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

CONSPECTUS:

Cross-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 and 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 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. These 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.

Graphical Abstract

1. Introduction

Coupling reactions that connect abundant building blocks are widely used synthetic tools in medicinal chemistry and contribute to success in drug discovery and development. The most prominent and widely used cross-coupling methods consist of amide bond formation from amines and carboxylic acids, and palladium-catalyzed cross-coupling reactions of aryl halides.^5,6 These and many related methods form bonds at sp²-hybridized carbon atoms, resulting in limited topological diversity among the products and suboptimal physical chemical properties.⁷ These limitations have contributed to the growing interest in functionalizing sp³-hybridized carbon atoms as a means to access molecules with more three-dimensional character.⁸ The utility of cross-coupling reactions often correlates with substrate availability. For example, extensive efforts have focused on developing Pd-catalyzed cross-coupling reactions with aryl chlorides, owing to their abundance relative to aryl bromides and aryl iodides (Figure 1A). Benzylic C(sp³)–H bonds adjacent to aromatic and heteroaromatic rings are prevalent in pharmaceutical building blocks, exceeding the number of aryl chlorides by a factor of two and benzylic halides by nearly two orders of magnitude (Figure 1A).^9,10 The scarcity of commercially available benzylic halides probably reflects multiple factors, including the lack of effective methods to produce them, in addition their instability, which complicates storage. Recently, benzylic carboxylic acids have emerged as effective partners for decarboxylative coupling reactions,^{11, 12} though the lower abundance of these building blocks (Figure 1A)¹³ constrains their utility. Benzylic C(sp³)–H bonds are intrinsically reactive due to their comparatively low bond strength¹⁴ and, thus, should be amenable to site-selective functionalization with organic molecules that have many other C(sp³)–H bonds. Benzylic C–H bonds are common metabolic "hot spots", and their selective replacement has the potential to significantly improve metabolic stability and other pharmacological properties of drug molecules.¹⁵ Collectively, these considerations motivated our recent efforts to develop synthetic methods that could use C(sp³)–H bonds adjacent to aromatic and heteroaromatic rings as a site for cross coupling with diverse nucleophiles (Figure 1B). Efficient, selective activation of benzylic C(sp³)–H bonds under mild conditions would also enable late-stage functionalization of pharmaceuticals or advanced intermediates, which could play a key role in the discovery and development of new drug candidates.¹⁶

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.

Recent advances in benzylic C(sp³)–H functionalization have led to site-selective methods for installation small functional groups. Representative examples include oxygenation, ^{17 , 18} animation,¹⁹ and various (pseudo)halogenation reactions.^20-27 These methods are complemented by reactions that functionalize benzylic C–H bonds in low-cost alkylarene feedstocks.^28-30 The work outlined in the present Account complements these methods and was motivated by several criteria that would need to be met to realize the full potential of C–H cross coupling reactions. The reaction should (1) employ diverse, readily accessible pools of substrates as coupling partners in rections with benzylic C–H bonds, (2) enable use of the benzylic C–H substrate as the limiting reagent, and (3) exhibit broad functional-group compatibility in both reaction partner and tolerate substrates with diverse electronic and steric profiles. Here, we outline our results with Cu-catalyzed benzylic C(sp³)–H functionalization methods that employ N-fluorobenzenesulfonimide (NFSI) as an oxidant and proceed via a radical-relay mechanism. The reactions satisfy each of the key cross-coupling criteria, enabling site-selective cross coupling of benzylic C–H substrates as limiting reagents with various nucleophilic coupling partners and supporting the synthesis of diverse libraries of molecules with enhanced three-dimensional properties. In multiple cases, the success of the method relies on the use of a "redox buffer", a sacrificial reductant that sustains the activity of the Cu catalyst throughout the reaction. The scope of these methods includes direct C–H cross-coupling reactions and tandem C–H functionalization/diversification methods. These different reaction classes are elaborated below, together with a presentation of important mechanistic features and a cheminformatics analysis of enumerated products showing how benzylic C(sp³)–H cross-coupling reactions can rapidly access products with drug-like physicochemical properties with improved three-dimensionality.

