A new convenient way to synthesize 1,3,4-thiadiazol-2-yl urea derivatives under microwave irradiation

Article abstract of DOI:10.1002/hc.20489

A simple and efficient method was developed for the synthesis of 1-(substituted)-3-(5-(substituted)-1,3,4-thiadiazol-2-yl) ureas from heterocyclic amino compounds and phenyl-5-(pyridine-3-yl)-1,3,4-thiadiazol-2- ylcarbamate(2) or phenyl-5-(trifluoro-methyl)-1,3,4-thiadiazol-2-ylcarbamate(5) under solvent conditions using microwave irradiation. The products were obtained in satisfactory yield as we expected. The reactions can be realized by conventional heating, but we find that the condition of microwave is better according to the reaction time. New J-(substituted)-3-(5-(substituted)-1,3,4- thiadiazol-2-yl) urea derivatives are reported. The products were characterized by ¹H NMR, ESI-MS, and Elemental analysis. The crystal structure of compound 6h was determined by X-ray single crystal diffraction.

Full text of DOI:10.1002/hc.20489

Heteroatom Chemistry
Volume 19, Number 6, 2008
A New Convenient Way to Synthesize
1,3,4-Thiadiazol-2-yl Urea Derivatives under
Microwave Irradiation
Kejian Li1 and Wenbin Chen2
1Department of the Public Security, Sichuan Police College, Luzhou 646000,
People’s Republic of China
2Institute of Elemento-Organic Chemistry, National Key Laboratory of Elemento-Organic
Chemistry, Nankai University, Tianjin 300071, People’s Republic of China
Received 7 November 2006; revised 9 March 2008
INTRODUCTION
ABSTRACT: A simple and efficient method was
developed for the synthesis of 1-(substituted)-3-(5-
(substituted)-1,3,4-thiadiazol-2-yl) ureas from hete-
rocyclic amino compounds and phenyl-5-(pyridine-
3-yl)-1,3,4-thiadiazol-2-ylcarbamate(2) or phenyl-5-
(trifluoro-methyl)-1,3,4-thiadiazol-2-ylcarbamate(5)
under solvent conditions using microwave irradia-
tion. The products were obtained in satisfactory yield
as we expected. The reactions can be realized by con-
ventional heating, but we find that the condition of mi-
crowave is better according to the reaction time. New
1-(substituted)-3-(5-(substituted)-1,3,4-thiadiazol-2-
yl) urea derivatives are reported. The products were
characterized by 1H NMR, ESI-MS, and Elemental
analysis. The crystal structure of compound 6h
was determined by X-ray single crystal diffraction.
Microwave-assisted organic chemistry (MAOC) has
been developed to be a valuable tool for chemistry
research during the past 20 years [1–2] and has re-
ceived widespread acceptance [3]. The recent avail-
ability of commercial microwave systems specific
for synthesis makes this technique more convenient
and accessible, because of the improved opportu-
nities for reproducibility, rapid synthesis, rapid re-
action optimization, and the potential discovery of
new chemistries. Therefore, the beneficial effects
of microwave irradiation are becoming more and
more remarkable, especially when ordinary reac-
tions require forcing conditions or prolonged reac-
tion times.
The 1-(substituted)-3-(5-(substituted)-1,3,4-thiadi-
azol-2-yl) urea is an important heterocyclic scaffold
in the field of medicinal and pesticide chemistry as
the derivatives are well known for their diverse bio-
logical activities [4–6]. Although there are many fea-
sible routes for the synthesis of 1,3,4-thiadiazol-2-
yl urea derivatives, the products are often limited
to 5-(substituted)-1,3,4-thiadiazol-2-amine and het-
erocyclic isocyanates [7–10]. To develop multifunc-
tional libraries of 1-(substituted)-3–5-(substituted)-
1,3,4-thiadiazol-2-yl) urea derivatives, we herein
report a new convenient way to synthesize 1,3,4-
thiadiazol-2-yl urea derivatives from heterocyclic
amino compounds using MAOC condition.
ꢀ
C
2008 Wiley Periodicals, Inc. Heteroatom Chem
19:621–629, 2008; Published online in Wiley InterScience
(www.interscience.wiley.com). DOI 10.1002/hc.20489
Correspondence to: Kejian Li; e-mail: likejian@syn.nankai.
edu.cn.
Contract grant sponsor: National Natural Science Foundation
of China.
Contract grant number: 20432010.
Contract grant sponsor: Ministry of Science and Technology of
the People’s Republic of China.
Contract grant number: 2003CB114400.
Contract grant sponsor: Ministry of Education of China.
