Research Journal of Chemical Sciences ______________________________________________ ISSN 2231-606X Vol. 3(7), 45-53, July (2013) Res. J. Chem. Sci. International Science Congress Association 45 Facile Synthesis of Novel C-3 Monosubstituted 3-phenylthio--lactamsBari S.S.*, Bhalla Aman, Venugopalan P. and Hundal Qudrat Department of Chemistry and Centre of Advanced Studies in Chemistry, Panjab University, Chandigarh-160014, INDIAAvailable online at: www.isca.in Received 6th June 2013, revised 26th June 2013, accepted 15th July 2013Abstract An efficient and operationally simple strategy for the synthesis of C-3 monosubstituted monocyclic -lactams is described. Treatment of ethyl 2-phenylthioethanoate (1) with SOCl in dry methylene chloride at 0C yields ethyl 2-chloro-2-phenylthioethanoate(2). Lewis acid (TiCl, SnCl and ZnCl) mediated functionalization of (2) using various aliphatic and aromatic compounds (nucleophiles) gives monosubstituted phenythioethanoates (3a-e). These esters on basic hydrolysis and subsequent acidification gave monosubstituted phenythioethanoic acids (4a-e). Reaction of these phenythioethanoic acids and appropriate imines in the Staudinger reaction using POCl as condensing agent led to the synthesis of novel C-3 monosubstituted 3-phenylthio--lactams. Keywords: 3-phenylthio- -Lactam, Lewis acid, nucleophiles, cis- and trans-3-monosubstituted-3-phenylthio--lactams. Introduction The -lactam heterocycle is the key structural unit of the most widely used -lactam antibiotics1-3The discovery of new biologically active -lactams such as I as cholesterol acyl transferase inhibitors, II as thrombin inhibitors, antitumor active -lactams have motivated growing interest in the synthesis of new -lactam systems. -Lactams containing Pyrazoline ring have also been reported to have antimicrobial properties. Biologically active derivatives of 1,3-diketones have been recently synthesized using aromatic amines/diazonium salts and N-benzy-N-phenylhydrazine and with aromatic aldehydes and N-benzyl-N-phenyl hydrazine. They show biological activity against gram-positive Cocci and Bacilli, and gram-negative Bacilli. Abdoulaye et al10 have synthesized 4-Acyl isochroman-1,3-Diones and demonstrated their anti-oxidant properties. The biological activity of the azetidin-2-one ring is greatly influenced by the type of substitution attached to the ring. Therefore, functionalization of the azetidin-2-one framework, bearing a varied array of appendages at C-3 and C-4, is pivotal for the development of new -lactam antibiotics. In our earlier studies towards C-3 functionalization of azetidin-2-ones11-18, the synthetic potential of cationic -lactam equivalent of type IIIhas been explored for the synthesis of C-3 substituted azetidin-2-ones. N OCH OCH H O H I H2N N NH N S O O O H COOCH H IIFigure-1 Biologically active monocyclic -lactams O R2 R1 R H III Figure-2 Cationic -lactam equivalent These studies revealed that cis-3-chloro-3-phenyl/benzyl/methylthio--lactams are capable of functioning as -lactam carbocation equivalents in the presence of a Lewis acid (TiCl or SnCl) and react with a number of active aromatic, heterocyclic and aliphatic compounds (nucleophiles) to afford substitution at C-3 of -lactam ring. 3-Benzylthio and 3-methylthio--lactams favoured monosubstitution at C-3 of lactams whereas cis-3-chlorophenylthio--lactams preferentially undergo C-3 disubstitution and produced mainly cis-3-disubstituted -lactams (scheme-1). Research Journal of Chemical Sciences ___________________________________________________________ ISSN 2231-606XVol. 3(7), 45-53, July (2013) Res. J. Chem. Sci. International Science Congress Association 46 N O R 2 H R1 Cl R N O R2 H R Nu R1 R = PhSNu O R 2 H R1 Nu Nu R = MeS, PhCHNuScheme-1 Lewis acid mediated functionalization of cis-3-chloro-3-phenyl/benzyl/methylthio--lactams Thus, in order to prepare C-3 monosubstituted phenylthio-lactams it was envisaged to synthesize various -substituted 2-phenylthioethanoates and corresponding 2-phenylthioethanoic acids by using an efficient and operationally simple strategy. These -substituted 2-phenylthioethanoic acids may serve as suitable synthons for synthesis of desired C-3 monosubstituted phenylthio--lactams via the Staudinger