Unusual Peptidomimetic Reaction of 1,2-Diaza-1,3-butadienes: Straightforward Entry to 2,3,6-Triazabicyclo[3.2.1]oct-3-enes, 5-Oxo-4,5-dihydro-2-pyrazines, and 2-Carbonyl-2-oxopropylaminoacetates

Abstract

The peptido-mimetic reaction between 4-dialkylamino­carbonyl-1,2-diaza-1,3-butadienes and sarcosine ethyl ester gave α-aminohydrazones. These compounds, in ethanol under reflux with sodium hydride, furnished new and unexpected 7-oxo-8-oxa-2,3,6-triazabicyclo[3.2.1]oct-3-ene-2-carboxylates and 5-oxo-4,5-dihydro-2-pyrazines. By treatment with Amberlyst 15H in acetone-water (10:1), the same hydrazones were converted into the ­corresponding ethyl 2-[{1-[(diethylamino)carbonyl]-2-oxoprop­yl}(methyl)amino]acetates.

Key words

Michael additions - amino acids - 1,2-diaza-1,3-butadienes - triazabicyclo derivatives - pyrazines

References and Notes

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• 4c Knapp S. Advances in Amino Acid Mimetics and Peptidomimetics   Vol. 2:  Abell A. JAI Press; Stamford: 1999. 
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• 6 Sheldrick GM. SHELXL-97, Rel. 97-2, A Program for Crystal Structure Refinement   Göttingen University; Germany: 1997. 
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• 8b Fadda E. Caida ME. Salahub DR. J. Phys. Chem. A  2003,  107:  9924 
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• 14 SciFinder Scholar, CAS   American Chemical Society; Columbus Ohio: 2004. 
• 15a Attanasi OA. De Crescentini L. Filippone P. Mantellini F. Santeusanio S. ARKIVOC  2002,  (xi):  274 
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• 16a In Comprehensive Heterocyclic Chemistry   Vol. 3:  Katritzky AR. Rees CW. Pergamon Press; Oxford: 1984.  p.191-197  
• 16b In Comprehensive Heterocyclic Chemistry   Vol. 3:  Katritzky AR. Rees CW. Pergamon Press; Oxford: 1984.  p.430-456  

2

α-Aminohydrazones 3a-f; General Procedure: To a magnetically stirred solution of sarcosine ethyl ester hydro-chloride 2 (1 mmol) and sodium acetate trihydrate (1 mmol) in MeOH (3 mL) a solution of the appropriate 1,2-diaza-1,3-butadienes 1a-f (1 mmol) in THF (5 mL) was added dropwise. The mixture was stirred at r.t. until the aza-alkene 1 disappeared (TLC, 0.5-1.0 h), then poured into a sat. aq solution of NaHCO₃ (150 mL), and extracted twice with EtOAc. The organic layer was dried over Na₂SO₄, eva-porated to dryness and the crude products were purified by column chromatography on silica gel. Products 3a-c were crystallized from EtOAc-PE (bp 40-60 °C), while 3d-f were oils.
tert-Butyl 2-{3-(Dimethylamino)-2-[(ethoxycarbonyl)-(methyl)amino]-1-methyl-3-oxopropylidene}-1-hydrazine-carboxylate (3c): White solid; mp 142-144 °C. IR (nujol): 3264, 1756, 1733, 1635 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆, 25 °C): δ = 1.14 (t, 3 H, J = 7.0 Hz), 1.42 (s, 9 H), 1.77 (s, 3 H), 2.33 (s, 3 H), 2.78 (s, 3 H), 2.94 (s, 3 H), 3.32 and 3.40 (AB system, 2 H, J = 17.2 Hz), 4.04 (q, 2 H, J = 7.0 Hz), 4.40 (s, 1 H), 9.56 (br s, 1 H). ¹³C NMR (100 MHz, DMSO-d ₆, 25 °C): δ = 14.8 (q), 15.0 (q), 28.9 (q), 36.0 (q), 36.1 (q), 37.6 (q), 55.0 (d), 60.5 (t), 69.8 (t), 79.9 (s), 151.1 (s), 153.5 (s), 169.2 (s), 171.5 (s). MS (EI): m/z = 358 (1) [M⁺], 343 (1), 286 (100). Anal. Calcd for C₁₆H₃₀N₄O₅: C, 53.61; H, 8.44; N, 15.63. Found: C, 53.74; H, 8.61; N, 15.81.

