Synthesis and biological activity of some novel N-aryl-nprime;-[5-(pyrid-4- yl)-1,3,4-thiadiazol-2-yl]ureas

Article abstract of DOI:10.1080/10426500701415857

With the aim of searching for biologically active urea compounds, a series of new N-aryl-N'-[5-(pyrid-4-yl)-1,3,4-thiadiazol-2-yl]ureas have been designed and synthesized. Their structures were confirmed by IR, 1H NMR, and elemental analysis. The crystal

Full text of DOI:10.1080/10426500701415857

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Synthesis and Biological
Activity of Some Novel N-
Aryl-N′-[5-(pyrid-4-yl)-1,3,4-
thiadiazol-2-yl]ureas
Xin-Jian Song a b , Xiao-Hong Tan b & Yan-Gang Wang
c
a Key Laboratory of Biological Resources Protection
and Utilization of Hubei Province , Hubei Institute
for Nationalities , Enshi, Hubei, Peoples Republic of
China
b School of Chemical and Environmental
Engineering , Hubei Institute for Nationalities ,
Enshi, Hubei, Peoples Republic of China
c College of Chemistry , Central China Normal
University , Wuhan, Hubei, Peoples Republic of
China
Published online: 15 Jun 2007.
To cite this article: Xin-Jian Song , Xiao-Hong Tan & Yan-Gang Wang (2007) Synthesis
and Biological Activity of Some Novel N-Aryl-N′-[5-(pyrid-4-yl)-1,3,4-thiadiazol-2-
yl]ureas, Phosphorus, Sulfur, and Silicon and the Related Elements, 182:8, 1907-1913,
DOI: 10.1080/10426500701415857
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Phosphorus, Sulfur, and Silicon, 182:1907–1913, 2007
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500701415857
Synthesis and Biological Activity of Some Novel
N-Aryl-Nꢀ-[5-(pyrid-4-yl)-1,3,4-thiadiazol-2-yl]ureas
Xin-Jian Song
Key Laboratory of Biological Resources Protection and Utilization of
Hubei Province, Hubei Institute for Nationalities, Enshi, Hubei, Peoples
Republic of China; and School of Chemical and Environmental
Engineering, Hubei Institute for Nationalities, Enshi, Hubei, Peoples
Republic of China
Xiao-Hong Tan
Key Laboratory of Biological Resources Protection and Utilization of
Hubei Province, Hubei Institute for Nationalities, Enshi, Hubei, Peoples
Republic of China
Yan-Gang Wang
College of Chemistry, Central China Normal University, Wuhan, Hubei,
Peoples Republic of China
With the aim of searching for biologically active urea compounds, a series of new
N-aryl-Nꢀ-[5-(pyrid-4-yl)-1,3,4-thiadiazol-2-yl]ureas have been designed and syn-
thesized. Their structures were confirmed by IR, 1H NMR, and elemental analysis.
The crystal structure of 3f was further determined by single crystal X-ray diffraction
to obtain the structural information on this class of compounds. The preliminary
bioassay showed that the title compounds exhibit promising cytokinin activity.
Keywords 1,3,4-Thiadiazole; crystal structure; cytokinin activity; urea
INTRODUCTION
1,3,4-Thiadiazole derivatives have been attracting widespread at-
tention due to their significant biological activities, such as
fungicidal,1 insecticidal,2 plant-growth regulating,3 and pharmaco-
logical properties.4−7 In general, pyridine can serve as effective
bioisostere of benzene in drug design and considerable interest has been
Received March 6, 2007; accepted April 7, 2007.
Address correspondence to Xin-Jian Song, School of Chemical and Environmental
Engineering, Hubei Institute for Nationalities, Enshi, Hubei 445000, P. R. China. E-mail:
whxjsong@yahoo.com.cn
1907