Reaction.In this regards, we present here the synthesis and characterization of variety of structurally diverse substituted phenylthioethanoates and phenylthioethanoic acids and C-3 monosubstituted phenylthio--lactams. Material and Methods H and 13C NMR spectra were recorded at 300/400 and 75/100 MHz, respectively, in CDCl solution using JEOL 300 and BRUCKER AVANCE II 400 MHz NMR spectrometers. Chemical shifts are given in parts per million relative to tetramethylsilane as an internal standard (=0 ppm) for H NMR and CDCl (=77.0 ppm) for 13C NMR. IR spectra were taken on an FTIR spectrophotometer and are reported in cm-1. The elemental analysis (C, H, N) was carried out in microanalytical section of Sophisticated Analytical Instrumentation Facility (SAIF), Panjab University, Chandigarh using a PERKIN-ELMER 2400 elemental analyzer. Column chromatography was performed using Merck Silica Gel (60-120 mesh) using ethyl acetate/hexanes (8:92) as an eluent system. Thin-layer chromatography (TLC) was performed using Merck Silica Gel G using ethyl acetate/hexanes (10:90) as an eluent system. For visualization, TLC plates were stained with iodine vapours. Melting points are uncorrected. All commercially available compounds/reagents were used without further purification. Dichloromethane and Chloroform distilled over P was redistilled over CaH before use. Toluene was distilled over sodium-benzophenone immediately before use. Crystallographic data (excluding structure factors) of compound 6h19 in CIF format have been deposited with the Cambridge Crystallographic Data Centre . Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road, Cambridge CB21 EZ, UK [Fax: (internet) +44 1223/336033; e-mail: deposit@ccdc.cam.ac.uk ]. All other relevant information regarding the data and supplementary publication CCDC number is presented in respective reference. Compounds ethyl 2-phenylthioethanoate and ethyl 2-chloro-2-phenylthioethanoate 2 were prepared by the procedures11 and characterized as described in the cited reference (scheme 2). Synthesis of ethyl -substituted-2-phenylthioethanoate 3(a-e): Compounds 3(a-e) were prepared by using the same method as reported for C-3 substituted -lactams12 in the cited reference, starting from chloro--lactams. Ethyl 2-(2',5'-dimethoxyphenyl)-2-phenylthioethanoate (3a): To a well stirred solution of (1 mmol) in 10 mL dry methylene chloride was added 1,4-dimethoxybenzene (1.1 mmol) followed by stannic chloride (1.2 mmol) via a syringe, under inert atmosphere, at 0 °C. The reaction mixture was stirred for 1h at the same temperature. The progress of the reaction was checked by TLC. The work-up was done as usual to give the product as a colourless oil. Yield: 65%. I.R. (cm-1, CHCl): 1737 (C=O). H NMR ( ppm): 7.29-6.61 (8H, m, Ar-), 5.24 (1H, s, C), 4.00 (2H, q, J = 7.2 Hz, OC), 3.62 (3H, s, OC), 3.60 (3H, S, OC), 1.07 (3H, t, J = 7.2 Hz, C). 13C NMR ( ppm): 170.3, 153.6, 150.7, 134.3, 132.6, 128.7, 127.6, 125.2, 114.7, 114.6, 111.9, 61.3, 56.2, 55.5, 48.6, 14.1. Analysis calculated for C1820SO: C, 65.04; H, 6.06; S, 9.65. Found: C, 64.42; H, 6.04; S, 9.60%. Ethyl 2-(2'-methoxynaphthyl)-2-phenylthioethanoate (3b): colourless oil. Yield: 55%. I.R. (cm-1, CHCl): 1735 (C=O). H NMR ( ppm): 7.98-6.98 (11H, m, Ar-), 5.46 (1H, s, C), 4.04 (2H, q, J = 7.2 Hz, OC), 3.89 (3H, s, OC), 1.04 (3H, t, J = 7.2 Hz, C). 13C NMR ( ppm): 170.3, 158.2, 134.6, 132.9, 132.7, 130.4, 130.0, 129.5, 128.9, 128.0, 127.8, 127.5, 123.0, 118.6, 61.6, 54.3, 29.8, 14.2. Analysis calculated for 2120SO: C, 71.56; H, 5.72; S, 9.10. Found: C, 70.76; H, 5.68; S, 9.06%. Ethyl 2-(allyl)-2-phenylthioethanoate (3c): yellow oil. Yield: 75%. I.R. (cm-1, CHCl): 1732 (C=O), 1641 (C=C). H NMR (ppm): 7.39-7.18 (5H, m, Ar-), 5.79-5.66 (1H, m, CH=CH), 5.08-5.00 (2H, m, CHCH=C), 4.01 (2H, q, J = 7.2 Hz, OC), 3.62-3.57 (1H, m, C), 2.60-2.38 (2H, m, CH=CH), 1.10 (3H, t, J = 7.2 Hz, C). 13C NMR ( ppm): 171.4, 133.8, 133.2, 133.1, 128.8, 127.9, 117.9, 60.9, 50.2, 35.8, 14.0. Analysis calculated for C1316SO: C, 66.07; H, 6.82; S, 13.57. Found: C, 66.02; H, 6.43; S, 13.76%. Ethyl 2-(prop-2-enyloxy)-2-phenylthioethanoate (3d): colourless oil. Yield: 60%. I.R. (cm-1, CHCl): 1737 (C=O), 1562 (C=C). H NMR ( ppm): 7.41-7.19 (5H, m, Ar-), 5.88-5.75 (1H, m, OCH=CH), 5.24-5.10 (3H, m, OCHCH=Cand C), 4.35-4.09 (2H, m, OCCH=CH), 4.01 (2H, q, J = 7.2 Hz, OC), 1.13 (3H, t, J = 7.2 Hz, C). 