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.