C(sp ³ )–H methylation enabled by peroxide photosensitization and Ni-mediated radical coupling

Abstract

The “magic methyl” effect describes the change in potency, selectivity, and/or metabolic stability of a drug candidate associated with addition of a single methyl group. We report a synthetic method that enables direct methylation of C(sp3)–H bonds in diverse drug-like molecules and pharmaceutical building blocks. Visible light–initiated triplet energy transfer promotes homolysis of the O–O bond in di-tert-butyl or dicumyl peroxide under mild conditions. The resulting alkoxyl radicals undergo divergent reactivity, either hydrogen-atom transfer from a substrate C–H bond or generation of a methyl radical via β-methyl scission. The relative rates of these steps may be tuned by varying the reaction conditions or peroxide substituents to optimize the yield of methylated product arising from nickel-mediated cross-coupling of substrate and methyl radicals.

Electronic control over site-selectivity in hydrogen atom transfer (HAT) based C(sp3)–H functionalization promoted by electrophilic reagents

“…Scheme 16 Normalized gas-phase free energy barriers (in kJ mol À1 ) for HAT from the C-H bonds of CH 3 (CH 2 ) 5 Z substrates to the Cl and NH 2 Me 2 B radicals. ligand transfer from a metal complex (b) 69 or metal-catalyzed cross coupling (c), [70][71][72][73] enabling different CÀH to C-FG transformations, thus providing access to a variety of functionalized products. It is worth mentioning that HAT from a suitable thiol donor to R has been successfully exploited to promote C-H bond epimerization in mono-and oligosaccharides and deuteration and tritiation in pharmaceutical compounds.…”

“…Protonation of basic nitrogen centers is increasingly employed as a strategy to implement site-selectivity in HATbased aliphatic C-H bond functionalization procedures. 70,145,163 By inverting the polarity of the nitrogen functionality, strong electronic deactivation at proximal sites occurs enabling functionalization at remote and intrinsically less activated C-H bonds. 38 In the oxidation of abiraterone acetate and a g-secretase inhibitor analogues with hydrogen peroxide catalyzed by [Fe((R,R)-CF 3 pdp)], selective functionalization at the least electronically deactivated methylene site was observed in both cases following protonation by HBF 4 (structures VIII and IX).…”

Nickel‐Catalyzed Thermal Redox Functionalization of C(sp3)−H Bonds with Carbon Electrophiles**

“…Tracking the reaction progress of 1 with 4‐bromoanisole indicated slow consumption of DTBP; ≈40 % of DTBP remained intact after 8 hours (Figure S1) [36] . Exposure of DTBP to a mixture of Zn and (dtbbpy)NiBr 2 in DMSO at 50 °C resulted in appreciable amount of t BuOH and acetone after 1 h (Figures 5b and S19), indicative of formation of t BuO radical, [42] likely due to reduction of DTBP with putative (dtbbpy)Ni I Br generated by reduction of (dtbbpy)NiBr 2 with Zn [43] . By contrast, Zn or (dtbbpy)NiBr 2 alone did not react with DTBP, nor was (dtbbpy)Ni 0 (COD)/Zn or [(dtbbpy)Ni I Cl] 2 [ I‐1 ] 2 (Figures 5b, c and S14–21) [36] .…”

Photoredox catalysis in nickel-catalyzed C–H functionalization

“…Based on the detailed mechanistic studies, the authors proposed a catalytic cycle involving the generation of methyl radicals via β-scission of a tertiary radical which in turn was generated from trimethyl orthoformate by a photogenerated chlorine radical-mediated HAT process (Figure 14) [92]. Recently, Stahl devised a photoredox nickel-catalyzed methylation of benzylic and α-amino C(sp 3 )-H bonds using di-tertbutyl peroxide (DTBP) or dicumyl peroxide (DCP) as the methyl source under mild conditions [93]. Based on the substrate structure and peroxide choice, the authors developed four sets of reaction conditions (Scheme 29) [93].…”

“…Recently, Stahl devised a photoredox nickel-catalyzed methylation of benzylic and α-amino C(sp 3 )–H bonds using di- tert -butyl peroxide (DTBP) or dicumyl peroxide (DCP) as the methyl source under mild conditions [ 93 ]. Based on the substrate structure and peroxide choice, the authors developed four sets of reaction conditions ( Scheme 29 ) [ 93 ]. In these reaction conditions, photocatalyst Ir[dF(CF 3 )ppy] 2 (dtbbpy)PF 6 and nickel catalyst NiCl 2 ·glyme were identified to be optimal and common.…”