13C NMR ( Research Journal of Chemical Sciences ___________________________________________________________ ISSN 2231-606XVol. 3(7), 45-53, July (2013) Res. J. Chem. Sci. International Science Congress Association 47 ppm): 166.4, 133.1, 131.8, 130.2, 127.8, 127.6, 118.2, 82.7, 67.9, 60.6, 13.1. Analysis calculated for C1316SO: C, 61.88; H, 6.39; S, 12.71. Found: C, 6O.58; H, 6.31; S, 12.62%. Ethyl 2-(prop-2-ynyloxy)-2-phenylthioethanoate (3e): colourless oil. Yield: 58%. I.R. (cm-1, CHCl): 2361 (CC), 1751 (C=O). H NMR ( ppm): 7.51-7.27 (5H, m, Ar-), 5.49 (IH, s, C), 4.66 (1H, dd, J = 2.4 Hz, J = 15.9 Hz, OC), 4.48 (1H, dd, J = 2.4 Hz, J = 15.9 Hz, OCH), 4.11 (2H, q, J = 7.2 Hz, OC), 2.48 (1H, t, J = 2.4 Hz, CCH), 1.10 (3H, t, J = 7.2 Hz, C). 13C NMR ( ppm): 167.0, 134.3, 130.5, 128.9, 128.8, 82.6, 78.1, 76.2, 61.7, 54.9, 13.9. Analysis calculated for 1314SO: C, 62.38; H, 5.64; S, 12.81. Found: C, 61.78; H, 5.58; S, 12.73%. Synthesis of -substituted-2-phenylthioethanoic acid 4(a-e):Compounds 4(a-e) were prepared by using the same method as reported for phenylselenoalkanoic acids in the cited reference142-(2',5'-Dimethoxyphenyl)-2-phenylthioethanoic acid (4a): To a solution of potassium hydroxide (1.4 mmol) in methanol/water (3/1; 4 mL) at 0°C, ethyl 2-(2',5'-dimethoxyphenyl)-2-phenylthioethanoate 3a (1 mmol) in methanol (60 mL) was added dropwise. The resultant mixture was stirred for 1h. Progress of the reaction was monitored by TLC. The precipitates obtained were further dissolved in a minimum amount of water and acidified with conc. hydrochloric acid. The completion of the reaction was monitored by change of pH, which was checked at regular intervals. The work-up was done as usual to give the product 4a. Yield: 83%. I.R. (cm-1, CHCl): 3380 (O-H), 1708 (C=O). H NMR ( ppm): 10.33 (1H, bs, O-), 7.28-6.60 (8H, m, Ar-), 5.21 (1H, s, C), 3.58 (3H, s, OC), 3.56 (3H, S, OC). 13C NMR ( ppm): 170.3, 153.6, 150.7, 134.3, 132.6, 128.7, 127.6, 125.2, 114.7, 114.6, 111.9, 56.2, 55.5, 48.6. Analysis calculated for C1616SO: C, 63.14; H, 5.30; S, 10.54. Found: C, 63.10; H, 5.12; S, 10.42%. 2-(2'-Methoxynaphthyl)-2-phenylthioethanoic acid (4b): Yield: 80%. I.R. (cm-1, CHCl): 3360 (O-H), 1710 (C=O). H NMR ( ppm): 10.25 (1H, bs, O-), 7.98-6.98 (11H, m, Ar-), 5.46 (1H, s, C), 3.89 (3H, s, OC). 13C NMR ( ppm): 170.3, 158.2, 134.6, 132.9, 132.7, 130.4, 130.0, 129.5, 128.9, 128.0, 127.8, 127.5, 123.0, 118.6, 61.6, 54.3, 29.8, 14.2. Analysis calculated for C1916SO: C, 71.56; H, 5.72; S, 9.10. Found: C, 70.76; H, 5.68; S, 9.06%. 2-(Allyl)-2-phenylthioethanoic acid (4c): Yield: 85%. I.R. (cm-1, CHCl): 3380 (O-H), 1708 (C=O), 1583 (C=C). H NMR ppm): 10.54(1H, bs, O-), 7.40-7.06 (5H, m, Ar-), 5.79-5.68 (1H, m, CH=CH), 5.10-5.02 (2H, m, CHCH=C), 3.58-3.53 (1H, m, C), 2.59-2.40 (2H, m, CCH=CH). 13C NMR ( ppm): 171.4, 133.8, 133.2, 133.1, 128.8, 127.9, 117.9, 50.2, 35.8. Analysis calculated for C1112SO: C, 63.43; H, 5.81; S, 15.40. Found: C, 63.32; H, 5.68; S, 14.56%. 2-(Prop-2-enyloxy)-2-phenylthioethanoic acid (4d): Yield: 82%. I.R. (cm-1, CHCl): 3358 (O-H), 1710 (C=O), 1556 (C=C). H NMR ( ppm): 8.96 (1H, bs, O-), 7.41-7.22 (5H, m, Ar-), 5.81-5.79 (1H, m, OCH=CH), 5.24-5.10 (3H, m, OCHCH=C and C), 4.35-4.14 (2H, m, OCCH=CH). 13C NMR ( ppm): 166.4, 133.1, 131.8, 130.2, 127.8, 127.6, 118.2, 82.7, 67.9. Analysis calculated for C1112SO: C, 58.90; H, 5.39; S, 14.30. Found: C, 58.86; H, 5.31; S, 13.69%. 2-(Prop-2-ynyloxy)-2-phenylthioethanoic acid (4e): Yield: 85%. I.R. (cm-1, CHCl): 3360 (O-H), 2361 (CC), 1708 (C=O). H NMR ( ppm): 8.94 (1H, bs, O-H), 7.51-7.27 (5H, m, Ar-), 5.49 (IH, s, C), 4.66 (1H, dd, J = 2.4 Hz, J = 15.9 Hz, OC), 4.48 (1H, dd, J = 2.4 Hz, J = 15.9 Hz, OCH), 2.48 (1H, t, J = 2.4 Hz, CCH). 