untitled European Journal of Chemistry 6 (4) (2015) 387‐393 European Journal of Chemistry ISSN 2153‐2249 (Print) / ISSN 2153‐2257 (Online)  2015 Atlanta Publishing House LLC ‐ All rights reserved ‐ Printed in the USA http://dx.doi.org/10.5155/eurjchem.6.4.387‐393.1306 European Journal of Chemistry Journal webpage: www.eurjchem.com An unexpected tandem cycloaddition reaction of α,β‐unsaturated acid chloride with amines: Synthesis of dihydropyrancarboxamide derivatives and biological activity Abdel‐Zaher Abdel‐Aziz Elassar Chemistry Department, Faculty of Science, Ain Helwan, Helwan University, Cairo, 11795, Egypt * Corresponding author at: Chemistry Department, Faculty of Science, Ain Helwan, Helwan University, Cairo, 11795, Egypt. Tel.: +2.01.014451887. Fax: +2.02.25552468. E‐mail address: aelassar@yahoo.com (A.Z.A.A. Elassar). ARTICLE INFORMATION ABSTRACT DOI: 10.5155/eurjchem.6.4.387‐393.1306 Received: 20 July 2015 Accepted: 22 August 2015 Published online: 31 December 2015 Printed: 31 December 2015 Tandem cycloaddition reaction of α,β‐unsaturated acid chloride with amines afforded in situ N‐acylated amines, which undergoes cycloaddition reaction with other molecule of acid chloride to give dihydropyran carboxamide derivatives as an unexpected product. 2‐Amino benzimidazole, 2‐aminobenzthiazole, 2‐aminothiazole, anthranilic acid, o‐pheneylenediamine, and 3‐methyl‐1H‐pyrazol‐5(4H)‐one are reacted with methacryloyl chloride at 0 °C to give different derivatives of dihydropyran carboxamide. The latter compound was obtained through acylation of the organic amines followed by tandem cycloaddition reaction. In contrast acryloyl chloride afforded only N‐acylated derivatives. Both products are characterized by single crystal X‐ray diffraction method. Bioactivity of the newly synthesized products was studied against Gram‐positive, Gram‐negative bacteria and fungus. KEYWORDS Synthesis Biological activity Cycloaddition reaction Single crystal structure Tandem cycloaddition reaction Dihydropyrancarboxamide derivatives Cite this: Eur. J. Chem. 2015, 6(4), 387‐393 1. Introduction There are several kinds of known organic reactions available to use in tandem cycloaddition reactions those are particularly attractive in organic synthesis [1‐5]. Tandem reac‐ tions are referred to multistep one‐pot reactions [6], these have many advantages over a series of individual reaction where it allow construction of complex structure in as few steps as possible, no need for a purification step, save on cost and amounts of reagents and reduce the amount of waste that is generated. On the other hand, cycloaddition reactions are considered as one of the most important synthetic processes, with both synthetic and mechanistic interest in organic chemistry. In the last decades the cycloaddition reactions of carbonyl compounds with conjugated dienes have been developed and mainly focused on reactions leading to optically active compounds. The cycloaddition reaction of conjugated dienes with carbonyl compounds, known as the hetero‐Diels‐Alder reaction, has been, since its discovery, one of the cornerstone reactions in organic synthesis for the construction of six‐ membered rings containing an oxygen atom [7‐11]. In this article, we are aimed to prepare N‐acylated derivatives from the reaction of metacryloyl chloride and heterocyclic amines or organic amines then used in the synthesis of heterocyclic compounds. 