Synthesis and Antibacterial Studies of 2-Pyrazoline based Bis Heterocycles
K. Babu
PG and Research Department of Chemistry, Rajah Serfoji Government College (Auto), Thanjavur, Tamil Nadu, India.
*Corresponding Author E-mail: kbabu.chemistry@gmail.com
ABSTRACT:
Here in, I have described synthesis, spectral characterization and antibacterial activities of some novel five membered bis-heterocyclic compounds comprising both 2-pyrazoline and pyrazole related moiety. The target products were obtained by applying well known reactions such as, aldol condensation, diazotization, diazocoupling and cyclisation reactions. The structures of synthesized compounds were confirmed by the help of Melting point, TLC, FT-IR, 1H-NMR and 13C-NMR spectra. The invitro antibacterial activities were examined and most of the compounds showed very good inhibition zone against selective bacteria.
KEYWORDS:Diazotization, Active methelene compounds, Aldol condensation, coupling reaction, Pyrazoline.
Five-membered heterocyclic compounds occupy an important place in the realm of natural and synthetic organic chemistry and are occurred widely in the form of alkaloids, vitamins, pigments, constituents of plants and animal cells. Among these, Pyrazoline based five membered heterocycles plays a crucial role in the development of theory of heterocyclic chemistry and is also extensively used as synthons in organic synthesis [1-8]. The 2-pyrazoline heterocycles are synthesized by using various synthetic methods and are described in the literature [9-11]. However, the most common and popular procedure is reaction between α,β-unsaturated aldehydes or ketones with different hydrazines .[12-17]. Furthermore, literature survey revealed that their broad spectrum of biological activities such as antibacterial [18-21] antifungal [22-24], anti-inflammatory [25], analgesic [26], antipyretic [27], insecticidal [28], diuretic [29], cardiovascular [30] and antidepressant activities [31-33].
In this regard, I have focused on the synthesis of novel pyrazoline and related compounds, thereby already contributing the research towards biologically important heterocycles [34-35]. In the current study, the aim was to obtain new bis heterocycles containing both pyrazoline and pyrazoline related moiety in a structure in order to enhance their biological activities.
MATERIAL AND METHODS:
General: All the chemicals required for research were purchased from Avra, Loba, and S.D fine chemicals (India). Melting points are uncorrected. Infrared spectra were recorded on a Perkin-Elmer Paragon 1000 FTIR spectrophotometer as potassium bromide pellet. 1H-NMR and 13C-NMR spectra were obtained on a Brucker (300MHz) instrument in CDCl3 solutions using tetramethylsilane (TMS) as an internal standard and chemical shift values are given in δ ppm.
Procedure for preparation of Chalcone 3:
A mixture of 0.01mol p-Aminoacetophenone 1 and 0.01mol of p-Methoxybenzaldehyde 2were taken in conical flask. To this mixture, 20 ml ethanol and 5 ml 40% aqueous NaOH were added. This mixture was stirred for 2 hour continuously at room temperature and reaction monitored by TLC. After completion of the reaction, the mixture was poured in to crushed ice and acidified with dilute hydrochloric acid. The yellow color solid was filtered, dried and recrystallized from ethanol.
Procedure for preparation of Aryl diazoniumchloride salt 4:
The 2g chalcone 3 was dissolved in 5 mL conc HCl which was heated to get complete dissolution. The clear solution was diazotized below 5°C with sodium nitrite solution (1g) for 30 min.
General procedure for preparation of coupling products 6a-d:
The cold diazonium solution obtained from above step was added slowly to the ice cold solution of various active methelene compounds (2mL) in ethanol containing sodium acetate (1g) over the course of 30 min. During the addition process solid formed which was stirred vigorously to complete the reaction. After complete addition, small amount of urea was added to decompose the unreacted nitrous acid. The product was collected by vacuum filtration and pure product obtained by recrystalization of crude sample in ethanol.
General procedure for preparation of Bis heterocycles 7a-d:
The coupling products 6a-d (1 equivalent)andphenyl hydrazine hydrochloride (2 equivalents) were refluxed in ethanol with catalytic amount of acetic acid by using round bottom flask. The reaction mixture was refluxed for 3-4 hrs and the progress of the reaction was monitored by TLC. After completion of the reaction, the content were cooled and poured into crushed ice, the solid formed was filtered, washed with water and recrystalyzed from ethanol.
