One pot synthesis and characterization of some novel Schiff bases with 1,3,4-thiadiazole unit

Article abstract of DOI:10.14233/ajchem.2015.17802

A series of novel benzimidazole substituted Schiff bases were synthesized by the reaction of aromatic aldehydes with the corresponding ethyl acetoacetate or methyl acetoacetate and 1,3,4-thiadiazole. These compounds have been characterized by ¹

Full text of DOI:10.14233/ajchem.2015.17802

Asian Journal of Chemistry; Vol. 27, No. 4 (2015), 1331-1334
A
SIAN
J
OURNAL OF HEMISTRY
C
http://dx.doi.org/10.14233/ajchem.2015.17802
One Pot Synthesis and Characterization of Some Novel Schiff Bases with 1,3,4-Thiadiazole Unit
*
MENGJIE ZHAO, XIAO LI, CHENGXIANG SHANG and JIAN ZHANG
College of Chemistry and Materials, South-Central University for Nationalities, Wuhan 430074, P.R. China
*Corresponding author: Tel: +86 27 62357762; E-mail: jianzhangye@gmail.com
Received: 11 April 2014;
Accepted: 17 June 2014;
Published online: 4 February 2015;
AJC-16785
A series of novel benzimidazole substituted Schiff bases were synthesized by the reaction of aromatic aldehydes with the corresponding
1
ethyl acetoacetate or methyl acetoacetate and 1,3,4-thiadiazole. These compounds have been characterized by H NMR, IR and mass
spectra.
Keywords: Schiff bases, 1,3,4-Thiadiazole, Aromatic aldehydes.
INTRODUCTION
EXPERIMENTAL
Schiff bases are an important class of organic compounds
widely used in the manufacture of medicinal and pharma-
ceutical products. Thus, development and synthesis of novel
Schiff base derivatives as potential chemotherapeutics attracts
much attention of organic and medicinal chemists1. Schiff
bases, derived mostly from various heterocyclic compounds,
were reported to possess a wide variety of biological activities
including antiviral2, anticancer3, cytotoxic4, antimicrobial5,
antibacterial6,7 and anticonvulsant8. Besides their potential
application as biologically active agents, Schiff bases constitute
one of the most relevant synthetic ligand systems in asymmetric
catalysis9. New optical and organic conducting materials and
polymers can be prepared by Schiff bases. Benzimidazole and
its derivatives have potential uses as therapeutics because the
benzimidazole nucleus is a very important pharmacophore in
modern drug discovery and a constituent of vitamin B12.
Thus it is not surprising that benzimidazoles display diverse
biological activities such as antimicrobial10,11, antifungal,
antitumor12-14, antiviral15,16 antihistaminic17 etc. Benzimidazole
and its derivatives have been additionally found applications
in several other areas such as optical laser and polymer dyes
in optoelectronics18, organic luminophores, fluorescent
tags for detection of biological important molecules such as
DNA, RNA or proteins and enzymes. These considerations
prompted us to explore the synthesis of a new series of benzi-
midazole substituted Schiff bases with different aromatic rings
as well as different substituent on the benzimidazole nuclei.
The synthesis and spectroscopic characterization are reported
here.
All chemicals were of reagent grade, purchased from com-
mercial sources and used without further purification.Aromatic
aldehydes, ethyl acetoacetate phosphorus oxychloride and
hydrazine were purchased from Aladdin Chemical Company
and were used without further purification. All the solvents
were dried using standard methods before use. 1H NMR and
13C NMR were recorded on a Bruker 400 for CDCl3 solutions.
X4-digital melting point reader was used to determine the
melting points. Mass spectra were obtained on a LCQ DECA
XP (Thermo Company). Elemental analyses were performed
in a Fash-1112 instrument.
In order to synthesize the following 9 novel Schiff bases
1,3,4-thiadiazole derivatives were designed and synthesized
via the route as shown in Fig. 1.
