Microwave assisted synthesis and biological activity of n-aryl-n'-nicotinoyl thiourea

Article abstract of DOI:10.14233/ajchem.2013.14444

A series of N-aryl-N'-nicotinoyl thiourea derivatives were synthesized using microwave irradiation. The synthesized compounds were characterized by 1H NMR, IR, MS and elemental analysis. Fungicidal activity of the compounds were evaluated through G. zeae

Full text of DOI:10.14233/ajchem.2013.14444

Asian Journal of Chemistry; Vol. 25, No. 10 (2013), 5420-5422
http://dx.doi.org/10.14233/ajchem.2013.14444
Microwave Assisted Synthesis and Biological Activity of N-Aryl-N'-nicotinoyl Thiourea
1
2,*
JIAN-YING TONG , NA-BO SUN1,* and HONG-KE WU
1College of Biology and Environmental Engineering, Zhejiang Shuren University, Hangzhou 310015, Zhejiang, P.R. China
2College of Chemical Engineering and Materials Science, Zhejiang University of Technology, Hangzhou 310014, Zhejiang, P.R. China
*Corresponding authors: E-mail: jianyington@gmail.com
(Received: 16 August 2012;
Accepted: 10 April 2013)
AJC-13220
A series of N-aryl-N'-nicotinoyl thiourea derivatives were synthesized using microwave irradiation. The synthesized compounds were
characterized by 1H NMR, IR, MS and elemental analysis. Fungicidal activity of the compounds were evaluated through G. zeae Petch,
B. cinerea Pers, Phytophthora infestans (Mont.) de Bary, Botryosphaeria berengeriana f. sp. piricola (Nose) koganezawa et Sakuma,
Fusarium oxysporum f. sp. cucumerinum and Cercospora arachidicola. tests, their activity are moderate.
Key Words: Microwave irradiation, Acyl thiourea, Nicotinic acid, Fungicidal activity.
bromide tablets. 1H NMR spectra were measured on a Bruker
AC-P500 instrument (300 MHz) using tetramethyl-silane as
INTRODUCTION
Research on the synthesis and biological activity of
an internal standard and deuterochloroform as solvent. Mass
heterocyclic compounds is an important developmental
spectra were recorded on a Thermo Finnigan LCQAdvantage
LC/mass detector instrument. Elemental analyses were
oriental in pesticide and medicine chemistry1. It is well known
that nicotinic acid and their derivatives exhibit excellent
performed on a Yanaco MT-3CHN elemental analyzer.
Preparation of N-aryl-N'-nicotinoyl thiourea: Nicotinic
biological activity. Novel pyridine and related derivatives2 are
attractive molecules because their structure is present in several
acid (5 g, 40 mmol) was added thionyl chloride 10 mL and the
natural compounds, drugs or argochemicals. Additionally,
mixture was refluxed for 3 h to give acid chloride. Powdered
various types of acyl-thiourea derivatives had comprehensive
bioactivities, due to they held amide group3 and thioamide
g, 10 mmol), PEG-600 (0.18 g, 3 % with respect to ammonium
ammonium thiocyanate (1.14 g, 15 mmol), acid chloride (1.04
group.
thiocyanate) methylene chloride (25 mL) and pyridine were
placed in a dried round-bottomed flask containing a magnetic
Microwave technique, meanwhile, has been widely used
for a variety of organic reactions, such as Claisen, hetero-
stirrer bar and stirred at room temperature for 1 h. Then
cyclic synthesis, oxidation, hydrolysis, esterification, etheri-
fication and so on. Many reports4 have been published in favour
dichloride (10 mL) was added drop wise over 0.5 h and the
substituted substituted aniline (4.5 mmol) in methylene
of its considerable accelerations of the reaction rates and
satisfactory yields.
In order to search for new compounds with good biolo-
mixture was stirred for 15 min under microwave irradiation.
The corresponding thiourea precipitated immediately. The
product was filtered and recrystallized from DMF-EtOH-H2O,
gical activity, ten thiourea derivatives (3a-j) were synthesized
afforded a light yellow solid (Scheme-I).
under microwave irradiation. Their structures are confirmed
by 1H NMR, IR, MS and elemental analysis. The preliminary
N-2,4,5-trichlorophenyl-N'-nicotinoyl thiourea (3a):
The compound was obtained in 67.1 % yield as a yellow crystal;
1
m.p. 199-200 ºC; H NMR (CDCl3, 300 MHz), δ: 12.44 (s,
biological tests show that these compounds had moderate
fungicidal activity.
NH, 1H), 11.90 (s, NH, 1H), 7.09-8.26 (m, ArH and Py, 6H).
IR (KBr, νmax, cm-1): 3321, 3104 (NH), 1670 (C=O), 1151
(C=S). MS (ESI), m/z: 359 (M -1). Elemental anal. (%), calcu-
EXPERIMENTAL
Nicotinic acid, substituted aniline were commercially
available. Melting points were determined using a X-4 melting
apparatus and were uncorrected. Infrared spectra were recorded
on a Bruker Equinox55 spectrophotometer as potassium
lated: C, 43.29; H, 2.24; N, 11.65; found: C, 43.50; H, 2.41;
N, 11.51.
N-2,5-dichlorophenyl-N'-nicotinoyl thiourea (3b):The
compound was obtained in 67.1 % yield as a yellow crystal;

