Fundamentals of Medicinal Chemistry

Table 10.3 Examples of most useful disconnections and reconnection systems. The compounds used for

the reconnection reactions are those normally associated with the synthons for the disconnection. These

reactions are not the only reactions that could be used for the reconnection. Source:Organic Synthesis, the

Disconnection Approach, S Warren, Wiley. 1982

Disconnections Examples of reconnection reactions

Functional group disconnections:

Ether:

For methyl ethers use dimethyl sulphate instead of R^2 I

Amide:

Note: The acid anhydride will give the same compound but by a less vigorous reaction.

Ester:

Note: The acid anhydride will give the same compound but by a less vigorous reaction.

Lactone:

R^1 −O−R^2 +

+

R^2

R^1 NH COR^2 +R^2 − C+

O

Na

R^1 −OH R^1 −− O−− R^2

R^2 −I

Source of the

electrophile

All types

of amines

Suitable acid

derivatives

R^1 NH 2 +R^2 COCl R^1 NH COR^2

Source of the

nucleophile

Source of the

electrophile

R^1 C+ + R^2 O−

O

R^1 CO OR^2 R^1 COCl + R^2 OH R^1 CO-OR^2

Source of the

nucleophile

Source of the

All types of electrophile

alcohol and phenol

Suitable acid

derivatives

OH

COOH H

+ O

CO

Source of both the nucleophile

and electrophile

O

CO

+C

O−

O

Source of the

nucleophile

R^1 −− O−

R^1 −− O− Na+

R^1 −−NH

Carbon–carbon disconnections:

Carbanion–electrophile disconnections:Disconnection should normally occur adjacent to an electron

withdrawing group. In each case, one of the compounds derived from the synthon should be able to form a

carbanion whilst the structure of other should contain an electrophilic centre. Reconnection is by means of

a suitable carbanion substitution or condensation reaction.

218 AN INTRODUCTION TO LEAD AND ANALOGUE SYNTHESES