ll Article A general N-alkylation platform via copper metallaphotoredox and silyl radical activation of alkyl halides Nathan W. Dow, Albert Cabre´, David W.C. MacMillan [email protected] Highlights General, room temperature N- alkylation via copper metallaphotoredox catalysis Broad reactivity across diverse alkyl bromides, N-heterocycles, and pharmaceuticals Convenient approach to N- cyclopropylation using easily handled bromocyclopropane Readily extended to functionalization of unactivated secondary alkyl chlorides Traditional substitution reactions between nitrogen nucleophiles and alkyl halides feature well-established, substrate-dependent limitations and competing reaction pathways under thermally induced conditions. Herein, we report that a metallaphotoredox approach, utilizing a halogen abstraction-radical capture (HARC) mechanism, provides a valuable alternative to conventional N-alkylation. This visible-light-induced, copper-catalyzed protocol is successful for coupling >10 classes of N-nucleophiles with diverse primary, secondary, or tertiary alkyl bromides. Moreover, this open-shell platform alleviates outstanding N-alkylation challenges regarding regioselectivity, direct cyclopropylation, and secondary alkyl chloride functionalization. Dow et al., Chem 7,1–16 July 8, 2021 ª 2021 Elsevier Inc. https://doi.org/10.1016/j.chempr.2021.05.005 Please cite this article in press as: Dow et al., A general N-alkylation platform via copper metallaphotoredox and silyl radical activation of alkyl halides, Chem (2021), https://doi.org/10.1016/j.chempr.2021.05.005 ll Article A general N-alkylation platform via copper metallaphotoredox and silyl radical activation of alkyl halides Nathan W. Dow,1 Albert Cabre´ ,1 and David W.C. MacMillan1,2,* SUMMARY The bigger picture The catalytic union of amides, sulfonamides, anilines, imines, or N-het- Alkylamines and their N- erocycles with a broad spectrum of electronically and sterically diverse heterocyclic derivatives are key alkyl bromides has been achieved via a visible-light-induced metalla- structural features in molecules photoredox platform. The use of a halogen abstraction-radical capture central to the medical, 3 (HARC) mechanism allows for room temperature coupling of C(sp )- agroscience, and materials bromides using simple Cu(II) salts, effectively bypassing the prohibi- science industries. Although N- tively high barriers typically associated with thermally induced SN2or alkylation using nitrogen SN1 N-alkylation. This regio- and chemoselective protocol is compat- nucleophiles and halides has ible with >10 classes of medicinally relevant N-nucleophiles, including historically been accomplished via established pharmaceutical agents, in addition to structurally diverse nucleophilic substitution, this primary, secondary, and tertiary alkyl bromides. Furthermore, the ca- process is frequently inefficient pacity of HARC methodologies to engage conventionally inert and poorly selective under coupling partners is highlighted via the union of N-nucleophiles with thermal activation. We report a cyclopropyl bromides and unactivated alkyl chlorides, substrates that kinetically facile, room are incompatible with nucleophilic substitution pathways. Preliminary temperature N-alkylation mechanistic experiments validate the dual catalytic, open-shell nature achieved via underexplored of this platform, which enables reactivity previously unattainable in halogen abstraction-radical traditional halide-based N-alkylation systems. capture pathways mediated by independent photoredox and INTRODUCTION copper catalytic cycles. With a broad scope and late-stage The societal need to discover and produce pharmaceuticals, agrochemicals, and applicability, even for traditionally functional materials has long established a demand for new C–N bond-forming re- inert cyclopropane and chloride actions that are successful across diverse combinations of complex substrates.1–3 electrophiles, this protocol offers Indeed, over the last 2 decades, palladium-, nickel- and copper-catalyzed protocols new and efficient strategies for such as Buchwald-Hartwig,4,5 Ullmann-Goldberg,6 and Chan-Evans-Lam7 C(sp2)–N modern amine synthesis. These cross-couplings have emerged as mainstay strategies to generically access versatile developments can ideally provide N-aryl structural motifs (Scheme 1).8,9 In contrast, transition-metal-mediated cou- 3 medicinal chemists with single- plings affording C(sp )–N bonds are comparatively underdeveloped as broadly 3 step access to valuable sp -rich applicable synthetic technologies,10 despite growing recognition of the importance 3 chemical diversity in drug of C(sp )-incorporation when designing new drugs and agrochemicals.11–13 Instead, 3 discovery, including alkylamine