Tandem Aza-Michael and Intramolecular Amidic Ring-Opening Reactions of β-Lactams: A Facile Synthesis of 4-Oxo-4,5-dihydro-1H-pyrroles from β-Lactam Synthons

Abstract

Tandem aza-Michael addition of 3-amino-2-azetidinones with acetylenic esters and subsequent intramolecular amidic ring opening of the initially formed azetidin-3-ylaminoprop- or -but-2-enoic ester is described. The reaction provides a facile route for the formation of functionalized 4-oxo-4,5-dihydro-1H-pyrroles in good yields.

Key words

aza-Michael reaction - 3-amino-2-azetidinone - DMAD - 4-oxo-4,5-dihydro-1H-pyrrole - lactam synthon methodology

• References and Notes

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• 13 General Procedure for the Synthesis of 3 and 4 DMAD (2a; 1.4 mmol) was added to a well-stirred solution of 3-amino-2-azetidinone (1 mmol) in anhydrous solvent (10 mL) at the reaction temperature. The progress of the reaction was monitored by TLC taking the 3-amino-2-azetidinone as the limiting reactant. After completion of reaction, all solvent was removed under reduced pressure. The crude reaction mixture was purified by column chromatography using EtOAc–hexane (20:80) as eluent. The compounds were recrystallized using a mixture of CHCl₃ and hexane (20:80) to obtain 3a–i and 4a–i as pure compounds. For percentage yields and ratios of 3 and 4, see Tables 1 and 2.
• 14 2-(2-Oxo-1-p-chlorophenyl-4-styryl-azetidin-3-ylamino)-but-2-enedioic Acid Dimethyl Ester (3c) White solid; mp 170–172 °C. ¹H NMR (300 MHz, CDCl₃): δ = 3.64 (s, 3 H), 3.80 (s, 3 H), 4.94 (dd, J = 5.1, 7.5 Hz, 1 H), 5.431 (s, 1 H), 5.50 (dd, J = 5.1, 8.1 Hz, 1 H), 6.19 (dd, J = 8.1, 15.9 Hz, 1 H), 6.80 (d, J = 15.9 Hz, 1 H), 7.11 (t, J =7.5 Hz, 2 H), 7.25–7.39 (m, 5 H), 7.46 (dd, J = 12.0, 1.2 Hz, 2 H), 8.62 (d, J = 7.0 Hz, 1 H). ^I3C NMR (75 MHz, CDCl₃): δ = 51.1, 52.8, 61.1, 64.4, 92.3, 117.2, 122.1, 124.4, 126.8, 128.3, 128.6, 129.1, 135.80, 136.8, 137.5, 147.7, 163.5, 163.6, 169.8. LRMS: 441.1 [M + 1]. IR (KBr): ν_max = 1752.36 (carbonyl of esters), 1736.38 (keto group of lactam), 1515.2, 1390, 1257.13 cm^–1. HRMS: m/z calcd for C₂₃H₂₁ClN₂O₅ [M + H⁺]: 441.1217; found: 441.1219.
• 15 4-Oxo-5-(3-phenyl-1-p-tolylamino-allyl)-4,5-dihydro-1H-pyrrole-2,3-dicarboxylic Acid Dimethyl Ester (4b) Pale yellow solid; mp 154–155 °C. ¹H NMR (300 MHz, CDCl₃): δ = 2.31 (s, 3 H), 3.93 (s, 3 H), 3.97 (s, 3 H), 5.18 (dd, J = 5.4, 8.4 Hz, 1 H), 5.89 (dd, J = 8.4, 15.9 Hz, 1 H), 6.40 (d, J = 5.4 Hz, 1 H), 6.82 (d, J = 15.9 Hz, 1 H), 7.13–7.24 (m, 7 H), 7.41 (d, J = 11.4 Hz, 2 H). ^I3C NMR (75 MHz, CDCl₃): δ = 21.0, 52.8, 53.6, 60.3, 67.0, 117.3, 120.1, 126.8, 128.7, 128.9, 129.7, 130.0, 134.5, 134.8, 134.9, 138.8, 139.9, 157.1, 158.6, 160.0. LRMS 421.2 [M + 1]. IR (KBr): ν_max = 1747.24 (carbonyl of esters), 1681.99 (keto group of pyrrole), 1515.2, 1390, 12.57.13 cm^–1. HRMS: m/z calcd for C₂₄H₂₅N₂O₅ [M + H⁺]: 421.1763; found: 421.1762.