Photoredox-Catalyzed Alkylarylation of N-Aryl Bicyclobutyl Amides with α-Carbonyl Alkyl Bromides: Access to 3-Spirocyclobutyl Oxindoles

Abstract

A visible-light-induced radical alkylarylation of N-aryl bicyclobutyl amides with α-carbonyl alkyl bromides for the synthesis of functionalized 3-spirocyclobutyl oxindoles is described in which β-selective radical addition of the alkyl radical to N-aryl bicyclobutyl amides forms a key radical intermediate followed by interception with intrinsic arene functional group. This approach can be applicable to a wide range of α-carbonyl alkyl bromides, including primary, secondary, and tertiary α-bromoalkyl esters, ketones, nitriles, and nitro compounds.

Oxidative Difunctionalization of N-Aryl Bicyclobutyl Amides with Aldehydes: Divergent Synthesis of Acylated and Alkylated 3-Spirocyclobutyl Oxindoles

“…Currently, a few examples of difunctionalization of BCBs have been established. , For example, Mykhailiuk and Anderson reported a halosulfonylation of BCBs with sulfinate salts and halogen reagents in the presence of catalytic Et 3 B (Scheme a) . In addition, photoinduced difunctionalizations of BCBs with a diverse array of functional reagents have been successfully achieved (Scheme b). ,, Despite all these noteworthy advancements, reports of dicarbofunctionalization of BCBs remains scarce …”

“…Recently, our group developed a radical approach for the oxidative cyclization of N -aryl BCB-amides, that is, a visible-light-induced alkylarylation of BCBs with α-carbonyl alkyl bromides and a sulfonylarylation of BCBs with 4-alkyl 1,4-dihydropyridines (DHPs) and Na 2 S 2 O 5 (Scheme c), which offers a new synthetic toolkit toward functionalized 3-spirocyclobutyl oxindoles . To further expand the applications of this strategy in difunctionalization of BCBs, we envisioned the possibility of developing a new dicarbofunctionalization reaction of N -aryl BCB-amides with readily available aldehyde feedstocks .…”

Photoredox-Catalyzed Strain-Release-Driven Synthesis of Functionalized Spirocyclobutyl Oxindoles

“…Among these motifs, spirocyclobutyl oxindoles have drawn the immense interest of researchers in recent years not only due to their presence in natural products but also for their broad spectrum of biological activities, including antifungal activity, action as phosphodiesterase inhibitors (for the treatment of Parkinson’s disease), and bromodomain inhibition (Scheme A). Despite these attractive features, there is a limited range of strategies available for the synthesis of spirocyclobutyl oxindoles . Although these strategies are very effective, they either require stoichiometric oxidants or are limited to carbon-centered radicals .…”