454-458A series of 3-(2-substituted sulfanyl-imidazo [2,1-b][1,3,4] thiadiazol-6-yl)-chromen-2-ones (3) have been synthesized from 3-(2-bromo acetyl) chromen-2-ones 1 and 2-amino-5-thio substituted[1,3,4]thiadiazole 2 in anhydrous ethanol. The 7,8-benzo analogs of 3-(2-substituted sulfanyl-imidazo[2,1-b][1,3,4] thiadiazol-6-yl)-chromen-2-ones 5 have been synthesized under similar conditions. All the synthesized compounds have been characteriszed by analytical and spectral data

Kumar, P Vijaya

Rao, V Rajeswar

Reddy, K Manohar

English

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  Indian Journal of Chemistry Vol. 59B, April 2020, pp. 454-458        Synthesis of some 3-(2-substituted sulfanyl-imidazo [2,1-b][1,3,4] thiadiazol-6-yl)-chromen-2-one and its derivatives P Vijaya Kumar, K Manohar Reddy & V Rajeswar Rao* Department of Chemistry, National Institute of Technology, Warangal 506 009, India E-mail: vrajesh@yahoo.com Received 9 January 2019; accepted (revised) 14 October 2019 A series of 3-(2-substituted sulfanyl-imidazo [2,1-b][1,3,4] thiadiazol-6-yl)-chromen-2-ones (3) have been synthesized from 3-(2-bromo acetyl) chromen-2-ones 1 and 2-amino-5-thio substituted[1,3,4]thiadiazole 2 in anhydrous ethanol.  The 7,8-benzo analogs of 3-(2-substituted sulfanyl-imidazo[2,1-b][1,3,4] thiadiazol-6-yl)-chromen-2-ones 5 have been synthesized under similar conditions. All the synthesized compounds have been characteriszed by analytical and  spectral data.  Keywords: Chromen-2-ones, coumarin, heterocyclic systems, biological activity The Imidazo[2,1-b][1,3,4]thiadiazoles and their analogs have been used for anticancer1, antitubercular2, antibacterial3, antitumor4, anti-inflamatory5 activities. The imidazo[2,1-b][1,3,4]thiadiazole system is present on Levamisole, a well known immuno modulator6. The thiazole (sulfathiazole / cerfixime)7, imidazo[2,1-b]thiazole and their bio-isosteric derivatives of thiadiazole (acetazolamide)8, imidazo[2,1-b][1,3,4]-thiadiazole9 are regarded as safer and better drug molecules that are found to possess diversified biological activities10. In continuation of our earlier work on the synthesis of heterocyclic systems derived from coumarin11-13 and also our search for biologically active imidazo [2,1-b][1,3,4] thiadiazoles14, we report here in the synthesis and preliminary biological evaluation of some 3-(2-substituted sulfanyl-imidazo [2,1-b][1,3,4] thiadiazol-6-yl)-chromen-2-ones and its derivatives.  