practical approaches to forging C(sp )–N bonds remain generally limited to classical motifs unattainable via methods, including Mitsunobu substitution,14 Curtius rearrangements,15 olefin hy- conventional N-alkylation droamination,16,17 or reductive amination.18 methods. Among the traditional N-alkylation strategies, direct SN2orSN1substitutionofalkyl halides with N-nucleophiles remains the most adopted technology for generating al- kylamine-bearing biomedical agents19,20 and among the most frequently utilized transformations across all chemical industries.21,22 Despite the long-standing popu- larity of this closed-shell N-alkylation pathway, substitution reactions typically face substantial halide-dependent activation barriers, which renders numerous Chem 7, 1–16, July 8, 2021 ª 2021 Elsevier Inc. 1 Please cite this article in press as: Dow et al., A general N-alkylation platform via copper metallaphotoredox and silyl radical activation of alkyl halides, Chem (2021), https://doi.org/10.1016/j.chempr.2021.05.005 ll Article Scheme 1. Catalytic N-alkylation via HARC coupling of alkyl bromides substrates (in particular strained or hindered halides) inert to functionalization (Scheme 1).21,22 Even for reactive halides, elevated barriers for substitution result in high-temperature requirements that impose broad limitations, including low selectivity for a single constitutional isomer (or regioisomer), non-controlled overal- kylation events, and competing elimination pathways.21,22 Whileinsomecases, metal-mediated variants of halide N-alkylation have removed these limitations,23,24 there remains an outstanding need to identify new, robust mechanisms that allow such couplings across an expansive range of complex halide and N-heterocyclic sys- tems while employing ambient, low-temperature conditions. 3 Within the select C(sp )–N cross-coupling methods already disclosed, copper catalysis has increasingly been featured as a key component for enhancing effi- ciency and scope, exploiting the well-precedented capacity for high-valent Cu(III) states to induce carbon-heteroatom bond formation via reductive elimination.25,26 Buchwald, Hartwig, Ko¨ nig, Watson, and others have elegantly engaged several abundant alkyl feedstocks in such protocols, including olefins,27,28 boronic acids and esters,29–32 hydrocarbons (activated in situ via hydrogen atom transfer),33,34 and carboxylic acids (typically deployed as redox-active electrophiles).35–38 How- ever, platforms for copper-catalyzed N-alkylation using alkyl halides, which are readily available, and prototypical SN2 electrophiles, are currently restricted by limited mechanistic approaches and reduced generality in substrate scope. Within this area, the groups of Fu and Peters have made notable advances by designing several distinct organohalide-based N-alkylation platforms, primarily using tran- siently generated Cu(I)-amido intermediates for aliphatic radical generation via sin- 1Merck Center for Catalysis at Princeton gle-electron transfer (SET).39–43 In these systems, successful activation of both University, Princeton, NJ 08544, USA coupling partners by a single (often photoactive) copper complex has frequently 2Lead contact enabled N-alkylation using readily reducible electrophiles (i.e., iodides and a-hal- *Correspondence: [email protected] ocarbonyls), with additional examples demonstrated using aliphatic bromides in https://doi.org/10.1016/j.chempr.2021.05.005 2 Chem 7, 1–16, July 8, 2021 Please cite this article in press as: Dow et al., A general N-alkylation platform via copper metallaphotoredox and silyl radical activation of alkyl halides, Chem (2021), https://doi.org/10.1016/j.chempr.2021.05.005 ll Article tandem with amide- or indole-derived nucleophiles.39–43 Ultimately, these reports from Fu and Peters have conclusively established that merging open-shell and 3 copper-mediated activation modes can indeed facilitate catalytic C(sp )–N bond formation.44 Over the past decade, metallaphotoredox catalysis has emerged as a powerful plat- form to employ open-shell intermediates in concert with transition-metal-catalyzed cross-coupling under mild conditions.45,46 This approach has recently been com- bined with copper catalysis,47 in particular for forging traditionally elusive 48–52 35–37 C–CF3 and C–N bonds. In the context of organohalide functionalization, such strategies have most notably enabled Ullmann-Goldberg couplings of diverse (hetero)aryl bromides at room temperature using a previously unreported mecha- nistic approach.53 This transformation utilizes photoredox-generated silyl radicals, which rapidly convert aryl bromides to radical intermediates via halogen atom trans- fer, to facilitate ambient or low-temperature coupling by replacing sluggish Cu(I) oxidative