2. Experimental 2.1. Instrumentation All melting points are uncorrected. IR spectra were recorded in KBr with an IR spectrophotometer Shimadzu 408. 1H and 13C NMR spectra were recorded on Varian EM‐390 MHz spectrometer using TMS as internal reference and chemical shifts are expressed as δ ppm. Mass spectra were measured on a Shimadzu GCMS‐QP 1000 Ex mass spectrometer. Microanalytical data were obtained from the Microanalytical Data Unit at Cairo University, Egypt. 2.2. General method for the preparation of compound 9 and 10a‐f Ice‐cold solution (0 °C) of methacryloyl chloride (0.01 mole) in acetone or THF (20 mL) was added drop‐wise to another ice‐cold solution of 4‐aminopyridine or 2‐aminobenz‐ 388 Elassar / European Journal of Chemistry 6 (4) (2015) 387‐393 Cl O OCl O O Cl Cl O O Cl 3 4 5 Het HN O OCl O ClHet NH2 O Het N H 1 + 2 Scheme 1 Scheme 2 thiazole or 1,3,4‐thiadiazol‐3(2H)‐amine or anthranilic acid or o‐phenylene diamine or 3‐methyl‐1H‐pyrazol‐5(4H)‐one (0.01 mole) or 2‐aminobenzimidazole (1:1 or 1:2 molar ratio) in acetone or THF (30 mL) (Scheme 1). The reaction mixture then treated with ammonium hydrogen carbonate or sodium hydrogen carbonate. The solid product, so formed, was collected by filtration and recrystallized from ethanol (Scheme 2 and 3). 6‐Chloro‐2, 5‐dimethyl‐N‐(pyridin‐4‐yl)‐3, 4‐dihydro‐2H‐ pyran‐2‐carboxamide (9): Color: White platelet crystals. Yield: 80%. M.p.: 133‐134 °C. FT‐IR (KBr, , cm‐1): 3223 (NH), 3063 (CH‐aromatic), 2945 (CH‐aliphatic), 1694 (CO). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 10.14 (br, 1H, NH, D2O‐exchange), 8.44 (d, 2H, J = 6.4 Hz, Pyridine‐H), 7.70 (d, 2H, J = 6 Hz, pyridine‐H), 2.34‐1.72 (m, 4H, 2CH2, Pyran‐H), 1.72 (s, 3H, CH3), 1.56 (s, 3H, CH3). 13C NMR (100 MHz, DMSO‐d6 δ, ppm): 172.25, 150.70, 145.74, 135.18, 114.50, 105.02, 82.71, 30.86, 25.18, 23.84, 18.42. MS (EI, m/z (%)): 266 (M+, 100). HRMS (EI, m/z) calcd. for C13H15ClN2O2: 266.72; found 266.38. Anal. calcd. for C13H15ClN2O2: C, 58.54; H, 5.67; N, 10.50. Found: C, 58.59; H, 5.80; N, 10.41%. 6‐Chloro‐N‐(1‐methacryloyl‐1H‐benzo[d]imidazol‐2‐yl)‐2, 5‐ dimethyl‐3,4‐dihydro‐2H‐pyran‐2‐carboxamide hydrate (10a): Color: Yellow crystals. Yield: 60%. M.p.: 143‐144 °C. FT‐IR (KBr, , cm‐1): 3428 (H2O), 3326 (NH), 3057 (CH‐aromatic), 2945 (CH‐aliphatic), 1665 (CO). 1H NMR (400 MHz, DMF‐d7, δ, ppm): 8.95 (br, 1H, NH, D2O‐exchange), 7.82‐7.19 (m, 4H, C6H4), 7.98 (d, 1H, J = 12 Hz, =CH2), 6.31 (d, 1H, J = 12 Hz, =CH2), 4.69‐4.30 (m, 4H, 2CH2), 3.50 (br., 2H, H2O), 2.12 (s, 3H, CH3), 1.34 (s, 3H, CH3), 1.20 (s, 3H, CH3). 13C NMR (100 MHz, DMF‐d7, δ, ppm): 171.10, 170.30, 155.22, 141.39, 138.52, 134.50, 132.32, 130.01, 123.01, 119.08, 111.51, 103.30, 78.80, 30.51, 22.34, 21.50, 18.43. MS (EI, m/z (%)): 391.30 (M+, 100). HRMS (EI, m/z) calcd. for C19H22ClN3O4: 391.85; found 391.30. Anal. calcd. for C19H22ClN3O4: C: 58.24; H: 5.66; N: 10.72. Found: C: 58.19; H: 5.76; N: 10.53%. N‐(benzo[d]thiazol‐2‐yl)‐6‐chloro‐2,5‐dimethyl‐3,4‐dihydro‐ 2H‐pyran‐2‐carboxamide (10b): Color: White crystals. Yield: 78%. M.p.: 