13C NMR ( ppm): 167.0, 134.3, 130.5, 128.9, 128.8, 82.6, 78.1, 76.2, 54.9. Analysis calculated for C1110SO: C, 59.44; H, 4.54; S, 14.43. Found: C, 59.38; H, 4.52; S, 13.88%. Synthesis of cis-and trans-C-3 monosubstituted phenylthio--lactams 6(a-j) and 7(a-j): Compounds 6(a-j) and 7(a-j) were prepared by using the same method as for C-3 substituted phenylthio--lactams11,12 in the cited reference, starting from the appropriate Schiff’s base and -substituted phenylthioethanoic acids 4(a-e). The spectroscopic data of compounds 6c12, 7e18have been reported in the cited reference. cis-1-(4'-Methoxyphenyl)-3-(2',5'-dimethoxyphenyl)-3-phenythio-4-phenylazetidin-2-one (6a): Toa solution of 2-(2',5'-Dimethoxyphenyl)-2-phenylthioethanoic acid 4a (1.5 mmol), N-(4’-methoxyphenyl)benzylidine 5a (1 mmol) and triethylamine (3 mmol) in 25 mL dry methylene chloride was added dropwise, under nitrogen atmosphere at 0 °C, a solution of phosphorus oxychloride (POCl) (1.5 mmol) in 10 mL dry methylene chloride with constant stirring. The reactants were stirred at room temperature and the progress of the reaction was followed by TLC. The work-up was done as usual to give the compound 6a as a white solid. Yield: 45%. mp 122-125 C. I.R. (cm-1, CHCl): 1740 (C=O). H NMR ( ppm): 7.23-6.23 (17H, m, Ar-), 5.02 (1H, s, C4-), 3.62 (3H, s, OC), 3.59 (3H, s, OC), 3.20 (3H, s, OC). 13C NMR ( ppm): 164.2, 156.1, 152.8, 135.9, 134.2, 129.2, 128.3, 128.1, 127.4, 118.8, 115.2, 114.7, 114.1, 68.1, 67.6, 55.7, 55.2, 54.5. Analysis calculated for C3027NOS: C, 72.41; H, 5.47; N, 2.81; S, 6.44. Found: C, 71.29; H, 5.30; N, 2.78; S, 6.22%. trans-1-(4'-Methoxyphenyl)-3-(2',5'-dimethoxyphenyl)-3-phenythio-4-phenylazetidin-2-one (7a): White semisolid. Yield: 20%. I.R. (cm-1, CHCl): 1749 (C=O). H NMR ( ppm): 7.32-6.48 (17H, m, Ar-), 5.41 (1H, s, C4-), 3.71 (3H, s, OC), 3.64 (3H, s, OC), 3.41 (3H, s, OC). cis-1-(4'-Methoxyphenyl)-3-(2',5'-dimethoxyphenyl)-3-phenythio-4-(4'-methoxyphenyl)-azetidin-2-one (6b): white solid. mp 130-135 C. Yield: 30 %. I.R. (cm-1, CHCl): 1741 (C=O). H NMR ( ppm): 7.44-6.27 (16H, m, Ar-), 4.98 (1H, Research Journal of Chemical Sciences ___________________________________________________________ ISSN 2231-606XVol. 3(7), 45-53, July (2013) Res. J. Chem. Sci. International Science Congress Association 48 s, C4-), 3.60 (3H, s, OC), 3.58 (3H, s, OC), 3.57 (3H, s, OC), 3.24 (3H, s, OC). 13C NMR ( ppm): 164.0, 156.0, 153.5, 151.2, 150.1, 137.2, 133.8, 131.2, 129.2, 128.6, 128.1, 127.8, 127.6, 126.7, 118.7, 114.7, 114.4, 114.2, 113.2, 66.9, 65.2, 56.0, 55.8, 55.5, 55.0. Analysis calculated for 3129NOS: C, 70.57; H, 5.54; N, 2.65; S, 6.08. Found: C, 70.42; H, 5.45; N, 2.55; S, 6.00%. trans-1-(4'-Methoxyphenyl)-3-(2',5'-dimethoxyphenyl)-3-phenythio-4-(4'-methoxyphenyl)-azetidin-2-one (7b): yellow oil. Yield: 30 %. I.R. (cm-1, CHCl): 1741 (C=O). H NMR (ppm): 7.53-6.60 (16H, m, Ar-), 5.39 (1H, s, C4-), 3.78 (3H, s, OC), 3.76 (3H, s, OC), 3.66 (3H, s, OC), 3.42 (3H, s, OC). cis-1-(4'-Methoxyphenyl)-3-(2'-methxynaphthyl)-3-phenythio-4-(4'-methoxyphenyl)-azetidin-2-one (6d): yellow oil. Yield: 35 %. I.R. (cm-1, CHCl): 1730 (C=O). H NMR (ppm): 8.40-6.20 (19H, m, Ar-), 5.20 (1H, s, C4-), 3.70 (3H, s, OC), 3.66 (3H, s, OC), 3.60 (3H, s, OC) (for one isomer) and 8.50-6.60 (19H, m, Ar-), 5.30 (1H, s, C4-), 3.75 (3H, s, OC), 3.68 (3H, s, OC), 3.64 (3H, s, OC) (for other isomer).The H NMR spectrum showed it to be a mixture of two rotamers as evident from the appearance of two signals for C4-H and a downfield appearance of an aromatic proton. Analysis calculated for C3429NOS: C, 74.56; H, 5.34; N, 2.56; S, 5.85. Found: C, 74.43; H, 5.28; N, 2.38; S, 5.67%. cis-1-(4'-Methoxyphenyl)-3-allyl-3-phenythio-4-phenyl-azetidin-2-one (6e): yellow oil. Yield: 19 %. I.R. (cm-1, CHCl): 1741 (C=O). H NMR ( ppm): 7.51-6.60 (14H, m, Ar-), 5.98-5.76 (1H, m, CH=CH), 5.00-4.65 (3H, m, CHCH=C, CHCH=CH and C4-H), 3.70 (3H, s, OC), 2.60 (2H, m, CCH=CH). 13C NMR ( ppm): 164.1, 155.6, 135.2, 133.7, 132.8, 131.0, 130.7, 129.3, 128.2, 128.1, 126.3, 119.4, 118.5, 114.4, 65.9, 63.6, 55.1, 38.0. Analysis calculated for C2523NOS: C, 74.78; H, 5.77; N, 3.49; S, 7.99. Found: C, 74.40; H, 5.48; N, 3.23; S, 7.77%. cis-1-(4'-Methoxyphenyl)-3-allyl-3-phenythio-4-(4'-methoxyphenyl)-azetidin-2-one (6f): colourless oil. Yield: 20 %. I.R. (cm-1, CHCl): 1740 (C=O). H NMR ( ppm): 7.41-6.20 (13H, m, Ar-), 5.80-5.72 (1H, m, CH=CH), 5.10-4.78 (3H, m, CHCH=C, CHCH=CH and C4-), 3.70 (3H, s, OC), 3.61 (3H, s, OC), 2.48 (2H, m, CCH=CH). 