2. Redox Buffering: Mechanistic Insights that Expand the Synthetic Scope of Cu-Catalyzed Benzylic C–H Cross Coupling.

The Kharasch-Sosnovky reaction was first reported more than 60 years ago and represents a seminal example of C(sp³)–H functionalization.³¹ These Cu-catalyzed reactions are commonly proposed to proceed via a three-step radical-relay mechanism (Figure 2A), and they serve as a prototype for the reactions outlined herein. Nonetheless the common requirements for excess C–H substrates and elevated temperatures have limited the synthetic utility of these methods. Recent collaborative and independent efforts involving our group and Liu and coworkers have shown that Cu-catalyzed radical-relay reactions with NFSI as the oxidant can be used to support benzylic C–H functionalization reactions,^32,33 with cyanation as the first prominent example (Figure 2B).³⁴ Good-to-excellent high yields of benzylic C–H cyanation products were obtained with excellent enantioselectivity. This work provided a foundation for complementary C–H functionalization methods, including trifluoromethylation,³⁵ and azidation³⁶, in addition to C–H cross-coupling reactions, such as arylation, ^{37 , 38} carbamation, ³⁹ and alkynylation ⁴⁰ (Figure 2C, Selected Examples). These methods often can use the benzylic C–H substrate as the limiting reagent, avoiding one of the main limitations of Kharasch-Sosnovky reactions. Building on our initial report of C–H cyanation,³⁴ we targeted benzylic C–H etherification via cross-coupling with methanol and more complex alcohols as coupling partners. Initial studies, however, led to negligible yield of the desired product and little conversion of the C–H substrate and NFSI.¹ Similar challenges became evident in other attempted coupling reactions with heteroatom nucleophiles (Figure 2C, Challenging Targets). These observations could not be readily rationalized by a three-step radical-relay mechanism similar to that proposed for the Kharasch-Sosnovsky reaction (cf. Figure 2A).

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. 41. Copyright 2023 American Chemical Society.

Our mechanistic assessment of the Cu/NFSI reactions was influenced by problems we encountered with the widely accepted mechanism for the Kharasch-Sosnovsky reaction. Specifically, energy barriers estimated for the three steps featured in the Kharasch-Sosnovsky mechanism predict the reaction should be complete in < 1 min at room temperature (Figure 2A),⁴¹ not require many hours at elevated temperature. We rationalized this discrepancy by postulating that the Cu^I catalyst rapidly deactivates by reacting with the oxidant (peroxide or NFSI) in a 2:1 ratio, causing the catalyst to pool as a Cu^II species. The absence of Cu^I significantly slows activation of the oxidant, which is needed to generate the reactive radical that promotes hydrogen-atom transfer from the substrate.

Density-functional theory (DFT) calculations show how similar considerations impact Cu/NFSI reactions (Figure 3A).¹ The reaction of NFSI with Cu^I has a low barrier and is thermodynamically favorable (−15.2 kcal/mol) to generate a Cu^II–F species and N-sulfonimidyl radical (•NSI) (Figure 3B). The •NSI species can promote HAT from the substrate, but it can undergo even more favorable reaction with Cu^I to form a Cu^II–NSI species. This 2:1 Cu^I:NFSI reactivity will eventually convert all Cu^I in the reaction mixture to Cu^II and stall the reaction. Trimethylsilyl cyanide and phenylboronic acid undergo effective Cu/NFSI-catalyzed coupling with benzylic C–H bonds, and control experiments showed that these substrates react with Cu^II to undergo oxidative homocoupling, to afford cyanogen (NC–CN) or biphenyl and Cu^I.¹ By extension, we postulated that Cu/NFSI-catalyzed benzylic C–H coupling reactions were only successful with coupling partners that could undergo slow background reaction with Cu^II to generate the active Cu^I form of the catalyst. We further postulated that unsuccessful reaction might be ‘turned on’ by introducing a mild sacrificial reductant that could slowly reduce Cu^II to Cu^I without undergoing direct reaction with the NFSI oxidant. This “redox buffer” concept, depicted in the dual redox-cycle mechanism in Figure 3B, may be used to rationalize the outcomes of many different Cu-catalyzed benzylic C–H coupling reactions. The redox buffer may consist of a coupling partner (cyanide, arylboronic acid), an added sacrificial reductant (dialkylphosphite, alkylboronic acid), or light irradiation, which can promote ligand-to-metal charge transfer as a means to reduce Cu^II to Cu^I.⁴¹ Dialkyl phosphites were identified as a promising redox buffer for etherification reactions (Figure 3C),¹ while MeB(OH)₂ in the presence of Li₂CO₃ provide more effective in supporting benzylic C–H fluorination reactions (Figure 3D). Different reactions employ different quantities of reductant, presumably reflecting the need to balance kinetics of NFSI activation by Cu^I and reduction of Cu^II to regenerate Cu^I. The use of chemical reductants was recently complemented by a "photochemical redox buffering" strategy, using light to promote benzylic esterification (Figures 3E). Specifically, photoinduced ligand-to-metal charge transfer leads to reduction of Cu^II by the carboxylate ligand, providing a mechanism for in situ generation of Cu^I, which can then activate the peroxide-based oxidant. Little conversion of the benzylic C–H substrates was observed in the absence of the different (photo)chemical redox buffers, and this approach and mechanistic insight has greatly expanded the scope and synthetic utility of Cu-catalyzed radical-relay benzylic C(sp³)–H functionalization and cross-coupling reactions, which will be elaborated in the following sections.

