Martin Silicates as Partners in Photoredox/Ni Dual Catalysis for the Installation of CH ₃ , CH ₂ D, CD ₂ H, CD ₃ and ¹³ CH ₃ Groups onto (Hetero)Arenes

The introduction of a methyl group and its 13C 2H labeled analogs on Csp2-centers remains challenging issue in synthetic chemistry. While the photoredox/Ni dual catalysis has proven to constitute valuable methodology for forging Csp2?Csp3 bonds, high difficulty generate radical control reactivity severely limited development reliable processes. Herein, we introduce easily prepared bench-stable Martin methylsilicates bearing two C,O-bidentate hexafluorocumyl alcohol ligands as class precursors enabling chemoselective methylation (hetero)aryl halides acyl chlorides well access corresponding CD3, CD2H, CHD2 13CH3 good yields. Despite obvious interest, if only medicinal chemistry,1 commonly referred “magic effect”,2 installation group, isotopic analogues, aromatic heterocyclic backbones remained synthetically challenging. Metal-catalyzed cross-coupling reactions such Kumada-Corriu or Negishi coupling represent options.3 However, order enable based CH3? synthon, these processes rely use stoichiometric nucleophilic organometallic reagents that potentially promote adverse reactivities. recent trimethylboroxine reagent Pd-catalyzed partly alleviates some issues but temperature conditions are still required.4 Alternatively, intervention CH3+ synthon (CH3I related reagents), electrophile cross-coupling5 C?H activation reactions6 also by substrates must not exhibit strongly functions. Notwithstanding potential polarity mismatches, series have been recently developed CH3/CD3 group,7-9 their cannot be extended other more costly analogs, they generally used large excess even solvents. It is therefore surprising pathways involving neutral CH3? appeared alternatives witnessed intense developments.10 very energy species can generated harsh thermal photochemical conditions, instance scission peroxides using di-tert-butylhyponitrite.11 A seminal redox alternative was proposed Minisci consisted Ag(II)-mediated decarboxylation acetic acid provide readily adds heterocycles.12 Very recently, photoredox tremendously changed venues formation species, notably from various including methane.13 second benefit this approach it merged with transition metal-catalysis, nickel (photoredox/Ni catalysis), which allows an tamed species.14 This principle single-electron transmetalation15 initially devised alkyl-carboxylates16 trifluoroborates17 oxidizable undergone significant found applications Csp2 centers. Doyle co-workers elegant employing trimethyl orthoformate18 benzaldehyde di(alkyl) acetals19 through photo-induced ?-scission acetal moiety (Scheme 1). Employing Chatchilialoglu halide abstraction, MacMillan photocatalyzed cross-electrophile coupling20 CT3, 13CD3, 14CH3 11CH3 groups pharmaceutical platforms.21 MacMillan22 Li23 designed methylations pyridine derivatives C2 C4 positions, methanol alkylating agent. Photoredox/Ni catalyzed methylations. All protocols own virtues limitations terms ease use, functions compatibility and/or stoichiometry convenient versatile isotope labeling. We surmised would useful devise library photooxidative process. Such already self-excitable borates liberate under blue LEDs irradiation,24 however relative stability24a unsuitability labeling appear limitations.[24b} Our group25 one Molander26 alkyl bis-catecholatosilicates precursors,27 competent photoredox/nickel yields products great function tolerance. notable exception biscatecholatosilicate derivative, provided single imine addition adduct fairly moderate yield,28 given any conditions.27, 29 Nevertheless, alkylsilicates 2,2,2,2’,2’,2’-hexafluorocumylalcohol dianion C,O-bidendate ligand, type silicates,30 attracted our attention years.31 During course investigations reactivity, Morofuji Kano evidenced those derivatives, although having higher oxidation potentials (?1.50 V vs SCE) than (<1.0 SCE), radicals32 engaged Giese reactions.32b Reasonable photocatalytic generation 1 Scheme tert-butyl-10-phenylacridinium tetrafluoroborate ([Mes-Acr+], Nicewicz's catalyst)33 trapping Michael acceptors were reported.32b complementarity between bis-catecholato- silicates led us consider latter partners fragments platforms Additional interesting features consist easy preparation gram scale air moisture stability.31c In context, tetraethylammonium silicate 1-d, 1-d2, 1-d3 1-13C routes 2). Preparation precursors. Cyclic voltammetry showed peak at 1.50 SCE confirmed necessity highly oxidizing photocatalysts acridiniums.34 unclear how set reaction optimize concurrent operation catalytic cycles particular find complexes compatible oxidative photocatalysts. literature survey paucity cases best knowledge, reports highlighted both systems, first Rueping dealing cyclic precursors,35 Xiao germanes.36 Thus, optimized varying key parameters process (see Table & SI). Using 2 electrophile, combination catalysts mixture 10 mol% catalyst 5 NiBr2(BPhen). DCM solvent proved beneficial compared widely DMF typical Ni/photoredox (entry 3) running 0.2 M better 0.1 (entries 4). Except 9-mesityl-10-methylacridinium perchlorate (Fukuzumi photocatalyst, entry 8, 51% 3 a), all Ir(dF(CF3)ppy)2(dtbbpy) (PF6) 4CzIPN inefficient photocatalyst 6–8). ligand importance. Indeed, ?