Efficient, intermolecular, oxidative radical alkylation of heteroaromatic systems under “tin-free” conditions

Abstract

Novel and efficient radical alkylation of several heterocyclic systems including pyrroles, indoles, furan and thiophenes is described using xanthate based radical chemistry. The present methodology could be used to provide rapid access to various nonsteroidal antiinflammatory drugs.

Powerful CarbonCarbon Bond Forming Reactions Based on a Novel Radical Exchange Process

“…This is indicated by the banal conversion into two amides by exposure to cyclopropylamine and to a piperidine derivative. It is also worth mentioning that intermolecular reactions can be accomplished in some cases, as demonstrated by the expedient synthesis of ethyl 2-indole acetate 60, recently reported by Miranda et al [55] Furans often behave differently and their reactions can reveal the reality of the radical-polar crossover. [56] Instead of the expected fused structure, the ring closure leads to a spiro-intermediate 61, which is oxidised by the peroxide into cation 62, as delineated in Scheme 31.…”

Five‐Membered Heterocycles: Furan

“…For example, an acetyl radical, generated from a xanthate, reacts with 2-acetylfuran to provide the a-substituted product [167]. As illustrated in Scheme 6.89, addition of the alkenyl radical generated from the cyclohexenyl bromide 192 to the pendant furan moiety gives the spirodihydrofuran radical intermediate 193.…”

Five‐Membered Heterocycles: Pyrrole and Related Systems

“…Alternative procedures for the synthesis of pyrrole-2-acetic acid derivatives involve generation of radicals from various iodoacetates induced by stannanes [423] or under conditions avoiding stannanes, by irradiation [423,424] or epoxydecane as the HI trap [425]. Pyrroles possessing electron-withdrawing groups at C2 undergo related alkylation reactions at C5 with a-acetyl or a-acetonyl radicals generated by exposure of suitable xanthate based precursors to dilauroyl peroxide [426]. Similar intramolecular processes provide routes to fused pyrroles, as illustrated by the manganese(III) acetate generated in situ induced conversion of the 2-aroylpyrrole 284 into the fused system 285 (Scheme 4.81), a useful precursor to the analgesic molecule ketorolac (10) [427].…”