Synthesis of 5-phenyl-1,3,4-thiadiazol-2-amine (3): A
stirring mixture of benzoic acid (50 mmol), N-aminothiourea
(50 mmol) and POCl3 (13 mL) was heated at 75 °C for 0.5 h.
The reaction mixture was cooled down to room temperature
and add amount of water. The reaction mixture was refluxed
for 4 h and cooled; the mixture was basified to pH 8 by the
dropwise addition of 50 % NaOH solution under stirring19.
The precipitate was filtered and recrystallized with ethanol to
yield 7 g (79.1 %) of the title compound 3 as white solid; m.p.:
224-226 °C; IR (KBr, νmax, cm-1): 3276, 3114 (t N-H), 1634 (t
C=N), 691 (t C-S); 1H NMR (DMSO-d6): δ 7.40 (s, 2H), 7.43-
7.49 (dd, J = 6.38 Hz, J = 14.00 Hz, 2H), 7.74-7.76 (d, J =
6.94 Hz, 2H).
Synthesis of compound 5 i.e., (2Z,3E)-methyl 3-(5-
phenyl-1,3,4-thiadiazol-2-ylimino)-2-benzylidenebutanoate

1332 Zhao et al.
Asian J. Chem.
S
S
N
NH2
A
H2N
COOH
N
H
N
NH2
1
2
3
O
O
S
NH2
R
CHO
OR1
N
N
4a-4i
3
R
O
B
S
N
N
O
R1
N
5a-5i
A: POCl3 110 °C, B: few drops of piperidine and acetic acid CH3CH2OH
R = aromatic aldehyde
Fig. 1. Synthetic route of schiff bases containing 1,3,4-thiadiazole unit
R1=-CH2,-CH2CH3
(5a): In a reaction flask, 0.01 mol of benzaldehye, 0.01 mol
of 5-phenyl-1,3,4-thiadiazol-2-amine and 0.012 mol of methyl
acetoacetate were dissolved in 200 mL ethanol. Three drops
of piperidine and four drops of ice acetic acid were added as
catalyst. The mixture was refluxed for 4 h and monitored by
TLC. The solvent was removed under reduced pressure, cooled
to room temperature and the precipitate was filtered off and
recrystallized with ethanol to give a brown crystals. m.p.: 156-
157 °C.Yield: 80.2 %. IR (KBr, νmax, cm-1): 3453, 2950.1699,
m/z [M + H]+ 398.3.Anal. Calcd for C20H16N3O2SCl, C, 60.37;
H, 4.05; Cl, 8.91; N, 10.56; S, 8.06. Found C, 60.38; H, 4.13;
Cl, 8.83; N, 10.49; S, 8.19
(2Z,3E)-Ethyl 2-(4-chlorobenzylidene)-3-(5-phenyl-
1,3,4-thiadiazol-2-ylimino)butanoate (5d): Brown crystals,
m.p.: 143-146 °C. Yield: 85.3 %, IR (KBr, νmax, cm-1): 3452,
2945, 1697, 1589,1502. 1H NMR (400 MHz, CDCl3) δ 7.65
(d, J = 7.0 Hz, 2H, Ar-H), 7.55-7.29 (m, 7H, Ar-H), 6.47 (s,
1H, =CH), 4.11 (q, J = 7.2 Hz, 2H-OCH2-), 2.53 (s, 3H, -CH3),
1.20 (t, J = 7.1 Hz, 3H-CH2CH3). ESI-MS: m/z [M + H]+ 412.2.
Anal. Calcd for C21H18N3O2SCl, C, 61.23; H, 4.40; Cl, 8.61; N,
10.20; S, 7.78. Found C, 61.34; H, 4.47; N, 10.10; S, 7.58.