-system mandatory since no observed bipyridyl while phenantroline efficiency 9). influence difference bathophenantroline Lower amounts 11 12), lower loading 5) detrimental yield, could rationalized fact amount necessary reaction. case, did neither result improvement (82% a, 13). After turned toward scope 3). Electronically less depleted (iodobenzene, 44% b 2-iodonaphthalene, 21% c) enriched (4-iodoanisole, 0% d) significantly Conversely, electrophilic CF3 (3 g) enables alkylation aryl moieties ester e, 74% l, 86%) formyl f, 65%). observed. Another example higher-yielding 4-iodophenylboronic (Bpin)ester i, 80%) boronic h, 23%). performed larger (0.76 mmol iodide partner) i 62% yield. Scope oxygen nitrogen furfuryl m) quinoline p) successfully reaction, chromones n o), scaffolds drug-design37, 38 indazoles q, r) known biological properties.39 case indazole precursor, hydrogenated product r-H isolated 40% yield originate homolysis photosensitive Ni(II) complex 4).40 Possible mechanism methylation. Based 4-iodoacetophenone (Table 1), comparable a-d3, a-d2, a-d, a-13C complete control. erosion incorporation benzylic position, side organic backbone Similarly, l-d3, l-13C o-d3 n-d synthesized chemoselectively. Finally, electrophiles41 s s-d3 formed 58% 62%. pointed out different modulate efficiency. An electron poor will favorable explains obtained heteroaryls g k). naphtyl scaffold epitomizes point. substitution remote position exerts positive effect bromide precursor (86% l non-substituted naphthalene c). consistent absence electron-richer systems 4-iodo-anisole. poison 4-iodobenzaldehyde f dropped 26% presence 4-iodoanisole. Consistent findings, reported oxidize anisole non-productive pathway may intervene.42 suggests tolerance electron-withdrawing fragile functions, setting stage late-stage functionalization. demonstrated synthesis previously undescribed monodeuterated analog nonsteroidal anti-inflammatory celecoxib u-d) iodinated u 5). There indeed continuing interest analogues drugs containing p-tolyl prone metabolic group.21, 43-46 Overall, offers general problem deuterium challenging.47-50 Synthesis d-celecoxib via last-stage u. proposal drawn several elements. First, quenching constant acridinium's excited state determined 1.3×1011 L.mol?1.s?1 SET event controlled diffusion. low viscosity solvent, short-lived acridinium (t=13.8 ns)51 react electron-transfer, thermodynamically favored (2.10 [Mes-Acr+]*/[Mes-Acr?] a). methylsilicate photoexcited liberates radical, presumably trapped nickel(II) originating arylhalide. Ni(III) then undergoes reductive elimination methylated Ni(I) further reduced radical. Ni(0) followed give same intermediate.52 study, method smooth chloride limitation electron-rich substrates, broadly mono- di- tri-deuterated 13C-labeled derivatives. addition, uses non-sensitive methylating agents, diminishing drastically experiment cautions, time thus transformation cost. elements bioactive molecules targeted suggest functionalization, alleviating tedious protection steps. d-celecoxib. Moreover, advantages number incorporated newly created so, without over-labeling scrambling during drug design. flame-dried Schlenk flask added d3-iodomethane CD3-I (0.22 mL, 3.49 mmol, 1.1 equiv.) Et2O (5 mL). resulting solution cooled down ?78 °C tert-BuLi 1.7 pentane (4 6.86 2.2 dropwise stirred 30 minutes. spirosilane (1.60 g, 3.12 1.0 (20 mL) white solution, warmed up room overnight. quenched abs. EtOH solvents removed vacuo. oily residue dissolved (25 mL), (2.62 12.48 4.0 4 h. HCl layer washed water times), dried over MgSO4, filtered concentrated pressure. yellowish crude minimal volume precipitation triggered pentane. Filtration afforded a-d3 solid (1.48 72%). sealed microwave tube purged three argon/vacuum cycles, (263 mg, 0.40 2.0 equiv.), NiBr2(BPhen) (5.5 0.01 mol%), [Mes-Acr+] (11.5 0.02 mol%) introduced argon (49 0.20 equiv.). Distilled (1 degassed freeze pump thaw cycles. irradiated LED 24 h temperature. saturated aqueous K2CO3 extracted Et2O/Water (3×10 mL each). combined layers vacuum purified flash chromatography (20.7 77%). L.F., C.O. G.L. acknowledge Sorbonne Université, CNRS, IUF financial support. authors thank Fédération de Chimie Moléculaire analytical Gilles Clodic HRMS. As service readers, journal provides supporting information supplied authors. materials peer reviewed re-organized online delivery, copy-edited typeset. 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