A simple synthetic procedure for preparation of 1,4-dioxanes or 1,3-dioxolanes from styrene oxides is described. Electron-donating groups on the aromatic ring of the styrene oxides were found to favour formation of 1,4-dioxanes while electron-withdrawing groups favoured formation of 1,3-dioxolanes. Antibacterial activities of the prepared cyclodimers are reported. KEY WORDS: Dioxanes, Dioxolanes, Styrene, Epoxidation, Cyclodimerization, Antibacterial activities Bull. Chem. Soc. Ethiop. 2011, 25(2), 299-304

B. Masesane, Ishmael

Mazimba, Ofentse

R. Majinda, Runner

Bulletin of the Chemical Society of Ethiopia

English

AJOL - African Journals Online

Bull. Chem. Soc. Ethiop. 2011, 25(2), 299-304.                                                                              ISSN 1011-3924 Printed in Ethiopia                                                                                           2011 Chemical Society of Ethiopia  __________ *Corresponding author. E-mail: MASESANE@mopipi.ub.bw SHORT COMMUNICATION  SYNTHESIS AND ANTIBACTERIAL ACTIVITIES OF CYCLODIMERS OF STYRENE OXIDES  Ofentse Mazimba, Runner R. Majinda and Ishmael B. Masesane*  Chemistry Department, University of Botswana, Private Bag 00704, Gaborone, Botswana  (Received May 26, 2010; revised November 18, 2010)  ABSTRACT. A simple synthetic procedure for preparation of 1,4-dioxanes or 1,3-dioxolanes from styrene oxides is described. Electron-donating groups on the aromatic ring of the styrene oxides were found to favour formation of 1,4-dioxanes while electron-withdrawing groups favoured formation of 1,3-dioxolanes. Antibacterial activities of the prepared cyclodimers are reported.  KEY WORDS: Dioxanes, Dioxolanes, Styrene, Epoxidation, Cyclodimerization, Antibacterial activities  INTRODUCTION  Epoxides, readily available and inexpensive materials, have been used extensively in organic syntheses and generally react stereospecifically with several nucleophiles producing highly-functionalized molecules which may further be transformed. Nucleophilic ring-opening reactions of epoxides can be catalysed under either acidic or basic conditions. Among the more efficient nucleophiles are water, alcohols, thiols, amines, halides and pseudohalides [1, 2].   In connection with our study of the usefulness of epoxides in organic synthesis, we earlier reported on the cyclodimerization of styrene oxide and its chloro derivatives into 2,4-disubstituted 1,3-dioxolanes [3] which are widely used as protecting groups for ketones, aldehydes and 1,2-diols in organic synthesis [4]. In this paper, we report on the effects of electron-donating groups (methoxy and methyl) as opposed to a mildly electron withdrawing-group (chloro) on the outcome of the cyclodimerization reaction of styrene oxides and the biological activities of the resulting dimers.   RESULTS AND DISCUSSION  Styrene oxide 2 was prepared in good yield by the reaction of styrene 1 with m-chloroperbenzoic acid (m-CPBA) in dichloromethane. Subsequent treatment of 2 with phosphoric acid (H3PO4) afforded two dioxolane isomers viz., trans-3 and cis-3 with the trans-isomer being the major (Scheme 1). The reaction is thought to proceed through a critical 1,2-hydride shift [3].  Scheme 1. Reagents and conditions: (i) m-CPBA, CH2Cl2, NaHCO3, 25 oC, 88%; (ii) H3PO4, 25 oC, 61% (trans-3:cis-3, 75:25). Ofentse Mazimba et al. Bull. Chem. Soc. Ethiop. 