of t h e s t a b i l i s e d c a r b a n i o n
derived f r o m cyanoester 8.29 with iodide 8.28 to give adduct 8.30

Cycloaddition with sodium azide followed by acidification during aqueous

w o r k u p a f f o r d s tetrazole 8 . 3 1 .

NaN, N - N11 HCl N-N

R-CEN 7
' N 11 N
N
Na
e 8.32 H 8.31

N o t e t h a t t h e f i r s t - f o r m e d p r o d u c t f r o m t h e c y c l o a d d i t i o n is a c t u a l l y t h e
s o d i u m t e t r a z o l a t e salt 8 . 3 2 . P r o t o n a t i o n a f f o r d s t h e n e u t r a l t e t r a z o l e 8 . 3 1 .
P r o l o n g e d acidic h y d r o l y s i s a c c o m p l i s h e s s e v e r a l t r a n s f o r m a t i o n s : h y d r o l y t i c
r e m o v a l of b o t h t h e p h t h a l i m i d e a n d a c e t y l n i t r o g e n p r o t e c t i n g g r o u p s , a n d
h y d r o l y s i s / d e c a r b o x y l a t i o n of t h e ester. T h e n e t r e s u l t is to p r o d u c e t h e t a r g e t
tetrazole 8.27 as its dihydrochloride salt. This tetrazole-assisted
d e c a r b o x y l a t i o n is m e c h a n i s t i c a l l y v e r y s i m i l a r t o t h e d e c a r b o x y l a t i o n of
malonyl half-esters 8.33.

8.33
8.5 Problems
1. Triazoles and tetrazoles can be alkylated on nitrogen under basic
c o n d i t i o n s , as in t h e s y n t h e s i s of the c l i n i c a l l y - u s e d a n t i f u n g a l d r u g 8 . 3 5 in
w h i c h l|,2,4-triazole is a l k y l a t e d by a c h l o r o m e t h y l k e t o n e a n d an e p o x i d e ,
b o t h g o o d a l k y l a t i n g a g e n t s . W h a t is t h e m e c h a n i s m of f o r m a t i o n of e p o x i d e
8 . 3 4 ? O f c o m p o u n d s 8 . 3 4 a n d 8.35, w h i c h is achiral a n d w h i c h is r a c e m i c ?

F 8.34
2. W h a t is t h e m e c h a n i s m of f o r m a t i o n of o x a d i a z o l e 8 . 2 2 ?

NH
N-
Na N
OMe H —>

N EtOH, heat JN
8.21 8.22

8.6 References
Butler, R.N. (1977). Adv. heterocyclic chem., 21, 323 (tetrazoles).
C l a p p , L . B . ( 1 9 7 6 ) . Adv. heterocyclic chem, 2 0 , 65, ( 1 , 2 , 4 - o x a d i a z o l e s ) .
Gilchrist, T.L. ( 1 9 8 5 ) . Heterocyclic chemistry, p.81 (1,3-dipolar
c y c l o a d d i t i o n s in h e t e r o c y c l i c synthesis). L o n g m a n , H a r l o w .
Gilchrist, T.L. and Gymer, G.E. (1974). Adv. heterocyclic chem., 16, 33
(1,2,3-triazoles).
Grimmett, M.R. (1979). I n Heterocyclic chemistry (ed. P . G . S a m m e s )
( V o l . 4 of Comprehensive organic chemistry, ed. D. Barton and
W . D . Ollis), p . 3 5 7 (triazoles a n d tetrazoles). P e r g a m o n Press, O x f o r d .
 Six-membered ring
heterocycles containing one
oxygen atom

9.1 Introduction
T h e p y r i l i u m cation 9.1, 2 - p y r o n e 9.2, 4 - p y r o n e 9.3, and their b e n z o - f u s e d
a n a l o g u e s the b e n z o p y r i l i u m cation 9.4, c o u m a r i n 9.5, c h r o m o n e 9.6, are the
parent structures of a series of s i x - m e m b e r e d ring heterocycles containing one
o x y g e n a t o m . T h e i m p e t u s f o r research in this area c o m e s f r o m the e n o r m o u s
n u m b e r of p l a n t - d e r i v e d n a t u r a l p r o d u c t s b a s e d o n t h e b e n z o p y r i l i u m ,
c o u m a r i n , and c h r o m o n e structures.

cr ^-o
i2 9.1 9.2

In natural product chemistry, the

9.5 acetal formed between an aliphatic
or aromatic alcohol and a sugar is
T h e red, violet, and b l u e p i g m e n t s of f l o w e r petals are called anthocyanins,
termed a glycoside.
a n d are g l y c o s i d e s of v a r i o u s b e n z o p y r i l i u m cations. D e l p h i n i d i n c h l o r i d e
9.7, f o r e x a m p l e , is a b l u e p i g m e n t . K h e l l i n 9.8 is a natural p r o d u c t w h i c h
has f o u n d clinical a p p l i c a t i o n in t h e t r e a t m e n t of b r o n c h i a l a s t h m a and has
b e e n t h e starting p o i n t f o r the d e s i g n of m a n y totally synthetic c h r o m o n e s
with i m p r o v e d biological properties.
OH OMe O

OH

OMe
OH
9.8
C o u m a r i n 9.5 is itself a natural p r o d u c t w h i c h occurs in l a v e n d e r oil and has
been f o u n d in o v e r sixty species of plants.
 T h e p y r y l i u m c a t i o n 9 . 1 is t h e o x y g e n a n a l o g u e of p y r i d i n e a n d is a six
Tc-electron a r o m a t i c s y s t e m . N e v e r t h e l e s s , b e i n g a c a t i o n it is r e a c t i v e
t o w a r d s n u c l e o p h i l e s a n d is r e a d i l y h y d r o l y s e d to g i v e d i a l d e h y d e 9 . 9 . T h e s e
r e a c t i o n s a r e r e v e r s i b l e , a f a c t w h i c h h a s b e e n u s e d in a s y n t h e s i s of 9 . 1 f r o m
9 . 9 . A t l o w p H ( h i g h a c i d i t y ) t h e e q u i l i b r i u m lies t o t h e s i d e of t h e p y r y l i u m
s p e c i e s 9 . 1 b u t if t h e m e d i u m is b a s i f i e d t h e n h y d r o l y s i s of 9 . 1 o c c u r s t o
g i v e 9.9. T h i s is b e c a u s e o n e m o l e of h y d r o x i d e is c o n s u m e d o n g o i n g f r o m
p y r y l i u m cation 9.1 to n e u t r a l a l d e h y d e 9.9. Increasing t h e hydroxide
c o n c e n t r a t i o n t h e r e f o r e f o r c e s t h e e q u i l i b r i u m f r o m l e f t to right.

