Asymmetric Henry reactions catalyzed by copper(II) complexes of chiral 1,2,4-triazine-oxazoline ligands: the impact of substitution in the oxazoline ring on ligand activity

An enantiomerically pure 1,2,4-triazine-oxazoline ligand with an indanol-derived substituent in the oxazoline ring has been synthesized using Buchwald–Hartwig amination of 3-bromo-1,2,4-triazine. The catalytic efficiency of the ligand was estimated in the asymmetric nitroaldol (Henry) reaction of nitromethane with several aromatic and aliphatic aldehydes. The appropriate nitroaldol products were formed in good yields (up to 91%) and with up to 92% ee. In order to investigate the influence of the conformational rigidity and the additional stereocenter in the oxazoline ring on the catalytic activity of the ligand, a 1,2,4-triazine-oxazoline ligand with two phenyl substituents in the oxazoline ring was synthesized and tested in the asymmetric nitroaldol reaction.

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N-{2-[(3aR,8aS)-8,8a-Dihydro-3aH-indeno[1,2-d]oxazol-2-yl]phenyl}-5-phenyl-1,2,4-triazin-3-amineC25H19N5O[α]D20 = −408.4 (c 0.55, CH2Cl2)Absolute configuration: (3aR,8aS)Source of chirality: (1R,2S)-1-amino-2-indanol

2-[(4R,5S)-4,5-Diphenyl-4,5-dihydrooxazol-2-yl]anilineC21H18N2O[α]D20 = −13.3 (c 1.00, CH2Cl2)Absolute configuration: (4R,5S)Source of chirality: (1S,2R)-2-amino-1,2-diphenylethanol

N-{2-[(4R,5S)-4,5-Diphenyl-4,5-dihydrooxazol-2-yl]phenyl}-5-phenyl-1,2,4-triazin-3-amineC30H23N5O[α]D20 = −170.5 (c 0.77, CH2Cl2)Absolute configuration: (4R,5S)Source of chirality: (1S,2R)-2-amino-1,2-diphenylethanol

(R)-2-Nitro-1-(3-nitrophenyl)ethanolC8H8N2O5ee = 44%[α]D20 = −21.0 (c 1.00, CH2Cl2)Absolute configuration: (R)Source of chirality: asymmetric nitroaldol reaction

(R)-2-Nitro-1-phenylethanolC8H9NO3ee = 77%[α]D20 = −42.5 (c 1.00, CH2Cl2)Absolute configuration: (R)Source of chirality: asymmetric nitroaldol reaction

(R)-2-Nitro-1-(2-nitrophenyl)ethanolC8H8N2O5ee = 62%[α]D20 = +147.5 (c 0.23, CH2Cl2)Absolute configuration: (R)Source of chirality: asymmetric nitroaldol reaction

(R)-2-Nitro-1-(4-nitrophenyl)ethanolC8H8N2O5ee = 44%[α]D20 = −21.1 (c 0.30, CH2Cl2)Absolute configuration: (R)Source of chirality: asymmetric nitroaldol reaction

(R)-1-(2-Chlorophenyl)-2-nitroethanolC8H8ClNO3ee = 77%[α]D20 = −46.6 (c 2.50, CH2Cl2)Absolute configuration: (R)Source of chirality: asymmetric nitroaldol reaction

(R)-1-(3-Chlorophenyl)-2-nitroethanolC8H8ClNO3ee = 74%[α]D20 = −31.2 (c 0.50, CH2Cl2)Absolute configuration: (R)Source of chirality: asymmetric nitroaldol reaction

(R)-1-(4-Chlorophenyl)-2-nitroethanolC8H8ClNO3ee = 78%[α]D20 = −36.9 (c 1.76, CH2Cl2)Absolute configuration: (R)Source of chirality: asymmetric nitroaldol reaction

(R)-1-(2-Bromophenyl)-2-nitroethanolC8H8BrNO3ee = 77%[α]D20 = −38.6 (c 1.00, CH2Cl2)Absolute configuration: (R)Source of chirality: asymmetric nitroaldol reaction

(R)-1-(2-Methylphenyl)-2-nitroethanolC9H11NO3ee = 92%[α]D20 = −45.1 (c 1.00, CH2Cl2)Absolute configuration: (R)Source of chirality: asymmetric nitroaldol reaction

(R)-1-(3-Methylphenyl)-2-nitroethanolC9H11NO3ee = 76%[α]D20 = −21.2 (c 0.30, CH2Cl2)Absolute configuration: (R)Source of chirality: asymmetric nitroaldol reaction

(R)-1-(4-Methylphenyl)-2-nitroethanolC9H11NO3ee = 77%[α]D20 = −34.4 (c 1.00, CH2Cl2)Absolute configuration: (R)Source of chirality: asymmetric nitroaldol reaction

(R)-1-(2-Methoxylphenyl)-2-nitroethanolC9H11NO4ee = 76%[α]D20 = −38.4 (c 1.00, CH2Cl2)Absolute configuration: (R)Source of chirality: asymmetric nitroaldol reaction

(R)-1-(3-Methoxylphenyl)-2-nitroethanolC9H11NO4ee = 82%[α]D20 = −30.3 (c 0.30, CH2Cl2)Absolute configuration: (R)Source of chirality: asymmetric nitroaldol reaction

(R)-1-(4-Methoxyphenyl)-2-nitroethanolC9H11NO3ee = 79%[α]D20 = −38.0 (c 0.50, CH2Cl2)Absolute configuration: (R)Source of chirality: asymmetric nitroaldol reaction

(R)-1-(3,4-Dimethoxylphenyl)-2-nitroethanolC10H13NO5ee = 70%[α]D20 = −22.3 (c 0.44, CH2Cl2)Absolute configuration: (R)Source of chirality: asymmetric nitroaldol reaction

(R)-1-(1-Naphthyl)-2-nitroethanolC12H11NO3ee = 75%[α]D20 = −22.8 (c 1.00, CH2Cl2)Absolute configuration: (R)Source of chirality: asymmetric nitroaldol reaction

(R)-1-Nitro-4-phenylbutan-2-olC10H13NO3ee = 60%[α]D20 = +9.2 (c 1.00, CH2Cl2)Absolute configuration: (R)Source of chirality: asymmetric nitroaldol reaction

(R)-1-Nitrohexan-2-olC6H13NO3ee = 65%[α]D20 = −7.0 (c 0.40, CH2Cl2)Absolute configuration: (R)Source of chirality: asymmetric nitroaldol reaction