Synthesis of some novel and biologically active schiff bases bearing a 1,3,4-thiadiazole moiety under acidic and PTC conditions

Article abstract of DOI:10.4067/S0717-97072011000300020

The synthesis of some new Schiff bases bearing a 1,3,4-thiadiazole moiety, 3a-l, by reaction of 2-amino-5-mercapto-1,3,4-thiadiazole with aromatic aldehydes under acidic and phase transfer catalyst (PTC) conditions was studied. The structure of all the Schiff bases was characterized using FT-IR and NMR spectroscopy, and elemental analyses. The antibacterial activity of these compounds was investigated against Staphylococcus aureus (RTCC, 1885), and Escherichia coli (ATCC, 35922).

Full text of DOI:10.4067/S0717-97072011000300020

J. Chil. Chem. Soc., 56, Nº 3 (2011)
SYNTHESIS OF SOME NOVEL AND BIOLOGICALLY ACTIVE SCHIFF BASES BEARING A
1,3,4-THIADIAZOLE MOIETY UNDER ACIDIC AND PTC CONDITIONS
A. MOBINIKHALEDI*,1 M. JABBARPOUR1 AND A. HAMTA2
1Department of Chemistry, Faculty of Science, Arak University, Arak 38156-8-8349, Iran
2Department of Biology, Faculty of Science, Arak University, Arak 38156-8-8349, Iran
(Received: March 31, 2011 - Accepted: May 31, 2011)
ABSTRACT
The synthesis of some new Schiff bases bearing a 1,3,4-thiadiazole moiety, 3a-l, by reaction of 2-amino-5-mercapto-1,3,4-thiadiazole with aromatic aldehydes
under acidic and phase transfer catalyst (PTC) conditions was studied. The structure of all the Schiff bases was characterized using FT-IR and NMR spectroscopy,
and elemental analyses. The antibacterial activity of these compounds was investigated against Staphylococcus aureus (RTCC, 1885), and Escherichia coli
(ATCC, 35922).
Key words: Schiff base, 1,3,4-thiadiazole, biological activities, PTC
Synthesis of Schiff bases 3a-l with PTC
INTRODUCTION
A mixture of 2-amino-5-mercapto-1,3,4-thiadiazole 1 (1 mmol), the
corresponding aromatic aldehyde 2 (1 mmol) and benzyl triethylammonium
chloride (BTEAC, 10 mol%) was heated in an oil bath at 90 ºC for an
appropriate time as presented in Table 1. The liquid mixture was cooled to
room temperature to give a solid mass after 5-20 min, which was washed with
H2O/EtOH (1:1, 10 ml) to give the pure product 3.
There has been considerable attention to the chemistry of Schiff bases
because of their wide range of applications in many fields including biological,
organic, inorganic and analytical chemistry. They are used as pigments,
dyes, catalysts, intermediates in organic and inorganic synthesis and polymer
stabilizers.1-4 Schiff bases containing heterocyclic rings are known to show
cytotoxic, anticonvulsant, antimicrobial, anticancer, antifungal, antimalarial,
antiviral, antidepressant and enzyme inhibitor activities.5-11 Furthermore, some
Schiff bases are used in ion sensors and electrochemical sensors to empower
detection with enhanced selectivity and sensitivity.12,13
Due to the importance and diverse structural aspects of Schiff bases,
several methods and procedures have been reported for synthesis of these
compounds.14-19 These methods usually involve the straightforward acid-
catalyzed reaction of a primary amine and a carbonyl group in organic solvents.
However, in spite of their advantages, most of them use procedures in which
the chemical safety and yields of products are the main considerations. Hardly
ever has attention been concentrated on the fact that some of these established
methods use toxic solvents, special apparatus, or strong acid conditions.
Consequently, in order to overcome these limitations, the introduction of more
efficient methods for the synthesis of Schiff bases is still a challenge. Recently,
significant research has been directed toward the solvent-free reaction in
order to improve classical procedures and make them cleaner and easier to
carry out.20,21 Keeping these reports in mind and also due to our interest in the
synthesis of Schiff bases16,22-24 we wished to study the synthesis of some novel
and biologically active Schiff bases bearing a 1,3,4-thiadiazole moiety under
both solvent-free and acidic conditions.