H,o.

-H,0 O
OH,
+ H©
9.1 9.9
\
T h e c a r b o n y l g r o u p s of 4 - p y r o n e In c o n t r a s t , 2 - a n d 4 - p y r o n e s a r e c o n s i d e r e d t o h a v e r e l a t i v e l y little
a n d 4 - p y r i d o n e a b s o r b at a r o m a t i c c h a r a c t e r . W h e r e a s in a n a n a l o g o u s n i t r o g e n series 4 - p y r i d o n e 5 . 2 3
approximately 1650 cm"1 and
has significant aromatic character (mesomeric representation 5.23a m a k i n g a
1 5 5 0 c m " 1 respectively. T h e
c o n s i d e r a b l e c o n t r i b u t i o n to the overall electronic distribution), a r o m a t i c
l o w e r e n e r g y of the p y r i d o n e
a b s o r p t i o n reflects greater single m e s o m e r i c r e p r e s e n t a t i o n 9 . 3 a m a k e s l e s s of a c o n t r i b u t i o n t o t h e o v e r a l l
bond character, and hence e l e c t r o n i c s t r u c t u r e of 4 - p y r o n e . A s w i t h f u r a n , t h e h i g h e r e l e c t r o n e g a t i v i t y
g r e a t e r delocalisation. of o x y g e n leads to h e t e r o c y c l e s of little a r o m a t i c i t y in c a s e s where
d e l o c a l i s a t i o n o f e l e c t r o n d e n s i t y f r o m t h e h e t e r o a t o m is a p r e r e q u i s i t e f o r
that a r o m a t i c i t y .

9.3 9.3a 5.23 5.23a

L e t u s n o w c o n s i d e r t h e s y n t h e s i s of a p y r y l i u m salt, a c o u m a r i n , a n d a
chromone.

9.2 Synthesis of a pyrylium salt

A t y p i c a l p y r i l i u m salt s y n t h e s i s is i l l u s t r a t e d b y t h e p r e p a r a t i o n of salt
9 . 1 2 . T h e p r e c u r s o r t o 9 . 1 2 is p y r a n 9 . 1 1 , a v a i l a b l e b y d e h y d r a t i o n of 1,5-
d i k e t o n e 9 . 1 0 . N o t e t h e s i m i l a r i t y of this s e q u e n c e to t h e H a n t z c h p y r i d i n e
s y n t h e s i s , C h a p t e r 5. A l s o , t h e d e h y d r a t i v e c y c l i s a t i o n of a d i k e t o n e to
o x y g e n h e t e r o c y c l e 9 . 1 1 is r e m i n i s c e n t of f u r a n s y n t h e s i s , C h a p t e r 2.

9.10 9.11 9.12 C10 4 °

 O n e h y d r o g e n a t o m h a s to b e r e m o v e d f r o m t h e C 4 p o s i t i o n of p y r a n 9 . 1 1 NM&j
t o p r o d u c e t h e p y r y l i u m c a t i o n , b u t it is i m p o r t a n t t o r e a l i s e t h a t the
h y d r o g e n a t o m is l o s t n o t as a p r o t o n b u t as a negatively-charged hydride
ion. T h e p r o c e s s is t h e r e f o r e a n oxidation of p y r a n 9 . 1 1 .

J
Ph Ph Ph Ph
9.13 9.14a 9.14b 9.15

A s u i t a b l e o x i d a n t is c a t i o n 9 . 1 4 a , b , d e r i v e d f r o m a , ( 3 - u n s a t u r a t e d k e t o n e
9 . 1 3 b y p r o t o n a t i o n u n d e r s t r o n g l y a c i d i c c o n d i t i o n s in t h e a b s e n c e of w a t e r .
Q u e n c h i n g o f this c a t i o n w i t h a h y d r i d e i o n ( f r o m t h e C 4 p o s i t i o n of 9 . 1 1 )
p r o d u c e s t h e saturated k e t o n e 9 . 1 5 . T h e b a l a n c e d e q u a t i o n is s h o w n b e l o w .

H H

HCIO,

Ph Ph
+ Ph Ph Ph
+ Ph
Most pyrylium salts have electron-
Ph O O, p h donating aromatic substituents at
CIO® the C2, C4, or C6 positions w h i c h
9.13 9.11 9.12 9.15 serve to stabilise the positive charge
by resonance.
9.3 Synthesis of coumarins
Let us consider the synthesis of b r o m o c o u m a r i n 9.16, a c o m p o u n d which
exhibits biological activity against parasitic trematodes that cause
s c h i s t o s o m i a s i s , a v e r y c o m m o n d i s e a s e in t h e t r o p i c s . Retrosynthetic
c l e a v a g e of l a c t o n e 9 . 1 6 g i v e s d i e s t e r 9 . 1 7 , w h i c h in p r i n c i p l e c a n b e d e r i v e d
f r o m c o n d e n s a t i o n of o / t / z o - h y d r o x y b e n z a l d e h y d e 9 . 1 8 a n d diethyl m a l o n a t e .

H
Br CO,Et C0 2 Et C0 2 Et

O-^O
C0 2 Et
^oct +r C0 2 Et

9.16 9.18
In p r a c t i s e a K n o e v e n a g e l c o n d e n s a t i o n r e a c t i o n y i e l d s c o u m a r i n 9 . 1 6
d i r e c t l y , w i t h o u t i s o l a t i o n of d i e s t e r 9 . 1 7 . T h e m e c h a n i s m is s h o w n b e l o w .

