Design of New Amino Tf-Amide Organocatalysts: Environmentally Benign Approach to Asymmetric Aldol Synthesis

Published as part of the 30 Years SYNLETT – Pearl Anniversary Issue

Abstract

A new type of optically pure primary amino aromatic Tf-amide organocatalyst can be easily prepared from 8-amino-1-tetralone, and its chemical behavior was investigated in the context of asymmetric aldol and Mannich reactions. Most notably, the asymmetric aldol reaction proceeded smoothly in brine.

Key words

asymmetric synthesis - aldol reaction - organocatalyst - brine - Mannich reaction

• References and Notes


Recent reviews on amine-based organocatalysts:
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Recent reviews on amino-catalyzed asymmetric aldol and Mannich reactions:
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See also:
• 3f Kano T, Ueda M, Takai J, Maruoka K. J. Am. Chem. Soc. 2006; 128: 6046
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• 6 Moteki SA, Xu S, Arimitsu S, Maruoka K. J. Am. Chem. Soc. 2010; 132: 17074
• 7 The synthesis of the primary amino aromatic Tf-amide organocatalysts 6–10 was carried out according to Scheme 2 (see Supporting Information for details).
• 8 The absolute configurations of the catalysts were assigned based on the X-ray diffraction analysis of the sulfonamide intermediate of catalyst 9b. The corresponding data have been deposited at the Cambridge Crystallographic Data Center and can be obtained free of charge via www.ccdc.cam.ac.uk/getstructures. CCDC 1870339 contains the supplementary crystallographic data for this paper.

Reviews of amino-catalyzed asymmetric aldol reaction in aqueous media:
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Selected examples for asymmetric aldol reaction in water or brine:
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• 10e Hu X.-M, Zhang D.-X, Zhang S.-Y, Wang P.-A. RSC Adv. 2015; 5: 39557
• 11 General Procedure for the Asymmetric Aldol Reaction Using the Catalyst 9 for the Preparation of 11 To a mixture of catalyst 9 (3 mg, 5 mol%) and benzaldehyde (0.2 mmol) in brine (1.2 mL) was added ketone (6.0 mmol). The homogenous mixture was stirred at room temperature for the appropriate time until the reaction was completed (TLC). Then, a saturated NH₄Cl solution was added, and the mixture was extracted with dichloromethane. The organic layer was dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was then purified by silica gel column chromatography (EtOAc/hexane = 1:3) to afford the product 11. (R)-2-[(S)-Hydroxy(4-nitrophenyl)methyl]cyclohexan-1-one (anti-11a) White solid. ¹H NMR (CDCl₃, 500 MHz): δ = 8.22–8.11 (m, 2 H), 7.52–7.49 (m, 2 H), 4.90 (d, J = 8.0 Hz, 1 H), 4.07, (br s, 1 H), 2.61–2.56 (m, 1 H), 2.52–2.47 (m, 1 H), 2.40–2.33, (m, 1 H), 2.14–2.08 (m, 1 H), 1.85–1.80 (m, 1 H), 1.72–1.62 (m, 1 H), 1.60–1.51 (m, 2 H), 1.42–1.33 (m, 1 H). ¹³C NMR (CDCl₃, 125 MHz): δ = 214.7, 148.3, 147.5, 127.8, 123.5, 74.0, 57.1, 42.6, 30.7, 27.6, 24.6. HRMS (ESI): m/z calcd for C₁₃H₁₅O₄NNa: 272.0893 [M + Na]⁺; found: 272.0895. [α]_D ²⁴ –11.2 (CHCl₃, c 0.9, 99% ee).
• 12 General Procedure for the Asymmetric Mannich Reaction Using Catalyst 9 for the Preparation of 13 To a mixture of catalyst 9 (3 mg, 5 mol%) and α-imino ester 12 (42 mg, 0.2 mmol) in THF (1.2 mL) was added ketone (6.0 mmol). The mixture was stirred at room temperature for 12 h. Then, a saturated NH₄Cl solution was added, and the mixture was extracted with EtOAc. The organic layer was dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was then purified by silica gel column chromatography (EtOAc/hexane = 1:4) to afford the product 13. Ethyl (R)-2-[(4-Methoxyphenyl)amino]-2-[(S)-2-oxocyclohexyl]-acetate (anti-13a) Colorless oil. ¹H NMR (CDCl₃, 500 MHz): δ = 6.77–6.73 (m, 2 H), 6.64–6.61 (m, 2 H), 4.24 (br s, 1 H), 4.18–4.10 (m, 2 H), 3.98 (d, J = 4.5 Hz, 1 H), 3.73 (s, 3 H), 3.12–3.08 (m, 1 H), 2.45–2.40 (m, 1 H), 2.35–2.29 (m, 1 H), 2.13–2.09 (m, 1 H), 2.07–2.02 (m, 1 H), 1.96–1.87 (m, 2 H), 1.78–1.62 (m, 2 H), 1.21 (t, J = 7.5 Hz, 3 H). ¹³C NMR (CDCl₃, 125 MHz): δ = 210.9, 173.0, 152.7, 142.1, 115.6, 114.7, 61.1, 59.0, 55.7, 53.5, 41.8, 30.5, 26.8, 24.5, 14.1. HRMS (ESI): m/z calcd for C₁₇H₂₃O₄NNa: 328.1519 [M + Na]⁺; found: 328.1526. [α]_D ²⁴ –22.4 (CHCl₃, c 0.7, 95% ee).