Copper-catalysed benzylic C-H coupling with alcohols via radical relay enabled by redox buffering

Abstract

Cross-coupling reactions enable rapid, convergent synthesis of diverse molecules and provide the foundation for modern chemical synthesis. The most widely used methods employ sp²-hybridized coupling partners, such as aryl halides or related pre-functionalized substrates. Here, we demonstrate copper-catalysed oxidative cross coupling of benzylic C-H bonds with alcohols to afford benzyl ethers, enabled by a redox-buffering strategy that maintains the activity of the copper catalyst throughout the reaction. The reactions employ the C-H substrate as the limiting reagent and exhibit broad scope with respect to both coupling partners. This approach to direct site-selective functionalization of C(sp³)-H bonds provides the basis for efficient three-dimensional diversification of organic molecules and should find widespread utility in organic synthesis, particularly for medicinal chemistry applications.

Fig. 1.. Cross-coupling reactions of benzylic C–H bonds and alcohols via a radical relay pathway.

a, Conceptual similarity between traditional cross-coupling reactions of aryl halides and the targeted benzylic C–H functionalization reactions. b, Important examples of existing drug molecules containing benzylic ether moieties. c, Proposed radical relay mechanism for benzylic C–H etherification enabling the coupling of two diverse pools of substrates.

Fig. 2.. Cu-catalysed benzylic C–H functionalization with NFSI as the oxidant.

a, Cu-catalysed benzylic C–H functionalization reactions14^,34. b, Changes in the Cu redox state between +1 (brown) and +2 (blue-green) upon addition of NFSI to a solution of the Cu^I catalyst precursor, followed by addition of cross-coupling partners. c, Modified radical relay mechanism (cf. Fig. 1c) to account for quenching of the •NSI by Cu^I and regeneration of Cu^I by a reducing substrate or additive. d, Reaction time course for benzylic etherification conducted in the absence (red) and presence of 0.5 equiv of dimethylphosphite (blue). Reaction conditions: 4-ethylbiphenyl (0.2 mmol), NFSI (0.4 mmol), MeOH (1.0 mmol), CuCl (0.02 mmol), 2,2’-bioxazoline (0.02 mmol), DCM (1 mL), room temperature.

Fig. 3.. Electronic effects and site selectivity observed in the oxidative coupling of ethylarenes and methanol.

a, Results observed from the reaction under standard (red) and individually optimized (blue) conditions (¹H NMR yields with CH₂Br₂ as the internal standard. Modified conditions: X = OMe: 20 mol % Cu/biox in DCM at r.t.; X = Br: 5 mol % Cu/biox; X = OAc: 20 mol % Cu/biox at 50 °C. b, Analysis of benzylic versus tertiary site selectivity observed in etherification of isobutylbenzene and ibuprofen methyl ester (see Fig. 4 for reaction conditions).

Fig. 4.. Calculated reaction pathways and energy landscape for (biox)Cu^I/NFSI-mediated methoxylation of ethylbenzene.

(Gibbs free energies at 313.15 K; computed at M06-L/basis-II/SMD(ε = 10.6)//B3LYP-D3(BJ)/basis-I/SMD(ε = 10.6) level of theory).

Fig. 5.. Assessment of different benzylic C–H substrates in oxidative cross-coupling reactions with methanol.

Isolated yields unless otherwise noted. ^{a 1}H NMR yield; isolated yield unavailable due to compound volatility. ^b See Fig. 3a for optimized conditions. ^c 15 mol % Cu/biox. ^d Reaction yield at 4 h. ^e At room temperature. ^f DCM as the solvent. ^g 20 mol % Cu/biox. ^h Only one regioisomer was observed. ⁱ At 30 °C. ^j 30 mol % Cu/biox. ^k Two regioisomers were observed with a ratio of 9:1.

Fig. 6.. Assessment of different alcohols and C–H/alcohol coupling partners in benzylic C–H etherification reactions. a, Benzylic C–H etherification of a canagliflozin precursor with various alcohols. b, Cross coupling of medicinally relevant benzylic C–H substrates and alcohols.

Isolated yields are reported. ^{a 1}H NMR yield with 30 mol % Cu/biox. ^b Conducted with 3.0 equiv. alcohol. ^c Conducted with 1.1 equiv. alcohol. ^d 50 °C. ^e r.t. in DCM.