Direct Synthesis of Unsymmetrical Dithioacetals

Abstract

Dithioacetals are a frequently used motif in synthetic organic chemistry and have recently seen increasing attention as structural motif in promising antiviral agents against plant pathogens. Most existing reports, however, only discuss symmetrical dithioacetals. Examples of mixed dithioacetals are scarce and no general method for the selective synthesis of these compounds exists. Herein, a synthetically simple general one‐step protocol was developed for the synthesis of a broad range of unsymmetrical dithioacetals consisting of one aromatic and one aliphatic thiol moiety from the corresponding aldehyde/thiol mixture. The mixed S,S‐acetals were obtained in high yields, and a great variety of functional groups was tolerated. Kinetic control enabled an excellent selectivity in regard to the unsymmetrical dithioacetal.

Sulfur in Dynamic Covalent Chemistry

“…The van Gemmeren group used dithioacetal formation and exchange under kinetic control to develop a general protocol for the direct synthesis of unsymmetrical dithioacetals based on one aromatic and one aliphatic thiol moiety [129] . High selectivity led to high yields of mixed dithioacetals, which, in addition to tolerance to a wide range of functional groups, makes this a valuable strategy to prepare unsymmetrical dithioacetals.…”

A Modular Olefination of Aldehydes with Thiols as Coupling Partners

“…However, no general method for the selective formation of such mixed compounds existed at the outset of our studies, prompting us to develop a kinetically controlled protocol for the selective formation of mixed dithioacetals (Scheme 2b), which can then be converted to the respective bissulfones. [19] Overall, our approach relies on the formation of a mixed dithioacetal 5', its oxidation to an unsymmetric bissulfone 3', and a Ramberg-Bäcklund-type olefin formation. Importantly, due to the kinetically controlled dithioacetal formation a strong selectivity for the mixed bissulfone (3') is observed.…”

“…We hypothesized that a protocol using equimolar amounts of both reaction partners might be enabled by the formation of mixed dithioacetals ( 5’ ) and bissulfones ( 3’ ), in which the role of each thiol, either as part of the product or the leaving group, would be defined by using one aromatic and one aliphatic thiol. However, no general method for the selective formation of such mixed compounds existed at the outset of our studies, prompting us to develop a kinetically controlled protocol for the selective formation of mixed dithioacetals (Scheme 2b), which can then be converted to the respective bissulfones [19] …”

Chemoselective Synthesis of Unsymmetrical Dithioacetals through Sequential Carbene Insertion and Acetal Exchange of Acylsilanes and Thiols under Visible Light Irradiation

“…However, these protocols have been demonstrated only for a limited number of examples with varying reaction conditions. Reacting an aldehyde with two different thiols with differing reactivities in one step has been developed as a synthetically simple general protocol for unsymmetrical dithioacetals synthesis (Scheme B, (ii)) . However, this protocol remained limited to dithioacetals composed of aliphatic thiols and aromatic or electron-poor nitrogen-containing heteroaromatic thiols.…”