Design and application of bifunctional organic catalysts

Abstract

N,N Diisopropylbenzylamine-2-boronic acid 80a has been shown to be an effective catalyst under refluxing fluorobenzene conditions for direct amide formation between equimolar amounts of carboxylic acids and amines, and under these conditions the catalyst 80a has been shown to be stable. A comparison with other boronic acid catalysts and boric acid has shown 80a to be more effective for more difficult substrates, and evidence for the cooperative effect of the boronic acid and amine moieties, as well as for reaction intermediates, has been obtained. The synthesis of novel derivatives of 80a have allowed the factors affecting direct amide formation to be probed further. The addition of an electron withdrawing group does increase the reactivity of these systems, however, the effect of an electron donating group is more pronounced and results in a substantial decrease in activity. The importance of solvent choice, concentration and water removal has been demonstrated through parallel experiments and Design of Experiments. A non-linear effect for catalyst loading was shown, where a 5 mol% loading of 80a had a similar effect to 10 mol%. Furthermore, the application of chiral amino-boronic acid 111 to the kinetic resolution via direct amide formation of racemic amines from achiral carboxylic acids, has shown promising levels of enantioselectivity, even in refluxing fluorobenzene (bp 85 С).A novel pyrrolidine-based amino-boronic acid (S)-268a has been synthesised via (-)- sparteine-mediated lithiation in high yield and enantioselectivity. The application of (S)-268a to the direct enantioselective aldol reaction has shown the boronic acid moiety does participate, and the solution behaviour of (S)-268a has also been investigated.