untitled European Journal of Chemistry 2 (3) (2011) 356‐358 European Journal of Chemistry ISSN 2153‐2249 (Print) / ISSN 2153‐2257 (Online)  2011 EURJCHEM DOI:10.5155/eurjchem.2.3.356‐358.389 European Journal of Chemistry Journal homepage: www.eurjchem.com Regioselective synthesis of new 2‐(E)‐cyano(oxazolidin‐2‐ylidene)thiazoles Mehdi Bakavolia,*, Hamid Beyzaeib, Mohammad Rahimizadeha and Hossein Eshghia a Department of Chemistry, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, 91375‐1436, Iran b Department of Chemistry, Faculty of Science, University of Zabol, Zabol, 98615‐538, Iran *Corresponding author at: Department of Chemistry, Faculty of Science, Ferdowsi University of Mashhad, Mashhad, 91375‐1436, Iran. Tel.: +98.511.8797022; fax: +98.511.8796416. E‐mail address: mbakavoli@yahoo.com (M. Bakavoli). ARTICLE INFORMATION ABSTRACT Received: 13 January 2011 Accepted: 21 February 2011 Online: 30 September 2011 KEYWORDS Reaction of 2‐(oxazolidin‐2‐ylidene)malononitrile (1) with phosphorus pentasulfide gave the corresponding thioamide derivative (2a) in a regioselective manner. Reaction of this compound with several α‐bromocarbonyl compounds gave new 2‐(E)‐cyano(oxazolidin‐2‐ ylidene)thiazoles (3a‐g). The chemical structures of novel compounds were confirmed by 1H NMR, elemental analysis, FT‐IR spectrometry and mass spectrophotometric analyses. Thiazole Oxazolidine Hantzsch’s synthesis Heterocyclization Regioselective synthesis Phosphorus pentasulfide 1. Introduction Thiazole is an important scaffold in heterocyclic chemistry and 1,3‐thiazole ring is present in many pharmacologically active substances [1]. For example, thiazole‐5‐ylacetic acid derivatives possess strong anti‐inflammatory activity [2]. Other compounds containing the thiazole ring have been reported as being histamine H3 antagonists [3], with herbicidal [4], antimicrobial [5], antitumoral [6] and selective cardio‐ depressant activities [7]. Several methods for the synthesis of thiazole derivatives have been developed [8‐12], the most widely used method being the Hantzsch’s synthesis utilizing thioamides and α‐halocarbonyl compounds as the starting materials [13]. Also the factors which affect on the orientation of cyclization reactions of functionalized 1,2,4‐triazine derivatives with α‐halocarbonyl compounds were reviewed [14]. In connection with our interest in the synthesis of new polyfunctionalized thiazoles as potential precursors for the synthesis of biologically important fused thiazoles, we previously described the regioselective synthesis of new 2‐(E)‐ cyano(thiazolidin‐2‐ylidene)thiazoles from reaction of (E)‐2– cyano‐2‐(thiazolidin‐2‐ylidene)ethanethioamide with various α‐bromocarbonyl compounds. Corresponding thioamide was prepared as pure geometric isomer from the reaction of 2‐(thiazolidin‐2‐ylidene)malononitrile with sodium hydrosulfide hydrate (Scheme 1) [15]. To extend the scope of this reaction, we have studied the reaction of (E)‐2‐cyano‐2‐(oxazolidin‐2‐ylidene)ethanethio‐ amide (2a) with several α‐bromocarbonyl compounds in order to synthesize the new 2‐(E)‐cyano(oxazolidin‐2‐ylidene) thiazoles (3a‐g). 