Antibacterial study
The agar diffusion test, or Kirby-Bauer disk-diffusion method was used
for this purpose. Each chemically synthesized material (5 mg) was dissolved
in 250 µl of DMSO and 100 µl of the solution of the test compounds was
introduced onto the disks (0.7 cm diameter). The disks were then placed on
top of the medium previously inoculated with the bacteria. 100 µl of solvent
(DMSO) was added to another disk and implanted as a negative control on
each plate along with the standard drugs. The plates were incubated overnight
at 37°C. The inhibition zones were measured and compared with the controls.
For the zone size interpretations were used recommendations of the National
Committee of Clinical Laboratory Standards (NCCLs). The results are given
in Table 2.
2-(Benzylideneamino)-5-mercapto-1,3,4-thiadiazole (3a). m.p 259-261
˚C. IR (KBr): νmax 3043 (CHaromatic), 1606 (C=N), 1572 (C=C). 1H-NMR: δH
14.56 (s, 1H, S-H) 8.73 (s, 1H, CH=N), 7.68-7.45 (m, 5H, Haromatic), 13C-NMR:
δC 193.5 (C-N), 169.3 (Cimine), 135.0 (C-S), 130.4, 129.9, 129.5, 129.3 (CHarom).
Anal. Calcd for: C H N3S2, C, 48.85; H, 3.19; N, 18.99; S, 28.98%. Found: C,
48.65; H, 3.01; N, 9197.18; S, 29.25%.
2-(2-Hydroxybenzylideneamino)-5-mercapto-1,3,4-thiadiazole (3b).
EXPERIMENTAL
1
m.p 252-254 ˚C. IR (KBr): ν 3070 (CHaromatic), 1562 (C=N). H-NMR: δH
14.54 (s, 1H, S-H) 11.14 (s, 1mHax, OH), 8.86 (s, 1H, CH=N), 7.86-6.95 (m, 4H,
Haromatic), 13C-NMR: δC 192.4 (C-N), 181.3 (CHaromatic), 161.9 (Cimine), 161.1 (C-
S), 136.8, 129.9, 122.6, 119.9, 117.6 (CHaromatic). Anal. Calcd for: C H N OS2,
C, 45.55; H, 2.97; N, 17.71; S, 27.02%. Found: C, 45.60; H, 2.71;9N7, 137.95;
S, 27.26%.
All reagents were commercially available without further purification.
Melting points were determined with an Electrothermal WRS-1B apparatus.
The IR spectra were recorded on a Galaxy FTIR 5000 spectrometer using
KBr discs. The NMR spectra were recorded on a Bruker Avance spectrometer
(300 MHz) using DMSO-d6 as a solvent and TMS as an internal standard.
Microanalyses were performed using the (Elemental, Vario EL III) Elemental
Analyzer at Arak University. Reactions were monitored by thin layer
chromatography (TLC) using silica gel F -coated aluminum sheets (Merck).
The microbial strains, Staphylococcus 25a4ureus (RTCC, 1885) and and
Escherichia coli (ATCC, 35922) were obtained from the Pasteur Institute of
Iran. The culture medium was Mueller Hinton Agar (MH).
2-(2-Methoxybenzylideneamino)-5-mercapto-1,3,4-thiadiazole (3c).
m.p 148-149˚C. IR (KBr): νmax 3003 (CH
), 2937- 2835 (CHaliphatic), 1599
(C=N). H-NMR: δH 14.51 (s, 1H, S-H), a8ro.m8a2tic (s, 1H, CH=N), 7.78-7.00 (m,
4H, Haromatic), 3.86 (s, 3H, CH3), 13C-NMR: δC 189.5 (C-N), 187.0 (CHaromatic),
1
163.4 (CHimine), 160.9 (C-S), 136.4, 128.0, 122.3, 121.4, 112.8 (CH
), 56.5
(OCH3). Anal. Calcd for: C10H N3OS2, C, 47.79; H, 3.61; N, 16.72;aSrom, a2tic5.52%.
Found: C, 47.96; H, 3.51; N, 196.51; S, 25.26%.
