Research Journal of Chemical Sciences ______________________________________________ ISSN 2231-606X Vol. 2(1), 59-64, Jan. (2012) Res.J.Chem.Sci. International Science Congress Association 59 Facile and Stereoselective Synthesis of Novel trans-3-Monosubstituted- 3-benzylseleno--lactams Bhalla Aman*, Bari S.S.*, Vats Sunil and Sharma M.L. Department of Chemistry & Centre of Advanced Studies in Chemistry, Panjab University, Chandigarh-160014, INDIA Available online at: www.isca.in (Received 7th November 2011, revised 24th November 2011, accepted 7th December 2011)Abstract A facile and stereoselective synthesis of novel trans-3-monosubstituted-3-benzylseleno--lactams () via Lewis acid mediated functionalization of -lactam carbocation equivalents () with active aromatic and heterocyclic compounds (nucleophiles) is described. The structures of these novels -lactams have been established on the basis of spectroscopic studies (FTIR, H NMR, 13C NMR, 77Se NMR, GCMS) and elemental analysis. The cis or trans configuration of the hydrogen/chloro /nucleophile substitutent at C-3 was assigned with respect to C4-H. Keywords: -Lactams, Lewis acid, nucleophiles, trans-3-monosubstituted-3-benzylseleno--lactams.Introduction -Lactams are one of the best known and extensively investigated heterocyclic ring systems and as a result of both their biological activity as antibiotics and their utility as synthetic intermediatesThe discoveries of monocyclic biologically active -lactams such as cholesterol acyl transferase inhibitors and B (figure 1), thrombin inhibitors, human cytomegalovirus protease inhibitors, matrix-metalloprotease inhibitors, human leukocyte elastase, cysteine protease8 and apoptosis inductors have provided motivation for the development of new -lactam (azetidin-2-ones) systems. Very recently, the 1,3-diketones and 4-acyl isochroman-1,3-diones have been shown to posses antibacterial and antioxidant potentialities, respectively10-11. The ever-increasing bacterial resistances to -lactam antibiotics have renewed chemist’s interest towards new lactam chemistry involving skeletal modification of naturally occurring -lactam antibiotics. Therefore, the development of convenient approaches for the synthesis of seleno-lactams continues to be an area of active research. In continuation to our earlier studies12-23 towards the synthesis of novel selenoalkanoic acids as -lactam precursors, monocyclic 3-thio/seleno--lactams and their Lewis acid mediated functionalization, spirocyclic--lactams, 3-allylidene--lactams and 3-keto--lactams, we wish to report here the synthesis of novel trans-3-monosubstituted-3-benzylseleno--lactams.Figure-1 Cholesterol acyl transferase inhibitors OCHOCHOCHHH O OCH HH HO O OH Research Journal of Chemical Sciences __________________________________________________________ ISSN 2231-606X Vol. 2(1), 59-64, Jan. (2012) Res.J.Chem.SciInternational Science Congress Association 60 Our previous studies have revealed12-23cis-3-chloro-3-phenylthio/seleno--lactams on treatment with a number of active aromatic and heterocyclic compounds (nucleophiles) in the presence of a Lewis acid (TiCl or SnCl) preferentially afforded C-3 disubstituted -lactams. However, the presence of benzylthio (PhCHS-) group at C-3 position led to the exclusive formation of trans-3-monosubstited-3-benzylthio--lactams from cis-3-chloro-3-benzylthio--lactams12. Since C-3 monosubstituted -lactams are very important synthons from the biological point of view, it is proposed to employ the above reported methodology for the stereoselective synthesis of novel