Dodecanoyl Thiosemicarbazide Derivatives As Useful Synthons in the Synthesis Of

Dodecanoyl thiosemicarbazide derivatives as useful synthons in the synthesis of

1,2, 4-triazole, 1, 3, 4-thiadiazole and 1, 3-benzothiazole derivatives

Magdy M. Hemdan, wael S. I. Abou Elmagd,* Sandy S. Samy and Ahmed S. A. Youssef

Chemistry Department, Faculty of Science, Ain Shams University, Abassia, Cairo,

Egypt.*E-mail::

Experimental Section

Melting points of the reaction products were measured in open capillary tubes on an electrothermal melting point apparatus and were uncorrected. The elemental analyses were performed on a Perkin-Elemer 2400 CHN elemental analyzer. The infrared spectra were recorded on Perkin-Elemer Modle 297 Infrared spectrometer using the KBr wafer technique. The 1H- and 13C-NMR spectra were measured on Varian Gemini 300 and 75 MHz spectrometer, with chemical shift (δ) expressed in ppm downfield with tetramethylsilane (TMS) as internal standard, in DMSO-d6 and coupling constants J in Hz. Mass spectra were determined on Shimadzu GC-MSQP 1000 EX instrument operating at 70 eV. Thin layer chromatography (TLC) was run using TLC aluminum sheets silica gel F254 (Merck). It was carried out the monitoring of the progress of all reactions and homogeneity of the synthesized compounds. The antimicrobial activity was done at Micro Analytical Center at Cairo University.

Synthesis of the thiosemicarbazide derivatives 3a and 3b

General method

A solution of lauroyl isothiocyanate 3 mmol and hydrazide derivatives 1a or 1b

3 mmol in 30 ml dry acetonitrile was stirred at room temperature for 2h. The resulting yellow solid product was collected by filtration and recrystallized from benzene to give the corresponding compounds 3a or 3b, respectively.

1-(2-Benzamido-3-phenylacryloyl)-4-dodecanoylthiosemicarbazide (3a):

Yellow crystals (86%), m.p 164-166 °C (benzene);FTIR (KBr) cm-1: 3382, 3243, 3191 (NH), 3051, 3022 (aryl-H), 2954, 2919, 2850 (alkyl-H), 1689, 1661, 1643 (CO), 1287 (CS), 689, 762 δ5H. 1HNMR (DMSO-d6): δ 0.85 (t, J = 6.9, 6.3 Hz, 3H, CH3(CH2)8CH2CH2CO), 1.25 (m, 16H, CH3(CH2)8CH2CH2CO), 1.55 (m, 2H, CH3(CH2)8CH2CH2CO), 2.42(t, J = 7.5, 7.2 Hz, 2H, CH3(CH2)8CH2CH2CO), 7.34-7.41 (m, 4H, (3PhH+1CH=)), 7.50-7.62 (m, 5H, Ph-H), 7.99 (d, J = 7.2 Hz, 2H), 10.11 (br. s, 1H, CSNHNHCO, exchangeable), 10.76 (br.s, 1H, CSNHNHCO, exchangeable), 11.56 (br. s, 1H, NHCOPh, exchangeable), 12.51 (br. s, 1H, CONHCS, exchangeable). MS (70eV) m/z (%): 522 (M+., 1), 504 (27), 445 (90), 262 (100), 183 (97), 145 (45).Anal. Calcd. for C29H38N4O3S (522.70): C, 66.64; H, 7.33; N, 10.72. Found C, 66.32; H, 7.11; N, 10.56%.

1-(2-Benzamido-3-(1, 3-diphenyl-1H-pyrazol-4-yl)acryloyl)-4-dodecanoylthio- semicarbazide (3b): Yellow crystals (81%), m.p 170-172 °C (EtOH);FTIR (KBr) cm-1: 3284, 3196 (NH), 3059 (aryl-H), 2923, 2851 (alkyl-H), 1693, 1644 (CO), 1243 (CS), 692, 750 δ5H.1HNMR (DMSO-d6): δ 0.85 (t,J = 6.6 Hz, 3H, CH3(CH2)8CH2CH2CO), 1.24 (m, 16H, CH3(CH2)8CH2CH2CO), 1.54 (m, 2H, CH3(CH2)8CH2CH2CO), 2.42 (t, J = 7.5, 7.2 Hz, 2H, CH3(CH2)8CH2CH2CO), 7.35 (t, J = 7.5 Hz, 2H, Ar-H), 7.44-7.60 (m. 9, (7Ph-H+ 1CH=, pyrazolo-H)), 7.73 (t, J = 9.0 Hz, 4H), 8.03 (d, J = 7.2 Hz, 2H), 8.66 (br.s, 1H, CSNHNHCO, exchangeable), 9.91 (br.s, 1H, CSNHNHCO, exchangeable), 10.77 (br.s, 1H, NHCOPh, exchangeable), 11.54 (br. s, 1H, CONHCS, exchangeable). MS (70eV) m/z (%): 664 (M+., 0), 392 (0.5), 391 (8),298 (10), 244 (7), 242 (2), 197 (9), 105 (39), 80 (100).

