The Synthesis of New C₂-Symmetric Chiral 1,4-Diamino Motif and Application in Catalytic Asymmetric Alkynylation of meso-Epoxides

Abstract

The efficient asymmetric preparation of the C₂-symmetric chiral 1,4-diamine, (1R,2S,4R,5S)-1,4-diamino-2,5-dimethylcyclohexane (5), and its salen ligands is described. With the Mitsunobu reaction as the key step, the overall yield of the four-step synthesis of 5 is 45%. The enantioselective alkynylation of meso- epoxides catalyzed by chiral gallium complexes is also achieved.

1,4-diamine - salen ligand - alkynylation - gallium complex - asymmetric synthesis

References

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8

(1S,2S,4S,5S)-(+)-1,4-dihydroxy-2,5-Dimethylcyclohexane(3): white solid, mp 120-121 °C. [α]_D ²⁵ +32.7 (c 1.0, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃):
δ = 3.51-3.57 (m, 2 H), 1.87-1.93 (m, 2 H), 1.68-1.78 (m, 4 H), 1.53-1.59 (m, 2 H), 1.01 (d, J = 6.9 Hz, 6 H) ppm. IR (KBr): ν_OH = 3313.8 cm^-1. MS (EI): m/z (%) = 144.1 (4) [M⁺], 126.0 (4), 111.1 (10), 72 (100). Anal. Calcd for C₈H₁₆O₂: C, 66.63; H, 11.18. Found: C, 66.34; H, 11.22.

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11

(1R,2S,4R,5S)-(-)-1,4-diazido-2,5-dimethylcyclohexane(4): yellow oil. [α]_D ²⁵ -44.6 (c 0.2, THF). ¹H NMR (300 MHz, CDCl₃): δ = 3.59-3.64 (m, 2 H), 1.95 (br. s, 2 H), 1.83 (ddd, J = 13.5, 7.5, 4.2 Hz, 2 H), 1.64 (ddd, J = 13.5, 7.5, 4.2 Hz, 2 H), 1.11 (d, J = 7.0 Hz, 6 H) ppm. IR (KBr): ν (-N₃) = 2097.9 cm^-1. MS (EI): m/z (%) = 194.0 (1) [M⁺], 166.1 (1), 141.0 (1), 109.1 9 (7), 81.0 (20), 42 (100). Anal. Calcd for C₈H₁₄N₆: C, 49.47; H, 7.27; N, 43.27. Found: C, 49.32; H, 7.23, N 43.41.

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13

Dihydrochloride of (1R,2S,4R,5S)-(+)-1,4-diamino-2,5-dimethylcyclohexane(5): white solid, mp >200 °C. [α]_D ²⁵ +3.3 (c 0.5, H₂O). ¹H NMR (300 MHz, D₂O): δ = 3.40-3.45 (m, 2 H), 2.13-2.18 (m, 2 H), 1.75-1.88 (m, 4 H), 1.00 (d, J = 7.3 Hz, 6 H) ppm. IR (KBr): ν = 3456.1, 3022.3, 2895.0, 1652.9, 1558.8, 1465.2, 1454.8, 1399.5 cm^-1. MS (EI): m/z (%) = 142.1(2) [M⁺- 2HCl], 125.1 (7), 110.1 (6), 83.1 (6), 72.0 (100). Anal. Calcd for C₈H₁₈N₂Cl₂: C, 45.08; H, 8.51; N, 13.14. Found: C, 44.93; H, 9.30; N, 13.25.

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19

Spectroscopic data for compound 6 and 7: For 6: yellow crystals, mp 154-156 °C. [α]_D ²⁵ +21.6 (c 2.0, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ = 13.57 (s, 2 H), 8.40 (s, 2 H), 7.28-7.36 (m, 4 H), 6.88-7.02 (m, 4 H), 3.50 (d, J = 3.0 Hz, 2 H), 2.00-2.08 (m, 4 H), 1.81-1.85 (m, 2 H), 1.06 (d, J = 6.6 Hz, 6 H) ppm. IR (KBr): ν_C=N = 1627.6 cm^-1. MS (EI): m/z (%) = 350.2 (100) [M⁺], 335.1 (3), 320.1 (2), 229.1 (43), 188.1 (57), 122.1 (78). Anal. Calcd for C₂₂H₂₆N₂O₂: C, 75.40; H, 7.48; N, 7.99. Found: C, 75.21; H, 7.44; N, 7.83. For 7: yellow solid, mp >210 °C. [α]_D ²⁵ +17.5 (c 2.0, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ = 13.78 (s, 2 H), 8.42 (s, 2 H), 7.42 (d, J = 2.1 Hz, 2 H), 7.14 (d, J = 2.1 Hz, 2 H), 3.43-3.46 (m, 2 H), 2.01-2.07 (m, 4 H), 1.82-1.88 (m, 2 H), 1.49 (s, 18 H), 1.36 (s, 18 H), 1.06 (d, J = 5.9 Hz, 6 H) ppm. IR (KBr): ν_C=N = 1628.8 cm^-1. MS (EI): m/z (%) = 574.2 (100) [M⁺], 559.3 (17), 544.3 (2), 341.3 (29), 272.1 (32), 69.0 (100). Anal. Calcd for C₃₈H₅₈N₂O₂: C, 79.39; H, 10.17; N, 4.87. Found: C, 79.30; H, 10.23; N, 4.72.

