The direct arylation of allylic sp(3) C-H bonds via organic and photoredox catalysis

Abstract

The direct functionalization of unactivated sp(3) C-H bonds is still one of the most challenging problems facing synthetic organic chemists. The appeal of such transformations derives from their capacity to facilitate the construction of complex organic molecules via the coupling of simple and otherwise inert building blocks, without introducing extraneous functional groups. Despite notable recent efforts, the establishment of general and mild strategies for the engagement of sp(3) C-H bonds in C-C bond forming reactions has proved difficult. Within this context, the discovery of chemical transformations that are able to directly functionalize allylic methyl, methylene and methine carbons in a catalytic manner is a priority. Although protocols for direct oxidation and amination of allylic C-H bonds (that is, C-H bonds where an adjacent carbon is involved in a C = C bond) have become widely established, the engagement of allylic substrates in C-C bond forming reactions has thus far required the use of pre-functionalized coupling partners. In particular, the direct arylation of non-functionalized allylic systems would enable access to a series of known pharmacophores (molecular features responsible for a drug's action), though a general solution to this long-standing challenge remains elusive. Here we report the use of both photoredox and organic catalysis to accomplish a mild, broadly effective direct allylic C-H arylation. This C-C bond forming reaction readily accommodates a broad range of alkene and electron-deficient arene reactants, and has been used in the direct arylation of benzylic C-H bonds.

Figure 1. The direct arylation of allylic C–H bonds via the synergistic merger of photoredox and organic catalysis

Arylation of allylic bonds is generally accomplished via transition metal-catalyzed couplings with pre-functionalized substrates (a). Installation of heteroatoms via direct allylic C–H functionalization is widely precedented (b). Direct C–H arylation is proposed via the synergistic merger of photoredox and organic catalysis (c).

Figure 2. Proposed mechanism for the direct arylation of allylic C–H bonds via photoredox and organic catalysis

The catalytic cycle is initiated via excitation of photocatalyst 1 to give the excited state 2. Single-electron reduction of 4-cyanopyridine (6) generates the radical anion 8 along with oxidant 3. In the presence of a base, oxidant 3 is capable of oxidising the thiol catalyst 4 to give the thiyl radical 5 along with the regenerated photocatalyst 1. The thiyl radical 5 abstracts an allylic hydrogen atom from cyclohexene (7) to generate allylic radical 9. A radical–radical coupling and subsequent elimination of cyanide serve to construct the new C–C bond and form the arylation product 10.

Figure 3. Substrate scope for the direct allylic arylation reaction

A range of alkenes are efficiently arylated under the standard reaction conditions (top, generalized reaction). The substrate scope includes both cyclic and acyclic alkenes (a). A range of arenes bearing electron withdrawing substituents can be employed as coupling partners under the standard conditions (b). Isolated yields are indicated below each entry. * Isomers observed; In all cases the major isomer is depicted. Yields refer to the combined yield of all isomers. Ratios of isomers where applicable: (±)-16 (2.2:1.0 E:Z), (±)-17 (>20:1), 18 (>10:1), (±)-19 (1.4:1.0), (±)-20 (4.9:1.0), (±)-21 (1.4:1.0), (±)-23 (1.1:1.0), (±)-24 (2.1:1.0), (±)-25 (>19:1), (±)-26 (∼1:1), (±)-28 (1.2:1.0), (±)-29 (1.1:1.0). ‡ Yield from silyl enol ether (83%), yield from 2-cyclohexen-1-ol (62%). † Additional thiol or base required; See Supplementary Information for experimental details.

Figure 4. Expanding the scope of the direct C–H arylation protocol

Substrates bearing boronic esters substituents are tolerated, providing a means to rapidly access functionalized building blocks (a). The mild conditions allow for late-stage functionalization of advanced synthetic intermediates and bioactive natural products (b). Silyl ketene acetals are compatible with the reaction conditions, yielding β-aryl lactones (c). Arylation is not limited to allylic C–H bonds; benzylic C–H bonds can also be arylated (d). The reactivity is governed by bond strengths, with the weaker allylic bond undergoing exclusive functionalization in a direct competition experiment (e). * Isomers observed; In all cases the major isomer is depicted. Yields refer to the combined yield of all isomers. Ratios of isomers where applicable: (±)-39 (6:1), (±)-41 (>10:1). See Supplementary Information for experimental details.