American Journal of Heterocyclic Chemistry
Volume 2, Issue 1, December 2016, Pages: 32-38

Synthesis of Some New N-[1-(Benzocoumarin-3`-yl)Ethylidene]Hydrazonothiazolidine, Thiazole and 1, 3, 4-Thidiazole Derivatives

Hussein A. Emam1, Saber M. Hassan1, Ahmed M. El-Agrody1, Ahmed H. Bedair1, Mahmoud M. Abdelall1, 2, *

1Chemistry Department, Faculty of Science, Al-Azhar University, Nasr City, Cairo, Egypt

2Chemistry Department, Faculty of Science and Arts, Al-Baha University, Al-Baha, Saudi Arabia

Email address:

(M. M. Abdelall)

*Corresponding author

To cite this article:

Hussein A. Emam, Saber M. Hassan, Ahmed M. El-Agrody, Ahmed H. Bedair, Mahmoud M. Abdelall. Synthesis of Some New N-[1-(Benzocoumarin-3`-yl)Ethylidene]Hydrazonothiazolidine, Thiazole and 1, 3, 4-Thidiazole Derivatives. Frontiers in Heterocyclic Chemistry. Vol. 2, No. 1, 2016, pp. 32-38. doi: 10.11648/j.ajhc.20160201.16

Received: December 10, 2016; Accepted: December 22, 2016; Published: January 12, 2017


Abstract: Condensation of 3-acetylbenzo[5,6]coumarin (1) with hydrazine-carbodithioate esters and/or thiocarbohydrazide gave the corresponding N-[1-(benzocoumarin-3`-yl)ethylidene]hydrazonecarbodithioate (2a,b) and 1,5-bis[1-(benzocoumarin-3`-yl)ethylidene]thiocarbohydrazide (3) respectively. Treatment of 2a with ethanolic ammonia solution and/or amines gave the corresponding thiosemicarbazone derivatives (4a-f). The reactions of 4a-f with ethyl bromoacetate/AcONa and ω-bromo derivatives were investigated, where thiazolidinones 5, 6 and thiazoles (9a,b) were obtained. Moreover, hydrazonecarbodithioate (2) underwent heterocycliczation upon treatment with hydrazonoyl halides (10) with Et3N to give the corresponding 2,3-dihydro-1,3,4-thiadiazoles (11a-d) via 1,3-dipolar cycloaddition and/or nuclophilic substiution. The structures of the new derivatives were elucidated by elemental analysis, IR, PMR and mass spectra.

Keywords: Benzocoumarin, 1,3,4-Thiadiazol, Thiazolidinone


1. Introduction

Coumarin nucleus is found in a variety of natural products exhibiting various pharmacological effects. Derivatives of coumarin also form component of important drugs having varied properties. There are excellent monographs and review articles [1-5] describing the structure, synthetic reaction and properties of coumarins. Neumerous reports in the literature describing antimicrobial [6, 7], antiradiation [8, 9], anti-coagulants [10-12] and their biological activities [13, 14].

2. Results and Discussion

3-Acetylbenzo[5,6]coumarin (1) was used as our starting material [15]. Thus, treatment of 1 with methyl/ or benzyl hydrazinecarbodithioate [16, 17] in ethanol afforded the corresponding dithioesters (2a,b). The structure of 2 was confirmed by elemental analysis and spectral data. The mass spectra of 2a,b gave a fragment peaks corresponding to ([M+]-CH3SH/or C6H5CH2SH) instead of molecular ion peak. Condensation of 1 with thiocarbohydrazide in hot dioxane afforded1,5-bis[1-(benzocoumarin-3`-yl)ethylidene]thiocar- bohydrazide (3), its structure was confirmed by elemental analysis and spectral data. The mass spectrum showed a fragment peak corresponding to ([M+]-[1-(benzo[5,6]-coumarin-3-yl)ethylidene]hydrazone. Treatment of 2 with ethanolic ammonia solution or amine afforded the corresponding thiosemicarbazone derivatives (4a-f, Figure 1).

Figure 1. Condensation of 3-Acetylbenzo[5,6]coumarin with hydrazine derivatives.