179‐180 °C. FT‐IR (KBr, , cm‐1): 3294 (NH), 3049 (CH‐aromatic), 2965 (CH‐aliphatic), 1651 (CO). Elassar / European Journal of Chemistry 6 (4) (2015) 387‐393 389 NH O O Cl 10a COOH N N 10b 10d10c 10e 10f N N O O NH O O Cl N S O O Cl NH O O Cl O O Cl NH2 NH O O Cl H2O NH S N Scheme 3 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 10.26 (br, 1H, NH, D2O‐exchange), 7.90 (d, 1H, J = 8 Hz, Aromatic‐H), 7.57 (d, 1H, J = 8 Hz, Aromatic‐H), 7.44 (d, 1H, J = 7.6 Hz, Aromatic‐H), 7.30 (d, 1H, J = 7.6 Hz, Aromatic‐H), 2.57‐2.00 (m, 4H, 2CH2), 1.70 (s, 3H, CH3), 1.60 (s, 3H, CH3). 13C NMR (100 MHz, DMSO‐d6, δ, ppm): 177.88, 177.75, 138.44, 127.94, 126.71, 124.24, 124.12, 123.61, 122.22, 114.45, 73.60, 32.61, 26.36, 21.75, 17.35. MS (EI, m/z (%)): 322.28 [M•+, 100]. HRMS (EI, m/z) calcd. for C15H15ClN2O2S: 322.81; found 322.28. Anal. calcd. for C15H15ClN2O2S: C, 55.81; H, 4.68; N, 8.68. Found: C, 55.78; H, 4.66; N, 8.68%. 6‐Chloro‐2, 5‐dimethyl‐N‐(thiazol‐2‐yl)‐3,4 ‐dihydro‐2H‐ pyran‐2‐carboxamide (10c): Color: White crystals. Yield: 68 %. M.p.: 145‐146 °C. FT‐IR (KBr, , cm‐1): 3115 (NH), 3088 (CH‐ aromatic), 2978 (CH‐aliphatic), 1685 (CO). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 9.22 (br, 1H, NH, D2O‐exchange), 7.40 (s, 1H, thiazole‐H), 6.45 (s, 1H, thiazole‐H), 2.50‐1.78 (m, 4H, 2CH2), 1.60 (s, 3H, CH3), 1.54 (s, 3H, CH3). 13C NMR (100 MHz, DMSO‐d6, δ, ppm): 171.03, 161.28, 141.83, 138.20, 110.92, 103.80, 81.75, 30.41, 24.61, 21.12, 14.94. MS (EI, m/z (%)): 272.05 (M+, 100). HRMS (EI, m/z) calcd. For C11H13ClN2O2S: 272.04; found 272.05. Anal. calcd. for C11H13ClN2O2S: C, 48.44; H, 4.80; N, 10.27. Found: C, 48.66; H, 4.68; N, 10.33%. 2‐(6‐Chloro‐2, 5‐dimethyl‐3, 4‐dihydro‐2H‐pyran‐2‐carbox amido)benzoic acid (10d): Color: White crystals. Yield: 87 %. M.p.: 138‐140 °C. FT‐IR (KBr, , cm‐1): 3358 (NH), 3088 (CH‐ aromatic), 2978 (CH‐aliphatic), 1684, 1656 (CO). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 10.50 (br, 1H, OH), 9.97 (br, 1H, NH, D2O‐exchange), 7.94‐7.14 (m, 4H, aromatic‐H), 2.28‐ 1.75 (m, 4H, 2CH2), 1.71 (s, 3H, CH3), 1.60 (s, 3H, CH3). 13C NMR (100 MHz, DMSO‐d6, δ, ppm): 177.81, 175.76, 143.63, 140.57, 135.21, 130.62, 125.84, 121.05, 119.78, 104.88, 75.18, 29.51, 23.93, 19.08, 17.32. MS (EI, m/z (%)): 309.22 (M+, 100). HRMS (EI, m/z) calcd. for C15H16ClNO4: 309.74; found 309.22. Anal. calcd. for C15H16ClNO4: C, 58.16; H, 5.21; N, 4.52; Found: C, 58.09; H, 5.13; N, 4.35%. N‐(2‐Aminophenyl)‐6‐chloro‐2, 5‐dimethyl‐3,4‐dihydro‐2H‐ pyran‐2‐carboxamide (10e): Color: Pink crystals. Yield: 76 %. M.p.: 230‐231 °C. FT‐IR (KBr, , cm‐1): 3325, 3215 (NH2 & NH), 3088 (CH‐aromatic), 2978 (CH‐aliphatic), 1661 (CO). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 9.80, 9.45, 9.30 (br, 3H, NH & NH2, D2O‐exchange), 7.80‐7.00 (m, 4H, aromatic‐H), 2.50‐1.94 (m, 4H, 2CH2), 1.63 (s, 3H, CH3), 1.60 (s, 3H, CH3). 13C NMR (100 MHz, DMSO‐d6, δ, ppm): 177.39, 149.91, 139.53, 125.98, 125.72, 123.86, 121.07, 118.79, 117.50, 70.44, 25.21, 22.89, 22.72, 16.66. MS (EI, m/z (%)): 280.27 (M+, 100). HRMS (EI, m/z) calcd. for C14H17ClN2O2: 280.75; found 280.27. Anal. calcd. for C14H17ClN2O2: C, 59.89; H, 6.10; N, 9.98; Found: C, 60.01; H, 5.99; N, 10.01%. 