Synthesis of Functionalized 5-Oxo-2,5-dihydro-1H-pyrroles from Primary Alkylamines, Oxalyl Chloride, and Dimethyl Acetylenedicarboxylate

Abstract

An efficient synthesis of dimethyl 1-alkyl-2,4-dihydroxy-5-oxo-2,5-dihydro-1H-pyrrole-2,3-dicarboxylates is described via a three-component reaction between primary alkylamines, oxalyl chloride, and dimethyl acetylenedicarboxylate.

Key word

oxalyl chloride - 3-pyrroline-2-one - enaminone - acetylenic ester - multicomponent reaction - alkylamines

References and Notes

• 1 Ikeguky SM. Sawaki M. Yoshii H. Maeda K. Morishima Y. J. Pestic. Sci.  2000,  25:  107 
• 2 Broggini G. Zecchini G. Synthesis  1999,  905 
• 3 Beck B. Picard A. Herdtweck E. Dömling A. Org. Lett.  2004,  6:  39 
• 4 Nair V. Mathen JS. Viji S. Srinivas R. Nandakumar MV. Varma L. Tetrahedron  2002,  58:  8113 
• 5 Yavari I. Bayat M. Synth. Commun.  2002,  32:  2527 
• 6 Grison C. Genève S. Coutrot P. Tetrahedron Lett.  2001,  42:  3831 
• 7 Ghelfi F. Stevens CV. Laureyn I. Van Meenen E. Rogge TM. De Buyck L. Nikitin KV. Grandi R. Libertini E. Pagnoni UM. Schenetti L. Tetrahedron  2003,  59:  1147 
• 8 Kang SK. Kim KJ. Yu CM. Hwang JW. Do YK. Org. Lett.  2001,  3:  2851 
• 9 Naitoh R. Nakamura Y. Katano E. Nakamura Y. Okada E. Asaoka M. Heterocycles  2004,  63:  1009 
• 10 Bouillon JP. Tinant B. Nuzillard JM. Portella C. Synthesis  2004,  711 
• 11 Pal M. Swamy NK. Hameed PS. Padakanti S. Yeleswarapu KR. Tetrahedron  2004,  60:  3987 
• 12 Tsolomiti G. Tsolomitis A. Tetrahedron Lett.  2004,  45:  9353 
• 13 Snider BB. Neubert BJ. J. Org. Chem.  2004,  69:  8952 
• 14 Verniest G. Boterberg S. Bombeke F. Stevens CV. De Kimpe N. Synlett  2004,  1059 
• 15 Yavari I. Souri S. Synlett  2007,  19:  2969 