Spectral data of selected coupling products and Bis heterocycles:
Ethyl 2-(2-(4-((Z)-3-(4-methoxyphenyl)acryloyl) phenyl)hydrazono)-3-oxobutanoate (6a):
FT-IR (KBr, cm-1): 3364.42 (NH), 3003.03 ( Ar-CH), 2927.05 (Aliphatic-CH), 1658.21 (CO), 1689.70 (Ester-involved in H-bond), 1604.30 (C=N), 1251.02 (Ar-C-N), 1H-NMR (CDCl3, δ): 1.39-1.43 (t, 3H, CH3), 2.53 (s, 3H, COCH3), 3.86 (s, 3H, OCH3), 4.39-4.40 (q, 2H, CH2), 6.93-6.95 (d, 1H, CH), 7.60-7.63 (d, 1H, CH), 7.26-8.11 (8H, Ar-CH), 12.77 (s, 1H, NH); 13C-NMR (CDCl3,δ), 14.10 (CH3), 26.94 (COCH3), 55.45 (OCH3), 61.78 (CH2), 114.45, 115.13, 119.23, 130.27, 130.49 (8Ar-CH), 127.63, 134.63, 144.56 (CH-Olefin), 144.49 (CH-olefin), 161.72 (4Ar-C), 163.48 (COO), 188.64 (COCH), 194.44 (COCH3).
Ethyl 2-cyano-2-(2-(4-((Z)-3-(4-methoxyphenyl) acryloyl)phenyl)hydrazono)acetate (6b):
FT-IR (KBr, cm-1): 3424.13 (NH), 3064.33 ( Ar-CH), 2920.01 (Aliphatic-CH), 2222.90 (-CN), 1659.91 (CO), 1719.36 (Ester), 1601.89 (C=N), 1255.80 (Ar-C-N); 1H-NMR (CDCl3, δ): 1.39-1.42 (t, 3H, CH3), 3.86 (s, 3H, OCH3), 4.35-4.41 (q, 2H, CH2), 6.94-6.96 (d, 1H, CH), 7.63-7.64 (d, 1H, CH), 7.46-8.11 (8H, Ar-CH), 13.18 (s, 1H, NH); 13C-NMR (CDCl3,δ), 14.39 (CH3), 55.44 (OCH3), 61.64 (CH2), 143.97 (CH-Olefin), 144.55 (CH-olefin), 114.46, 115.74, 116.76, 119.12, 129.94, 130.31, 130.39, (8Ar-CH), 127.40, 127.55, 134.10 (4Ar-C), 161.60 (COO), 188.64 (COCH).
3-(2-(4-(3-(4-methoxyphenyl)acryloyl)phenyl) hydrazono)pentane-2,4-dione (6c):
FT-IR (KBr, cm-1): 3333.88 (NH), 3018.02 ( Ar-CH), 2970.95 (Aliphatic-CH), 1677.70 (CO), 1603.70, 1294.79 (Ar-C-N), 1H-NMR (CDCl3, δ): 2.54 (s, 3H, COCH3), 2.64 (s, 3H, COCH3), 3.88 (s, 3H, OCH3), 6.95-6.97 (d, 1H, CH), 7.62-7.64 (d, 1H, CH), 7.28-8.13 (8H, Ar-CH), 14.65 (s, 1H, NH); 13C-NMR (CDCl3,δ), 26.70 (COCH3), 31.83 (COCH3), 55.45 (OCH3), 144.76 (CH-Olefin), 144.90 (CH-olefin), 114.47, 115.88, 119.17, 127.58, 130.30, 130.43 (8Ar-CH), 134.19, 135.45, 161.67 (4Ar-C), 188.65 (COCH), 197.08 (COCH3), 198.40 (COCH3).