2008 Wiley Periodicals, Inc.
c
ꢀ
621

622 Li and Chen
RESULTS AND DISCUSSION
stable at room temperature and can be stored for a
long time. (Schemes 1 and 2)
Previously, a preparation of the 1,3,4-thiadiazol-2-yl
urea derivatives has been reported. The synthe-
sis is accomplished by the reaction of heterocyclic
amino compounds with heterocyclic isocyanato
compounds in the presence of anhydrous solvent
[11–15]. In this report, we find that the heterocyclic
isocyanato compounds must be freshly made be-
cause these compounds are unstable and the re-
action is very sensitive to water. To get the 1,3,
4-thiadiazol-2-yl urea derivatives in a convenient
way, we make an effort to prepare relatively stable
compounds 2 and 5 as the intermediates from com-
pounds 1 and 4.
The compounds 1 and 4 were synthesized from
the thiosemicarbazide and their carboxylic acids, re-
spectively. Because of the violent reaction condition
of preparing compound 1, we use 1,4-dioxane as sol-
vent and drop POCl3 slowly into the reaction mix-
ture. Then, the reaction was kept at 120◦C for 5 h.
The reaction of preparing the compound 4 was rel-
atively mild compared with the first reaction. Then,
we performed the reaction in polyphosphoric acid.
Both of the two reactions gave reasonable yield,
and we successfully got the two compounds. Com-
pound 1 or 4 was then treated with diphenyl car-
bonate and NaH in anhydrous THF to give phenyl-5-
(substituted)-1,3,4-thiadiazol-2-ylcarbamate(2 or 5)
in acceptable yield. We found that this substance is
Pyridines, pyrimidines, and their derivatives
have been studied for more than one century due
to their diverse biological activities [16–18]. They
possess antibacterial, antiviral, antitumor, antihy-
pertensive, and anti-inflammatory activities [19–28].
Because of the potential bioactivity of pyridines and
pyrimidines, we designed 20 compounds, 3a–j and
6a–j, including these groups, which are listed in
Schemes 1 and 2.
The compound 2 or 5 could be converted into
the target molecule 3 or 6 by simple aminolysis. We
first attempted this aminolysis reaction in the con-
ventional heating condition. The mixture must be
refluxed in THF or toluene for 24 h to give an ac-
ceptable yield. The product could crystallize from
the solution. After a simple recrystallization, we got
20 pure products (3a–j and 6a–j) (Table 1).
To improve the reaction condition, we attempted
to use MAOC. When compound 2 or 5 reacted with
amines under the condition of MAOC, the reaction
was accomplished within only 30 min and gave simi-
lar product yields from the former condition. Table 1
lists the reaction time and product yields of different
derivatives in the two different reaction conditions.
We can see that the aminolysis process can be treated
under either conventional heating or MAOC. Yet per-
forming the process under MAOC, the reaction can
be completed in much less time.
N
S
O
O
N
S
C
COOH
O
POCl3, 0 C
NH2
+
NH2
NH2 NH
N
THF, NaH, 0 C,
3 h
Ar
120 C, reflux
N
1
rt, 72 h
N
N
N
S
N
O
H
N
Ar
NH2
S
N
H
NH
O
C
N
tol unene, M.W.,0.5 h
N
O
2
3
3a
3b
3c
3d
CH3
3e
H3C
H3C
N
N
H3C
N
N
3f
3j
3h
3i
3g
N
Br
Cl
Cl
Br
N
N
N
N
SCHEME 1
Heteroatom Chemistry DOI 10.1002/hc

A New Convenient Way to Synthesize 1,3,4-Thiadiazol-2-yl Urea Derivatives under Microwave Irradiation 623
O
O
F
O
NH2
S
S
C
polyphosphoric acid
CF3COOH
F
NH2 NH
NH2
THF, NaH,0 C,
rt, 72 h
3 h
N
N
F
120 C, reflux
4
H
F
H
N
NH
S
F
N
O
S
N
NH2
Ar
F
Ar
F
N
O
F
N
O
N
F
THF, M.W., 0.5 h
5
6
6a
6b
6c
6d
CH3
6e
H3C
H3C
N
N
H3C
N
N
6f
6j
6h
6i
6g
N
Br
Cl
Cl
Br
N
N
N
N
SCHEME 2
etate solution. The crystal data, data collection, and
refinement parameter for the compound are listed in
Table 2. Data were collected with a crystal-clear de-
tector, graphite monochromatized MoKα radiation
Structures of the Products
The structures of all the 1,3,4-thiadiazol-2-yl
ureas were confirmed by elemental analysis, 1H
NMR, and ESI-MS. One structure of the prod-
ucts, compound 6h, was confirmed by X-ray.
Single-crystal structure of 1-(2-chloropyridin-3-
yl)-3-(5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl) urea
(6h) was obtained by slow evaporation of an ethyl ac-
˚
(λ = 0.71073A) being used. The structure was solved
by direct methods, using the SHELXS-97 package
and refined on F2, using the data (I > 2σ (I)) by
the full-matrix least-squares procedures using the
SHELXL-97 package.