Synthesis of Schiff bases 3a-l with H2SO
To a mixture of 2-amino-5-mercapto-1,34,4-thiadiazole 1 (0.133 g, 1 mmol)
and corresponding aromatic aldehyde 2 (1 mmol) in ethanol (10 ml) was added
3-4 drops of concentrated sulfuric acid. The reaction mixture was refluxed for
an appropriate time as presented in Table 1. After completion of the reaction,
controlled by TLC, the reaction mixture was cooled to room temperature giving
a solid product after 10-30 min, which was filtered and washed with a mixture
of hot water and ethanol (1:1, 10 ml) to afford the pure product 3.
2-(2-Chlorobenzylideneamino)-5-mercapto-1,3,4-thiadiazole (3d). m.p
1
242-244 ˚C. IR (KBr): νmax 3068 (CH
), 1560 (C=N). H-NMR: δH 14.56
(s, 1H, S-H), 8.98 (s, 1H, CH=N), 7.a6ro8m-a7tic.46 (m, 4H, H
). 13C-NMR: δC
190.2 (C-N), 164.3 (CHimine), 136.1 (C-S), 131.3, 131.1, a1ro3m0ati.c9, 130.0, 128.4,
128.3 (CHaromatic). Anal. Calcd for: C9H6ClN3S2, C, 42.27; H, 2.36; N, 16.43; S,
25.08%. Found: C, 42.01; H, 2.30; N, 16.59; S, 25.28%.
e-mail: akbar_mobini@yahoo.com
812

J. Chil. Chem. Soc., 56, Nº 3 (2011)
2-(5-Bbromo-2-hydroxybenzylideneamino)-5-mercapto-1,3,4-
thiadiazole (3e). m.p 254-255 ˚C. IR (KBr): νmax 3086 (CHaromatic), 1612
(C=N), 1512 (C=C). 1H-NMR: δH 14.57 (s, 1H, S-H), 11.28 (s, 1H, OH), 8.79
(s, 1H, CH=N), 7.98-6.96 (m, 3H, Haromatic), 13C-NMR: δ 187.1 (C-N), 164.4
(CHaromatic), 164.2 (CHimine), 159.6 (C-S), 138.2, 131.4, C122.2, 119.8, 111.3
Reaction of 2-amino-5-mercapto-1,3,4-thiadiazole 1 with corresponding
aromatic aldehyde 2 under acidic conditions or in the presence of BTEAC
catalyst afforded 5-mercapto-1,3,4-thiadiazole Schiff bases 3a-l. The reaction
was carried out with different aromatic aldehydes bearing electron-withdrawing
groups (such as nitro, halide), or electron-releasing groups (such as methyl,
NMe2). The results are summarized in Table 1.
(CH
). Anal. Calcd for: C9H6BrN3OS2, C, 34.19; H, 1.91; N, 13.29; S,
20.2a8ro%ma.ticFound: C, 34.30; H, 2.21; N, 13.19; S, 20.16%.
Table 1. Synthesis of Schiff bases 3a-l under acidic and solvent free
conditions.
2-(3-Bromobenzylideneamino)-5-mercapto-1,3,4-thiadiazole
(3f).
m.p 235-237 ˚C. IR (KBr): νmax 3078 (CH
), 1568 (C=N), 1510 (C=C).
Timeb
(min)
30
Yieldb
(%)
Timec
(min)
20
Yieldc
(%)
80
1H-NMR: δH 14.62 (s, 1H, S-H), 8.72 (s,aro1mHati,c CH=N), 8.15-7.50 (m, 4H,
Entry
R
Producta
Haromatic). 13C-NMR: δC 192.3 (C-N), 137.4 (CHimine), 136.8 (C-S), 132.4, 131.7,
1
2
H
2-OH
3a
3b
3c
3d
3e
3f
65
129.9, 129.1, 128.6, 122.8 (CH
). Anal. Calcd for: C H BrN S , C, 36.01;
H, 2.01; N, 14.00; S, 21.36%. Faoroumnatdic: , C, 36.14; H, 2.11; 9N,614.093 ;2S, 21.17%.
