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Synlett 2014; 25(12): 1705-1708
DOI: 10.1055/s-0034-1378275
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© Georg Thieme Verlag Stuttgart · New York

An Efficient Approach to the Synthesis of Alkyl 7-Hydroxy-1-oxo-1,2,3,4- tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylates via a One-Pot, Three-Component Reaction

Abdolali Alizadeh*
Department of Chemistry, Tarbiat Modares University, P.O. Box 14115-175, Tehran, Iran   Fax: +98(21)88006544   Email: abdol_alizad@yahoo.com   Email: aalizadeh@modares.ac.ir
,
Marziyeh Hossein Abadi
Department of Chemistry, Tarbiat Modares University, P.O. Box 14115-175, Tehran, Iran   Fax: +98(21)88006544   Email: abdol_alizad@yahoo.com   Email: aalizadeh@modares.ac.ir
,
Rashid Ghanbaripour
Department of Chemistry, Tarbiat Modares University, P.O. Box 14115-175, Tehran, Iran   Fax: +98(21)88006544   Email: abdol_alizad@yahoo.com   Email: aalizadeh@modares.ac.ir
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Further Information

Publication History

Received: 22 March 2014

Accepted after revision: 09 May 2014

Publication Date:
12 June 2014 (online)

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Abstract

An efficient synthesis of alkyl 7-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylate derivatives by reaction between diamines, dialkyl acetylenedicarboxylates, and alkyl or aryl glyoxales is reported. Ease of handling, easy purification, and good yields are the main advantages of the presented method.

Key words

diamine - dialkyl acetylenedicarboxylate - glyoxale - ­alkyl 7-hydroxy-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylate - one-pot, three-component reaction
 