Vol. 25, No. 10 (2013)
Microwave Assisted Synthesis and Biological Activity of N-Aryl-N'-nicotinoyl Thiourea 5421
S
O
O
O
R
R
NH2
NCS
N
H
NH4NCS
N
H
Cl
MW
PEG-600/CH2Cl2
N
N
N
1
2
3
Scheme-I: Synthesis route for the title compounds
1
m.p. 206-207 ºC; H NMR (CDCl3, 300 MHz), δ: 11.98 (s,
NH, 1H), 11.78 (s, NH, 1H), 7.23-8.14 (m, ArH and Py, 7H).
IR (KBr, νmax, cm-1): 3301, 3112 (NH), 1668 (C=O), 1157
(C=S). MS (ESI), m/z : 325 (M-1). Elemental anal. (%),
calculated: C, 47.87; H, 2.78; N, 12.88; found: C, 47.99; H,
2.44; N, 12.85.
(C=S). MS (ESI), m/z: 324 (M-1). Elemental anal. (%), calcu-
lated: C, 51.69; H, 3.10; N, 12.92; found: C, 51.45; H, 3.09;
N, 13.05.
N-4-chlorophenyl-N'-nicotinoyl thiourea (3i): The
compound was obtained in 67.1 % yield as a yellow crystal;
1
m.p. 232-234 ºC; H NMR (CDCl3, 300 MHz), δ: 12.12 (s,
N-3-methylphenyl-N'-nicotinoyl thiourea (3c): The
compound was obtained in 67.1 % yield as a yellow crystal;
NH, 1H), 11.88(s, NH, 1H), 7.22-8.25 (m, ArH and Py, 8H).
IR (KBr, νmax, cm-1): 3352, 3156 (NH), 1669 (C=O), 1154
(C=S). MS (ESI), m/z: 291 (M-1). Elemental anal. (%), calcu-
lated: C, 53.52; H, 3.45; N, 14.40; found: C, 53.48; H, 3.65;
N, 14.12.
1
m.p. 106-107 ºC; H NMR (CDCl3, 300 MHz), δ: 11.98 (s,
NH, 1H), 11.81 (s, NH, 1H), 7.12-8.66 (m, ArH and Py, 8H),
2.55 (s, CH3, 3H). IR (KBr, νmax, cm-1): 3221, 3089 (NH), 1672
(C=O), 1151 (C=S). MS (ESI), m/z: 270 (M-1). Elemental
anal. (%), calculated: C, 61.97; H, 4.83; N, 15.49; found: C,
61.89; H, 4.65; N, 15.45.
N-2-trifluoromethylphenyl-N'-nicotinoyl thiourea (3j):
The compound was obtained in 67.1 % yield as a yellow
crystal; m.p. 203-204 ºC; 1H NMR (CDCl3, 300 MHz), δ: 12.15
(s, NH, 1H), 12.03 (s, NH, 1H), 7.19-8.26 (m, ArH and Py,
8H). IR (KBr, νmax, cm-1): 3291, 3144 (NH), 1670 (C=O), 1155
(C=S). MS (ESI), m/z: 324 (M-1). Elemental anal. (%), calcu-
lated: C, 51.69; H, 3.10; N, 12.92; found: C, 51.45; H, 3.43;
N, 13.21.
N-3-chlorophenyl-N'-nicotinoyl thiourea (3d): The
compound was obtained in 67.1 % yield as a yellow crystal;
1
m.p. 153-154 ºC; H NMR (CDCl3, 300 MHz), δ: 12.32 (s,
NH, 1H), 11.78 (s, NH, 1H), 7.33-8.34 (m, ArH and Py, 8H).
IR (KBr, νmax, cm-1): 3345, 3132 (NH), 1665 (C=O), 1147
(C=S). MS (ESI), m/z: 291 (M -1). Elemental anal. (%),
calculated: C, 53.52; H, 3.45; N, 14.40; found: C, 53.88; H,
3.47; N, 14.56.
Bioassay of fungicidal activities: The method for
testing the primary biological activities was performed in an
isolated culture. Under a sterile condition, 1 mL of sample
was added to the culture plates, followed by the addition of 9
mL of culture medium. The final mass concentration was 50
µg/mL. The blank assay was performed with 1 mL of sterile
water. Circle mycelium with a diameter of 4 mm was cut using
a drill. The culture plates were cultivated at ( 24 1) ºC. The
extended diameters of the circle mycelium were measured after