20

A Typical Procedure for the Ring Opening of meso Epoxides by Phenylethynyl Lithium: GaMe₃ (0.2 mL, 0.1 mmol, 0.5 M in toluene) was added dropwise to the toluene solution of ligand 7 (57 mg, 0.10 mmol) under argon atmosphere. The mixture was stirred for 2 h at r.t. to form the salen-Ga complex. The toluene solution of phenylethynyl lithium, which was prepared from the reaction of n-BuLi (1.6 mmol in 1 mL hexane) and phenylacetylene (153 mg, 1.5 mmol) at -78 °C before use, was transferred to above solution of salen-Ga complex at 0 °C and stirred for another 1 h. Then the cyclohexene oxide (101 µL, 1.0 mmol) was added slowly to the mixture using a syringe at 0 °C. The resulting mixture was stirred for 48 h at the same temperature before being quenched with a sat. NH₄Cl solution and extracted with EtOAc. The organic phase was dried over Na₂SO₄, and removed the solvent. After being separated by preparative silica gel TLC, 2-(2-phenylethynl)-1-cyclohexanol (120 mg) was obtained as yellow oil in the yield of 60% with 55% ee. [α]_D ²⁵ -57.2 (c 0.7, CHCl₃). The ee value was determined by HPLC analysis (DAICEL CHIRAL OD-H column, hexane/i-PrOH = 30:1, 0.5 mL/min, 254 nm): t_R = 22.35 min, 23.77 min. ¹H NMR [16] (300 MHz, CDCl₃): δ = 7.39-7.48 (m, 2 H), 7.30-7.39 (m, 3 H), 3.53-3.60 (m, 1 H), 2.46-2.48 (m, 1 H), 1.24-2.11 (m, 9 H) ppm. IR(neat): ν = 3429.4, 2229.8 cm^-1.

21 Hill MS. Wei P. Atwood DA. Polyhedron  1998,  17:  811 

22

Identification of the pre-catalysts. Analytical data of the complex formed from ligand 6 and GaMe₃ (1:1 molar ration at r.t. in toluene): ¹H NMR (300 MHz, CDCl₃): δ = 13.43 (s, 1 H), 8.36 (s, 1 H), 8.11 (s, 1 H), 7.30-7.39 (m, 4 H), 6.73-7.01 (m, 4 H), 3.90-3.94 (m, 1 H), 3.38-3.44 (m, 1 H), 2.37-2.39 (m, 1 H), 2.20-2.24 (m, 2 H), 1.93-2.20 (m, 2 H), 1.59-1.63 (m, 1 H), 1.00-1.02 (d, J = 7.3 Hz, 6 H), -0.21 (s, 3 H), -0.31 (s, 3 H) ppm. MS (EI): m/z (%) = 434.9 (6) (M⁺ - 15), 417.0 (100), 333.0 (2), 222.9 (5), 188.9 (8), 122.0 (7), 109.0 (3), 68.9 (12). Anal. Calcd for C₂₄H₃₁N₂O₂Ga: C, 64.17; H, 6.95; N, 6.24. Found: C, 64.35; H, 7.10; N, 6.38. Analytical data of the complex formed from ligand 7 and GaMe₃ (1:1 molar ration at r.t. in toluene): ¹H NMR (300 MHz, CDCl₃): δ = 13.55 (s, 1 H), 8.11 (s, 1 H), 8.08 (s, 1 H), 7.42-7.43 (d, J = 2.3 Hz, 1 H), 7.13-7.14 (d, J = 2.3 Hz, 1 H), 7.03-7.04 (d, J = 2.5 Hz, 1 H), 6.90-6.91 (d, J = 2.5 Hz, 1 H), 3.50-3.51 (m, 1 H), 3.37-3.39 (m, 1 H), 1.51-2.42 (m, 6 H), 1.48 (s, 9 H), 1.48 (s, 9 H) 1.33 (s, 9 H), 1.31 (s, 9 H), 0.99-1.02 (d, J = 6.3 Hz, 6 H), -0.21 (s, 3 H), -0.36 (s, 3 H). MS (EI): m/z (%) = 657.4 (14) (M⁺ - 15), 642.4 (100), 321.6 (5), 313.8 (10), 68.9 (9). Anal. Calcd for C₄₀H₆₃N₂O₂Ga: C, 71.32; H, 9.43; N, 4.16. Found: C, 71.54; H, 9.52; N, 3.98.

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