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. 1, 41, and 48. Copyright 2020 Nature Publishing Group, 2020 American Chemical Society and 2023 American Chemical Society.

3. Direct Benzylic C–H Cross Couplings

3.1. Benzylic C–H Cross Coupling with Alcohols

Benzylic ethers are prevalent motifs in drug molecules and medicinally relevant compounds. In addition, late-stage methoxylation of C–H bonds has been identified as a strategic target, analogous to methylation, owing to the ability of a methoxy group to improve potency with little perturbation on lipophilicity and molecular size.¹⁶ We envisioned that a radical-relay strategy, initiated by HAT from a benzylic C–H bond, could enable activation of substrates with broad electronic profile relative to reactions initiated by electron or hydride transfer, which tend to be limited to electron-rich aromatic substrates.⁴²

The use of a redox buffering strategy enabled C–H etherification to proceed with CuCl as the catalyst, 2,2'-bis(2-oxazoline) (biox) as the ligand, NFSI as the oxidant, dimethylphosphate as a reductant (redox buffer), and methanol as the coupling partner (Figure 4A).¹ The reactivity showed broad scope with benzylic C–H substrates, including alkylbenzenes, benzhydryl derivatives, and heterobenzylic scaffolds, such as thiophene, chroman, benzothiazole and indazole. This methoxylation method was successfully applied to an array of pharmaceuticals and bioactive molecules with moderate to high yields. The utility of this C(sp³)–O coupling method was further demonstrated in the diversification of a canagliflozin precursor, exhibiting good reactivity with structurally diverse alcohols that included a gram-scale synthesis of a complex benzylic ether (Figure 4B), and a series of cross-coupling reactions with other substrate pairs (Figure 4C).

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. 1. Copyright 2020 Nature Publishing Group.

3.2. Benzylic C–H Cross Coupling with N–H Azoles

N-benzylic azoles are an important class of pharmacophores with broad utility in medicinal chemistry.⁹ The ambident reactivity of many azoles, such as pyrazoles, presents challenges in achieving selective control over site-selective reaction of the heterocycle. By using a dialkyl phosphite redox buffer, we identified Cu/NFSI conditions for cross coupling of (hetero)benzylic C–H substrates with pyrazoles and other N–H heterocycles. ⁴³ Excellent and tunable N-site selectivity was achieved in the pyrazole coupling reactions, with the preferred site of N-reactivity controlled by an additive, tetrabutylammonium chloride (TBACl) or a Lewis acid, such as trimethylsilyl triflate (TMSOTf) or BF₃•OEt₂ (Figure 5A). A broad array of (hetero)benzylic C–H substrates were effective and useful N–H heterocycles included pyrazoles, purines, triazoles and tetrazoles. Cross coupling reactions of more complicated C–H scaffolds and N–H heterocycles also proved successful (Figure 5B), and this reactivity was extended beyond azoles to other N–H heterocycles, including β-lactams and sultams. The control over N-site selectivity is rationalized by a switch between kinetically and thermodynamically controlled pathways (Figure 5C, top). Under these base-free reaction conditions, reactivity is kinetically favored at the site with a free N² lone pair, contrasting the selectivity observed in basic nucleophilic substitution reactions, where reactivity is favored at the N¹ site of the deprotonated pyrazolide.⁴⁴ The kinetically favored N² coupling product undergoes isomerization to the thermodynamically favored N¹-coupled product in the presence of a strong Lewis acid, such as a trimethylsilyl (TMS) cation. Overall, the high benzylic C–H site selectivity and the ability to control N-site selectivity make this benzylic C(sp³)–N coupling method uniquely appealing to access these structures. Even where imperfect selectivity is observed, the major isomer is readily purified.