72 h. The relative inhibition rate of the circle mycelium
compared to blank assay was calculated via the following
equation:
N-2-chlorophenyl-N'-nicotinoyl thiourea (3e): The
compound was obtained in 67.1 % yield as a yellow crystal;
1
m.p. 210-211 ºC; H NMR (CDCl3, 300 MHz), δ: 12.12 (s,
NH, 1H), 11.98 (s, NH, 1H), 7.21-8.25 (m, ArH and Py, 8H).
IR (KBr, νmax, cm-1): 3341, 3189 (NH), 1669 (C=O), 1158
(C=S). MS (ESI), m/z: 291 (M-1). Elemental anal. (%), calcu-
lated: C, 53.52; H, 3.45; N, 14.40; found: C, 53.77; H, 3.33;
N, 14.51.
N-3-trifluoromethylphenyl-N'-nicotinoyl thiourea (3f)
: The compound was obtained in 67.1% yield as a yellow
crystal; m.p. > 250 ºC; 1H NMR (CDCl3, 300 MHz), δ: 11.95
(s, NH, 1H), 11.67 (s, NH, 1H), 7.14-8.33 (m, ArH and Py,
8H). IR (KBr, νmax, cm-1): 3245, 3111 (NH), 1665 (C=O), 1144
(C=S). MS (ESI), m/z : 324 (M-1). Elemental anal. (%),
calculated: C, 51.69; H, 3.10; N, 12.92; found: C, 51.80; H,
3.48; N, 12.64.
dex − dex'
×100%
Relative inhibition rate (%) =
dex
where dex is the extended diameter of the circle mycelium
during the blank assay; and d’ex, is the extended diameter of
the circle mycelium during testing.
N-2-iodophenyl-N'-nicotinoyl thiourea (3g): The com-
pound was obtained in 67.1 % yield as a yellow crystal; m.p.
1
238-240 ºC; H NMR (CDCl3, 300 MHz), δ: 12.11 (s, NH,
RESULTS AND DISCUSSION
Biological activities: Fungicidal activities of compounds
3a, 3c, 3e, 4a, 4c, 4e against G. zeae Petch, Phytophthora
infestans (Mont.) de Bary, Botryosphaeria berengeriana f. sp.
piricola (Nose) koganezawa et Sakuma, Fusarium oxysporum
f.sp. cucumerinum and Cercospora arachidicola. The
fungicidal activities of the title compounds were determined.
The results were shown in Table-1. It was also found that
some of these compounds displayed moderate fungicidal
activity.
1H), 11.99 (s, NH, 1H), 7.05-8.23 (m, ArH and Py, 8H). IR
(KBr, νmax, cm-1): 3334, 3144 (NH), 1668 (C=O), 1161 (C=S).
MS (ESI), m/z: 382 (M-1). Elemental anal. (%), calculated:
C, 40.75; H, 2.63; N, 10.97; found: C, 40.45; H, 2.41; N, 10.57.
N-4-trifluoromethylphenyl-N'-nicotinoyl thiourea
(3h): The compound was obtained in 67.1 % yield as a yellow
crystal; m.p. 121-123 ºC; 1H NMR (CDCl3, 300 MHz), δ: 12.05
(s, NH, 1H), 11.99 (s, NH, 1H), 7.16-8.39 (m, ArH and Py,
8H). IR (KBr, νmax, cm-1): 3318, 3096 (NH), 1650 (C=O), 1145

5422 Tong et al.
Asian J. Chem.
TABLE-1
FUNGICIDAL ACTIVITY OF TESTED COMPOUNDS AT 50 ppm
Phytophthora infestans
(Mont.) de Bary
Botryosphaeria berengeriana f. sp.
piricola (Nose) koganezawa et Sakuma
Fusarium oxysporum
f.sp. cucumerinum
Cercospora
arachidicola
No
G. zeae Petch
10
25
5
23
34
40
0
57
45
21
49
8
26
32
45
38
62
55
24
25
25
48
0
3a
3b
3c
3d
3e
3f
65
45
0
28
51
0
21
35
34
18
36
35
15
8
41
51
28
27
36
42
15
48
34
24
33
34
15
3g
3h
3i
3j
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