2. Experimental 2.1. Instrumentation Compound 1 was obtained according to the published method [16]. All reagents and chemicals were purchased from commercial sources and used without further purification. Melting points were taken on an Electrothermal type 9100 melting point apparatus and are uncorrected. The 1H NMR spectra were recorded on a Bruker AC 100 spectrometer with Me4Si as an internal standard. Chemical shifts are reported in parts per million (ppm) from the tetramethylsilane resonance in the indicated solvent. Coupling constants are reported in Hertz (Hz), spectral splitting partners are designed as follow: singlet (s); doublet (d); triplet (t); quartet (q); multiplet (m). The mass spectra were obtained with a Varian Mat. CH‐7 at 70 ev. The FT‐IR spectra were recorded with a 4300 Shimadzu spectrometer in KBr discs and only noteworthy absorptions are listed. Elemental analyses were performed on a Thermo Finnigan Flash EA microanalyzer. 2.2. Synthesis 2.2.1. Preparation of (E)‐2‐cyano‐2‐(oxazolidin‐2‐ylidene) ethanethioamide (2a) The title compound was synthesized according to a literature procedure [17] with slight modification as follows: to a stirred solution of P4S10 (4.44 g, 0.02 mol) in methanol (20 mL), dinitrile 1 (2.70 g, 0.02 mol) was added and the resulting mixture was stirred for another 2 h. The precipitated solid was filtered, washed with methanol, air dried, and crystallized from acetonitrile to give 2a (Scheme 2). White needles. Yield: 86 %. M.p.: 290‐291 oC. FT‐IR (KBr, cm‐1): 3455, 3170 (NH, NH2), 2197 (C≡N), 1622 (C=C). 1H NMR (Aceton‐d6): 4.05 (t, J = 8.4 Hz, 2H, NCH2), 4.77 (t, J = 8.4 Hz, 2H, OCH2), 7.48 (br., 2H, NH2, D2O exchangble), 11.38 (br., 1H, NH, D2O exchangble). Bakavoli et al. / European Journal of Chemistry 2 (3) (2011) 356‐358 357 Scheme 1 MS (EI, m/z(%)): 169 (M+, 5 %). Anal. calcd. for C6H7N3OS: C, 42.59; H, 4.17; N, 24.83; S, 18.95. Found: C, 42.66; H, 4.25; N, 24.80; S, 18.88%. 2.2.2. Preparation of 2‐(E)‐Cyano(oxazolidin‐2‐ylidene) thiazoles (3a‐g) General Procedure: A suspension of thioamide 2a (0.34 g, 2 mmol), the appropriate α‐bromocarbonyl (2 mmol) and sodium bicarbonate (0.17 g, 2 mmol) in DMF (1 mL) was stirred at room temperature for 2‐8 h. After dilution with water, the solid obtained was filtered off, washed with water and ethanol, air dried, and crystallized from acetonitrile to give 3a‐g. Ethyl 2‐((E)‐cyano(oxazolidin‐2‐ylidene)methyl)thiazole‐4‐ carboxylate (3a): White needles. Yield: 68 %. M.p.: 203‐204 oC. FT‐IR (KBr, cm‐1): 3413 (NH), 2196 (C≡N), 1733 (C=O), 1620 (C=C). 1H NMR (DMSO‐d6): 1.27 (t, J = 6.7 Hz, 3H, CH3), 3.80 (t, J = 8.4 Hz, 2H, NCH2), 4.26 (q, J = 6.7 Hz, 2H, OCH2CH3), 4.69 (t, J = 8.4 Hz, 2H, OCH2), 8.10 (s, 1H, C=C‐H), 9.30 (br., 1H, NH, D2O exchangble). MS (EI, m/z(%)): 265 (M+, 7). Anal. Calcd. for C11H11N3O3S: C, 49.80; H, 4.18; N, 15.84; S, 12.09. Found: C, 49.78; H, 4.21; N, 15.84; S, 12.14%. (E)‐2‐(4‐Methylthiazol‐2‐yl)‐2‐(oxazolidin‐2‐ylidene)aceto‐ nitrile (3b): White needles. Yield: 72 %. M.p.: 164‐165 oC. FT‐IR (KBr, cm‐1): 3426 (NH), 2202 (C≡N), 1613 (C=C). 