(2Z,3E)-methyl 3-(5-phenyl-1,3,4-thiadiazol-2-ylimino)-
2-((thiophen-2-yl)methylene)butanoate (5e): Brown crystals,
m.p. 166-167 °C. Yield: 79.6 %. IR (KBr, νmax, cm-1): 3452,
2942, 1684, 1588, 1506. 1H NMR (400 MHz, CDCl3) δ 7.70
(d, J = 7.3 Hz, 2H, Ar-H), 7.55-7.35 (m, 3H, Ar-H), 7.25 (d,
J = 5.0 Hz, 1H, Ar-H), 7.06 (d, J = 3.5 Hz, 1H, Ar-H), 6.97-
6.87 (m, 1H, Ar-H), 6.77 (s, 1H, =CH), 3.72 (s, 3H, -OCH3),
2.52 (s, 3H, -CH3). ESI-MS: m/z [M + H]+ 370.2. Anal. Calcd
for C18H15N3O2S2, C, 58.52; H, 4.09; N, 11.37; S, 17.36. Found
C, 58.42; H, 4.20; N, 11.39; S, 17.27.
(2Z,3E)-Ethyl 3-(5-phenyl-1,3,4-thiadiazol-2-ylimino)-
2-((thiophen-2-yl)methylene)butanoate (5f): Brown crystals,
m.p. 155-156 °C. Yield: 78.2 %. IR (KBr, νmax, cm-1): 3360,
2949, 1680, 1602, 1509. 1H NMR (400 MHz, CDCl3) δ 7.72-
7.70 (m, 2H, Ar-H), 7.49-7.46 (m, 3H, A, r-H), 7.26-6.93 (m,
3H, Ar-H), 6.78 (s, 1H, =CH), 4.19-4.15 (m, 2H, -CH2-), 2.52
(s, 3H, -CH3), 1.25-1.21 (t, 3H, -CH3). ESI-MS: m/z [M + H]+
384.2. Anal. Calcd for C19H17N3O2S2, C, 59.51; H, 4.47; N,
10.96; S, 16.72. Found C, 59.49; H, 4.39; N, 10.78; S, 16.30.
(2Z,3E)-Methyl 2-(2-methoxybenzylidene)-3-(5-
phenyl-1,3,4-thiadiazol-2-ylimino)butanoate (5g): Brown
1
1582, 1494. H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 7.1
Hz, 2H), 7.51-7.38 (m, 5H), 7.34 (dd, J = 15.8, 8.1 Hz, 2H),
7.27 (s, 1H), 6.48 (s, 1H), 3.65 (s, 3H), 2.52 (s, 3H). ESI-MS:
m/z [M + H]+ 364.2. Anal. Calcd for C20H17N3O2S: C, 66.10;
H, 4.71; N, 11.56; O, 8.80; S, 8.82. Found C, 66.20; H, 4.81;
N, 11.26.
Compounds 5b-i were prepared using the same procedure
as 5a
(2Z,3E)-Ethyl-3-(5-phenyl-1,3,4-thiadiazol-2-ylimino)-
2-benzylidenebutanoate (5b): Brown crystals, m.p.: 161-163
°C. Yield: 80.9 %; IR (KBr, νmax, cm-1): 3359, 2944, 1678,
1601, 1509. 1H NMR (400 MHz, CDCl3) δ 7.67-7.59 (m, 2H,
Ar-H), 7.49-7.39 (m, 5H, Ar-H), 7.38-7.29 (m, 3H, Ar-H),
7.27 (d, J = 1.3 Hz, 1H, Ar-H), 6.48 (s, 1H, =CH), 4.10 (dd,
J = 7.1, 1.4 Hz, 2H, -CH2-), 2.52 (s, 3H, -CH3), 1.18 (t, J = 7.1
Hz, 3H-CH2CH3). ESI-MS: m/z [M + H]+ 378.2. Anal. Calcd
for C21H19N3O2S: C, 66.82; H, 5.07; N, 11.13; O, 8.48; S, 8.49.
Found C, 66.92; H, 5.14; N, 11.02; S, 8.39.