20
60
60
40
20
30
30
45
60
40
----
71
40
56
40
65
40
56
30
38
33
-----
10
30
----
30
20
20
10
30
----
35
30
89
61
----
72
75
71
95
65
----
53
83
3
2-OMe
2-Cl
2-(4-Isopropylbenzylideneamino)-5-mercapto-1,3,4-thiadiazole
4
(3g). m.p 237-239 ˚C. IR (KBr): ν 3092 (CHaromatic), 2960 (CHaliphatic), 1566
(C=N). H-NMR: δH 14.53 (s, 1H,mSax-H), 8.68 (s, 1H, CH=N), 7.93-7.43 (m,
5
2-OH, 5-Br
3-Br
1
4H, Haromatic), 3.02-2.87 (m, 1H, CH), 1.23- 1.21 (dd, 6H, CH3). 13C-NMR: δC
6
193.0 (C-N), 169.0 (CHimine), 130.7 (CHaromatic), 130.2 (C-S), 127.6, 127.5, 127.2
CHaromatic), 34.1 (C-Mes), 23.8 (3CH3). Anal. Calcd for: C12H13N3S2, C, 54.72;
H, 4.97; N, 15.95; S, 24.35%. Found: C, 54.58; H, 4.83; N, 16.21; S, 24.49%.
7
4-Isopropyl
4- NMe2
4- NO2
4- OCH2Ph
4-Cl
3g
3h
3i
(
8
9
10
11
3j
2-(4-Dimethylaminobenzylideneamino)-5-mercapto-1,3,4-thiadiazole
(3h). m.p 246-248 ˚C. IR (KBr): ν 3086 (CHaromatic), 2893 (CHaliphatic), 1591
3k
3l
(C=N). H-NMR: δH 14.26 (s, 1H,mSax-H), 8.41 (s, 1H, CH=N), 7.81-6.79 (m,
1
12
4-F
4H, Haromatic), 3.07 (s, 6H, CH ). 13C-NMR: δ 186.0 (C-N), 167.6 (CHimine),
154.4 (CHaromatic), 132.8 (C-S)3, 121.5, 112.0,C111.4 (CHaromatic), 65.0 (CH3).
Anal. Calcd for: C H12N4S , C, 49.97; H, 4.58; N, 21.19; S, 24.26%. Found: C,
49.78; H, 4.49; N,121 1.36; S2, 24.14%.
a
All compounds form yellow crystals except for 3d and 3h which are
white and orange, respectively.
b catalyzed by H2SO4.
c catalyzed by BTEAC.
2-(4-Nitrobenzylideneamino)-5-mercapto-1,3,4-thiadiazole (3i). m.p
259-261 ˚C. IR (KBr): νmax 3014 (CHaromatic), 1610 (C=N), 1568 (C=C), 1521,
1352 (NO2). 1H-NMR: δH 14.71 (s, 1H, S-H), 8.87 (s, 1H, CH=N), 8.40- 8.22
The good yields of products, the use of safe and mild reaction conditions
and the shorter reaction time are some advantages of the method for the
synthesis of Schiff bases in the presence of BTEAC as compared to that carried
out with sulfuric acid.
IR and NMR spectra data as well as elemental analyses are consistent
with the expected structures. In the 1H NMR spectra of all the Schiff bases
synthesized here, the appearance of singlets at 8.41-8.98 and 14.26-14.71
ppm related to the resonance of vinyl and SH protons, respectively, is good
evidence for the expected reactions. Also, In the IR spectra of compounds 3a-l
the absence of the absorption related to the NH group of the starting material
is in support of the reactions having taken place2.
The antibacterial screening data revealed that none of the compounds
showed antibacterial activity against E. coli, as an example of gram negative
bacteria (Table 2). Compounds 3b-j and 3l showed good inhibition against S.
aureus comparable to penicillin. Also, the anti-S. aureus activity of compounds
3c, 3e and 3h is better than that of the other compounds.
(m, 4H, Haromatic). 13C-NMR: δ 181.3 (C-N), 167.5 (CHimine), 131.5 (CH
),
130.1 (C-S), 128.8, 124.6, 12C4.0 (CH
). Anal. Calcd for: C9H6N4Oa2rSom2,atiCc ,
40.59; H, 2.27; N, 21.04; S, 24.08%a.roFmaotiuc nd: 40.71; H, 2.35; N, 21.19; S,
24.17%.