These products were obtained directly from condensation of 1 with thiosemicarbazide derivatives (m. p and mixed m. p and identical spectra). The mass spectrum of 4c showed no molecular ion peak, but the loss of C6H5NH2 fragment support the proposed structure. Cyclocondensation of 4a-f with an equimolar ratio of ethyl bromoacetate afforded the corresponding thiazolidin-4-one derivatives 5a-f respectively. Treatment of 4a with two moles of ethyl bromoacetate gave N-ethoxycarbonylmethyl-thiazolidin-4-one derivatives (6). The structure 6 was further confirmed unequivocally by an independent synthesis from 5a and ethyl bromoacetate in ethanolic AcONa (Figure 2).

Condensation of 5c with different aromatic aldehydes gave the corresponding arylidenes 7a-c (Figure 2). These products 7a-c could be alternatively prepared by the reaction of 5c with arylidene malononitriles under Michael reaction conditions (Figure 2). Treatment of 4a with phenacyl bromide and/or 3-(2-bromoacetyl)benzocoumarin (8) gave the corresponding hydrazonothiazole derivatives (9a,b) respectively (figure 2).

Figure 2. Synthesis of thiazolidinone and thiazole from cyclocondensation of hydrazone with α-halo carbonyl compounds.

Interaction of hydrazonecarbodithioate 2a,b with hydrazonyl halides 10a-d in ethanol containing triethylamine gave the corresponding 2,3-dihydro-1,3,4-thidiazoles 11a-d. The formation of 11 can be rationalized via elimination of alkyl mercaptan from the corresponding cycloadduct B, which is assumed to be formed from 1,3-dipolar cycloaddition of nitrileimines to the thiocarbonyl double bond. Also, alternatively, the formation of 11 can be explained by a stepwise involving substitution to give a cylic hydrazone A, which was readily cyclized to afford the cyclic adduct B (Figure 3).

Figure 3. Reaction of dithioesters with hydrazonyl halides to produce 1, 3, 4-thiadiazole.

The above structures were established from elemental analysis (table 2,3) and spectral data. Also, the mass spectra fragmentations added further support to the proposed above structures

Figure 4. The proposed pathway fragmentation for the EI spectra of substituted benzocoumarin-3`-yl derivatives 2a, b, 3, 4a, c, 5a and 6.

The most important peaks observed in the mass spectra of the substituted benzocoumarin-3`-yl derivatives 2a, b, 3, 4a, 4c, 5a and 6 are listed in (table 1) and are arranged in columns according to the presumed composition. In the EI spectra the molecular ion of compounds 2a,b, 3, 4c are not detected but the corresponding detected fragment ion was formed by elimination of the methylmercaptan, benzyl-mercaptan, aniline and 3-acetylbenzocoumarin hydrazone as neutral fragment, respectively. Also, the molecular ion was detected at low intensity for compounds 4a and 6, these peaks undergoes further fragmentation to the main fragment ion (m/z 294) by the elimination of NH3 in case of compound 4a and to the base peak (m/z 351) by the elimination of γ-butyrolactone (C4H6O2) for compound 6. The mass spectrum of compound 5a is characterized by molecular ion at high abundance. The main fragment at m/z (294) undergoes fragmentation by successive elimination of NCS, acetonitrile, CO, CO2), and cyclobutadiene. The elimination of thiazolid-inonehydrazone fragment cation at m/z (130) as very intense peak exhibit benzocoumarin cation fragment m/z (195) which underwent further fragmentation.

Table 1. Significant peaks in the EI (70 eV) spectra of compounds 2a,b, 3, 4a,c, 5a and 6.

