Manganese-Catalyzed Oxidative Azidation of C(sp³)–H Bonds under Electrophotocatalytic Conditions

Abstract

The selective installation of azide groups into C­(sp3)–H bonds is a priority research topic in organic synthesis, particularly in pharmaceutical discovery and late-stage diversification. Herein, we demonstrate a generalized manganese-catalyzed oxidative azidation methodology of C­(sp3)–H bonds using nucleophilic NaN3 as an azide source under electrophotocatalytic conditions. This approach allows us to perform the reaction without the necessity of adding an excess of the substrate and successfully avoiding the use of stoichiometric chemical oxidants such as iodine­(III) reagent or NFSI. A series of tertiary and secondary benzylic C­(sp3)–H, aliphatic C­(sp3)–H, and drug-molecule-based C­(sp3)–H bonds in substrates are well tolerated under our protocol. The simultaneous gram-scale synthesis and the ease of transformation of azide to amine collectively advocate for the potential application in the preparative synthesis. Good reactivity of the tertiary benzylic C­(sp3)–H bond and selectivity of the tertiary aliphatic C­(sp3)–H bond in substrates to incorporate nitrogen-based functionality at the tertiary alkyl group also provide opportunities to manipulate numerous potential medicinal candidates. We anticipate our synthetic protocol, consisting of metal catalysis, electrochemistry, and photochemistry, would provide a new sustainable option to execute challenging organic synthetic transformations.

Mangana(iii/iv)electro-catalyzed C(sp3)–H azidation

“…Key features of our findings include (a) C(sp 3 )–H azidation via synergistic electrosynthesis and an Earth-abundant manganese catalyst, (b) mild and chemical oxidant-free reaction conditions, (c) high regio- and chemoselectivity, (d) and late-stage azidation of bioactive compounds. It is noteworthy that efficient manganese-catalyzed electro-azidation occurred in the absence of photochemical irradiation, 15 with detailed mechanistic studies being supportive of a manganaelectro( iii / iv ) regime. We initiated our studies by probing various reaction parameters for the envisioned manganaelectro-catalyzed C(sp 3 )–H azidation of unactivated alkane 1b (BDE C–H: 95.7 kcal mol −1 , 30 E ox ≥ 2.5 V 31 ) ( Tables 1 and S-2–S-5 in the ESI † ).…”

“… 9 Due to this key importance, 10 a plethora of functional group interconversion strategies have been developed, exploiting inter alia organic halides, alcohols, epoxides, and aldehydes. However, more step-economical methods that directly install the azido-group into otherwise inert C(sp 3 )–H bonds continue to be scarce 11 and generally require stoichiometric amounts of strong indiscriminate chemical oxidants, such as persulfates, 12 N -fluorobenzenesulfonimide (NFSI), 13 hypervalent iodine reagents 14 or photochemical 15 irradiation. 16 In previous reports on selective electrochemical vicinal diazidation of olefins, a metal-free approach was introduced by Schäfer in 1970 ( Scheme 1a ).…”

Photochemical and Electrochemical Strategies towards Benzylic C−H Functionalization: A Recent Update

“…Finally, there is a recently published work from Lei's group regarding C( sp 3 )−H bonds azidation (Scheme 53). [106] Their approach has lifted manganese‐catalysed oxidative azidation by replacing stoichiometric amounts of external oxidants under photoelectrochemical conditions. The photocatalyst, upon excitation, activates the C( sp 3 )−H bond via HAT.…”

Site‐Selective Electrochemical Benzylic C−H Amination

“…[2] Previously reported C-(sp 3 )-H amination reactions usually involve transition metalcatalyzed nitrene insertion [3] or photochemically promoted hydrogen atom transfer (HAT). [4,5] While excellent efficiencies have been observed for benzylic C À H amination employing alkanes as the limiting agent, ample room exists for further development to address site-and chemoselectivities and avoid using stoichiometric oxidants such as hypervalent iodine reagents.…”