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

Jun Ki Kim,Hwan Jung Lim,Kyung Chae Jeong,Seong Jun Park

doi:10.3762/bjoc.14.16

Jun Ki Kim, Hwan Jung Lim + Show 2 more

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https://doi.org/10.3762/bjoc.14.16

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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.

Highlights

As part of our ongoing efforts to discover small molecule modulators of protein–protein interactions (PPIs), we are interested in coplanar compounds that mimic β-strand side-chain distributions [39,40,41,42,43]
We are fascinated with thienyl–pyridyl ring systems [43] and have explored facile synthetic procedures to facilitate their production
We have shown that sulfur ylide-like intermediates 7, which are converted into the desired thiophenes 8, can be generated in situ by S-alkylation of the intermediate thiolate salts

Summary

Introduction

Since the discovery of stable sulfonium ylides 1 in 1930 [1] and the pioneering work of several research groups during the 1960s (2 and 3) [2,3,4,5,6,7,8,9], these carbene precursors have been played an important role in organic chemistry [10,11,12,13,14,15,16,17,18,19,20,21,22]. The stability of sulfonium ylides is determined by the electron delocalization of the carbanionic center and the substituents on the sulfur atom [10]. These reagents are often applied in the preparation of simple small rings [13], such as epoxides [1418], cyclopropanes [19,20,21,22], aziridines [23], indoles [24], pyrroles [24], and indolines [25]. Shen and co-workers reported the use of trifluoromethyl-substituted sulfonium ylide 5 in elec-. We investigated the synthesis of thienylpyridines using a metal-free approach

Results and Discussion

Conclusion

23. Recent literature