2011, 25(2) 300  p-Methylstyrene, 4a was subjected to the epoxidation conditions and the resulting epoxide 5a was treated with H3PO4 as described earlier. Interestingly, the six-membered dimer, 1,4-dioxane 6a was isolated in 83 % yield as the only isomer (Scheme 2). m-Methylstyrene oxide 5b also afforded the corresponding 1,4-dioxane 6b signifying that the position of the electron-donating methyl group on the aromatic ring does not affect the outcome of the reaction.   R RO4a. R = p-CH3C6H4            5a                                 6a 4b. R = m-CH3C6H4            5b                                 6b(i) (ii)OORR  Scheme 2. Reagents and conditions: (i) m-CPBA, CH2Cl2, NaHCO3, 25 oC, 82%; (ii) H3PO4, 25 oC, 6a 83%, 6b 76%.   In addition, two 1,4-dioxanes 6c and 6d with electron-donanting methoxy groups on the aromatic ring were prepared from the corresponding methoxystyrenes in high yields using the epoxidation procedure described above. It is worth noting that for the methoxy-substituted styrene substrates, it was not possible to isolate the epoxides 5c and 5d as the reaction proceeded directly to give the 1,4-dioxanes under the epoxidation conditions [3] (Scheme 3).   R RO4c. R = p-CH3OC6H4         5c                                 6c4d. R = 3,4-(CH O) C H   5d                                 6d(i)OORR  Scheme 3. Reagents and conditions: (i) m-CPBA, CH2Cl2, NaHCO3, 25 oC, 6c 85%, 6d 96%.   Placement of electron-donating methoxy group on the double bond instead of the aromatic ring also gave 1,4-dioxane. Thus, treatment of the β-methoxystyrene 7 with m-CPBA led to the isolation of dioxane 9 as the only product (Scheme 4). The absence of NOESY correlations between H-2(axial) and H-3(axial) and the coupling constants (5.4 Hz) of the two hydrogens were used to suggest the trans relative configuration. It is worthy mentioning that dioxane 9 has been reported in literature as a product of the acid-catalysed dimerization of hydroxyphenylethanal in methanol [5]. However, no spectral data was reported. NOESY correlations were observed between H-2 and H-6 and that confirmed the structure of 9.    Scheme 4. Reagents and conditions: (i) m-CPBA, CH2Cl2, NaHCO3, 25 oC, 96%.   Alternatively, when styrene substrates containing the electron-withdrawing chloro group were subjected to the epoxidation conditions and the resulting epoxides treated with phosphoric acid, cyclodimerization occurred to give 1,3-dioxolanes. Thus, treatment of o-chlorostyrene 10a with m-CPBA in CH2Cl2 afforded epoxide 11a (73%) which when subjected to phosphoric acid treatment produced the 1,3-dioxolanes 12a and 13a in a 75:25 ratio, respectively and a yield of Short Communication  Bull. Chem. Soc. Ethiop. 2011, 25(2) 30172%. The procedure was repeated for m-chlorostyrene 10b and p-chlorostyrene 10c which afforded 1,3-dioxolanes 12b and 12c, respectively, as the major cyclodimers [3] (Scheme 5). The relative stereochemistry of the 1,3-dioxolanes was based on the NOESY spectral correlations. Thus the trans relationship for 12 between H-2 and H-4 protons is suggested due to the absence of any NOE correlation between these two protons whereas it was observed for the cis-isomers 13. R RO10a. R = o-ClC6H4 11a 12a 13a10b. R = m-ClC6H4         11b                            12b                                       13b10c. R = p-ClC6H4          11c                            12c                                       13c(i) (ii)OO RROO RR+  Scheme 5. Reagents and conditions: (i) m-CPBA, CH2Cl2, NaHCO3, 25 oC, 73-75%; (ii) H3PO4, 25 oC, 72% (12a:13a, 75:25), 62% (12b:13b, 75:25), 84% (12c:13c, 100:0).   