Microwave-assisted synthesis of 1,3,4-thiadiazole aroylurea derivatives

Article abstract of DOI:10.3184/030823409X12559709808197

A rapid and efficient microwave-assisted synthesis method for the preparation of 1-aroyl-3-(5-aryl-1,3,4-thiadiazol-2-yl)urea is described. These 1,3,4-thiadiazole aroylureas (5a-f) were identified by IR, ¹H NMR, elemental analyses and N-[5-(4-methoxyphenyl)-1,3,4-thiadiazol-2-ylcarbamoyl]-2, 6-difuorobenzamide was confirmed by single-crystal X-ray diffraction. The target compounds were prepared under microwave in a shorter reaction time compared with conventional heating methods.

Full text of DOI:10.3184/030823409X12559709808197

674 RESEARCH PAPER
NOVEMBER, 674–676
JOURNAL OF CHEMICAL RESEARCH 2009
Microwave-assisted synthesis of 1,3,4-thiadiazole aroylurea derivatives
Feng Han, Rong Wan*, Peng Wang, Yao Wang and Jintang Wang
College of Sciences, Nanjing University of Technology, Nanjing 210009, P.R. China
A rapid and efficient microwave-assisted synthesis method for the preparation of 1-aroyl-3-(5-aryl-1,3,4-thiadiazol-
1
2-yl)urea is described. These 1,3,4-thiadiazole aroylureas (5a–f) were identified by IR, H NMR, elemental analyses
and N-[5-(4-methoxyphenyl)-1,3,4-thiadiazol-2-ylcarbamoyl]-2,6-difluorobenzamide was confirmed by single-crystal
X-ray diffraction. The target compounds were prepared under microwave in a shorter reaction time compared with
conventional heating methods.
Keywords: 1,3,4-thiadiazole, aroylurea, microwave-assisted synthesis, crystal structure
During recent years there has been intense investigation of
different thiadiazole compounds. Many of them are well known
topossessinterestingbiologicalpropertiessuchasantimicrobial,
antituberculosis, anti-inflammatory, anticonvulsant, antihyper-
tensive, anticancer, and hypoglycemic activities.1-8
Benzoylureas are promising and effective insecticides used
for the control of insects attacking a wide range of crops.
These compounds are generally recognised as insect growth
regulators which interfere with chitin synthesis in target
pests, causing death or abortive development.9,10 Due to
their attractive properties such as high selectivity, low acute
toxicity for mammals, and high biological activity,11 they are
considered to be a fourth generation of insecticides.
isocyanate was added dropwise to the solution of substituted
aryl amines in toluene, and then refluxed for several hours.
In this study, the 1-aroyl-3-(5-aryl-1,3,4-thiadiazol-2-yl)
urea (5a–f) were prepared by the reaction of 2-amino-5-aryl-
1,3,4-thiadiazole (3a–d) and aroyl isocyanate (4a–c) under
microwave irradiation as shown in Scheme 1. The results are
reported in Table 1.
In conclusion, we have developed a fast, convenient, and
efficient draft for the preparation of 1-aroyl-3-(5-aryl-1,3,4-
thiadiazol-2-yl)urea under MW irradiation. The ease of
the reaction procedure and workup, high yields, and a very
short reaction time make this procedure useful and attractive
compared with the currently available methods.
Conventional synthesis reactions suffered from drawbacks
such as the use of high boiling solvents, long reaction time
and lower yields. Compared with the traditional heating
reactions, the microwave (MW) reaction technique is often
rapid, more convenient and has environmental, and economic
advantages.12 MW irradiation is currently used to carry out a
wide range of reactions.13,14
In connection with our research interest directed toward the
synthesis of novel aroylurea derivatives, we have designed
and synthesised a series of new compounds containing the
1,3,4-thiadiazole and aroylurea under microwave irradiation.
Experimental
Instrumentation and chemicals
Melting points were recorded on an X-4 binocular microscope
melting point apparatus. 1H 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 a Perkin-Elmer PE-683 IR spectrometer. Elemental
analyses were performed on an Elementer Vario EL III elementary
analysis instrument. MW experiments were carried out on a WF-
4000M microwave fast reaction system (Shanghai Qiyao Analysis
Instrument Co., Shanghai, China). Crystal structure determination
was carried out on an Enraf-Nonius CAD-4 diffractometer.
