CF₂Br₂ as a Source for Difluoroolefination of 1,3-Enynes via N-Heterocyclic Carbene Catalysis

Abstract

Commercially available CF 2 Br 2 has been used as a convenient source for the rapid and reliable incorporation of the gem-difluorovinyl motif into an allene framework via an Nheterocyclic carbene catalyzed difluoroolefination of 1,3-enynes. The reaction proceeds through a cascade three-component radical relay/elimination process. This protocol is distinguished by its mild conditions, readily accessible starting materials, wide substrate scope, and ease of late-stage functionalization, thus unlocking an untraditional strategy to construct a new class of functionalized gem-difluorovinyl allenes.O rganic backbones bearing the terminal gem-difluorovinyl (CF 2 �C) moiety are frequently found in the field of pharmaceuticals, agrochemicals, functional materials, and life science (Scheme 1a). 1 In particular, gem-difluoroalkenes are regarded as the ideal carbonyl bioisostere, mimicking the reactivity and property of the carbonyl group to improve bioactivity, metabolic stability, and target specificity in drug design. 2 Moreover, gem-difluoroalkenes are valuable building blocks in synthetic chemistry because they can be conveniently converted into diversely fluorinated compounds. 3 Likewise, the allene motif represents a privileged structure in numerous natural products and pharmacological agents. Given the importance of both gem-difluoroalkenes and allenes, the combination of these two scaffolds in one molecule seems to be a promising "hybrid pharmacophore" strategy in drug discovery. However, to the best of our knowledge, there is no approach to synthesize gem-difluorovinyl allenes.In recent years, great efforts have been devoted to developing new methods for the synthesis of functionalized gem-difluoroalkenes. 4 Traditional methods mainly focus on three different strategies (Scheme 1b): (1) difluoroolefination of alkyl halides, carbonyl, or diazo compounds; 5 (2) transitionmetal (TM)-catalyzed cross-coupling reaction of gem-difluorovinyl tosylate; 6 (3) defluorinative functionalization of αtrifluoromethyl alkenes 7 typically through defluorinative nucleophilic substitution, 8 TM-catalyzed defluorinative coupling reaction, 9 and photoredox-catalyzed or electrochemically promoted radical addition. 5g,10 Despite the impressive progress, the development of simple and more environmental benign metal-free methods for the synthesis of structurally diverse gem-difluoroalkenes from readily accessible starting materials is still in high demand. In this context, the pursuit of

Remote Radical 1,3-, 1,4-, 1,5-, 1,6- and 1,7-Difunctionalization Reactions

“…The final allenyl ketone products 33 are generated from M-77 after elimination of NHC. Recently, Du et al, applied a similar reaction for making gem -difluorovinylcarbonylated allenes 34 ( Scheme 33 ) [ 67 ]. The Huang and Yang groups also reported this kind of reactions for the synthesis of 1,4-alkylcarbonylated allenes 35 ( Scheme 34 ) [ 68 , 69 ].…”

Facile access to gem-difluorocyclopropanes via an N-heterocyclic carbene-catalyzed radical relay/cyclization strategy

“…Therefore, the combination of the Breslow enolate intermediate with redox potential matched radical precursors could give birth to the NHC-bound ketyl radicals and other active radicals like the alkyl radical simultaneously via the SET process. Following this strategy, NHC-bound ketyl radicals have been successfully applied in the alkylation-acylation of unsaturated compounds like alkenes [47][48][49][50][51][52][53][54][55] and 1,3-enynes [56][57][58][59] in the presence of various suitable alkyl radical precursors, thus allowing a facile construction of complex carbonyl-containing molecules. Given the promising compatibility of Breslow enolate intermediates with alkyl radical precursors in the SET-involved process [47][48][49][50][51][52][53][54][55]57,[60][61][62] and the importance of developing more general synthetic approaches to gem-difluorocyclopropanes, we recognized an opportunity to exploit a cascade radical-relay/cyclization mode for the difluorocyclopropanation of alkenes via NHC-catalysis using commercially available CF 2 Br 2 as a convenient difluoromethylating source (Scheme 1c).…”

Visible light-mediated NHC and photoredox co-catalyzed 1,2-sulfonylacylation of allenesviaacyl and allyl radical cross-coupling

“…N-heterocyclic carbenes (NHCs) 9 could stabilize acyl radicals 10 and open a new avenue for single-electron-transfer (SET)-mediated radical acylation chemistry. 11 Since the pioneering works of Studer 12 and Ohmiya, 13 a elegant progress has been achieved in NHC-involved cross-couplings of ketyl radicals with O-centered radicals, 12 alkyl radicals, 13–18 and highly active allene radicals 19 by employing aldehydes or derivatives of carboxylic acid (Scheme 1b). The attachment of NHCs could modulate the stability of transient acyl radicals to persistent ones, which may offer the opportunity for radical acylation of allyl radicals.…”