N-Iodosuccinimide-Promoted Hofmann–Löffler Reactions of Sulfonimides under Visible Light

Abstract

ABSTRACT:Conditions for an attractive and productive protocol for the position-selective intramolecular C-H amination of aliphatic groups (Hofmann-Löffler reaction) are reported employing sulfonimides as nitrogen sources. N-Iodosuccinimide is the only required promoter for this transformation, which is conveniently initiated by visible light. The overall transformation provides pyrrolidines under mild and selective conditions as demonstrated for 17 different substrates.The intramolecular C-H amination of aliphatic groups has recently attracted significant interest from the synthetic community. Major work has focused on the identification of suitable transition metal catalysts to provide the aforementioned transformation. 1 Directed evolution of metalloproteins has recently emerged as a complimentary approach. 2 An alternative consists of the use of small organocatalysts 3 as non-metallic promoters, which, due to their capability to avoid metal contamination, is of major importance to fields such as biological and medicinal synthesis.From a historical perspective, the halide-mediated C-N bond formation at non-activated hydrocarbons was discovered over a century ago and is well established as the Hofmann-Löffler reaction. 4 The general conditions call for preformation of a halogenated amine, which upon irradiation in the presence of strong acid promotes C-H halogenation, which is usually followed by basemediated pyrrolidine formation. A useful modification providing significantly milder reaction conditions was introduced by Suarez, 5 who reported that Hofmann-Löffler-type cyclization reactions can be conducted in the presence of a mixture of molecular iodine and a hypervalent iodine reagent of the general structure ArI(O 2 CR) 2 . 6 This protocol was employed by Fan, who demonstrated its compatibility with sulfonamides as nitrogen sources. 7 We have recently demonstrated that this reaction can be conducted with catalytic amounts of iodine and the use of a single equivalent of hypervalent iodine(III) as the terminal oxidant. 8 This accomplishment has demonstrated that iodine catalysis is indeed feasible within the borders of the Hofmann-Löffler reaction, provided that the iodine concentration is maintained at a sufficient level to perpetuate the two intertwined catalytic cycles. However, the permanent requirement of using a hypervalent iodine reagent as a terminal oxidant 9 has triggered interest in whether the reaction could also be conducted with just a single amount of halide reagent as a stoichiometric promoter. Such a reaction would serve as an important addition to the existing protocols for Hofmann-Löffler reactions.

Role of Lewis‐Base‐Coordinated Halogen(I) Intermediates in Organic Synthesis: The Journey from Unstable Intermediates to Versatile Reagents

“…The most commonly used, and commercially available, NI reagent is N ‐iodosuccinimide (NIS). Some important reactions in which NIS is used as a reagent are depicted in Figure , …”

Selective Piperidine Synthesis Exploiting Iodine-Catalyzed Csp3–H Amination under Visible Light

“…We previously reported that iodinated reagents such as NIS 1b effectively provide intermediates for exclusive Hofmann-Löffler reactions. 12 As a consequence of this observation and in order to prevent potential background reactions, we turned to less reactive bromine-based reagents. Catalytic amounts of molecular iodine 13 were pursued to generate low amounts of free radicals as the reaction carriers and thus to minimize potential side reactions.…”

Multiple Halogenation of Aliphatic C−H Bonds within the Hofmann–Löffler Manifold

“…The same occurred for the related tetrahydronaphthalene substrates, which displayed additional selective C−H bromination from 1,5‐ and 1,6‐HAT, affording products 6 e , f , which are also formed in a completely diastereoselective manner. In case of a higher excess of hydantoin 2 b , dibrominated ketone 6 d was obtained as a single diastereomer, in which the carbonyl group was formed from hydrolysis of the geminal dibromination product . Use of a longer propyl spacer provided the tribrominated products 6 g , h without cyclization.…”