Asymmetric Michael Reaction of Malononitrile and α,β-Unsaturated Aldehydes Catalyzed by Diarylprolinol Silyl Ether

Abstract

An asymmetric Michael reaction of malononitrile and α,β-unsaturated aldehydes catalyzed by a diarylprolinol silyl ether was developed. Michael products were obtained in good yields and with excellent enantioselectivities without the formation of overreaction products. As a malononitrile moiety can be transformed into an alkoxy or amino carbonyl moiety by oxidative transformation, α-chiral esters or amides with all-carbon quaternary centers can be synthesized with excellent enantioselectivities.

Key words

organocatalysis - Michael reaction - asymmetric catalysis - diarylprolinol silyl ethers - malononitrile - carbon quaternary centers

Publication History

Received: 23 March 2022

Accepted after revision: 08 May 2022

Accepted Manuscript online:
08 May 2022

Article published online:
09 June 2022

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• 28 Asymmetric Michael Reaction; General Procedure To a solution of malononitrile (150 mg, 2.25 mmol) and the appropriate α,β-unsaturated aldehyde 2 (0.750 mmol) in toluene (7.5 mL) were added the diarylprolinol silyl ether organocatalyst (45.2 mg, 0.0750 mmol) and BzOH (9.2 mg, 0.0750 mmol) at 0 °C, and the mixture was stirred at 0 °C until the reaction was complete. CH(OMe)₃ (0.410 mL, 3.75 mmol) and TsOH·H₂O (43.2 mg, 0.225 mmol) were added, and the mixture was stirred for 1 h at 0 °C. The reaction was then quenched with sat. aq NaHCO₃, and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried (Na₂SO₄), and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel). [(1R)-3,3-Dimethoxy-1-phenylpropyl]malononitrile (4a) White solid; yield: 84%; mp 67–69 °C. [α]_D ²⁶ +29.0 (c 1.00, CHCl₃). IR (neat): 2910, 2835, 2255, 1497, 1455, 1370, 1281, 1237, 1189, 1126, 1055, 954, 917, 760, 702, 578 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.44–7.25 (m, 5 H), 4.34 (d, J = 5.6 Hz, 1 H), 4.27 (dd, J = 6.0, 3.6 Hz, 1 H), 3.46 (dt, J = 5.6, 7.2 Hz, 1 H), 3.35 (s, 3 H), 3.34 (s, 3 H), 2.37 (ddd, J = 14.4, 7.2, 6.0 Hz, 1 H), 2.16 (ddd, J = 14.4, 7.2, 3.6 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 136.90, 129.24, 128.94, 127.85, 112.07, 111.90, 102.69, 54.30, 53.95, 41.80, 34.96, 29.57. HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₄H₁₆N₂NaO₂: 267.1104; found: 267.1109.