Stereoselective Synthesis of 3-(5-Benzoyl-1-methyl-1H-pyrrol-2-yl)-2-azetidinone Derivatives via an in Situ Generated Ketene

Abstract

A short route toward β-lactams from tolmetin has been developed. In the key step, a ketene was generated on the C-2 of pyrrole ring and reacted with aromatic imines to form trans-β-lactams as the only observed products. The identification of the ketene was confirmed by reaction with the stable free radical TEMPO (TO·).

Key words

tolmetin - ketenes - electrocyclic reaction - azetidinones - imines

• References and Notes

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• 43 Reaction of Tolmetin Ketene with TEMPO: [1-Methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]acetic acid (2; 0.25 g, 1 mmol) and Mukaiyama’s reagent (3; 0.31 g, 1.2 mmol) were stirred in anhyd CH₂Cl₂ (15 mL) at r.t. under nitrogen for 5 min. Then Et₃N (0.50 mL, 3.6 mmol) was added. A solution of TEMPO (6; 0.47 g, 3.0 mmol) in CH₂Cl₂ (5 mL) was added and the suspension was stirred for 17 h. The solvent was evaporated and the excess of TEMPO removed by sublimation. Then the residue was washed with 5% aq HCl followed by H₂O. The organic layer was separated and dried over Na₂SO₄ and the solvent was filtered and removed under reduced pressure. The product was purified by column chromatography (silica gel, n-hexane–EtOAc, 10:2) to furnish 7 as a yellow oil; yield: 193 mg (35%). IR (νmax): 1766, 1657 (C=O) cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.71 (2 H, Ar), 7.25 (2 H, Ar), 6.69 (d, ³ J _H–H = 4.0 Hz, 1 H), 6.17 (d, ³ J _H–H = 4.0 Hz, 1 H), 4.42 (s, 3 H, Me), 3.77 (s, 1 H, CH), 4.02 (s, 3 H, Me), 1.21–1.72 (m, 12 H, 6 × CH₂), 1.27 (s, 6 H, 2 × Me), 1.09 (s, 9 H, 3 × Me), 1.02 (s, 9 H, 3 × Me). ¹³C NMR (100 MHz, CDCl₃): δ = 185.94, 168.81, 141.92, 137.33, 134.37, 131.30, 129.45, 128.88, 128.70, 128.11, 122.27, 109.58, 60.25, 39.01, 33.30, 31.82, 31.73, 29.71, 21.56, 20.48, 16.86. Anal. Calcd for C₃₃H₄₉N₃O₄ (551.76): C, 71.83; H, 8.95; N, 7.62. Found: C, 71.4; H, 8.6; N, 7.8.Typical Procedure for the Preparation of Compounds 5a–m: [1-Methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]acetic acid (2; 0.51 g, 2 mmol) was mixed with Mukaiyama’s reagent (3; 0.53 g, 2.1 mmol) and Et₃N (0.20 mL, 2 mmol) in anhyd CH₂Cl₂ (25 mL) under nitrogen and heated to reflux for 10 h. A solution of the N-benzylideneaniline (4; 0.37 g, 2 mmol) in anhyd CH₂Cl₂ (10 mL) and Et₃N (0.20 mL, 2.0 mmol) was then added and refluxing was continued for an additional 10 h. The solution was washed with H₂O, 5% HCl and again with H₂O. The organic layer was separated and dried over Na₂SO₄ and the solvent was filtered and removed under reduced pressure. The products were purified by column chromatography (silica gel, n-hexane–EtOAc, 10:2). Analytical data for trans-3-[1-methyl-5-(4-methylbenzoyl)-1H-pyrrol-2-yl]-1,4-diphenylazetidin-2-one (5a): white solid; yield: 253 mg (60%); mp 152–154 °C. IR (KBr): 1744, 1624 (C=O) cm^–1. ¹H NMR (400 MHz, CDCl3): δ = 7.00–7.65 (14 H, Ar), 6.64 (d, ³ J _H–H = 4.0 Hz, 1 H), 6.25 (d, ³ J _H–H = 4.0 Hz, 1 H), 4.34 (d, ³ J _H–H = 2.8 Hz, 1 H), 4.94 (d, ³ J _H–H = 2.8 Hz, 1 H) 3.77 (s, 3 H, Me), 2.35 (s, 3 H, Me). ¹³C NMR (100 MHz, CDCl₃): δ = 186.19, 163.32 (C=O), 142.21, 137.32, 137.04, 136.76, 135.17, 132.08, 129.54, 129.49, 129.19, 128.79, 126.04, 124.39, 122.29, 117.20, 107.62, 62.10, 57.84, 33.78, 21.58.