16

Dimethyl 1-Benzyl-2,4-dihydroxy-5-oxo-2,5-dihydro-1 H -pyrrole-2,3-dicarboxylate (4a)
To a stirred solution of DMAD (0.34 g, 2.4 mmol) and alkylamine (0.20 g, 2 mmol) in CH₂Cl₂ (10 mL) was added oxalyl chloride (0.17 mL, 2 mmol) at r.t. The reaction mixture was then stirred for 24 h. The solvent was removed under reduced pressure and the precipitate was purified by recrystallization from Et₂O to give 4a.
Compound 4a: white powder; 170-171 °C (decomp.); yield 0.57 g (90%). IR (KBr): ν_max = 3360, 3135, 1741, 1705, 1674, 1425, 1311 cm^-1. ¹H NMR (500.1 MHz, CDCl₃): δ = 3.19 (3 H, s, OMe), 3.73 (3 H, s, OMe), 4.28 (1 H, d, ³ J = 15.5 Hz, CH), 4.77 (1 H, br s, OH), 4.80 (1 H, d, ³ J = 15.5 Hz, CH), 7.24-7.30 (5 H, m, CH), 9.09 (1 H, br s, OH) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ = 42.7 (NCH₂), 51.8 (OMe), 53.2 (OMe), 85.7 (C-OH), 112.4 (C), 128.2 (CH), 129.0 (CH), 129.3 (CH), 137.4 (C), 156.4 (=COH), 163.3 (C=O), 164.6 (C=O), 169.7 (CON) ppm. MS: m/z (%) = 321 (8) [M⁺], 262 (70), 244 (100), 91 (50), 77 (64). Anal. Calcd (%) for C₁₅H₁₅NO₇ (321.28): C, 56.08; H, 4.71; N, 4.36. Found: C, 56.31; H, 4.82; N, 4.39.
Similarly, the following compounds were prepared. All compounds gave satisfactory analytical and spectroscopic data. Compound 4b: white powder; 150-152 °C (decomp.); yield 0.63 g (95%). IR (KBr): ν_max = 3380, 3140, 1744, 1699, 1671, 1429, 1388, 1234 cm^-1. ¹H NMR (500.1 MHz, CDCl₃): δ = 2.29 (3 H, s, Me), 3.17 (3 H, s, OMe), 3.80 (3 H, s, OMe), 4.13 (1 H, d, ³ J = 14.6 Hz, CH), 4.74 (1 H, br s, OH), 4.93 (1 H, d, ³ J = 14.6 Hz, CH), 7.06 (2 H, d, ³ J = 7.9 Hz, CH), 7.15 (1 H, d, ³ J = 7.9 Hz, CH), 9.07 (1 H, br s, OH) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ = 20.4 (Me), 41.5 (NCH₂), 51.6 (OMe), 53.0 (OMe), 83.5 (COH), 110.2 (C), 128.3 (CH), 128.4 (CH), 131.6 (C), 137.0 (C), 157.9 (=COH), 162.5 (C=O), 163.6 (C=O), 169.3 (CON) ppm. MS: m/z (%) = 335 (18) [M⁺], 276 (70), 244 (100), 91 (50), 77 (64). Anal. Calcd (%) for C₁₆H₁₇NO₇ (335.31): C, 57.31; H, 5.11; N, 4.18. Found: C, 57.46; H, 5.06; N, 4.23. Compound 4c: white powder; 157-158 °C (decomp.); yield: 0.63 g (90%). IR (KBr): ν_max = 3363, 3130, 1745, 1710, 1674, 1425, 1308, 1236 cm^-1. ¹H NMR (500.1 MHz, CDCl₃): δ = 3.23 (3 H, s, OMe), 3.74 (3 H, s, OMe), 3.76 (3 H, s, OMe), 4.21 (1 H, d, ³ J = 15.2 Hz, CH), 4.70 (1 H, br s, OH), 4.74 (1 H, d, ³ J = 15.2 Hz, CH), 6.85 (2 H, d, ³ J = 8.5 Hz, CH), 7.19 (1 H, d, ³ J = 8.5 Hz, CH), 9.09 (1 H, br s, OH) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ = 42.2 (NCH₂), 51.8 (OMe), 53.3 (OMe), 55.5 (OMe), 85.6 (COH), 112.3 (C), 114.4 (CH), 129.2 (C), 130.8 (CH), 156.3 (C), 160.1 (=COH), 163.4 (C=O), 164.4 (C=O), 169.8 (CON) ppm. MS: m/z (%) = 351 (18) [M⁺], 292 (70), 244 (100), 91 (50), 77 (64). Anal. Calcd (%) for C₁₆H₁₇NO₈ (351.31): C, 54.70; H, 4.88; N, 3.99. Found: C, 54.50; H, 4.96; N, 4.08. Compound 4d: white powder; 160-162 °C (decomp.); yield 0.64 g (90%). IR (KBr): ν_max = 3365, 3135, 1743, 1700, 1671, 1428, 