Thiazolylcyanocyclopropanes: Novel Donor-Acceptor Cyclopropanes for Accessing Thiazole-Containing Targets

Abstract

Donor-acceptor (D-A) cyclopropanes are important precursors in the synthesis of complex molecules due to their bidentate character and high reactivity. Among them, cyclopropane-1,1-dicarbonitriles are less commonly reported in modern literature, primarily because of the high reactivity of the nitrile groups and their limited compatibility with metal-catalyzed processes, which is caused by the geometrical constraints imposed by the linear cyano substituents. While the cyano groups can be seen as a limitation, they also offer synthetic versatility by serving as handles for further functionalization. In this work, we performed a cycloaddition reaction with mercaptoacetaldehyde, leading to a new class of DA cyclopropanes bearing a thiazole moiety. This one-pot, two-step transformation requires only a single purification step. The resulting thiazolyl-substituted cyclopropanes were subjected to ring strain-release reactions, showing reactivity comparable to the parent cyclopropane-1,1-dicarbonitriles.

Keywords: cycloaddition; donor–acceptor cyclopropanes; phase-transfer catalysis; ring-strain release; thiazoles.

Scheme 1

Zwitterionic relationship and reactivity of D–A cyclopropanes.

Scheme 2

Representative transformations of donor–acceptor cyclopropanes leading to sulfur-containing compounds. Refs. [35,36,37,38,39,40,41,42,43,44,45].

Scheme 3

Formation of 2-mercaptoacetaldehyde 2m from 1,4-dithiane-2,5-diol 2.

Scheme 4

D–A cyclopropanes reactions with mercaptoacetaldehyde reported in the literature: (a) Ref. [47]; (b) Ref. [48]; (c) Refs. [49,50]; (d) Ref. [51]; (e) Ref. [52]. * = Asymmetic center.

Scheme 5

Divergent reactivity of cyclopropane-1,1-dicarbonitriles 1 with thioacetic acid.

Scheme 6

Reaction of cyclopropane-1,1-dicarbonitrile 1a with 1,4-dithiane-2,5-diol 2.

Scheme 7

Optimized conditions for the one-pot reaction.

Scheme 8

Reduction of the nitrile group of 5a.

Scheme 9

Reaction scope (isolated yields, dr determined by ¹H NMR on the crude reaction mixture, structure of the major trans product).

Scheme 10

Plausible mechanism for the one-pot procedure: synthesis of hydroxythiazolines 4 (step 1) and their subsequent dehydration to thiazolyl derivatives 5 (step 2).

Scheme 11

Structure modification of thiazolyl-substituted D–A cyclopropanes 5: (a) dichlorination; (b) reductive ring opening; (c) arylation.

Scheme 12

Synthesis of D–A cyclopropanes 1a–1r.