Results and Discussions The compounds (3) were synthesized by the reaction of various 3-(2-bromacetyl)-chromen-2-ones (1) with 2-amino-5-thiomethyl/benzyl [1,3,4] thiadiazole (2) in anhydrous ethanol, (Scheme I). The experimental procedure is very simple and products obtained were in good yields (80-90%). Structures of all the newly synthesized compounds are well supported by spectral data such as IR, NMR, Mass and elemental analysis. The proton NMR spectrum of 3a showed characteristic peaks at  2.75 (s, 3H of SCH3), C4-H of coumarin at  8.50 (S,1H) and imidazo[2,1-b][1,3,4] thiadiazoles proton at  8.62 (s,1H), the remaining aromatic protons were appeared at usual region. The molecular ion peak showed at m/z 316. In the first step of the reaction between 1 and 2, the cyclic secondary nitrogen of the thiadiazole replaces the bromine of the 3-(2-bromo acetyl) coumarin to give the intermediate (6). This on subsequent cyclodehydration yields the products (3 and 5, Scheme II). Attempts to isolate the intermediate were futile as the final product was directly obtained under different reaction conditions and media. The prepared final compounds 3 and 5 were tested chemically and proved to have sulphur (Lassigne’s test) but no halogen (Beilstein’s test and Lassaigne’s test). Another possible isomeric structure (7) (Figure 1) can be proposed for the prepared compounds. However this structure (7) can be readily discarded basing on the fact that in the thiadiazole system, the most nucleophilic site is the cyclic secondary nitrogen at 3rd position15, 16. Hence, the preferential attack starts with this center leading to structure 3 and 5 only.  Experimental Section Melting points were determined on a Cintex melting  point  apparatus   and  are  uncorrected.   The  KUMAR et al.: CHROMEN-2-ONE AND DERIVATIVES   455    Scheme I    Scheme II    Figure 1  purity of compounds was checked by TLC plates (E. Merck, Mumbai, India). IR spectra (KBr) were recorded on a Bruker WM-400 spectrometer. 1H-NMR spectra were recorded on Buckner WM-300 spectrometer (in  ppm) using TMS as internal standard. Mass Spectra (EI-MS) were determined on Jeol-D-300 Spectrometer at 70 ev. The 3-(2-bromoacetyl)-chromen-2-ones17 and [1,3,4] thiadiazoles16  were prepared by reported procedures17. General procedure for the synthesis 3-(2-substituted sulfanyl-imidazo[2,1-b][1,3,4]thiadiazol -6-yl)-chromen-2-one (3a-m and 5a-b). Compound 1 (or) 4 (0.001 mole) was dissolved in anhydrous ethanol (10ml) then added compound 2 (0.001 mole). The reaction mixture was refluxed for 3-4 hours. Then the mixture was cooled at room temperature. The solid separated was filtered and washed with cold ethanol, water, dried and recrystallised from INDIAN J. CHEM., SEC B, APRIL 2020   456 methanol. All the other compounds were synthesized similarly (3b-m and 5a-b). 