-o
Br
3 CO,Et
H e
OH
r C0 2 Et

Br CO,Et

9.16 9.17 H
 9.4 Synthesis of c h r o m o n e s
L e t u s c o n s i d e r t h e s y n t h e s i s of f l a v o n e 9 . 1 9 , w h i c h is t h e p a r e n t of a l a r g e
s e r i e s of n a t u r a l p r o d u c t s . D i s c o n n e c t i o n of t h e c a r b o n - o x y g e n b o n d in t h e
u s u a l w a y r e s u l t s in e n o l 9 . 2 0 w h i c h e x i s t s as 1 , 3 - d i k e t o n e 9 . 2 1 . T h i s 1,3-
d i c a r b o n y l r e l a t i o n s h i p c a n b e e x p l o i t e d in t h e c l a s s i c a l m a n n e r y i e l d i n g
<?7-//zo-hydroxyacetophenone 9.22. The synthetic problem centres on
m e t h o d o l o g y f o r t h e C - b e n z o y l a t i o n of t h e e n o l a t e d e r i v e d f r o m 9 . 2 2 w i t h
s o m e a c t i v a t e d b e n z o i c acid d e r i v a t i v e 9.23.
O o O

OH
+ O ^ P h
9.23
o OH
"Ph OH "Ph O •Ph OH
9.19 9.20 9.21 9.22 X = Leaving group
In practice, the Konstanecki-Robinson synthesis of chromones
c o m m e n c e s w i t h O - b e n z o y l a t i o n n o t C - b e n z o y l a t i o n , to a f f o r d e s t e r 9 . 2 4 .
B a s e - c a t a l y s e d r e a r r a n g e m e n t p r o d u c e s t h e r e q u i r e d 1 , 3 - d i k e t o n e 9 . 2 1 , via
i n t r a m o l e c ul a r b e n z o y l a t i o n of the intermediate enolate. Acid-catalysed
d e h y d r a t i o n t h e n a f f o r d s f l a v o n e 9.19.

O O o
Ph
A CI l.KOH AC0H/H 2 S0 4

Pyridine 2. AcOH OH
OH O "Ph
9. 22 9.24 Ph 9.21

9.5 Reactions with nucleophiles

A l t h o u g h s o m e e x a m p l e s of e l e c t r o p h i l i c s u b s t i t u t i o n a r e k n o w n , t h e
chemistry o f t h e s e s e r i e s is d o m i n a t e d b y n u c l e o p h i l i c ring-opening
r e a c t i o n s , s o m e t i m e s f o l l o w e d b y r i n g - c l o s u r e to g i v e n e w h e t e r o c y c l e s . F o r
i n s t a n c e , a m i n o l y s i s of 9.1, 9 . 2 , a n d 9 . 3 l e a d s to p y r i d i n e 5 . 1 a n d p y r i d o n e s
5.22 a n d 5.23.
NH,
H,0
N
5.1

NH,

H,0 N
5.22

NH,

H,0
 T h e m e c h a n i s m of t h e c o n v e r s i o n of 4 - p y r o n e to 4 - p y r i d o n e i n v o l v e s a n
initial M i c h a e l r e a c t i o n f o l l o w e d b y r i n g - o p e n i n g . T a u t o m e r i s a t i o n of e n o l
9 . 2 5 to a l d e h y d e 9 . 2 6 , f o l l o w e d b y c y c l i s a t i o n , a f f o r d s 4 - p y r i d o n e 5 . 2 3 .

9.25

9.26
5.23

T h e r e a c t i o n of p y r i l i u m salts w i t h n u c l e o p h i l e s m a y i n v o l v e e l e c t r o c y c l i c
r i n g - o p e n i n g of t h e i n t e r m e d i a t e d i e n e s , as in t h e f o r m a t i o n o f k e t o n e 9 . 2 7 .

Clo4

A s i m i l a r s u s c e p t i b i l i t y to n u c l e o p h i l i c a t t a c k is o b s e r v e d in t h e b e n z o -
f u s e d s e r i e s . C o u m a r i n 9 . 5 is h y d r o l y s e d b y h y d r o x i d e to c a r b o x y l a t e salt
9.28. T h i s p r o c e s s is r e v e r s i b l e , a n d a c i d i f i c a t i o n r e g e n e r a t e s t h e l a c t o n e .

NaOH

HCl o 0 - o
H e a
9.5 9.28 Na

A n i m p o r t a n t d i f f e r e n c e b e t w e e n t h e m o n o c y c l i c a n d b e n z o - f u s e d series is
t h a t r e a c t i o n s w i t h a m i n e s d o n o t l e a d t o t h e c o r r e s p o n d i n g h e t e r o c y c l e s in
t h e b e n z o - f u s e d s e r i e s . F o r i n s t a n c e , a m i n o l y s i s of c h r o m o n e 9 . 2 9 a f f o r d s
p h e n o l 9 . 3 0 . B e n z o p y r i d o n e 9 . 3 2 is n o t p r o d u c e d . T h e f a c i l e t a u t o m e r i s a t i o n P h e n o l s d o not exist or react in
b e t w e e n 9 . 2 5 a n d 9 . 2 6 w o u l d a n a l o g o u s l y g i v e k e t o n e 9 . 3 1 in this s e r i e s . their t a u t o m e r i c keto forms.
T h i s h i g h - e n e r g y i n t e r m e d i a t e is n o t a r o m a t i c , a n d t h e r e a c t i o n s t o p s at
phenol 9.30.
O O
NH,

O NH,
9.30
9.29
9.6 Problems
1. W h a t is t h e m e c h a n i s m of the c o n v e r s i o n of p y r o n e 9 . 2 to p y r i d o n e 5 . 2 2
by aminolysis?

