Microwave-assisted synthesis of 1,3,4-thiadiazole Schiff base derivatives

Article abstract of DOI:10.3184/174751911X13128202305728

A rapid and efficient microwave-assisted synthesis method for the preparation of 1,3,4-thiadiazole Schiff base derivatives is described. These 1,3,4-thiadiazole Schiff bases (5a-h) were identified by IR, ¹H NMR, elemental analyses. The target c

Full text of DOI:10.3184/174751911X13128202305728

442 RESEARCH PAPER
AUGUST, 442–443
JOURNAL OF CHEMICAL RESEARCH 2011
Microwave-assisted synthesis of 1,3,4-thiadiazole Schiff base derivatives
Jun Hua, Jianguang Sunb, Taoyu Zhoua and Yanhua Xua*
aCollege of Environment, Nanjing University ofTechnology/Jiangsu Key Laboratory of Industrial Water-Conservation & Emission Reduction,
Nanjing 210009, P. R. China
bFaculty of Foreign Languages, Huaiyin Institute ofTechnology, Huaian 223003, P. R. China
A rapid and efficient microwave-assisted synthesis method for the preparation of 1,3,4-thiadiazole Schiff base deriv-
atives is described. These 1,3,4-thiadiazole Schiff bases (5a-h) were identified by IR, 1H NMR, elemental analyses. The
target compounds were performed in a shorter reaction time compared with conventional heating methods.
Keywords: 1,3,4-thiadiazole, Schiff base, microwave-assisted synthesis
In recent years, there has been intense investigation of differ-
ent 1,3,4-thiadiazole compounds. Derivatives of 1,3,4-thiadia-
zole compounds have diverse pharmacological activities such
as fungicidal, insecticidal, bactericidal, herbicidal, anti-tumor,
antituberculosis, anti-inflammatory properties.1–7 The 1,3,4-
thiadiazole nucleus with N–C–S linkage exhibits a large
number of biological activities.8
Organic compounds containing Schiff base are of increasing
interest because of their diverse biological properties such
as antifungal, antibacterial, antiparasitic, anti-inflammatory,
analgesic, and antitumoural activities.9–13
Conventional synthesis reactions suffered from drawbacks
such as the use of high boiling solvents, long reaction time and
lower yields.14 Microwave-assisted heating under controlled
conditions is an invaluable technology for medicinal chemistry
and drug discovery applications because it often dramatically
reduces reaction times, typically from days or hours to minutes
or even seconds.15–17
Results and discussion
Previously the imines were synthesised by substitutedd aryl
amine and substituted benzaldehyde with yields of 80–90%.
In this paper, the N-(substituted benzylidene)-5-(substituted
phenyl)-1,3,4-thiadiazol-2-amine (5a–h) was designed and
prepared by the reaction of 2-amino-5-aryl-1,3,4-thiadiazole
and substituted benzaldehyde under microwave irradiation as
shown in Scheme1. The results are reported in Table 1.
In conclusion, we have developed a fast, convenient, and
efficient draft for the preparation of N-(substituted benzyli-
dene)-5-(substituted phenyl)-1,3,4-thiadiazol-2-amine under
MW irradiation. The ease of the reaction procedure and
workup, high yields, and very short reaction time make this
procedure useful and attractive compared with the currently
available methods.18
The compound (E)-N-[4-(methylsulfanyl)benzylidene]-5-
(3,5-dimethylphenyl)-1,3,4-thiadiazol-2-amine (5a) was sub-
jected to single crystal X-ray diffraction.19
In connection with our research interest directed toward
the synthesis of novel N-(substitutedd benzylidene)-5-
(substitutedd phenyl)-1,3,4-thiadiazol-2-amine derivatives, we
have designed and synthesised a series of new compounds
containing the 1,3,4-thiadiazole and Schiff base under
microwave irradiation.
Experimental
Melting points were recorded on an X-4 binocular microscope melt-
ing point apparatus. H NMR spectra were recorded on an Avance
Bruker-500 instrument and chemical shifts in ppm are reported with
TMS as the internal standard. IR spectra in KBr were recorded by
1
Scheme 1 The synthetic route for compounds 5a–h.
* Correspondent. E-mail: yhxu2008@163.com

