Decarboxylative thiolation of redox-active esters to free thiols and further diversification

Abstract

Thiols are important precursors for the synthesis of a variety of pharmaceutically important sulfur-containing compounds. In view of the versatile reactivity of free thiols, here we report the development of a visible light-mediated direct decarboxylative thiolation reaction of alkyl redox-active esters to free thiols based on the abundant carboxylic acid feedstock. This transformation is applicable to various carboxylic acids, including primary, secondary, and tertiary acids as well as natural products and drugs, forging a general and facile access to free thiols with diverse structures. Moreover, the direct access to free thiols affords an advantage of rapid in situ diversification with high efficiency to other important thiol derivatives such as sulfide, disulfide, thiocyanide, thioselenide, etc.

Single Electron Transfer-Induced Redox Processes Involving N-(Acyloxy)phthalimides

“…Very recently, Liao developed a visible-light-mediated Eosin Y−Na 2 -catalyzed direct decarboxylative thiolation of primary, secondary, and tertiary alkyl-NHPI esters 1 using aryl thioamide 173 as the effective sulfur donor to afford corresponding free thiols 174 in moderate to good yields (Scheme 76b). 139 Pleasingly, an in situ diversification approach allowed rapid conversion of thusgenerated alkyl thiols to pharmaceutically relevant sulfides, disulfides, thioselenides, and thiocyanides through trapping with various electrophiles or Michael acceptors. Furthermore, the Liao group also developed a method for thioesterification of aliphatic NHPI esters 1 by merging Ru photoredox catalysis with copper catalysis (Scheme 77).…”

“…The latter gets dimerized to the corresponding diaryl disulfide and subsequently reacts with the alkyl radical to furnish the corresponding product 172 . Very recently, Liao developed a visible-light-mediated Eosin Y–Na 2 -catalyzed direct decarbox­ylative thiolation of primary, secondary, and tertiary alkyl-NHPI esters 1 using aryl thioamide 173 as the effective sulfur donor to afford corresponding free thiols 174 in moderate to good yields (Scheme b) . Pleasingly, an in situ diversification approach allowed rapid conversion of thus-generated alkyl thiols to pharmaceutically relevant sulfides, disulfides, thio­selenides, and thio­cyanides through trapping with various electrophiles or Michael acceptors.…”

Photocatalytic C(sp3) radical generationviaC–H, C–C, and C–X bond cleavage

“…One recent photocatalytic example was Liao's report of decarboxylative thiolation of N-(acyloxy)phthalimides utilizing Na 2 -eosin Y in the presence of sulfur donor and amine reductant (Scheme 23B). 93 Mindful of the sensitivity of thiol products toward oxidative conditions, reductive generation of Rc from photocatalytic decarboxylation could effectively avoid the undesired sulfur oxidation. Under the photoreduction conditions, RAE underwent a SET/ fragmentation sequence to release CO 2 and phthalimide, giving the Rc to be thiolated subsequently.…”

Synthesis of Sulfur-Containing Analogues of Hedychenone, a Labdane Diterpenoid from Hedychium spicatum

“…Semisynthesis, the method of preparing new bioactive compounds via the modification of metabolites isolated from natural sources, is very much useful nowadays in the drug discovery process. , Diverse studies have been accomplished on the carbon – sulfur (C–S) bond formations that hold a prominent position in the race for the synthesis of valuable chemical entities because organosulfur compounds are widely present in nature and various biological systems. , Different classes of sulfur-containing synthetic drugs and bioactive natural products received considerable attention owing to their numerous biological and pharmaceutical applications. − For instance, all of the 10 top selling drugs worldwide in 2012 were organosulfur compounds . To date, significant progress has been achieved for the construction of new C–S bonds, mainly involving addition, substitution, radical thiolation, and sulfenylation strategies. ,− Most of these methods involve the metal-catalyzed C–S bond formation. However, the use of expensive and toxic metal catalysts and harmful reaction conditions limit the scope of these methodologies.…”