Asymmetric Mannich Reaction of N-Boc Imines with Alkylmalononitriles Catalyzed by Dinuclear PhosphoiminoBINOL-Pd Complex

Abstract

PhosphoiminoBINOL-Pd₂(OAc)₂ complex catalyzed asymmetric Mannich reaction of N-Boc imines with alkyl malononitriles, with assistance of Zn(OAc)₂ gave chiral amines with adjacent all-carbon quaternary carbon centers in up to 99% yield with 94% ee.

Key words

Mannich - asymmetric catalyst - chiral amine - quaternary carbon center

• References and Notes


Reviews of catalytic asymmetric Mannich reaction:
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• 9 Typical Experimental Procedures A mixture of 3,3′-bis(phosphoimino)binaphthol (0.005 mmol) and Pd(OAc)₂ (0.01 mmol) was stirred in anhydrous chloroform (4.0 mL) for 12 h at 60 °C. After adding Zn(OAc)₂ (0.005 mmol) to the mixture, the solution was further stirred for 12 h at 60 °C to give the catalyst solution. The Mannich reaction was started by adding alkyl malononitrile (0.1 mmol) and N-Boc aldimine (0.11 mmol) to the catalyst solution at rt. After being stirred for 4 h at rt, the reaction mixture was quenched with H₂O, and then the products were extracted three times with dichloromethane. The collected organic layer was dried over Na₂SO₄. After removal of the solvent under reduced pressure, the residue was purified by a silica gel column chromatography. The enantiomeric excesses of the products were determined by chiral stationary phase HPLC using Daicel Chiralpak IA or AD-H column.
• 10 Characterization Data of 3aa [α]_D ^20.4 +30.5° (c 1.0, CHCl₃, 93% ee). ¹H NMR (400 MHz, CDCl₃): δ = 7.51–7.45 (m, 5 H), 7.41–7.38 (m, 5 H), 5.54 (d, J = 9.6 Hz, 1 H), 5.32 (d, J = 9.6 Hz, 1 H), 3.27 (d, J = 14.0 Hz, 1 H), 3.17 (d, J = 13.6 Hz, 1 H), 1.47 (s, 9 H). ¹³C NMR (100 MHz, CDCl₃): δ = 154.8, 130.1, 129.4, 128.5, 127.0, 111.1, 110.8, 81.7, 55.5, 29.6, 28.1. IR (neat): 3347, 2980, 1706, 1521, 1498, 1368, 1250, 1167, 762, 705 cm^–1. HRMS (ESI+): m/z calcd for C₂₂H₂₄O₂N₃ [M + H]⁺: 362.1863; found: 362.1860. Enantiomeric excess was determined by HPLC with a Chiralpak IA column (hexane/2-propanol = 80:20, 1.0 mL/min, 254 nm); major enantiomer t _R = 9.7 min, minor enantiomer t _R = 6.0 min, 93% ee.

Pd-catalyzed asymmetric amination:
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