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 43. Copyright 2021 American Chemical Society.

4. Benzylic C–H Functionalization/Diversification Reactions

The appeal of direct C–H cross-coupling reactions, such as those in Figures 4 and 5, is partially offset by challenges encountered from the chemical incompatibility of electron-rich nucleophiles, such as amines, thiols, and phenols, with the NFSI oxidant. This incompatibility has prevented several appealing direct C–H coupling reactions from being developed. To overcome this problem, we have begun developing tandem benzylic C–H functionalization/diversification methods, whereby the initial C–H functionalization step creates a versatile synthetic linchpin that can undergo subsequent reactions with diverse nucleophiles in the absence of the NFSI oxidant. These tandem reactions greatly expand the scope of coupling partners that may be used to achieve net benzylic C–H cross coupling.

4.1. Benzylic C–H Fluorination/Diversification Sequence

Methods for C(sp³)–H fluorination have been widely pursued as a means to block metabolism or other undesirable reactivity in bioactive molecules, without significantly altering the steric profile of a molecule. Benzylic fluorides, however, are very susceptible to hydrolysis or nucleophilic substitution when they are activated by a Brønsted or Lewis acid.⁴⁵ We (re)discovered this reactivity when attempting to isolate benzylic fluorides obtained from Cu/NFSI-catalyzed reactions, prompting us to consider benzylic fluoride as linchpins for tandem C–H fluorination/substitution.

The first example of Cu/NFSI-catalyzed functionalization led to formation of benzylic sulfonimides derived from benzylic coupling with the NSI fragment of NFSI.⁴⁶ Early in our efforts to explore Cu/NFSI reactivity, we reinvestigated this C–N coupling method and found that making changes to the reaction conditions switched in reaction outcome, leading to coupling with the fluoride rather than the NSI fragment from NFSI (Figure 6A, left versus right arrow).⁴⁷ The modified conditions include MeB(OH)₂ as a redox buffer, which significantly improves conversion of benzylic C–H substrates analogous to observations with dialkylphosphite in etherification and azole-coupling reactions. Li₂CO₃ is included as a Brønsted base to sequester the HN(SO₂Ph)₂ byproduct before it promotes displacement of the fluoride. Further optimization of the reaction led to good yields of benzylic fluorides, with a variety of ancillary substituents.

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 47 and 48. Copyright 2020 American Chemical Society.

Recognizing that the benzylic fluorides are too labile to be useful end products, we sought conditions that could use these compounds as reactive intermediates amenable to nucleophilic substitution (Figure 6B).⁴⁸ Activation of benzylic fluorides by a strong hydrogen-bond donor like hexafluoroisopropanol (HFIP) or a Lewis acid like BF₃·Et₂O supports rapid displacement of the fluoride with a variety of oxygen-, nitrogen- and carbon-based nucleophiles. The benzylic fluoride is not isolated in this sequence, and the tandem approach allows successful coupling with many nucleophiles and formation of many products that would not be compatible with direct coupling reactions conducted with NFSI.

4.2. Benzylic C–H Chlorination/Diversification Sequence

Benzylic chlorides exhibit reactivity complementary to benzylic fluorides and represent another appealing linchpin for tandem functionalization/diversification reactions. This consideration motivated our efforts to develop Cu/NFSI conditions and compare their reactivity to classical radical-chain chlorination and recent methods that have been used to achieve selective benzylic chlorination.^2,49-50 The optimized conditions employed KCl as a chloride source and required a redox buffer ((ⁱPrO)₂P(O)H) (Figure 7). The poor solubility of KCl appears to play an important role, as soluble sources of chloride (NB₄Cl) or NCSI, the N-chloro analog of NFSI, were less effective.² A set of substrates was used to compare reactivity with a series of other chlorination conditions, and the results showed that the Cu/NFSI method exhibits superior yield and benzylic site-selectivity relative to other methods. The reaction also shows good scope, including electron-deficient heterocycle substrates. The intermediate benzylic chlorides undergo facile nucleophilic substitution with phenols, thiophenols and amines (Figure 7), none of which would be compatible with NFSI in direct coupling reactions. Complementary reactivity of benzylic chlorides and fluorides is evident in reactions with phenol coupling partners; the displacement of fluoride under acidic conditions leads to Friedel-Crafts C–C coupling with the phenol, while the displacement of chloride under basic conditions forms the aryl ether product via C–O coupling (cf. Figures 6B and 7).