Anal. Calcd. for C38H44N6O3S (664.86): C, 68.65; H, 6.67; N, 12.64. Found C, 68.49; H, 6.53; N, 12.37%.

Formation of compounds 4, 5, 7.

General method

To a solution of compound 3a 3 mmol in ethanol 30 mL, hydrazine hydrate 3 mmol was added. The reaction mixture was refluxed for 3 h. then, cooled to room temperature. A solid was obtained that was filtered off to give a mixture of 4 and 1a. Boiling the product with light petroleum ether 60-80 gave compound 4, the residue was crystalized from ethanol to give 1a. The same procedure was done phenylhydrazine and 2-aminothiophenol to give compounds 5 and 7. n-Butanol was used as a reaction medium in case of reaction of 3a with 2-aminothiophenol. The progress of all reactions and homogeneity of the synthesized compounds were monitored by TLC. The solid obtained for each case was recrystalized from a suitable solvent to give the corresponding compound.

1-(5-Undecyl-1H-1, 2, 4-triazol-3-yl) hydrazine (4): Colorless crystals (36%), m.p 104-106 °C (petroleum ether 60-80 oC);IR (KBr) υmax /cm-1:3316, 3291, 3179 (NH), 2957, 2919, 2850 (alkyl-H), 1630 (C=N); 1HNMR (DMSO-d6)δ/ ppm: 0.84 (t, 3H,J = 6.6 Hz,CH3(CH2)8CH2CH2CO,), 1.24 (m, 16H, CH3(CH2)8CH2CH2CO), 1.47 (m, 2H, CH3(CH2)8CH2CH2CO), 1.99 (t, 2H,J = 7.2, 7.5 Hz, CH3(CH2)8CH2CH2CO,), 3.18 (br. s, 1H,NH2NH, exchangeable),4.09 (br. s, 2H, NH2NH, exchangeable), 8.83 (br. s, 1H,NH-triazolo, exchangeable); 13C NMR (DMSO-d6) δ/ ppm: 13.87 (CH3), 22.02 (CH3CH2-), 25.15 (CH3CH2CH2-), 28.59 (CH3(CH2)2CH2-), 28.63 (CH3(CH2)3CH2-), 28.69 (CH3(CH2)4CH2CH2-), 28.86(CH3(CH2)6CH2-), 28.94 (CH3(CH2)7CH2-), 31.22 (CH3(CH2)8CH2-), 33.36 (CH3(CH2)9CH2-), 171.54 (NH2NHC=N), 172 (C11H23C=N).MS (70eV) m/z: 253 (M+., 5), 252 (8), 236 (12), 225 (30), 215 (100), 183(79), 165 (21), 123 (80).

Anal. Calcd. for C13H27N5 (253.39): C, 61.62; H, 10.74; N, 27.64. Found C, 61.39; H, 10.57; N, 27.43.

2-Benzamido-3-phenylacrylohydrazide (1a): Colorless crystals (43%), m.p 188-190 °C (EtOH) (Lit. m.p.[25] 198-200oC);FTIR (KBr) cm-1: 3307, 3186 (NH), 3060, 3029 (aryl-H), 1663, 1631 (C=O), 1530 (C=C), 693, 751 δ5H.. 1HNMR (DMSO-d6) δ: 4.24 (br. s, 2H, NH2NH-, exchangeable), 7.13-7.52 (m, 9H, (8Ar-H+ 1CH=), 7.77-7.80 (m, 2H, Ar-H), 8.51 (br. s, 1H, NH2NH, exchangeable), 9.26 (br. s, 1H, NHCO, exchangeable).