TABLE 1 Preparation of the Title Compounds (3, 6)
Conventional Heating
Microwave Irradiation
Entry
Compound
Time (h)
Yield (%)
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
3g
3h
3i
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
87.0
80.2
80.0
85.0
76.5
80.3
85.5
83.3
82.7
85.6
55.3
56.3
60.0
55.7
56.0
85.3
80.0
57.3
63.2
57.0
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
86.0
83.3
84.1
91.7
80.5
81.5
91.1
86.1
83.7
87.5
56.4
55.0
61.8
58.2
58.2
86.4
79.5
58.9
66.7
58.1
9
10
11
12
13
14
15
16
17
18
19
20
3j
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
Heteroatom Chemistry DOI 10.1002/hc

624 Li and Chen
TABLE 2 Crystallographic Data for Compound 6h
Empirical formula
CCDC deposit no.
Color
Crystal size (mm)
Crystal system
Space group
C9H5ClF3N5OS
293781
Colorless
0.24 × 0.20 × 0.18
Monoclinic
P2(1)/c
˚
Unit-cell dimensions (A)
8.642 (2)
7.7641 (17)
17.923 (4)
˚
a (A)
˚
b (A)
˚
c (A)
90
α (deg)
β (deg)
γ (deg)
Volume (A )
Z
100.953 (4)
90
1180.7 (5)
4
323.69
3
˚
Formula weight
Density (calcd.) (mg/m3)
Absorption coefficient (mm−1
F(000)
Diffractometer scan wavelength (A)
Temperature (K)
1.821
0.543
648
)
SMART CCD 1000
˚
0.71070
113 (2)
θRange for data collection (deg)
Index ranges
No. of data collected
2.31–27.88
−10< = h< = 11, −10< = k < = 10, −20< = l< = 23 14282
14,282
No. of unique data
No. of refined parameters
Absorption correction
2,820
191
Semiempirical from equivalents
Full-matrix least-squares on F2
2820/0/191
Refinement method
Data/restraints/parameters Goodness-of-fit on F2
Final R indices [I > 2σ (I )]
R indices (all data)
1.065
R1 = 0.0272
3
˚
Largest diff. peak and hole (e A )
wR2 = 0.0735
R1 = 0.0357
wR2 = 0.0769
0.331/−0.282
The crystal structure of 6h is shown in Figs. 1
and 2. Figure 1 is a perspective view of the compound
showing the atomic numbering scheme, whereas
Fig. 2 is the unit cell of complex 6h. All no hydro-
gen atoms were refined anisotropically. Hydrogen
atoms were located from difference maps and then
added geometrically, refined isotropically with a
riding model. The fractional coordinates of non-
hydrogen atoms and equivalent isotropic thermal
parameters are given in Table 3, and selected bond
FIGURE 1 The molecular structure of complex 6h.
Heteroatom Chemistry DOI 10.1002/hc

A New Convenient Way to Synthesize 1,3,4-Thiadiazol-2-yl Urea Derivatives under Microwave Irradiation 625
FIGURE 2 The unit cell of complex 6h.
lengths and angles are listed in Table 4. The bond
In summary, we have synthesized twenty 1-
(substituted)-3-(5-(substituted)-1,3,4-thiadiazol-2-yl)
urea derivatives, using a simple efficient proce-
dure from the heterocyclic amino compounds
˚
length of C(3)–N(4)[1.3696(18) A] is shorter than
˚
that of C(5)–N(4)[1.3983(19) A] that is closed to
˚
the value of C(3)–O(1)[1.2172(15) A] and C(3)–
˚
N(3)[1.3796(18) A] bond. Similarly, the bond length
and
phenyl-5-(substituted)-1,3,4-thiadiazol-2-yl-
˚
of C(2)–N(3)[1.3605(18) A] is shorter than that of
carbamate under solvent conditions. The reaction
can be realized in similar yield under conventional
heating condition or MAOC condition. In addition,
˚
C(5)–N(4)[1.3983(19) A] that is closed to the thiadi-
azol ring.
