Reprogramming Borohydride Reactivity by Integrating Titanium and Chromium in Cooperative Catalysis

Abstract

Cooperative catalysis can enable reactivity and selectivity not achievable with a single catalyst, making it a key strategy for developing sustainable reactions. In this work, the unique reactivities of two earth-abundant metals, titanium and chromium, were coupled in a reactive network, allowing the use of readily available, affordable, and reasonably safe borohydrides as hydrogen atom and electron donors in the cooperative catalysis of radical reactions. The system synergizes titanocene catalysts, efficient in radical epoxide opening reactions, and a chromium hydride complex, a well-established radical hydrogenation catalyst.<br/> The reprogramming of the borohydride reactivity is achieved by an unprecedented relay hydrogen atom transfer, from the borohydride via a titanocene hydride species to chromium, simultaneously activating both catalysts. This process completely outcompetes the usual nucleophilic reduction character of the BH4^– anion. The mechanistic details of the system have been investigated through both computational and experimental studies, leading to the successful experimental realization of the proposed catalytic 'globe'. Pairing the strongly reducing and <em>Lewis</em> acidic LiBH₄ with 1,4-dioxane enables precise reagent delivery by controlling the reactivity of the borohydride through solubility.<br/> The system facilitated reductive epoxide openings for preparation of various <em>anti-Markovnikov</em> alcohols with a broad functional group tolerance, and as well C–C bond-forming cyclization. Moreover, the integration of regiodivergent epoxide openings into cooperative catalysis was realized using enantiopure titanocenes in combination with sulfonamide additives. This method allows the synthesis of enantiopure 1,3- and 1,4-difunctionalized units from common starting materials. Particularly attractive is the possibility to directly obtain unprotected 1,3- and 1,4-diols, avoiding the need for additional protection group introduction and removal. Such reactions were unattainable through previous radical cooperative catalysis or epoxide reductions involving <em>Meinwald</em> rearrangement and carbonyl reduction.<br/> The advantage of these systems over previous titanocene-catalyzed epoxide openings is the elimination of the need for stoichiometric acids and toxic hydrogen atom donors. The only stoichiometric reagent required is the borohydride, thus improving atom economy and sustainability. Additionally, the use of pressurized, flammable hydrogen gas is avoided by providing borohydrides as a safer and more manageable alternative for research laboratories.