1-(2-Benzamido-3-phenyl-3-(2-phenylhydrazinyl) acryloyl)-4-dodecanoylthio- semicarbazide(5):Yellow crystals (56%), m.p 138-140- °C (EtOH);IR (KBr) υmax /cm-1: 3387, 3246 (NH), 3056, 3026 (aryl-H), 2956, 2919, 2850 (alkyl-H), 1661 (C=O), 693, 761 δ5H;1HNMR (DMSO-d6)δ/ ppm: 0.86 (t, J = 6.9, 6.3 Hz, 3H, CH3(CH2)8CH2CH2CO,), 1.25 (m, 16H, CH3(CH2)8CH2CH2CO), 1.33 (m, 2H, CH3(CH2)8CH2CH2CO), 2.40 (t, J = 7.5 Hz, 2H, CH3(CH2)8CH2CH2CO), 6.54, (br. s, 1H, NHNH-Ph, exchangeable), 7.11 (br. s, 1H, NHNH-Ph, exchangeable), 7.34-7.62 (m, 13H, Ar-H), 7.99 (d, 2H, Ar-H), 10.06 (br. s, 1H, CSNHNHCO), 10.69 (br. s, 1H, CSNHNHCO), 11.52 (br. s, 1H, NHCOPh), 12.55 (br. s, 1H, NHCOC11H23); 13CNMR (DMSO-d6) δ/ ppm: 13.88 (CH3), 22.04 (CH3CH2-), 24.31 (CH3CH2CH2-), 25.05 (CH3(CH2)2CH2-), 28.37 (CH3(CH2)3CH2-), 28.66 (CH3(CH2)4CH2-), 28.77 (CH3(CH2)5CH2-), 28.81 (CH3(CH2)6CH2-), 28.96 (CH3(CH2)7CH2-), 31.24 (CH3(CH2)8CH2-), 35.08 (CH3(CH2)9CH2-), 120.55, 127.78, 128.37, 128.59, 129.12, 129.55, 131.00, 132.00, 133.31, 133.46, 162.28, 166.14 (NHNHC=O), 174.23 (PhCONH), 175.21 (NHCOC11H23), 177.12 (C=S).

MS (70eV) m/z (%): 628 (M+., 0.5), 560 (4), 445 (M+.-C11H23CO, 100), 356 (4), 323 (6), 305 (57), 246 (90),183 (C11H23CO, 97), 105 (88), 77 (56).Anal. Calcd. for C35H44N6O3S (628.83): C, 66.85; H, 7.05; N, 13.36. Found C, 66.47; H, 6.81; N, 13.11.

Anal. Calcd. for C35H44N6O3S (628.83): C, 66.85; H, 7.05; N, 13.36. Found C, 66.47; H, 6.81; N, 13.11.

N-(benzo[d]thiazol-2-yl)dodecanamide (7):Yellow crystals (41%), m.p 170-172 °C (EtOH);IR (KBr) υmax /cm-1: 3245, 3118 (NH), 3031 (aryl-H), 2953, 2924, 2851 (alkyl-H), 1645 (C=O), 1602 (C=N); 1HNMR (DMSO-d6)δ/ ppm: 0.86 (t, J = 6.0, 7.2 Hz, 3H, CH3(CH2)8CH2CH2CO), 1.24 (m, 16H, CH3(CH2)8CH2CH2CO), 1.59 (m, 2H, CH3(CH2)8CH2CH2CO), 2.46 (t, J = 7.5 Hz, 2H, CH3(CH2)8CH2CH2CO), 7.24-8.0 (m, 4H, Ar-H), For 7b: 12.98 (br. s, 1H, NH, benzothiazol, exchangeable), For 7a: (13.10 (br. s, 1H, NHCO, exchangeable); 13CNMR (DMSO-d6)δ/ ppm: 13.87 (CH3), 22.03 (CH3CH2-), 24.89 (CH3CH2CH2-), 26.19 (CH3(CH2)2CH2-), 28.18 (CH3(CH2)3CH2-), 28.18 (CH3(CH2)4CH2-), 28.47 (CH3(CH2)4CH2CH2-), 28.64 (CH3(CH2)6CH2-), 28.78 (CH3(CH2)7CH2-), 28.93 (CH3(CH2)8CH2-), 31.24 (CH3(CH2)9CH2-), 12.49, 120.55, 128.00. 129.1, 133.00, 139.10, 152.40 (C=N), 165.90 (C=O).

MS (70eV) m/z (%): 332 (M+., 9), 183 (100), 177 (13), 155 (23), 149 (14), 90 (7).Anal. Calcd.for C19H28N2OS (332.5): C, 68.63; H, 8.49; N, 8.42. Found C, 68.27; H, 8.13; N, 8.11.