1908
X.-J. Song et al.
shown in pyridine derivatives in the field of modern agrochemistry
and medicinal chemistry because substitution of benzene by pyri-
dine may result in the good biological activity and low toxicity of
molecules.8,9 Not only N6-substituted adenine derivatives, like benzy-
ladenine or furfuryladenine (kinetin), but also substituted urea deriva-
tives, like N-phenyl-Nꢀ-(1,2,3-thiadiazol-5-yl)urea (thidiazuron, TDZ),
show cyokinin activity,10,11 which seems to be a property of the two
classes of compounds. Moreover, it is generally believed that the active
site of purine and urea cytokinins are common,12 so that no special
molecular shape other than flatness is required for activity.13 In our
continuing search for new urea cytokinins, we would like to synthesize
the urea molecules characterized by plane structure and incorporating
both 1,3,4-thiadiazole and pyridine rings for evaluating their cytokinin
activity. The synthetic route of the title compounds 3 is depicted in
Scheme 1.
SCHEME 1
RESULTS AND DISCUSSION
The required 2-amino-5-(pyrid-4-yl)-1,3,4-thiadiazole 1 was obtained
via the oxidative cyclization of thiosemicarbazone in the presence of
ferric chloride hexahydrate according to the literature method.14 Acyl
azides were efficiently prepared directly from carboxylic acids, ethyl
chloroformate and sodium azide by one-pot procedure, undergoing facile
Curtius rearrangement at elevated temperature to isocyanates, then re-
act with 2-amino-5-(pyrid-4-yl)-1,3,4-thiadiazole resulting in the forma-
tion of the corresponding ureas. This general method involves readily

Synthesis and Biological Activity of Some Arylureas
1909
available starting material, mild reaction conditions, simple handling
procedure, and avoids the unstable and toxic isocyanates being directly
employed.
The structures of compounds 3 were verified spectroscopically. For
example, the IR spectra contained absorption bands due to stretching
vibrations of the two NH groups (two broadened bands in the regions
3360–3390 and 3180–3210 cm−1), and carbonyl group (1700–1735 cm−1
)
in the urea bridge. In the 1H NMR spectra (DMSO-d6) compounds 3a–
3h displayed the pyridyl signals from protons as a pair of doublets
(AAꢀBBꢀ system), each appearing near 7.90 and 8.70 ppm and J = 5.2
Hz, while the aromatic signals appeared between δ 6.88–8.14ppm as
multiplets. Each NH groups showed a broadened singlet at δ 8.90–9.30
1
and 11.20–11.45 ppm. Thus it can be seen that the data of H NMR,
IR and elemental analysis for the products are in good agreement with
the structures of the title compounds.
The structure of product 3f was unambiguously proved by the X-ray
diffraction data, for the purpose of obtaining the structural feature of
this class of compounds. The molecular structure is shown in Figure 1.
The X-ray diffraction reveals that the title molecule 3f which consists of
three rings is essentially planar, the dihedral angles formed by the thia-
diazole ring with the pyridine and benzene planes being only 6.82(14)◦
and 3.64(12)◦, respectively. It is obvious that the flatness of the molecule
can be attributed to the presence of the extended π conjugated system
throughout the whole molecule.
The cytokinin activity of all the title compounds 3 was investigated
by the method of cucumber cotyledon expansion.15 Their promotive per-
centages tested at the concentration of 10 ppm were 45.1%, 34.2%,
38.0%, 23.6%, 32.7%, 41.6%, 19.5% and 21.8% respectively. The re-
sults of preliminary bioassay indicated that these new urea derivatives
exhibit moderate-to-good cytokinin activity, especially the promotive
FIGURE 1 Molecular structure of compound 3f with the atomic labeling.

1910
X.-J. Song et al.
percentage reached above 40% as for compounds 3e and 3g, which de-
serve further research. We would conclude therefore that such good
biological effects could be ascribed to the flatness of the molecule to-
gether with introduction of the 1,3,4-thiadiazole heterocycle and the
pyridyl group into the urea molecule.
EXPERIMENTAL
All chemicals and solvents used for the preparation the compounds
were of analytical grade. The 1H NMR spectra were obtained on a Var-
ian Mercury Plus-400 MHz Spectrometer with TMS as internal stan-
dard and DMSO-d6 as the solvent. The IR spectra were recorded in the
range 4000–400 cm−1 on a Nicolet NEXUS 470 FT-IR spectrophotome-
ter, using KBr pellets. Elemental analysis was performed by a Vario
EL III analyzer. Melting points were determined by an X-4 microscopic
melting apparatus and uncorrected.
General Method for the Synthesis of Compounds 3
To the solution of substituted benzoic acid (11 mmoles) in 10 mL of
acetone was successively added triethylamine (1.21 g, 12 mmoles) and
the solution of ethyl chloroformate (1.52 g, 14 mmoles) in 4 mL of ace-
tone below 5◦C. After the mixture was stirred for 30 min, the solution
of sodium azide (0.98 g, 15 mmoles) in 5 mL of water was added drop-
wise below 5◦C. The reaction mixture was stirred at 0–5◦C for a further
1.5 h and then filtrated. The clear filtrate was extracted with toluene
(2 × 4 mL), and the combined organic layer were washed with brine
and dried over MgSO4. The solution of acyl azide 2 obtained was added
dropwise to the solution of intermediate 1 (1.78 g, 10 mmoles) in 5 mL
of freshly dried dimethylformide (DMF), which had been preheated to
70–75◦C. The resulting reaction mixture was stirred at this tempera-
ture for another 3.5–4 h. The mixture was then cooled, and the solid
was filtrated and recrystallized from ethanol/DMF to give the desired
products 3a–3h as yellowish crystal. m.p. >300◦C.
N-Phenyl-Nꢀ-[5-(pyrid-4-yl)-1,3,4-thiadiazol-2-yl]urea (3a)
1
Yield: 71.8%; H NMR (400 MHz, DMSO-d6): δ 11.27 (bs, 1H, NH),
9.12 (bs, 1H, NH), 8.73 (d, 2H, J = 5.2 Hz, pyridyl 2,6-H), 7.89 (d, 2H,
J = 5.2 Hz, pyridyl 3,5-H), 7.06–7.53 (m, 5H, Ar-H); IR (KBr, ν in cm−1):
3379, 3198 (N H), 1725 (C O); Anal. Calcd for C14H11N5OS: C 56.55;
H 3.73; N 23.55. Found: C 56.72; H 3.55; N 23.63.