2-(4-Benzyloxybenzylideneamino)-5-mercapto-1,3,4-thiadiazole (3j).
mp 215-217 ˚C. IR (KBr): νmax 3036 (CHaromatic), 2982 (CHaliphatic), 1610 (C=N),
1568 (C=C). 1H-NMR: δ 14.46 (s, 1H, S-H), 8.62 (s, 1H, CH=N), 7.95-7.00
(m, 9H, H
(CH
), 5.22-5.H15 (d, 2H, CH ). 13C-NMR: δ 186.9 (C-N), 168.3
),ar1om6a5tic.3 (CHimine), 163.4 (C-S)2, 136.7, 132.7,C128.9, 128.5, 128.3,
127.a5ro,m1at1ic5.9 (CHaromatic), 70.1 (CH2). Anal. Calcd for: C16H N3OS , C, 58.69;
H, 4.00; N, 12.83; S, 19.59%. Found: C, 58.83; H, 4.11; N,113 2.61;2S, 19.77%.
2-(4-Chlorobenzylideneamino)-5-mercapto-1,3,4-thiadiazole
(3k).
m.p 222-224 ˚C. IR (KBr): νmax 3016 (CH
), 1610 (C=N), 1564 (C=C).
1H-NMR: δH 14.50 (s, 1H, S-H), 8.74 (s,aro1mHati,c CH=N), 7.67-7.47 (m, 4H,
Table 2: Inhibition zone diameter for Schiff bases 3a-l.
Haromatic). 13C-NMR: δC 187.0 (C-N), 168.1 (CHimine), 138.8 (C-S), 133.4, 131.9,
Entry
Compounds
S. aureus (mm) E. coli (mm)
129.8, 129.4 (CH
). Anal. Calcd for: C9H ClN3S , C, 42.27; H, 2.36; N,
16.43; S, 25.08%.aFromoauticnd: C, 42.09; H, 2.50; N6, 16.112; S, 25.24.
1
2
3a
3b
—
—
—
—
—
—
—
—
—
—
—
—
—
—
15±0.1
25±0.2
7±0.1
32±0.2
9±0.1
8±0.2
29±0.2
17±0.1
17±0.1
—
2-(4-Flurobenzylideneamino)-5-mercapto-1,3,4-thiadiazole
(3l).
3
3c
m.p 233-234 ˚C. IR (KBr): ν 3009 (CH
), 1606 (C=N), 1564 (C=C).
1H-NMR: δH 14.54 (s, 1H, Sm-Hax ), 8.73 (s, a1romHat,ic CH=N), 8.09- 7.38 (m, 4H,
Haromatic). 13C-NMR: δC 187.2 (C-N), 168.1 (CHimine), 167.4 (Caromatic, JC-F = 240.1
Hz), 133.4 (C-S), 133.0 (Caromatic, J = 3.0 Hz), 129.6 (Caromatic, J = 7.4 Hz),
116.7 (Caromatic, JC-F = 20.1 Hz). AnaCl.-FCalcd for: C9H6FN3S , C, 45C.1-F7; H, 2.53;
N, 17.56; S, 26.80%. Found: C, 45.30; H, 2.47; N, 16.21;2S, 25.09.
4
3d
5
3e
6
3f
7
3g
8
3h
RESULTS AND DISCUSSION
9
3i
10
11
12
3j
The synthetic route for the preparation of the target compounds is outlined
in Scheme 1.
3k
3l
9±0.1
—
13
DMSO
Gentamicin
18mm
10 U Penicillin 33 mm
Standard drugs
— indicates resistance of bacteria to compounds. The inhibition zone
numbers are the averages of three independent experiments.
Scheme 1. Preparation of Schiff bases 3a-l
813

J. Chil. Chem. Soc., 56, Nº 3 (2011)
9. Z. L. You, D. H. Shi, Ch. Xu, Q. Zhang, H. L. Zhu, Eur. J. Med. Chem. 43,
862 (2008).
