Rational Design of New Dihydrobenzooxophosphole-Based Lewis Base Organocatalysts

Published as part of the ISySyCat2019 Special Issue

Abstract

A series of new dihydrobenzooxophosphole-based Lewis base organocatalysts were designed and synthesized. They are shown to be effective in trichlorosilane-mediated stereoselective conjugate reductions of C=C bonds. DFT calculations reveal that the strong hydrogen bonds between the amide linker and the chloride on silicon in the transition state contribute to the high reactivity of the catalyst.

Key words

chiral Lewis base - organocatalyst - enone reduction - hydrogen bonds

• References

• 1 Current address: TCG Lifesciences Private Limited, 737 North 5th Street, Richmond, Virginia 23219, US.
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• 12 General procedure for catalyst preparation: To a solution of carboxylic acid phosphine oxide (5.0 g, 17.6 mmol, 2.2 equiv), diamine (8.0 mmol, 1 equiv) and triethylamine (32.0 mmol, 4 equiv) in acetonitrile at room temperature was added propylphosphonic anhydride (T₃P) solution in DMF (16.0 mmol, 2 equiv) in portions over 3 h. The reaction was stopped after complete consumption of the carboxylic acid. The mixture was then treated with 50% aqueous NaOH (10 mL) and stirred at 35 °C for 3 h. The suspension was diluted with water and the resulting clear solution was extracted three times with EtOAc. The combined organic layer was washed with brine, dried with MgSO₄ and concentrated, and the crude mixture was purified by chromatography on silica (100% EtOAc to 10% MeOH/EtOAc) to obtain a white solid after drying.(2R,2′R,3S,3′S)-N,N′-((1R,2R)-cyclohexane-1,2-diyl)bis(3-(tert-butyl)-4-methoxy-2H-benzo[d][1,3]oxaphosphole-2-carboxamide 3-oxide) (3a): Yield: 3.67 g (71%). ¹H NMR (500 MHz, CDCl₃): δ = 7.46 (t, J = 8.23 Hz, 2 H), 6.80 (br d, J = 6.70 Hz, 2 H), 6.71 (dd, J = 8.3, 2.8 Hz, 2 H), 6.54 (dd, J = 8.2, 4.4 Hz, 2 H), 4.93 (s, 2 H), 3.88 (s, 6 H), 3.80 (br s, 2 H), 2.11 (br d, J = 7.3 Hz, 2 H), 1.65 (br s, 2 H), 1.37 (d, J = 17.0 Hz, 18 H), 1.25–1.23 (m, 4 H). ¹³C NMR (125 MHz, CDCl₃): δ = 165.2 (d, J = 2.7 Hz), 164.5 (d, J = 14.2 Hz), 161.1 (d, J = 2.4 Hz), 136.9 (d, J = 0.87 Hz), 106.6 (d, J = 5.3 Hz), 104.1 (d, J = 5.7 Hz), 102.70 (d, J = 90.8 Hz), 75.4 (d, J = 48.4 Hz), 55.6, 53.7, 34.07 (d, J = 74.5 Hz), 32.4, 25.1 (d, J = 0.96 Hz), 24.5. ³¹P NMR (202 MHz, CDCl₃): δ = 62.83. HRMS (ESI): m/z [M + H]⁺ calcd for C₃₂H₄₅O₈N₂P₂: 647.26457; found: 647.26495.