13C NMR ( ppm): 162.1, 157.4, 156.3, 136.4, 135.1, 134.2, 132.1, 129.1, 129.3, 128.8, 127.8, 126.4, 119.4, 117.8, 113.7, 68.9, 62.5, 55.5, 55.3, 38.0. trans-1-(4'-Methoxyphenyl)-3-allyl-3-phenythio-4-(4'-methoxyphenyl)-azetidin-2-one (7f): semisolid. Yield: 45 %. I.R. (cm-1, CHCl): 1741 (C=O). H NMR ( ppm): 7.51-6.40 (13H, m, Ar-), 5.88-5.64 (1H, m, CH=CH), 5.17 (1H, bs, CHCH=C), 5.12 (1H, m, CHCH=CH), 4.95 (1H, s , C4-), 3.76 (3H, s, OC), 3.63 (3H, s, OC), 2.56 (2H, d, J = 7.2 Hz, CCH=CH). 13C NMR ( ppm): 163.1, 158.1, 156.4, 135.2, 132.7, 131.8, 130.0, 129.7, 129.3, 128.2, 128.0, 126.6, 119.4, 118.8, 114.4, 65.9, 63.6, 55.9, 55.1, 43.0. Analysis calculated for C2625NOS: C, 72.36; H, 5.84; N, 3.25; S, 7.43. Found: C, 72.18; H, 5.32; N, 3.17; S, 7.37%. cis-1-(4'-Methoxyphenyl)-3-(prop-2-enyloxy)-3-phenythio-4-phenyl-azetidin-2-one (6g): yellow oil. Yield: 35 %. I.R. (cm-1, CHCl): 1740 (C=O). H NMR ( ppm): 7.48-6.65 (14H, m, Ar-), 5.58-5.47 (1H, m, OCH=CH), 4.99-4.78 (3H, m, CHCH=C, CHCH=CH and C4-), 4.36-4.30 (1H, m, OCaHCH=CH), 4.15-4.09 (1H, m, OCHaCH=CH), 3.60 (3H, s, OC). 13C NMR ( ppm): 162.0, 155.6, 136.3, 133.2, 131.8, 130.6, 130.2, 129.8, 129.1, 128.6, 128.2, 126.4, 124.9, 118.6, 116.7, 114.2, 113.8, 102.1, 68.9, 68.0, 55.9. Analysis calculated for C2523NOS: C, 71.92; H, 5.55; N, 3.35; S, 7.68. Found: C, 71.56; H, 5.42; N, 3.27; S, 7.65%. trans-1-(4'-Methoxyphenyl)-3-(prop-2-enyloxy)-3-phenythio-4-phenyl-azetidin-2-one (7g): colourless oil. Yield: 33 %. I.R. (cm-1, CHCl): 1750 (C=O). H NMR ( ppm): 7.50-6.68 (14H, m, Ar-), 5.99-5.90 (1H, m, OCH=CH), 5.24-5.14 (1H, m, CHCH=C), 5.12-5.07 (1H, m, CHCH=CH), 5.07 (1H, s, C4-H), 4.49-4.43 (1H, m, OCaHCH=CH), 4.24-4.18 (1H, m, OCHaCH=CH), 3.87 (3H, s, OCH), 3.73 (3H, s, OCH). 13C NMR ( ppm): 162.4, 156.4, 154.4, 135.3, 133.3, 133.0, 130.3, 128.9, 128.6, 128.3, 127.8, 126.3, 119.0, 117.8, 114.4, 97.3, 68.2, 68.1, 55.6, 55.3. cis-1-(4'-Methoxyphenyl)-3-(prop-2-enyloxy)-3-phenythio-4-(4'-methoxyphenyl)-azetidin-2-one (6h): white crystalline solid. mp: 128-132 C. Yield: 42 %. I.R. (cm-1, CHCl): 1750 (C=O). H NMR ( ppm): 7.41-6.63 (13H, m, Ar-), 5.63-5.51 (1H, m, OCH=CH), 4.94-4.85 (3H, m, OCHCH=C, OCHCH=CH and C4-), 4.37-4.31 (1H, m, OCaHCH=CH), 4.14-4.08 (1H, m, OCHaCH=CH), 3.68 (3H, s, OC), 3.63 (3H, s, OC). 13C NMR ( ppm): 161.2, 159.9, 154.4, 133.3, 133.1, 132.8, 131.4, 130.5, 129.4, 128.9, 128.3, 128.1, 124.9, 118.9, 116.7, 114.3, 113.8, 96.2, 68.8, 66.9, 55.2, 55.0. Analysis calculated for C2625NOS: C, 69.78; H, 5.63; N, 3.13; S, 7.16. Found: C, 69.66; H, 5.52; N, 3.10; S, 7.02%. trans-1-(4'-Methoxyphenyl)-3-(prop-2-enyloxy)-3-phenythio-4-(4'-methoxyphenyl)-azetidin-2-one (7h): colourless oil. Yield: 20 %. I.R. (cm-1, CHCl): 1750 (C=O). H NMR ( ppm): 7.52-6.68 (13H, m, Ar-), 5.85-5.72 (1H, m, OCH=CH), 5.24-5.18 (1H, m, CHCH=C), 5.12-5.08 (1H, m, CHCH=CH), 5.07 (1H, s, C4-), 4.49-4.43 (1H, m, OCaHCH=CH), 4.24-4.18 (1H, m, OCHaCH=CH), 3.87 (3H, s, OC), 3.73 (3H, s, OC). 13C NMR ( ppm): 162.4, 156.4, 154.4, 135.3, 133.3, 133.0, 130.3, 128.9, 128.6, 128.3, 127.8, 126.3, 119.0, 117.8, 114.4, 97.3, 68.2, 68.1, 55.6, 55.3. cis-1-(4'-Methoxyphenyl)-3-(prop-2-ynyloxy)-3-phenythio-4-phenyl-azetidin-2-one (6i): semi-solid. Yield: 35%. I.R. (cm-1, CHCl): 1755 (C=O). H NMR ( ppm): 7.53-7.20 (14H, m, Ar- Research Journal of Chemical Sciences ___________________________________________________________ ISSN 2231-606XVol. 3(7), 45-53, July (2013) Res. J. Chem. Sci. International Science Congress Association 49 ), 5.04 (IH, s, C4-), 4.58 (1H, dd, J = 2.4 Hz, J = 15.9 Hz, OC), 4.40 (1H, dd, J = 2.4 Hz, J = 15.9 Hz, OCH), 3.67 (3H, s, OC), 2.27 (1H, t, J = 2.4 Hz, CCH). 13C NMR (ppm): 161.1, 158.9, 133.3, 133.0, 132.8, 131.4, 130.9, 129.0, 128.9, 128.3, 128.1, 125.9, 118.0, 115.7, 114.3, 112.8, 98.2, 78.7, 76.8, 68.7, 55.9, 55.0. Analysis calculated for 2521NOS: C, 72.27; H, 5.09; N, 3.37; S, 7.72. Found: C, 71.10; H, 5.00; N, 3.28; S, 7.67%. trans-1-(4'-Methoxyphenyl)-3-(prop-2-ynyloxy)-3-phenythio-4-phenyl-azetidin-2-one (7i): oil. Yield: 20%. I.R. (cm-1, CHCl): 1755 (C=O). H NMR ( ppm): 7.53-7.30 (14H, m, Ar-), 5.24 (IH, s, C4-), 4. 