Scope and Limitations of Xanthate-Mediated Synthesis of Functional γ-Thiolactones

Abstract

A modular platform based on free-radical xanthate addition to alkenes enables access to a large series of functional γ-thiolactones. This methodology includes two different pathways based on xanthate chemistry involving radical addition and Chugaev elimination steps. The first method uses the addition of an ester-functionalized xanthate to various commercially functional alkenes, whereas the second one is based on the addition of functional xanthates to an ester-functionalized alkene. In both cases, a series of xanthate/alkene monoadducts was obtained, and their thermolysis and subsequent cyclization led to a library of functional γ-thiolactones in moderate to good yield. For a few cases where it may not be possible to directly incorporate some targeted functional groups via the proposed process involving free radicals and high temperature, a bromo-functionalized thiolactone was used as a starting material for chemical transformations.

Radical‐Mediated Approaches for the Synthesis of Thiolactones

“…In 2018 Destarac and co‐workers reported a highly modular approach based on a radical peroxide‐mediated xanthate addition to alkenes which enables access to a range of functionalized γ‐thiolactones, in a related approach to that employed by Zard and co‐workers ( vide supra ), employing an ester as a pendent electrophile for thiol addition in place of a nitrile (Scheme 2). [23] This methodology includes two different reaction pathways based on xanthate chemistry involving radical addition, however the crux of this methodology which allows for the preparation of the thiolactone core is Chugaev elimination to liberate a free thiol which condenses onto the ester. The initial step in each reaction sequence is the bromide displacement from an alklyl bromide with a readily available potassium xanthate salt 8 to introduce the xanthate moiety.…”

5‐exo versus 6‐endo Thiyl‐Radical Cyclizations in Organic Synthesis

“…Thiolactones have proven highly valuable in synthesis and biology . The synthesis of thiolactones has been an area of interest for synthetic chemists for well over a century, with attention being reinvigorated recently . Unlike their homologues, lactones, the strategies that have thus far been developed for the synthesis of thiolactones are somewhat limited and underexamined .…”

“…[70,71] The synthesis of thiolactones has been an area of interest for synthetic chemists for well over a century, with attention being reinvigorated recently. [72][73][74][75][76] Unlike their homologues, lactones, the strategies that have thus far been developed for the synthesis of thiolactones are somewhat limited and underexamined. [72] The majority of methods reported for the synthesis of thiolactones involve the use of a lactone as starting material.…”

The reaction of potassium xanthates with five-membered cyclic carbonates: selectivity of the underlying cascade reactions and mechanistic insights

“…6 The latter methodology has been further expanded by Zard to include not only primary, tertiary and a,a-triuoromethylaminyl radicals [7][8][9] but also to demonstrate some novel radical cascade reactions of xanthates. 10,11 The synthesis of various functional compounds, including g-thiolactones, [12][13][14] pyridine alkaloid xestamines, 15 thiopyranones, 16 thiophenes, 17 dichloroketones, 18 etc., based on free-radical xanthate addition to alkenes has been described in numerous recent works by Zard and Destarac.…”