Efficient Syntheses of β-Amino-N-acylbenzotriazoles and Cinnamides through Regioselective 1,4- or 1,2-Addition of Amines to N-Cinnamoylbenzotriazoles

 

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Abstract

Amines react with N-cinnamoylbenzotriazoles to afford either β-amino-N-acylbenzotriazoles or cinnamides depending on the structure of the amines. Aromatic amines react with N-­cinnamoylbenzotriazoles via 1,4-addition to give β-amino-N-acylbenzotriazoles in good yields. For o-phenylenediamine, the 1,4-addition products were further acylated to provide a facile route to substituted 1,3,4,5-tetrahydro-1,5-benzodiazepine-2-ones. Ali­phatic amines, however, react exclusively through the 1,2-addition pathway to produce cinnamides in good yields.

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Typical Experimental Procedure.
A mixture of aromatic or aliphatic amine (1.1 mmol),
N-cinnamoybenzotriazole (1 mmol) and Et₃N (1 mL) was refluxed in dry THF (10 mL) for the indicated time (monitored by TLC). Removal of THF and Et₃N under reduced pressure afforded a residue, which was separated by preparative TLC on silica gel with EtOAc and cyclohexane (1:6) as eluent to afford β-amino N-acylbenzotriazoles. Alternatively, Et₂O was added to the reaction mixture, followed by washing with sat. Na₂CO₃ solution, drying with anhyd MgSO₄ and removal of the solvent under reduced pressure. The residue solidified and was recrystallized from EtOH or other appropriate solvent to afford pure α,β-unsaturated amides.

Physical Data of Selected Compounds.
1-{(1 H -Benzo[ d ][1,2,3]triazol-1-yl)-3-phenyl-3-phenyl-amino}propan-1-one (3a). Mp 167-169 °C. IR: ν_max = 3299 (NH), 3257, 3138, 3085, 1682 (C=O), 1602, 1548 (Ar) cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 8.02 (d, 1 H, J = 8.2 Hz, ArH), 7.97 (br, 1 H, NH), 7.23-7.46 (m, 12 H, ArH), 7.03-7.06 (m, 1 H, ArH), 6.45 (dd, 1 H, J = 5.2, 10.0 Hz, CH), 4.09 (dd, 1 H, J = 10.0, 15.2 Hz, CH), 3.46 (dd, 1 H, J = 5.20, 15.2 Hz, CH). ¹³C NMR (100 MHz, CDCl₃): δ = 167.5, 146.0, 138.7, 137.7, 129.1, 129.0, 128.9, 128.6, 127.7, 126.6, 124.5, 124.4, 120.2, 119.6, 110.1, 56.0, 43.6. Anal. Calcd for C₂₁H₁₈N₄O: C, 73.67; H, 5.30; N, 16.36. Found: C, 73.36; H, 5.36; N, 16.28.

1,3,4,5-Tetrahydro-4-aryl-1,5-benzodiazepine-2-one (4a). Decomposed beyond 83 °C. IR: ν_max = 3345 (NH), 3178, 3060, 2958, 2904, 1666 (C=O), 1596 (Ar) cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 7.92 (s, 2 H, ArH, NH), 7.30-7.45 (m, 5 H, ArH), 7.07-7.09 (m, 1 H, ArH), 6.94-6.96 (m, 1 H, ArH), 6.85 (d, 1 H, J = 8.0 Hz, ArH), 5.04 (dd, 1 H, J = 4.0, 12.0 Hz, CH), 3.85 (br, 1 H, NH), 2.91 (dd, 1 H, J = 12.0, 4 Hz, CH), 2.78 (dd, 1 H, J = 12.0, 4.0 Hz, CH). ¹³C NMR (100 MHz, CDCl₃): δ = 172.8, 144.2, 138.5, 129.0, 128.2, 127.7, 126.3, 126.1, 122.6, 121.6, 121.2, 63.5, 41.8. Anal. Calcd for C₁₅H₁₄N₂O: C, 75.61; H, 5.92; N, 11.76. Found: C, 75.38; H, 5.97; N, 11.69.
(E )- N -Cyclohexyl-3- p -tolylacrylamide (5a).
Mp 166-167 °C. IR: ν_max = 3288 (NH), 3072, 3025, 2927, 2853, 1660 (C=O), 1618, 1553 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 7.57 (1 H, d, J = 15.6 Hz, C=CH), 7.39 (2 H, d, J = 8.0 Hz, ArH), 7.16 (2 H, d, J = 8.0 Hz, ArH), 6.31 (1 H, d, J = 15.6 Hz, C=CH), 5.44 (1 H, br d, J = 6.1 Hz, NH), 3.90-3.92 (1 H, m, CH), 2.36 (3 H, s, CH₃); the following peaks all result from cyclohexyl: 1.97-2.00 (2 H, m), 1.72-1.75 (2 H, m), 1.36-1.43 (2 H, m), 1.14-1.25 (4 H, m). ¹³C NMR (100 MHz, CDCl₃): δ = 165.1, 140.6, 139.8, 132.2, 129.5, 127.7, 120.1, 48.3, 33.3, 25.6, 24.9, 21.4. Anal. Calcd for C₁₆H₂₁NO: C, 78.97; H, 8.70; N, 5.76. Found: C, 78.66; H, 8.81; N, 5.71.