1310, 1237 cm^-1. ¹H NMR (500.1 MHz, CDCl₃): δ = 3.27 (3 H, s, OMe), 3.81 (3 H, s, OMe), 4.17 (1 H, d, ³ J = 15.3 Hz, CH), 4.72 (1 H, br s, OH), 4.88 (1 H, d, ³ J = 15.3 Hz, CH), 7.22 (2 H, d, ³ J = 8.3 Hz, CH), 7.27 (2 H, d, ³ J = 8.3 Hz, CH), 9.10 (1 H, br s, OH) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ = 42.5 (NCH₂), 53.1 (OMe), 54.7 (OMe), 84.9 (COH), 111.8 (C), 129.4 (CH), 131.2 (CH), 134.7 (C), 156.4 (C), 159.6 (=COH), 163.8 (C=O), 165.1 (C=O), 170.8 (CON) ppm. MS: m/z (%) = 355 (18) [M⁺], 296 (100), 276 (70), 91 (50), 77 (64). Anal. Calcd (%) for C₁₅H₁₄ClNO₇ (355.72): C, 50.65; H, 3.97; N, 3.94. Found: C, 50.52; H, 4.03; N, 3.91. Compound 4e: white powder; 160-164 °C (decomp.); yield 0.64 g (90%). IR (KBr): ν_max = 3310, 3305, 1747, 1680, 1675, 1462, 1430, 1400 cm^-1. ¹H NMR (500.1 MHz, CDCl₃): δ = 3.39 (3 H, s, OMe), 3.75 (3 H, s, OMe), 4.64 (1 H, d, ³ J = 16.3 Hz, CH), 4.70 (1 H, d, ³ J = 16.3 Hz, CH), 4.75 (1 H, br s, OH), 7.26-7.29 (3 H, m, CH), 7.39 (1 H, m, CH), 9.12 (1 H, br s, OH) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ = 40.5 (NCH₂), 51.9 (OMe), 53.4 (OMe), 86.1 (COH), 112.8 (C), 127.8 (CH), 129.8 (CH), 130.1 (CH), 130.4 (CH), 133.6 (C), 134.4 (C), 156.1 (=COH), 163.4 (C=O), 164.7 (C=O), 169.5 (CON) ppm. MS: m/z (%) = 355 (18) [M⁺], 296 (100), 276 (70), 91 (50), 77 (64). Anal. Calcd (%) for C₁₅H₁₄ClNO₇ (355.72): C, 50.65; H, 3.97; N, 3.94. Found: C, 50.73; H, 4.02; N, 3.90. Compound 4f: white powder; 166-167.5 °C (decomp.); yield 0.72 g (98%). IR (KBr): ν_max = 3330, 3140, 1747, 1676, 1671, 1462, 1399, 1363 cm^-1. ¹H NMR (500.1 MHz, CDCl₃): δ = 2.54 (3 H, s, OMe), 3.77 (3 H, s, OMe), 4.59 (1 H, d, ³ J = 14.9 Hz, CH), 4.81 (1 H, br s, OH), 5.63 (1 H, d, ³ J = 14.9 Hz, CH), 7.39-7.57 (4 H, m, CH), 7.84 (2 H, m, CH), 8.15 (1 H, m, CH), 9.18 (1 H, br s, OH) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ = 41.2 (NCH₂), 52.1 (OMe), 52.8 (OMe), 84.5 (COH), 111.2 (C), 124.0 (CH), 125.0 (CH), 126.1 (CH), 126.8 (CH), 128.3 (CH), 129.3 (CH), 129.4 (CH), 129.9 (C), 131.6 (C), 133.6 (C), 158.8 (=COH), 162.7 (C=O), 164.3 (C=O), 169.4 (CON) ppm. MS: m/z (%) = 371 (18) [M⁺], 312 (100), 276 (70), 91 (50), 77 (64). Anal. Calcd (%) for C₁₉H₁₇NO₇ (371.34): C, 61.46; H, 4.61; N, 3.77. Found: C, 61.59; H, 4.65; N, 3.82. Compound 4g: white powder; 132-133 °C (decomp.); yield 0.51 g (90%). IR (KBr): ν_max = 3350, 3140, 1745, 1674, 1670, 1460, 1389, 1360 cm^-1. ¹H NMR (500.1 MHz, CDCl₃): δ = 0.85 (3 H, t, ³ J = 7.0 Hz, Me), 1.26 (2 H, q, ³ J = 7.3 Hz, CH₂), 1.42 (2 H, m, CH₂), 3.23 (2 H, m, CH₂), 3.78 (3 H, s, OMe), 3.79 (3 H, s, OMe), 4.77 (1 H, s, OH), 9.12 (1 H, br s, OH) ppm. ¹³C NMR (125.7 MHz, CDCl₃): δ = 13.5 (CH₃), 20.0 (CH₂), 30.1 (CH₂), 39.5 (NCH₂), 52.1 (OMe), 54.1 (OMe), 85.3 (COH), 110.5 (C), 157.4 (=COH), 163.7 (C=O), 163.8 (C=O), 170.4 (CON) ppm. MS: m/z (%) = 287 (18) [M⁺], 276 (70), 228 (100), 91 (50), 77 (64). Anal. Calcd (%) for C₁₂H₁₇NO₇ (287.26): C, 50.17; H, 5.96; N, 4.88. Found: C, 50.00; H, 5.91; N, 4.92.