The antibacterial activities of the prepared major cyclodimers were evaluated on two Gram-positive bacteria (Staphylococcus aureus and Bacillus subtilis) and two Gram-negative bacteria (Escherichia coli and Pseudonomas aeruginosa) using the agar-overlay bioautography method. Results are summarized in Table 1. Antimicrobial activities of the prepared compounds were compared, using chloramphenicol as the reference antibacterial agent. All the compounds showed activities against both Gram-negative and Gram-positive bacteria with a minimum inhibitory concentration (MIC) between 0.5 and 100 mg/mL. Bacillus subtilis was most sensitive to dioxanes 6a, 6c and 6d with a MIC of 0.5 mg/mL. The same MIC was observed for the activity of dioxolane 12c on Escherichia coli. Both the prepared dioxanes and dioxolanes are relatively non-polar compounds, therefore, their biological activity can be attributed to the lipophilicity of the dimers of styrene oxides [6, 7].   Table 1. Antibacterial activities of the prepared cyclodimers of styrene oxides.  Compounds Bacteria and minimum inhibitory quantity (MIQ) in µg  S. aureus B. subtilis E. coli P. aeruginosa Trans-3 50 50 10 10 6a 10 0.5 10 10 6b 10 10 50 100 6c 10 0.5 10 10 6d 10 0.5 10 10 9 10 10 10 10 12a 10 10 10 10 12b 50 10 10 50 12c 50 10 0.5 10 Chloramphenicol 0.001 0.001 0.001 0.001 Results are means of three replicates measurements.   We have demostrated that the acid-mediated cyclodimerizations of styrene oxides can be directed to either dioxanes or dioxolanes by the nature of the substituent(s) on the aromatic ring. The resulting cyclodimers exhibited antibacterial activities against both Gram-positive and Gram-negative bacteria. Further work is on-going in our laboratory on the cyclodimerizations of epoxides of 1,2-diphenylethene derivatives, vinylfurans and vinylpyridines. Ofentse Mazimba et al. Bull. Chem. Soc. Ethiop. 2011, 25(2) 302EXPERIMENTAL  General procedure for the reaction of m-CPBA and derivatives of styrene. m-CPBA (2 mmol) in dichloromethane (50 mL) was added slowly over a period of 10 min to a stirred and cooled (0 oC) mixture of the styrene substrate (1 mmol) and NaHCO3 (3 mmol) in dichloromethane (50 mL). The reaction mixture was stirred at room temperature for 2 hours and then saturated NaHCO3 (60 mL) was added. The organic layer was removed. The aqueous phase was extracted with dichloromethane (3 x 30 mL) and the organic fractions were combined, dried (MgSO4) and concentrated.  5a. Clear oil, 0.73 g, 82%; δH (300 MHz, CDCl3): 2.38 (3H, s, 4-Me), 2.83 (1H, dd, J = 2.4, 5.7 Hz, H-8a), 3.17 (1H, dd, J = 4.2, 5.4 Hz, H-8b), 3.88 (1H, dd, J = 2.7, 3.9 Hz, H-7), 7.21 (4H, br s, H-2, 3, 5 and 6). δC (75 MHz, CDCl3): 51.1 (C-8), 52.4 (C-7), 125.5 (C-2 and 6), 129.2 (C-3 and 5), 134.5 (C-1) and 137.9 (C-4). HR-TOF EIMS found M+, 134.0737. C9H10O requires 134.0732.  5b. Clear oil, 0.41 g, 82%; δH (300 MHz, CDCl3): 2.84 (1H, dd, J = 2.4, 5.7 Hz, H-8a), 3.17 (1H, dd, J = 3.9, 6.3 Hz, H-8b), 3.87 (1H, dd, J = 2.4, 3.9 Hz, H-7), 7.16 (2H, br s, H-4 and 6), 7.27 (2H, m, H-2 and 3). δC: 51.1 (C-8), 52.4 (C-7), 122.7 (C-2), 126.1 (C-6), 128.4 (C-4), 128.9 (C-3), 137.5 (C-1) and 138.2 (C-5). HR-TOF EIMS found M+, 134.0737. C9H10O requires 134.0732.  