N-Containing Heterocycles on Demand by Merging Ni Catalysis and Photoredox PCET

Abstract

Nitrogen-containing heterocycles are among the most ubiquitous motifs in pharmaceuticals. Therefore, the design of mild, practical, and modular protocols for their synthesis is still in high demand. In this issue of Chem, Molander and co-workers report the merger of visible-light photoredox proton-coupled electron transfer (PCET) with nickel catalysis as a vehicle for rapidly accessing privileged five-membered heterocyclic cores from simple precursors. Nitrogen-containing heterocycles are among the most ubiquitous motifs in pharmaceuticals. Therefore, the design of mild, practical, and modular protocols for their synthesis is still in high demand. In this issue of Chem, Molander and co-workers report the merger of visible-light photoredox proton-coupled electron transfer (PCET) with nickel catalysis as a vehicle for rapidly accessing privileged five-membered heterocyclic cores from simple precursors. The presence of nitrogen-containing heterocycles in more than half of the small-molecule drugs approved by the US FDA is so pervasive that the inclusion of these structures is often visualized as a necessary requisite in industrial endeavors.1Vitaku E. Smith D.T. Njardarson J.T. Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among U.S. FDA approved pharmaceuticals.J. Med. Chem. 2014; 57: 10257-10274Crossref PubMed Scopus (2957) Google Scholar Among these, particularly prevalent are five-membered nitrogen-containing heterocycles, such as pyrrolidones, oxazolidinones, or imidazolidinones, among many others.2Caruano J. Muccioli G.G. Robiette R. Biologically active γ-lactams: synthesis and natural sources.Org. Biomol. Chem. 2016; 14: 10134-10156Crossref PubMed Google Scholar Although significant progress has been made for preparing these rather appealing structures by a myriad of synthetic methods, it is a worthwhile endeavor to contemplate possible alternative ways to synthesize them with improved flexibility, generality, and practicality. Driven by the favorable attributes of visible-light-mediated photoredox catalysis—an emerging new synthetic tool that enables challenging bond-forming reactions that are oftentimes not accessible under standard approaches3Shaw M.H. Twilton J. MacMillan D.W.C. Photoredox catalysis in organic chemistry.J. Org. Chem. 2016; 81: 6898-6926Crossref PubMed Scopus (1713) Google Scholar—chemists have been challenged to forge C(sp3)–N bonds via light-induced processes. Among various conceivable scenarios, the ability to harness the inherent reactivity of amidyl radicals might open a gateway to nitrogen-containing heterocycles. Any synthetic approach aimed at accessing well-defined amidyl radicals from ubiquitous N–H bonds under mild conditions, however, might face notorious chemical constraints: (1) the N–H bond-dissociation free energy is exceptionally high (∼100 kcal/mol), so homolytic cleavage is thermodynamically uphill; and (2) conventional methods for generating amidyl radicals via N–H scission typically require strong stoichiometric oxidants (DMP, IBX, or peroxides), whereas harsh conditions such as UV light irradiation and/or reducing agents are needed when pre-functionalized N–X motifs (X = Cl, SPh, OAr or SO2Ar) are employed. This limits the synthetic utility of these protocols, particularly when these technologies are applied within the context of late-stage functionalization of advanced synthetic intermediates. Therefore, one could conclude that a milder method capable of accessing amidyl radicals in a practical and reliable manner might provide a new fertile ground for applications on industrial venues while offering new reactivity principles for the total synthesis of structurally complex natural products. In 2015, Knowles and co-workers demonstrated that amidyl radicals could be generated under exceptionally mild conditions from unfunctionalized amides via concerted proton-coupled electron transfer (PCET) in combination with photoredox catalysis,4Choi G.J. Knowles R.R. Catalytic alkene carboaminations enabled by oxidative proton-coupled electron transfer.J. Am. Chem. Soc. 2015; 137: 9226-9229Crossref PubMed Scopus (213) Google Scholar thus opening new chemical space for the synthesis of amides and related compounds via C–N bond-forming reactions.5Davies J. Sheikh N.S. Leonori D. Photoredox imino functionalizations of olefins.Angew. Chem. Int. Ed. 2017; 56: 13361-13365Crossref PubMed Scopus (166) Google Scholar Although recent disclosures have shown that