Synthesis of New Chiral 4,5,6,7-Tetrahydro[1,2,3]triazolo[1,5-a]pyrazines from α-Amino Acid Derivatives under Mild Conditions

Abstract

A practical and efficient regioselective synthesis of several new chiral 4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyrazines is described from α-amino acid derivatives following intramolecular ‘click’ reaction as the key step. The method obviates product ­purification; to obtain the pure triazole products, only the solvent needs to be evaporated.

Key words

pyrazine - 1,2,3-triazole - α-amino acid - click chemistry - 1,3-dipolar cycloaddition

References and Notes

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Analytical and Spectral Data
Compound 3a: [α]_D ²⁵ -47.76 (c 1.2, CHCl₃). IR (CHCl₃): 3023, 1696, 1497, 1223 cm^-1. ¹H NMR (200 MHz, CDCl₃): δ = 0.92 (d, 3 H, J = 6.6 Hz), 0.99 (d, 3 H, J = 6.5 Hz), 1.50 (s, 9 H), 1.53-1.65 (m, 1 H), 4.22 (dd, 1 H, J = 14.0, 4.5 Hz), 4.33 (m, 2 H), 4.76 (d, 1 H, J = 12.5 Hz), 5.13 (m, 1 H), 7.53 (s, 1 H). ¹³C NMR (50 MHz, CDCl₃): δ = 18.7, 19.5, 26.6, 27.8, 36.1, 46.3, 54.3, 55.6, 80.6, 128.6, 128.9, 153.8. ESI-MS: m/z = 267 [M + H]⁺. Anal. Calcd (%) for C₁₃H₂₂N₄O₂: C, 58.62; H, 8.33; N, 21.04. Found: C, 58.51; H, 8.47; N, 20.88.
Compound 3c: [α]_D ²⁵ -40.21 (c 1.1, CHCl₃). IR (CHCl₃): 2980, 1697, 1395, 1218, 1167 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.16 (d, 3 H, J = 7.3 Hz), 1.51 (s, 9 H), 4.32-4.37 (m, 2 H), 4.47 (d, 1 H, J = 13.2 Hz), 4.92 (m, 1 H), 5.07 (d, 1 H, J = 17.4 Hz), 7.56 (s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 15.7, 28.1, 36.1, 45.0, 50.1, 81.0, 128.9, 129.1, 153.7. ESI-MS: m/z = 239 [M + H]⁺, 261 [M + Na]⁺. Anal. Calcd (%) for C₁₁H₁₈N₄O₂: C, 55.45; H, 7.61; N, 23.51. Found: C, 55.67; H, 7.69; N, 23.42.
Compound 3d: [α]_D ²⁵ -30.74 (c 0.95, CHCl₃). IR (CHCl₃): 3020, 1703, 1508, 1407, 1215 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 0.84 (d, 3 H, J = 6.5 Hz), 0.87 (d, 3 H, J = 6.4 Hz), 1.06-1.12 (m, 1 H), 1.25-1.31 (m, 1 H), 1.40 (s, 9 H), 1.43-1.48 (m, 1 H), 4.12 (d, 1 H, J = 17.6 Hz), 4.21 (dd, 1 H, J = 12.8, 4.8 Hz), 4.36 (d, 1 H, J = 12.8 Hz), 4.72 (m, 1 H), 5.04 (d, 1 H, J = 17.6 Hz), 7.41 (s, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 21.9, 22.6, 24.7, 28.1, 35.9, 38.6, 47.3, 49.1, 80.9, 128.7, 128.9, 153.7. ESI-MS: m/z = 281 [M + H]⁺, 303 [M + Na]⁺. Anal. Calcd (%) for C₁₄H₂₄N₄O₂: C, 59.98; H, 8.63; N, 19.98. Found: C, 59.87; H, 8.71; N, 19.76.
Compound 3i: [α]_D ²⁵ +98.54 (c 1.1, CHCl₃). IR (CHCl₃): 3020, 1508, 1409, 1215 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 1.61-1.69 (m, 1 H), 1.92-2.05 (m, 2 H), 2.10-2.17 (m, 1 H), 2.36 (q, 1 H, J = 8.8 Hz), 2.68 (m, 1 H), 3.24-3.27 (ddd, 1 H, J = 8.81, 7.5, 2.8 Hz), 3.38 (d, 1 H, J = 14.6 Hz), 3.95 (dd, 1 H, J = 12.5, 10.6 Hz), 4.29 (d, 1 H, J = 14.6 Hz), 4.68 (dd, 1 H, J = 12.5, 3.9 Hz), 7.42 (s, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 22.2, 27.5, 46.8, 51.2, 53.3, 59.6, 128.4, 131.8. ESI-MS: m/z = 165 [M + H]⁺, 187 [M + Na]⁺. Anal. Calcd (%) for C₈H₁₂N₄: C, 58.52; H, 7.37; N, 34.12. Found: C, 58.37; H, 7.11; N, 33.98.

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X-ray intensity data was collected on Bruker SMART APEX CCD diffractometer with graphite-monochromated (MoKα = 0.71073 Å) radiation at r.t. All the data were corrected for Lorentzian, polarization and absorption effects using Bruker’s SAINT and SADABS programs. SHELX-97 (ShelxTL) [25] was used for structure solution and full matrix least squares refinement on F ². Hydrogen atoms were included in the refinement as per the riding model.

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Crystallographic data for the structures in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 633496 for 3i. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK [fax: [phone]; or e-mail: [e-mail]].