Aliphatic C–H bond methylation enabled by hydrogen atom transfer

In a recent Science paper, Stahl and co-workers describe direct C(sp3)−H methylation via Ni-catalyzed cross-coupling of radical pair deriving from divergent hydrogen atom transfer (HAT) C–Me cleavage pathways in photogenerated alkoxyl radical. The implications these findings for the rapidly expanding field C−H are discussed. Replacing bond drug lead molecule with methyl group can induce profound changes its pharmacological properties, sometimes leading to exceptional improvements potency, so-called “magic effect” (Figure 1A).1Barreiro E.J. Kümmerle A.E. Fraga C.A.M. effect medicinal chemistry.Chem. Rev. 2011; 111: 5215-5246Crossref PubMed Scopus (473) Google Scholar,2Sun S. Fu J. Methyl-containing pharmaceuticals: design.Bioorg. Med. Chem. Lett. 2018; 28: 3283-3289Crossref (46) Scholar This has been attributed multiple factors, including favorable desolvation energetics, metabolic stability alterations, specific interactions biological receptor, induced conformational effects.3Aynetdinova D. Callens M.C. Hicks H.B. Poh C.Y.X. Shennan B.D.A. Boyd A.M. Lim Z.H. Leitch J.A. Dixon D.J. Installing methyl” – C–H synthesis.Chem. Soc. 2021; 50: 5517-5563Crossref addition, methylated analog displays lipophilicity molecular weight that very similar those parent molecule. Although not every incorporation translates into such an effect, potential associated this transformation is too high be underestimated, particularly if strategically performed on privileged sites or affect (ortho-C−H bonds biaryls, α-C−H saturated heterocycles, free rotatable bonds; see Figure 1A). Methyl groups ubiquitous small-molecule drugs, but no general method available their late-stage bonds. Accordingly, exploring generally requires de novo syntheses candidates, slowing down overall process discovery optimization. Along line, as pointed out by Schönherr Cernak 2013,4Schönherr H. T. Profound effects call new reactions.Angew. Int. Ed. 2013; 52: 12256-12267Crossref (505) there strong urgent need synthetic procedures able implement site-selective late stage plan. After call, number transition-metal-catalyzed direct-radical-addition approaches site-selectively target aromatic heteroaromatic C(sp2)−H have emerged,3Aynetdinova Scholar,5Chen Y. Recent advances methylation: guide selecting reagents.Chem. Eur. 2019; 25: 3405-3439Crossref (104) Scholar, 6Friis S.D. Johansson M.J. Ackermann L. Cobalt-catalysed diversification.Nat. 2020; 12: 511-519Crossref (82) 7Ni Hribersek M. Baddigam S.K. Ingner F.J.L. Orthaber A. Gates P.J. Pilarski L.T. Mechanochemical solvent-free catalytic methylation.Angew. 60: 6660-6666Crossref (35) synthesis variety products preparatively useful yields. predominantly occurs directed metal-mediated activation addition (or equivalents) electron-deficient heterocycles. Unfortunately, strategies do provide access more attractive challenging methylations that, compared counterparts, stronger impact 3D shape hence bear higher chances inducing drastic structural often magic effect. functionalization typically reaction because strength bonds, multitude, difficulty controlling site selectivity discriminating among different characterized reactivities steric accessibilities between targeted other reactive functional groups. Very recently, breakthrough was achieved through development two methylation, both initiated substrate bond.8Feng K. Quevedo R.E. Kohrt J.T. Oderinde M.S. Reilly U. White Late-stage oxidative C(sp3)–H methylation.Nature. 580: 621-627Crossref (65) Scholar,9Vasilopoulos Krska S.W. S.S. enabled peroxide photosensitization Ni-mediated coupling.Science. 372: 398-403Crossref (39) first reported co-workers, who developed two-step featuring HAT-based hydroxylation followed hydroxyl-group toward nucleophilic AlMe3 1B).8Feng By leveraging use hindered manganese catalyst, Mn(CF3pdp), could discriminate basis electronic effects, combination acetic acid, fine-tuning experimental conditions (catalyst H2O2 loading), authors achieve product-chemoselective hydroxylation. Hydroxyl-group then obtained treatment diethylaminosulfur trifluoride boron diethyl etherate (BF3⋅Et2O) formation intermediate iminium oxonium ions, which were subsequently trapped AlMe3. successfully applied adjacent N and, few examples, O centers heterocyclic cores commonly found pharmaceuticals (lactams, oxazolidinones, pyrrolidines, piperidines, azepanes, quinolines) drugs natural products. Aryl halide, ketone, ester, acetate, nitrile functionalities well tolerated. These activated, strategic they substantial More procedure where C-centered generated HAT cross-coupled process.9Vasilopoulos Synergistic cooperation three steps key outcome: (1) visible-light-photosensitized parent, commercially generate tert-alkoxyl radicals (R′C(Me)2O⋅: tert-butoxyl [R′ = Me] cumyloxyl Ph]); (2) competitive reactions radicals, abstract H bimolecular (to form [R⋅]) undergo unimolecular C−Me β-cleavage Me⋅; (3) Me⋅ R⋅ afford desired product R−Me 1C). match relative rates competing involving (the nature photosensitizer peroxide, concentration, temperature, solvent), identification set efficiently employed classes. extensively benzylic substrates, structurally varied acyclic (amide carbamate) (azetidine, pyrrolidine, piperidine, piperazine) derivatives. Remarkably, previously described procedure, operationally simpler mild enables application densely functionalized molecules. Overall, compatibility aryl alkyl chloride, tertiary alcohol, carboxylic amide, sulfonamide observed. Again, unlocks improved probing operation scope procedures,8Feng protonation basic (primary, secondary, amine, pyridine) also powerful strategy electronically deactivate proximal polarity reversal10Bietti Activation deactivation promoted medium selective aliphatic functionalization.Angew. 57: 16618-16637Crossref (47) promote at remote intrinsically less activated sites. Employing several (fenspiride, pozanicline, citalopram, safinamide, trimethobenzamide, cinacalcet, abiraterone acetate analog), suggestion find broad utility pharmaceutical building blocks molecules, feature amine functionalities. Together, methods unlock classes molecules products, bond-functionalization toolbox include transformation. results will fuel methodologies pave way broader exploration discovery.