photochemically driven hydrogen-atom-transfer pathways can successfully be interfaced with nickel-catalyzed cross-coupling reactions,6Heitz D.R. Tellis J.C. Molander G.A. Photochemical nickel-catalyzed C-H arylation: synthetic scope and mechanistic investigations.J. Am. Chem. Soc. 2016; 138: 12715-12718Crossref PubMed Scopus (313) Google Scholar, 7Shields B.J. Doyle A.G. Direct C(sp3)-H cross coupling enabled by catalytic generation of chlorine radicals.J. Am. Chem. Soc. 2016; 138: 12719-12722Crossref PubMed Scopus (379) Google Scholar, 8Shen Y. Gu Y. Martin R. sp3 C-H arylation and alkylation enabled by the synergy of triplet excited ketones and nickel catalysts.J. Am. Chem. Soc. 2018; 140: 12200-12209Crossref PubMed Scopus (201) Google Scholar, 9Perry I.B. Brewer T.F. Sarver P.J. Schultz D.M. DiRocco D.A. MacMillan D.W.C. Direct arylation of strong aliphatic C-H bonds.Nature. 2018; 560: 70-75Crossref PubMed Scopus (276) Google Scholar the ability to synergistically combine the modularity of PCET with the flexibility in synthetic design offered by transition-metal catalysts has still remained an unexplored cartography. In this issue of Chem, Molander and co-workers report the successful realization of this goal by taming the reactivity of amidyl radical intermediates as a gateway to enabling the visible-light-mediated photochemical difunctionalization of unactivated olefins en route to a variety of medicinally relevant five-membered nitrogen-containing heterocycles via sequential C(sp3)–N and C(sp2)–C(sp3) bond formations (Figure 1).10Zheng S. Gutiérrez-Bonet A. Molander G.A. Merging photoredox PCET with Ni-catalyzed cross-coupling: cascade amidoarylation of unactivated olefins.Chem. 2019; 5PubMed Google Scholar Preliminary mechanistic experiments suggest the initial PCET-mediated formation of an amidyl radical that subsequently triggers a rapid 5-exo-trig cyclization with a pending olefin, leading to a transient alkyl radical intermediate. Although there exists a reasonable ambiguity on whether the alkyl radical is intercepted by either LnNi(0) or aryl-Ni(II)Ln oxidative addition species, a final reductive elimination would ultimately deliver the targeted products. The resulting LnNi(I) is then interfaced with the photochemical regime by a final single-electron transfer event, thus recovering back the propagating catalytic species. The transformation is distinguished by a broad scope, including particularly challenging substrate combinations, and an excellent chemoselectivity profile, allowing access to a variety of five-membered nitrogen-containing heterocycles in a cascade-type fashion from simple precursors. These virtues allow pyrrolidinone, oxazolidinone, and imidazolidinone formation to take place at late stages of syntheses, as illustrated by the successful preparation of aryl glycosides or zolmitriptan analogs, among others. In light of the data provided, it is fairly apparent that the approach reported by Molander and co-workers opens an orthogonal gateway that complements existing methodologies for accessing N-heterocyclic products. In addition, this method provides a glimpse at the inherent potential that PCET and nickel catalysis offer for innovative heterocyclic chemistry. In view of the growing interest in nickel-catalyzed reactions and visible-light-mediated photoredox endeavors, it is inevitable to predict that this new technique will serve as the blueprint to even more demanding targets, including the always-elusive densely functionalized heterocyclic cores possessing quaternary carbon centers, the means to switch the site-selectivity pattern for accessing a different set of nitrogen-containing heterocycles, and the development of enantioselective variants of this or related processes. Merging Photoredox PCET with Ni-Catalyzed Cross-Coupling: Cascade Amidoarylation of Unactivated OlefinsZheng et al.ChemJanuary 3, 2019In BriefA rapid, highly diastereoselective amidoarylation of unactivated olefins was achieved to render medicinally privileged pyrrolidinone structures. Taking advantage of a photoredox proton-coupled electron transfer process, amidyl radicals were obtained from non-prefunctionalized N–H bonds under mild conditions, which were subsequently trapped by pendant olefins, delivering alkyl radicals for nickel-catalyzed cross-coupling. Mechanistic studies revealed the key balance between thermodynamically-driven radical generation and kinetically-driven cyclization, which led to expanding the scope toward urea and carbamate substrates. Full-Text PDF Open Archive