Synthesis and Biological Activity of Some Arylureas
1911
N-(3-Fluorophenyl)-N ꢀ-[5-(pyrid-4-yl)-1,3,4-thiadiazol-2-yl]urea
(3b)
1
Yield: 66.2%; H NMR (400 MHz, DMSO-d6): δ 11.53 (bs, 1H, NH),
9.38 (bs, 1H, NH), 8.72 (d, 2H, J = 5.2 Hz, pyridyl 2,6-H), 7.88 (d, 2H,
J = 5.2 Hz, pyridyl 3,5-H), 6.88–7.53 (m, 4H, Ar-H); IR (KBr, ν in cm−1):
3382, 3208 (N H), 1725 (C O); Anal. Calcd for C14H10FN5OS: C 53.33;
H 3.20; N 22.21. Found: C 53.45; H 2.97; N 22.39.
N-(4-Fluorophenyl)-N ꢀ-[5-(pyrid-4-yl)-1,3,4-thiadiazol-2-yl]urea
(3c)
1
Yield: 67.1%; H NMR (400MHz, DMSO-d6): δ 11.36 (bs, 1H, NH),
9.17 (bs, 1H, NH), 8.72 (d, 2H, J = 5.2 Hz, pyridyl 2,6-H), 7.88 (d, 2H,
J = 5.2 Hz, pyridyl 3,5-H), 7.15–7.55 (m, 4H, Ar-H); IR (KBr, ν in cm−1):
3378, 3201 (N–H), 1728 (C O); Anal. Calcd for C14H10FN5OS: C 53.33;
H 3.20; N 22.21. Found: C 53.12; H 3.06; N 22.43.
N-(2-Chlorophenyl)-N ꢀ-[5-(pyrid-4-yl)-1,3,4-thiadiazol-2-yl]urea
(3d)
1
Yield: 64.2%; H NMR (400 MHz, DMSO-d6): δ 11.92 (s, 1H, NH),
8.81 (s, 1H, NH), 8.74 (d, 2H, J = 5.2 Hz, pyridyl 2,6-H), 7.90 (d, 2H,
J = 5.2 Hz, pyridyl 3,5-H), 7.15–8.14 (m, 4H, Ar-H); IR (KBr, ν in cm−1):
3356, 3180 (N–H), 1711 (C O); Anal. Calcd for C14H10ClN5OS: C 50.68;
H 3.04; N 21.11. Found: C 50.59; H 2.87; N 20.92.
N-(3-Chlorophenyl)-N ꢀ-[5-(pyrid-4-yl)-1,3,4-thiadiazol-2-yl]urea
(3e)
1
Yield: 66.0%; H NMR (400 MHz, DMSO-d6): δ 11.43 (bs, 1H, NH),
9.35 (bs, 1H, NH), 8.74 (d, 2H, J = 5.2 Hz, pyridyl 2,6-H), 7.90 (d, 2H,
J = 5.2 Hz, pyridyl 3,5-H), 6.89–7.55 (m, 4H, Ar-H); IR (KBr, ν in cm−1):
3381, 3190 (N–H), 1709 (C O); Anal. Calcd for C14H10ClN5OS: C 50.68;
H 3.04; N 21.11. Found: C 50.80; H 2.91; N 21.29.
N-(4-Chlorophenyl)-N ꢀ-[5-(pyrid-4-yl)-1,3,4-thiadiazol-2-yl]urea
(3f)
1
Yield: 67.5%; H NMR (400 MHz, DMSO-d6): δ 11.36 (bs, 1H, NH),
9.27 (bs, 1H, NH), 8.73 (d, 2H, J = 5.2 Hz, pyridyl 2,6-H), 7.89 (d, 2H,
J = 5.2 Hz, pyridyl 3,5-H), 7.38–7.57 (m, 4H, Ar-H); IR (KBr, ν in cm−1):
3375, 3206 (N–H), 1731 (C O); Anal. Calcd for C14H10ClN5OS: C 50.68;
H 3.04; N 21.11. Found: C 50.73; H 2.95; N 20.96.