(2R,2′R,3S,3′S)-N,N′-((1S,2S)-cyclohexane-1,2-diyl)bis(3-(tert-butyl)-4-methoxy-2H-benzo[d][1,3]oxaphosphole-2-carboxamide 3-oxide) (3b): Yield: 3.36 g (65%). ¹H NMR (400 MHz, CDCl₃): δ = 7.43 (t, J = 8.2 Hz, 2 H), 6.86 (br d, J = 6.0 Hz, 2 H), 6.62 (dd, J = 8.2, 3.0 Hz, 2 H), 6.50 (dd, J = 8.1, 4.4 Hz, 2 H), 5.22 (s, 2 H), 3.80 (s, 6 H), 3.73 (br s, 2 H), 2.12 (br d, J = 6.6 Hz, 2 H), 1.69 (br s, 2 H), 1.31–1.26 (overlapping d, J = 17.0 Hz, and m, 22 H). ¹³C NMR (100 MHz, CDCl₃): δ = 165.7 (d, J = 2.0 Hz), 165.3 (d, J = 15.3 Hz), 161.3 (d, J = 2.1 Hz), 136.8, 106.4 (d, J = 5.4 Hz), 103.8 (d, J = 5.8 Hz), 101.6 (d, J = 91.6 Hz), 74.6 (d, J = 48.3 Hz), 55.6, 53.5, 34.3 (d, J = 74.0 Hz), 32.2, 24.6, 24.5. ³¹P NMR (162 MHz, CDCl₃): δ = 62.36. HRMS (ESI): m/z [M + H]⁺ calcd for C₃₂H₄₅O₈N₂P₂: 647.26457; found: 647.26433.(2R,2′R,3S,3′S)-N,N′-(1,2-phenylene)bis(3-(tert-butyl)-4-methoxy-2H-benzo[d][1,3]oxaphosphole-2-carboxamide 3-oxide) (3c): Yield: 3.07 g (60%); ¹H NMR (400 MHz, CDCl₃): δ = 8.65 (s, 2 H), 7.54 (m, 2 H), 7.44 (t, J = 8.2 Hz, 2 H), 7.16 (m, 2 H), 6.68 (dd, J = 8.3, 2.8 Hz, 2 H), 6.54 (dd, J = 8.2, 4.4 Hz, 2 H), 5.33 (s, 2 H), 3.86 (s, 6 H), 1.34 (d, J = 17.1 Hz, 18 H); ¹³C NMR (100 MHz, CDCl₃): δ = 165.2 (d, J = 14.9 Hz), 164.5 (d, J = 2.6 Hz), 161.3 (d,J = 2.2 Hz), 137.0, 129.9, 126.7, 126.2, 106.5 (d, J = 5.4 Hz), 104.1 (d, J = 5.8 Hz), 102.0 (d, J = 91.6 Hz), 75.5 (d, J = 47.5 Hz), 55.7, 34.4 (d, J = 73.8 Hz), 24.7. ³¹P NMR (202 MHz, CDCl₃): δ = 63.9. HRMS (ESI): m/z [M + H]⁺ calcd for C₃₂H₃₉O₈N₂P₂: 641.21762; found: 641.21767.(2R,2′R,3S,3′S)-N,N′-((1R,2R)-1,2-dicyclohexylethane-1,2-diyl)bis(3-(tert-butyl)-4-methoxy-2H-benzo[d][1,3]oxaphosphole-2-carboxamide 3-oxide) (3d): Yield: 3.03 g (50%); ¹H NMR (400 MHz, CDCl₃): δ = 7.45 (t, J = 8.2 Hz, 2 H), 6.72–6.68 (overlapping s and dd, J = 8.2, 3.0 Hz, 4 H), 6.54 (dd, J = 8.1, 4.3 Hz, 2 H), 4.92 (d, J = 0.48 Hz, 2 H), 4.06–4.00 (m, 6 H), 3.88 (s, 6 H), 1.74–1.67 (m, 9 H), 1.54–1.34 (overlapping d, J = 17.0 Hz, and m, 24 H), 1.22–1.02 (m, 10 H), 0.9–0.81 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 165.1 (d, J = 2.3 Hz), 164.4 (d, J = 13.9 Hz), 161.1 (d, J = 2.1 Hz), 136.7, 106.5 (d, J = 5.2 Hz), 104.1 (d, J = 5.7 Hz), 103.1 (d, J = 90.5 Hz), 75.6 (d, J = 48.9 Hz), 55.6, 54.7, 38.9, 34.1 (d, J = 74.4 Hz), 30.5, 27.3, 26.2, 26.16, 26.11, 25.2. ³¹P NMR (162 MHz, CDCl₃): δ = 61.64. HRMS (ESI): m/z [M + H]⁺ calcd for C₄₀H₅₉O₈N₂P₂: 757.37412; found: 757.37417.