(4-(2-(4-(5-(4-methoxyphenyl)-1-phenyl-4,5-dihydro-1H-pyrazol-3yl)benzyl)hydrazono)-3-methyl-1-phenyl -1H-pyrazol-5(4H)-one (7a):
FT-IR (KBr, cm-1): 3400.00 (NH), 3029.78 (Ar-CH), 2921.45 (Aliphatic-CH), 1251.73 (Ar-C-N), 1657.70 (N-CO); 1H-NMR (CDCl3, δ): 2.38(s, 3H, CH3), 3.88 (s, 3H, OCH3), 3.10-3.20 (dd, 1H, C4-H, Pyrazoline) 5.50-5.15 (dd, 1H, C4-H, Pyrazoline), 5.20-5.30 (dd, 1H, C5-H, Pyrazoline), 6.76-7.98 (m, 14H, Ar-CH), 13.67 (s, 1H, NH); 13C-NMR (CDCl3,δ), 14.26 (CH3), 43.05 (CH2, C4-C, Pyrazoline ), 55.33 (OCH3), 61.34 (CH, C5-C, Pyrazoline), 114.20, 114.79, 115.18, 115.74, 117.50, 1227.46, 128.34, 1128.79, 129.02, 129.64, 130.38, 130.68, 139.30, 143.59, 152.50, 157.32, 157.76, 160.50 (24 Ar-C), 165.95 (CO).
3-amino-4-((4-(5-(4-methoxyphenyl)1-phenyl-4,5-dihydro-1H-pyrazol-3yl)benzyl)diazenyl)-1-phenyl-1H-pyrazol-5(4H)-one (7b):
FT-IR (KBr, cm-1): 3064.82 (Ar-CH), 2924.37 (Aliphatic-CH), 1604.57 (C=N), 1511.18, 1244. 18 (Ar-C-N), 1H-NMR (CDCl3, δ): 3.77 (s, 3H, OCH3), 3.00-3.10 (dd, 1H, C4-H, Pyrazoline) 4.34-4.41 (dd, 1H, C4-H, Pyrazoline), 5.22-5.27 (dd, 1H, C5-H, Pyrazoline), 6.77-7.73 (m, 14H, Ar-CH), 9.50 (s, 1H, NH), 13.21 (s, 2H, NH2);13C-NMR (CDCl3,δ), 45.45 (C4-C, Pyrazoline), 55.29 (OCH3), 62.45 (CH2, C5-C, Pyrazoline), 104.57, 104.75, 113.45, 114.04, 114.53, 115.32, 115.90, 115.90, 115.99, 115.12, 119.27, 125.49, 127.03, 127.28, 128.94, 129.06, 130.07, 130.45, 130.73, 134.40, 140.18, 140.56, 144.55, 145.64, 159.02 (24 Ar-C), 162.54 (CO).
(4-((4-(5-(4-methoxyphenyl)-1-phenyl-4,5-dihydro-1H-pyrazol-3-yl)benzyl)diazenyl)-3,5-dimethyl-1-phenyl-1H-pyrazole (7c):
FT-IR (KBr, cm-1): 3044.30( Ar-CH), 2970.62 (Aliphatic-CH), 1214.13(Ar-N), 1571.04 (C=N); 1H-NMR (CDCl3, δ): (s, 3H, CH3), 2.60 (s, 3H, CH3), 3.89 (s, 3H, OCH3), 3.20 (dd, 1H, C4-H, Not clear which merged with DMSO water), 4.60-4.65 ( dd, 1H, C4-H), 5.20-5.30 (dd, 1H, C5-H, Pyrazoline) 6.90-8.24 (m, 14H, Ar-CH); 13C-NMR (CDCl3,δ), 26.65 (CH3), 31.66 (CH3), 42.0 (C4-C, Pyrazoline), 55.34 (C5-C, Pyrazoline), 55.47 (OCH3), 105.05, 113.87, 114.24, 116.32, 116.62, 127.04, 127.64, 127.77, 128.05, 128.22, 128.90, 129.06, 129.32, 155.90, 159.35, 159.56, 164.39 (24 Ar-C).