88 (1H, dd, J = 2.4 Hz, J = 15.9 Hz, OC), 4.67 (1H, dd, J = 2.4 Hz, J = 15.9 Hz, OCH), 3.76 (3H, s, OC), 2.54 (1H, t, J = 2.4 Hz, CCH). cis-1-(4'-Methoxyphenyl)-3-(prop-2-ynyloxy)-3-phenythio-4-(4'-methoxyphenyl)-azetidin-2-one (6j): semi-solid. Yield: 27 %. I.R. (cm-1, CHCl): 1755 (C=O). H NMR ( ppm): 7.41-7.20 (13H, m, Ar-), 4.93 (IH, s, C4-), 4.46 (1H, dd, J = 2.4 Hz, J = 15.9 Hz, OC), 4.34 (1H, dd, J = 2.4 Hz, J = 15.9 Hz, OCH), 3.59 (3H, s, OC), 3.48 (3H, s, OC), 2.21 (1H, t, J = 2.4 Hz, CCH). 13C NMR ( ppm): 160.1, 158.9, 154.7, 133.3, 133.0, 132.8, 131.4, 130.9, 129.0, 128.9, 128.3, 128.1, 125.9, 118.0, 115.7, 114.3, 112.8, 96.2, 78.7, 76.0, 68.7, 55.9, 55.2, 55.0. Analysis calculated for C2623NOS: C, 70.09; H, 5.20; N, 3.14; S, 7.20. Found: C, 70.00; H, 5.10; N, 3.08; S, 7.17%. trans-1-(4'-Methoxyphenyl)-3-(prop-2-ynyloxy)-3-phenythio-4-(4'-methoxyphenyl)-azetidin-2-one (7j): semi-solid. Yield: 25 %. I.R. (cm-1, CHCl): 1755 (C=O). H NMR ( ppm): 7.51-7.27 (13H, m, Ar-), 5.17 (IH, s, C4-), 4. 72 (1H, dd, J = 2.4 Hz, J = 15.9 Hz, OC), 4.51 (1H, dd, J = 2.4 Hz, J = 15.9 Hz, OCH), 3.73 (3H, s, OC), 3.60 (3H, s, OC), 2.44 (1H, t, J = 2.4 Hz, CCH). 13C NMR ( ppm): 161.9, 156.3, 155.4, 135.2, 133.2, 130.2, 129.6, 129.0, 128.8, 128.3, 128.1, 127.9, 125.7, 119.0, 114.4, 97.6, 79.2, 75.7, 67.7, 55.9, 55.3, 53.1. Results and Discussion Preparation of -organylsulfanyl carbocations requires the use of sulfoxides(Pummerer Reaction),20 -chloro-organylsulfanylalkanes21 and bis (organylsufanyl)alkanes (S,S-acetals)22,23 as precursors. Yoshimatsu et. al24 have used fluoro--organylsulfanylalkanes as precursors for the carbocations and have used Sc(OTf) as the Lewis acid because -chloro--organylsulfanylalkanes are difficult to prepare. Nchlorosuccinimide is the most popular reagent for the chlorination of the organylsulfanylalkanes. Marzorati et.al.25have synthesized various -phenylsulfanylarylacetates by the monosulfanylation of carboxylic esters. In our earlier studies11-18, various nucleophile substituted phenylthioethanoates have been prepared. However, the nuclephiles attached were limited to only few alkoxy groups. Therefore, it was considered to extend this synthetic approach for the preparation of various aliphatic and aromatic substituted esters and acids. The reaction of ethyl chloroacetate with thiophenol in the presence of sodium in toluene at refluxing temperature gave a quantitative yield of ethyl 2-phenylthioethanoate 1, whichwas further treated with 1 equiv. of SOCl in dry methylene chloride at 0C, to yield ethyl 2-chloro-2-phenylthioethanoate 2. This -chlorophenylthioacetate was treated with various aliphatic and aromatic nuclephiles in the presence of a Lewis acid to afford in excellent yield (scheme 2). PhSH Na,Cl O CHCH O PhS O CHCH O NucleophileLewis Acid PhS O CHCH O Cl PhS O CHCH O Nu 3 SOClCHCl, 0 C(a-e)Nucleophile: SiMe OH HCC CHOH CO OCH OCH Lewis acid: TiCl, SnCl, ZnClScheme-2 Synthesis of C-3 nucleophile substituted phenylthioethanoate Research Journal of Chemical Sciences ___________________________________________________________ ISSN 2231-606XVol. 3(7), 45-53, July (2013) Res. J. Chem. Sci. International Science Congress Association 50 The potential of these -chlorosulfides as reactive intermediates has already been explored. These have been found to be useful and reactive electrophiles for many of sulphur-mediated alkylation reactions of aromatic substrates26, alkenes27 and trimethylsilylenol ethers28 etc. The various -substituted esters 3(a-e) were further hydrolysed with KOH in methanol to afford potassium phenylthioethanoates which on acidification with conc. HCl gave phenylthioethanoic acids in high yields. Table-1 Synthesis of Nuclephile substituted phenylthioesters 3(a-e) from ethyl 2-chloro-2-phenylthioethanoate 2 Entry Nuclepohile Lewis Acid Compound 3 Yield (%) 1 SnCl4 a 65 2 SnCl4 b 55 3 TiCl4 c 7529 4 ZnCl2 d 60 5 HCC CHOH ZnCl2 e 58 Yields quoted are for the isolated products. 