Stereoselective Synthesis of New β-Lactams from 2-(1H-Pyrrol-1-yl)-1-propen-1-one as a Novel Ketene

Abstract New trans-β-lactams have been stereoselectively prepared by the reaction of N-pyrrolylpropanoic acid with 2-chloro-1-methylpyridinium iodide and aromatic imines in the presence of triethylamine as a base via in situ generation of methyl-2-(1H-pyrrol-1-yl)ketene as a novel heteroarylketene. The trans-β-lactam was formed either as a single isomer or as the major isomer.

Herein we describe the synthesis of new β-lactams by the reaction of imines with methyl N-pyrrolylketene 11, as a novel ketene, generated in situ from N-pyrrolylpropanoic acid (9).
The starting acid 9 was synthesized from alanine and dimethoxytetrahydrofuran following the reported procedure. 36a,b Treatment of imines 12 with methyl Npyrrolylketene 11 generated in situ from N-pyrrolylpropanoic acid (9) and Mukaiyama's reagent (10) in the presence of Et 3 N resulted in β-lactams 13 (Scheme 3). Ketene 11 reacted with several imines, forming the trans-lactams 13a-c as single isomers, whereas in other cases (13d-f) the trans-isomers were formed as major products ( Table  1). The structures of the products were fully characterized by IR, 1 H NMR, and 13 C NMR spectra (see Supporting In- Cr(CO) 3  ) along with elemental analysis data. 1 H NMR spectroscopy is generally used for distinguishing between cis-and trans β-lactam isomers using H-H coupling constants. The J value is smaller (2.0-2.5 Hz) in a trans β-lactam than in a cis-β-lactam (5.0-6.0 Hz). However, in the 1 H NMR spectrum of 13 the proton on the azetidinone ring appeared as a singlet. Therefore, we resorted to NOE experiments. Irradiation of the methyl signal at δ = 2.07 ppm in the 1 H NMR of cis-13f caused the intensity of the methyl signal at δ = 5.08 ppm to increase by 15%, whereas, when the methyl signal δ = 1.43 ppm in the 1 H NMR of trans-13f was saturated, no increase was observed.

Scheme 3
The 1 H NMR spectrum of 13a exhibited two singlets at δ = 1.44 and 5.17 ppm for methyl and methine, respectively, two triplets at δ = 6.31 and 6.99 ppm for the pyrrole ring along with a multiplet at δ = 7.12-7.45 ppm for two phenyl rings. The 1 H-decoupled 13 C NMR spectrum of 13a showed 14 distinct resonances in agreement with the proposed structure. Characteristic 13 C NMR signals were shown due to one carbonyl group at δ = 164.74 and signals at δ = 73.63, 68.85, and 29.76 ppm for methine, CH, and methyl groups, respectively. The 1 H and 13 C NMR of 13b-f are similar to those for 13a except for the aromatic moieties.
The mechanistic pathway that best explains the formation of these isomers is depicted in Scheme 4. It is generally accepted 37-39 that the stereochemistry in the ketene-imine cycloaddition involves initial attack of the imine to ketene with the formation of zwitterionic intermediates 14a which undergo competitive ring closure to cis-β-lactams 13 and isomerization to less crowded intermediates 14b and ring closure to trans-β-lactams 13.

Scheme 4
In conclusion, we synthesized new β-lactams from the reaction of N-pyrrolylpropanoic acid with imines and Mukaiyama's reagent in the presence of Et 3 N via in situ generation of methyl N-pyrrolylketene as a novel ketene. NOE experiments were used for assignment of the structure of the isomers. β-Lactams 13; Typical Procedure 2-(1H-Pyrrol-1-yl) propanoic acid (9, 0.139 g, 1.0 mmol) was mixed with 2-chloro-N-methylpyridinium iodide (10, 0.30 g, 1.2 mmol) and dry Et 3 N (0.50 mL, 3.6 mmol) in anhyd CH 2 Cl 2 (30 mL) under a nitrogen atmosphere at r.t. The suspension was stirred for 5 min and then a solution of N-benzylideneaniline (0.20 g, 1.1 mmol) in dry CH 2 C1 2 (5 mL) was added, and the reaction mixture was stirred overnight. The red solution was washed with 8% aq HCl and then with H 2 O. The organic layer was dried over CaSO 4 , filtered, and the solvent removed under reduced pressure. The product was purified by column chromatography using n-hexane-EtOAc (19:1 v/v) as eluent. trans-3-Methyl-1,4-diphenyl-3-(1H-pyrrol-1-yl)-2azetidinone (13a) was obtained as sole product.