Catalytic Asymmetric Mannich-Type Reaction Enabled by Efficient Dienolization of α,β-Unsaturated Pyrazoleamides†

(E)-α,β-Unsaturated pyrazoleamides undergo facile dienolization to furnish copper(I)-(1Z,3Z)-dienolates as the major in the presence of a copper(I)-(R)-DTBM-SEGPHOS catalyst and Et₃N, which react with aldimines to afford syn-vinylogous products as the major diastereoisomers in high regio- and enantioselectivities. In some cases, the diastereoselectivity is low, possibly due to the low ratio of copper(I)-(1Z,3Z)-dienolates to copper(I)-(1Z,3E)-dienolates. (Z)-Allylcopper(I) species is proposed as effective intermediates, which may form an equilibrium with copper(I)-(1Z,3Z)-dienolates. Interestingly, the present methodology is a nice complement to our previous report, in which (E)-β,γ-unsaturated pyrazoleamides were employed as the prenucleophiles in the copper(I)-catalyzed asymmetric vinylogous Mannich-Type reaction and anti-vinylogous products were obtained. In the previous reaction, copper(I)- (1Z,3E)-dienolates were generated through α-deprotonation, which might form an equilibrium with (E)-allylcopper(I) species. Therefore, it is realized in the presence of a copper(I) catalyst that (E)-α,β-unsaturated pyrazoleamides lead to syn-products and (E)-β,γ-unsaturated pyrazoleamides lead to anti-products. Finally, by use of (E)-β,γ-unsaturated pyrazoleamide, (E)-α,β-unsaturated pyrazoleamide, (R)-DTBM-SEGPHOS, and (S)-DTBM-SEGPHOS, the stereodivergent synthesis of all four stereoisomers is successfully carried out. Then by following a three-step reaction sequence, all four stereoisomers of N-Boc-2-Ph-3-Me-piperidine are synthesized in good yields, which potentially serve as common structure units in pharmaceutically active compounds.