JOURNAL OF CHEMICAL RESEARCH 2011 443
Table 1 Synthesis of compounds 5a–h
Entry
R1
R2
Mode of activation
Time
Power/temp.
Yield / %
5a
5b
5c
5d
5e
5f
5g
5h
5b
3,5-Dimethyl
H
4-Methylsulfanyl
4-Methylsulfanyl
4-Methylsulfanyl
4-Methylsulfanyl
4-Nitro
MW
MW
MW
MW
MW
MW
MW
MW
CH
7 min
7 min
7 min
7 min
7 min
7 min
7 min
7 min
8 h
300 W
300 W
300 W
300 W
300 W
300 W
300 W
300 W
110 °C
83
79
82
89
88
85
82
80
48
4-Fluoro
4-Methoxy
2,4-Dichloro
4-Methyl
4-Methyl
4-Bromine
H
4-Nitro
4-Chloro
4-Chloro
4-Methylsulfanyl
MW, microwave irradiation; CH conventional heating.
a Perkin-Elmer PE-683 IR spectrometer. Elemental analyses were
performed on an Elementer Vario EL III elementary analysis instru-
ment. MW experiments were carried out on a WF-4000M microwave
fast reaction system (Shanghai Qiyao Analysis Instrument Co.,
Shanghai, China).
(KBr)υ: 1350 (N-O), 1425 (C–N), 1582 (C=N, ring), 1675 (C=N,
imine), 2935 (CH3–H), 3031 (ArH) cm−1;Anal. Calcd for C16H12N4O2S:
C, 59.25; H, 3.73; N, 17.27; S, 9.89. Found: C, 59.32; H, 3.88; N,
17.21; S, 9.92%.
(E)-N-(4-Chlorobenzylidene)-5-p-tolyl-1,3,4-thiadiazol-2-amine
1
(5g): (85%): M.p. 176–179 °C; H NMR (DMSO-d6, 300MHz) δ:
Synthesis of 3; general procedure
2.34 (s, 3H, CH3), 7.39–8.43 (m, 8H, ArH), 9.23 (s, 1H, H–C=N); IR
(KBr)υ: 1185 (C–Cl), 1592 (C=N, ring), 1685 (C=N, imine), 2942
(CH3–H), 3059 (ArH) cm−1; Anal. Calcd for C16H12ClN3S: C, 61.24;
H, 3.85; N, 13.39; S, 10.22. Found: C, 61.32; H, 3.88; N, 13.51;
S, 10.17%.
(E)-5-(4-Bromophenyl)-N-(4-chlorobenzylidene)-1,3,4-thiadiazol-
2-amine (5h): (85%): M.p. 168–170 °C; 1H NMR (DMSO-d6,
300MHz) δ: 7.67–8.11 (m, 8H, ArH), 9.10 (s, 1H, H–C=N); IR
(KBr)υ: 515 (C-Br), 1203 (C–Cl), 1616 (C=N, ring), 1692 (C=N,
imine), 3093 (ArH) cm−1; Anal. Calcd for C15H9BrClN3S: C, 47.58; H,
2.40; N, 11.10; S, 8.47. Found: C47.62; H, 2.38; N, 11.01; S, 8.52%.
To a mixture of substitutedd benzoic acid 1 (0.1 mol) and thiosemicar-
bazide (0.1 mol) was added POCl3 (0.3 mol) dropwise at 0–5 °C and
maintained for 30 minutes. The reaction mixture was heated to reflux
and stirred for 4 h. After cooling, water (50 mL) was added to the reac-
tion mixture. The pH of the reaction solution was adjusted to the range
of 8–9 with 50% NaOH solution. The crude product was precipitated,
filtered, washed with water, dried, and recrystallised from ethanol to
afford compounds 3.
Synthesis of 5; general procedure
A mixture of compounds 3 (0.01 mol), 4 (0.014 mol) and a few drops
of acetic acid in toluene was stirred and irradiated in a WF-4000M
