One-pot sequential synthesis of tetrasubstituted thiophenes via sulfur ylide-like intermediates

Abstract

Herein, we describe a novel approach for the practical synthesis of tetrasubstituted thiophenes 8. The developed method was particularly used for the facile preparation of thienyl heterocycles 8. The mechanism for this reaction is based on the formation of a sulfur ylide-like intermediate. It was clearly suggested by (i) the intramolecular cyclization of ketene N,S-acetals 7 to the corresponding thiophenes 8, (ii) ¹H NMR studies of Meldrum's acid-substituted aminothioacetals 9, and (iii) substitution studies of the methoxy group on Meldrum's acid containing N,S-acetals 9b. Notably, in terms of structural effects on the reactivity and stability of sulfur ylide-like intermediates, 2-pyridyl substituted compound 7a exhibited superior properties over those of others.

Keywords: 5-(heterocyclic)thiophenes; one-pot sequential synthesis; sulfur ylide; tetrasubstituted thiophene.

Figure 1

The selected examples of sulfur(IV) and sulfur(VI) ylides 1 [1], 2 [–7], 3 [–79], 4 [–12], 5 [–34], 6 [–38].

Figure 2

Metal-free synthesis of thiophene-based heterocycles (A) [–55], (B) [56].

Scheme 1

One-pot sequential synthesis of the trisubstituted 5-(pyridine-2-yl)thiophenes 8a. Substrate: ^amalonitrile; ^b5,5-dimethylcyclohexane-1,3-dione.

Figure 3

X-ray crystal structures of 8ad and 8an [68].

Figure 4

The proposed structure of sulfur ylide-like intermediates; resonance contributors (mesomeric structures) [–7278].

Scheme 2

The substitution reaction with MeOH.