trans3-monosubstituted-3-benzylseleno--lactams. Further, to explore the comparative study of thio- and seleno--lactams for understanding the mechanism as well as produce new chemical entities, which might have different biological activity. The strategy involves the introduction of active aromatic and heterocyclic compounds (nucleophiles) at C-3 of cis-3-chloro-3-benzylseleno--lactams (4) in the presence of Lewis acid to furnish steroselective trans-3-monosubstituted-3-benzylseleno--lactams 5(a-e). Material and Methods H, 13C NMR and 77Se NMR spectra were recorded at 300, 75 and 57 MHz respectively, in CDCl solution using JEOL 300 MHz NMR spectrometer. Chemical shifts are given in parts per million relative to tetramethylsilane as an internal standard ( = 0 ppm) for H NMR, CDCl ( = 77 ppm) for 13C NMR and MeSe ( = 0 ppm) for 77Se spectra. IR spectra were taken on FTIR spectrophotometer and are reported in cm-1. Mass Spectra (GCMS) were recorded on Polaris Q (MS 211858). The elemental analysis (CHN) was carried out using Elementar (VARIO EL). Column chromatography was performed using Merck silica gel (60-120 mesh). Thin layer chromatography (TLC) was performed using Merck silica gel G. For visualization, TLC plates were stained with iodine vapors. Melting points are uncorrected. All commercially available compounds/reagents were used without further purification. Dichloromethane and carbon tetrachloride distilled over P were redistilled over CaH before use. Toluene was distilled over sodium-benzophenone immediately before use. Synthesis of trans-1-(4-methylphenyl)-3-benzylseleno-4-(4-chlorophenyl)azetidin-2-one (2): Compound 2 was prepared by the procedure described in the cited reference12. mp: 107-108 C. I.R. (KBr, cm-1): 1764 (C=O). H NMR (ppm): 7.22-6.93 (13H, m, Ar-), 4.45 (1H, d, = 1.8 Hz, C3-), 3.95 (2H, s, CSe), 3.90 (1H, d, = 2.1 Hz, C4-), 2.21 (3H, s, C). 13C NMR ( ppm): 159 (=O), 142-117 (Ar-), 52 (-3), 39 (-4), 31 (), 28 (). Analysis calculated for C2320ClNOSe: C, 62.70; H, 4.60; N, 3.20. Found: C, 62.56; H, 4.48; N, 3.10%. Synthesis of cis-1-(4-methylphenyl)-3-chloro-3-benzylseleno-4-(4-chlorophenyl)azetidin-2-one (3): Compound 3 was prepared by the procedure described in the cited reference12. mp: 137-138 C. I.R. (KBr, cm-1): 1753 (C=O) H NMR ( ppm): 7.24-6.99 (13H, m, Ar-), 5.25 (1H, s, C4-), 4.41-4.38 (1H, d, = 10.5 Hz, CSe), 4.12-4.08 (1H, d, = 10.5 Hz, CHSe), 2.24 (3H, s, C). 13C NMR ( ppm): 162 (=O), 136-118 (Ar-), 78 (-3), 70 -4), 61 (), 21 (). Analysis calculated for 2319ClNOSe: C, 58.10; H, 4.00; N, 2.90. Found: C, 57.01; H, 3.92; N, 2.88%. Synthesis of trans-3-monosubstituted-3-benzylseleno-bblactams5(a-e): Compounds 5(a-e) were prepared by the procedure described in the cited reference12. trans-1-(4-Methylphenyl)-3-(2,5-dimethoxyphenyl)-3-benzylseleno-4-(4-chlorophenyl)azetidin-2-one (5a):mp:152-154 C. I.R. (KBr, cm-1): 1772 (C=O). HMR ( ppm): 7.48-6.76 (16H, m, Ar-), 5.18 (1H, s, C4-), 4.12-4.09 (1H, d, = 10.5 Hz, CSe), 3.77 (3H, s, OC), 3.71 (3H, s, OC), 3.44-3.40 (1H, d, = 10.5 Hz, CHSe), 2.19 (3H, s, C). 13C NMR ( ppm): 167 (=O), 130-113 (Ar-), 73 (-3), 69 (-4), 56 (O), 55 (O), 29 (), 25 (). 77Se NMR ( ppm): 439 (Se). Analysis calculated for C3128ClNOSe: C, 64.50; H, 4.90; N, 2.40. Found: C, 63.41; H, 4.88; N, 2.37%. GCMS: m/z (assignment): 578 (M+1). trans-1-(4-Methylphenyl)-3-(4-methoxyphenyl)-3-benzylseleno-4-(4-chlorophenyl)azetidin-2-one (5b): mp:144-145 C. I.R. (KBr, cm-1): 1761 (C=O). HMR ( ppm): 7.62-6.92 (17H, m, Ar-), 5.33 (1H, s, C4-), 4.34-4.31 (1H, d, = 10.2 Hz, CSe), 3.97 (3H, s, OC), 3.60-3.56 (1H, d, = 10.2 Hz, CHSe), 2.40 (3H, s, C). 