Key Role of Ti(IV) in the Selective Radical−Radical Cross-Coupling Mediated by the Ingold-Fischer Effect

Abstract

We report an innovative approach for the selective synthesis of polyfunctional derivatives by cross-combination of different radicals generated under mild conditions. The coordinating effect of Ti(IV) plays a key role in the reaction mechanism: due to its chelating action on the hydroxyl groups, it promotes the homolytic C-C bond cleavage of R,β-dihydroxy ketones by enhancing the captodative effect and the consequent stabilization of the corresponding R-hydroxy-R-carbonyl radicals. When these radicals are generated in the presence of stoichiometric amounts of TiCl 4 and 2,2′-azo-bis-isobutyronitrile (AIBN) is employed as a source of R-cyanoisopropyl radicals, the selective radical-radical cross-coupling is observed, affording the corresponding β-hydroxynitriles in high yields. This innovative methodology allows application of the well-known Ingold-Fischer effect to a wider range of stabilized carbon-centered radicals, whose formation derives from the chelating action of Ti(IV).

Stabilization of Two Radicals with One Metal: A Stepwise Coupling Model for Copper-Catalyzed Radical–Radical Cross-Coupling

“…The stabilization of free radicals is necessary to avoid these problems. Fortunately, the introduction of a transition metal into the radical combination reactions provides an efficient approach to stabilize the radicals and protect them from being quenched by homo-coupling or fragmentation1011121314. Moreover, the interplay between a transition metal and radicals would be able to tune the reactivity of radicals and enable specific radical–radical cross-combination10151617.…”

“…Fortunately, the introduction of a transition metal into the radical combination reactions provides an efficient approach to stabilize the radicals and protect them from being quenched by homo-coupling or fragmentation1011121314. Moreover, the interplay between a transition metal and radicals would be able to tune the reactivity of radicals and enable specific radical–radical cross-combination10151617. Transition metal-mediated or -catalyzed radical–radical cross-coupling is thereby established as an innovative strategy for the construction of carbon–carbon and carbon–heteroatom bonds101819202122.…”

“…Moreover, the interplay between a transition metal and radicals would be able to tune the reactivity of radicals and enable specific radical–radical cross-combination10151617. Transition metal-mediated or -catalyzed radical–radical cross-coupling is thereby established as an innovative strategy for the construction of carbon–carbon and carbon–heteroatom bonds101819202122.…”

Metal-free direct cyanoisopropylation/arylation of N-arylacrylamides or N-alkyl-N-(arylsulfonyl)acrylamides with AIBN: a simple and mild approach to cyano-containing oxindoles

“…10 However, in 2008, Punta pioneered the application of AIBN as a "C(Me) 2 CN" source in the synthesis of important organic molecules: β-hydroxynitriles. 11 Until recently, the groups of Wang and Tang successfully achieved the oxidative, copper-catalyzed synthesis of cyano-containing oxindoles from activated alkenes through a free radical cyanoisopropylation/cyclization cascade reaction by using AIBN as a source of C(Me) 2 CN radical. 12,13 These reports were closely followed by an independent publication by Kuang et al in which the essentially identical transformation was described with superstoichiometric amounts of DTBP as the oxidant.…”

Retropinacol/Cross-pinacol Coupling Reactions - A Catalytic Access to 1,2-Unsymmetrical Diols

“…Since a low-valent metal as well as a reactive radical species is formed simultaneously in situ, unsymmetrical diols could be formed exclusively in the presence of a suitable carbonyl reactant. To the best of our knowledge such a method has not been reported before (Porta et al described a comparable pinacol cleavage and subsequent coupling by the additional deployment of stoichiometric amounts of AIBN (2,2′-azo-bis-isobutyronitrile) to generate the required radicals) 13 . Herein a protocol is visualized which provides a rapid and operationally simple access to unsymmetrical 1,2-diols.…”