General synthetic procedure for the preparation of 3a–d
Results and discussion
A mixture of substituted benzoic acid 1a–d (0.1 mol) and
thiosemicarbazide (0.1 mol) was added POCl3 (0.3 mol) dropwise at
0–5°C and maintained for 30 min. The reaction mixture was allowed
Previously the aroylureas were synthesised by substituted aryl
amines and aroyl isocyanate with yields of 47–60%. Aroyl
O
S
N
NH2
OH
NH2
POCl3
H2N
+
N
N
S
R1
3
R1
1
O
O
C
O
NH2
N
O
1,2-dichloroethane
reflux 4h
Cl
+
Cl
O
O
R2
S
R2
2
4
C
H
H
N
S
NH2
N
N
O
toluene
MW
+
R2
N
N
O
O
N
N
R1
R2
3
4
R1
5
3a R1=4-methoxy 3b R1=3,5-dimethyl 3c R1=2,4-dichloro 3d R1=3-fluoro
4a R2=2,6-difluoro 4b R2=4-methoxy
5a R1=4-methoxy R2=2,6-difluoro
5c R1=2,4-dichloro R2=4-methoxy
4c R2=H
5b R1=3,5-dimethyl R2=2,6-difluoro
5d R1=3,5-dimethyl R2=4-methoxy
5f R1=4-methoxy R2= H
5e R1=3-fluoro
R2= H
Scheme 1 The synthetic route of compounds 5a–f.
* Correspondent. E-mail: rwan@njut.edu.cn
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JOURNAL OF CHEMICAL RESEARCH 2009 675
Table 1 Synthesis of compounds 5a–f
Entry
R1
R2
Mode of
activation
Time
Power/
temp.
Yield/%
5a
5b
5c
5d
5e
5f
4-Methoxy
3,5-Dimethyl
2,4-Dichloro
3,5-Dimethyl
3-Fluoro
2,6-Difluoro
2,6-Difluoro
4-Methoxy
4-Methoxy
H
MW
MW
MW
MW
MW
MW
6 min
7 min
6 min
6 min
6 min
6 min
300 W
300 W
300 W
300 W
300 W
300 W
87
83
82
78
90
85
4-Methoxy
H
5a
4-Methoxy
2,6-Difluoro
CH
5 h
110oC
52
MW = microware irradiation; CH = conventional heating.
to raise temperature until reflux and stirred for 4 h. After cooling,
50 mL water was added into the reaction mixture. The pH of the
reaction solution was adjusted to the range of 8–9 with 50% NaOH
solution. The crude product precipitated, filtered, washed with water,
dried, and recrystallised from ethanol to afford compounds 3a–d.
N-[5-(3-fluorophenyl)-1,3,4-thiadiazol-2-ylcarbamoyl]benzamide 5e:
(90%): M.p. 249–250°C, H NMR(DMSO-d6, 300 MHz) d: 7.37–
1
8.06 (m, 9H, ArH), 11.66 (s, 1H, NH),12.22 (s, 1H, NH), IR(KBr)
υ: 680 (C-S), 1594 (C=N), 3296 (N-H), 1691 (C=O) cm-1; Anal.
Calcd for C16H11FN4O2S: C, 56.13; H, 3.24; N, 16.37. Found: C,
56.17; H, 3.28; N, 16.30%.
N-[5-(4-methoxyphenyl)-1,3,4-thiadiazol-2-ylcarbamoyl]benzamide
5f: (85%): M.p. 296–297°C, 1H NMR(DMSO-d6, 300 MHz) d: 3.84
(s, 3H, OCH3), 6.99–8.04 (m, 9 H, ArH), 11.61 (s, 1H, NH),12.12
(s, 1H, NH), IR(KBr)υ: 669 (C-S), 1604 (C=N), 3236 (N-H), 1703
(C=O) cm-1; Anal. Calcd for C17H14N4O3S: C, 57.62; H, 3.98; N,
15.81. Found: C, 57.57; H, 3.90; N, 15.93%.
The compound 5a was subjected to single crystal X-ray
crystallography and intensity data were collected 298(2) K on the
Enraf-Nonius CAD-4 diffractometer and use graphite Monochromatic
MoKa radiation (l = 0.71073Å). The structure was solved and refined
with the SHELXL-97 program.15 All H atoms bonded to the C atoms
were placed geometrically and constrained to ride on their parent
atoms. The thermal ellipsoids were plotted with the SHELXL-97
program at 50% probability. The molecular structure is shown in Fig. 1.