3-(2-Methyl sulfanyl-imidazo[2,1-b][1,3,4]thiadiazol-5-yl) -chromen-2-one (3a): Brown Solid. Yield 90%. m.p. 228-230oC. IR (KBr): 1725 (lactone, -C=O), 1602 (-C=N) cm-1; 1H NMR (200 MHz, DMSO-d6):  2.75 (s, 3H, -CH3), 7.35-7.96 (m, 4H, Ar-H), 8.45 (s, 1H, C4-H of Coumarin); 8.55 (s, 1H, imidazo thiazole proton); MS: m/z 315 (Molecular ion). Anal. calcd. for C14H9N3S2O2: C, 53.32; H, 2.888; N, 13.32. Found: C, 53.27; H, 2.80; N, 13.24.  3-(2-Benzyl sulfanyl-imidazo[2,1-b][1,3,4]thiadiazol-6-yl) -chromen-2-one (3b): Brown Solid. Yield 85%. m.p. 223-225oC. IR (KBr): 1722.28 (lactone, -C=O), 1601 (-C=N) cm-1; 1H NMR (200 MHz, DMSO-d6):  4.56 (s, 2H, benzyl-CH2-S), 7.35-7.78 (m, 9H, Ar-H), 8.50 (s, 1H, C4-H of Coumarin); 8.66 (s,1H, imidazo thiazole proton); MS: m/z 391 (Molecular ion). Anal. calcd. for C20H13N3S2O2: C, 61.36; H, 3.35; N, 10.73, Found: C, 61.25; H, 3.26; N, 10.68. 3-(2-Benzylsulfanyl-imidazo[2,1-b][1,3,4]thiadiazol-6-yl) -8-methoxy-chromen-2-one (3c). Brown Solid. Yield 87%. m.p. 227-229oC. IR (KBr): 1720 (lactone, -C=O), 1602 (-C=N) cm-1; 1H NMR (200 MHz, DMSO-d6):  4.60 (s, 3H, -OCH3), 4.55 (s, 2H, -S-CH2-), 7.26-7.82 (m, 8H, Ar-H), 8.45 (s, 1H, C4-H of coumarin); 8.63 (s, 1H, imidazo thiazole proton); MS: m/z 421 (Molecular ion). Anal. calcd. for C21H15N3S3O2: C, 59.84; H, 3.59; N, 9.97, Found: C, 59.76; H, 3.47; N, 9.83. 3-(2-Benzylsulfanyl-imidazo[2,1-b][1,3,4]thiadiazol-6-yl) -6-chloro-chromen-2-one (3d): Brown Solid. Yield 83%. m.p. 161-163oC. IR (KBr): 1720 (lactone, -C=O), 1601 (-C=N) cm-1; 1H NMR (200 MHz, DMSO-d6):  4.60 (s, 2H, -S-CH2-for benzyl), 7.27-7.50 (m, 3H, Ar-H), 7.55-7.88 (m, 5H, Ar-H); 8.40 (s, 1H, C4-H of coumarin); 8.66 (s,1H, imidazo thiazole proton); MS: m/z 425 (Molecular ion). Anal. calcd. for C20H12ClN3O2S2: C, 56.40; H, 2.84; N, 9.87, Found: C, 56.33; H, 2.76; N, 9.73. 3-(2-Benzyl sulfanyl-imidazo [2,1-b] [1,3,4] thiadiazol-6-yl)-6,8-dichloro-chromen-2-one (3e): Brown Solid. Yield 86%. m.p. 198-200oC. IR (KBr): 1722 (lactone, -C=O), 1606 (-C=N) cm-1; 1H-NMR (200MHz, DMSO-d6):  4.56 (s, 2H, -S-CH2-for benzyl), 7.20 (d, 1H, Ar-H, J = 3Hz), 7.47 (d, 1H, Ar-H, J = 3Hz); 7.50-7.87 (m, 5H, Ar-H), 8.48 (s,1H, C4-H of coumarin); 8.68 (s, 1H, imidazo thiazole proton); MS: m/z 460 (Molecular ion). Anal. calcd. for C20H11Cl2N3O2S2: C, 52.18; H, 2.41; N, 9.13, Found: C, 52.06; H, 2.34; N, 9.08. 3-(2-Benzyl sulfanyl-imidazo [2,1-b] [1,3,4] thiadiazol-6-yl)-6-bromo-chromen-2-one (3f): Brown Solid. Yield 84%. m.p. 216-218oC. IR (KBr): 1726 (lactone, -C=O), 1610 (-C=N) cm-1; 1H NMR (200 MHz, DMSO-d6):  4.56 (s, 2H, -S-CH2-for benzyl), 7.45 (d, 1H, J = 7Hz, C8-H of coumarin), 7.66 (d, 1H, J = 8Hz, C7 or coumarin); 7.84 (d, 1H,  J = 2Hz, C5 of coumarin); 7.88-8.20 (m, 5H, Ar-H); 8.69 (s, 1H, C4 of coumarin), 8.80 (s, 1H, imidazo thiazole proton); MS: m/z 470 (Molecular ion). Anal. calcd. for C20H12BrN3O2S2: C, 51.07; H, 2.57; N, 8.93, Found: C, 51.01; H, 2.49; N, 8.86. 