HARC as an open-shell strategy to bypass oxidative addition in Ullmann–Goldberg couplings Marissa N. Lavagninoa, Tao Lianga, and David W. C. MacMillana,1 aMerck Center for Catalysis, Department of Chemistry, Princeton University, Princeton, NJ 08544 Contributed by David W. C. MacMillan, July 8, 2020 (sent for review June 11, 2020; reviewed by Scott J. Miller and F. Dean Toste) The copper-catalyzed arylation of unsaturated nitrogen heterocy- achieving high levels of reaction efficiency under ambient or low cles, known as the Ullmann–Goldberg coupling, is a valuable trans- temperature control. formation for medicinal chemists, providing a modular disconnection Over the past 6 years, metallaphotoredox has become a broadly for the rapid diversification of heteroaromatic cores. The utility of the employed strategy for merging photocatalyst-derived organic coupling, however, has established limitations arising from a high- radicals with transition-metal cycles (16). A fundamental advan- barrier copper oxidative addition step, which often necessitates the tage of metallaphotoredox has been that feedstock substrates use of electron-rich ligands, elevated temperatures, and/or activated bearing native functional groups, such as carboxylic acids, amines, aryl electrophiles. Herein, we present an alternative aryl halide acti- alcohols, and C–H bonds, can be converted to high-energy, open- vation strategy, in which the critical oxidative addition (OA) mecha- shell intermediates that rapidly participate in transition-metal capture nism has been replaced by a halogen abstraction–radical capture (16). This step has been exploited broadly in the realm of nickel and (HARC) sequence that allows the generation of the same Cu(III)-aryl copper catalysis to deliver a series of new fragment coupling pathways 3 intermediate albeit via a photoredox pathway. This alternative mech- that include deoxygenative C(sp )-arylation (17), decarboxylative 3 3 anistic paradigm decouples the bond-breaking and bond-forming C(sp )-arylation (18), decarboxylative C(sp )-amination (19), as well 3 steps of the catalytic cycle to enable the use of many previously inert as hydrogen atom transfer (HAT) C(sp )-trifluoromethylation (20). aryl bromides. Overall, this mechanism allows access to both tradi- In the latter two cases, these copper-based couplings take advantage – tional C N adducts at room temperature as well as a large range of of 1) Cu(II)’s capacity to capture alkyl radicals at near-diffusion rates – previously inaccessible Ullmann Goldberg coupling products includ- (21, 22) and 2) Cu(III)’s established propensity to undergo reductive ing sterically demanding ortho-substituted heteroarenes. elimination (RE) steps that are traditionally difficult for more com- CHEMISTRY monly utilized metal catalysts (23). – photoredox catalysis | C N coupling | halogen atom abstraction Among numerous strategies to access alkyl and aryl radicals via photoredox, perhaps the most commonly employed within the 3 he arylation of nitrogen nucleophiles has found broad ap- pharmaceutical sciences has been halide abstraction from C(sp )–Br 2 Tplication in many synthetic fields, including materials science, and C(sp )–Br moieties using photogenerated, electron-rich silyl medicinal chemistry, and natural product synthesis (1, 2). While radicals (24–27). In particular, the nickel-catalyzed cross-electrophile 3 2 the development of nitrogen arylation protocols has been re- coupling to forge C(sp )–C(sp ) bonds via a halogen abstraction– cently dominated by palladium catalysis (3, 4), the first stoi- radical capture (HARC) mechanism has been adopted broadly due chiometric (5) and catalytic (6) systems reported over a century to its remarkable scope and functional group tolerance (28). This ago employed copper, an abundant and inexpensive first-row silyl-mediated HARC mechanism has also been interfaced recently transition metal. The “Ullmann–Goldberg” coupling was lim- with copper catalysis to enable the incorporation of moieties that are ited for many years by the need for high reaction temperatures, stoichiometric copper, and activated electrophiles (e.g., aryl io- Significance dides) (7). Notably, the work of Buchwald and others led to the development of chelating diamine ligands (8–10) that prevent nu- Copper-catalyzed carbon–nitrogen bond formation has the po- cleophile aggregation on copper, which in turn has enabled milder tential to provide efficient synthetic access to medicinally relevant reaction conditions and broader scope (11). Recent work by Fu and organic molecules, but broad use of the coupling has been ham- Peters has also shown that direct reduction of the aryl halide by pered by the requirement for an energetically challenging sub- photoexcited, nucleophile-ligated