Diarylmethylamine (‘Butterfly’-Type Amine) Unit: A Useful Unit for the Modulation of the Catalytic Activity of Aminothiourea Catalysts

Abstract

We investigated the effects of substituents on the aromatic rings in a diarylmethylamine unit (which we have named the ‘butterfly’-type amine unit) in an aminothiourea catalyst. Detailed examination of the electronic effects of the aromatic rings revealed that the catalyst having a 3,5-bis(trifluoromethyl)phenyl group was the best, realizing an excellent chemical yield and enantioselectivity in an asymmetric Michael reaction between nitrostyrene and dimethyl malonate. Importantly, its catalytic ability as a chiral catalyst is superior to that of the well-known aminothiourea catalyst, the Takemoto catalyst, and this characteristic was observed in various asymmetric reactions.

Key words

thiourea catalysis - asymmetric catalysis - diarylmethylamines - organocatalysis - Michael reaction

Publication History

Received: 05 April 2023

Accepted after revision: 23 May 2023

Article published online:
27 June 2023

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• 23 N-{Bis[3,5-bis(trifluoromethyl)phenyl]methyl}-N′-[(1R,2R)-2-(dimethylamino)cyclohexyl]thiourea (9a): Typical Procedure To a solution of the commercially available aldehyde 1a (767 mg, 3.17 mmol) in THF (12.3 mL) at 0 °C was added [3,5-bis(trifluoromethyl)phenyl]magnesium bromide (2a), prepared from Mg (110.7 mg, 4.61 mmol) and 1-bromo-3,5-bis(trifluoromethyl)benzene (0.640 mL, 3.78 mmol). The mixture was stirred for 19 h at r.t., then the reaction was quenched by adding sat. aq NH₄Cl. The crude product was extracted with EtOAc (×3), and the combined organic extracts were washed with brine, dried (Na₂SO₄), and concentrated in vacuo. The residue was purified by column chromatography [silica gel, hexane–EtOAc (4:1)] to give alcohol 3a as a white solid; yield: 1.44 g (quant); mp 92–94 °C. IR (KBr): 3338, 3105, 2918, 2849, 1626, 1466, 1363, 1319, 1278, 1131, 937 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 7.86 (s, 6 H), 6.07 (br s, 1 H), 2.71 (br s, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 144.5, 151.3 (q, J _C–F = 33.3 Hz), 126.6, 123.0 (q, J _C–F = 270 Hz), 122.5 (m), 74.1. ¹⁹F NMR (283 MHz, CDCl₃): δ = –62.6. Anal. Calcd for C₁₇H₈F₁₂O: C, 44.76; H, 1.77. Found: C, 44.98; H, 1.96. Et₃N (0.900 mL, 6.46 mmol) and MsCl (0.300 mL, 3.88 mmol) were successively added to a solution of alcohol 3a (1.44 g, 3.15 mmol) in CH₂Cl₂ (31.7 mL) at 0 °C, and the mixture was stirred for 19 h at r.t. The crude products were concentrated in vacuo, and the residue was purified by column chromatography [silica gel, hexane–EtOAc (4:1)] to give mesylate 4a as a white solid; yield: 1.02 g (60%); mp 105–108 °C. IR (KBr): 3584, 3063, 2913, 2846, 1626, 1466, 1378, 1340, 1280, 1173, 1131, 958 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 7.95 (s, 2 H), 7.82 (s, 4 H), 6.85 (s, 1 H), 3.04 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 139.6, 132.9 (q, J _C–F = 33.9 Hz), 127.3 (m), 123.6 (m), 122.7 (q, J _C–F = 271.3 Hz), 79.5, 39.4. ¹⁹F NMR (283 MHz, CDCl₃): δ = –62.8. Anal. Calcd for C₁₈H₁₀F₁₂O₃S: C, 40.46; H, 1.89. Found: C, 40.72; H, 1.64. NaN₃ (68.2 mg, 1.05 mmol) was added to a solution of mesylate 4a (485 mg, 0.91 mmol) in DMF (0.962 mL) at r.t., and the mixture was stirred for 14 h at r.t. The reaction was quenched by adding H₂O, and the crude products were extracted with EtOAc (×3). The combined organic extracts were washed with brine, dried (Na₂SO₄), and concentrated in vacuo. The residue was purified by column chromatography [silica gel, hexane–EtOAc (4:1)] to give azide 5a; yield: 403 mg. At this stage, some impurities, which were hard to separate, were present and, consequently, this material was used for the next reaction without further purification. To a solution of 5a in MeOH (8.5 mL) was added 10% Pd/C (43.8 mg) at r.t., and the mixture was stirred under H₂ (1 atm) at r.t. for 1 h. The mixture was then filtered through a Celite pad and concentrated in vacuo to give amine 6a (382 mg) as a yellow oil. This material was used in a subsequent reaction with isothiocyanate 8 without further purification.> Thiophosgene (0.198 mL, 2.60 mmol) was added to a solution of [(1R,2R)-2-aminocyclohexyl]dimethylamine (7; 339.8 mg, 2.39 mmol) in CH₂Cl₂ (13.4 mL) and sat. aq NaHCO₃ (13.4 mL) at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. The crude products were extracted with CH₂Cl₂ (×3), and the combined organic extracts were washed with sat. aq NaHCO₃, dried (Na₂SO₄), and concentrated in vacuo to give isothiocyanate 8 (261.2 mg), which was used in the next reaction without further purification. To a solution of amine 6a in CH₂Cl₂ (6.01 mL) was added a solution of isothiocyanate 8 in CH₂Cl₂ (2.62 mL) at r.t., and the mixture was stirred for 40.5 h at r.t. The crude products were concentrated in vacuo, and the residue was purified by column chromatography [silica gel, CH₂Cl₂–MeOH (20:1)] to give thiourea 9a as a yellow amorphous solid; yield: 475 mg (82% from 4a); [α]_D ²⁵ +36.6 (c 1.00, CHCl₃). IR (neat): 3219, 3055, 2941, 2866, 1556, 1467, 1375, 1279, 1173, 1132 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.92 (s, 2 H), 7.83 (s, 1 H), 7.82 (s, 1 H), 7.73 (s, 2 H), 7.02 (d, J = 8.0 Hz, 1 H), 4.38 (br s, 1 H), 3.17 (br s, 1 H), 2.59 (br s, 6 H), 2.40–2.32 (m, 1 H), 2.07–1.94 (m, 2 H), 1.85–1.78 (m, 1 H), 1.46–1.12 (m, 4 H). ¹³C NMR (100 MHz, CDCl₃): δ = 182.9, 143.2, 142.7, 132.6 (q, J _C–F = 33.4 Hz), 132.2 (q, J _C–F = 33.4 Hz), 128.2, 127.9, 124.5 (q, J _C–F = 270.8 Hz), 124.3 (q, J _C–F = 270.8 Hz), 67.3, 60.7, 55.1, 39.1, 32.8, 29.7, 24.4, 24.1, 22.7. ¹⁹F NMR (283 MHz, CDCl₃): δ = –62.6 (s, 6 F), –62.8 (s, 6 F). Anal. Calcd for C₂₆H₂₅F₁₂N₃S: C, 48.83; H, 3.94; N, 6.57. Found: C, 48.68; H, 4.05; N, 6.36.