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Synlett 2006(15): 2403-2406  
DOI: 10.1055/s-2006-950409
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Orazio A. Attanasia, Lucia De Crescentini*a, Paolino Filipponea, Gianluca Giorgib, Fabio Mantellinia, Andrea Mazzantic
a Instituto di Chimica Organica, Facoltà di Scienze Matematiche, Fisiche e Naturali, Università degli Studi di Urbino ‘Carlo Bo’, Via Sasso 75, 61029 Urbino, Italy
b Dipartimento di Chimica, Università degli Studi di Siena, Via Aldo Moro, 53100 Siena, Italy
c Dipartimento di Chimica Organica ‘A. Mangini’, Università degli Studi di Bologna, Viale Risorgimento 4, 40136 Bologna, Italy
e-Mail: l.decrescentini@uniurb.it;
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Publication History

Received 12 May 2006
Publication Date:
08 September 2006 (online)

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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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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: +44 (1223)336033 or e-mail: deposit@ccdc.cam.ac.uk].

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.