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

Abstract

Asymmetric catalysis | Vinylogous reaction | Pyrazoleamide | Copper catalyst | Dienolization (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 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)-(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.

Copper(I)-Catalyzed Asymmetric Synthesis of α-Allenylamines and β-Lactams through Regioselective Mannich-Type Reactions

“…Bisphosphines bearing a ferrocene-core, such as ( R )-( S )-JOSIPHOS and ( R , R P )-TANIAPHOS, were acceptable ligands due to high yields and high regio-, and high enantioselectivities even though the diastereoselectivity was moderate (entries 9 and 10). The ligand screening of commercially available bisphosphines revealed again that ( R )-DTBM-SEGPHOS was a privileged ligand in the copper­(I)-catalyzed asymmetric vinylogous and alkynylogous reactions. ,,,,− Screening of organic bases identified TMG as the best choice as up to >99% yield was obtained (entry 11). The loading of copper­(I)-( R )-DTBM-SEGPHOS and TMG was successfully reduced to 2 mol % but with moderate yield (entry 12).…”

“…Previously, it was revealed that pyrazoleamides of α,β-unsaturated acids underwent facile dienolization in the presence of Et 3 N and the copper­(I)-bisphosphine complex, which enabled a direct vinylogous Mannich-type reaction. , Allylcopper­(I) species were proposed as the operating nucleophiles in direct vinylogous Mannich-type reactions. − Based on these interesting findings, it was envisioned that pyrazoleamides of acetylenic acids could be used as efficient pronucleophiles, which would undergo facile γ-deprotonation to give propargyl copper­(I) species and thus react with N -Boc aldimines with α-selectivity (Scheme c). To our joy, the reaction indeed occurred.…”

Chiral bisphosphine Ph-BPE ligand: a rising star in asymmetric synthesis

“…2). 130 In another report on Mannich-type reaction of aldimines and cyclopropanols, Ph-BPE was used but no enantioselectivity was detected. 131…”

Progress in Catalytic Asymmetric Reactions with 7-Azaindoline as the Directing Group

“…At present, the main types of directing groups are as follows: 2-oxazolidone (A) [29][30][31][32][33][34][35][36][37][38][39][40], tetrahydropyrrole 2,5-dione (B) [41][42][43], pyrazole or 3,5-dimethylpyrazole (C or D) [44][45][46][47][48][49][50][51][52][53][54][55][56], and 8-aminoquinoline (E) [57][58][59][60][61][62][63][64][65]. They coordinate with metals to form stable five-or six-membered ring complexes that control the stereoselectivity of the reaction through a specific chiral environment (Scheme 1).…”