Radical aryl migration enables diversity-oriented synthesis of structurally diverse medium/macro- or bridged-rings

Abstract

Medium-sized and medium-bridged rings are attractive structural motifs in natural products and therapeutic agents. Due to the unfavourable entropic and/or enthalpic factors with these ring systems, their efficient construction remains a formidable challenge. To address this problem, we herein disclose a radical-based approach for diversity-oriented synthesis of various benzannulated carbon- and heteroatom-containing 8–11(14)-membered ketone libraries. This strategy involves 1,4- or 1,5-aryl migration triggered by radical azidation, trifluoromethylation, phosphonylation, sulfonylation, or perfluoroalkylation of unactivated alkenes followed by intramolecular ring expansion. Demonstration of this method as a highly flexible tool for the construction of 37 synthetically challenging medium-sized and macrocyclic ring scaffolds including bridged rings with diverse functionalities and skeletons is highlighted. Some of these products showed potent inhibitory activity against the cancer cell or derivative of human embryonic kidney line in preliminary biological studies. The mechanism of this novel strategy is investigated by control experiments and DFT calculations.

Alkene 1,2‐Difunctionalization by Radical Alkenyl Migration

“…Vicinal difunctionalization through radical perfluoroalkylation and subsequent intramolecular formyl,8a aryl,8b cyano,8c and heteroaryl4e, 8d migration has been documented previously (Scheme 1). Moreover, Zhu and co‐workers and our group reported cascade reactions involving a radical 1,4‐alkynyl‐group migration 9.…”

9‐Membered Carbocycles: Strategies and Tactics for their Synthesis

“…Buildingu pon their previous work on the constructiono f benzannulated medium-sizedr ings via ring-expansion, the Liu group reported on the synthesis of carbocycles of medium and large ring size by using ar adical ipso-substitution strategy in 2016. [33] Generation of the radicals was realized by using hypervalent iodine(III) reagents and copper(I) cyanide( R = N 3 , CF 3 ), alkyl or aryl sulfonyl chlorides (R = SO 2 R',C 4 F 9 )a nd copper(I) iodide, or diphenylphosphine oxide and silver(I) nitrate (R = P(O)Ph 2 ). The first step of their procedure is the addition of the generated radicals to the terminal alkene of substrate 48 (Scheme13).…”

Recent Applications of the Zhdankin Reagent in Organic Synthesis

“…The latter methodology allows the generation of radicals under particularly mild conditions. The Zhdankin reagent is frequently employed in tandem with a metal catalyst such as copper [7][8][9][10][11][12] or iron. [13,14] This article highlights some notable applications of molecule 3 that have appeared since 2016.…”