N-(1-(5-dodecanamido-1, 3, 4-thiadiazol-2-yl)-2-phenylethenyl) benzamide (8):Compound 3a 3 mmol in phosphoryl trichloride 30 mL was heated for 2 h. The reaction mixture was cooled to room temperature, and then poured into ice/cold water. A solid product was obtained that was filtered off and recrystallized from EtOH to give compound 8:Colorless crystals (68%), m.p 208-210 °C; FTIR (KBr) cm-1: 3281, 3153 (NH), 3056, 3027 (aryl-H), 2921, 2851 (alkyl-H), 1696, 1669 (C=O), 1562 (C=N), 692, 751 δ5H..1HNMR (DMSO-d6): δ 0.82 (t, J = 6.9 Hz, 3H, CH3(CH2)8CH2CH2CO), 1.24 (m, 16H, CH3(CH2)8CH2CH2CO), 1.58 (m, 2H, CH3(CH2)8CH2CH2CO), 2.44 (t, J = 7.2 Hz, 2H, CH3(CH2)8CH2CH2CO), 7.31-7.38 (m, 3H), 7.47 (s, 1H, CH=), 7.57 (d, J = 7.8 Hz, 3H), 7.60 (d, J = 7.2 Hz, 2H), 8.00 (d, J = 7.5Hz, 2H), 10.44(br. s, 1H, NHCOPh, exchangeable), 12.53(br. s, 1H, NHCOC11H23, exchangeable). MS (70eV) m/z (%): 504(M+., 0), 503 (100), 475 (12), 445 (4), 415 (53), 375 (23), 322 (97), 279 (93), 217 (90), 183 ((36), 142 (30).

Anal. Calcd. for C29H36N4O2S (504.69): C, 69.02; H, 7.19; N, 11.10. Found C, 69.22; H, 6.89; N, 10.83.

Synthesis of 5-(ethoxy(phenylmethyl)-3-phenyl-1,2,4-triazin-6(5H)-one (10):

A mixture of compound 3a 3 mmol, 5M HCl 20 ml, and 30% hydrogen peroxide 5 ml was refluxed for 2h. The reaction mixture was cooled to room temperature and then, neutralized by addition of 5 M sodium carbonate solution. A solid was obtained, filtered off and recrystallized from petroleum ether 60-80 oC to give compound 10 as colorless crystals (39%), m.p 86-88 °C (petroleum 60-80 oC);FTIR (KBr) cm-1: 3060, 3032 (aryl-H), 2979, 2952, 2930 (aryl-H), 1733 (C=O), 1633 (C=N), 694, 746 δ5H. 1HNMR (DMSO-d6): 1.13 (t, 3H,J = 6.9, 7.2 Hz, OCH2CH3), 3.10-3.13 (m, 1H, Hb), 4.08 (q, 2H, J = 7.2 HzOCH2CH3), 4.63 (m, 1H, Ha), 7.19-7.31 (m, 3H, Ar-H), 7.43-7.50 (m, 2H, Ar-H), 7.54 (d, 1H, J = 6.9 Hz), 7.79 (d, 2H, J = 7.5 Hz), 8.79 (d, 2H, J = 7.8 Hz). MS (70eV) m/z (%): 307 (M+., 0.02), 279 (M+.-CO, 0.1), 252 (0.5), 206 (1), 176 (29), 148 (7), 131 (13), 105 (100), 91 (9), 77 (40).

Anal. Calcd. for C18H17N3O2 (307.35): C, 70.34; H, 5.58; N, 13.67. Found C, 70.38; H, 5.37; N, 13.42.

Synthesis of compounds 11 and 12

A solution of compound 3a 3 mmol in acetic acid 15 mL and 5 M HCl 15 mL, was refluxed for 3h. The reaction mixture was cooled to room temperature; a solid product was obtained, filtered off and separated by fractional crystallization. Boiling the crude precipitate with light petroleum ether 60/80 oC-benzene gavecompound 11ascolorless crystals; the residue was recrystallized from ethanol to obtain yellow crystals of compound 12.