Compd. M+ m/z (intensity %)
2a 342   294 236 195 167 151 139 87    
(0)   (30.8) (15.8) (8.1) (2.1) (3.3) (100) (7.5)    
2b 418   294 236 195 167 151 139 87    
(0)   (23.2) (13.2) (3.9) (1.3) (2) (61.6) (4.9)    
3 546   294 236 195 167 151 139 87 252  
(0)   (54) (26.1) (13.6) (5.6) (6.5) (100) (9.7) (11.3)  
4a 311   294 236 195 167 151 139 87    
(4.6)   (19.4) (19.8) (17.7) (5.6) (8.1) (100) (11.9)    
4c 387   294 236 195 167 151 139 87 93  
(0)   (16.9) (19.3) (13.7) (5.6) (7.9) (90) (12) (100)  
5a 351       195 167 151 139 87 166 130
(90.2)       (47.7) (5.5) (90.2) (92.8) (23) (17.5) (100)
6 437 351 (100)     195 167 151 139 87 166 130
(13.9)       (36.8) (16.7) (14) (73.3) (21.4) (16.7) (86.8)

3. Experimental

All melting points are uncorrected. IR spectra (KBr) were recorded on a FTIR 5300 spectrometer (ν, cm-1). The 1H NMR spectra were recorded in DMSO-d6 at 300 MHz on a Varian Gemini NMR spectrometer (δ, ppm) using TMS as an internal standard. Mass spectra were obtained on GC Ms-QP 1000 EX mass spectrometer at 70 ev. Elemental analyses were carried out by the Microanalytical Research Center, Faculty of Science, Cairo University.

3.1. N`-[1-(benzo[5`,6`]coumarin-3`-yl)ethylidene] hydrazinearbodithioate derivatives 2a,b

A mixture of 3-acetylbenzo[5,6]coumarin (0.01 mol) and alkyl hydrazine carbodithioate (0.012 mol) in ethanol (50 ml) was refluxed for one hour. The separated solid on heating was filtered off and recrystallized from the proper solvent to give (2a,b), (Table 2).

3.2. Reaction of 3-acetylbenzo[5,6]oumarin with thiocarbohydrazide

A solution of 3-acetyl[5,6]benzocoumarin (0.01 mol) in dioxane

(30 ml) and thiocarbohydrazide (0.01 mol) was refluxed for 1h.

A solution of 3-acetyl[5,6]benzocoumarin (0.01 mol) in dioxane (30 ml) and thiocarbohydrazide (0.01 mol) was refluxed for 1h, the obtained product on heating was collected and recrystallized from DMF to give 1,5-bis[1-(benzocoumarin-3`-yl)ethylidene]thiocarbohydrazide (3), (Table 2).

3.3. N`-[1-(benzocoumarin-3`-yl)ethylidene]thiosemi-carbazone derivatives 4a-e

3.3.1. Method A

A mixture of 2a or 2b (0.01 mol) and primary amine (0.012 mol) in ethanol (50 ml) was refluxed for 5h. The separated solid on heating was filtered off and recrystallized from the proper solvent to give (4a-e).

3.3.2. Method B

A solution of 3-acetylbenzo[5,6]coumarin (0.01mol) in dioxane (30ml) and aryl or alkylthiosemicarbazides [18, 19] (0.01mol) was refluxed for 2h. After cooling, the solid product which formed was collected and recrystallized from the proper solvent to give 4a-e, m.p. and mixed m.p. determined with authentic sample gave no depression (Table 2).

Table 2. Characteristics data for prepared compounds.