microwave fast reaction system under 300W for a few minutes at
110 °C. After cooling and filtering, crude compound 5 was obtained.
The pure compound was obtained by recrystallisation from ethanol.
(E)-N-[4-(Methylsulfanyl)benzylidene]-5-(3,5-dimethylphenyl)-
The generous financial support of this work from the National
High Technology Research and Development (863 Program)
of China (No. 2007AA06A402), Key Projects in the National
ScienceandTechnologyPillarProgram(No. 2006BAC02A15),
Key Projects in the National Water pollution control and
management Pillar Program (No. 2008ZX07101-003), PhD
thesis innovation fund of Nanjing University of Technology
(No. BSCX201003).
1
1,3,4-thiadiazol-2-amine (5a): (89%): M.p. 184–185 °C; H NMR
(DMSO-d6, 300 MHz) δ: 2.37 (s, 6H, CH3), 2.57 (s, 3H, S–CH3),
7.22–7.99 (m, 7H, ArH), 8.99 (s, 1H, H–C=N); IR(KBr)υ: 683 (C–S),
1558 (C=N, ring), 1654 (C=N, imine), 2856, 2920 (CH3–H), 3128
(ArH)cm−1; Anal. Calcd for C18H17N3S2: C, 63.68; H, 5.05; N, 12.38;
S, 18.89. Found: C, 63.56; H, 5.11; N, 12.30; S, 19.01%.
(E)-N-[4-(Methylsulfanyl)benzylidene]-5-phenyl-1,3,4-thiadiazol-
2-amine (5b): (83%): M.p. 180–183 °C; 1H NMR(DMSO-d6,
300 MHz) δ: 2.58 (s, 3H, S–CH3), 7.44–7.99 (m, 9H, ArH), 9.00
(s, 1H, H–C=N); IR (KBr)υ: 658 (C–S), 1552 (C=N, ring), 1683
(C=N, imine), 2910 (CH3–H), 3004 (ArH) cm−1; Anal. Calcd for
C16H13N3S2: C, 61.71; H, 4.21; N, 13.49; S, 20.59. Found: C, 61.78;
H, 4.25; N, 13.41; S, 20.62%.
(E)-5-(4-Fluorophenyl)-N-[4-(methylsulfanyl)benzylidene]-1,3,4-
thiadiazol-2-amine (5c): (82%): M.p. 190–192 °C; 1H NMR (DMSO-
d6, 300MHz) δ: 2.58(s, 3H, S–CH3), 7.40–8.05(m, 8H, ArH), 8.99(s,
1H, H–C=N); IR (KBr)υ: 667 (C–S), 1558 (C=N, ring), 1683 (C=N,
imine), 2905 (CH3-H), 3062 (ArH)cm−1; Anal. Calcd for C16H12FN3S2:
C, 58.34; H, 3.67; N, 12.76; S, 19.47. Found: C, 58.30; H, 3.72;
N, 12.82; S, 19.52%.
(E)-5-(4-Methoxyphenyl)-N-[4-(methylsulfanyl)benzylidene]-1,3,4-
thiadiazol-2-amine (5d): (79%): M.p. 194–195 °C; 1H NMR (DMSO-
d6, 300MHz) δ: 2.57 (s, 3H, S–CH3), 3.85 (s, 3H, OCH3), 7.12–7.97
(m, 8H, ArH), 8.97 (s, 1H, H–C=N); IR (KBr)υ: 653 (C–S), 1584
(C=N, ring), 1609 (C=N, imine), 2912 (CH3–H), 3064 (ArH)cm−1;
Anal. Calcd for C17H15N3OS2: C, 59.80; H, 4.43; N, 12.31, S, 18.78.
Found: C, 59.67; H, 4.52; N, 12.29; S, 18.81%.
Received 22 May 2011; accepted 11 July 2011
Paper 1100708 doi: 10.3184/174751911X13128202305728
Published online: 29 August 2011
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