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. 2. Copyright 2022 American Chemical Society.

4.3. Benzylic C–H Isocyanation/Amine Coupling Sequence

Functional groups beyond halides can be considered for functionalization/diversification protocols with benzylic C–H bonds. Benzylic isocyanates represent versatile linchpins to generate diverse ureas via amine addition. When we began our effort, the best available benzylic C–H isocyanation method featured moderate to good reactivity for an array of different benzylic C–H substrates as well as a few other unactivated aliphatic C–H bonds;⁵¹ however, this method required portion-wise addition of the iodosylbenzene oxidant, in addition to the Me₃Si–NCO coupling partner, throughout the reaction to access good yield of the final product. Efforts to develop a more practical protocol led to Cu/NFSI conditions with (ⁱPrO)₂P(O)H as the redox buffer, that features entirely commercially available catalysts and reagents, uses the C–H substrate as the limiting reagent, and is amenable to high-throughput experimentation (HTE) methods (Figure 8).³ This C–H isocyanation method exhibits exquisite benzylic site-selectivity, which is emerging as a characteristic feature of Cu/NFSI reactions. The practicality of the tandem isocyanation/amine addition method is enhanced by the ability to perform this sequence without work-up or isolation of the isocyanate intermediate.

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. 3. 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.

The HTE compatibility of this protocol was demonstrated by preparing three different benzylic isocyanates derived from bioactive molecules or drug precursors, and then subjecting them to a 96-well array of primary, secondary, alkyl and aryl amine coupling partners. Selected benzylic urea products, illustrated in Figure 8B, were obtained in moderate to good yields. Analysis of the physicochemical properties for the full set of 3 × 96 benzylic ureas revealed that these products align with the “oral druggable space beyond Rule of 5 (bRO5)”,⁵² highlighting the drug-like physicochemical properties relevant to applications in drug discovery.

5. Benzylic C–H Cross Coupling Improves 3D Structural Diversity

The C(sp³)–H cross-coupling methods presented herein appear to be ideally suited to to address strategic goals in medicinal chemistry by providing efficient access to diverse libraries of molecules. The methods are compatible with HTE techniques, and the resulting products feature three-dimensional diversity that should lead to favorable physicochemical properties. A cheminformatics approach was used to evaluate a large collection of possible benzylic cross-coupling product derived from C–H etherification¹ and isocyanation/amine coupling³ (Figure 9A).⁴ Molecular properties of more than 360,000 enumerated products were evaluated and compared with a collection of more than 9400 clinically investigated compounds, including approved drug molecules. The benzylic C(sp³)–H cross-coupling products exhibit high three-dimensionality, as indicated by comparison of their principal moments of inertia (PMI)⁵³ and 3D scores⁵⁴ relative to their C(sp²) counterparts. This outcome is as exemplified by a specific scaffold in Figure 9B. Increased three-dimensionality is especially present in rigid scaffolds, such as benzylic sites on aliphatic rings fused to aromatic cores. A significant drop in 3D scores was observed for coupling products obtained from coupling to benzylic sites in acyclic substituents (Figure 9B).

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. 4. Copyright 2023 Nature Publishing Group.

Comparison of the physicochemical properties between benzylic cross-coupling products and clinically investigated compounds demonstrated the relevance of these benzylic products in a drug-like chemical space (Figure 9C). The assessment included principal components analysis (PCA), a dimensionality reduction method that simplifies visualization of multiple chemical properties.⁵⁵ The significant overlap between the PCA plots for the benzylic cross-coupling products and existing drug candidates confirms that the benzylic coupling products closely resemble bioactive molecules (Figure 9C). Selected drug-like benzylic cross-coupling products were then prepared by using high-throughput experimentation (HTE) methods, validating the synthetic accessibility of products identified using the cheminformatics methods (Figure 9D). These results demonstrate the utility of benzylic C(sp³)–H cross-coupling reactions to support rapid access to 3D, drug-like molecules.