NH,

^N o
H
9.2 5.22

2. E x p l a i n the f o r m a t i o n of p y r a z o l e 9.33.

H,N— NH,

OH
9.6 9.33

3. H o w c a n c h r o m o n e 9 . 3 4 b e c o n v e r t e d to 9.35?
o o
9 NMe2

OMe 9.34 OMe 9.35

4. W h a t is the m e c h a n i s m of this c y c l i s a t i o n ?

o o

AcOH

OH^/^ph
L Jl
"O Ph
9.21 9.19

9.7 References
Horing, E.C. et al. ( 1 9 5 5 ) . Organic synthesis, Coll. Vol. Ill, 165
( e x p e r i m e n t a l details of a K n o e v e n a g e l c o n d e n s a t i o n to g i v e a c o u m a r i n
ester).
L i v i n g s t o n e , R . ( 1 9 7 7 ) . In R o d d ' s Chemistry of carbon compounds, Vol.
I V , p . 2 ( p y r i l i u m salts; 2- a n d 4 - p y r o n e s ) ; p . 6 9 ( b e n z o p y r i l i u m salts); p . 9 6
( c o u m a r i n s ) ; p . 1 3 8 ( c h r o m o n e s ) . Elsevier, A m s t e r d a m .
S t a u n t o n , J. ( 1 9 7 9 ) . I n Heterocyclic chemistry (ed. P . G . S a m m e s ) ( V o l . 4
of Comprehensive organic chemistry, e d . D . B a r t o n a n d W . D . Ollis), p . 6 0 7
(pyrilium salts); p . 6 2 9 (2-pyrones and coumarins); p . 6 5 9 (4-pyrones
a n d c h r o m o n e s ) . P e r g a m o n Press, O x f o r d .
W h e e l e r , T . S . ( 1 9 6 3 ) . Organic synthesis, Coll. V o l . IV, 4 7 9 ( e x p e r i m e n t a l
details f o r the p r e p a r a t i o n of f l a v o n e ) .
 10. Pyrimidines

10.1 Introduction
F o r m a l r e p l a c e m e n t of a C H unit in p y r i d i n e 5.1 by a nitrogen a t o m leads to
the series of three p o s s i b l e diazines, p y r i d a z i n e 10.1, p y r i m i d i n e 10.2, and
p y r a z i n e 10.3. Like p y r i d i n e they are fully a r o m a t i c heterocycles. T h e e f f e c t
of an a d d i t i o n a l n i t r o g e n a t o m as c o m p a r e d to p y r i d i n e a c c e n t u a t e s t h e
essential f e a t u r e s of pyridine chemistry. Electrophilic substitution is difficult
in s i m p l e u n a c t i v a t e d diazines b e c a u s e of b o t h e x t e n s i v e p r o t o n a t i o n u n d e r
strongly acidic conditions and the inherent lack of reactivity of the f r e e base.
Nucleophilic displacements are comparatively easier.
4 4 V 4 4
5 R^^I 3 5 ,-C^N 3 5

n;
N 2 6 L^. J ) 2 6 o :n,
: 0 n'J

10.1 10.2 10.3 5.1

Interestingly, the second electronegative heteroatom reduces the capacity of
t h e d i a z i n e s to t o l e r a t e t h e p o s i t i v e c h a r g e r e s u l t i n g f r o m p r o t o n a t i o n .
P y r i d a z i n e 10.1 ( p ^ a = 2.24), p y r i m i d i n e 10.2 ( p K a = 1.23), and p y r a z i n e
10.3 ( p ^ a = 0.51) are all far less basic than pyridine ( p ^ a = 5.23).
T h e m o s t i m p o r t a n t of t h e d i a z i n e s is p y r i m i d i n e 1 0 . 2 . P y r i m i d i n e
derivatives uracil 10.4, t h y m i d i n e 10.5, and cytosine 10.6 are the m o n o c y c l i c
'bases' of nucleic acids. T h e bicyclic bases are the p u r i n e s a d e n i n e 10.7 and
g u a n i n e 10.8. T h e p u r i n e ring is essentially a f u s i o n of the p y r i m i d i n e and
imidazole rings.

O O NH2 NH2 O

H
H H H
10.4 10.5 10.6 10.7 10.8

Nucleotides are the monomeric

building blocks of
deoxyribonucleic acid (DNA) in
T h e actual b i o s y n t h e s i s of p u r i n e s (illustrated b e l o w in a b b r e v i a t e d f o r m which is stored the genetic
for the nucleotide adenosine m o n o p h o s p h a t e A M P 1 0 . 9 ) involves information of the cell.
construction of a pyrimidine ring onto a p r e - f o r m e d imidazole.
 ~nh2

"NH,

T h e e n z y m e s that m a n i p u l a t e n u c l e o t i d e s , n u c l e i c acids, etc. a r e t h e p o i n t s

of t h e r a p e u t i c i n t e r v e n t i o n f o r a n u m b e r of d i s e a s e s i n v o l v i n g cell r e p l i c a t i o n
NH
d i s o r d e r s s u c h as c a n c e r s a n d v i r a l i n f e c t i o n s . F o r i n s t a n c e , A Z T 1 0 . 1 0 , a n
HO— | ^ N - ^ O i n h i b i t o r of t h e e n z y m e r e v e r s e t r a n s c r i p t a s e , is a n anti-viral d r u g c u r r e n t l y
u s e d in t h e t r e a t m e n t of A I D S .
W e s h a l l n o w g o o n to c o n s i d e r t h e s y n t h e s i s a n d c h e m i s t r y of t h e
N3 10.10 pyrimidine ring system.

10.2 Synthesis of pyrimidines

D i s c o n n e c t i o n of t h e N 1 - C 6 b o n d in g e n e r a l i s e d p y r i m i d i n e 1 0 . 1 1 in t h e
u s u a l w a y p r o d u c e s e n o l 1 0 . 1 2 , w h i c h e x i s t s as k e t o n e 1 0 . 1 3 . Similarly,
disconnection of t h e c a r b o n - n i t r o g e n d o u b l e b o n d in 1 0 . 1 3 y i e l d s a
dicarbonyl compound 1 0 . 1 4 a n d an a m i d i n e 1 0 . 1 5 . T h i s retrosynthetic
a n a l y s i s , s u g g e s t i n g t h e c o m b i n a t i o n of b i s - e l e c t r o p h i l i c a n d b i s - n u c l e o p h i l i c
c o m p o n e n t s , is t h e b a s i s of a v e r y g e n e r a l p y r i m i d i n e s y n t h e s i s .
R3 R3