13C NMR ( ppm): 168 (=O), 133-113 (Ar-), 71 (-3), 66 (4), 55 (O), 29 (), 24 (). Analysis calculated for 3026ClNOSe: C, 65.90; H, 4.80; N, 2.60. Found: C, 65.79; H, 4.69; N, 2.48%. trans-1-(4-Methylphenyl)-3-(4-bromophenyl)-3-benzylseleno-4-(4-chlorophenyl)azetidin-2-one (5c): Yellowish oil. I.R. (CHCl, cm-1): 1764 (C=O). HMR (ppm): 7.43-6.70 (17H, m, Ar-), 5.13 (1H, s, C4-), 4.14-4.11 (1H, d, = 10.5 Hz, CSe), 3.40-3.37 (1H, d, = 10.5 Hz, CHSe), 2.20 (3H, s, C). 13C NMR ( ppm): 170 (=O), 130-113 (Ar-), 69 (-3), 61 (-4), 30 (), 25 ). Analysis calculated for C2923BrClNOSe: C, 58.50; H, 3.90; N, 2.40. Found: C, 58.41; H, 3.76; N, 2.39%. trans-1-(4-Methylphenyl)-3-(4-hydroxyphenyl)-3-benzylseleno-4-(4-chlorophenyl)azetidin-2-one (5d): mp:137-138 C. I.R. (KBr, cm-1): 1777 (C=O). H NMR (ppm): 7.29-6.95 (17H, m, Ar-), 4.81 (1H, s, C4-), 4.14-4.10 (1H, d, = 10.5 Hz, CSe), 4.02-3.96 (1H, d, = 10.8 Hz, CHSe), 2.24 (3H, s, C). 13C NMR ( ppm): Research Journal of Chemical Sciences __________________________________________________________ ISSN 2231-606X Vol. 2(1), 59-64, Jan. (2012) Res.J.Chem.SciInternational Science Congress Association 61 164 (=O), 152-118 (Ar-), 79 (-3), 62 (-4), 29 (), 24 ). Analysis calculated for C2924ClNOSe: C, 65.40; H, 4.50; N, 2.60. Found: C, 65.21; H, 4.33; N, 2.53%. trans-1-(4-Methylphenyl)-3-(2'-furanyl)-3-benzylseleno-4-(4-chlorophenyl)azetidin-2-one (5e): mp: 145-147 C. I.R. (KBr, cm-1): 1769 (C=O). H NMR ( ppm): 7.45-7.39 (1H, dd, J = 0.8, 0.8 Hz, CO), 7.40-6.65 (13H, m, Ar-), 6.29-6.23 (1H, dd, J = 0.8, 0.8 Hz, CO), 6.12-6.06 (1H, dd, J = 1.8, 1.8 Hz, CO), 5.50 (1H, s, C4-), 2.74-2.71 (1H, d, = 10.5 Hz, CSe), 2.54-2.51 (1H, d, = 10.5 Hz, CHSe), 2.23 (3H, s, C). 13C NMR ( ppm): 161 (=O), 152-117 (Ar-C and furanyl-), 74 (-3), 65 (4), 29 (), 23 (). Analysis calculated for 2722ClNOSe: C, 64.00; H, 4.40; N, 2.80. Found: C, 63.88; H, 4.31; N, 2.76%. GCMS: m/z (assignment): 507 (M+1). Results and Discussion Starting substrate, trans-3-benzylseleno--lactam (was prepared by treatment of 2-benzylselenoethanoic acid (with Schiff base () in the presence of triethylamine (EtN) and phosphorus oxychloride (POCl) acting as base and condensing agent respectively, according to the procedure reported in our previous publication (scheme-1)12. The structure of this -lactam was confirmed by spectral data (FTIR, H NMR, 13C NMR). Further, spatial juxtaposition of the C3-H and C4-H was assigned trans on the basis of coupling constant values ( = 1.8-2.1 Hz) and the stereochemistry was confirmed with correlation to X-ray analysis of trans-3-phenylseleno--lactam12,17. -lactam carbocation equivalent, cis-3-chloro-3-benzylseleno--lactams (4), suitable substrate for Lewis acid mediated functionalizationwas synthesized successfully by treatment of 3 with -chlorosuccinimide (NCS) and catalytic amount of AIBN in refluxing carbon tetrachloride (scheme-1)12,17. The structure of 4 was confirmed from FTIR, H NMR and 13C NMR spectroscopic analysis. The stereochemistry was assigned cis with respect to C4–H on the basis of correlation of H and 13C NMR data of 4 with that of cis-3-chloro-3-phenyl/benzylthio--lactams, whose stereochemistry has already been established by X-ray crystallographic analysis12. Scheme-1 Synthesis of trans-3-monosubstituted-3-benzylseleno-bb-lactams 5(a-e) PhCHSeOH POCl, EtToluene, Reflux NCS,AIBNCClReflux POCl, EtToluene, Reflux SnCl, CHClNucleophile125(a-e) CH Cl PhCHSe Cl CH PhCHSeCl Cl CH PhCHSeNu Cl CH OCHCO OH Nu = Br OCH Research Journal of Chemical Sciences __________________________________________________________ ISSN 2231-606X Vol. 2(1), 59-64, Jan. (2012) Res.J.Chem.SciInternational Science Congress Association 62 We envisaged functionalization of cis-3-chloro-3-benzylseleno--lactam employing Lewis acid catalyzed substitution reactions with different active aromatic and heterocyclic compounds (nucleophiles) to afford stereoselectively trans-3-monosubstituted 3-benzylseleno-lactams. Initial studies were carried out by reacting cis-3-chloro-3-benzylseleno--lactam 4 with 1, 4-dimethoxy-benzene as the active aromatic nucleophle in the presence of one equiv. of SnCl in dichloromethane at 0 C (scheme-1, table-1, entry-1). This reaction surprisingly resulted in the formation of only monosubstituted product, 5a, in excellent yield. The product, after column chromatographic purification, was identified as trans-1-(4'-methylphenyl)-3-(2',5'-dimethoxyphenyl)-3-benzylseleno-4-(4'-chlorophenyl)azetidin-2-oneon the basis of its spectral analysis such as FTIR, H NMR, 13C NMR, 77Se NMR, GSMS and elemental analysis. Various reactions of -lactam carbocation equivalent 4 were performed successfully with different active aromatic and heterocyclic compounds (nucleophiles) (scheme-1) and the results are summarized in table-1. Interestingly, all the active compounds (nucleophiles) react with -lactam 4 to give exclusively the trans-3-monosubstituted-3-benzylseleno-lactams 5(b-e)(table-1, entries 2-5). No formation of 3,3-disubstituted product was observed by H NMR spectroscopy. However, earlier reports12 revealed that presence of benzylthio (PhCHS-) group at C-3 led to the formation of varying amounts of 3,3-bis(arylthio)azetidin-2-ones along with 3,3-disubstituted azetidin-2-ones. The spatial juxtaposition of the C4-H and the new substitutent at C-3 in case of 5(a-e) was assigned trans on the basis of correlation of H NMR and 13C NMR data with that of trans-3-monosubstituted-3-benzylthio--lactams12Table-1 Reaction of 4 with various active aromatic and heterocyclic compounds (nucleophiles) using SnCl4 as the Lewis acid Entry Compounds (Nucleophiles) Product (5) Yield a - b % 1 5a 81 2 5b 79 3 5c 75 4 5d 68 5 5e 76 a All new compounds were characterized by FTIR, H NMR, 13C NMR, 77Se NMR, GCMS and CHN analysis. b Isolated yields after purification by column chromatography. Scheme-2 A plausible mechanism for the formation of trans-3-monosubstituted-3-benzylseleno-bb-lactams 5(a-e) OCHCO OCH Br OH O C (Complex) SnClNu PhCHSeCl Cl CH PhCHSeNu Cl CH PhCHSeClClSn Cl CH Nu Research Journal of Chemical Sciences __________________________________________________________ ISSN 2231-606X Vol. 2(1), 59-64, Jan. (2012) Res.J.Chem.SciInternational Science Congress Association 63 A plausible mechanism for the formation of trans-3-monosubstituted-3-benzylseleno--lactams 5a-e is presented in scheme- 2. The Lewis acid SnCl first forms a complex with -lactam 4, which being bulkier in size, prevents the approach of the incoming nucleophiles from its side. Thus, the nucleophiles attack from the opposite side of C4-H via an 2 mechanism. Conclusion In conclusion, we have developed a highly stereoselective synthesis of novel trans-3-monosubstituted-3-benzylseleno--lactams from cis-3-chloro-3-benzylseleno--lactams using various active aromatic and heterocyclic compounds (nucleophiles) in the presence of Lewis acid SnCl. Further elaboration of the trans-3-monosubstituted-3-benzylseleno--lactams to potential spirocyclic and bicyclic -lactams is underway in our laboratory. 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