1912
X.-J. Song et al.
N-(3-Methylphenyl)-N ꢀ-[5-(pyrid-4-yl)-1,3,4-thiadiazol-2-
yl]urea (3g)
1
Yield: 60.3%; H NMR (400 MHz, DMSO-d6): δ 11.30 (bs, 1H, NH),
9.04 (bs, 1H, NH), 8.73 (d, 2H, J = 5.2 Hz, pyridyl 2,6-H), 7.89 (d, 2H,
J = 5.2 Hz, pyridyl 3,5-H), 6.89–7.36 (m, 4H, Ar-H), 2.31(s, 3H, CH3);
IR (KBr, ν in cm−1): 3388, 3207 (N–H), 1729 (C O); Anal. Calcd for
C15H13N5OS: C 57.86; H 4.21; N 22.49. Found: C 58.01; H 3.98; N 22.38.
N-(4-Methylphenyl)-N ꢀ-[5-(pyrid-4-yl)-1,3,4-thiadiazol-2-
yl]urea (3h)
1
Yield: 62.7%; H NMR (400 MHz, DMSO-d6): δ 11.23 (bs, 1H, NH),
9.03 (bs, 1H, NH), 8.73 (d, 2H, J = 5.2 Hz, pyridyl 2,6-H), 7.89 (d,
2H, J = 5.2 Hz, pyridyl 3,5-H), 7.14–7.41 (m, 4H, Ar-H), 2.27 (s, 3H,
CH3); IR (KBr, ν in cm−1): 3381, 3202 (N–H), 1709 (C O); Anal. Calcd
for C15H13N5OS: C 57.86; H 4.21; N 22.49. Found: C 57.75; H 4.14;
N 22.62.
X-Ray Crystallography of Compound 3f
A single crystal of compound 3f with dimensions of 0.30 × 0.20 ×
0.04 mm3 was mounted on a BRUKER SMART APEX-CCD diffrac-
tometer equipped with a graphite-monochromated Mo Kα (λ = 0.71073
˚
A) radiation at 292(2) K. A total of 5529 reflections were collected in the
range of 1.28 ≤ θ ≤ 26.00◦ by using a ψ-ω scan mode with 2742 indepen-
dent ones (Rint 0.0247), of which 2001 with I > 2σ(I) were considered
as observed and used in the succeeding refinements. Triclinic crystals
with the following unit cell parameters: a = 5.8550(8), b = 7.5668(10),
◦
◦
◦
˚
c = 16.416(2) A; α = 78.364(2) , β = 81.204(2) , γ = 84.749(2) ; V =
702.58(16) A ; M = 331.79; Z = 2; Dcalc = 1.568 g/cm3; µ = 4.29 cm−1
;
3
˚
¯
F(000) = 340; space group P1. The structure was solved by direct
Fourier methods. The non-hydrogen atoms were refined anisotropically,
and the hydrogen atoms were added according to theoretical models.
Full-matrix least-squares refinement was based on F2 using SHELXL-
97 program.16 The final refinement gave R = 0.0442 and wR = 0.1092
1
2
(w = 1/[σ2(Fo2) + (0.0705P)2], where P = (Fo2 + 2F2)/3). The maximum
and minimum residual peaks on the final diffecrence Fourier maps
3
˚
amounted to 0.275 and −0.254 e/A , respectively.
ACKNOWLEDGMENTS
We are grateful to the National Natural Science Foundation of China
(Grant No. 20072009), Natural Science Foundation of Hubei Province

Synthesis and Biological Activity of Some Arylureas
1913
(2007), and the Scientific Research Fund for Distinguished Young
Scholar from Hubei Provincial Department of Education (Grant No.
Q200729001) for generous financial support.
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