4
3 2
˚
TABLE 3 Atomic Coordinates (×10 ) and Equivalent Isotropic Displacement Coefficients (10 A ) for Compound 6h
Atom
x
y
z
U (equiv)
Cl (1)
S (1)
F (1)
F (2)
F (3)
O (1)
N (1)
N (2)
N (3)
N (4)
N (5)
C (1)
C (2)
C (3)
C (4)
C (5)
C (6)
C (7)
C (8)
C (9)
1779 (1)
2620 (1)
3039 (1)
660 (1)
1144 (1)
3728 (1)
286 (1)
−1557 (1)
5974 (1)
9279 (2)
8872 (1)
10679 (1)
2867 (1)
7803 (2)
6376 (2)
3838 (2)
1193 (2)
3090 (2)
7751 (2)
5316 (2)
2634 (2)
9156 (2)
253 (2)
−598 (1)
1900 (1)
2773 (1)
2910 (1)
2092 (1)
1567 (1)
1218 (1)
769 (1)
678 (1)
525 (1)
197 (1)
1814 (1)
1053 (1)
972 (1)
2397 (1)
649 (1)
154 (1)
769 (1)
31 (1)
22 (1)
59 (1)
43 (1)
45 (1)
27 (1)
26 (1)
24 (1)
23 (1)
25 (1)
28 (1)
23 (1)
21 (1)
23 (1)
29 (1)
23 (1)
24 (1)
28 (1)
30 (1)
27 (1)
318 (1)
1682 (1)
2727 (1)
4231 (1)
1401 (2)
1466 (2)
2808 (2)
1572 (2)
3706 (2)
3397 (2)
5488 (2)
5899 (2)
5009 (2)
−1667 (2)
−3218 (2)
−1906 (2)
−414 (2)
1292 (1)
1234 (1)
Heteroatom Chemistry DOI 10.1002/hc

626 Li and Chen
TABLE 4 Selected Bond Lengths and Bond Angles for Compound 6h
˚
Atoms
Bond Lengths (A)
Atoms
Bond Angels (deg)
C(1)–C(6)
S(1)–C(1)
S(1)–C(2)
F(1)–C(4)
F(2)–C(4)
F(3)–C(4)
O(1)–C(3)
N(1)–C(1)
N(1)–N(2)
N(2)–C(2)
N(3)–C(2)
N(3)–C(3)
N(3)–H(1)
N(4)–C(3)
N(4)–C(5)
N(5)–C(6)
N(5)–C(7)
C(1)–C(4)
C(5)–C(9)
C(5)–C(6)
C(7)–C(8)
C(8)–C(9)
1.7500(14)
1.7249(15)
1.7274(13)
1.3212(16)
1.3386(17)
1.3261(18)
1.2172(15)
1.2959(17)
1.3723(17)
1.3144(17)
1.3605(18)
1.3796(18)
0.880(17)
1.3696(18)
1.3983(19)
1.313(2)
C(1)–S(1)–C(2)
C(1)–N(1)–N(2)
C(2)–N(2)–N(1)
C(2)–N(3)–C(3)
C(3)–N(4)–C(5)
C(6)–N(5)–C(7)
N(1)–C(1)–C(4)
N(1)–C(1)–S(1)
C(4)–C(1)–S(1)
N(2)–C(2)–N(3)
N(2)–C(2)–S(1)
N(3)–C(2)–S(1)
O(1)–C(3)–N(4)
O(1)–C(3)–N(3)
N(4)–C(3)–N(3)
F(1)–C(4)–F(3)
F(1)–C(4)–F(2)
F(3)–C(4)–F(2)
F(1)–C(4)–C(1)
F(3)–C(4)–C(1)
F(2)–C(4)–C(1)
C(9)–C(5)–N(4)
C(9)–C(5)–C(6)
N(4)–C(5)–C(6)
N(5)–C(6)–C(5)
N(5)–C(6)–C(1)
C(5)–C(6)–C(1)
N(5)–C(7)–C(8)
C(9)–C(8)–C(7)
C(8)–C(9)–C(5)
85.24(7)
111.26(11)
112.14(11)
122.47(12)
126.90(12)
117.44(13)
120.76(13)
116.40(11)
122.82(10)
120.12(12)
114.96(11)
124.92(11)
125.93(13)
121.95(13)
112.11(11)
108.10(13)
107.20(12)
106.00(12)
111.47(12)
112.25(12)
111.52(13)
124.80(13)
115.83(14)
119.37(12)
125.73(13)
115.81(11)
118.46(12)
121.76(14)
119.86(14)
119.37(14)
1.3479(19)
1.499(2)
1.3907(19)
1.404(2)
1.385(2)
1.384(2)
the MAOC allows us to obtain target compounds
in relative good yields within a short time. The
bioactivity studies of these compounds are under
way.
ature of about 120◦C for about 5 h. Then the mix-
ture was poured into 1 L ice water. Fifty percent of
NaOH solution was added until the solution became
basic. Yellow solid precipitated and was filtered off,
washed with water, and air-dried. The dried solid
was recrystallized from aqueous ethanol to yield yel-
low products as 5-(pyridin-3-yl)-1,3,4-thiadiazol-2-
amine in 63.5% yield. mp 232–233◦C, 1H NMR: [300
MHz] δ: 8.944(d, J = 2.1 Hz, 1H), 8.622–8.602 (m,
1H), 8.157–8.125 (m, 1H), 7.548 (s, 2H, NH), 7.523–
7.481(m, 1H); ESI-MS: (M+) m/z(%) = 179.36(100).