RESULTS AND DISCUSSION:
This work explains about synthesis of some novel bis heterocyclic derivatives by using following synthetic steps. The p-Aminoacetophenone 1 reacts with p-Methoxybenzaldehyde 2 produced chalcone 3. Diazoniumchloride 4 is formed by diazotization of 3 by using well known procedure which further coupled with various active methelene compounds 5a-d such as Ethylacetoacetate, Ethylcyanoacetate, Acetylacetone and Malononitrileproducedcorresponding coupling products 6a-d. The final bis heterocyclic compounds 7a-7d obtained by cyclisation of 6a-d with phenylhydrazine hydrochloride in ethanol under reflux condition.
Table-1: Physical data of coupling products 6a-d and bis heterocycles 7a-d
|
Comp. code |
Yield (%) |
Mp (oC) |
Color |
Rf value (Hex: EA, 2:1) |
|
6a |
96 |
184-186 |
Pale yellow |
0.61 |
|
6b |
90 |
164-166 |
Dark yellow |
0.67 |
|
6c |
90 |
180-182 |
Dark yellow |
0.60 |
|
6d |
85 |
148-1150 |
Dark yellow |
0.50 |
|
7a |
72 |
140-142 |
Brown |
0.58 |
|
7b |
75 |
218-220 |
Brown |
0.48 |
|
7c |
70 |
200-202 |
Brown |
0.47 |
|
7d |
65 |
106-108 |
Brown |
0.40 |
The physical data such as, melting point, Color, Rf values (Table-1) and spectral data such as, FT-IR, 1H-NMR and 13C-NMR were well supported the formation of the desired products (detailed data given in experimental section). Antibacterial activity of some selected compounds 6a, 7a-d were examined and observed very good response with bacteria (Table-2).
Table-2: Antibacterial activity data of coupling product 6a and bis heterocycles (7a-d)
(Compounds 6a and 7a-d are kept in clockwise direction from empty disk)
|
S. No. |
Sample |
Zone of Inhibition (mm in diameter), Std: Gentamicin (10 µg) |
|||
|
E. coli |
Pseudomonas aeruginosa |
Bacillus subtilis |
Staphylococcus aureus |
||
|
1 |
Std |
08 |
18 |
20 |
18 |
|
2 |
Empty |
- |
- |
- |
- |
|
3 |
6a |
16 |
14 |
16 |
22 |
|
4 |
7a |
15 |
16 |
18 |
12 |
|
5 |
7b |
11 |
18 |
19 |
10 |
|
6 |
7c |
16 |
18 |
19 |
26 |
|
7 |
7d |
18 |
20 |
19 |
28 |
CONCLUSION:
I reported synthesis of some novel pyrazoline based bis-heterocycles and were obtained in very good yield by applying simple procedures. The obtained spectral data were well supported the structures and biological study revealed that their very good antibacterial activity against bacteria.
ACKNOWLEDGMENT:
I express my sincere thanks to HOD Department of chemistry and Principal Rajah Serfoji Government College for providing lab facilities.
REFERENCES:
1. Bhaskar reddy D, Padmaja A, Ramanareddy PV, Seenaiah B. Sulfur Lett 1993; 16: 227.
2. Klimova EI, Marcos M, Klimova TB, Cecilio AT, Lena RR. J Organometallic Chem 1999; 585: 106.
3. Bhaskarreddy D, Chandrasekhar BN, Padmavathi V, Sumathi RP. Synthesis, 1998; 491-495.
4. Sobhia HR, Yaminib Y, Esrafili A, Adiba M. J Pharm Biomed Anal. 2008; 45:316-320.
5. Nauduri D, Reddy GB, Chem Pharm. Bull. Tokyo, 1998; 46: 1254.
6. BS Vikram, T Srinivas Rao K Ramesh; Asian J. Research Chem. 2009; 10(6): 285-288 micro)
7. Sharma Bindiya, Jain Anamika, Sharma Dipak, Dubey Arti; Asian J. Research Chem. 5(1):2012; Page 103-107
8. Sivagurunathan K., S. Raja Mohamed Kamil; Asian J. Research Chem. 5(3): March 2012; Page 401-404
9. Parjanya Kumar Shukla, Amita Verma, Prateek, Pragya Mishra; Asian J. Research Chem. 2017; 10(6):771-782
10. Vijay N. Bhosale, Gopinath S. Khansole, Jaman A. Angulwar, Sunil S. Choudhare, Ashok R. Karad, Navanand Wadwale Asian J. Research Chem. 2017; 10(6):745-749.