  • References and Notes

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  • 21 To a solution of ethylenediamine (1 mmol) in EtOH (2 mL), dimethyl acetylenedicarboxylate (1 mmol) was added dropwise at r.t. After 30 min, methylglyoxal (1 mmol) and PTSA (0.1 mmol) were added to the reaction mixture, and the solution was stirred for 2.5 h at reflux conditions. Upon completion (3 h), monitored by TLC, the solvent was cooled at an ice bath, and the precipitate was filtered to afford the pure products 3a–f. Methyl 7-Hydroxy-6-methyl-1-oxo-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazine-8-carboxylate (3a) Pale orange powder; 0.156 g, 70% yield; mp 187–189 °C. IR (KBr): 3211 (NH), 3099 (OH), 1715 (CO2Me), 1675 (NCO), 1219 and 1146 (CO) cm–1. 1H NMR (400 MHz, CDCl3): δ = 2.20 (s, 3 H, CH3), 3.65–3.68 (m, 2 H, CH2NH), 3.94 (s, 3 H, OMe), 3.95 (t, 3 J HH = 5.6 Hz, 2 H, CH2N), 7.28 (s, 1 H, NH), 8.39 (s, 1 H, OH). 13C NMR (100 MHz, CDCl3): δ = 7.9 (CH3), 39.3 (CH2NH), 41.6 (CH2N), 52.1 (OMe), 103.4 (C6), 114.4 (C8), 118.2 (C8a), 145.9 (COH), 159.3 (CO2CH3), 167.5 (NCO). MS: m/z = 225 [M+ + 1], 224 [M+], 192, 164, 136, 123, 107, 95, 79, 66, 53. Anal. Calcd (%) for C10H12N2O4: C, 53.57; H, 5.39; N, 12.40. Found: C, 53.51; H, 5.46; N, 12.38. Ethyl 7-Hydroxy-6-methyl-1-oxo-1,2,3,4-tetrahydro-pyrrolo[1,2-a]pyrazine-8-carboxylate (3b) Pale brown powder; 0.178 g, 74%; mp 178–179 °C. IR (KBr): 3393 (NH), 3193 (OH), 1710 (CO2Et), 1668 (NCO), 1335, 1225 and 1150 (CO) cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.34 (t, 3 J HH = 7.0 Hz, 3 H, CH2CH 3), 2.12 (s, 3 H, CH3), 3.56–3.59 (m, 2 H, CH2NH), 3.87 (t, 3 J HH = 5.7 Hz, 2 H, CH2N), 4.32 (q, 3 J HH = 7.0 Hz, 2 H, CH 2CH3), 7.01 (s, 1 H, NH), 8.28 (s, 1 H, OH). 13C NMR (100 MHz, CDCl3): δ = 7.9 (CH3), 14.2 (CH3), 39.3 (CH2NH), 41.6 (CH2N), 60.9 (OCH2), 103.9 (C6), 114.3 (C8), 118.3 (C8a), 145.8 (COH), 159.2 (CO2Et), 166.9 (NCO). MS: m/z = 239 [M+ + 1], 238 [M+], 192, 164, 136, 123, 107, 95, 80, 67, 53. Anal. Calcd (%) for C11H14N2O4: C, 55.46; H, 5.92; N, 11.76. Found: C, 55.36; H, 5.87; N, 11.82. Methyl 7-Hydroxy-1-oxo-6-1,2,3,4-tetrahydrophenyl-pyrrolo[1,2-a]pyrazine-8-carboxylate (3c) Pale yellow powder; 0.238 g, 83% yield; mp 90–92 °C. IR (KBr): 3350 (NH), 3235 (OH), 1706 (CO2Me), 1664 (NCO), 1580 and 1481 (Ar), 1348, 1225 and 1141 (CO) cm–1. 1H NMR (300.13 MHz, CDCl3): δ = 3.69–3.65 (m, 2 H, CH2NH), 3.98 (s, 3 H, OMe), 4.11 (t, 3 J HH = 5.9 Hz, 2 H, CH2N), 6.59 (s, 1 H, NH), 7.35–7.39 (m, 1 H, CH para of Ph), 7.44–7.50 (m, 4 H, 2 × CH ortho and 2 × CH meta of Ph), 8.80 (s, 1 H, OH). 13C NMR (75 MHz, CDCl3): δ = 39. 