EXPERIMENTAL
Microwave irradiation is initiator 8 (Biotage). Melt-
ing points were determined using Yanaco MP-500
apparatus and were incorrect. Nuclear magnetic res-
onance spectra were recorded on Varian Mercury
Plus 400 NMR and Bruker AVANCE-300 NMR in-
strument in (CD3)2SO. Tetramethylsilane (TMS) was
used as an internal standard for 1H NMR spec-
troscopy. Elemental analysis was carried out on a
Yana MT-3 instrument.
Phenyl-5-(pyridin-3-yl)-1,3,4-thiadiazol-2-
ylcarbamate (2)
NaH (8.1 g, 0.337 mole, 3 equiv) in anhydrous THF
(300 mL) was slowly added to an ice-bathed solu-
tion of 5-(pyridin-3-yl)-1,3,4-thiadiazol-2-amine (1)
(20 g, 0.112 mol, 1 equiv). The mixture was stirred
for 2 h. Then the diphenyl carbonate (29 g, 0.134 mol,
1.2 equiv) was added to the flask. The resulting mix-
ture was stirred at 0◦C for 30 min and then warmed to
room temperature and stirred for additional 2 days.
About 300 mL of ethyl acetate was then added. The
5-(Pyridin-3-yl)-1,3,4-thiadiazol-2-amine (1)
POCl3 of 138 g (0.9 mole, 3 equiv) was added slowly
to the ice-bathed mixture of 37 g (0.3 mole, 1
equiv) of nicotinic acid, 27.3 g (0.3 mole, 1 equiv)
of thiosemicarbazide, and 180 mL 1,4-dioxane. The
mixture was then heated to and held at a temper-
Heteroatom Chemistry DOI 10.1002/hc

A New Convenient Way to Synthesize 1,3,4-Thiadiazol-2-yl Urea Derivatives under Microwave Irradiation 627
organic layer was wash with saturated salt water and
was oil-heated under reflux for 24 h. When the solu-
tion was cooled at room temperature, many precipi-
tated solid products were deposited from the solvent,
which were filtered off, dried, and crystallized from
the appropriate solvents.
dried by anhydrous Na2SO4. The solvent was evapo-
rated at reduced pressure, and the residue was sub-
jected to chromatography on silica gel using ethyl ac-
etate/methanol (20:1) as eluent. The yield was 70.5%.
1H NMR [300M Hz] δ: 13.013 (s, 1H, NH), 9.081 (s,
1H), 8.075 (s, 1H), 8.295–8.275 (m, 1H), 7.544–7.524
(t, J = 4.0 Hz, 1H), 7.433 (d, J = 7.2 Hz, 2H), 7.278
(d, J = 7.6 Hz, 2H). ESI-MS: (M+) m/z (%) = 297.3
(100).
Method B. A mixture of equimolar amounts
(1 equiv) of either 2 or 5 and heterocyclic amino
compounds (2 equiv) in toluene or THF (15 mL)
was treated in a microwave synthetic reactor un-
der these reaction conditions: The temperature was
150◦C, the absorption level was normal, and the reac-
tion time was 30 min. When the solution was cooled
at room temperature, many precipitated solid prod-
ucts were deposited from the solvent. After the yel-
low solvent was removed under reduced pressure,
the residue was gained and washed with ethanol.
The residue was recrystallized from the appropriate
solvents to yield a pure product as solid.
2-Amino-5-trifluoromethyl-1,3,4-thiadiazole (4)
Trifluoroacetic acid of 114.02 g (0.73 mole) was
added to 47.42 g (0.52 mol) of thiosemicarbazide
in 135 g of polyphosphoric acid. The mixture was
heated to and held at a temperature of about 110◦C
for about 8 h. It was then poured into 1 kg of ice.
The yellow solid was filtered off, washed with wa-
ter, and air-dried. The dried solid was recrystal-
lized from aqueous ethanol to yield yellow product
as 2-amino-5-trifluoromethyl-1,3,4-thiadiazole [5] in
63.2% yield. mp 230–232◦C, ESI-MS: (M+) m/z(%) =
168.37.
3a: White solid, yield 86%, mp >300◦C, 1H NMR
(400 MHz) δ: 10.018 (s, 1H, NH), 9.094 (d, J = 1.6 Hz,
1H), 8.680–8.665 (m, J = 2.0 Hz, 1H), 8.348–8.296
(m, J = 5.6 Hz, 2H), 7.843–7.800 (m, J = 3.3 Hz, 1H),
7.561–7.530 (m, J = 4.0 Hz, 2H), 7.124–7.033 (m,
1H). ESI-MS (M−) m/z (%): 297 (100), 298.2 (20);
Anal. Calcd. for C13H10N6OS. (298.3): C, 52.34; H,
3.38; N, 28.17. Found: C, 52.32; H, 3.48; N, 28.17.
