Copper-catalyzed enantioselective Sonogashira-type oxidative cross-coupling of unactivated C(sp3)−H bonds with alkynes

Abstract

Transition metal-catalyzed enantioselective Sonogashira-type oxidative C(sp3)—C(sp) coupling of unactivated C(sp3)−H bonds with terminal alkynes has remained a prominent challenge. The difficulties mainly stem from the regiocontrol in unactivated C(sp3)—H bond functionalization and the inhibition of readily occurring Glaser homocoupling of terminal alkynes. Here, we report a copper/chiral cinchona alkaloid-based N,N,P-ligand catalyst for asymmetric oxidative cross-coupling of unactivated C(sp3)—H bonds with terminal alkynes in a highly regio-, chemo-, and enantioselective manner. The use of N-fluoroamide as a mild oxidant is essential to site-selectively generate alkyl radical species while efficiently avoiding Glaser homocoupling. This reaction accommodates a range of (hetero)aryl and alkyl alkynes; (hetero)benzylic and propargylic C(sp3)−H bonds are all applicable. This process allows expedient access to chiral alkynyl amides/aldehydes. More importantly, it also provides a versatile tool for the construction of chiral C(sp3)—C(sp), C(sp3)—C(sp2), and C(sp3)—C(sp3) bonds when allied with follow-up transformations.

Catalytic enantioselective C(sp3)–H functionalization involving radical intermediates

“…At the same time, Liu's group has also found mildly oxidative N-fluoroamide is well compatible with their Cu(I)/ cinchona alkaloid-derived N,N,P-ligand catalyst 16 (Fig. 6d) [72][73][74][75][76][77] , which readily reduces N-fluoroamide to amidyl radicals for highly regioselective intramolecular 1,5-HAA under ambient conditions 78 . Accordingly, highly regioselective and enantioselective benzylic C(sp 3 )-H alkynylation is achieved with terminal alkynes, of which the undesired Glaser homocoupling is efficiently suppressed.…”

Copper-Catalyzed Benzylic C–H Bond Thiocyanation: Enabling Late-Stage Diversifications

“…20 Apparent constraints must be overcome to expand the utility of these methods, such as using large excess of C-H substrates and restricted functional group diversity. [21][22][23][24][25] Recently, our group [26][27][28][29][30][31] and others [32][33][34][35][36][37] have developed a copper-catalyzed radical relay strategy for selective benzylic C(sp 3 )-H bond functionalization with N-F reagents (e.g., N-fluorobenzenesulfonimide [NFSI]) as oxidant that features high site selectivity and uses C-H substrates as limiting reagents (Scheme 1b). Many functional groups have been incorporated by varying the nucleophiles, highlighting the efficacy of this approach.…”

Asymmetric benzylic C(sp3)−H acylation via dual nickel and photoredox catalysis

“…Despite that initial progress 38 , no examples of enantioselective benzylic C−H acylation have been reported. In addition, there is an increasing demand for the development of benzylic C−H functionalization reactions for the synthesis of high value-added molecules from simple alkylarenes 39 – 50 . In this work, we report an enantioselective benzylic C−H acylation of alkylarenes with in situ-activated carboxylic acids enabled by nickel and photoredox dual catalysis (Fig.…”