An approach to direct and catalyzed alkylation reaction: Synthesis of N-acyl-1,3-thiazinane-2-thiones and N-acyl-1,3-thiazolidine-2-thiones

Abstract

Stereoselective construction of carbon-carbon bonds is the key step in the synthesis of natural products with biological activity. Therefore, the reactions involving metal enolates, capable of reacting with a wide range of electrophiles to generate new C-C bonds, occupy a preeminent position in organic synthesis. Thus, in last decades, stereoselective methodologies have been developed that use metal enolates in alkylation, aldol and Michael reactions. In most synthetic approaches, stereochemical control has gone through substrate control or the use of chiral auxiliaries. However, in both methodologies, the reactions take place in stages -first the enolization and then the reaction with the electrophile- and stoichiometric amounts of metal are always required. In this context, the emergence of asymmetric catalysis has paved the way for direct and catalytic reactions using chiral metal complexes to generate enolates. However, very few of these complexes can promote the selective enolization of an activated carboxylic acid derivative and provide a suitable environment for reacting enantioselectively with electrophiles. In recent years, our group has developed a new methodology in which chiral complexes of Ni(II) are used to catalyze direct and enantioselective alkylation reactions of N-acyl-1,3-thiazinane-2-thiones with electrophiles. Initially, the formation of a single stereocenter was studied, using electrophiles activate with TESOTf to generate oxocarbenium cations and also stable carbocations. The asymmetric formation of two chiral centers is currently being evaluated by direct catalytic reactions with acetals and aldehydes, in both cases activated with a Lewis acid. In this context, this project aims to obtain 1,3-thiazinane-2-thione on a large scale and to carry out a wide range of acylation reactions with this platform and also with 1,3-thiazolidin-2-thione, to prepare different N-acylthiomides, which may be used in the above-mentioned reactions. Finally, a first assay of a direct alkylation reaction was also performed with a commercial and aquiral nickel catalyst and methyl orthoformate activated with TESOTf as an electrophile