1‐(6‐Chloro‐2, 5‐dimethyl‐3, 4‐dihydro‐2H‐pyran‐2‐carbon yl)‐3‐methyl‐1H‐pyrazol‐5(4H)‐one (10f): Color: White crystals. Yield: 70 %. M.p.: 186‐188 °C. FT‐IR (KBr, , cm‐1): 3088 (CH‐ aromatic), 2972 (CH‐aliphatic), 1675, 1658 (CO). 1H NMR (400 MHz, DMSO‐d6, δ, ppm): 2.42‐1.88 (m, 6H, 3CH2), 1.59 (s, 3H, CH3), 1.50 (s, 3H, CH3), 1.25 (s, 3H, CH3). 13C NMR (100 MHz, DMSO‐d6, δ, ppm): 178.16, 177.00, 158.00 136.37, 121.84, 102.27, 85.86, 40.17, 31.14, 25.82, 19.27, 18.61. MS (EI, m/z (%)): 270.09 (M+, 100). HRMS (EI, m/z) calcd. for C12H15ClN2O3: 270.71; found 270.09. Anal. calcd. for C12H15ClN2O3: C, 53.24; H, 5.58; N, 10.35; Found: C, 53.33; H, 5.47; N, 10.22%. 2.3. Biological activities A solution or suspension of the tested compounds (prepared by dissolving 400 μg/mL (w:v) in sterile DMSO) was poured aseptically in a well of 6 mm diameter made by a borer in the seeded agar medium. After transferring via pipetting the same volume in wells of all tested microorganisms, bacteria test plates were incubated at 37 °C for 24 h and fungal test plates were incubated at 25 °C for 48 h. The activities were expressed as inhibition zones (mm, diameter, as clear areas). The least concentration, which showed the inhibitory effect on any specific microorganism, was considered as the minimum inhibitory concentration (MIC) which was determined using streptomycin and Mycostatin (50 μg/mL) as the references. 2.4. X‐ray crystallography Data collection of compound 9 (Deposit number CCDC 1027749‐1027750): A colorless platelet crystal of C13H15Cl N2O2 having approximate dimensions of 0.200×0.200×0.040 mm was mounted on a glass fiber. The crystal to detector distance was 127.40 mm. Data collection of N,N’‐1,2‐phenylene‐bis‐2‐propenamide (Deposit number CCDC 1030018‐1030019): A colorless prism crystal of C12H12N2O2 having approximate dimensions of 0.300×0.100×0.040 mm was mounted on a glass fiber. All measurements were made on a Rigaku R‐AXIS RAPID 390 Elassar / European Journal of Chemistry 6 (4) (2015) 387‐393 diffractometer using filtered Mo‐Kα radiation. The crystal to detector distance was 127.40 mm. 3. Results and discussion 3.1. Chemistry In last few years, we are involved in a program aimed to prepare different monomers. While we are trying to prepare heterocyclic monomers 1, (Scheme 1), from reaction of methacryloyl chloride (MAC) and different heterocyclic amine, we observe that the target monomers are not afforded but another reaction product 2 was obtained, where the mass spectrum referred to molar mass equal to the summation of two molecules of MAC and one molecule of amines with the elimination of HCl molecule. This result prompted us to look in literature to see what is about dimerization of MAC. Searches in literature provided very limited information about dimer of MAC. The literature has been described as impurities in samples of commercial methacryloyl chloride. To our knowledge, only four publica‐ tions describe a study on structure elucidation of MAC dimmers [12‐15]. In addition, compound 3 was found to be present in PubChem [16] without any details about preparation, purification, and no spectral characterization is available. Therein, a mixture of three different dimers was proposed by Fisher et al. [12] as a common MAC impurity. However, only