(2Z,3E)-Methyl 2-(4-chlorobenzylidene)-3-(5-phenyl-
1,3,4-thiadiazol-2-ylimino)butanoate (5c): Brown crystals,
m.p.: 161-163 °C. Yield 85.3 %; IR (KBr, νmax, cm-1): 3452,
2975, 1698, 1588, 1498. 1H NMR (400 MHz, CDCl3) δ 7.65
(d, J = 7.4 Hz, 2H, Ar-H), 7.52-7.29 (m, 7H, Ar-H), 6.46 (s,
1H, =CH), 3.66 (s, 3H, -OCH3), 2.52 (s, 3H,-CH3). ESI-MS:

Vol. 27, No. 4 (2015)
One Pot Synthesis and Characterization of Some Novel Schiff Bases with 1,3,4-Thiadiazole Unit 1333
crystals, m.p.: 160-162 °C; yield: 70.7 %. IR (KBr, νmax, cm-1):
3452, 2945, 1697, 1589, 1502. 1H NMR (400 MHz, CDCl3) δ
7.62 (d, J = 6.9 Hz, 2H. Ar-H), 7.42 (dd, J = 14.9, 7.5 Hz, 4H,
Ar-H), 7.25 (d, J = 7.8 Hz, 1H, Ar-H), 6.93 (dd, J = 15.1, 7.5
Hz, 2H, Ar-H), 6.80 (s, 1H, =CH), 3.89 (s, 3H, -OCH3), 3.63
(s, 3H, CH3O-Ph), 2.47 (s, 3H, -CH3). ESI-MS: m/z [M + H]+
394.3. Anal. Calcd for C21H19N3O3S C, 64.10; H, 4.87; N,
10.68; S, 8.15 Found C, 64.29; H, 4.73; N, 10.47; S, 8.27.
(2Z,3E)-Ethyl 2-(2-methoxybenzylidene)-3-(5-phenyl-
1,3,4-thiadiazol-2-ylimino)butanoate (5h): Brown crystals,
m.p.: 168-170 °C; yield: 72.6 %. IR (KBr, νmax, cm-1): 3428,
2986, 1671, 1582, 1499. 1H NMR (400 MHz, CDCl3) δ 7.61
(d, J = 6.7 Hz, 2H, Ar-H), 7.48-7.34 (m, 4H, Ar-H), 7.24 (d,
J = 8.1 Hz, 1H, Ar-H), 6.92 (dd, J = 17.4, 8.0 Hz, 2H, Ar-H),
6.82 (s, 1H, =CH), 4.07 (q, J = 7.1 Hz, 2H, -CH2-CH3), 3.89
(s, 3H, -OCH3), 2.48 (s, 3H, -CH3), 1.18 (t, J = 7.1 Hz, 3H,
CH3-CH2-). ESI-MS: m/z [M + H]+ 408.3. Anal. Calcd for
C22H21N3O3S, C, 64.85; H, 5.19; N, 10.31; S, 7.87 Found C,
64.78; H, 5.26; N, 10.28; S, 7.79.
(2Z,3E)-Ethyl 2-(4-bromobenzylidene)-3-(5-phenyl-
1,3,4-thiadiazol-2-ylimino)butanoate (5i): Brown crystals,
m.p.: 151-152 °C; yield: 82.7 %. IR (KBr, νmax, cm-1): 3376,
2947, 1685, 1599, 1503. 1H NMR (400 MHz, CDCl3) δ 7.65
(d, J = 7.1 Hz, 2H, Ar-H), 7.52-7.40 (m, 5H, Ar-H), 7.33 (d,
J = 8.4 Hz, 2H, Ar-H), 6.45 (s, 1H, Ar-H), 4.11 (q, J = 7.1 Hz,
2H-CH2CH3), 2.51 (s, 3H, -CH3), 1.20 (t, J = 7.1 Hz, 3H, CH3-
CH2-). ESI-MS: m/z [M + H]+ 455.2. Anal. Calcd for
C21H18BrN3O2S C, 55.27; H, 3.98; Br, 17.51; N, 9.21; S, 7.03.