R i ^ o h h n ^ R 4 H N ^ I

10.11 10.12 10.13

W h e r e R 4 is a h y d r o g e n o r c a r b o n a t o m , 1 0 . 1 5 is s i m p l y a n a m i d i n e .
NH 2 H o w e v e r , u r e a 1 0 . 1 6 , t h i o u r e a 1 0 . 1 7 , o r g u a n i d i n e 1 0 . 1 8 a n d their d e r i v a t i v e s
m a y be used. T h e s e nucleophiles m a y be condensed with ester and nitrile
f u n c t i o n a l i t i e s as w e l l as w i t h a l d e h y d e s a n d k e t o n e s . S u c h c o n d e n s a t i o n s t o
a f f o r d p y r i d i m i d i n e d e r i v a t i v e s are usually facilitated b y a c i d or b a s e catalysis,
NH2 a l t h o u g h c e r t a i n c o m b i n a t i o n s of r e a c t i v e e l e c t r o p h i l i c a n d n u c l e o p h i l i c
H s 1017 c o m p o u n d s r e q u i r e n o c a t a l y s t at all. S o m e e x a m p l e s a r e s h o w n b e l o w .

NH 2
c
L f o NH 2 HCl
H2N"^NH 10.18 L + L EtOH
^ H,N 0 Heat
 H OEt

•epared by in situ hydrolysis of [ OEt

H ^ O E t
OEt

N o t e that s e v e r a l of t h e s e e x a m p l e s p r o d u c e p y r i m i d o n e s , a n a l o g o u s to t h e
p y r i d o n e s p r e v i o u s l y e n c o u n t e r e d in C h a p t e r 5. A r e p r e s e n t a t i v e m e c h a n i s m
is s h o w n f o r t h e p r e p a r a t i o n o f 2 - p y r i m i d o n e 1 0 . 1 9 , a n d is s i m p l y t w o
consecutive condensations.
 10.3 Electrophilic substitution of pyrimidones
A s m e n t i o n e d earlier, e l e c t r o p h i l i c s u b s t i t u t i o n o n u n a c t i v a t e d p y r i m i d i n e s is
of little i m p o r t a n c e . B u t , as w i t h p y r i d i n e , t h e p y r i m i d i n e n u c l e u s c a n b e
a c t i v a t e d t o w a r d s e l e c t r o p h i l i c a t t a c k b y e m p l o y i n g N - o x i d e s or p y r i m i d o n e s ,
f o r t h e s a m e r e a s o n s as w e r e d i s c u s s e d in C h a p t e r 5.
F o r i n s t a n c e , n i t r a t i o n of 2 - p y r i m i d o n e 1 0 . 2 0 a f f o r d s n i t r o p y r i m i d o n e
1 0 . 2 1 . W i t h d o u b l y - a c t i v a t e d s y s t e m s s u c h as 1 0 . 2 2 , n i t r a t i o n to g i v e 1 0 . 2 3
can occur without heating.

O
NO- NO. A
HNO 3 HNO, V NH
Cl Heat T l Cz
H H H H
10.20 10.21 10.22 10.23

10.4 Nucleophilic substitution of pyrimidines

L e a v i n g g r o u p s at t h e C 2 , C 4 , a n d C 6 p o s i t i o n s of p y r i m i d i n e s c a n b e
displaced by nucleophiles, with the negative charge of the intermediate
delocalised over both nitrogen atoms.

ac Y <t-
N J x
,e

X = Nucleophile
N X

Y = Leaving group
PhNH,

N Cl NPh
H
Na © ©OMe

N Cl OMe

Chlorinated pyrimidines themselves are often accessible f r o m the

corresponding pyrimidones by reaction with phosphorus oxychloride.
( A g a i n , s e e C h a p t e r 5 f o r a n e x p l a n a t i o n o f t h i s s o r t of r e a c t i o n . ) F o r
i n s t a n c e , a m i n o p y r i m i d i n e 1 0 . 2 4 c a n b e s y n t h e s i s e d b y the c l a s s i c a l s e q u e n c e
depicted b e l o w .

OEt

HN
10.5 Problems
1. W r i t e a m e c h a n i s m f o r this n i t r a t i o n , b u t s t a r t i n g f r o m an a l t e r n a t i v e
m e s o m e r i c r e p r e s e n t a t i o n of 1 0 . 2 0 t h a t h e l p s to e x p l a i n the i n c r e a s e d
susceptibility of such p y r i m i d o n e s to electrophilic attack.

N
N HNQ3 ^ °2-vj^N
Heat
N ^ O ^ N ^ O
H H

10.20 10.21

2. B a r b i t u r a t e s ( p y r i m i d i n e t r i o n e s such as 1 0 . 2 5 ) used to b e w i d e l y u s e d as
s e d a t i v e s , but h a v e n o w largely b e e n s u p e r s e d e d by d r u g s with f e w e r side-
e f f e c t s . S u g g e s t a synthesis of 10.25.

O ^ N ^ O
H
10.25

3. T h e r e are several p r e p a r a t i o n s of c y t o s i n e 1 0 . 6 available, o n e of w h i c h is

the c o n d e n s a t i o n of nitrile 1 0 . 2 6 with u r e a 10.16. P r o p o s e a m e c h a n i s m f o r
this reaction.