5-Undecyl-1, 2-dihydro-1, 2, 4-triazole-3-thione (11):Colorless crystals (36%), m.p 148-150 °C (light petroleum ether 60/80 oC-benzene);FTIR (KBr) cm-1: 3235, 3120 (NH), 2955, 2922, 2851 (alkyl-H), 1601(C=N), 1209 (C=S).1HNMR (DMSO-d6): δ 0.85 (t, J = 6.3, 6.9 Hz, 3H, CH3 (CH2)8CH2CH2CO,), 1.24 (m, 16H, CH3(CH2)8CH2CH2CO), 1.58 (t, J = 6.6, 6.9 Hz, 2H, CH3(CH2)8CH2CH2CO), 2.46 (t, J = 8.1 Hz, 2H, CH3(CH2)8CH2CH2CO,), 13.02, 13.14 (two br. s, 2H, NH, exchangeable). MS (70eV) m/z (%): 255 (M+., 21), 240 (2), 226 (7), 212 (9), 198 (7), 184 (9), 170 (10), 156 (6), 142 (16), 128 (92), 115 (100).Anal. Calcd. for C13H25N3S (255.42): C, 61.13; H, 9.87; N, 16.45. Found C, 60.93; H, 9.64; N, 16.14.

4-Benzylidene-2-phenyloxazol-5(4H)-one (12):Yellow crystals (41%), m.p. 164-166 0C (EtOH) (Lit. m.p.[26] 170-171oC); FTIR (KBr) cm-1: 1793, 1768 (CO), 1652(C=N), 768, 687 δ5H.1H-NMR (DMSO-d6): δ 7.36 (s, 1H, CH=), 7.51-7.76 (m, 6H, Ar-H), 8.12-8.16 (m, 2H, Ar-H), 8.29-8.32 (m, 2H, Ar-H).

N-(2-phenyl-1-(5-thioxo-2,5-dihydro-1H-1,2,4-triazol-3-yl)vinyl)benzamide (13) A solution of compound 3a 3 mmol in ethanol 20 mL and 3M sodium hydroxide 5 mL was refluxed for 2h. The reaction mixture was cooled to room temperature, and then acidified by dilute HCl. A solid product was obtained, filtered off and recrystallized from benzene to give compound 13 aspale yellow crystals (67%), m.p. 170-172 °C;FTIR (KBr) cm-1: 3320, 3240, 3182 (NH), 3062 (aryl-H), 1645(C=O), 1563 (C=N), 691, 753 δ5H. 1HNMR (DMSO-d6): δ 7.11-7.59 (m, 9H, 8 Ar-H+ 1CH=), 7.99 (d, J = 6.9 Hz, 2H), For isomer 13a: 14.09 (br. s, 1H, NHCOPh, exchangeable), 10.35 (br. s, 1H, NHCS, exchangeable), 8.32 (br. s, 1H, NHNHCS, exchangeable); For isomer 13b: 13.62 (br. s, 1H, NHCOPh, exchangeable), 10.11 (br. s, 2H, NHCS, exchangeable); For isomer 13c: 13.51 (br. s, 1H, NHCOPh, exchangeable), 9.42 (br. s, 1H, NH-triazolo, exchangeable) 4.26 (br. s, 1H, SH, exchangeable). MS (70eV) m/z (%): 322 (M+., 100), 321 (62), 203 (47), 289 (46), 275 (73), 248 (86), 218 (73), 217 (55), 204 (66), 105 (96), 76 (43).Anal. Calcd. for C17H14N4OS (322.38): C, 63.33; H, 4.38; N, 17.38. Found C, 63.45; H, 4.22; N, 17.09.

Measurement of antimicrobial activity using Kirby-Bauer method

Plates inoculated with filamentous fungi as Aspergillus fluvs at 25oC for 48 hours; Gram-positive bacteria, as Staphylococcus aureus; Gram-negative bacteria as Escherichia coli they were incubated at 35-37 oC for 24-48 hours and yeast as Candida albicans incubated at 30 oC for 24-48 hours and then the diameters of the inhibition zones were measured in millimeters. Standard discs of Tetracycline (antibacterial agent) and Amphotericin (antifungal agent) were served as positive controls for antimicrobial activity, but filter discs impregnated with 10 μl of DMSO were used as a negative control. The agar used is Meuller-Hinton agar. Blank paper disks (Schleicher & Schull, Spain) with a diameter 8.0 mm were impregnated 10 μl of tested concentration of the stock solutions. When a filter paper disc impregnated with a tested chemical is placed on agar the chemical will diffuse from the disc into the agar. This diffusion will place the chemical in the agar only around the disc. The solubility of the chemical and its molecular size will determine the size of the area of chemical infiltration around the disc. If an organism is placed on the agar it will not grow in the area around the disc if it is susceptible to the chemical, this area of no growth around the disc is known as "zone of inhibition" of "clear zone".