the formation of dimers 4 and 5 was proved on the basis of 1H NMR spectra, while the existence of compound 3 could not been directly verified and no investigations on the mechanism of their formation have been reported. However, Azov et al. [13,14] isolate 6‐chloro‐3,4‐dihydro‐2,5‐dimethyl‐2H‐pyran‐2‐ carbonyl chloride (3) from commercial methacryloyl chloride samples after keeping a sample of MAC at 40 °C for two months. Earlier Fisher et al. [12] mentioned that the same product isolated after storing a commercial sample in the dark at room temperature for several years. The formation of compound 3 formally explained by a hetero‐Diels‐Alder reaction between two methacryloyl chloride molecules, which is similar to the dimerization reactions of many compounds [17‐24]. Single crystal structure of compound 5 was reported [14]. In this article, we report the reaction of methacryloyl chloride with aromatic or heterocyclic amines to give the N‐ acylated product which undergoes tandem cycloaddition reaction in situ with another molecule of methacryloyl chloride to give dihydropyrancarboxamide derivatives in one‐ pot reaction. One can postulate that the dimer of MAC first formed followed by reaction with amine to give the final isolated product. This postulation may be ruled out based on the previous publications which refer to the formation of the dimer in many weeks. While here MAC reacted with heterocyclic amines at 0 °C to give compound 2 as a final product. Thus, one can assume that the formation of quatranry ammonium salt 8, (Scheme 2) first formed followed by oxo‐ Diels‐Alder cycloaddition to give the final isolated product, 9. The fast of the reaction may be due to the formation of pyridinium salt which may be acts as a catalyst for cycloaddition step and as a reactant in the same time, which accelerate, the cycloaddition step. For example, 4‐amino pyridine reacted with MAC to give 6‐chloro‐2,5‐dimethyl‐N‐ (pyridin‐4‐yl)‐3, 4‐dihydro‐2H‐pyran‐2‐carboxamide, 9. This reaction was believed to processed via addition of amino group in aminopyridine to the electrophilic carbonyl carbon to give the intermediate 6 which followed by loss of one molecule of HCl to give N‐(pyridin‐4‐yl)methacrylamide 8 through compound 7. The latter compound 8 undergoes oxo‐Diel Alder [4+2] cycloaddition with another molecule of methacryloyl chloride to give the final isolated product 6‐chloro‐2, 5‐ dimethyl‐N‐(pyridin‐4‐yl)‐3, 4‐dihydro‐2H‐pyran‐2‐carbox‐ amide (9) as a colorless crystals. In continuation to understand this unexpected product, as it known in Diels Alder reaction electron rich diene component is preferable and electron poor dienophiles due to electron withdrawing substituents are the best. The initial bonding interaction reflects this electron imbalance, with the two new sigma‐bonds being formed simultaneously, but not necessarily at equal rates. Thus, in our case the formation of amine salt result from interaction between HCl, generated in situ as a by‐product from the first step, acts as a catalyst in addition the quaternary ammonium salt can acts as electron withdrawing group which increase the dienophile activity, while presence of methyl group in the diene, methacryloyl chloride, make it more