NH-
CN
NH
2 HCL
OEt I 1
H \ ,T X T x t s - n H , 0 / EtOH
OEt H2N O

10.26 10.16

10.6 References
Brown, D.J. ( 1 9 6 2 ) . In The pyrimidines (The chemistry of heterocyclic
compounds [ed. A . W e i s s b u r g e r a n d E . C . T a y l o r ] , V o l . 16). W i l e y
Interscience, N e w York.
Brown, D.J. (1970). In The pyrimidines (The chemistry of heterocyclic
compounds (ed. A . W e i s s b u r g e r a n d E . C . T a y l o r ] , V o l . 16, S u p p l e m e n t s 1
a n d 2). W i l e y Interscience, N e w Y o r k .
F u r n i s s , B . S . , H a n n a f o r d , A.J., S m i t h , P . W . G . , a n d T a t c h e l l , A . R . (1989).
Vogel's textbook of practical organic chemistry (5th e d n ) , p . 1 1 7 7
(preparation of barbiturate 10.25). L o n g m a n , H a r l o w .
H u r s t , D . T . ( 1 9 8 0 ) . An introduction to the chemistry and biochemistry of
pyrimidines, purines, and pteridines. Wiley, New York.
 11. Answers to problems

11.1 Answers to problems in Chapter 2

Note that the reaction p r o c e e d s 1. R e a c t i o n of d i k e t o n e 2 . 4 6 w i t h a m i n o k e t o n e 2 . 4 7 p r o d u c e s e n a m i n e 2 . 4 8
with attack of the a m i n o g r o u p o n
w h i c h is n o t i s o l a t e d , b u t c y c l i s e s directly to g i v e p y r r o l e 2 . 4 3 .
t h e least h i n d e r e d k e t o n e .
O

MeN
o
MeN
4-
H9N -h2O
H
2.46 2.47

2. T h e l o n e p a i r of e l e c t r o n s of 2 . 4 4 is d e l o c a l i s e d on to t h e c a r b o n y l g r o u p
as s h o w n , i n c r e a s i n g t h e e l e c t r o n d e n s i t y at t h e a l d e h y d i c c a r b o n a t o m . T h i s
r e n d e r s it less r e a c t i v e to n u c l e o p h i l i c attack.

e
N FFIN
H H H H
2.44

U n d e r a c i d i c c o n d i t i o n s a l c o h o l 2 . 4 5 r e a d i l y g i v e s c a t i o n 2 . 4 9 a , b w h i c h is
s t a b i l i s e d b y a s i m i l a r d e l o c a l i s a t i o n of t h e n i t r o g e n l o n e p a i r .

-H,0
H
OH" OH7 fn kx]

H
2.45 2.49a 2.49b
T h i s h i g h l y e l e c t r o p h i l i c s p e c i e s t h e n r e a c t s w i t h a l c o h o l 2 . 4 5 to g i v e d i m e r
2 . 5 0 . R e p e t i t i o n of this p r o c e s s l e a d s t o p o l y m e r i c m a t e r i a l .

OH OH- polymer
N' "N
H ® H
2.45 2.50

3. A s d i s c u s s e d in C h a p t e r 2 , i n t e r c e p t i o n of c a t i o n 2 . 3 1 w i t h a n u c l e o p h i l i c
counterion such as acetate p r o d u c e s the 2,5-addition product 2.32.
T e t r a f l u o r o b o r a t e is a n o n - n u c l e o p h i l i c c o u n t e r i o n a n d h e n c e t h e only
p a t h w a y a v a i l a b l e to 2 . 3 1 is loss of a p r o t o n to g i v e n i t r o f u r a n 2 . 3 3 d i r e c t l y .
 0
Direct loss of H
4. T h e m e c h a n i s m is a straightforward F r i e d e l - C r a f t s acylation.

11.2 Answers to problems in Chapter 3

1. A p p l i c a t i o n of o u r g e n e r a l i s e d o x a z o l e r e t r o s y n t h e s i s leads to a simple
glycine derivative.
H

T h e f o r w a r d synthesis is s h o w n b e l o w :
ur

2. T h e m e c h a n i s m of this o x a z o l e f o r m a t i o n is identical to that of the

H a n t z c h thiazole synthesis. H o w e v e r , b e c a u s e of the reduced nucleophilicity
of a c a r b o n y l g r o u p as c o m p a r e d to a t h i o c a r b o n y l ( d u e to t h e h i g h e r
e l e c t r o n e g a t i v i t y of o x y g e n ) , this s y n t h e s i s only p r o c e e d s u n d e r v i g o r o u s
conditions (high temperatures, a m i d e c o m p o n e n t as solvent, etc).

T h e alternative s e q u e n c e w o u l d g i v e a positional isomer of oxazole 3.44.

 3. B r o m i n a t i o n o f 3 . 4 5 g i v e s a b r o m o k e t o n e w h i c h is c o n d e n s e d with
t h i o u r e a to g i v e a m i n o t h i a z o l e e s t e r 3 . 4 7 . T h i s is t h e n h y d r o l y s e d to a c i d
3.46.

CO,R
CO,Et
Br,
MeO. MeO
"N
NH,
3.45 3.46 R = H

K e t o n e 3 . 4 5 i t s e l f is r e a d i l y p r e p a r e d b y n i t r o s a t i o n of e t h y l a c e t o a c e t a t e
followed by O-methylation.

CO,Et C0 2 Et C0 2 Et
0 = N-0C,H,
McI
. HO. ^ MeO, O
1> N
AcOH K,CO,
3.45

11.3 Answers to problems in Chapter 4

1. T h e r e a c t i o n is a M i c h a e l a d d i t i o n f o l l o w e d b y e l i m i n a t i o n of c y a n i d e i o n .

H
0
3©x
\ „ NTH
H
c K J
e s NH 2 NH, CN NH
N ; C— S ~swJ " S
I -
CN rA."7 CN 4.39
R

2. T h e o v e r a l l s t r a t e g y is to p r o t e c t t h e n i t r o g e n of p y r a z o l e (as an a c e t a l ) ,
d e p r o t o n a t e , i n t r o d u c e t h e side c h a i n as an e l e c t r o p h i l e , then d e p r o t e c t .

HC(OMe)3
N N "BuLV Li® © < N
N N
N"
H
.C-OMe
H .C-OMe
OMe OMe

oh jn.N HC1/H 2 0 OH
// \\ P- LAr2CO
„N 2.NH4CI / H 2 0
4.40 N'
Ar Ar f j At
Ar '
„ . C-OMe
H \
OMe
3. O x i d a t i o n o f o x i m e 4 . 4 1 p r o d u c e s n i t r i l e o x i d e 4 . 4 6 w h i c h c y c l i s e s to
isoxazole 4.47.