7 (CH2NH), 43.1 (CH2N), 52.2 (OMe), 103.7 (C6), 118.7 (C8), 119.6 (C8a), 128.0 (CH para of Ph), 128.3 (C ipso ), 128.7 (2 × CH ortho of Ph), 129.4 (2 × CH meta of Ph), 146.6 (COH), 158.9 (CO2Me), 167.6 (NCO). MS: m/z = 287 [M+ + 1], 287 [M+], 279, 262, 254, 219, 205, 167, 149, 132, 121, 113, 104, 93, 83, 71, 57. Anal. Calcd (%) for C15H14N2O4: C, 62.93; H, 4.93, N, 9.79. Found: C, 62.97; H, 5.01; N, 9.86. Ethyl 7-Hydroxy-1-oxo-6-1,2,3,4-tetrahydrophenyl-pyrrolo[1,2-a]pyrazine-8-carboxylate (3d) Pale yellow powder; 0.198 g 66% yield; mp 213–214 °C. IR (KBr): 3184 (NH), 3064 (OH), 1708 (CO2Et), 1665 (NCO), 1580 and 1481 (Ar), 1300, 1239 and 1197 (CO) cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.45 (t, 3J HH = 7.2 Hz, 3H, CH2CH 3), 3.10–3.64 (m, 2 H, CH2NH), 4.11 (t, 3 J HH = 5.6 Hz, 2 H, CH2N), 4.45 (q, 3J HH = 7.2 Hz, 2 H, CH 2CH3), 7.12 (s, 1 H, NH), 7.36–7.40 (m, 1 H, CH para of Ph), 7.46–7.51 (m, 4 H, 2 × CH ortho and 2 × CH meta of Ph), 8.75 (s, 1 H, OH). 13C NMR (100 MHz, CDCl3): δ = 14.2 (CH3), 39.6 (CH2NH), 43.1 (CH2N), 61.1 (OCH2), 104.1 (C6), 118.6 (C8), 119.8 (C8a), 127.9 (CH para of Ph), 128.4 (C ipso ), 128.7 (2 × CH ortho of Ph), 129.4 (2 × CH meta of Ph), 146.4 (COH), 159.2 (CO2Et), 166.9 (NCO). MS: m/z = 301 [M+ + 1], 300 [M+], 254, 225, 211, 198, 183, 169, 155, 141, 128, 115, 104, 95, 77, 67, 53. Anal. Calcd (%) for C16H16N2O4: C, 63.99; H, 5.37, N, 9.33. Found: C, 64.01; H, 5.49; N, 9.30. Methyl 7-Hydroxy-1-oxo-6-(4-chlorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylate (3e) Pale beige powder; 0.245 g, 86% yield; mp 203–204 °C. IR (KBr): 3325 (NH), 3200 (OH), 1710 (CO2Me), 1660 (NCO), 1574 and 1481 (Ar), 1299, 1233 and 1138 (C–O) cm–1. 1H NMR (400 MHz, CDCl3): δ = 3.63–3.68 (m, 2 H, CH2NH), 3.99 (s, 3 H, OMe), 4.10 (t, 3 J HH = 5.8 Hz, 2 H, CH2N), 6.84 (s, 1 H, NH), 7.41 (d, 3 J HH = 8.8 Hz, 2 H, 2 × CH of Ar), 7.46 (d, 3 J HH = 8.4 Hz, 2 H, 2 × CH of Ar), 8.85 (s, 1 H, OH). 13C NMR (100 MHz, CDCl3): δ = 39.6 (CH2NH), 43.1 (CH2N), 52.3 (OMe), 103.7 (C6), 117.5 (C8), 120.0 (C8a), 126.7 (C ipso ), 129.0 (2 × CH of Ar), 130.7 (2 × CH of Ar), 133.9 (C ipso Cl), 146.8 (COH), 158.9 (CO2Me), 167.5 (NCO). MS: m/z = 322 [M+ + 2], 321 [M+ + 1], 320 [M+], 288, 262, 253, 232, 189, 175, 162, 151, 137, 123, 111, 95, 80, 67, 53. Anal. Calcd (%) for C15H13ClN2O4: C, 66.02; H, 5.30; N, 13.39. Found: C, 65.98; H, 5.45; N, 13.43. Ethyl 7-Hydroxy-1-oxo-6-(4-chlorophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylate (3f) Yellow powder; 0.223 g, 66% yield; mp 243–244 °C. IR (KBr): 3181 (NH), 3073 (OH), 1713 (CO2Et), 1677 (NCO), 1566 and 1476 (Ar), 1302, 1224 and 1150 (CO) cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.45 (t, 3 J HH = 7.0 Hz, 3 H, CH2CH 3), 3.63–3.68 (m, 2 H, CH2NH), 4.10 (t, 3 J HH = 5.8 Hz, 2 H, CH2N), 4.46 (q, 3 J HH = 7.0 Hz, 2 H, CH 2CH3), 6.51 (s, 1 H, NH), 7.41 (d, 3 J HH = 8.8 Hz, 2 H, 2 × CH of Ar), 7.46 (d, 3 J HH = 8.8 Hz, 2 H, 2 × CH of Ar), 8.84 (s, 1 H, OH). 13C NMR (100 MHz, CDCl3): δ = 14.2 (CH3), 39.7 (CH2NH), 43.1 (CH2N), 61.3 (OCH2), 104.2 (C6), 117.4 (C8), 120.1 (C8a), 126.8 (C ipso ), 129.0 (2 × CH of Ar), 130.5 (2 × CH of Ar), 133.9 (C ipso Cl), 146.7 (COH), 158.7 (CO2Et), 166.9 (NCO). MS: m/z = 336 [M+ + 2], 335 [M+ + 1], 334 [M+], 288, 259, 245, 232, 203, 189, 175, 162, 138, 123, 111, 95, 80, 67, 53. Anal. Calcd (%) for C16H15ClN2O4: C, 57.41; H, 4.52; N, 8.37. Found: C, 57.32; H, 4.47; N, 8.31.