1H NMR (DMSO‐d6): 2.30 (s, 3H, CH3), 3.83 (t, J = 8.5 Hz, 2H, NCH2), 4.66 (t, J = 8.5 Hz, 2H, OCH2), 6.83 (s, 1H, C=C‐H), 9.48 (br., 1H, NH, D2O exchangble). MS (EI, m/z(%)): 207 (M+, 4 %). Anal. Calcd. for C9H9N3OS: C, 52.16; H, 4.38; N, 20.27; S, 15.47. Found: C, 52.23; H, 4.45; N, 20.24; S, 15.41%. ((E)‐2‐(4‐(4‐Chlorophenyl)thiazol‐2‐yl)‐2‐(oxazolidin‐2‐yli‐ dene)acetonitrile (3c): Yellow needles. Yield: 76 %. M.p.: 240‐ 241 oC. FT‐IR (KBr, cm‐1): 3423 (NH), 2203 (C≡N), 1617 (C=C). 1H NMR (DMSO‐d6): 3.90 (t, J = 8.4 Hz, 2H, NCH2), 4.68 (t, J = 8.4 Hz, 2H, OCH2), 7.44 (d, J = 8.3 Hz, 2H, Ar‐H), 7.76 (s, 1H, C=C‐H), 8.08 (d, J = 8.3 Hz, 2H, Ar‐H), 9.26 (br., 1H, NH, D2O exchangble). MS (EI, m/z(%)): 304 (M+, 24 %). Anal. Calcd. for C14H10ClN3OS: C, 55.35; H, 3.32; N, 13.83; S, 10.56. Found: C, 55.29; H, 3.40; N, 13.88; S, 10.51%. ((E)‐2‐(4‐(4‐Bromophenyl)thiazol‐2‐yl)‐2‐(oxazolidin‐2‐yli‐ dene)acetonitrile (3d): Yellow needles. Yield: 77 %. M.p.: 245‐ 246 oC. FT‐IR (KBr, cm‐1): 3433 (NH), 2203 (C≡N), 1610 (C=C). 1H NMR (DMSO‐d6): 3.89 (t, J = 8.3 Hz, 2H, NCH2), 4.68 (t, J = 8.3 Hz, 2H, OCH2), 7.56 (d, J = 8.3 Hz, 2H, Ar‐H), 7.76 (s, 1H, C=C‐H), 8.00 (d, J = 8.3 Hz, 2H, Ar‐H), 9.25 (br.,1H, NH, D2O exchangble). MS (EI, m/z(%)): 348 (M+, 18 %). Anal. Calcd. for C14H10BrN3OS: C, 48.29; H, 2.89; N, 12.07; S, 9.21. Found: C, 48.26; H, 2.93; N, 12.02; S, 9.27%. (E)‐2‐(5‐Aacetyl‐4‐methylthiazol‐2‐yl)‐2‐(oxazolidin‐2‐yli‐ dene)acetonitrile (3e): Yellow needles. Yield: 79 %. M.p.: 296‐ 297 oC. FT‐IR (KBr, cm‐1): 3441 (NH), 2200 (C≡N), 1648 (C=O), 1606 (C=C). 1H NMR (DMSO‐d6): 2.44 (s, 3H, COCH3), 2.61 (s, 3H, CH3), 3.88 (t, J = 8.5 Hz, 2H, NCH2), 4.71 (t, J = 8.5 Hz, 2H, OCH2), 9.75 (br., 1H, NH, D2O exchangble). MS (EI, m/z(%)): 249 (M+, 9 %). Anal. Calcd. for C11H11N3O2S: C, 53.00; H, 4.45; N, 16.86; S, 12.86. Found: C, 53.08; H, 4.49; N, 16.80; S, 12.82%. Ethyl 2‐((E)‐cyano(oxazolidin‐2‐ylidene)methyl)‐4‐methyl thiazole‐5 carboxylate (3f): White needles. Yield: 75 %. M.p.: 247‐248 oC. FT‐IR (cm‐1): 3447 (NH), 2204 (C≡N), 1696 (C=O), 1612 (C=C). 1H NMR (DMSO‐d6): 1.23 (t, J = 7.0 Hz, 3H, CH2CH3), 2.55 (s, 3H, CH3), 3.57 (t, J = 8.5 Hz, 2H, NCH2), 4.18 (q, J = 7.0 Hz, 2H, OCH2CH3), 4.68 (t, J = 8.5 Hz, 2H, OCH2), 9.67 (br., 1H, NH, D2O exchangble). MS (EI, m/z(%)): 279 (M+, 10 %). Anal. Calcd. for C12H13N3O3S: C, 51.60; H, 4.69; N, 15.04; S, 11.48. Found: C, 51.59; H, 4.75; N, 14.97; S, 11.53%. (2E)‐2‐(4,5‐Dihydro‐4‐oxothiazol‐2‐yl)‐2‐(oxazolidin‐2‐yli‐ dene)acetonitrile (3g): Red needles. Yield: 70 %. M.p.: 222‐223 oC. FT‐IR (KBr, cm‐1): 3442 (NH), 2205 (C≡N), 1684 (C=O), 1618 (C=C). 1H NMR (DMSO‐d6): 3.87 (t, J = 8.6 Hz, 2H, NCH2), 3.98 (s, 2H, COCH2), 4.76 (t, J = 8.6 Hz, 2H, OCH2), 10.00 (br., 1H, NH, D2O exchangble). MS (EI, m/z(%)): 209 (M+, 11 %). Anal. Calcd. for C8H7N3O2S: C, 45.92; H, 3.37; N, 20.08; S, 15.33. Found: C, 45.84; H, 3.40; N, 20.13; S, 15.39%. 