Substituent-Dependent Divergent Synthesis of 2-(3-Amino-2,4-dicyanophenyl)pyrroles, Pyrrolyldienols and 3-Amino-1-acylethylidene-2-cyanopyrrolizines via Reaction of Acylethynylpyrroles with Malononitrile

Abstract

An efficient method for the synthesis of pharmaceutically and high-tech prospective 2-(3-amino-2,4-dicyanophenyl)pyrroles (in up to 88% yield) via the reaction of easily available substituted acylethynylpyrroles with malononitrile has been developed. The reaction proceeds in the KOH/MeCN system at 0 °C for 2 h. In the case of 2-acylethynylpyrroles without substituents in the pyrrole ring, the reaction changes direction: instead of the target 2-(3-amino-2,4-dicyanophenyl)pyrroles, the unexpected formation of pyrrolyldienols and products of their intramolecular cyclization, 3-amino-1-acylethylidene-2-cyanopyrrolizines, is observed.

Keywords: 2-(3-amino-2,4-dicyanophenyl)pyrroles; 3-amino-1-acylethylidene-2-cyanopyrrolizines; acylethynylpyrroles; malononitrile; pyrrolyldienols.

Figure 1

Biologically active and high-tech 2,6-dicyanoaniline derivatives.

Scheme 1

Methods for the synthesis of 3,5-disubstituted 2,4-dicyanoanilines with heterocyclic substituents: previous works. The reaction of 2-arylidenemalononitrile with 2-(1-arylethylidene)malononitrile (a). The reaction of ethylenic ketones with malononitrile (b). The reaction of cyclization of acetylenic ketones with malononitrile (c).

Scheme 2

Synthesis of 2-acylethynylpyrroles 1a–p.

Scheme 3

Reaction of acylethynylpyrroles 1n–p with malononitrile in the KOH/MeCN system.

Scheme 4

Synthesis of pyrrolizine 6a by intramolecular cyclization of enol 4a.

Figure 2

Main NOESY () and HMBC () correlations for pyrolizine 6c.

Scheme 5

Possible scheme of formation of 2-(3-amino-2,4-dicyanophenyl)pyrroles 3 from 2-acylethynylpyrroles 1 and malononitrile 2.

Scheme 6

The resonance forms of the deprotonated monoadducts.