3

7-Oxo-8-oxa-2,3,6-triazabicyclo[3.2.1]oct-3-ene-2-carboxylates 6a-f and 5-Oxo-4,5-dihydro-2-pyrazines 7a and 7b; General Procedure: To a solution of α-amino-hydrazones 3a-f (1 mmol) in EtOH (10 mL), a stoichio-metric amount of NaH (1 mmol) was added, and the resulting mixture was heated at reflux until 3 was completely consumed (2-6 h). TLC analysis revealed the formation of two major components corresponding to 7-oxo-8-oxa-2,3,6-triazabicyclo[3.2.1]oct-3-ene-2-carboxylates 6a-f and 5-oxo-4,5-dihydro-2-pyrazines 7a and 7b that were purified by column chromatography on silica gel. Products 6a-f were crystallized from EtOAc-PE (40-60 °C), while 7a and 7b were crystallized from Et₂O-PE.
tert-Butyl 5-[(dimethylamino)carbonyl]-4,6-dimethyl-7-oxo-8-oxa-2,3,6-triazabicyclo[3.2.1]oct-3-ene-2-carboxylate (6c): White solid; mp 135-139 °C. IR (nujol): 1733, 1719, 1658 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆, 25 °C): δ = 1.45 (s, 9 H), 2.01 (s, 3 H), 2.92 (s, 3 H), 2.94 (s, 3 H), 3.03 (s, 3 H), 6.44 (s, 1 H). ¹³C NMR (100 MHz, DMSO-d ₆, 25 °C): δ = 20.7 (q), 28.4 (q), 29.2 (q), 36.4 (q), 37.1 (q), 80.3 (d), 83.5 (s), 89.0 (s), 147.0 (s), 149.9 (s), 162.4 (s), 166.3 (s). MS (EI): m/z = 326 (5) [M⁺], 226 (17), 197 (57), 182 (35), 170 (64), 155 (40), 141 (35), 126 (100). Anal. Calcd for C₁₄H₂₂N₄O₅: C, 51.52; H, 6.79; N, 17.17. Found: C, 51.59; H, 6.85; N, 17.58.
N2,N2,3-Trimethyl-5-oxo-4,5-dihydro-2-pyrazinecarbox-amide (7a): White solid; mp 173-175 °C. IR (nujol): 3425, 1688, 1632 cm^-1. ¹H NMR (599.7 MHz, CDCl₃, 25 °C): δ = 2.47 (s, 3 H), 3.01 (s, 3 H), 3.17 (s, 3 H), 8.00 (s, 1 H), 13.34 (br s, 1 H). ¹³C NMR (150.8 MHz, CDCl₃, 25 °C): δ = 16.5 (q), 33.5 (q), 38.8 (q), 129.8 (s), 139.0 (s), 143.4 (d), 158.1 (s), 166.5 (s). ¹⁵N NMR (60.8 MHz, CDCl₃, 25 °C, external reference CH₃NO₂ at 380.0): δ = 105.7, 182.5, 342.7. MS (EI): m/z (%) = 181 (91) [M ⁺ ], 166 (3), 152 (6), 137 (20), 124 (19), 109 (100). Anal. Calcd for C₈H₁₁N₃O₂: C, 53.05; H, 6.12; N, 29.19. Found: C, 53.18; H, 6.22; N, 29.02.

7

Crystallographic data (excluding structure factors) for compounds 6c and 8a have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication, numbers CCDC 617309 (6c) and CCDC 617310 (8a). 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]].

9

5-[(Dimethylamino)carbonyl]-6-methyl-2-pyrazinyl benzoate (8a); General Procedure: To a solution of N2,N2,3-trimethyl-5-oxo-4,5-dihydro-2-pyrazine-carboxamide (7a) (1 mmol) in THF (6 mL) at -15 °C, py (2 equiv, 2 mmol) was added. The mixture was allowed to stand under these conditions for 0.1 h and then a solution of PhCOCl (1 mmol) in THF (6 mL) was added slowly. After 0.5 h, TLC analysis revealed the formation of product 8a which was purified by column chromatography on silica gel and crystallized from dioxane.
Whitish solid; mp 94-98 °C. IR (nujol): 1738, 1656 cm^-1. ¹H NMR (599.7 MHz, CDCl₃, 25 °C): δ = 2.62 (s, 3 H), 2.94 (s, 3 H), 3.19 (s, 3 H), 7.53 (t, 2 H, J = 7.9 Hz), 7.68 (t, 1 H, J = 7.9 Hz), 8.23 (d, 2 H, J = 7.9 Hz), 8.45 (s, 1 H). ¹³C NMR (150.8 MHz, CDCl₃, 25 °C): δ = 20.6 (q), 34.8 (q), 38.1 (q), 128.0 (s), 128.6 (d), 130.3 (d), 134.2 (d), 143.4 (d), 146.6 (s), 150.8 (s), 153.4 (s), 164.0 (s), 166.5 (s). ¹⁵N NMR (60.8 MHz, CDCl₃, 25 °C, external reference CH₃NO₂ at 380.0): δ = 105.1, 312.0, 337.6. MS (EI): m/z (%) = 285 (75) [M⁺], 228 (20), 105 (100). Anal. Calcd for C₁₅H₁₅N₃O₃: C, 63.15; H, 5.30; N, 14.73. Found: C, 63.28; H, 5.21; N, 14.91.

11

2-[{1-[(Dimethylamino)carbonyl]-2-oxopropyl}(methyl)-amino]acetates (9a and 9b); General Procedure: To a solution of α-aminohydrazones 3c or 3f (1 mmol) in acetone-water (9:1), Amberlyst 15H (1 equiv, 1 mmol) was added. The mixture was heated at reflux for 3-5 h until 3 was consumed. After filtration of the resin and evaporation of the reaction solvent, products 9a and 9b were purified by column chromatography on silica gel and obtained as yellow oils.
Ethyl 2-[{1-[(Dimethylamino)carbonyl]-2-oxopropyl}-(methyl)amino]acetate (9a): Yellow oil. IR (neat film): 1754, 1734, 1642 cm^-1. ¹H NMR (400 MHz, CDCl₃, 25 °C): δ = 1.22 (t, 3 H, J = 7.2 Hz), 2.16 (s, 3 H), 2.52 (s, 3 H), 2.94 (s, 3 H), 3.15 (s, 3 H), 3.54 and 3.60 (AB system, 2 H, J = 18.0 Hz), 4.10 (q, 2 H, J = 7.2 Hz), 4.47 (s, 1 H). ¹³C NMR (100 MHz, CDCl₃, 25 °C): δ = 14.1 (q), 28.0 (q), 35.7 (q), 37.5 (q), 40.6 (q), 54.7 (t), 60.4 (t), 73.8 (d), 167.5 (s), 171.4 (s), 205.0 (s). MS (EI): m/z (%) = 244 (3) [M⁺], 201 (100). Anal. Calcd for C₁₁H₂₀N₂O₄: C, 54.08; H, 8.25; N, 11.47. Found: C, 53.99; H, 8.44; N, 11.53.