Typical procedure for the acid-mediated cyclodimerization reaction. H3PO4 (0.20 mL, 0.86 mol) was added drop-wise to styrene epoxide 5a (0.71 g, 4.27 mmol) and the mixture was stirred at room temperature for 120 minutes. Saturated NaHCO3 (20 mL) was added and the mixture was extracted with dichloromethane (2 x 15 mL) and the organic fractions were combined, dried (MgSO4) and concentrated under reduced pressure. The residue was subjected to flash chromatography eluting with petroleum ether/ethyl acetate (PE; 4:1) to give a clear gum 6a.  6a. Colourless gum, 0.59 g, 83%; νmax (KBr) 2922, 2855, 1605, 1280, 1251, 1115, 1022, 831, 744 cm-1; δH: 2.26 (6H, s, Me-4'', 4'), 3.83 (2H, dd, J = 4.2, 7.8 Hz, H-3a, 6a), 3.96 (2H, dd, J = 4.2, 7.8 Hz, H-3b, 6b), 5.99 (2H, dd, J = 4.2, 7.5 Hz, H-2, 5), 7.12 (2H, d, J = 7.8 Hz, H-2'', 6'', 2', 6') and 7.26 (6H, d, H-3'', 5'', 3', 5'). δC: 21.1 (Me-4´,4´´), 65.9 (C-3, 6), 77.8 (C-2, 5), 126.6 (C-2'', 6'', 2', 6'), 129.4 (C-3'', 5'', 3', 5'), 133.7 (C-1'', 1'), 138.5 (C-4'', 4'). HR-TOF EIMS found M+, 268.0529. C18H20O2 requires 268.1463.  6b. Colourless gum, 0.29 g, 76%; νmax (KBr): 2922, 2855, 1605, 1280, 1251, 1115, 1022, 831, 744 cm-1.δH: 2.41 (6H, s, Me-3'', 3'), 4.46 (2H, dd, J = 3.6, 8.1 Hz, H-3a, 6a), 4.55 (2H, dd, J = 3.6, 8.1 Hz, H-3b, 6b), 5.11 (2H, dd, J = 3.6, 8.1 Hz, H-2, 5), 7.16 (2H, d, J = 6.9 Hz, H-2', 2'') and 7.29 (6H, br s, H-4'', 5'', 6'', 4', 5', 6'). δC: 21.4 (Me-3´,3´´), 70.1 (C-3, 6), 72.6 (C-2, 5), 123.2 (C-6'', 6'), 126.8 (C-5'', 5'), 128.5 (C-4'', 4'), 129.1(C-2'', 2'), 138.4 (C-1'', 1'), 139.7 (C-3'', 3'). HR-TOF EIMS found M+, 268.0529. C18H20O2 requires 268.1468. The epoxidation procedure directly led to formation of dioxanes 6c, 6d and 9 without the isolation of epoxides 5c, 5d and 8.  6c. Yellow gum, 0.34 g, 85%; νmax (KBr): 2923, 2856, 1606, 1290, 1251, 1118, 1029 cm-1; δH (300 MHz, CDCl3): 3.71 (6H, s, 2 x MeO), 3.81 (2H, dd, J = 12.1 Hz, 3.9 Hz, H-3a, 6a), 3.94 (2H, dd, J = 12.1 Hz, 7.8 Hz, H-3b, 6b), 6.05 (2H, dd, J = 7.8 Hz, 3.9 Hz, H-2, 5), 6.83 (4H, d, J = 8.7 Hz, H-2’, 6’, 2’’, 6’’), 7.33 (4H, d, J = 8.7 Hz, H-3’, 5’, 3’’, 5’’); δC (75 MHz, CDCl3): 55.2 (2 x MeO), 65.5 (C-3, 6), 77.6 (C-2, 5), 114.1 (C-2’, 6’, 2’’, 6’’), 128.2 (3’, 5’, 3’’, 5’’), Short Communication  Bull. Chem. Soc. Ethiop. 2011, 25(2) 303129.1 (1’, 1’’), 159.7 (4’, 4’’). HR-TOF EIMS found M+, 300.1435. C18H20O4 requires 300.1362.   6d. Brown gum, 0.53 g, 96%; νmax (KBr): 2914, 2829, 1593, 1456, 1247, 1134, 1020, 806, 746 cm-1; δH (300 MHz, CDCl3): 3.82 (6H, s, 2 x MeO), 3.85 (6H, s, 2 x MeO), 3.87 (2H, s, H-3a, 6a), 4.00 (2H, dd, J = 12.1 Hz, 8.1 Hz, H-3b, 6b), 6.01 (2H, dd, J = 8.1 Hz, 3.9 Hz, H-2, 5), 6.81 (2H, d, J = 8.1 Hz, H-5’, 5’’), 6.94 (2H, d, J = 1.8 Hz, H-2’, 2’’), 6.96 (2H, dd, J = 8.1 Hz, 1.8 Hz, H-6’, 6’’); δC (75 MHz, CDCl3): 55.8 (2 x MeO-4'), 55.9 (2 x MeO-3’), 65.6 (C-3, 6), 77.8 (C-2, 5), 110.1 (C-2’, 2’’), 111.2 (C-5’, 5’), 119.2 (C-6’, 6’’), 129.4 (1’, 1’’), 148.9 (3’, 3’’), 149.1 (4’, 4’’). HR-TOF EIMS found M+, 360.1559.  C20H24O6 requires 360.1573.  9. Colourless gum, 0.79 g, 96%; νmax (KBr): 3076, 2933, 2829, 1573, 1290, 1257, 1199, 1082, 935, 750 cm-1; δH (300 Hz, CDCl3): 3.40 (6H, s, MeO-2, 5), 4.88 (2H, d, J = 5.4 Hz, H-3, 6), 6.11 (2H, d, J = 5.4 Hz, H-2, 5), 7.29-7.37 (6H, m H-3'',4'', 5'', 3', 4', 5')  and 7.44-7.52 (4H, m, H-2'',6'', 2' 6'). δC (75 MHz, CDCl3): 57.8 (MeO-2, 5), 74.4 (C-3, 6), 100.8 (C-2, 5), 127.1 (C-2'', 6'', 2', 6'), 128.0 (C-4'', 4'),  (C-6'', 6'), 128.3 (3'', 5'', 3', 5'), 138.5 (1'', 1'). HR-TOF EIMS found M+, 300.1179. C18H20O4 requires 300.1362).  