3(a-e)KOH/MeOH K conc. HCl4(a-e) PhS O O Nu PhS O O Nu PhS O OH Nu Scheme-3 Synthesis of C-3 nucleophile substituted phenylthioethanoic acids Table-2 Synthesis of Nuclephile substituted Phenylthioethanoic acids 4(a-e) from 3(a-e) Entry Nucleophile Compound 4 Yield (%) 1 a 83 2 b 80 3 c 85 4 d 82 5 HCC CHOH e 85 Yields quoted are for the isolated product OCH CO OCH SiMe OH OCH CO OCH SiMe OH Research Journal of Chemical Sciences ___________________________________________________________ ISSN 2231-606XVol. 3(7), 45-53, July (2013) Res. J. Chem. Sci. International Science Congress Association 51 Initial studies for synthesis of C-3 monosubstituted -lactams were carried out by treating 4a with Schiff’s base 5a in the presence of POCl as a condensing agent and triethylamine as a base in dichloromethane at 0C. After usual work-up and purification the product was found to be a mixture of cis- and trans-lactams 6a and 7a (C-4 H being cis- or trans- to C-3 PhS respectively). These were separated by column chromatography on Silica gel (60-120 mesh) using ethyl actate/hexanes (8:92) as an eluent system. The reaction conditions were optimised by varying the solvent and reaction temperature. As indicated in table 3, high reaction temperature did not favour the increase in selectivity. However, dichloromethane at 0C was considered as most suitable reaction conditions for the reaction. Employing these optimum reaction conditions, a variety of cis-and trans- C-3 monosubstituted phenylthio--lactams, 6(a-j)and 7(a-j), were prepared in good yields (Scheme 5). It is clearly evident from Table-4 that in some cases (entries 3, 4, 7 and 8) formation of only cis-lactams was favoured. OH Nu O +N R1 H R2 N O R2 R1 Nu H PhS O R2 R1 Nu H PhS4(a-e)5(a,b)5a : R=Ph R=Ph(OMe)5b : R=Ph(OMe) R=Ph(OMe6(a-j)7(a-j)cisbb-lactamtransbb-lactamPhSPOClEtScheme-4 Synthesis of cis- and trans-C-3-monosubstituted phenylthio--lactamsTable-3 Synthesis of 3-(1,4-Dimethoxybenzene)-3-phenylthio--lactams in different solvent and temperature conditions Entry Solvent Temperature (C) Ratio 6a:7a (cis : trans) 1 Dichloromethane 0 70:30 2 Dichloromethane 40(reflux) 73:27 3 Toluene 110(reflux) 63:37 Table-4 Synthesis of C-3 monosubstituted phenythio--lactams Entry 4(Substrate) Schiff’s base 5 Product of type(% Yield) 6 7 (cis--lactam) (trans--lactam) 1 4a 5a 6a(45) 7a(20) 2 4a 5b 6b(30) 7b(30) 3 4b 5a 6c (40) 7c(-) 4 4b 5b 6d(35) 7d(-) 5 4c 5a 6e(19) 7e(51) 6 4c 5b 6f(20) 7f(45) 7 4d 5a 6g(35) 7g(-) 8 4d 5b 6h(42) 7h(-) 9 4e 5a 6i(35) 7i(20) 10 4e 5b 6j(27) 7j(25) Research Journal of Chemical Sciences ___________________________________________________________ ISSN 2231-606XVol. 3(7), 45-53, July (2013) Res. J. Chem. Sci. International Science Congress Association 52 The structures of these -lactams 6(a-j) and 7(a-j) were established by spectroscopic studies such as FTIR, H NMR and 13C NMR and elemental analysis. The stereochemical assignment of the substituent at C-3 of -lactam 6h with respect to C4-H was established as cis- through single crystal X-ray structure analysis as shown in ORTEP diagram (figure 3). Figure-3 ORTEP diagram of 6h Conclusion In conclusion, we have developed a novel synthetic route to cis- and trans-C-3 monosubstituted phenylthio--lactams. Methodology for novel -monosustituted phenythioethanoates and phenythioethanoic acids has also been developed. The X-ray crystallographic analysis of compound 6h allowed establishment of stereochemistry at C-3 of cis-1-(4'-Methoxyphenyl)-3-(prop-2-enyloxy)-3-phenythio-4-(4'methoxyphenyl)-azetidin-2-one. Acknowledgement We gratefully acknowledge the financial support to Ms. Qudrat Hundal for this work from the Council of Scientific and Industrial Research, New Delhi. Reference 1.Chu D. T. W., Plattner J. J. and Katz L., New Directions in Antibacterial Research, J. Med. Chem., 39, 3853 (1996) 2.Southgate R., Contemp. Org. Synth., , 417(1994) 3.de Kimpe N., In Comprehensive Heterocyclic Chemistry II, Padwa A., Ed., Elsevier: Oxford, UK, 536 (1996) 4.Burnett D. A., Caplen M. A., Davis H. R. Jr., Burrie R. E. and Clader J. W., 2-Azetidinones as inhibitors of cholesterol absorption, J. Med. Chem., 37, 1733 (1994) 5.Han W. T., Trehan A. K., Wright J. J. K., Federici M. E., Seiler S. M. and Meanwell N. A., Azetidin-2- one derivatives as inhibitors of thrombin, Bioorg. Med. Chem., , 1123, 1995 6.Smith D. M., Kazi A., Smith L., Long T. E., Heldreth B., Turos E. and Dou Q. P., A Novel -Lactam Antibiotic Activates Tumor Cell Apoptotic Program by Inducing DNA Damage, Mol. Pharmacol., 61, 1348 (2002) 7.Shah S. H., Patel P. S., Synthesis and Antimicrobial Activity of Azetidin-2-one Containing Pyrazoline Derivatives, Res. J. Chem. Sci., 2(7), 62, (2012) 8.Mulongo G., Mbabazi J., Odongkara