3b: White solid, yield 86%, mp >300◦C, 1H NMR
(400 MHz) δ: 12.674 (s, 1H, NH), 9.992 (s, 1H), 9.075
(s, 1H), 8.659 (s, 1H), 8.283 (d, J = 6.4 Hz, 1H), 7.698–
7.662 (m, J = 4.8 Hz, 1H), 7.533 (d, J = 4.0 Hz, 1H),
7.287 (d, J = 2.8 Hz, 1H), 6.948 (d, J = 6.8 Hz, 1H),
2.433 (s, 3H). ESI-MS (M−) m/z (%): 313.2 (100),
314.2 (15); Anal. Calcd. for C14H12N6OS. (312.3): C,
53.83; H, 3.87; N, 26.91. Found: C, 53.82; H, 3.80; N,
26.89.
Phenyl 5-(trifluoromethyl)-1,3,4-thiadiazol-2-
ylcarbamate (5)
5-(Trifluoromethyl)-1,3,4-thiadiazol-2-amine
(4)
was dissolved in 60 mL dry THF and added to 6 g
(0.355 mol, 3 equiv) of NaH in 25 mL of dry THF
under ice-bath. Then diphenyl carbonate was added
to the flask slowly under ice-bath. After 2 days, it
was then poured onto 250 mL filler. Ethyl acetate of
60 mL was added. The organic layer was washed
with saturated salt water and dried by anhy-
drous Na2SO4. The solvent was evaporated at
reduced pressure, and the residue was subjected
to chromatography on silica gel, using petroleum
ether/ethyl acetate (1:1) as eluent. The yield was
61.3%. 1H NMR [400 MHz] δ: 7.401–7.362 (t, J = 7.8
Hz, 2H), 7.218 (d, J = 7.2 Hz, 1H), 7.182–7.160
(t, J = 4.4 Hz, 2H); ESI-MS: (M+) m/z (%) =
288.06(100).
3c: White solid, yield 84%, mp >300◦C, 1H NMR
(400 MHz) δ: 9.893 (d, J = 3.6 Hz, 1H), 9.088 (s,
1H), 8.674–7.665 (m, J = 1.8 Hz, 1H), 8.309–8.288 (t,
J = 4.2 Hz, 1H), 8.168 (s, 1H), 7.658–7.637 (m, 1H),
7.555–7.475 (m, 2H), 2.234 (s, 3H). ESI-MS: (M−)
m/z (%) = 313 (100); Anal. Calcd. for C14H12N6OS.
(312.3): C, 53.83; H, 3.87; N, 26.91. Found: C, 53.89;
H,3.99; N, 26.83.
3d: White solid, yield 92%, mp >300◦C, 1H NMR
(300 MHz) δ: 10.017 (s, 1H), 9.087 (s, 1H), 8.672
(d, J = 4.8 Hz, 1H), 8.312–8.289 (m, J = 3.8 Hz, 1H),
8.198 (d, J = 4.8 Hz, 1H), 7.558–7.528 (m, 1H), 7.313
(s, 1H), 6.954 (d, J = 5.2 Hz, 1H), 2.305 (s, 3H);
ESI-MS: (M−) m/z(%) = 312 (100); Anal. Calcd. for
C14H12N6OS. (312.3): C, 53.83; H, 3.87; N, 26.91.
Found: C, 53.61; H, 3.85; N, 26.90.
General Procedure for the Synthesis of
1-(Substituted)-3-(5-(substituted)-1,3,4
-thiadiazol-2-yl) Urea Derivatives (6a–j
and 3a–j)
General Procedure
Method A. A mixture of equimolar amounts
(1 equiv) of either 2 or 5 and heterocyclic amino
compounds (2 equiv) in toluene or THF (15 mL),
3e: White solid, yield 81%, mp >300◦C, 1H NMR
(400 MHz) δ: 11.107 (s, 1H, NH), 9.064 (s, 1H), 8.957
(s, 1H), 8.659 (d, J = 4.4 Hz, 1H), 8.263 (d, J = 8.0
Heteroatom Chemistry DOI 10.1002/hc

628 Li and Chen
1
6c: White solid, yield 62%, mp 234–236◦C; H
Hz, 1H), 7.546–7.514 (m, J = 4.3 Hz, 1H), 7.358 (d,
J = 8.0 Hz, 2H), 7.109 (d, J = 8.0 Hz, 2H), 2.231 (s,
3H, CH3); ESI-MS: (M−) m/z (%) = 312.0 (100).
