Thorpe–Ingold Effect on High-Performance Chiral π–Copper(II) Catalyst

Abstract

The Thorpe–Ingold effect was applied to the design of a chiral ligand of π–copper(II) catalysts for the enantioselective α-fluorination of N-acyl-3,5-dimethylpyrazoles, and also for the enantioselective Mukaiyama–Michael, Diels–Alder, and 1,3-dipolar cycloaddition reactions of N-acryloyl-3,5-dimethylpyrazoles. The use of β,β-dimethyl-β-arylalanine-type ligand gave desired products with higher enantioselectivity compared to with previously reported β-arylalanine-type ligands.

Key words

π–copper(II) catalyst - chiral catalyst - Lewis acid - enantio­selective - Diels–Alder reaction - Mukaiyama–Michael reaction - 1,3-dipolar cycloaddition - α-fluorination

Publication History

Received: 18 December 2021

Accepted after revision: 25 January 2022

Accepted Manuscript online:
26 January 2022

Article published online:
21 February 2022

• References and Notes

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For representative examples of Thorpe–Ingold effects of the ligand on enantioselectivity, see:
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• 6 Procedure for the Enantioselective Diels–Alder Reaction of 2 with Isoprene Using Cu(NTf₂)₂·(R)-1e To a mixture of (R)-1e (11.2 mg, 0.033 mmol) and Cu(NTf₂)₂ (18.7 mg, 0.030 mmol) in a heat-gun-dried 20 mL Schlenk flask in MeCN (2.4 mL, dried over activated 4 Å molecular sieves) was added 2 (66.7 mg, 0.30 mmol) and stirred for 5 min. To the mixture was added isoprene (600 μL, 6.0 mmol) at 23 °C. The reaction mixture was stirred at 23 °C for 72 h. The reaction was quenched with a few drops of triethylamine. The product was washed with saturated aqueous NaHCO₃ solution, extracted with EtOAc, dried over MgSO₄, filtered, and concentrated in vacuo. Purification by chromatography on neutral silica gel (hexane–EtOAc) afforded the desired product 4 (78.5 mg, 90% yield, regioisomeric ratio (4a/4b) = 96:4, >99% ee/97% ee). Regioisomeric ratio was determined by crude NMR. The ee value was determined by HPLC analysis. Ethyl (1S,6S)-6-(3,5-Dimethyl-1H-pyrazole-1-carbonyl)-3-methylcyclohex-3-ene-1-carboxylate (4a) ^{1a 1}H NMR (400 MHz, CDCl₃): δ = 5.95 (s, 1 H), 5.47–5.38 (m, 1 H), 4.21–3.99 (m, 3 H), 3.07 (dt, J = 11.4, 5.7 Hz, 2 H), 2.68–2.57 (m, 1 H), 2.51 (d, J = 0.9 Hz, 3 H), 2.42–2.33 (m, 1 H), 2.25–2.03 (m, 2 H), 2.23 (s, 3 H), 1.71 (s, 3 H), 1.18 (t, J = 7.2 Hz, 3 H), 2.23 (s, 3 H), 3.08 (quint, J = 7.8 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 176.6, 175.0, 152.1, 144.1, 132.3, 119.5, 111.3, 60.7, 42.0, 40.9, 32.9, 29.3, 23.1, 14.7, 14.2, 14.0. HPLC analysis: ID-3, n-hexane/i-PrOH = 99:1, 1.0 mL/min, t _R = 11.2 min (major, 4b), t _R = 13.5 min (major, 4a), t _R = 14.8 min (minor, 4a), t _R = 20.2 min (minor, 4b).
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