Procedure for antimicrobial testing. The antimicrobial activities were evaluated using agar-overlay bioautography method. Stock solutions of 10 mg/mL of the test sample were prepared and serially-diluted to obtain concentrations of 5.0, 1.0, 0.05, 0.001 mg/mL. An aliquot of 10 µL of each concentration was spotted on Merck pre-coated silica gel 60 HF 254 TLC plates (0.25 mm thickness; 10 cm x 10 cm), corresponding to loading quantities of 100, 50, 10, 0.5 and 0.01 µg. The spots were of the same size and the solvent was allowed to evaporate in the fume hood. The following microorganisms obtained for the Department of Biological Sciences, University of Botswana were used: Staphylococcus aureus (ATCC 9144), Escherichia coli (ATCC 11229), Bacillus subtilis (ATCC 6633) and Pseudonomas aeruginosa (NCTC 10332). 3.4.0. The seed layers were prepared by inoculating 10 mL aliquot of culture into 100 mL agar solution. Using a sterile Pasteur pipette the TLC plates were overlaid with the agar. Plates were run in duplicates. After solidification of the medium the TLC plates were incubated at 37 oC (S. aureus, E. coli) and 25 oC (B. subtilis, P. aeruginosa) for 24 h. The bio-autograms were sprayed with an aqueous solution of thiazoyl blue (methylthiazolyltetrazolium bromide; 200 mg in 100 mL distilled water) and further incubated for 4 hours after which results were scored. White spots against purple background indicated inhibition zones. The minimum inhibitory quantity (MIQ in µg) was taken as the lowest loading quantity to exhibit an inhibition zone.  ACKNOWLEDGEMENTS  We thank the Royal Society of Chemistry for the generous financial support for this work. O.M. acknowledges the financial support in the form of a fellowship from the Chemistry Department, University of Botswana. We also thank Miss G. Ramokongwa for assistance with NMR experiments, Dr K. Sichilongo for mass spectra, Mr I. Morobe (biological Sciences, University of Botswana) for antimacrobial testing and Dr P. G. Steel (University of Durham, UK) for donating columns for flash chromatography to our laboratory.  REFERENCES  1. Schneider, C. Synthesis 2007, 1589. 2. Smith, J.G. Synthesis 1984, 629. Ofentse Mazimba et al. Bull. Chem. Soc. Ethiop. 2011, 25(2) 3043. Mazimba, O.; Majinda, R.R.; Masesane, I.B. Tetrahedron Lett. 2009, 50, 5927. 4. Greene, T.W.; Wuts P.G.M. Protective Groups in Organic Synthesis, 2nd ed, John Wiley and Sons: New York; 1991; p 188. 5. Tinapp, P. Arch. Pharm. (Weinheim) 1977, 310, 89. 6. Baruah, N.C.; Sarma, J.C.; Barua, N.C.; Sarma, S.; Sharma, R.P. Phytochemistry 1994, 36,  29. 7. Skaltsa, H.; Lazari, D.; Panagouleas, C.; Georgiadou, E.; Garcia, B.; Sokovic, M.  Phytochemistry 2000, 55, 903.  

Synthesis and antibacterial activities of cyclodimers of styrene oxides

A simple synthetic procedure for preparation of 1,4-dioxanes or 1,3-dioxolanes from styrene oxides is described. Electron-donating groups on the aromatic ring of the styrene oxides were found to favour formation of 1,4-dioxanes while electron-withdrawing groups favoured formation of 1,3-dioxolanes. Antibacterial activities of the prepared cyclodimers are reported

Synthesis and antibacterial activities of cyclodimers of styrene oxides

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