ACKNOWLEDGEMENT
10 a) N. Rahman, S. Johnson Raja, J. Joseph, A. Sakthivel, J. Dhaveethu Raj,
J. Chil. Chem. Soc. 53, 1599, (2008). b) T. Sethi, A. Chaturvedi, R. K.
Upadhyay, S. P. Mathur, J. Chil. Chem. Soc. 52, 1206 (2007).
11. Z-L. You, D-H. Shi, H-L.Zhu, Inorg. Chem. Commun. 9, 642 (2006).
12. M. Parra, S. Hernandez , J. Alderete, J. Chil. Chem. Soc. 48 (2003).
13. S. E. Ibrahim, A. Sharif, E-J. Chem. 4, 531 (2007).
14. J. E. dos Santos, E. R. Dockal, E. T. G. Cavalheiro, Carbohydr. Polym. 60,
277 (2005).
15. H. Naeimi, J. Safari, A. Heidarnezhad, Dyes Pigments. 73, 251 (2007).
16 A. Mobinikhaledi, P. J. Steel, M. Polson, Synth. React. Inorg. M. 39, 189
(2009).
17. H. Khanmohammadi, H. Salehifard, M. H. Abnosi, J. Iran. Chem. Soc. 6,
300 (2009).
18. C. Ma, J. Sun, R. Zhang, D. Wang. J. Organomet. Chem. 692, 4029 (2007).
19. R. Zhang, Q. Wang, Q. Li, C. Ma. Inorg. Chim. Acta. 362, 2762 (2009).
20. A. Louri, Top. Curr. Chem. 206, 153 (1999).
21. A. Mobinikhaledi, N. Foroughifar, J. Alipour Safari, E. Amini, J.
Heterocyclic Chem. 44, 697 (2007).
22. A. Mobinikhaledi, N. Foroughifar, M. Kalhor, Turk. J. Chem. 34, 367
(2010).
23. A. Mobinikhaledi, N. Foroughifar, M. Kalhor, S. Ebrahimi, Eur. J. Chem.
1, 33 (2010).
We gratefully acknowledge financial support by the Chemistry Department
of Arak University.
References
1. a) D. N, Dhar, C. L. Taploo, J. Sci. Ind. Res. 41, 501 (1982). b) H-B. Zhu,
Z-Y. Dai, W. Haung, K. Cui, Sh-H. Gou, Ch-J. Zhu, Polyhedron. 23, 1131
(2004). c) M. Salavati-Niasari, E. Zamani, M. Bazarganipour, Applied
Clay. Sci, 38, 9 (2007). d) M. Colak, N. Demirel, Tetrahedron-Asymmetr.
19, 635 (2008).
2. N. Yoshikawa, M. Shibasaki, Tetrahedron. 58, 8289, (2002).
3. a) W. Radecka-Paryzek, V. Patroniak, J. Lisowski, Coord. Chem. Rev.
249, 2156 (2005). b M.Y. Khuhawar, M. A. Mughal, A. H. Channar, Eur.
Polym. J. 40, 805 (2004). c) K. C. Gupta, A. K. Sutar, Ch. Lin, Coord.
Chem. Rev. 253, 1926 (2009).
4. C. Spînu, M. Pleniceanu, C. Tigae. Turk. J. Chem. 32, 487, (2008).
5. N. Nishat, Sh. Parveen, S. Dhyani, Asma, T. Ahamad.. J. Appl. Polym.
Sci. 113, 1671 (2009).
6. Y-Y. Yu, H-D. Xian, J-F. Liu, G-L. Zhao, Molecules, 14, 1747 (2009).
7. A. Jarrahpour, D. Khalili, E. De.Clercq, C. Salmi, J. M. Brunel, Molecules.
12, 1720 (2007).
8. a) M. A. Ali, A. H. Mirza, R. J. Butcher, M. T. H. Tarafder, T. B. Keat, A.
M. Ali, J. Inorg. Biochem. 92, 141 (2002). b) G. B. Bagihalli, P. G. Avaji,
S. A. Patil, P. S. Badami, Eur. J. Med. Chem. 43, 2639 (2008).
24. A. Mobinikhaledi, M. Kalhor, L. Taheri, Asian J. Chem. 22, 7399 (2010).
814