Amide-directed photoredox-catalysed C-C bond formation at unactivated sp3 C-H bonds

Abstract

Carbon-carbon (C-C) bond formation is paramount in the synthesis of biologically relevant molecules, modern synthetic materials and commodity chemicals such as fuels and lubricants. Traditionally, the presence of a functional group is required at the site of C-C bond formation. Strategies that allow C-C bond formation at inert carbon-hydrogen (C-H) bonds enable access to molecules that would otherwise be inaccessible and the development of more efficient syntheses of complex molecules. Here we report a method for the formation of C-C bonds by directed cleavage of traditionally non-reactive C-H bonds and their subsequent coupling with readily available alkenes. Our methodology allows for amide-directed selective C-C bond formation at unactivated sp³ C-H bonds in molecules that contain many such bonds that are seemingly indistinguishable. Selectivity arises through a relayed photoredox-catalysed oxidation of a nitrogen-hydrogen bond. We anticipate that our findings will serve as a starting point for functionalization at inert C-H bonds through a strategy involving hydrogen-atom transfer.

Figure 1

Selectivity issues with C-H bond functionalization. a, Unactivated sp³ C-H bonds are similar in electronics and sterics, making them non-trivial to differentiate. b, Our proposed 1,5-hydrogen atom transfer strategy to cleave an unactivated C-H bond with a heteroatom radical. c, Proposed photocatalytic cycle for carbon-carbon bond formation at unactivated C-H bonds. Deprotonation of an acidified N-H bond and in situ oxidation delivers the nitrogen radical with subsequent HAT and functionalization occurring. Upon trapping, the resultant radical is reduced and protonated closing the catalytic cycle and delivering product. EWG: electron-withdrawing group; FG: functional group; HAT: hydrogen atom transfer; SET: single electron transfer.

Figure 2

Photoredox catalyzed C-C bond formation at unactivated sp³ C-H bonds. a, Trifluoroacetamide as the directing group for C-H functionalization. b, Scope of C-C bond formation with respect to the alkene. c, Scope of C-C bond formation with respect to the amine. Solvent is benzotrifluoride unless otherwise indicated. Bn: benzyl; Bu: butyl; dr: diastereomeric ratio; Et: ethyl; Me: methyl; rac: racemic; tBu: tert-butyl; TBS: tert-butyldimethylsilyl; Boc: tert-butyloxycarbonyl; Ph: phenyl; DMF: dimethylformamide; tAmOH: tert-amyl alcohol; dF-CF₃ppy: 2-(2,4-difluorophenyl)-5-trifluoromethylpyridine; dtbbpy: 4,4′-di-tert-butyl-2,2′-bipyridine.

Figure 3

Regioselective functionalization of sp³ C-H Bonds. a, The presence of a remote tertiary C-H bond does not affect the outcome of the reaction; good selectivity is obtained even with potential competition between 1,5 and 1,6 hydrogen atom transfer. b, Applications to medicinally relevant molecules. Bn: benzyl; Me: methyl; tBu: tert-butyl; TBS: tert-butyldimethylsilyl; tAmOH: tert-amyl alcohol; Ph: phenyl.