N®0 )
HO, NaOCl V [3+2]
^N
NaOH

4.41 4.46 4.47

4. R e a c t i o n w i t h h y d r o x y l a m i n e o c c u r s o n t h e a l d e h y d e g r o u p of t h e m o r e
reactive minor tautomer 4.43 affording isoxazole 4.44. Methoxide-induced
f r a g m e n t a t i o n as s h o w n g i v e s e n o l a t e 4 . 4 8 w h i c h is q u e n c h e d b y a p r o t o n in
t h e w o r k u p to a f f o r d 2 - c y a n o c y c l o h e x a n o n e 4.45.
 4.45 4.48

11.4 A n s w e r s to problems in Chapter 5

1. T h e p r o c e s s is e s s e n t i a l l y a n a l o g o u s to a M i c h a e l r e a c t i o n .

CO,Et

CO,Et

I ^ ^
CO,Et
© i e
COoEt (— OEt) CO,Et

2. A r e a s o n a b l e m e c h a n i s m is:-

H
H. -H
1
-H
Ac,0 U Zc.
N

- Ac,0

O J ^ HOAc O

3. P y r i d y l a m i d e 5 . 3 9 is e a s i l y m e t a l l a t e d at t h e C 3 p o s i t i o n . Q u e n c h i n g
w i t h t h e a l d e h y d e , a n d c y c l i s a t i o n of t h e r e s u l t i n g a l c o h o l 5 . 4 2 o n t o t h e
a m i d e group, produces lactone 5.40.
4. T h e r e a c t i o n p r o b a b l y p r o c e e d s via enaminoester formation then
cyclisation.
Fo

'C

In f a c t n u c l e o p h i l i c substitution of p y r i d i n e N - o x i d e s o c c u r s m o r e easily
t h a n o n s i m p l e p y r i d i n e s , as the nitrogen a t o m is positively c h a r g e d .

11.5 A n s w e r s to problems in Chapter 6

1. T h e q u i n o l o n e s y n t h e s i s i n v o l v e s an a d d i t i o n - e l i m i n a t i o n reaction
f o l l o w e d b y an intramolecular aromatic acylation.
T h e d i s p l a c e m e n t reaction occurs b y initial nucleophilic attack on the
benzenoid ring (with the negative charge being delocalised onto the oxygen
a t o m as s h o w n ) t h e n e l i m i n a t i o n of c h l o r i d e i o n . T h e p r e s e n c e of t h e f l u o r i n e
s u b s t i t u e n t is e s s e n t i a l f o r t h i s d i s p l a c e m e n t , a c t i v a t i n g t h e r i n g t o w a r d s
n u c l e o p h i l i c attack b y its e l e c t r o n - w i t h d r a w i n g i n d u c t i v e e f f e c t .

CO 2 H

2 . ' S t e p 1. C o n d e n s a t i o n o f t h e a l d e h y d e w i t h n i t r o m e t h a n e u n d e r b a s i c
conditions produces the a,(3-unsaturated nitro c o m p o u n d .

Ar £
O OH

H H
foil

H
_NO2 ^
Ar
„ NO,

'CH,NO,
OH

Step 2. L i t h i u m a l u m i n i u m h y d r i d e w a s u s e d , a l t h o u g h h y d r o g e n a t i o n c a n
a l s o e f f e c t this t y p e of r e d u c t i o n .
LiAIH4
NO, NH,
Ar' H,/Pd° Ar

Step 3. A c y l a t i o n of t h e a m i n e w i t h a n a c i d c h l o r i d e in t h e p r e s e n c e o f a n
appropriate base gave the amide.

RCH2COCl
NH,
Ar Ar
NEt,
O

Step 4. T h i s i s o q u i n o l i n e f o r m a t i o n is of c o u r s e a n e x a m p l e of t h e B i s c h l e r -
Napieralski synthesis, although p h o s p h o r u s trichloride was actually u s e d in
this e x a m p l e , n o t p h o s p h o r u s o x y c h l o r i d e .

Step 5. S o d i u m b o r o h y d r i d e w a s u s e d t o r e d u c e t h e i m i n e to t h e a m i n e .
H
R,.
r R2
^NR3 NaBH,
R^NR

H R2
3

Step 6. T h e c a t e c h o l i c a n d p h e n o l i c e t h e r s w e r e r e m o v e d b y t r e a t m e n t w i t h
h y d r o b r o m i c a c i d . B e n z y l e t h e r s a r e f r e q u e n t l y r e m o v e d b y r e d u c t i o n (e.g.
h y d r o g e n a t i o n ) b u t r e d u c t i o n , of c o u r s e , w o u l d n o t r e m o v e t h e m e t h y l e t h e r .
T h e m e c h a n i s m of t h e d e p r o t e c t i o n is s h o w n b e l o w .
R

OH
H ^©Br
11.6 A n s w e r s to problems in Chapter 7
1. I n d o l e 7 . 3 8 w a s p r e p a r e d b y a F i s c h e r i n d o l e synthesis f o l l o w e d b y N-
alkylation as s h o w n .

3. A s i n t e n d e d , C 2 c a r b a n i o n 7 . 4 7 a t t a c k e d t h e nitrile g i v i n g 7 . 4 8 , w h i c h
u n e x p e c t e d l y a t t a c k e d the a d j a c e n t s u l p h o n y l g r o u p g i v i n g indolyl a n i o n
7 . 4 9 . D u r i n g t h e a c i d i c a q u e o u s w o r k u p this a n i o n is q u e n c h e d a n d the
r e a c t i v e N - s u l p h o n y l i m i n e f u n c t i o n a l i t y is r e a d i l y h y d r o l y s e d a f f o r d i n g

7.45 FH

11.7 A n s w e r s to problems in Chapter 8

1. S u l p h u r ylid 8 . 3 6 is the k e y i n t e r m e d i a t e in the f o r m a t i o n of e p o x i d e
8.34. E p o x i d e 8 . 3 4 is r a c e m i c but alcohol 8 . 3 5 is achiral.
O O
c, H NaH p.
U
H
CH3-S(CH3)2 > CH2-S(CH3)2 Coreysylid
© (-H2) e
8.36
2. T h i s o x a d i a z o l e f o r m a t i o n i n v o l v e s O - a c y l a t i o n of the amidoxime
followed by a condensation.

