Controlling Radical Relay Processes with Visible Light

Harnessing free radical intermediates for selective functionalization of organic compounds has been widely demonstrated under photocatalytic conditions requiring a distinct photocatalyst. In this issue of Chem, Seo, Chang, and co-workers demonstrate an alternative photocatalyst-free light-mediated approach that allows efficient amidation of aldehydes via N-centered radical intermediate. Harnessing free radical intermediates for selective functionalization of organic compounds has been widely demonstrated under photocatalytic conditions requiring a distinct photocatalyst. In this issue of Chem, Seo, Chang, and co-workers demonstrate an alternative photocatalyst-free light-mediated approach that allows efficient amidation of aldehydes via N-centered radical intermediate. Reactions featuring free radical intermediates occupy an exceptional position in synthetic organic chemistry. On the one hand, such reactions are frequently associated with poor chemoselectivity due to the high free energy of the involved intermediates. On the other hand, free radicals display profoundly different patterns in stability and reactivity compared with those of classical closed-shell species, allowing a multitude of otherwise unfeasible synthetic strategies to be implemented. In recent years, the applicability of free radical reaction manifolds has been propelled by the developments in preparative photochemistry1Li P. Terrett J.A. Zbieg J.R. Visible-Light Photocatalysis as an Enabling Technology for Drug Discovery: A Paradigm Shift for Chemical Reactivity.ACS Med. Chem. Lett. 2020; 11: 2120-2130Crossref PubMed Scopus (22) Google Scholar and electrosynthesis.2Shatskiy A. Lundberg H. Kärkäs M.D. Organic Electrosynthesis: Applications in Complex Molecule Synthesis.ChemElectroChem. 2019; 6: 4067-4092Crossref Scopus (62) Google Scholar The recurring theme in these efforts has been the generation of free radicals in a controlled manner and retention of their concentration at a minimum level to prevent deleterious side-processes. In photochemistry, this is typically achieved through the use of photoredox catalysis, where a redox-active photocatalyst mediates electron or electron-proton transfer events within the photocatalytic cycle. In this issue of Chem, Seo, Chang, and co-workers demonstrate an alternative photocatalyst-free approach, where the photoactive species responsible for formation of the free radical intermediates is steadily generated throughout the course of the reaction, preventing accumulation of unstable intermediates.3Lee W. Jeon H.J. Jung H. Kim D. Seo S. Chang S. Controlled Relay Process to Access N-Centered Radicals for Catalyst-free Amidation of Aldehydes under Visible Light.Chem. 2020; 7: 495-508Abstract Full Text Full Text PDF Scopus (8) Google Scholar Following this strategy, the authors achieved efficient and selective C–H bond activation of aldehydes to form N-Boc-protected carboxamides via hydrogen atom transfer (HAT) between the aldehyde and a transient N-centered radical intermediate. The cornerstone of the synthetic strategy pursued by the authors relied on selecting a photostable amidating agent, which could be controllably converted into its photolabile form during the reaction. Inspired by the previously disclosed oxidative iodine-mediated protocols for in situ formation of N-iodoamine radical precursors,4Martínez C. Muñiz K. An Iodine-Catalyzed Hofmann-Löffler Reaction.Angew. Chem. Int. Ed. 2015; 54: 8287-8291Crossref PubMed Scopus (204) Google Scholar,5Wappes E.A. Fosu S.C. Chopko T.C. Nagib D.A. Triiodide-Mediated δ-Amination of Secondary C-H Bonds.Angew. Chem. Int. Ed. 2016; 55: 9974-9978Crossref PubMed Scopus (157) Google Scholar the authors selected N-chloro-N-sodio carbamate (1) as a cheap and bench-stable amidating agent.6Xie W. Yoon J.H. Chang S. (NHC)Cu-Catalyzed Mild C-H Amidation of (Hetero)arenes with Deprotectable Carbamates: Scope and Mechanistic Studies.J. Am. Chem. Soc. 2016; 138: 12605-12614Crossref PubMed Scopus (43) Google Scholar Photostability studies revealed that the sodium salt 1 is kinetically stable under visible light irradiation, whereas its protonated counterpart (N-chloroamide) promptly undergoes light-initiated homolytic N–Cl bond cleavage. The same photolability was expected from N-chloroamide 3, an acylated form of 1, obtained from the reaction between 1 and an acyl chloride 2 (Figure 1A). Indeed, the proof-of-concept reaction between 3 and benzaldehyde furnished the expected N-Boc-protected carboxamide 4 in high yield via a light-initiated HAT reaction between benzaldehyde and N-centered radical generated from 3 while also generating acyl chloride 2 as a by-product. Algebraically combining the two abovementioned reactions reveals that the acyl chloride by-product of the second reaction is also a reagent in the first reaction. Therefore, only a catalytic amount of acyl chloride 2 is needed for transforming N-chloro-N-sodio carbamate 1 and benzaldehyde into carboxamide 4 when the two reactions are