Asymmetric Morita-Baylis-Hillman Reaction Catalyzed by Simple Amino Alcohol Derived Thioureas

Abstract

Thioureas straightforwardly derived from commercially available enantiopure amino alcohols have been found to promote the asymmetric Morita-Baylis-Hillman reaction of 2-cyclohexen-1-one and different aldehydes in the presence of triethylamine under solvent-free conditions. The corresponding allylic alcohols were obtained in good to high yields and up to 88% ee.

Morita-Baylis-Hillman reaction - chiral thioureas - asymmetric organocatalysis - amino alcohols

References and Notes

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14 Procedure for the Synthesis of Catalysts 1 To a solution of amino alcohol (0.5 mmol) in CH₂Cl₂ (2 mL) was added dropwise 3,5-bis(trifluoromethyl)phenyl isothiocyanate (92 µL, 0.5 mmol) at 0 °C under N₂. After stirring the reaction mixture for 3-5 h at r.t., the solvent was removed under reduced pressure and residue was purified by flash chromatography (PE-Et₂O, 90:10) to provide 1.Spectral data for catalyst 1a: white solid, mp 145-147 °C; [α]_D ²⁰ -55.0 (c 0.30, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 8.56 (br s, 1 H), 7.80 (br s, 2 H), 7.67 (s, 1 H), 7.50-7.27 (m, 5 H), 6.91 (br s, 1 H), 5.02 (br s, 1 H), 4.18 (br s, 1 H), 3.65-3.56 (m, 2 H), 3.00 (br s, 1 H). ¹³C NMR (100.6 MHz, CDCl₃): δ = 180.7, 140.5, 138.9, 132.8, 128.9, 128.6, 125.7, 123.8, 119.4, 76.2, 52.1. IR (neat): 3261, 3066, 1538, 1385, 1278, 1133, 700, 682 cm^-1. MS (EI): m/z (%) = 271 (100), 213 (37), 202 (58), 163 (30).Catalyst 1d: white solid, mp 66-68 °C; [α]_D ¹⁹ -53.8 (c 0.34, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 8.5 (br s, 1 H), 7.70-7.20 (m, 14 H), 6.88 (br s, 1 H), 5.64 (br s, 1 H), 2.95 (br s, 1 H), 1.15 (br s, 3 H). ¹³C NMR (100.6 MHz, CDCl₃): δ = 178.8, 144.3, 138.4, 133.0, 128.9, 128.7, 127.7, 127.5, 126.0, 125.7, 125.4, 125.2, 123.5, 119.3, 81.3, 56.7, 14.9. IR (neat): 3369, 3062, 1528, 1449,1382, 1278, 1176, 1136, 701, 682 cm^-1. MS (EI): m/z (%) = 271 (100), 229 (42), 213 (72), 202 (76), 182 (48), 163 (50).Catalyst 1e: white solid, mp 66-68 °C; [α]_D ²⁰ -16.7 (c 0.32, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 8.64 (br s, 1 H), 7.71-7.18 (m, 12 H), 6.92-6.87 (m, 1 H), 5.59 (br s, 1 H), 2.84 (br s, 1 H), 2.04 (br s, 1 H), 1.03 (d, J = 6.8 Hz, 3 H), 0.85 (d, J = 6.8 Hz, 3 H). ¹³C NMR (100.6 MHz, CDCl₃): δ = 180.6, 144.9, 144.4, 138.4, 133.9, 128.5, 128.1, 127.3, 125.6, 125.5, 125.3, 125.1, 123.8, 122.8, 119.3, 83.1, 63.4, 29.7, 23.4, 18.4. IR (neat): 3350, 3063, 2963, 1562, 1449, 1277, 1381, 1176, 1135, 703, 683 cm^-1. MS (EI): m/z (%) = 271 (100), 229 (40), 202 (34), 182 (34), 163 (64).Catalyst 1f: white solid, mp 