those that give rise to either a stable species or occur by a feasible disconnection
mechanism, such as hydrolysis, because the latter are more likely to have a
corresponding reconnection reaction. At each stage in the disconnection, the
synthons are used as a guide to selecting a corresponding real reagent that could
be used in a reconversion synthesis. These reasgents are often compounds that
possess the relevant electrophilic or nucleophilic reaction centres. For example, a
carbanion synthon with the structure RCH 2 could correspond to a Grignard
reagent RCH 2 MgBr. Similarly, an electrophilic synthon R
þCO could correspond
to an acid halide RCOC1 or ester RCOOR’.
The basics of the technique of disconnection is illustrated by considering the
synthesis of the local anaesthetic benzocaine. The most appropriate disconnec-
tions are the ester and amine groups. At this point it is amatter of experienceas
to which disassembly route is followed. The normal approach is to pick the
synthons that give rise to reagents that can most easily be reformed into the
product. Consequently, in this case the ester disconnection would appear to be
the most profitable pathway, as ester formation is relatively easy, but it is
notpossible to directly introduce a nucleophilic amino group into a benzene
ring.
H 2 N H 2 NH 2 NC COOC 2 H 5OOC 2 H 5
H 2 N−
+Key:
Indicates the real compound (derived from the
synthon) that is used in the reconnection reaction.C+O+ C 2 H 5 O−CO+ C 2 H 5 OHOHBenzocaine+4-Aminobenzoic acid=Ethanol is a readily available starting material but 4-aminobenzoic acid is not.
Therefore, the next step is to consider the disconnection of the amino and
carboxylic acid groups of 4-aminobenzoic acid. However, there are no simple
inexpensive reactions for the reconnection of these groups. Consequently, the
next step has to be afunctional group interconversion(FGI). Disconnection arrows
are usually used for FGIs but as no synthons are involved it is customary to use
real structures in the relationships. FGIs are found by searching the literature for
suitable reactions. This search, in the case of the current example, reveals that
aromatic carboxylic acids may be produced by the oxidation of anaromatic
methyl group whilst an aromatic amine may be produced by reduction of
the corresponding nitro group. Since amino groups are sensitive to oxidation
the disconnection via functional group interconversion follows the order.
216 AN INTRODUCTION TO LEAD AND ANALOGUE SYNTHESES