3. Results and discussion 2‐(E)‐Cyano(oxazolidin‐2‐ylidene)thiazoles (3a‐g) were prepared in a two‐step procedure starting from the dinitrile (1) (Scheme 2). Reaction of 2‐(oxazolidin‐2‐ylidene)malononitrile (1) with phosphorus pentasulfide in methanol afforded 2‐ cyano‐2‐(oxazolidin‐2‐ylidene)ethanethioamide (2) as either E or Z isomers (2a,b). 358 Bakavoli et al. / European Journal of Chemistry 2 (3) (2011) 356‐358 Scheme 2 Table 1. Results of reaction 2a and α‐bromocarbonyl compounds. Compound R1 R2 α‐Bromocarbonyls Time, h 3a H CO2Et Ethyl bromopyruvate 2 3b H CH3 Bromoacetone 2 3c H p‐ClC6H4 p‐Chlorophenacylbromide 2 3d H p‐BrC6H4 p‐Bromophenacylbromide 2 3e COCH3 CH3 3‐Bromoacetylacetone 2 3f CO2Et CH3 Ethyl 2‐bromoacetoacetate 2 3g ‐ ‐ Ethyl bromoacetate 8 An unequivocal decision between these two geometric isomers was possible on the basis of our previously reported work on 2‐(E)‐cyano(thiazolidin‐2‐ylidene)thiazoles [15]. In this context, the E isomer is preferred over its Z counterpart. Subsequent reaction of this isomer with various α‐ bromocarbonyl compounds led to the formation of the new thiazole derivatives (3a‐g) (Table 1). The structural assignments of compounds 2a, 3a‐g were based on their analytical and spectral data. For example, the 1H NMR spectrum of compounds 2a and 3a‐g showed triplet signals due to two methylene groups of oxazolidine ring within δ = 3.57‐4.05 and 4.68‐4.77 ppm regions (J ≅ 8.5 Hz), and broad signals due to NH group within δ = 9.25‐11.38 ppm region. The FT‐IR spectra of 2a, 3a‐g in KBr disk showed the absorption bands within  = 3413‐3455 cm‐1 corresponding to NH groups, within  = 2196‐2205 cm‐1 belonging to nitrile groups and within  = 1606‐1622 cm‐1 attributed to the C=C exocyclic bonds. All this evidence plus the mass spectral and microanalytical data strongly support the formation of all products. 4. Conclusion In summary, several new functionalized thiazoles have been synthesized regioselectivly from the reaction of a single thioamide with several various α‐bromocarbonyl compounds. The thioamide itself was synthesized in a regioselective manner from functionalized oxazolidine with phosphorus pentasulfide. The geometry of the regioisomers was determined on the basis of our previously reported work. Synthesis of alternative thiazoles is currently in progress in our laboratory. Acknowledgement The authors would like to thank Dr. Ali Shiri for recording elemental analyses. References [1]. Masquelin, T.; Obrecht, D. Tetrahedron 2001, 6, 153‐156. [2]. Hirai, K.; Sugimoto, H.; Ishiba, T. J. Org. Chem. 1980, 45, 253‐260. [3]. Walczynski, K.; Zuiderveld, O. P.; Timmerman, H. Eur. J. Med. Chem. 2005, 40, 15‐23. [4]. Andreani, A.; Rambaldi, M.; Leoni, A.; Locatelli, A.; Andreani, F.; Gehret, J. C. Pharm. Acta Helv. 1996, 71, 247‐252. [5]. Ali, T. E.; El‐Kazak, A. M. Eur. J. 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