Sequential Selective C−H and C(sp³)−⁺P Bond Functionalizations: An Entry to Bioactive Arylated Scaffolds

Abstract

Organophosphonium salts containing C(sp 3 ) À + P bonds are among the most utilized reagents in organic synthesis for constructing CÀCd ouble bonds.H owever,t heir use as C-selective electrophilic groups is rare.Here,weexplore an efficient and general transition-metal-free method for sequential chemo-and regioselective C À Ha nd C(sp 3 ) À + P bond functionalizations.I nt he present study,C À Ha lkylation resulting in the synthesis of benzhydryl triarylphosphonium salts was achieved by one-pot, four-component cross-coupling reactions of simple and commercially available starting materials.T he utility of the resulting phosphonium salt building blocks was demonstrated by the chemoselective post-functionalization of benzylic C(sp 3 ) À + PPh 3 groups to achieve aminations,t hiolations,a nd arylations.I nt his way, benzhydrylamines,benzhydrylthioethers,and triarylmethanes, structural motifs that are present in many pharmaceuticals and agrochemicals,a re readily accessed. These include the synthesis of two anticancer agents from simple materials in only two to three steps.A dditionally,aprotocol for late-stage functionalization of bioactive drugs has been developed using benzhydrylphosphonium salts.T his new approach should providenovel transformations for application in both academic and pharmaceutical research.

DMSO-Promoted Difluoroalkylation of Organophosphonium Salts with Difluoroenol Silyl Ethers

“…Mayr’s photogeneration of benzhydryl carbocations from benzhydryl triarylphosphonium salts 1 demonstrated the feasibility of the heterolysis of the C­(sp 3 )–P bond (Scheme C, a) . Very recently, the resulting benzylic electrophilic cation derived from phosphonium salt was first applied in the chemoselective amination, thiolation, and arylation with various N -/ S -/ C -nucleophiles (Scheme C, b) . Encouraged by these findings and as a continuation of our research interests in organofluorine chemistry and organophosphorus chemistry, we decided to test whether the difluoroalkylation strategy could be combined with C–P bond functionalization using di­(hetero)­arylmethyl triarylphosphonium salts and DFESEs under solvent-mediated conditions without external transition-metal catalysts and sensitive additives, which would provide an alternative chance to rapidly access β,β-di­(hetero)­aryl-α,α-difluorinated ketones (Scheme D) …”

Unified synthesis of multiply arylated alkanes by catalytic deoxygenative transformation of diarylketones

“…Shu and coworkers discovered a nickel-catalyzed direct cross-coupling of benzylic alcohols with aryl triflates in the presence of DMO (dimethyl oxalate) to afford the corresponding diarylmethanes. 22 Masarwa and coworkers reported a unique synthetic method of triarylmethanes from aldehydes: 23 an aldehyde was mixed with an arene and triphenylphosphine in the presence of TfOH to generate a diarylphosphonium salt, followed by another arene in one pot to furnish the corresponding triarylmethane. This simple operation allowed for a one-pot synthesis of triarylmethanes from aldehydes, but this method is limited to the use of electron-rich arenes.…”

Photoredox‐Mediated Deoxygenative Radical Additions of Aromatic Acids to Vinyl Boronic Esters and gem‐Diborylalkenes**

“…[2] In this regard, the advancement of the photoredox‐mediated chemistry of carbocylic acids ( 1 ) has had an enormous impact on enabling new chemical reactions and has extended the scope of accessible molecular scaffolds (Figure 1 A and B). [ 2a , 2g , 2h , 2i , 3 ] These reactions are particularly attractive because, owing to the wide availability of carboxylic acids in natural products, for example, bioactive compounds [4] and drug molecules. [ 3f , 5 ] Moreover, these visible‐light transformations of carboxylic acids can be used as late‐stage transformations for building new libraries of these important compounds under mild reaction conditions.…”