copper complexes is an alterna- strate activation step (oxidative addition into an aryl halide). Here tive strategy for aryl halide activation by copper (12, 13). However, a 2 we report a mechanistic alternative that circumvents oxidative general, copper-catalyzed C(sp )–N Ullmann–Goldberg coupling het addition by cooperatively employing photochemically generated remains to be developed with respect to aryl position diversity and silicon-centered radicals and copper to activate aryl halides via a temperature burden, both critical requirements for the early-stage one-electron pathway. This dramatically increases the range of diversification of pharmaceutically relevant molecules. Recent accessible products, thereby allowing room-temperature synthesis mechanistic studies have attributed these deficiencies to a high- of a diverse electronic and steric range of products traditionally barrier oxidative addition (OA) step between the electronegative A considered inaccessible via copper catalysis due to the prohibi- copper(I) catalyst and the aryl halide coupling partner (Fig. 1 )(14, tively high barrier for direct copper oxidative addition. 15), a pathway that traditionally demands elevated thermal expo- ortho sure. Moreover, this step is often prohibitive with -substituted Author contributions: M.N.L., T.L., and D.W.C.M. designed research; M.N.L. and T.L. per- aryl bromides due to both steric and electronic factors, a barrier that formed research; M.N.L., T.L., and D.W.C.M. analyzed data; and M.N.L. and D.W.C.M. appears surmountable only via the use of copper-chelating substit- wrote the paper. uents or directing groups (7). With these considerations in mind, we Reviewers: S.J.M., Yale University; and F.D.T., University of California, Berkeley. recently sought to develop an alternative mechanistic paradigm that Competing interest statement: D.W.C.M. declares a competing financial interest with would alleviate the challenge of oxidative addition with copper(I) respect to the Integrated Photoreactor. salts across many reaction classes, while retaining the unique capacity Published under the PNAS license. of copper(III) to rapidly undergo reductive elimination (Fig. 1B). 1To whom correspondence may be addressed. Email: [email protected]. Herein, we report a photocatalytic approach to the Ullmann– This article contains supporting information online at https://www.pnas.org/lookup/suppl/ Goldberg coupling that allows a broad range of para-, meta-, and doi:10.1073/pnas.2011831117/-/DCSupplemental. ortho-substituted aryl rings to readily undergo heteroarylation, while www.pnas.org/cgi/doi/10.1073/pnas.2011831117 PNAS Latest Articles | 1of7 Downloaded by guest on September 29, 2021 Fig. 1. Silanol-mediated copper metallaphotoredox catalysis enables a C(sp2)–N coupling. (A) The Ullmann–Goldberg coupling features a high–barrier ox- idative addition step overcome typically by high reaction temperatures, but this limits the aryl bromide scope to activated electrophiles. Sterically congested, nondirecting ortho- groups are not well tolerated under this activation mode. (B) A low-barrier HARC sequence is proposed that will deliver a similar in- termediate at room temperature, while a facile reductive elimination step should furnish the C–N coupled product. This strategy will enable the use of sterically congested bromoarenes and those electronically deactivated toward oxidative addition. (C) Mechanistic design for silanol-mediated copper metallaphotoredox C(sp2)–N coupling. Both the photoredox and copper cycles require exogeneous oxidant to turn over. 3 often problematic in traditional cross-couplings such as C(sp )- and a mechanistic distinction that carries significant implications for 2 C(sp )-trifluoromethyl groups (29, 30). Apart from the inherent reaction scope, catalyst development, and substrate tolerance utility of a catalytic CF3-installation pathway, these studies also (7). More specifically, this HARC Ullmann–Goldberg coupling demonstrate that formal aryl and alkyl Cu(III) intermediates might might allow 1) the implementation of a large array of ortho- be accessed (31) without the requirement of a high-barrier copper/ substituted aryl halides that were previously problematic or in- aryl halide OA step. ert due to steric interactions in the thermal copper-OA step, 2) Recently, we hypothesized that a copper–HARC mechanism the widescale use of aryl bromides in lieu of aryl iodides, the would have significant implications for the Ullmann–Goldberg former being more broadly available in structurally diverse for- coupling. As shown in Fig. 1, the use of photogenerated super- mats, 3) the use of simple copper salts [e.g., Cu(acac)2, acac = silyl radicals, in conjunction with aryl bromides, NH-heteroaryls, acetylacetonate]