(2R,2′R,3S,3′S)-N,N′-((1R,2R)-1,2-diphenylethane-1,2-diyl)bis(3-(tert-butyl)-4-methoxy-2H-benzo[d][1,3]oxaphosphole-2-carboxamide 3-oxide) (3e): Yield: 2.98 g (50%); ¹H NMR (500 MHz, CDCl₃): δ = 7.52 (br d, J = 2.8 Hz, 2 H), 7.43 (t, J = 8.2 Hz, 2 H), 7.11–7.06 (m, 10 H), 6.70 (dd, J = 8.3, 2.5 Hz, 2 H), 6.50 (dd, J = 8.1, 4.3 Hz, 2 H), 5.40–5.38 (m, 2 H), 5.00 (s, 2 H), 3.85 (s, 6 H), 1.35 (d, J = 16.9 Hz, 18 H). ¹³C NMR (100 MHz, CDCl₃): δ = 165.5 (d, J = 2.4 Hz), 164.5 (d, J = 14.1 Hz), 161.1 (d, J = 2.3 Hz), 137.7, 136.8, 128.5, 127.74, 127.69, 106.5 (d, J = 5.3 Hz), 104.0 (d, J = 5.8 Hz), 102.7 (d, J = 91.1 Hz), 75.3 (d, J = 48.8 Hz), 59.1, 55.6, 34.1 (d, J = 74.5 Hz), 25.1 (d, J = 0.8 Hz). ³¹P NMR (202 MHz, CDCl₃): δ = 62.13. HRMS (ESI): m/z [M + H]⁺ calcd for C₄₀H₄₇O₈N₂P₂: 745.28022; found: 745.28012.General procedure for enone reduction: To a stirring solution of 1a (60 mg, 0.27 mmol) and catalyst 3a (0.027 mmol, 10 mol%) in acetonitrile (2 mL) at 0 °C was added HSiCl₃ (1.35 mmol, 5 equiv) dropwise, and the mixture was stirred at 0 °C for 20 h. The reaction was then quenched with a solution of 5N aqueous NaOH (2 mL), and the mixture was warmed to room temperature then diluted with EtOAc and water. The phases were separated, and the aqueous phase was further extracted once with EtOAc. The combined organic layers were washed with water followed by brine, dried with Na₂SO₄ and concentrated. The product was purified on silica with a mixture of hexanes/EtOAc (10:1) to obtain a colorless oil after drying.(S)-1,3-Diphenylbutan-1-one (2a): Yield: 90%; 89.2:10.8 er; SFC (ES Industries CCA column 4.6 × 100 mm, 3 μm: 35 °C, A: CO₂, B: isopropanol; gradient: 1% B to 3% B in 3 min, to 50% B in 5 min; 3 mL/min, λ = 220 nm): t_R = 2.50 (major), 2.80 (minor) min. NMR data match those reported in the literature.^{17 1}H NMR (500 MHz, CDCl₃): δ = 7.96 (d, J = 7.9 Hz, 2 H), 7.57 (t, J = 7.3 Hz, 1 H), 7.47 (t, J = 7.6 Hz, 2 H), 7.35–7.21 (m, 4 H), 7.35–7.28 (m, 2 H), 7.23 (t, J = 6.8 Hz, 1 H), 3.54 (sextet, J = 6.9 Hz, 1 H), 3.33 (dd, J = 16.5, 5.7 Hz, 1 H), 3.22 (dd, J = 16.5, 8.3 Hz, 1 H), 1.37 (d, J= 6.9 Hz, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 199.1, 146.6, 137.2, 133.0, 128.6, 128.5, 128.1, 126.9, 126.3, 47.0, 35.6, 21.9.