electron rich which increase its activity as a diene (Scheme 2). The structure of colorless crystals of compound 9 obtained by slowly evaporating a solution in ethanol (Deposit number CCDC 1027749‐1027750) was solved by X‐ray single crystal diffraction technique. Figure 1, Table 1 and 2 shows the crystal structure, crystal and structure refinement data and selected bond lengths and angles of 6‐chloro‐2,5‐dimethyl‐N‐(pyridin‐ 4‐yl)‐3,4‐dihydro‐2H‐pyran‐2‐carboxamide, 9, respectively. Figure 1. Crystal structure of 2H‐pyran‐2‐carboxamide derivative 9. Table 1. Crystal data and structure refinement for compound 9. Crystal data Chemical formula C13H15ClN2O2 Mr 266.73 Crystal system, space group Monoclinic, P21/c Temperature (K) 293 a, b, c (Å) 13.2310 (9), 9.4915 (5), 11.0814 (8) β (°) 103.477 (7) V (Å3) 1353.31 (16) Z 4 Radiation type Mo Kα µ (mm−1) 0.28 Crystal size (mm) 0.20 × 0.20 × 0.04 Data collection Diffractometer Rigaku R‐AXIS RAPID diffractometer Absorption correction Multi‐scan, ABSCOR (Rigaku, 1995) Tmin, Tmax 0.618, 0.989 No. of measured, independent and observed [F2 > 2.0σ(F2)] reflections 8591, 2742, 1762 Rint 0.031 (sin θ/λ)max (Å−1) 0.624 Refinement R[F2 > 2σ(F2)], wR(F2), S 0.042, 0.124, 1.10 No. of reflections 2742 No. of parameters 165 H‐atom treatment H‐atom parameters constrained Δρmax, Δρmin (e Å−3) 0.21, −0.35 Furthermore, 2‐aminobenzimidazole reacted with metha‐ cryloyl chloride (1:1 molar ratio) to give diacylated product which readily undergoes cycloaddition reaction to give 6‐chloro‐N‐(1‐methacryloyl‐1H‐benzo[d]imidazol‐2‐yl)‐2, 5‐di methyl‐3, 4‐dihydro‐2H‐pyran‐2‐carboxamide (10a). It was observed in this case that the reaction yield with 1:2 molar ratios is better than that in case of 1:1 molar ratio; in addition, in latter case a mixture of mono‐ and diacylated products was obtained. Monoacylated product was obtained insignificant yield and was detected by GC‐MS. Similarly, methacryloyl chloride reacted with 2‐aminobezthiazole, 1,3,4‐thiadiazol‐2‐ Elassar / European Journal of Chemistry 6 (4) (2015) 387‐393 391 amine, anthranilic acid, o‐phenylene diamine and 3‐methyl‐ 1H‐pyrazol‐5(4H)‐one to give N‐(benzo[d]thiazol‐2‐yl)‐6‐ chloro‐2, 5‐dimethyl‐3, 4‐dihydro‐2H‐pyran‐2‐carboxamide (10b), (6‐chloro‐2,5‐dimethyl‐3,4‐dihydro‐2H‐pyran‐2‐yl)(1, 3, 4‐thiadiazol‐3(2H)‐yl)methanone (10c), 2‐(6‐chloro‐2, 5‐di methyl‐3,4‐dihydro‐2H‐pyran‐2‐carboxamido) benzoic acid (10d), N‐(2‐aminophenyl)‐6‐chloro‐2,5‐dimethyl‐3,4‐dihydro‐ 2H‐pyran‐2‐carboxamide (10e) and 1‐(6‐chloro‐2,5‐dimethyl‐ 3, 4‐dihydro‐2H‐pyran‐2‐carbonyl)‐3‐methyl‐1H‐pyrazol‐5 (4H)‐one (10f), respectively. Table 2. Selected geometric parameters (Å, °) for compound 9. Cl1—C8 1.7270 (19) C2—C3 1.376 (3) O1—C6 1.217 (2) C4—C5 1.378 (3) O2—C7 1.447 (2) C6—C7 1.535 (3) O2—C8 1.368 (3) C7—C11 1.518 (3) N1—C3 1.331 (3) C7—C12 1.514 (3) N1—C4 1.332 (3) C8—C9 1.320 (3) N2—C1 1.411 (3) C9—C10 1.495 (3) N2—C6 1.357 (3) C9—C13 1.495 (4) C1—C2 1.383 (3) C10—C11 1.514 (4) C1—C5 1.383 (3) C7—O2—C8 115.48 (14) O2—C7—C11 110.27 (14) C3—N1—C4 115.23 (18) O2—C7—C12 104.73 (15) C1—N2—C6 126.49 (14) C6—C7—C11 110.88 (16) N2—C1—C2 123.80 (16) C6—C7—C12 108.26 (15) N2—C1—C5 118.43 (15) C11—C7—C12 112.27 (17) C2—C1—C5 117.76 (17) Cl1—C8—O2 108.03 (14) C1—C2—C3 118.20 (17) Cl1—C8—C9 123.92 (17) N1—C3—C2 125.37 (17) O2—C8—C9 128.05 (17) N1—C4—C5 124.4 (2) C8—C9—C10 118.77 (19) C1—C5—C4 119.05 (17) C8—C9—C13 123.99 (19) O1—C6—N2 124.44 (17) C10—C9—C13 117.24 (18) O1—C6—C7 119.77 (16) C9—C10—C11 111.70 (17) N2—C6—C7 115.71 (14) C7—C11—C10 111.65 (17) O2—C7—C6 110.25 (15) It is of value to mention here that the behavior of amines with MAC is different than that with acryloyl chloride (AC), as reported by our group [25‐28]. Thus, acryloyl chloride reacted with amines under similar condition to give the N‐acylated product without further cycloaddtion reaction. For example, o‐ phenylene diamine reacted with AC at 0 °C to give N,N’‐1,2‐ phenylene‐bis‐2‐propenamide. The structure of the latter compound was established based on X‐ray single crystal analysis (Deposit number CCDC 1030018‐1030019). Figure 2, Table 3 and 4 shows the crystal structure, crystal and structure refinement data and selected bond lengths and angles of N,N’‐1,2‐phenylene‐bis‐2‐propenamide. Figure 2. Crystal structure of N,N’‐1,2‐phenylene‐bis‐2‐propenamide. 3.2. Biological activities The various biological activities of tetrahydropyran [29‐ 32], thiazole [33‐36], benzthiazole [37‐39] and benzimidazole derivatives [40,41] and other hetertocyclic compounds [42,43] prompted us to study the antimicrobial activities of our newly synthesized products. The in vitro antibacterial activities of compounds 9 and 10a‐10f were evaluated against Gram positive and Gram negative bacteria (S. aureus, B. subtilis, E. coli and B. cereus) and fungus (Candida albicans) are reported in Table 5. Table 3. Crystal data and structure refinement for N,N’‐1,2‐phenylene‐bis‐2‐ propenamide. Crystal data Chemical formula C12H12N2O2 Mr 216.24 Crystal system, space group Monoclinic, P21/n Temperature (K) 293 a, b, c (Å) 4.1556 (18), 14.759 (6), 17.497 (8) β (°) 91.707 (7) V (Å3) 1072.6 (8) Z 4 Radiation type Mo Kα µ (mm−1) 0.09 Crystal size (mm) 0.30 × 0.10 × 0.04 Data collection Diffractometer Rigaku R‐AXIS RAPID diffractometer Absorption correction Multi‐scan ABSCOR (Rigaku, 1995) Tmin, Tmax 0.453, 0.996 No. of measured, independent and observed [F2 > 2.0σ(F2)] reflections 5641, 1921, 1010 Rint 0.064 (sin θ/λ)max (Å−1) 0.603 Refinement R[F2 > 2σ(F2)], wR(F2), S 0.061, 0.196, 1.03 No. of reflections 1921 No. of parameters 145 H‐atom treatment H‐atom parameters constrained Δρmax, Δρmin (e Å−3) 0.29, −0.28 Table 4. Selected geometric parameters (Å, °) for N,N’‐1,2‐phenylene‐bis‐2‐ propenamide. O1—C7 1.233 (4) C2—C3 1.383 (5) O2—C10 1.230 (4) C3—C4 1.366 (6) N1—C1 1.407 (4) C4—C5 1.383 (5) N1—C7 1.354 (4) C5—C6 1.382 (5) N2—C6 1.434 (4) C7—C8 1.476 (5) N2—C10 1.351 (4) C8—C9 1.303 (6) C1—C2 1.397 (5) C10—C11 1.473 (5) C1—C6 1.399 (5) C11—C12 1.305 (5) C1—N1—C7 129.1 (3) N2—C6—C5 119.3 (3) C6—N2—C10 122.4 (3) C1—C6—C5 120.3 (3) N1—C1—C2 123.0 (3) O1—C7—N1 123.7 (3) N1—C1—C6 118.7 (3) O1—C7—C8 122.6 (3) C2—C1—C6 118.3 (3) N1—C7—C8 113.6 (3) C1—C2—C3 120.1 (3) C7—C8—C9 122.3 (4) C2—C3—C4 121.4 (4) O2—C10—N2 122.3 (3) C3—C4—C5 119.1 (4) O2—C10—C11 122.8 (3) C4—C5—C6 120.8 (3) N2—C10—C11 114.9 (3) N2—C6—C1 120.4 (3) C10—C11—C12 121.8 (4) The growth of S. aureus is severe inhibited mainly by compounds 10a, 10b and 