6. Summary and Outlook

The results presented here show how mechanistic analysis of radical-relay catalysis, which originated with the Kharash-Sosovsky reaction, led to development of a redox-buffering strategy that greatly expanded the scope and utility of benzylic C(sp³)–H functionalization methods. Evolution of this strategy has resulted in a series of benzylic C–H cross-coupling reactions that can access a diversity of products far beyond that accessible with C–H functionalization reactions that support one-for-one swap of a C–H bond with another functional group. The cross-coupling methods include direct reactions of benzylic substrates with coupling partners (e.g., alcohols and azoles) and tandem functionalization/diversification methods that generate a synthetic linchpin, such as benzylic halide or isocyanate, that can undergo subsequent substitution or addition with an array of reaction partners. The latter methods are appealing because the intermediate linchpin often may be used from the initial functionalization reaction without isolation and/or purification, and this sequential strategy tolerates coupling partners that would not be compatible with NFSI or other components of the initial C–H functionalization steps.

These Cu-catalyzed benzylic C–H cross coupling strategies exhibit broad synthetic utility; however, the field would benefit from future advances that address existing limitations or additional opportunities. For example, NFSI has limited tolerance for aromatic nitrogen heterocycles, such as pyridines, and it is less effective with 1° and 3° benzylic C–H substrates, relative to 2° C–H bonds. New methods that operate by different mechanisms and/or employ alternative reagents will probably be needed to address this challenge.⁵⁶ Many of these Cu/NFSI reactions appear to proceed via a radical-polar crossover mechanism that complements other useful C–H coupling reactions. ^{57 , 58} On the other hand, such methods are not compatible with enantioselective reactivity. This limitation, which has been overcome with certain coupling partners,^34,38,40 represents an important target for future investigation and development. For example, the development of new catalyst systems that favor a pathway that proceeds via radical addition to Cu^II and reductive elimination from Cu^{III 34} provides a potential target for such studies.

Collectively, the Cu-catalyzed methods outlined herein show that benzylic C–H bonds may be viewed as viable cross-coupling partners, equipped to forge new bonds to C(sp³) carbon atoms with site-selectivity and synthetic scope that rival conventional cross-coupling reactions with organic halides. The resulting products uniquely populate three-dimensional, drug-like chemical space and have broad potential utility in medicinal chemistry and related applications.

Biographies

Si-Jie Chen obtained his B.A. in Chemistry in 2016 from Sun Yat-Sen University and Hong Kong Polytechnic University and a Ph.D. in 2021 from University of Wisconsin-Madison, under the supervision of Prof. Shannon S. Stahl. His doctoral studies focused on copper-catalyzed benzylic C–H cross-coupling reactions, mechanistic investigations into these reactions, and cheminformatic analyses of novel benzylic cross-coupling products. In 2021, he joined the Department of Discovery Chemistry at Merck & Co., Inc. in South San Francisco, California and began his research on medicinal chemistry.

Shane W. Krska received a B.S. in chemistry from the South Dakota School of Mines and Technology in 1992 and a Ph.D. in inorganic chemistry from the Massachusetts Institute of Technology in 1997 under the direction of Prof. Dietmar Seyferth. After conducting postdoctoral research with Professor Robert Bergman at the University of California, Berkeley, he joined Merck & Co., Inc. as a senior research chemist in 1999. Dr. Krska has held positions in chemical engineering research and development, process research, and, most recently, discovery chemistry. He currently serves as distinguished scientist in the high-throughput experimentation and lead discovery capabilities group within discovery chemistry. His research interests include the development of high-throughput experimentation workflows and applications of catalysis to drug discovery and development.

Shannon S. Stahl obtained his B.S. in Chemistry at the University of Illinois Urbana–Champaign and a Ph.D. in Chemistry from Caltech (Ph.D., 1997), under the supervision of Prof. John Bercaw. He was an NSF postdoctoral fellow with Prof. Stephen Lippard at Massachusetts Institute of Technology from 1997–1999. He is currently a Steenbock Professor of Chemical Sciences at the University of Wisconsin-Madison, where he began his independent career in 1999. His research group specializes in catalysis, with an emphasis on redox reactions, including C–H oxidation and oxidative coupling reactions, aerobic oxidation methods, and electrochemical synthesis. He was recently elected to the American Academy of Arts and Sciences and the National Academy of Sciences.