81-83 °C; [α]_D ²² -251.7 (c 0.34, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 8.00 (br s, 1 H), 7.68-7.59 (m, 3 H), 7.42-7.26 (m, 5 H), 7.15-7.05 (m, 8 H), 7.00-6.95 (m, 2 H), 6.46 (br s, 1 H), 2.76 (br s, 1 H). ¹³C NMR (100.6 MHz, CDCl₃): δ = 179.3, 143.6, 143.4, 138.3, 136.3, 133.2, 128.9, 128.7, 128.1, 127.9, 127.3, 125.9, 125.5, 123.7, 119.6, 81.7, 64.7. IR (neat): 3255, 3062, 1518, 1449, 1381, 1278, 1176, 1137, 699, 682 cm^-1. MS (EI): m/z (%) = 271 (100), 213 (34), 202 (28), 163 (42).Catalyst 1g: white solid, mp 79-82 °C; [α]_D ²¹ -75.1 (c 0.33, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 8.03 (br s, 1 H), 7.64-7.15 (m, 15 H), 7.03-7.00 (m, 2 H), 6.78 (s, 1 H), 5.91 (br s, 1 H), 3.17 (br s, 1 H), 2.85-2.78 (m, 2 H). ¹³C NMR (100.6 MHz, CDCl₃): δ = 179.5, 144.2, 138.0, 131.9, 129.5, 128.7, 128.6, 127.5, 127.4, 126.9, 126.4, 125.6, 125.2, 124.0, 122.7, 119.3, 81.8, 60.2, 37.4. IR (neat): 3320, 3063, 1539, 1449, 1383, 1277, 1181, 1135, 701, 681 cm^-1. MS (ESI⁺): m/z (%) = 575 (70) [M + H⁺], 557 (100) [M - 17].Catalyst 1h: white solid, mp 49-51 °C; [α]_D ²¹ -8.50 (c 0.30, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 8.08 (br s, 1 H), 7.67 (s, 1 H), 7.33-7.14 (m, 12 H), 5.84 (br s, 1 H), 5.38 (br s, 1 H), 4.90-4.85 (m, 1 H), 3.93 (d, J = 9.9 Hz, 1 H), 1.21 (d, J = 6.4 Hz, 3 H). ¹³C NMR (100.6 MHz, CDCl₃): δ = 179.5, 141.5, 141.1, 138.0, 133.2, 129.0, 128.9, 128.6, 128.3, 128.2, 127.9, 127.2, 127.1, 124.3, 122.7, 119.9, 58.1, 54.2, 19.6. IR (neat): 3063, 1532, 1382, 1279, 1176, 1135, 888, 752, 702 cm^-1. MS (ESI⁺): m/z (%) = 483 (100) [M + H⁺]

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17

The following solvents were employed at a concentration of 2 M with respect to the aldehyde: toluene, MeOH, MeCN, THF, CH₂Cl₂.

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19

Typical Procedure for the MBH Reaction To a capped vial containing catalyst 1f (22.4 mg, 0.04 mmol) was added 2-cyclohexen-1-one (78 mL, 0.8 mmol) and Et₃N (4.4 mL, 0.04 mmol). The mixture was stirred for 5 min and then the aldehyde was added (0.2 mmol). After 100-147 h, the reaction was directly purified by flash silica gel chromatography eluting with PE-Et₂O mixtures (98:2 to 80:20) to give a clear oil. Spectral data of allylic alcohols matched those reported in the literature.^2,3,5

20 A similar outcome for aliphatic aldehydes was observed in organocatalyzed MBH reaction, see ref. 5a,b, 8, and 9

21 The corresponding products are generally obtained in moderate yields and ee, see ref. 5a,b, 8, and 9

22 The best result achieved up to now for the allylic alcohol obtained when reacting benzaldehyde and 2-cyclohexen-1-one is 65% yield and 77% ee, see ref. 8b