Different Behavior of the Reaction between 1,2-Diaza-1,3-butadienes and 1,2-Diamines under Solvent or Solvent-Free Conditions

Abstract

New piperazinones are obtained in satisfactory yields by reaction of 1,2-diaza-1,3-butadienes with 1,2-diamines under solvent-free conditions. In polar solvents, the same reagents give rise to interesting dihydropyrazines and then to pyrazines by oxidation with PTAB or Pd/C.

Key word

Michael additions - regioselectivity - heterocyclic compounds - 1,2-diaza-1,3-butadienes - pyrazine derivatives

References

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8

General Procedure for the Synthesis of Piperazinones 5a,b and 4a-c. 1,2-Diaza-1,3-butadienes 1a,b (0.5 mmol) were slowly added to a solution of 1,2-diamines 2a-c (3 mmol) heated in an oil bath (for temperatures, see Table [1] ) with magnetic stirring. After the complete disappearance of 1,2-diaza-1,3-butadiene (monitored by silica gel TLC, 20 min) the crude reaction mixture was purified by chromatography on silica gel (elution mixture: EtOAc-MeOH, 90:10) for the products 5a,b and 4b. The excess of 1,2-diamine 2a was evaporated under reduced pressure and the crude reaction mixture was purified by crystallization from EtOAc-MeOH for the products 4a,c.
Data for tert-butyl 2-[1-(3-oxo-2-piperazinyl)ethylidene]-1-hydrazinecarboxylate (4c): white powder, mp 187-188 °C. IR (nujol): ν_max = 3229, 1723, 1698, 1659, 1541 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 1.43 (s, 9 H), 1.70 (s, 3 H), 2.76 (m, 1 H), 2,79 (br s, 1 H), 2.92 (m, 1 H), 3.04 (m, 1 H), 3.19 (m, 1 H), 3.80 (s, 1 H), 7.76 (s, 1 H), 9.47 (s, 1 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 13.55, 28.04, 41.21, 41.81, 66.07, 79.01, 150.82, 153.00, 167.82. MS: m/z (%) = 256 (2) [M⁺], 239 (1), 200 (5), 183 (2), 139 (26), 126 (8), 110 (8), 98 (30), 83 (16), 69 (24), 57 (100). Anal. Calcd for C₁₁H₂₀N₄O₃: C, 51.55; H, 7.87; N, 21.86. Found: C, 51.64; H, 7.81; N, 21.79.
Data for tert-butyl 2-[1-(3-oxo-3,4,4a,5,6,7,8,8a-octahydro-2-quinoxalinyl)ethylidene]-1-hydrazinecarboxylate (5b): white powder, mp 195-197 °C. IR (nujol): ν_max = 3223, 1738, 1717, 1697, 1531 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 1.23 (m, 4 H), 1.43 (s, 9 H), 1.68 (m, 2 H), 1.87 (m, 1 H), 1.95 (s, 3 H), 2.17 (m, 1 H), 2.98 (m, 1 H), 3.06 (m, 1 H), 8.45 (s, 1 H), 9.87 (s, 1 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 14.34, 23.15, 24.65, 27.97, 29.99, 31.23, 53.46, 62.49, 79.65, 147.01, 152.72, 156.55, 161.53.
MS: m/z (%) = 307 (2) [M⁺ - 1], 293 (2), 279 (2), 252 (2), 235 (2), 207 (4), 191 (4), 179 (10), 167 (10), 137 (10), 123 (10), 111 (16), 97 (28), 83 (30), 69 (44), 57 (100). Anal. Calcd for C₁₅H₂₄N₄O₃: C, 58.42; H, 7.84; N, 18.17. Found: C, 58.50; H, 7.79; N, 18.23.

9

General Procedure for the Synthesis of Substituted 5,6-Dihydropyrazines 6a-c and Substituted Pyrazines 7a-c. A stoichiometric amount of 1,2-diaza-1,3-butadiene 1a,b,d (1.0 mmol) was slowly added to a solution of 1,2-diamines 2b,c (1.0 mmol) in MeCN (50 mL). The reaction was allowed to stand at r.t. with magnetic stirring until complete disappearance of 1,2-diaza-1,3-butadiene (monitored by silica gel TLC, 1 h). The solvent was removed under reduced pressure and the products 6a-c were purified by chromatography on silica, (elution mixture: cyclohexane-EtOAc, 30:70). In order to obtain the oxidized products 7a-c, the crude mixture was dissolved with CH₂Cl₂ (150 mL) and PTAB (2 mmol) was slowly added. The crude reaction mixture was washed with H₂O (2 × 30 mL), the organic layer was dried over anhyd Na₂SO₄ and the solvent was evaporated under reduced pressure. The products 7a-c were purified by chromatography on silica (elution mixture: cyclohexane-EtOAc, 60:40).
Data for methyl (5R,6R)-3-methyl-5,6-diphenyl-5,6-dihydro-2-pyrazinecarboxylate (6b): ¹H NMR (400 MHz, CDCl₃): δ = 2.41 (d, ⁵ J = 2.4 Hz, 3 H), 3.95 (s, 3 H), 4.29 (dq, ^³ J = 14.8 Hz, ⁵ J = 2.4 Hz, 1 H), 4.37 (d, ^³ J = 14.8 Hz, 1 H), 6.95 (m, 4 H), 7.19 (m, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 22.87, 53.05, 65.27, 66.13, 126.55, 126.85, 127.34, 127.40, 128.13, 128.21, 139.35, 140.03, 153.24, 155.58, 164.36. MS: m/z (%) = 306 (100) [M⁺].
Data for methyl 3-methyl-5,6-diphenyl-2-pyrazinecarboxylate (7b) yellow powder, mp 102-104 °C. IR (nujol): ν_max = 1728, 1402, 1312 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 2.93 (s, 3 H), 4.01 (s, 3 H), 7.29 (m, 6 H), 7.48 (m, 4 H). ¹³C NMR (100 MHz, CDCl₃): δ = 22.73, 52.77, 128.21, 128.25, 128.64, 129.07, 129.58, 129.62, 137.59, 137.66, 139.40, 149.16, 151.91, 153.31, 165.87. MS: m/z (%) = 304 (100) [M⁺]. Anal. Calcd for C₁₉H₁₆N₂O₂: C, 74.98; H, 5.30; N, 9.20. Found: C, 74.89; H, 5.25; N, 9.14.

10

General Procedure for Synthesis of Ethyl 3-Methyl-pyrazine-2-carboxylate ( 7d). A solution of 1,2-diaza-1,3-butadienes 1c,d (1 mmol) in EtOH (10 mL) was added dropwise to a magnetically stirred solution of 1,2-ethanediamine 2a (1.0 mmol) in EtOH (50 mL). The reaction was allowed to stand at r.t. until complete disappearance of 1,2-diaza-1,3-butadiene (monitored by silica gel TLC, 1 h). The reaction was then treated with Pd/C (110 mg, 5%) with magnetic stirring and was refluxed for 14 h. The mixture was filtered and the solvent evaporated under reduced pressure. Product 7d was purified by chromatography on silica gel (elution mixture: cyclohexane-EtOAc, 70:30).