Selected crystal data and structure refinement details are listed in
Table 2. Selected bond distances and angles are listed in Table 3.
General synthetic procedure for the preparation of 4a–c
A mixture of substituted benzamide 2a–c (0.1 mol) and ethylene
dichloride was chilled in an ice bath and stirred while oxalyl
dichloride (0.24 mol) was added dropwise to the mixture.
The mixture was warmed and stirred for 1 h at room temperature,
and then heated to reflux for 5 h. After completion of the reaction, the
remaining oxalyl chloride was evaporated under reduced pressure.
The compounds 4a–c was collected under vacuum.
General synthetic procedure for the preparation of 5a–f
A mixture of compounds 3a–d (0.01 mol) and 4a–c (0.014 mol) in
toluene was stirred and irradiated in WF-4000M microwave fast
reaction system under 300W for minutes. After cooling and filtering,
crude compound 5a–f was obtained. Pure compound was obtained
by recrystallisation from DMF.
Crystals of (5a) suitable for X-ray diffraction were obtained by slow
evaporation of a DMF solution.
N-[5-(4-methoxyphenyl)-1,3,4-thiadiazol-2-ylcarbamoyl]-2,6-
difluorobenzamide 5a: (87%): M.p. 203–205°C, 1H NMR(DMSO-d6,
300 MHz) d: 3.84(s, 3H, OCH3), 7.07–7.90(m, 7H, ArH), 11.73(s,
2H, NH), IR(KBr)υ: 679(C-S), 1632(C=N), 3203(N-H), 1696(C=O)
cm-1; Anal. Calcd for C17H12F2N4O3S: C, 52.31; H, 3.10; N, 14.35.
Found: C, 52.26; H, 3.11; N, 14.30%.
N-[5-(3,5-dimethylphenyl)-1,3,4-thiadiazol-2-ylcarbamoyl]-2,6-
difluorobenzamide 5b: (83%): M.p. 256–257°C, 1H NMR(DMSO-d6,
300 MHz) d: 2.34 (s, 6H, CH3), 7.16–7.66 (m, 6H, ArH),11.72 (s,
2H, NH), IR(KBr)υ: 670 (C-S), 1625 (C=N), 3123 (N-H), 1695
(C=O) cm-1; Anal. Calcd for C18H14F2N4O2S: C, 55.66; H, 3.63; N,
14.43. Found: C, 55.62; H, 3.71; N, 14.41%.
N-[5-(2,4-dichlorophenyl)-1,3,4-thiadiazol-2-ylcarbamoyl]-4-
methoxybenzamide 5c: (82%): M.p. 272–274°C,1H NMR(DMSO-d6,
300 MHz) d: 3.86 (s, 3H, OCH3),7.09–8.28 (m, 7 H, ArH),11.52 (s,
1H, NH),12.37 (s, 1H, NH), IR(KBr)υ: 686 (C-S), 1604 (C=N), 3151
(N-H), 1699 (C=O) cm-1; Anal. Calcd for C17H12Cl2N4O3S: C, 48.24;
H, 2.86; N, 13.24. Found: C, 48.30; H, 2.82; N 13.20%.
N-[5-(3,5-dimethylphenyl)-1,3,4-thiadiazol-2-ylcarbamoyl]-4-
methoxybenzamide 5d: (78%): M.p. 264–265°C, 1H NMR(DMSO-d6,
300 MHz) d: 2.54 (s, 6H, CH3), 3.87 (s, 3H, OCH3), 7.09–8.09 (m, 7 H,
ArH), 11.51 (s, 1 H, NH),12.29 (s, 1H, NH), IR(KBr)υ: 688 (C-S), 1604
(C=N), 3286 (N-H), 1699 (C=O) cm-1; Anal. Calcd for C19H18N4O3S:
C, 59.67; H, 4.74; N 14.65. Found: C, 59.67; H, 4.72; N, 14.69%.
