Access to 3‐(2‐Oxoalkyl)‐azaspiro[4.5]trienones via Acid‐Triggered Oxidative Cascade Reaction through Alkenyl Peroxide Radical Intermediate

Abstract

Azaspiro[4.5]trienones bearing ketone side chains at the 3-position are prepared from Nalkyl-arylpropiolamides and ketones via oxidative 1,2-difunctionalization of alkynes. The cascade sequence starts with the generation of alkenyl peroxide intermediates, which are obtained by addition of tert-butyl hydroperoxide to ketones in presence of a catalytic amount of a strong acid. Then, the ketone radical adds to alkynes, followed by spirocyclization and dearomatization process. This method represents a new example of difunctionalization of alkynes with simultaneous formation of two carbonÀcarbon single bonds and one carbonÀoxygen double bond in one step.

The Persistent Radical Effect in Organic Synthesis

“…[59] Furthermore,m ore complex cascades were developed along those lines. [60,61] Another beautiful sequence taking advantage of the PRE with peroxyl radicals as in situ generated scavengers is shown in Figure 14 a. Thee sters and amides 44 derived from propiolic acid derivatives and anilines or phenols were used as radical acceptors.I nt he first step,at ransient radical generated by ar edox reaction adds regioselectively to the CÀCt riple bond of 44 to give av inyl radical 45.I ts ipso cyclization onto the arene of the aniline or phenol moiety leads to cyclohexadienyl radical 46,w hich is trapped by tertbutylperoxyl to give peroxide 47,which can undergo aK ornblum-DeLaMare rearrangement [62] to finally provide ketone 48.T his sequence was successfully conducted with various radicals RC using different radical precursors.A lkyl radicals derived from ethers, [63] ketones, [64] or alkanes, [65] acyl radicals from aldehydes, [66] CF 3 radicals from the Langlois reagent, [67] SCF 3 radicals from AgSCF 3 , [68] silyl radicals from silanes, [69] and sulfonyl radicals from sulfonylhydrazides engage in this spirocyclization cascade. [70] Recently,t he groups of Wu and Zhong presented an oxidative cyclization of ethylene-bridged aminoindoles 48 to afford peroxypyrroloindolines 49 with t-BuOOH as the oxidant in combination with TBAI ( Figure 14 b).…”

“…a) Radical spirocyclization with the tert-butylperoxyl radical as atrapping reagent. [63][64][65][66][67][68][69][70] b) Oxidative indole functionalization to access peroxypyrroloindolenines 49. [71] Figure 15.…”

“…using different radical precursors. Alkyl radicals derived from ethers, ketones, or alkanes, acyl radicals from aldehydes, CF 3 radicals from the Langlois reagent, SCF 3 radicals from AgSCF 3 , silyl radicals from silanes, and sulfonyl radicals from sulfonylhydrazides engage in this spirocyclization cascade …”

Recent Advances in the Construction of Spiro Compounds via Radical Dearomatization

“…[15] In 2019, Soulé and co-workers developed a TBHP-promoted difunctionalization of activated alkynes with ketones, which enabled radical cascade addition-spirocyclization-dearomatization process (Scheme 5). [16] Initially, the reaction was initiated by the formation of alkenyl peroxide intermediate 18 from ketones and tert-butyl hydroperoxide in the presence of p-TsOH. Then, 20 and 4 radical intermediates from 19 were generated through homolytic bond cleavage.…”

Der “Persistent Radical Effect” in der organischen Chemie

“…Diese Sequenz wurde mit einer Vielzahl verschiedener Radikale RC durchgeführt. In dieser spiro-Cyclisierung wurden Alkyl-Radikale von Ethern, [63] Ketonen [64] bzw.A lkanen, [65] Acyl-Radikale von Aldehyden, [66] CF 3 -Radikale vom Langlois-Reagenz, [67] SCF 3 -Radikale vom AgSCF 3 , [68] Silyl-Radikale von Silanen [69] und Sulfonyl-Radikale von Sulfonylhydraziden [70] eingesetzt.…”