10c showing inhibition zones varying between 25.00 and 40.00 mm. The nature of the azole ring fused with benzene ring or alone could be the origin of the noted activity in these compounds. A moderate effect was observed with compounds 9, 10d, 10e (500 μg/mL concent‐ ration) and 10f (250 & 500 μg/mL concentration). On the other hand, a slight inhibition was observed with compound 10e (100 & 250 μg/mL concentration) and compound 10f (100 μg/mL concentration). A severe effect against B. subtilis with compounds 10b and 10c may due to the presence of thiazole ring. On the other hand, moderate effect was observed with compounds 9, 10a, 10d (250 and 500 μg/mL concentration), 10e (500 μg/mL concentration). A slight effect was observed with 10d (100 μg/mL concentration), 10e (100 and 250 μg/mL concent‐ ration), and 10f. E. coli was very sensitive to compound 9 (250 and 500 μg/mL concentration), 10a (250 and 500 μg/mL concent‐ ration), 10b and 10c, which gave inhibition zones varying from 30.00 to 40.00 mm. A moderate effect was observed with compound 9 and 10a (100 μg/mL concentration) and10d‐10e (250 and 500 μg/mL concentration) other concentration showed slight effect. 392 Elassar / European Journal of Chemistry 6 (4) (2015) 387‐393 Table 5. Biological activities of some newly synthesized compounds *. Compound Concentration (μg/mL) S. aureus B. subtilis E. coli Salmonella Candida albicans 9 100 21.00 22.50 29.00 17.00 ‐ 250 23.50 26.50 35.50 20.50 5.00 500 28.00 29.50 37.00 25.00 7.50 10a 100 25.00 21.00 28.50 ‐ 12.00 250 31.50 24.50 32.50 ‐ 16.50 500 36.50 28.00 35.00 8.50 20.00 10b 100 31.00 30.00 32.00 20.25 21.00 250 34.50 36.50 37.50 25.00 26.50 500 39.00 38.50 40.00 29.50 29.50 10c 100 32.00 30.00 30.00 ‐ 30.25 250 36.50 32.50 34.25 10.50 35.50 500 40.50 35.25 37.00 15.00 37.00 10d 100 21.00 19.00 17.50 10.00 ‐ 250 24.50 21.50 20.00 15.25 9.00 500 29.50 23.00 22.50 17.50 13.00 10e 100 17.50 15.00 19.00 ‐ ‐ 250 19.00 17.50 21.50 5.00 6.50 500 22.00 21.25 24.50 8.50 10.00 10f 100 18.00 10.00 17.00 10.50 8.50 250 21.50 13.50 20.25 13.00 13.00 500 25.00 17.50 23.50 17.25 17.50 * Diameter of inhibition zone expressed in mm, Severe effect (>30 mm); Moderate effect (20‐29 mm); Slight effect (< 20 mm); ‐ Not active. Salmonella shows a moderate to slight effect with different tested compounds. Data shown that the fungus Candida albicans was very sensitive to compound 10c may be due to the presence of the thiazole ring and tetra hydropyan. Generally, the effect became visible since the concentration of 250 μg/mL and the highest inhibition was recorded at 500 μg/mL. Finally, the data reported in Table 5 indicates that the antibacterial activity of the tested compounds varied upon the concentrations used. The inhibition zones were more evident since the concentration of 250 μg/mL and the severe inhi‐ bitory effect was recorded at the concentration of 500 μg/mL with all tested compounds. Our results were concordance with that cited in the literature [27‐39]. 4. Conclusion Methacryloyl chloride reacted with different amines to give the N‐acylated product, which undergoes tandem cyclo‐ addition reaction in situ to give dihydropyran carboxamide derivatives. 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