Table 2 Crystal data and structure refinement for C17H12F2N4O3S
Empirical formula
Formula weight
Temperature
C17H12F2N4O3S
383.48 g mol-1
298(2) K
Wavelength
0.71073 Å
Crystal system
Space group
Monoclinic
C 2/c
23.853(5) Å
Unit cell dimensions
7.1360(14)Å b = 109.55(3)
22.370(5) Å
Volume
Z
Absorption correction
F(000)
Absorption coefficient
θrange for entire data collection
Reflections collected
Independent reflections
Data/restraints/parameters
Final R indices [I>2σ>(I)]
3588.2(12) Å-3
8
Psi-scan
1660
0.232 mm-1
1.81°to 25.34°
3354
3271 (Rint = 0.0360)
2331/0/254
R1 = 0.0817, wR2 = 0.1677
R1 = 0.0556, wR2 = 0.1468
1.005
Goodness-of-fit on F2
Final residual electron density
0.368 and –0.352 e. Å-3
Fig.1 A view of the molecular structure of 5a, showing atom displacement ellipsoids at the 50% level.
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676 JOURNAL OF CHEMICAL RESEARCH 2009
Table 3 Selected bond distances (Å) and angles (°) for compound (5a)
S– C9 1.710(3)
N2–C9 1.382(4)
C4–C7 1.489(4)
S–C10 1.736(3)
N2–C9 1.382(4)
C5–C6 1.372(5)
O1–C7 1.215(3)
O2–C8 1.214(3)
C2–C3 1.354(5)
O3–C14 1.366(4)
N3–C9 1.307(4)
N3–N4 1.374(3)
C3–C4 1.391(4)
N4–C10 1.300(4)
C4–C5 1.382(4)
C3–C4–C7 123.0(3)
F2–C5–C6 118.9(3)
F2–C5–C4 117.8(3)
C6–C5–C4 123.3(3)
C5–C6–C1 118.0(4)
O1–C7–N1 123.1(3)
O1–C7–C4 121.8(3)
N1–C7–C4 115.1(2)
O2–C8–N2 122.5(3)
O2–C8–N1 121.0(3)
N2–C8–N1 116.5(3)
N3–C9–N2 120.0(3)
N3–C9–S 115.2(2)
C10–C11 1.459(4)
C11–C12 1.390(4)
C11–C16 1.398(4)
C12–C13 1.378(4)
C13–C14 1.381(5)
C14–C15 1.388(5)
C15–C16 1.358(4)
F1–C3 1.358(4)
N1–C7 1.365(4)
N1–C8 1.387(4)
C1–C2 1.373(6)
C1–C6 1.383(5)
F2–C5 1.344(4)
N2–C8 1.351(4)
C9–S–C10 86.47(14)
C7–N1–C8 128.7(2)
C2–C1–C6 121.2(3)
C8–N2–C9 122.8(2)
C3–C2–C1 118.4(4)
C14–O3–C17 118.3(3)
C9–N3–N4 111.5(2)
C2–C3 F1 119.9(3)
C2–C3–C4 123.8(3)
F1–C3–C4 116.3(3)
C10–N4–N3 113.0(2)
C5–C4–C3 115.3(3)
C5–C4–C7 121.6(3)
N2–C9–S 124.7(2)
N4–C10–C11 123.7(3)
N4–C10–S 113.8(2)
C11–C10–S 122.5(2)
C12–C11–C16 117.4(3)
C12–C11–C10 122.1(3)
C15–C16–C11 121.6(3)
C13–C12–C11 121.5(3)
C12–C13–C14 119.7(3)
O3–C14–C13 124.9(3)
O3–C14–C15 115.6(3)
C13–C14–C15 119.6(3)
C16–C15–C14 120.3(3)
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Project (Agriculture) (BG2007329) from the Science and
Technology Department of Jiangsu Province and the Youth
Teacher Academic Foundation of Nanjing University
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Received 29 July 2009; accepted 24 September 2009
Paper 09/0708 doi: 10.3184/030823409X12559709808197
Published online: 16 November 2009
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PAPER: JC090708