Carbene reactivity from alkyl and aryl aldehydes.

Carbenes are highly enabling reactive intermediates that facilitate a diverse range of otherwise inaccessible chemistry, including small-ring formation and insertion into strong σ bonds. To access such valuable reactivity, reagents with high entropic or enthalpic driving forces are often used, including explosive (diazo) or unstable (gem-dihalo) compounds. Here, we report that common aldehydes are readily converted (via stable α-acyloxy halide intermediates) to electronically diverse (donor or neutral) carbenes to facilitate >10 reaction classes. This strategy enables safe reactivity of nonstabilized carbenes from alkyl, aryl, and formyl aldehydes via zinc carbenoids. Earth-abundant metal salts [iron(II) chloride (FeCl2), cobalt(II) chloride (CoCl2), copper(I) chloride (CuCl)] are effective catalysts for these chemoselective carbene additions to σ and π bonds.

Aza-Heterocycles via Copper-Catalyzed, Remote C-H Desaturation of Amines.

The majority of medicines contain a nitrogen atom within a five- or six- membered ring. To rapidly access both such aza-heterocycles, we sought to develop a remote C-H desaturation of amines. Inspired by the Hofmann-Löffler-Freytag synthesis of five-membered pyrrolidines, we tackled the century-old challenge of synthesizing six-membered piperidines by H-atom transfer. We present herein a double, vicinal C-H oxidation by dual catalysis, entailing Ir photocatalytic initiation of 1,5-HAT by an N-centered radical and Cu-catalyzed interception of the C-centered radical to facilitate desaturation. By this mechanism, two C-H bonds (δ and ε to N) are regioselectively removed from unbiased, remote positions of an alkyl chain. Over 50 examples illustrate efficiency, selectivity, functional group tolerance, and medicinal utility of this synthesis of both internal and terminal δ vinylic amines and aza-heterocycles. Mechanistic experiments probe the alkylcopper intermediate, as well as kinetics and regioselectivity of the HAT and elimination steps.

Synthesis of Chromenoisoxazolidines from Substituted Salicylic Nitrones via Visible-Light Photocatalysis.

This effort reports the first redox-neutral visible-light photocatalytic intramolecular dipolar cycloaddition for the diastereoselective synthesis of chromenoisoxazolidines. The authors have found that alkenylphenyl nitrones with a diverse substitution pattern on the aromatic ring and the alkenyl substituent undergo visible-light-promoted cycloadditions in the presence of catalytic amounts of Ru(bpy)3Cl2 in high yields and selectivities. Evidence indicates that the proposed redox-neutral pathway is the predominant photoredox mechanism for this transformation.