3-(2-Benzylsulfanyl-imidazo[2,1-b][1,3,4]thiadiazol- 6-yl)-6,8-dibromo-chromen-2-one (3g): Brown Solid. Yield 88%. m.p. 226-228oC. IR (KBr): 1721 (lactone, -C=O), 1606 (-C=N) cm-1; 1H NMR (200 MHz, DMSO-d6):  4.57 (s, 2H, -S-CH2-for benzyl), 7.33 (d, 1H, C7 of coumarin, J = 8Hz), 7.46 (d, 1H, C5 of coumarin, J = 2 Hz); 7.50-7.99 (m, 5H, Ar-H), 8.5(s, 1H, C4 of coumarin); 8.65 (s, 1H, imidazo thiazole proton); MS: m/z 549 (Molecular ion). Anal. calcd. for C20H11Br2N3O2S2: C, 43.74; H, 2.02; N, 7.65, Found: C, 43.66; H, 1.94; N, 7.54. 3-[2-(4-Nitro-benzylsulfanyl-imidazo[2,1-b][1,3,4] thiadiazol-6-yl)- chromen-2-one (3h): Brown Solid. Yield 78%. m.p. 206-208oC. IR (KBr): 1726 (lactone, -C=O), 1608 (-C=N) cm-1; 1H NMR (200 MHz, DMSO-d6):  4.56 (s, 2H, -S-CH2-for benzyl), 7.33-7.64 (m, 4H, Ar-H), 7.88-7.90 (d, d, 2H, Ar-H); 7.98-8.00  (d, d, 2H, Ar-H), 8.51 (s, 1H, C4 of coumarin); 8.60 (s, 1H, imidazo thiazole proton); MS: m/z 436 (Molecular ion). Anal. calcd. for C20H12N4O4S2: C, 55.04; H, 2.77; N, 12.84, Found: C, 57.96; H, 2.67; N, 12.75. 3-[2-(4-Nitro-benzylsulfanyl-imidazo[2,1-b][1,3,4] thiadiazol-6-yl)-8-methoxy-chromen-2-one (3i): Brown Solid. Yield 76%. m.p. 210-212oC. IR (KBr): 1725 (lactone, -C=O), 1604 (-C=N) cm-1; 1H NMR (200 MHz, DMSO-d6):  4.6 (s, 3H, -OCH3), 4.50  (s, 2H, -S-CH2- for benzyl), 7.33-7.60 (m, 3H, Ar-H); 7.71-7.78 (d, d, 2H, Ar-H), 7.80-7.88 (d, d, 2H, Ar-H); 8.55 (s, 1H, Ar-H); 8.60 (s, 1H, imidazo thiazole proton); MS: m/z 466 (Molecular ion). Anal. calcd. for C21H14N4O5S2: C, 54.07; H, 3.03; N, 12.01, Found: C, 53.96; H, 2.95; N, 11.94. 3-[2-(4-Nitro-benzylsulfanyl-imidazo[2,1-b][1,3,4] thiadiazol-6-yl)-6-chloro-chromen-2-one (3j). KUMAR et al.: CHROMEN-2-ONE AND DERIVATIVES   457 Brown Solid. Yield 76%. m.p. 204-208oC. IR (KBr): 1720 (lactone, -C=O), 1610 (-C=N) cm-1; 1H NMR (200 MHz, DMSO-d6):  4.54 (s, 2H, -S-CH2-for benzyl), 7.30-7.60 (m, 3H, Ar-H), 7.70-7.76 (d, d, 2H, Ar-H); 7.80-7.98 (d, d, 2H, Ar-H), 8.55 (s, 1H, C4 coumarin); 8.65 (s, 1H, imidazo thiazole proton); MS: m/z 470 (Molecular ion). Anal. calcd. for C20H11ClN4O4S2: C, 51.01; H, 2.35; N, 11.90, Found: C, 49.96; H, 2.27; N, 11.87. 3-[2-(4-Nitro-benzylsulfanyl-imidazo [2,1-b] [1,3,4] thiadiazol-6-yl)-6,8-dichloro-chromen-2-one (3k): Brown Solid. Yield 78%. m.p. 242-246oC. IR (KBr): 1723 (lactone, -C=O), 1609 (-C=N) cm-1; 1H NMR (200 MHz, DMSO-d6):  4.56 (s, 2H, -S-CH2 for benzyl), 7.35 (d, 1H, C7 of coumarin, J = 3Hz), 7.55 (d, 1H, C5 of coumarin); 7.60-7.75 (d, d, 2H, Ar-H), 7.80-7.92 (d, d, 2H, Ar-H); 8.54 (s, 1H, C4 of coumarin); 8.66 (s, 1H, imidazo thiazole proton); ); MS: m/z 505 (Molecular ion). Anal. calcd. for C20H10Cl2N4O4S2: C, 47.53; H, 47.53; N, 11.09, Found: C, 47.47; H, 1.85; N, 11.02. 