Reversible creation of non-inherent reactivity patterns in catalytic organic synthesis
Current methods in organic synthesis only enable reactions at the most reactive bonds or at bonds predisposed by specific directing groups. Consequently, many less reactive bonds, including numerous C-H and C-C bonds, cannot be functionalized, enormously limiting the scope of possible transformations. To overcome these limitations, I propose Reverse&Cat, a revolutionary strategy using a novel method to change the reactivity pattern of molecules. This strategy combines the dynamic equilibrium mediated by the first catalyst and a functionalization reaction catalyzed by the second catalyst. The originality of the transformation stems from exploiting three simultaneous processes: (i) the dynamic exchange of one functional group (FG) for another FG that modulates the reactivity of the substrate; (ii) the functionalization of the temporarily activated bond; and (iii) the restoration of the initial FG. In essence, the processes (i) and (iii) – the components of the dynamic equilibrium – realize the novel concept of the temporary creation of non-inherent reactivity of a substrate.
The program is divided in three phases, which will establish the full potential of the strategy. In phase A, I will develop a set of new reactions enabled by the bi-catalytic systems. I will exploit two types of reversible reactions: (1) reversible oxidation of alcohols, which delivers temporarily activated aldehydes/ketones, with the distinct reactivity of their C-H bonds; and (2) reversible retro-hydrofunctionalization of nitriles or their analogues, which delivers temporarily activated alkenes, containing allylic C-H and C=C bonds. In phase B, I will conduct detailed mechanistic studies to gain the mechanistic understanding and enable further rational development. In phase C, I will establish the utility of this new strategy in practical organic synthesis. Overall, the strategy will open a new dimension of reactivity, with prospective applications in production of fine-chemicals and materials.