Found C, 55.36; H, 3.78; Br, 17.46; N, 9.32; S, 7.09.
RESULTS AND DISCUSSION
We have developed a convenient, simplified and efficient
approach to synthesize Schiff bases via three component conden-
sation reaction. Compared with the reported synthesis, only
two steps were required to obtain the aimed product conve-
niently in high yield, as shown in Table-1.
We attempted to speculate the mechanism of the reaction
based on experimental facts. It is found that compound B was
O
O
EtO
EtO
N
O
H
HC
EtO
O
H3C
H3C
O
R
O
R
O
A
O
H
-H2O
H
O
EtO
OH
O
EtO
O
EtO
O
O
H
S
O
O
H2N
C
N
EtO
N
EtO
H2
N
S
OH
OH
N
B
N
O
O
H
EtO
H
EtO
N
H
S
N
S
H2O
N
H2O
N
N
N
O
-H
Et O
N
OEt
S
H
N
S
N
O
N
N
N
D
Fig. 2. A possible mechanisms for the synthesis 5a-i (the synthesis of 5a taken as an example)

1334 Zhao et al.
Asian J. Chem.
TABLE-1
SUBSTITUTION OF COMPOUND AND SYNTHESIS OF 5a-i
Yield (%)
Compound
R
R1
Time (h)
(One pot)
80.2
80.9
85.3
86.3
79.6
78.2
70.7
72.6
(Multistep)
40.6
Benzaldehyde
Benzaldehyde
Me
Et
Me
Et
Me
Et
Me
Et
4
4
4
4
4
4
4
4
4
5a
5b
5c
5d
5e
5f
5g
5h
5i
42.7
45.5
47.3
39.7
36.6
32.5
35.5
39.8
p-Chlorobenzaldehyde
p-Chlorobenzaldehyde
2-Thenaldehyde
2-Thenaldehyde
o-Anisaldehyde
o-Anisaldehyde
4-Bromobenzaldehyde
Et
80.7
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obtained when piperidine was added solely and compound D
was obtained when a few drops of acetic acid was added.
Furthermore, I2 is required for this reaction, compared with
the absence of I2, the aimed product would be obtained in
high yield when I2 was added, so a possible mechanism was
proposed (Fig. 2).
First, compound A was formed via Knoevenagel reaction
of methyl acetoacetate with aromatic aldehyde took place in
the presence of piperidine and then A was transformed to B
The carbonyl was activated by the addition of acetic acid, so it
is easy for compound C to attack B and formed compound D.
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Göker, Arch. Pharm. Chem. Life Sci., 339, 74 (2006).
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(2007).
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Conclusion
A novel, simple and efficient procedure for the preparation
of novel Schiff bases was demonstrated via a three component
condensation reaction of aromatic aldehyde, methyl or ethyl
acetoacetate and 5-phenyl-1,3,4-thiadiazol-2-amine, in refluxing-
ethanol. A variety of chosen common substrates participated
in the process with operational simplicity, excellent yields,
short reaction time and environmentally friendly.
ACKNOWLEDGEMENTS
17. J. Velík, V. Baliharová, J. Fink-Gremmels, S. Bull, J. Lamka and L.
Skálová, Res. Vet., 76, 95 (2004).
18. K. Cheng, Q.Z. Zheng, J. Hou, Y. Zhou, C.-H. Liu, J. Zhao and H.-L.
Zhu, Bioorg. Med. Chem., 18, 2447 (2010).
19. G.G. Tu, S.H. Li, H.M. Huang, G. Li, F. Xiong, X. Mai, H.W. Zhu,
B.H. Kuang and W.F. Xu, Bioorg. Med. Chem., 16, 6663 (2008).
Project was supported by the Nature Science Foundation
of Hubei Province of China (No. 2012FFB07410) and the
National Nature Science Foundation of China (No. 21302233)
for financial support.
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