r o N-
ETO-HA-N. R NH, " / \\
-H2O N
OMe -> HO O
8.21 NH, M
O-N
8.22

11.8 Answers to Problems in Chapter 9

1. T h e m e c h a n i s m is s i m i l a r to t h e 4 - p y r o n e e x a m p l e .

-H2O
- > o V ^
OH/^O
HH2N - O HO N O "N O
NH 2 H H
9.2 NH 3
2. T h e f i r s t s t a g e is t h e s a m e as t h e p r e p a r a t i o n of 9 . 3 0 , t h e n c y c l i s a t i o n 5.22
a f f o r d s the p y r a z o l e . H N

9.33
OH
3. T h i s is a M a n n i c h r e a c t i o n ( s e e C h a p t e r 2 ) a n d is a n u n u s u a l e x a m p l e of
an electrophilic substitution on a chromone.
O FF, O o
, CH 2 =NMe 2
J" ^• • NMe,

9.34 OMe OMe OMe 9.35

4. T h e r e a c t i o n is a s t r a i g h t f o r w a r d a c i d - c a t a l y s e d c o n d e n s a t i o n , p a s s i n g
t h r o u g h c a r b o n i u m ion 9 . 3 6 a , b .
O O

OH P£ °

-H

O Ph
9.19 9.36b
11.9 A n s w e r s to problems in Chapter 10
1. T h e o v e r a l l e l e c t r o n i c d i s t r i b u t i o n of 2 - p y r i m i d o n e h a s a c o n s i d e r a b l e
contribution f r o m m e s o m e r 1 0 . 2 0 a .

10.20 10.20a

T h e m e c h a n i s m of nitration is s h o w n b e l o w .

2. D i s c o n n e c t i o n of b a r b i t u r a t e 1 0 . 2 5 p r o d u c e s b i s - e l e c t r o p h i l e 1 0 . 2 7 and
urea. In practice m a l o n a t e ester 1 0 . 2 8 (X = O E t ) is used.

3. H y d r o l y s i s of acetal 10.26 leads to reactive aldehyde 10.29 in situ.

C o n d e n s a t i o n of a l d e h y d e 1 0 . 2 9 with u r e a f o l l o w e d b y cyclisation o n t o t h e
nitrile p r o d u c e s cytosine 10.6. O b s e r v e h o w cyclisation o n t o a nitrile a f f o r d s
the a m i n o f u n c t i o n a l i t y directly, as c o m p a r e d with the three step s e q u e n c e
u s e d in t h e synthesis of 1 0 . 2 4 w h e r e an ester is used in the cyclisation step.
 Index

a-effect 29 electrophilic substitution of oxazoles 26

acetyl nitrate 15 furan 14 pyridines 40
acid chlorides 6 imidazole 24 pyrimidines 76
a-aminoketone 13 indole 57 quinolines 49
ammonia 5 isoquinoline 49 thiazoles 26
AMP, biosynthesis of 74 isothiazole 32
anion chemistry of isoxazole 32 ornithine 64
furan 17 oxazole 24 ortho-activating substituents 43
imidazole 25 pyrazole 32 oxadiazoles 61
indole 59 pyridine 37 oxazoles 20
isoquinoline 50 pyridine N-oxide 38 oxazolidinones 8
isothiazole 32 pyridones 39
isoxazole 32 pyrimidones 76 Paal-Knorr synthesis (pyrrole,
pyrazole 32 pyrrole 14 thiophene, furan) 12
pyridine 42 quinoline 49 phosphorus oxychloride 15, 47
pyrrole 17 thiazole 24 phosphorus sulphide 12
quinoline 50 thiophene 14 Pictet-Spengler synthesis
thiazole 25 (isoquinoline) 48
anthocyanins 67 Fischer synthesis (indole) 54 pyrazole 28
aryl hydrazines 54 flavone 70 purine 73
1.2 azoles 28 furan 10 pyridine 35
1.3 azoles 20 pyridine N-oxide 38
A Z T 74 Gould-Jacobson synthesis pyridine sulphur trioxide complex 15,
(quinolone) 51 35
barbiturates 77 pyridones 39
benzene 2 Hantzsch pyridine synthesis 36 pyridontriazine 41
benzopyrilium cation 67 Hantzsch thiazole synthesis 23 pyrylium cation 67
bioisosteric replacement 63 heteroaromaticity 1 pyrimidines 73
Bischler-Napieralski synthesis histamine 20 pyrones 67
(isoquioline) 48 hydrazine 29 pyrrole 10
hydrogen sulphide 12
Chichibabin reaction 40 hydroxylamine 29 Quinoline 46
chlorophyll 11 5-hydroxytryptamine 54
chromone 67 resonance 2
Claison rearrangement 55 imidazole 20 retrosynthesis 4
condensation 3 imidoyl halide 22 Robinson-Gabriel synthesis
Cope rearrangement 55 indole 53 (oxazole) 21
coumarin 67 isoquinoline 46
cytosine 73 isothiazole 28 Skraup synthesis (quinoline) 46
isoxazole 28 synthesis of
delocalisation 3 chromones 70
delphinidin chloricje 67 Khellin 67 coumarins 69
dihydropyridines 37 Knorr synthesis (pyrrole) 14 furans 11
disconnection 4 Konstanecki-Robinson synthesis heterocycles, principles of 3-8
D N A 73 (chromone) 70 imidazoles 22
drugs for the treatment of indoles 54
A I D S 74 Leimgruber synthesis (indole) 56 isoquinolines 46
asthma 31 lysergic acid 54 isothiazoles 29
bacterial infection 27 oxadiazoles 62
depression 60 Mannich reaction 16,58 oxazoles 21
fungal infection 41, 66 pyrazoles 29
inflammation 22 neurotransmitters 54 pyridines 35
schizophrenia 18 nitrile oxides 30 pyrylium salt 68
senile dementia 45,63 nucleic acids 73 pyrimidines 74
sleep disorders 77 nucleophilic substitution of pyrroles 11
trematode infection 69 imidazoles 26 quinolines 46
ulcers 1,11 isoquinolines 49 tetrazoles 64