Sulfamyl Radicals Direct Photoredox-Mediated Giese Reactions at Unactivated C(3)–H Bonds

Abstract

Alcohol-anchored sulfamate esters guide the alkylation of tertiary and secondary aliphatic C(3)−H bonds. The transformation proceeds directly from N−H bonds with a catalytic oxidant, a contrast to prior methods which have required preoxidation of the reactive nitrogen center, or employed stoichiometric amounts of strong oxidants to obtain the sulfamyl radical. These sulfamyl radicals template otherwise rare 1,6-hydrogen-atom transfer (HAT) processes via seven-membered ring transition states to enable C(3)−H functionalization during Giese reactions.N itrogen-centered radicals are an important and versatile class of chemical intermediates. 1 Yet, nitrogen-centered radicals remain underutilized, as most methods for their generation rely on harsh conditions to oxidize the nitrogen center. Recently, photocatalytic strategies have been developed as mild processes to form nitrogen-centered radicals; 2−6 however, only amides, carbamates, and sulfonamides have served as precursors to neutral nitrogen-centered radicals. 4−6 These groups template position-selective C−H functionalization technologies, transforming C(4)−H bonds through 1,5-HAT processes (Scheme 1A). 7 In contrast, sulfamate esters guide functionalization to C(3)−H centers through otherwise rare 1,6-HAT processes (Scheme 1B), providing complementary positional selectivity to established processes. 8−16 As a complement to known guided methods, sulfamate esters are attractive directing groups because they derive from alcohols, which are ubiquitous in biologically active small molecules. To date, protocols templated by sulfamate ester substrates require preoxidation of the reactive nitrogen center, or the use of strong stoichiometric oxidants to access nitrogen-centered sulfamyl radicals. 14,15 As such, a strategy to facilitate sulfamyl radical formation directly from N−H bonds under mild conditions would enhance the substrate tolerance of these directing motifs, and could also enable previously unrealized synthetic disconnections. 17,18 Herein disclosed is the first catalytic process to access free sulfamyl radicals directly from N−H bonds. 19 These sulfamyl radicals have been engaged in Giese reactions, in the only examples of C(3)−H alkylation reactions guided by alcohol surrogates (Scheme 1C, 1 → 2).At the outset of these investigations, we sought conditions that would facilitate oxidation of sulfamate ester 1a to sulfamyl radical 3a. We envisioned that this could occur through an initial deprotonation to provide sulfamate ester anion 4a. Anion 4a could undergo single electron oxidation to generate sulfamyl radical 3a, with concurrent reduction of the excited iridium catalyst 6a (Scheme 2). Consistent with this proposal, in acetonitrile, sodiated 5-methylhexyl N-tert-butyl sulfamate ester anion 4a has a half-peak potential (E p/2 ) of +0.753 V

Radikal‐basierte Synthese und Modifikation von Aminosäuren

“…Mit dem Aufkommen der PRK hat die Verwendung von 13 in radikalischen Prozessen eine Renaissance erlebt. Infolgedessen wurden Methoden entwickelt, die Alkohole, [67] Heteroarylhalogenide, [68] Amine, [69] C(sp 3 )-H-Bindungen [70] oder a-Keto-und Carbonsäuren als Radikalvorläufer verwenden. [71] 2017 berichtete Jui über eine praktische und skalierbare lichtvermittelte Synthese von Heteroaryl-a-AS (Abbildung 22 A).…”

Radical‐Based Synthesis and Modification of Amino Acids

“…With the advent of PRC, the use of 13 in radical processes has experienced a resurgence. As a result, methods using alcohols, [67] heteroaryl halides, [68] amines, [69] C(sp 3 )−H bonds, [70] or α‐keto and carboxylic acids as radical precursors have been developed [71]…”

“…TheBeckwith-Karady alkene 13 is achiral Dha derivative developed in the early 1990s. [66] Over the years, 13 has been employed to establish highly diastereoselective routes for the synthesis of UAAs.W ith the advent of PRC,the use of 13 in radical processes has experienced ar esurgence.A sar esult, methods using alcohols, [67] heteroaryl halides, [68] amines, [69] C(sp 3 ) À Hb onds, [70] or a-keto and carboxylic acids as radical precursors have been developed. [71] In 2017, Juia nd co-workers reported ap ractical and scalable light-mediated synthesis of heteroaryl a-AAs (Scheme 22 A).…”

Organophotocatalytic dearomatization of indoles, pyrroles and benzo(thio)furans via a Giese-type transformation

“…Recent efforts on the study of photoredox catalysis under mild reaction conditions have made the process greener and more atom economical (Fig. 1b) [36][37][38][39][40][41][42][43][44][45][46][47] . In this process, the unsaturated C=C bond is transformed into a saturated C-C bond in a conjugate addition manner.…”

“…Nonetheless, the reversed reactivity of the addition of a nucleophilic radical to an electron-poor C 2 =C 3 bond of indoles is unknown. Moreover, even though incorporation of EWGs into the C 2 or C 3 positions of indoles could reverse the polarity from the innate nucleophilic to electrophilic system and serve as a potential radical acceptor, the weakly electron-deficient indoles render the Giese reaction more difficult because more electron deficient, less hindered α, β-unsaturated systems are generally used for effective nucleophilic radical addition [36][37][38][39][40][41][42][43][44][45][46][47] . Furthermore, in the photoredox process, possible oxidation of the weakly electron-deficient indole systems could complicate the process.…”