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

Main observation and conclusion ( E )‐α,β‐Unsaturated pyrazoleamides undergo facile dienolization to furnish copper(I)‐(1 Z ,3 Z )‐dienolates as the major in the presence of a copper(I)‐( R )‐DTBM‐SEGPHOS catalyst and Et 3 N, 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)‐(1 Z ,3 Z )‐dienolates to copper(I)‐(1 Z ,3 E )‐dienolates. ( Z )‐Allylcopper(I) species is proposed as effective intermediates, which may form an equilibrium with copper(I)‐(1 Z ,3 Z )‐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)‐ (1 Z ,3 E )‐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.