Selective sp3 C-H alkylation via polarity-match-based cross-coupling

Abstract

The functionalization of carbon-hydrogen (C-H) bonds is one of the most attractive strategies for molecular construction in organic chemistry. The hydrogen atom is considered to be an ideal coupling handle, owing to its relative abundance in organic molecules and its availability for functionalization at almost any stage in a synthetic sequence. Although many C-H functionalization reactions involve C(sp³)-C(sp²) coupling, there is a growing demand for C-H alkylation reactions, wherein sp³ C-H bonds are replaced with sp³ C-alkyl groups. Here we describe a polarity-match-based selective sp³ C-H alkylation via the combination of photoredox, nickel and hydrogen-atom transfer catalysis. This methodology simultaneously uses three catalytic cycles to achieve hydridic C-H bond abstraction (enabled by polarity matching), alkyl halide oxidative addition, and reductive elimination to enable alkyl-alkyl fragment coupling. The sp³ C-H alkylation is highly selective for the α-C-H of amines, ethers and sulphides, which are commonly found in pharmaceutically relevant architectures. This cross-coupling protocol should enable broad synthetic applications in de novo synthesis and late-stage functionalization chemistry.

Figure 1. Selective sp³ C–H alkylations via polarity-matched hydrogen-atom transfer (HAT)

A general and direct alkylation of sp³ C–H remains an elusive transformation in organic synthesis (top). Weak C–H bonds are typically functionalized as a result of the stability of the resulting radical. However, using the polarity-matching effect in HAT, an electrophilic radical should undergo selective hydrogen abstraction at the most hydridic C–H, owing to a lower kinetic barrier (middle). This effect enables selective functionalization beyond the conventional bond-dissociation-energy-driven model (bottom).

Figure 2. Proposed mechanism for the triple catalytic selective sp³ C–H alkylation

The photocatalyst is excited by visible light to produce a long-lived triplet excited state (2), which undergoes oxidation with quinuclidine 3 to yield quinuclidinium radical cation 4. This electrophilic radical species can participate in hydrogen-atom transfer (HAT) with amine 6, selectively abstracting the most hydridic C–H to yield the corresponding radical 7. The reactive carbon-centred radical intermediate reacts with Ni(0) species 9 to yield Ni(i) complex 10. This type of intermediate has been shown to undergo oxidative addition with alkyl bromides to yield Ni(iii) adduct 11. Reductive elimination gives the desired product 13. The photoredox and nickel catalytic cycles are turned over by single-electron transfer (SET) between the iridium and nickel species, while quinuclidine can be regenerated via deprotonation. Boc, tert-butoxycarbonyl.

Figure 3. The scope of the alkyl bromide coupling partner in the light-enabled selective sp³ C–H alkylation

A wide variety of alkyl bromides can be used in this triple catalytic protocol. Broad ranges of functional groups are well tolerated. Secondary–secondary couplings work in good yield. Cyclic and acyclic amines, as well as ethers and thioethers, are well tolerated in this protocol. Hydridic C–H of less sterically hindered carbon is selectively alkylated. In complex molecules, the most hydridic C–H is functionalized, while other neutral or acidic C–H bonds are left completely intact. Me, methyl; Et, ethyl; Ts, tosyl; Ac, acetyl; TBS, tert-butyldimethylsilyl; Ph, phenyl; ^tBu, tert-butyl; Cbz, carboxybenzyl; d.r., diastereomeric ratio; r.r., regiomeric ratio. All reactions were replicated at least three times for consistency. * See Supplementary Information for experimental details. †Yield determined by gas chromatography analysis versus biphenyl as the internal standard.

Figure 4. Application of direct sp³ C–H alkylation in late-stage functionalization of pharmaceutical compounds

N-Boc-Prozac was readily alkylated selectively at the methyl position with simple electrophiles to quickly gain access to a small library of alkylated products via polarity-match-based selective C–H alkylation.