Compd. M. P. (°C) Yield (%) Mol. Formula Required (found)
No. Recryst. Solvent (Colour) (M. wt) C H N
2a 214-216 87 C17H14N2O2S2 59.63 4.12 8.18
EtOH/Dioxane Pale yellow (342.44) 59.51 4.10 8.12
2b 210-212 90 C23H18N2O2S2 66.00 4.33 6.89
EtOH/Benzene Red (418.53) 66.02 4.20 6.82
3 215-216 82 C31H22N4O4S 68.12 4.06 10.25
DMF Pale yellow (546.60) 68.16 4.11 10.40
4a 216-218 79 C16H13N3O2S 61.72 4.21 13.50
Acetic acid Yellow (311.36) 61.74 4.12 13.47
4b 191-192 80 C23H19N3O2S 68.81 4.77 10.47
AcOH Yellow (401.48) 68.71 4.64 10.23
4c 211-213 77 C22H17N3O2S 68.20 4.42 10.85
AcOH Yellow (387.45) 68.01 4.33 10.82
4d 213-214 79 C22H16BrN3O2S 56.66 3.46 9.01
EtOH/Benzene Orange (466.35) 56.71 3.44 9.12
4e 193-195 71 C22H16ClN3O2S 62.63 3.82 9.96
AcOH Yellow (421.90) 62.43 3.72 9.91
4f 191-193 74 C23H19N3O2S 68.81 4.77 10.47
AcOH Yellow (401.48) 68.62 3.63 10.32
5a 271-273 75 C18H13N3O3S 61.53 3.73 11.96
Acetic acid Pale yellow (351.38) 61.43 3.67 11.92
5b 235-237 83 C25H19N3O3S 68.01 4.34 9.52
AcOH Yellow (441.50) 68.18 4.28 9.43
5c 289-290 78 C24H17N3O3S 67.43 4.01 9.83
DMF Yellow (427.48) 67.33 3.98 9.87
5d 306-308 75 C24H16BrN3O3S 56.93 3.18 8.30
DMF Pale Yellow (506.37) 56.92 3.02 8.24
5e 273-275 80 C24H16ClN3O3S 62.40 3.49 9.10
AcOH Pale Yellow (461.92) 62.34 3.44 9.21
5f 220-221 77 C25H19N3O3S 68.01 4.34 9.52
AcOH Pale Yellow (441.50) 68.12 4.29 9.41
6 238-240 63 C22H19N3O5S 60.40 4.38 9.61
Benzene Yellow (437.47) 60.35 4.36 9.57
7a 325-327 65 C31H21N3O3S 72.22 4.11 8.15
DMF Yellow (515.58) 72.12 4.06 8.04
7b 328-330 70 C32H23N3O4S 70.44 4.25 7.70
DMF Yellow (545.61) 70.32 4.31 7.65
7c 320-322 68 C24H16ClN3O3S 67.69 3.67 7.64
DMF Yellow (547.81) 67.52 3.71 7.53
9a 268-270 80 C24H17N3O2S 70.05 4.16 10.21
DMF Yellow (411.48) 70.12 4.20 10.22
9b 258-260 62 C31H19N3O4S 70.31 3.62 7.93
DMF Red (529.59) 70.25 3.57 7.85
11a 278-280 80 C25H18N4O3S 66.07 3.99 12.33
EtOH/Benzene Yellow (454.50) 66.05 3.83 12.24
11b 246-248 68 C26H19ClN4O4S 60.17 3.69 10.80
EtOH/Benzene Yellow (518.97) 60.11 3.63 10.73
11c 248-250 75 C30H20N4O3S 69.75 3.90 10.85
EtOH/DMF Yellow (516.57) 69.64 3.86 10.81
11d 280.282 77 C31H22N4O3S 70.19 4.18 10.56
Dioxane Pale yellow (530.60) 70.11 4.08 10.48
9b 258-260 62 C31H19N3O4S 70.31 3.62 7.93
DMF Red (529.59) 70.25 3.57 7.85
11a 278-280 80 C25H18N4O3S 66.07 3.99 12.33
EtOH/Benzene Yellow (454.50) 66.05 3.83 12.24
11b 246-248 68 C26H19ClN4O4S 60.17 3.69 10.80
EtOH/Benzene Yellow (518.97) 60.11 3.63 10.73
11c 248-250 75 C30H20N4O3S 69.75 3.90 10.85
EtOH/DMF Yellow (516.57) 69.64 3.86 10.81
11d 280.282 77 C31H22N4O3S 70.19 4.18 10.56
Dioxane Pale yellow (530.60) 70.11 4.08 10.48

3.4. 3-Substituted-2-({1-benzocoumarin-3`-yl]ethylidene}-hydrazono)thiazolidin-4-one 5a-e

A mixture of (4a-e) (0.01 mol), ethyl bromoacetate (0.01 mol) and fused sodium acetate (0.02 mol) in ethanol (40 ml) was refluxed for 2h. The obtained product was filtered off, washed with water (50 ml) and recrystallized from the proper solvent to give (5a-e), (Table 2).

Table 3. Spectral data of synthesized compounds.

