Cycloaddition of 4-Acyl-1 H-pyrrole-2,3-diones Fused at [ e]-Side and Cyanamides: Divergent Approach to 4 H-1,3-Oxazines

Abstract

4-Acyl-1H-pyrrole-2,3-diones fused at [e]-side with a heterocyclic moiety are suitable platforms for the development of a hetero-Diels-Alder-reaction-based, diversity-oriented approaches to series of skeletally diverse heterocycles. These platforms are known to react as oxa-dienes with dienophiles to form angular 6/6/5/6-tetracyclic alkaloid-like heterocycles and are also prone to decarbonylation at high temperatures resulting in generation of acyl(imidoyl)ketenes, bidentate aza- and oxa-dienes, which can react with dienophiles to form skeletally diverse products (angular tricyclic products or heterocyclic ensembles). Based on these features, we have developed an approach to two series of skeletally diverse 4H-1,3-oxazines (tetracyclic alkaloid-like 4H-1,3-oxazines and 5-heteryl-4H-1,3-oxazines) via a hetero-Diels-Alder reaction of 4-acyl-1H-pyrrole-2,3-diones fused at [e]-side with cyanamides. The products of these transformations are of interest for drug discovery, since compounds bearing 4H-1,3-oxazine moiety are extensively studied for inhibitory activities against anticancer targets.

Keywords: 4H-1,3-oxazine; acyl(quinoxalin-2-yl)ketene; cyanamide; cycloaddition; hetero-Diels–Alder reaction; heterocumulene; thermolysis.

Figure 1

4H-1,3-Oxazine based inhibitors and their 4H-pyran analogs.

Scheme 1

Modes of participation of FPDs 1 as heterodienes in HDA.

Scheme 2

Plausible pathway of formation of compounds 4 and G.