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Synlett 2004(15): 2824-2826  
DOI: 10.1055/s-2004-835628
LETTER
© Georg Thieme Verlag Stuttgart · New York

2,2′-Dibenzothiazolyl Disulfide: A Versatile Reagent for the Synthesis of 2-Azetidinones

S. D. Sharma*, Seema Kanwar
Department of Chemistry and Centre of Advanced Studies in Chemistry, Panjab University, Chandigarh 160 014, India
Fax: +91(172)2545074; e-Mail: sdsharmapu@yahoo.com;
Further Information

Publication History

Received 7 July 2004
Publication Date:
08 November 2004 (online)

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Abstract

2,2′-Dibenzothiazolyl disulfide has been found to be a versatile reagent that provides a convenient and efficient route for the synthesis of β-lactams from Schiff’s bases and alkoxy/aryloxy acetic acids. The process involves the formation of thioester of the corresponding acid. Finally, condensation of titanium enolates, ­derived from these esters, with imines completes the synthesis of 2-azetidinones.

Key words

2,2′-dibenzothiazolyl disulfide - MBTS/TPP - thiol ­ester enolate-imine condensation - 2-azetidinones

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General Procedure for the Formation of Thioesters: To the solution of phenoxy acetic acid (0.1 mmol) and PPh3 (0.12 mmol) in CH2Cl2, MBTS (0.11 mmol) was added and the contents were stirred for 24 h at r.t. The reaction was quenched by the addition of H2O and the organic layer separated, washed with H2O and dried over anhyd Na2SO4. The excess solvent was removed under vacuum to get phenoxythioacetic acid S-benzothiazol-2-yl ester.

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General Procedure for the Formation of 2-Azetidinones: To the thioester solution (0.05 M) of phenoxyacetic acid (0.1 mmol) in dry CH2Cl2 cooled at -78 °C, under nitrogen atmosphere, was added dropwise a TiCl4 solution (0.1 mmol) in CH2Cl2. The solution was stirred for 30 min at this temperature. To this solution Et3N (0.11 mmol) was added dropwise at -78 °C and stirred for 15 min. Then, the solution of benzylidene(4-methoxy-phenyl)amine (0.05 mmol) in dry CH2Cl2 was added dropwise at -78 °C and the reaction mixture was stirred for 5 h, and finally at r.t. overnight (reaction monitored by TLC). The reaction was quenched by the addition of sat. NH4Cl solution and filtered through celite. The aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over anhyd Na2SO4 and concentrated under pressure. The unreacted thioester was removed by 1 N KOH hydrolysis in THF at r.t. for 2-12 h, and the remained mixture was flash chromatographed over silica gel using Et2O-hexane (40:60) as eluent to give the required β-lactam.

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4-Benzo[1,3]dioxol-5-yl-3,3-dimethyl-1-(4-methoxy-phenyl)-azetidin-2-one(c). 1H NMR (300 MHz, CDCl3): δ = 0.80 (s, 3 H, CH3), 1.50 (s, 3 H, CH3), 3.75 (s, 3 H, OCH3), 4.4 (s, 1 H, C4H), 6.70-7.50 (m, 9 H, ArH). IR (CHCl3): 1748.1 cm-1. Anal. Calcd for C18H19NO2: C, 76.86; H, 6.76; N, 4.98. Found: C, 76.66; H, 6.90; N, 5.05.

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4-Benzo[1,3]dioxol-5-yl-3-thiophenyl-1-(4-methoxy-phenyl)-azetidin-2-one (f).
1H NMR (300 MHz, CDCl3): δ = 3.81 (s, 3 H, OCH3), 4.05 (d, 1 H, C3H, J = 1.0 Hz), 4.25 (d, 1 H, C4H, J = 1.0 Hz), 5.99 (s, 2 H, OCH2O), 6.75-7.57 (m, 12 H, ArH). IR (CHCl3): 1751.7 cm-1. Anal. Calcd for C23H19NO4S: C, 68.15; H, 4.69; N, 3.46. Found: C, 68.00; H, 4.60; N, 3.44.

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2-[1-(4-Methoxy-phenyl)-2-oxo-4-phenyl-azetidin-3-yl]-isoindole-1,3-dione (g).
1H NMR (300 MHz, CDCl3): δ = 3.73 (s, 3 H, OCH3), 5.41 (d, 1 H, C3H, J = 3.0 Hz), 5.56 (d, 1 H, C4H, J = 3.0 Hz), 6.63-8.13 (m, 13 H, ArH). IR (CHCl3): 1770 cm-1. Anal. Calcd for C24H18N2O4: C, 72.36; H, 4.52; N, 3.52. Found: C, 72.00; H, 4.36; N, 4.69.