Compd. No. IR (ν, cm-1) 1HNMR (d, ppm) (DMSO-d6)
2a 3194 (NH), 1710 (C=O) and 1323 (C=S). 2.45 (s, 3H, CH3-C=N), 2.70 (s, 3H, SCH3), 7.47-8.35 (6H, m, Ar-H), 9.01 (s, 1H, benzo-coumarin H-4) and 10.05 ppm (s, 1H, NH).
2b 3246 (NH), 1707 (C=O) and 1265 (C=S).  
3 3247 (NH) and 1708 (C=O).  
4a 3405, 3246, 3154 (NH,NH2), 1719 (C=O).  
4c 3147 (NH), 1727 (C=O) and 1343 (C=S). 2.42 (s, 3H, CH3-C=N), 7.18-8.17 (m, 11H, Ar-H), 9.16 (s, 1H, benzocoumarin H-4) and 10.27 & 10.87 ppm (2s, 2H, 2NH exchangeable with D2O).
4e 3196 (NH), 1711 (C=O) and 1340 (C=S).  
5a 3163 (NH), 1712 (C=O).  
5c 1722 (C=O), 1600 (C=N). 2.18 (s, 3H, CH3-C=N), 3.14 (s, 2H, CH2CO), 7.43-8.49 (m, 11H, Ar-H) and 8.93 ppm (s, 1H, benzocoumarin H-4).
6 1709 (C=O), 1627 (C=N). 1.33 (t, 3H, CH2-CH3), 2.48 (s, 3H, CH3-C=N), 3.88 (s, 2H, >N-CH2), 4.27 (2H, q, CH2-CH3), 4.59 (s, 2H, CH2CO), 7.45-8.32 (m, 6H, Ar-H) and 8.95 ppm (s, 1H, benzocoumarin H-4).
9a 3166 (NH) and 1727 (C=O).  
9b 3148 (NH) and 1716 (C=O).  
11a 1726 (C=O; δ lactone) and 1684 (C=O; CH3CO). 2.57 (s, 3H, CH3-C=N), 2.65 (s, 3H, COCH3), 7.36-8.32 (m, 11H, Ar-H) and 8.97 ppm (s, 1H, benzocoumarin H-4).
11b 1724 (C=O). 1.43 (t, 3H, CH2-CH3), 2.57 (s, 3H, CH3-C=N), 4.47 (q, 2H, CH2-CH3), 7.45-8.10 (m, 10H, Ar-H) and 8.93 ppm (s, 1H, benzocoumarin H-4).
11c 1724(C=O).  

3.5. 4-Oxo-2-{[1-(benzocoumarin-3`-yl)-ethylidene]-hydrazono} thiazolidin-3-yl) acetic acid ethyl ester (6)

3.5.1. Method A

A mixture of (5a; 0.01 mol), fused sodium acetate (0.02 mol) and ethyl bromoacetate (0.01 mol) in ethanol (30 ml) was refluxed for 3h, after cooling the solid which formed was collected and recrystallized from benzene to give (6) (63%) as yellow crystals, m. p. 238-240°C.

3.5.2. Method B

A mixture of (5a; 0.01 mol), ethyl bromoacetate (0.02 mol) and fused sodium acetate (0.02 mol) in ethanol (50 ml) was refluxed for 3h, after cooling, the obtained product was collected and recrystallized from benzene to give (6) in yield (74%), m. p. and mixed m. p. with product from procedure (A) gave no depression.

3.6. 3,5-Disubstituted-2-{[benzocoumarin-3`-yl]ethyl-idene]hydrazono}thiazolidin-4-one 7a-c

A mixture of (5a; 0.01 mol), the appropriate aromatic aldehydes and / or arylidenemalononitrile (0.0.1 mol) in dioxane (30 ml) and few drops of piperidine was refluxed for 3h, the solid product was collected by filtration and recrystallized from DMF to give 7a-c, (Table 2).

3.7. 4-Substituted-2-({1-Benzocoumarin-3`-yl]Ethylidene}-Hydrazono)Thiazole 9a,b

A mixture of (4a; 0.01 mol) and phenacyl bromide or bromoacetyl-benzocoumarin20 (0.01 mol) in ethanol (50 ml) was refluxed for 2hrs, the solid product which formed on heating was collected by filtration and recrystallized from the appreciate solvent to give 9a,b, (Table 2).