B., Twinomuhwezi H. and Mpango G. B., New biologically active compoundsfrom 1, 3-diketones, Res. J. Chem. Sci., 1(3), 102, (2011) 9.Mulongo G., Mbabazi J., Nnamuyomba P., Mpango G. B., Further Biologically Active Derivatives of 1, 3-Diketones, Res. J. Chem. Sci., 1(5), 80, (2011) 10.Abdoulaye D., Martin K., Moussa C., Léopold K., Odile N. G., Jean-Pierre A., Adama S., Antioxidant potentialities of 4-acyl isochroman-1,3-diones, Res. J. Chem. Sci., 1(5), 88, 2011) 11.Bhalla A., Venugopalan P. and Bari S. S., Facile stereoselective synthesis of cis- and trans-3-alkoxyazetidin-2-ones, Tetrahedron, 62, 8291 (2006) 12.Bhalla A., Madan S.,Venugopalan P. and Bari S. S., C-3 lactam carbocation equivalents: versatile synthons for C-3 substituted -lactams, Tetrahedron, 62, 5054 (2006) 13.Bhalla A., Rathee S., Madan S.,Venugopalan P. and Bari S. S., Lewis acid mediated functionalization of -lactams: mechanistic study and synthesis of C-3 unsymmetrically disubstituted azetidin-2-ones, Tetrahedron Lett., 47, 5255 2006) 14.Bhalla A., Sharma S., Bhasin K. K. and Bari S. S., Convenient preparation of Benzylseleno- and Phenylselenoalkanoic acids: Reagents for synthesis of Organoselenium compounds, Synth. Commun.,37, 783 2007) 15. Bari S. S., Reshma, Bhalla A. and Hundal G., Stereoselective synthesis and Lewis acid mediated functionalization of novel 3-methylthio--lactams, Tetrahedron,65, 10060 (2009)16.Bari S. S. and Bhalla A., Spirocyclic -lactams: synthesis and biological evaluation of novel heterocycles, Topics In Heterocyclic Chemistry: Heterocyclic Scaffolds I Lactams, Banik B. K., Ed., Springer-Verlog Berlin Heidelberg, Germany, 22, 49, ch. 2 (2010) 17. Bhalla A., Bari S. S., Vats S. and Sharma M. L., Facile and stereoselective synthesis of novel trans-3-monosubstituted-3-benzylseleno--lactams, Res. J. Chem. Sci., (1), 59 2012) Research Journal of Chemical Sciences ___________________________________________________________ ISSN 2231-606XVol. 3(7), 45-53, July (2013) Res. J. Chem. Sci. International Science Congress Association 53 18.Bari S. S., Venugopalan P. and Arora R., A facile Lewis acid-promoted allylation of azetidin-2-ones, Tetrahedron Lett., 44, 895 (2003) 19.Crystal data for 6h: monoclinic, P2/c; a=12.083(1) Å, b=18.480(2) Å, c=11.973(2) Å; =90°, =119.31(2)°, =90°; V=2331.4(5) Å; Z=4; calcd=1.275 Mg/m; (Mo )= 0.171 mm-1; full matrix least square on F, R=0.0446, wR=0.0947 for 2953 reflections [I�2(I)]. Crystallographic data (excluding structure factors) for the structure 6h in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 929819 20.Kennedy M. and McKervey M. A., Oxidation Adjacent to Sulfur In Comprehensive Organic Synthesis, Trost B. M., Ed., Pergamon Press, , 193 (1991) 21.Dilworth B. M. and McKervey M. A., Organic synthesis with -chlorosulfides, Tetrahedron, 42, 3731 (1986) 22.Mori I., Bartllett P. A. and Heathcock C. H., High diastereofacial selectivity in nucleophilic additions to chiral thionium ions, J. Am. Chem. Soc., 109, 7199 (1987) 23.Trost B. M. and Sato T., Dimethyl(methylthio)sulfonium tetrafluoroborate initiated organometallic additions to and macrocyclizations of thioketals, J. Am. Chem. Soc., 107, 719 (1985) 24.Yoshimatsu M., Kawamoto M. and Gotoh K., First Lewis Acid catalysed generation and reaction of -organylsulfanyl and -organylselanyl carbenium ions using Ethyl fluoroacetate derivatives, Eur. J. Org. Chem., 2884 (2005) 25.Marzorati L., da Silva M. A., Wladislaw B. and Vitta C. D., PTC Sulfanylation of Arylacetates, Synth. Commun., 33, 3491 (2003) 26.Tamura Y., Choi H. D., Shindo H., Uenishi J. and Ishibashi H., Introduction of -(acyl) methylthiomethyl group into the aromatic ring by Friedel-Crafts reaction, Tetrahedron Lett., 21, 2547 (1980) 27.Wada M., Shigeshisa T., Kitani H. and Akiba K., One-pot synthesis of -butyrolactones and 4,5-dihydrofurans from chloro--ketosulfides and olefins, Tetrahedron Lett., 24, 1715 (1983) 28.Paterson I. and Fleming I., -Alkylation and alkylidenation of carbonyl compounds: Lewis acid-promoted phenylthioalkylation of -silylated enolates, Tetrahedron Lett., 20, 2179 (1979) 29.Wada M., Shigeshisa T. and Akiba K., Chemoselective reaction of Allylsilanes with -chlorosulfides containing a carbonyl group, Tetrahedron Lett., 24, 1711 (1983)