11. Dipali Uthale, S. K. Mohite; Asian J. Research Chem 7(1): January 2014; Page 58-61
12. Manna, F., Chimenti, F., Bolasco, A., Secci, D., Bizzarri, B., Befani, O., Turini, P., Mondovi, B., Alcaro, S., Tafi, A.Bioorg. Med. Chem. Lett.2002,12, 3629-3633.
13. Levai, A., Patonay, T., Silva, A.M.S., Pinto, D.C.G.A., Cavaleiro, J.A. Heterocyclic Chem.2002,39, 751-758.
14. Levai, A. Heterocycl. Commun.2003,9, 287-292.
15. Cirilli, R., Torre, F.J. Med. Chem.2004,47, 2071-2074 .
16. Chimenti, F., Bizzarri, B., Manna, F., Boalsco, A., Secci, D., Chimenti, P., Granese, A., Rivanera, D., Lilli,, Scaltrito, M.M., Brenciaglia, M.I.Bioorg.Med.Chem.Lett.2005,15, 603-607.
17. Korgaokar SS, Patil PH, Shah MT, Parekh HH, Indian J. Pharm. Sci. 1996;58: 222.
18. K.Babu and K.Tharini. Asian Journal of Chemistry, 29, 1, 2017, 187-190.
19. Sk. Shaheda Sultana, P. Parveen, P. Usha, V. Vasu Naik, Rajesh Akki, M. Gayatri Ramya. Asian J. Research Chem 7(1): January 2014; Page 33-40
20. Pratap Kumar Patra, Ch. Niranjan Patra, Subasini Pattnaik. Asian J. Research Chem 7(1): 2014; Page 92-98
21. Udupi RH, Kushnoor AR, Bhat AR, Indian J. Heterocyclic Chem. 1998; 8:63.
22. Delay F (S. A Fermeinch) Patentschriff (Switz), C.A. 1992; 117:90276f.
23. Geigy JR, Belg, 466668, Aug.31, 1942; C.A., 1945; 39:7848.
24. Minakshi Shroff, S. J. Daharwal, Yashwant Swarnakar. Research J. Pharm. and Tech. 2017; 10(3): 677-682.
25. Reddy DB, Senshama T, Ramma Reddy BMV, Indian J. Chem., 1991;30(B), 46.
26. Zalgislaw K. Zbigniew, Acta.Pol Pharm, 1979; 36(6), 645:C.A., 1980; 93:204525e.
27. Mrs. Kokila Parmar, Kamlesh Kundariya , Prajapati and Rinku Patel; Asian J. Research Chem. 5(5): May 2012; Page 571-575
28. Yamashita, Hiroyuti, Odata Mocoto, Kawazara Hirahi., Eur. Patent appl.Ep1988; 295695CL.Co7D401/6) J. P. Appl.,1987;87/148919,C.A, 1989; 111:2351
29. Kokila Parmar, Kamlesh Kundariya, Sarju Prajapati, Rinku Patel; Asian J. Research Chem. 5(5): May 2012; Page 571-575
30. Bauer A.N., Kirby W.N.M., Sherries J.C., Truck M.: Am. J. Clin. Pathol. 1996, 45, 493.
31. Seebacher, W.; Michi, G.; Belaj, F.; Saf, R.;Weis, R. Tetrahedron 2003, 59, 2811-2819.
32. Kidwai, M.; Mishra, P. Synth. Commun. 1999, 29, 3237, 3250.
33. Babu. K, P. Pitchai, M. Sathiyaseelan and A. Nepolraj. Der Pharma Chemica, 2015, 7(6):95-98.
34. Babu K., Pitchai P. and Gengan R. M; J. Chem. Pharm. Res., 2015, 7(12):275-278.
35. K. Babu, D. Selvi and P. Pitchai. Der Pharma Chemica, 2015, 7 (10):89-92.
Received on 12.01.2018 Modified on 03.02.2018
Accepted on 28.02.2018 © AJRC All right reserved
Asian J. Research Chem. 2018; 11(2):319-328.
DOI:10.5958/0974-4150.2018.00059.7