combined in one pot (Figure 1B). This reaction then proceeds through a light-promoted catalytic relay mechanism, where the formation of the key N-centered radical intermediate via light-initiated homolytic N–Cl bond cleavage is controlled by the amount of the added acyl chloride 2. Indeed, conducting this reaction with 1 mol% of benzoyl chloride delivered the expected amidation product 4 in excellent yield (97%). Notably, the reaction also proceeded to the same extent even in the absence of the acyl chloride catalyst, although it required an induction period. During this period a small amount of free radical species needed to onset the catalytic cycle is likely being generated by slow decomposition of N-chloro-N-sodio carbamate 1. Further optimization of the reaction conditions and mechanistic studies revealed that although the light-mediated amidation of aromatic aldehydes proceeds efficiently in the absence of the acyl chloride catalyst, aliphatic aldehydes suffer from formation of aldol side-products and addition of the catalyst is strictly necessary. The acyl chloride catalyst for these reactions could be efficiently replaced by benzoic acid as an additive, which was shown to generate the corresponding acyl chloride in situ, further simplifying the developed protocol. Finally, the model reaction revealed a considerably high quantum yield (Φ = 19.5), indicating that an innate radical chain mechanism is operational in parallel to the initially envisioned light-mediated catalytic cycle. For such a mechanism the chain propagation and formation of the N-centered radical intermediate could proceed via Cl atom abstraction from 3 by an acyl radical intermediate. The disclosed protocol was applied to a broad range of aromatic and aliphatic aldehydes featuring numerous functional groups commonly encountered in synthetic organic chemistry (Figure 1C). The reaction proceeded swiftly by using near stoichiometric amounts of the aldehyde and the amidating agent, delivering the expected N-carbamate products in generally high yields (50%–90%). Furthermore, the benign character and synthetic utility of the developed transformation was demonstrated by late-stage functionalization of complex natural products, including betulin, (+)-δ-tocopherol, and β-estradiol, and by preparation of an analog of the synthetic drug febuxostat (Figure 1D). To conclude, the disclosed light-promoted protocol exemplifies a largely underdeveloped alternative to the now ubiquitous photoredox-catalyzed reaction manifolds. Most importantly, it exemplifies how highly unstable N-centered free radical intermediates can be harnessed for selective functionalization of organic compounds without the use of a photoredox catalyst and complex pre-functionalized starting materials, which is a common prerequisite for the related photocatalytic reactions.7Kärkäs M.D. Photochemical Generation of Nitrogen-Centered Amidyl, Hydrazonyl, and Imidyl Radicals: Methodology Developments and Catalytic Applications.ACS Catal. 2017; 7: 4999-5022Crossref Scopus (217) Google Scholar A peculiar feature of the protocol is also that formation of the C–N bond in the product proceeds through nucleophilic addition, whereas in many of the previously described C–N bond-forming reactions featuring N-centered radicals the new covalent bond is formed by addition of an N-centered radical to an unsaturated carbon center. Building on the synthetic approach disclosed by Seo, Chang, and co-workers could certainly lead to more general light-mediated strategies, especially in the context of the renewed interest by the synthetic community in innate radical chain reaction manifolds.8Studer A. Curran D.P. Catalysis of Radical Reactions: A Radical Chemistry Perspective.Angew. Chem. Int. Ed. 2016; 55: 58-102Crossref PubMed Scopus (675) Google Scholar,9Kärkäs M.D. Matsuura B.S. Stephenson C.R.J. Enchained by Visible Light-Mediated Photoredox Catalysis.Science. 2015; 349: 1285-1286Crossref PubMed Scopus (74) Google Scholar Financial support from FORMAS ( 2019-01269 ), the Swedish Research Council ( 2020-04764 ), the Magnus Bergvall foundation , and the KTH Royal Institute of Technology to M.D.K. is gratefully acknowledged. The Olle Engkvist Foundation and the Wenner-Gren Foundation are kindly acknowledged for postdoctoral fellowships to A.S. and J.L., respectively. Controlled Relay Process to Access N-Centered Radicals for Catalyst-free Amidation of Aldehydes under Visible LightLee et al.ChemDecember 31, 2020In BriefA catalyst-free approach for controlled access to N-centered radicals is described, which enables the conversion of aldehydes to amides via an unconventional relay process harnessing visible light. The key tactic relies on the use of photostable N-chloro-N-sodio-carbamate amidating reagent that leads to slow incorporations of a photoactive radical source via C–N formation and other involved intermediates thereafter. This methodology displays excellent applicability and sustainable chemistry credentials and, thus, holds a promise for finding broad applications. Full-Text PDF