Copper-Catalyzed Benzylic C-H Cross-Coupling Enabled by Redox Buffers: Expanding Synthetic Access to Three-Dimensional Chemical Space

Abstract

ConspectusCross-coupling methods are the most widely used synthetic methods in medicinal chemistry. Existing reactions are dominated by methods such as amide coupling and arylation reactions that form bonds to sp²-hybridized carbon atoms and contribute to the formation of "flat" molecules. Evidence that three-dimensional structures often have improved physicochemical properties for pharmaceutical applications has contributed to growing demand for cross-coupling methods with sp³-hybridized reaction partners. Substituents attached to sp³ carbon atoms are intrinsically displayed in three dimensions. These considerations have led to efforts to establish reactions with sp³ cross-coupling partners, including alkyl halides, amines, alcohols, and carboxylic acids. As C(sp³)-H bonds are much more abundant that these more conventional coupling partners, we have been pursuing C(sp³)-H cross-coupling reactions that achieve site-selectivity, synthetic utility, and scope competitive with conventional coupling reactions.In this Account, we outline Cu-catalyzed oxidative cross-coupling reactions of benzylic C(sp³)-H bonds with diverse nucleophilic partners. These reactions commonly use N-fluorobenzenesulfonimide (NFSI) as the oxidant. The scope of reactivity is greatly improved by using a "redox buffer" that ensures that the Cu catalyst is available in the proper redox state to promote the reaction. Early precedents of catalytic Cu/NFSI oxidative coupling reactions, including C-H cyanation and arylation, did not require a redox buffer, but reactions with other nucleophiles, such as alcohols and azoles, were much less effective under similar conditions. Mechanistic studies show that some nucleophiles, such as cyanide and arylboronic acids, promote in situ reduction of Cu^II to Cu^I, contributing to successful catalytic turnover. Poor reactivity was observed with nucleophiles, such as alcohols, that do not promote Cu^II reduction in the same manner. This insight led to the identification of sacrificial reductants, termed "redox buffers", that support controlled generation of Cu^I during the reactions and enable successful benzylic C(sp³)-H cross-coupling with diverse nucleophiles. Successful reactions include those that feature direct coupling of (hetero)benzylic C-H substrates with coupling partners (alcohols, azoles) and sequential C(sp³)-H functionalization/coupling reactions. The latter methods feature generation of a synthetic linchpin that can undergo subsequent reaction with a broad array of nucleophiles. For example, halogenation/substitution cascades afford benzylic amines, (thio)ethers, and heterodiarylmethane derivatives, and an isocyanation/amine-addition sequence generates diverse benzylic ureas.Collectively, these Cu-catalyzed (hetero)benzylic C(sp³)-H cross-coupling reactions rapidly access diverse molecules. Analysis of their physicochemical and topological properties highlights the "drug-likeness" and enhanced three-dimensionality of these products relative to existing bioactive molecules. This consideration, together with the high benzylic C-H site-selectivity and the broad scope of reactivity enabled by the redox buffering strategy, makes these C(sp³)-H cross-coupling methods ideally suited for implementation in high-throughput experimentation platforms to explore novel chemical space for drug discovery and related applications.

Figure 1.

Comparison between classical C(sp²)-centered cross-coupling reactions and emerging C(sp³)–H cross-coupling reactions. (A) Abundance of (hetero)aryl halides, (hetero)benzylic C–H substrates and (hetero)benzylic halides from commercial sources. (B) Conceptual similarity between traditional cross-coupling reactions of aryl halides and the targeted benzylic C–H cross-coupling reactions.

Figure 2.

(A) Kharasch-Sosnovsky reaction and proposed mechanism, with activation energies discerned from the literature. (B) Early report of Cu-catalyzed enantioselective cyanation of (hetero)benzylic C–H bonds with NFSI as the oxidant. (C) Selected successful and challenging examples of Cu-catalyzed benzylic C–H functionalization reactions that use NFSI as the oxidant. Mechanistic figure in panel A adapted with permission from ref. . Copyright 2023 American Chemical Society.

Figure 3.

(A) Modified radical relay mechanism to account for quenching of the •NSI by Cu^I and regeneration of Cu^I by a reducing substrate or additive, as well as reduction strategies of Cu^II to Cu^I identified in radical relay catalysis. (B) Calculated reaction pathways and energy landscape for reaction of •NSI with (biox)Cu^ICl and ethylbenzene. (C) Reaction time course for benzylic etherification conducted in the absence (red) and presence of 0.5 equiv. of dimethyl phosphite (blue). (D) Reaction time course for benzylic fluorination conducted in the absence (red) and presence of 2.0 equiv. of methylboronic acid (blue). (E) Photochemical reduction of [(biq)Cu^II(OBz)]PF₆ to biq/Cu^I shown in UV-visible absorption spectra. Adapted with permission from refs. , , and . Copyright 2020 Nature Publishing Group, 2020 American Chemical Society and 2023 American Chemical Society.

Figure 4.

(A) Selected substrate scope of benzylic C–H methoxylation. (B) Benzylic C–H etherification of a canagliflozin precursor with various alcohols. (C) Cross-coupling examples of medicinally relevant benzylic C–H substrates and alcohols. Adapted with permission from ref. . Copyright 2020 Nature Publishing Group.

Figure 5.

(A) Cross coupling of benzylic C–H cross and azoles with TBACl as the additive for N² selectivity and with TMSOTf or BF₃•OEt₂ for N¹ selectivity. (B) Cross-coupling examples medicinally relevant benzylic C–H substrates and N–H heterocycles. (C) Mechanism rationalizing origin of regioselectivity, reflecting kinetically or thermodynamically controlled reaction conditions. Adapted with permission from ref . Copyright 2021 American Chemical Society.

Figure 6.. Benzylic C(sp³)–H Fluorination/Diversification Sequence.

(A) Switch from C–N (left) to C–F (right) bond formation with Cu/NFSI (B) Benzylic C(sp³)–H cross couplings to C–O, C–N and C–C bonds via benzylic fluorides. Yields reported relative to the C–H substrate, following two-step fluorination/substitution. Adapted with permission from ref and . Copyright 2020 American Chemical Society.

Figure 7.

Selected substrate scope for Cu-catalyzed benzylic C–H chlorination/diversification sequence. Representative examples are shown for diversification of benzylic chlorides with phenols, thiophenols and amines. Adapted with permission from ref. . Copyright 2022 American Chemical Society.

Figure 8.

(A) Selective substrate scope for benzylic C–H isocyanation. (B) Representative benzylic ureas synthesized via benzylic C–H isocyanation/amine coupling sequence. Adapted with permission from ref. . Copyright 2021 the authors. Published by Royal Society of Chemistry under a Creative Commons Attribution-NonCommercial 3.0 Unported (CC BY-NC 3.0) License.

Figure 9.

Accessing 3D molecular diversity via benzylic C–H cross coupling. (A) Virtual enumeration of benzylic C(sp³)–H ethers and ureas and selection of bioactive molecules for comparison. (B) Comparative PMI and 3D score analysis of C(sp²), C(sp³) and acyclic C(sp³) cross-coupling products. (C) PCA comparison between bioactive molecules and benzylic cross-coupling products. (D) Selected examples of synthetically accessed benzylic ethers and ureas via high-throughput experimentation (HTE). Adapted with permission from ref. . Copyright 2023 Nature Publishing Group.