3-[2-(4-Nitro-benzylsulfanyl-imidazo[2,1-b][1,3,4] thiadiazol-6-yl)-6-bromo-chromen-2-one (3l): Brown Solid. Yield 76%. m.p. 250-252oC. IR (KBr): 1723 (lactone, -C=O), 1608 (-C=N) cm-1; 1H NMR (200 MHz, DMSO-d6):  4.53 (s, 2H, -S-CH2 for benzyl), 7.50-7.67 (m, 3H, Ar-H), 7.71-7.83 (d, d, 2H, Ar-H); 7.85-7.88 (d, d, 2H, Ar-H), 8.51 (s, 1H, C4 of coumarin); 8.66 (s, 1H, imidazo thiazole proton); MS: m/z 515 (Molecular ion). Anal. calcd. for C20H11BrN4O4S2: C, 46.61; H, 2.15; N, 10.87, Found: C, 46.54; H, 2.09; N, 10.81. 3-[2-(4-Nitro-benzylsulfanyl-imidazo[2,1-b][1,3,4] thiadiazol-6-yl)-6,8-dibromo-chromen-2-one (3m): Brown Solid. Yield 78%. m.p. 264-268oC. IR (KBr): 1720 (lactone, -C=O), 1606 (-C=N) cm-1; 1H NMR (200 MHz, DMSO-d6):  4.56 (s, 2H, -S-CH2 for benzyl), 7.45 (d, 1H, C7 of coumarin, J = 8 Hz), 7.69(d, 1H, C5 of coumarin, J = 2Hz); 7.75-7.78 (d, d, 2H, Ar-H), 7.81-7.96 (d, d, 2H, Ar-H), 8.54 (s, 1H, C4 of coumarin); 8.67 (s, 1H, imidazo thiazole proton); MS: m/z 594 (Molecular ion). Anal. calcd. for C20H10Br2N4O4S2: C, 40.42; H, 1.70; N, 9.43, Found: C, 40.38; H, 1.66; N, 9.37. 3-(2-Benzylsulfanyl-imidazo[2,1-b][1,3,4]thiadiazol -6-yl)-benzo[b]-chromen-2-one (5a). Brown Solid. Yield 80%. m.p. 177-179oC. IR (KBr): 1726 (lactone, -C=O), 1610 (-C=N) cm-1; 1H NMR (200 MHz, DMSO-d6):  4.67 (s, 2H, -S-CH2-for benzyl), 7.30-7.76 (m, 6H, Ar-H), 7.80-8.00 (m, 5H, Ar-H); 8.45  (s, 1H, C4 of coumarin), 8.87 (s, 1H, imidazo thiazole proton); MS: m/z 441 (Molecular ion). Anal. calcd. for C24H15N3O2S2: C, 65.29; H, 3.42; N, 9.52, Found: C, 65.21; H, 3.36; N, 9.45.  Conclusion In conclusion, we have described a series of sulfanyl-imidazo [2,1-b] [1,3,4]-thiadiazole and their derivatives have been synthesized from easily available starting materials. The title compounds were obtained by the single step, with a simple and convenient method (conventional) in good yields, without any side products.   Acknowledgements The authors are thankful to RSIC, IIT Chennai, for providing analytical and spectral data. The authors also thank the Director, NIT-Warangal for providing the necessary research facilities.  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Synthesis of some 3-(2-substituted sulfanyl-imidazo [2,1-b][1,3,4] thiadiazol-6-yl)-chromen-2-one and its derivatives

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Synthesis of some 3-(2-substituted sulfanyl-imidazo [2,1-b][1,3,4] thiadiazol-6-yl)-chromen-2-one and its derivatives

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