Direct α‐Tertiary Alkylations of Ketones in a Combined Copper–Organocatalyst System

Abstract

Herein, we report an efficient method for the tertiary alkylation of a ketone by using an α‐bromocarbonyl compound as the tertiary alkyl source in a combined Cu‐organocatalyst system. This dual catalyst system enables the addition of a tertiary alkyl radical to an enamine. Mechanistic studies revealed that the catalytically generated enamine is a key intermediate in the catalytic cycle. The developed method can be used to synthesize substituted 1,4‐dicarbonyl compounds containing quaternary carbons bearing various alkyl chains.

Multicomponent Bifunctionalization of Methyl Ketones Enabled by Heterogeneous Catalysis and Solar Photocatalysis in Water

“…All products were separated by silica gel (200−300 mesh) column chromatography with petroleum ether (PE) (60−90 °C) and ethyl acetate (EA). 1 H, 13 C, and 19 F NMR spectra were recorded on a Bruker Advance 500 spectrometer at ambient temperature with CDCl 3 or CD 3 SOCD 3 as the solvent and tetramethylsilane as the internal standard. Melting points were determined on an X-5 Data microscopic melting point apparatus.…”

“…19 Later, Nishikata and co-workers developed an efficient copperorganocatalyst system for the C−H alkylation of ketones (Scheme 1a, middle). 13 In the same year, Wu et al demonstrated a palladium-catalyzed denitrative α-arylation of ketones with nitroarenes (Scheme 1a, bottom). 14 Despite their utilities, most of these methods generally suffer from disadvantages such as toxicity associated with metal catalysts and promoters, stoichiometric amounts of oxidants or additives, air and moisture sensitivity, and harsh reaction conditions.…”

“…Over the past few decades, significant advances have been achieved in developing novel and efficient methods for the synthesis of α-functionalized ketones because such compounds are versatile intermediates for the construction of a variety of natural products, advanced materials, as well as pharmaceuticals and related compounds. , Recently, the direct C­(sp 3 )-H functionalization reactions have been regarded as a promising approach for the α-functionalization of ketones due to their advantages such as atom- and step-economy. Based on this strategy, various solutions to the formation of α-functionalized ketones have been provided, including the iodine-promoted transformation, − transition metal catalysis, − and so on. − For example, Maulide’s group in 2020 reported a triflic anhydride-mediated α-arylation of acetophenones via metal-free electrophilic activation (Scheme a, top) . Later, Nishikata and co-workers developed an efficient copper-organocatalyst system for the C–H alkylation of ketones (Scheme a, middle) .…”

“…Based on this strategy, various solutions to the formation of α-functionalized ketones have been provided, including the iodine-promoted transformation, − transition metal catalysis, − and so on. − For example, Maulide’s group in 2020 reported a triflic anhydride-mediated α-arylation of acetophenones via metal-free electrophilic activation (Scheme a, top) . Later, Nishikata and co-workers developed an efficient copper-organocatalyst system for the C–H alkylation of ketones (Scheme a, middle) . In the same year, Wu et al.…”

Radical/Iminium Domino Strategy (RIDS) for Rapid Construction of Sterically Congested γ‐Lactam‐Based Multiheterocycles

“…In our previous study, we successfully controlled enamine reactivity during the α-tertiary alkylations of ketones using αbromoesters as tertiary alkyl radical sources to produce acyclic 1,4-dicarbonyl compounds; [23] however, iminium ions did not participate in this CÀ C bond-forming process. Based on these previous reports, we envisaged the following multicyclization strategy that uses α-bromocarboxamides [24] (1) bearing nucleophilic moieties (4; Scheme 1): A tertiary alkyl radical species adds to the enamine to form A, which is subsequently oxidized with Cu II to produce iminium I (B) that undergoes the first cyclization to generate γ-lactam ring C. The resulting γ-lactam intermediate C generates the N-acyl iminium ion D (iminium II), [25] which eliminates a proton to produce 3 or undergoes a second cyclization to generate multiheterocycle 5.…”