Synthesis of a γ-Lactam Library via Formal Cycloaddition of Imines and Substituted Succinic Anhydrides

Formal cycloaddition reactions between imines and cyclic
anhydrides
serve as starting point for the synthesis of diverse libraries of
small molecules. The synthesis of succinic anhydrides substituted
with electron-withdrawing groups is facilitated by new mild conditions
for alkylation of aryl-substituted acetyl esters with ethyl bromoacetate.
These anhydrides are then used in formal cycloaddition reactions with
imines to produce γ-lactams. 2-Fluoro-5-nitrophenylsuccinic anhydride
reacts efficiently with imines to provide lactams that are
further diversified by conversion of the nitro group to either an
aniline and an azide for subsequent reactions with acylating agents
and alkynes, respectively. The synthesis of cyanosuccinic anhydride
is reported for the first time, and the use of this compound in reactions
with imines and subsequent functionalization of the resultant lactams
is demonstrated.