3f: White solid, yield 82%, mp >300◦C, 1H NMR
(400 MHz) δ: 11.912 (s, 1H, NH), 9.890 (s, 1H), 8.667
(s, 1H), 8.443 (s, 1H), 8.287 (d, J = 6.8 Hz, 1H), 8.019
(d, J = 8.4 Hz, 1H), 7.707 (d, J = 8.8 Hz, 1H), 7.541
(d, J = 4 Hz, 1H). ESI-MS (M−) m/z (%): 375.3(100),
376.1(96), 378.1(50); Anal. Calcd. for C13H9BrN6OS.
(377.2): C, 41.39; H, 2.40; N, 22.28. Found: C, 41.43;
H, 2.63; N, 22.41.
NMR (300 MHz) δ: 12.864 (s, 1H, NH), 10.037 (s, 1H,
NH), 8.202 (s, 1H), 7.712–7.677 (m, 1H), 7.467 (d,
J = 11.2 Hz, 1H), 2.267 (s, 3H, CH3). ESI-MS: (M−)
m/z (%) = 301(100); Anal. Calcd. for C10H8F3N5OS.
(303.3): C, 39.6; H, 2.66; N, 23.09; Found: C, 39.50;
H, 2.72; N, 23.13.
1
6d: White solid, yield 58%, mp 250–252◦C. H
NMR (300 MHz) δ: 13.065 (s, 1H, NH), 10.148 (s, 1H,
NH), 8.233 (d, J = 7.2 Hz, 1H), 7.334 (s, 1H), 7.006 (d,
J = 6.8 Hz, 1H), 2.339 (s, 3H, CH3). ESI-MS: (M−)
m/z (%) = 301(100); Anal. Calcd for C10H8F3N5OS.
(303.3): C, 39.6; H, 2.66; N, 23.09; Found: C, 40.06;
H, 2.61; N, 23.11.
3g: White solid, yield 91%, mp >300◦C, 1H NMR
(400 MHz) δ: 11.835 (s, 1H, NH), 9.888 (s, 1H), 9.087
(s, 1H), 8.675 (d, J = 3.6 Hz, 1H), 8.384 (d, J = 1.6 Hz,
1H), 8.298 (d, J = 8.0 Hz, 1H), 7.943–7.916 (m, 1H),
7.746 (d, J = 8.4 Hz, 1H), 7.560–7.529 (m, J = 4.4 Hz,
1H); ESI-MS (M−) m/z (%): 330.4 (100), 332.4 (30);
Anal. Calcd. for C13H9ClN6OS (332.8): C, 46.92; H,
2.73; N, 25.25; Found: C, 46.80; H, 2.97; N, 25.37.
3h: White solid, yield 86%, mp >300◦C, 1H NMR
(400 MHz) δ (ppm): 11.871 (s, 1H, NH), 9.084 (s,
1H), 8.885 (s, 1H), 8.684 (d, J = 4.4 Hz, 1H), 8.493
(d, J = 8.0 Hz, 1H), 8.290 (d, J = 8.0 Hz, 1H), 8.127
(d, J = 4.4 Hz, 1H), 7.559–7.528 (m, J = 4.1 Hz,
1H), 7.459–7.427 (m, J = 4.4 Hz, 1H). ESI-MS (M−)
m/z (%): 331.3 (100), 333.2 (35). Anal. Calcd. for
C13H9ClN6OS (332.8): C, 46.92; H, 2.73; N, 25.25;
Found: C, 47.05; H, 2.78; N, 24.82.
1
6e: White solid, yield 58%, mp 238–240◦C. H
NMR (300 MHz) δ: 11.63 (s, 1H, NH), 9.084 (s, 1H,
NH), 7.381 (d, J = 6.8 Hz, 2H), 7.154 (d, J = 11.2 Hz,
2H), 2.270 (s, 3H, CH3). ESI-MS: (M−) m/z (%) =
301(100); Anal. Calcd. for C11H9F3N4OS. (302.3): C,
43.71; H, 3.00; N, 18.54; Found: C, 43.61; H, 2.90; N,
18.82.
1
6f: White solid, yield 86%, mp 258–260◦C, H
NMR [400 MHz] δ: 12.224 (s, 1H, NH), 9.936 (s, 1H,
NH), 8.447 (s, 1H), 8.027 (d, J = 8.4 Hz, 1H), 7.695
(d, J = 8.4 Hz, 1H). ESI-MS (M−) m/z (%): 365 (100),
368 (85); Anal. Calcd. for C9H5BrF3N5OS. (368.1): C,
29.36; H,1.37; N, 19.02; Found: C, 29.57; H, 1.57; N,
19.10.