3.8. Reaction of 2a,b with Hydrazonoyl Halides

A mixture of (2a,b; 0.01 mol) and the appropriate hydrazonoyl halide 10a-d (0.01 mol) in ethanol (50 ml) triethylamine (0.5 ml) was added [21-23]. The reaction mixture was refluxed for 3h. The resulting product was collected by filtration and recrystallized from the proper solvent to give 11a-d, (Table 2).

4. Conclusions

In this study, N-[1-(benzocoumarin-3`-yl)ethylidene]-hydrazineecarbodithioate (2) it is very good starting material for the synthesis of 1,3,4-thiadiazole,thiazolidinone and thiazole derivatives which containing coumrin moiety which posses biological activity. However further studies are needed to complete these study for the biological activity.


References

  1. S. Wawzonek, Heterocyclic Compounds,2, 173, (1975).
  2. F. M. Dean, Naturally occurring oxygen ring compounds, (Butter Worths, London) 176, 1963.
  3. R. Livingstone, Rod's Chemistry of carbon compounds, Vol. 4, 2nd Edn (Elsevier, Amsterdam) 1996.
  4. A. R. Kartritzky, C. W. Rees; Comprehensive heterocyclic chemistry vol. 3 (Bergaman Press, Oxford) (1984).
  5. J. Starnoton, comprehensive organic chemistry Vol. 4, edited by DHR Barton, W D Ollis (Pergaman Press, Oxford 629, (1979).
  6. M. D. Freiendmann, P. L. Stoller, T. H. Porter, and K. J. Folkevs; J. Med. Chem., 16, 1314 (1973).
  7. A. S. Hamam, and H. S. El-Kasher, Egyptian Pharmaceutical Congress Cairo, 7-10 Dec. (1975).
  8. R. D. Westl, M. H. Lin, Cooly (Jr) R. A. Zuviester M. L., and M. M. Grenan, J. Med. Chem., 16, 328 (1973).
  9. P. S. Furmer, C. C. Heung, and M. K. Luie, J. Med. Chem., 16, 411 (1973).
  10. M. S. Y. Khan and P. Sharma, Indian. J. Chem., 32B, 374 (1993).
  11. D. I. Brahmbhatt, G. B. Radji, S. U. Pandya, and U. R. Pandya; Indian J. Chem., 38B, 212 (1999).
  12. M. S. Y. Khan and P. Sharma, Indian J. Chem., 34B, 237 (1995).
  13. H. Sun, W. Hua and L. Chen, Bull. Soc. Chem. Belg., 106, 47 (1997).
  14. H. Sun, W. Hua and L. Chen,Chem. J. Chin. Univ., 18, 730 (1997).
  15. G. S. S. Murthi, M. Basak, J. Indian Chem. Soc. 70 (2), 170 (1993).
  16. D. L. Klayman, J. F. Bartosevichm, T. S. Griffin, C. J. Mason and J. P. Scovill; J. Med. Chem., 22, 855 (1979).
  17. J. Korosi, Ger. Offen. 1, 934, 89929 Jan (1979), C. A. 72, 100334s (1970).
  18. U. Verabhadra and V. Rajeswar, J. Indian Chem. Soc., 67 (1), 81 (1990).
  19. V. Yakazakov and I. Ya Potovski, Inv. Yashikucheb. Zavedii Khim. Ikhim. Technol. 4, 238 (1961) C. A., 55, 23415 (1961).
  20. P.Czerny and H. Hartmann, J. Prakt. Chem., 325, 551 (1983).
  21. N. F. Weiss and A. O. Abdelhamide, J. Heterocycl. Chem.,17, 1713 (1980).
  22. M. Nagakura, T. Ota, N. Shimadzu, K. Kawamura, Y. Eto; and Y. Wada, J. of Med. Chem., 22, 48 (1979).
  23. A. S. Shawali and A. O. Abdelhamide, Bull. Soc. Japan, 49, 321 (1976).

Article Tools
  Abstract
  PDF(400K)
Follow on us
ADDRESS
Science Publishing Group
548 FASHION AVENUE
NEW YORK, NY 10018
U.S.A.
Tel: (001)347-688-8931