Iron‐Catalyzed Tertiary Alkylation of Terminal Alkynes with 1,3‐Diesters via a Functionalized Alkyl Radical

Abstract

Direct oxidative C(sp)−H/C(sp3)−H cross‐coupling offers an ideal and environmentally benign protocol for C(sp)−C(sp3) bond formations. As such, reactivity and site‐selectivity with respect to C(sp3)−H bond cleavage have remained a persistent challenge. Herein is reported a simple method for iron‐catalyzed/silver‐mediated tertiary alkylation of terminal alkynes with readily available and versatile 1,3‐dicarbonyl compounds. The reaction is suitable for an array of substrates and proceeds in a highly selective manner even employing alkanes containing other tertiary, benzylic, and C(sp3)−H bonds alpha to heteroatoms. Elaboration of the products enables the synthesis of a series of versatile building blocks. Control experiments implicate the in situ generation of a tertiary carbon‐centered radical species.

Tetrasubstituted Carbon Stereocenters via Copper-Catalyzed Asymmetric Sonogashira Coupling Reactions with Cyclic gem-Dihaloketones and Tertiary α-Carbonyl Bromides

“…One limitation of this method involves the incapability of normal alkyl alkynes, with the exception of cyclopropyl acetylene, which provided the desired product in equal efficiency ( c21 ). To further illustrate the functional-group tolerance and relevance of this method to drug discovery and complex natural product derivatization, the conditions for coupling were applied to functionalized acetylenes bearing adamantanol, borneol, menthol, and glucofuranose moieties. Over 90% ee values were observed for all of those cases ( c22 – c25 ).…”

Remote C(sp3)–H activation: palladium-catalyzed intermolecular arylation and alkynylation with organolithiums and terminal alkynes

“…21 In 2021, Hu reported an exemplary reaction for iron-catalyzed/silver-mediated alkylation of terminal alkynes with 1,3-dicarbonyl compounds. 22 Moreover, Shi 23 and Lei 24 have all contributed significantly to the cross-coupling reactions of C(sp)–H with C(sp 3 )–H. However, these approaches all depend on the oxidative functionalization of C(sp 3 )–H bonds.…”

Copper-Catalyzed Cross-Nucleophile Coupling of β-Allenyl Silanes with Tertiary C–H Bonds: A Radical Approach to Branched 1,3-Dienes

“…1,3-Dicarbonyl compounds have been recognized by many research groups including us as the sources of functionalized sp 3 carbon-centered radicals via single electron oxidation, and recently, our laboratory has documented their use in the tertiary alkylation of alkenes and alkynes . Features of note in our protocols include the following: (a) efficient generation of tertiary carbon-centered radicals from aliphatic C–H bonds, instead of prefunctionalized substrates, such as halides, alcohols, carboxylic acids, etc.…”

“…On the basis of the above results and literature precedence, ,, we propose a plausible reaction pathway shown in Scheme b. The coupling starts by thermal homolysis of DTBP to generate tert -butoxyl radicals, which abstracts a hydrogen atom from 2a to form the electrophilic 1,3-diester radical species A .…”