3i: White solid, yield 84%, mp >300◦C, 1H NMR
(400 MHz) δ: 11.835 (s, 1H, NH), 9.888 (s, 1H), 9.087
(s, 1H), 8.675 (d, J = 3.6 Hz, 1H), 8.384 (d, J = 1.6 Hz,
1H), 8.298 (d, J = 8.0 Hz, 1H), 7.943–7.916 (m, 1H),
7.746 (d, J = 8.4 Hz, 1H), 7.560–7.529 (m, J = 4.4 Hz,
1H); ESI-MS (M+) m/z (%): 330.4 (100), 332.4 (30).
3j: White solid, yield 88%, mp >300◦C. 1H NMR
[400 MHz] δ: 11.268 (s, 1H, NH), 9.237 (s, 1H), 9.006
(s, 1H), 8.668 (t, J = 2.2 Hz, 1H), 8.264 (t, J = 3.8 Hz,
1H), 7.553–7.521 (m, J = 4.3 Hz, 1H), 7.472 (s, 4H);
ESI-MS (M−) m/z (%): 374.5 (85), 376.4 (100), 377.3
(20).
1
6g: White solid, yield 80%, mp 262–265◦C, H
NMR [400 MHz] δ: 12.178 (s, 1H, NH), 9.945 (s,
1H, NH), 8.383 (s, 1H), 7.938 (d, J = 8.8 Hz, 1H),
7.732 (d, J = 8.8 Hz, 1H). ESI-MS: (M−) m/z (%) =
323(100); Anal. Calcd. for C9H5ClF3N5OS. (323.7): C,
33.40; H, 1.56; N, 21.64; Found: C, 33.39; H, 1.72; N,
21.56.
1
6h: White solid, yield 59%, mp 242–245◦C. H
NMR (300 MHz) δ: 12.286 (s, 1H, NH), 8.965 (s, 1H,
NH), 8.465 (d, J = 10.8 Hz, 1H), 8.165 (d, J = 4.8 Hz,
1H), 7.488–7.446 (m, J = 5.3 Hz, 1H). ESI-MS: (M−)
m/z (%) = 322 (100); Anal. Calcd. for C9H5ClF3N5OS.
(323.7): C, 33.40; H, 1.56; N, 21.64; Found: C, 33.59;
H, 1.42; N, 21.41.
1
6a: White solid, yield 56%, mp 225–227◦C; H
NMR (400 MHz) δ: 12.859 (s, 1H, NH), 10.123 (s,
1H, NH), 8.35 (d, J = 4 Hz, 1H), 7.861–7.817 (m, 1H),
7.528 (d, J = 8.4 Hz, 1H), 7.149–7.118 (t, J = 6.2 Hz,
1H); ESI-MS: (M−) m/z (%) = 287 (100); Anal. Calcd.
for C9H6F3N5OS. (289.2): C, 37.37; H, 2.09; N, 24.21;
Found: C, 37.27; H, 2.11; N, 24.25.
1
6i: White solid, yield 67%, mp 240–241◦C. H
NMR (300 MHz δ: 13.365 (s, 1H, NH), 11.249 (s,
1H, NH), 8.792 (d, J = 6.8 Hz, 2H), 7.302–7.270 (t,
J = 6.4 Hz, 1H). ESI-MS: (M−) m/z (%) = 289(100);
Anal. Calcd. for C8H5F3N6OS. (290.0): C, 33.11; H,
1.74; N, 28.96; Found: C, 32.95; H, 1.93; N, 28.90.
1
6b: White solid, yield 35%, mp 238–240◦C; H
1
6j: White solid, yield 28%, mp 248–250◦C, H
NMR [300 MHz] δ: 13.056 (s, 1H, NH), 10.130 (s, 1H,
NH), 7.746 (t, J = 10.6 Hz, 1H), 7.330 (d, J = 11.2
Hz, 1H), 7.016 (d, J = 10.0 Hz, 1H), 2.476 (s, 3H,
CH3). ESI-MS: (M−) m/z (%) = 302 (100); Anal.
Calcd. for C10H8F3N5OS. (303.3): C, 39.6; H, 2.66; N,
23.09; Found: C, 39.77; H, 2.51; N, 23.13.
NMR (300 MHz) δ: 11.778 (s, 1H, NH), 9.330 (s, 1H,
NH), 7.507–7.444 (q, J = 11.2 Hz, 4H); ESI-MS: (M+)
m/z (%) = 368(100); Anal. Calcd. for C10H6BrF3N4OS.
(367.1): C, 32.71; H, 1.65; N, 15.26; Found: C, 32.81;
H, 1.60; N, 15.19.
Heteroatom Chemistry DOI 10.1002/hc

A New Convenient Way to Synthesize 1,3,4-Thiadiazol-2-yl Urea Derivatives under Microwave Irradiation 629
[16] Wichmann, J.; Geo, A.; Koclzewski, S.; Vincent, M.;
Woletring, T. Bioorg Med Chem Lett 1999, 9(11),
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Heteroatom Chemistry DOI 10.1002/hc