(S)-1-Phenyl-3-(4-(trifluoromethyl)phenyl)butan-1-one (2b): Yield: 92%; 89.4:10.6 er; SFC (ES Industries CCA column 4.6 × 100 mm, 3 μm: 35 °C, A: CO₂, B: isopropanol; gradient: 1% B to 3% B in 3 min, to 50% B in 5 min; 3 mL/min, λ = 220 nm): t_R  = 1.69 (major), 1.91 (minor) min. NMR data match those reported in the literature.^{18 1}H NMR (400 MHz, CDCl₃): δ = 7.97–7.92 (m, 2 H), 7.60–7.56 (m, 3 H), 7.50–7.45 (m, 2 H), 7.41 (d, J = 8.3 Hz, 2 H), 3.69 (sextet, J = 6.9 Hz, 1 H), 3.35 (dd, J = 16.8, 6.4 Hz), 3.25 (dd, J = 16.9, 7.5 Hz, 1 H), 1.39 (d, J = 7.0 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 198.4, 150.6, 137.0, 133.2, 128.6, 128.0, 127.3, 125.5 (q, J = 3.8 Hz), 46.5, 35.3, 21.9.(S)-3-(4-Chlorophenyl)-1-phenylbutan-1-one (2c): Yield: 94%; 90.2:9.8 er; SFC (ES Industries CCA column 4.6 × 100 mm, 3 μm: 35 °C, A: CO₂, B: methanol; gradient: 1% B to 3% B in 3 min, to 50% B in 5 min; 3 mL/min, λ = 220 nm): t_R = 2.93 (major), 3.51 (minor) min. NMR data match those reported in the literature.^{18 1}H NMR (400 MHz, CDCl₃): δ = 7.95–7.92 (m, 2 H), 7.60–7.56 (m, 1 H), 7.50–7.45 (m, 2 H), 7.30–7.27 (m, 2 H), 7.25–7.21 (m, 2 H), 3.52 (sextet, J = 6.9 Hz, 1 H), 3.29 (dd, J = 16.7, 6.3 Hz), 3.2 (dd, J = 16.7, 7.7 Hz, 1 H), 1.35 (d, J= 7.0 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 198.7, 145.0, 137.1, 133.1, 131.9, 128.6, 128.3, 128.0, 46.8, 35.0, 22.0.(S)-3-(2-Methoxyphenyl)-1-phenylbutan-1-one (2d): Yield: 89%; 88.1:11.9 er; SFC (Lux Cel 1 column 4.6 × 100 mm, 3 μm: 35 °C, A: CO₂, B: methanol; gradient: 1% B to 3% B in 3 min, to 50% B in 5 min; 3 mL/min, λ = 220 nm): t_R = 3.94 (major), 4.27 (minor) min. NMR data match those reported in the literature.^{19 1}H NMR (500 MHz, CDCl₃): δ = 7.90 (d, J = 7.8 Hz, 2 H), 7.45 (t, J = 7.3 Hz, 1 H), 7.36 (t, J = 7.6 Hz, 2 H), 7.15 (d, J = 7.3 Hz, 1 H), 7.11 (t, J = 7.7 Hz, 1 H), 6.85 (t, J = 7.4 Hz, 1 H), 6.77 (d, J = 8.1 Hz, 1 H), 3.78–3.73 (m, 1 H), 3.73 (s, 3 H), 3.27 (dd, J = 15.8, 4.8 Hz, 1 H), 2.97 (dd, J = 15.7, 9.2 Hz, 1 H), 1.23 (d, J = 7.0 Hz, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 199.7, 156.9, 137.3, 134.5, 132.8, 128.5, 128.2, 127.2, 126.9, 120.7, 110.6, 55.3, 46.0, 29.6, 19.7.
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