Substituted-nicotinyl thiourea derivatives bearing pyrimidine moiety: Synthesis and biological evaluation

Article abstract of DOI:10.1007/s11164-010-0235-1

A series of substituted-nicotinyl thiourea derivatives containing pyrimidine ring were synthesized in good to excellent yield using PEG-400 as solid-liquid phase transfer catalyst under ultrasonic irradiation. The structures of all newly synthesized compounds were elucidated and confirmed by IR, ¹H NMR and elemental analysis. The preliminary biological tests show that some of the target compounds present good inhibitory activities against the root and stalk of dicotyledon plants and are safe for monocotyledon plants.

Full text of DOI:10.1007/s11164-010-0235-1

Res Chem Intermed (2011) 37:627–633
DOI 10.1007/s11164-010-0235-1
Substituted-nicotinyl thiourea derivatives bearing
pyrimidine moiety: synthesis and biological evaluation
•
Shaoyong Ke Xiufang Cao
Received: 22 December 2010 / Accepted: 27 December 2010 / Published online: 18 January 2011
Ó Springer Science+Business Media B.V. 2011
Abstract A series of substituted-nicotinyl thiourea derivatives containing
pyrimidine ring were synthesized in good to excellent yield using PEG-400 as
solid–liquid phase transfer catalyst under ultrasonic irradiation. The structures of all
1
newly synthesized compounds were elucidated and confirmed by IR, H NMR and
elemental analysis. The preliminary biological tests show that some of the target
compounds present good inhibitory activities against the root and stalk of dicoty-
ledon plants and are safe for monocotyledon plants.
Keywords Nicotinyl thiourea ꢀ PTC ꢀ Synthesis ꢀ Bioactivity
Introduction
Nitrogen heterocycles are extremely versatile building blocks for the manufacture of
active compounds such as antimicrobial, antibacterial, herbicides, fungicides, and
insecticides in the pharmaceutical drug design and agrochemical industries [1–7].
Among these, substituted nicotinic acid and its derivatives such as agricultural and
pharmaceutical intermediates are well established [8–11]. Moreover, acylthiourea
derivatives are well-known scaffolds for a wide range of biological activities such as
antioxidant, bactericidal, herbicidal, insecticidal and regulating activities for plant
growth [12–18].
S. Ke (&)
Hubei Biopesticide Engineering Research Center, Hubei Academy of Agricultural Sciences,
Wuhan 430064, People’s Republic of China
e-mail: keshaoyong@163.com
X. Cao (&)
College of Science, Huazhong Agricultural University, Wuhan 430070,
People’s Republic of China
e-mail: caoxiufang@mail.hzau.edu.cn
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S. Ke, X. Cao
O
S
X
Y
COOH
COCl
CONCS
i
iii
ii
N
HN
N
N
R
R
R
R
HN
N
N
N
1
2
3
4
i. R = 6-Cl, X = Cl, Y = OMe
j. R = 5,6-Cl2, X = Y = OMe
k. R = 5,6-Cl2, X = Y = OEt
l. R = 5,6-Cl2, X = Cl, Y = OMe
e. R = 2-Cl, X = Cl, Y = OEt
f. R = 2-Cl, X = Y = Cl
g. R = 6-Cl, X = Y = OMe
h. R = 6-Cl, X = Y = OEt
a. R = 2-Cl, X = Y = OMe
b. R = 2-Cl, X = Y = Me
c. R = 2-Cl, X = Y = OEt
d. R = 2-Cl, X = Cl, Y = OMe
Scheme 1 General synthetic route for substituted-nicotinyl thiourea 4a–l. Reagents and conditions:
I SOCl2; II KSCN, PEG-400, MeCN, USI; III substituted-pyrimidine, MeCN, USI
On the other hand, the phase transfer catalysis reaction technique has been widely
recognized as an efficient synthetic tool and has attracted much attention [19–23]. In
addition, the ultrasonic wave has been utilized in organic synthesis for its lower
reaction temperature and simple operation as compared with conventional heating
methods. A survey of the literature shows that many organic reactions have recently
been accelerated by ultrasonic irradiation [24–28]. In view of these observations, a
series of substituted-nicotinyl thiourea derivatives containing the pyrimidine ring
were synthesized (Scheme 1) and tested for their biological activity. In this paper,
we have conducted our reactions using PEG-400 as the solid–liquid phase transfer
catalyst under ultrasonic irradiation, which is an easy and convenient method for
access to nicotinyl-thiourea derivatives. Under ultrasonic irradiation, the interme-
diate acyl isothiocyanate undergoes a rapid reaction with an added amino
pyrimidine to give the corresponding target compounds in good yields. Our
ultrasonic irradiation method apparently improves the efficiency of the synthetic
process with a good yield and a shorter processing time: this modified method
shortened the reaction time from 5–6 to 1–1.5 h and yielded acylthiourea
derivatives in greater quantities compared with conventional methods.
Results and discussion
Synthesis for substituted-nicotinylthiourea derivatives 4a–l
The intermediate substituted-nicotinyl chloride 1 obtained by the reaction of
substituted-nicotinic acid with thionyl chloride was treated with potassium
thiocyanate using PEG-400 as the phase transfer catalyst under ultrasonic irradiation
to give substituted-nicotinyl isothiocyanate 2. It was found that the acyl chloride
was quantitatively converted to the corresponding acyl isothiocyanate. This
intermediate was then treated with 4,6-disubstituted-2-amino pyrimidine 3 to give
the desired substituted-nicotinyl thiourea derivatives 4 in good yields.
We know that the use of ultrasonic irradiation as a method of agitating a
heterogeneous reaction system is gaining recognition. In our search to improve methods
of preparing acylthiourea by reacting acyl isothiocyanates with nucleophiles, we have
found that the ultrasonic vibration of a mixture of acyl chloride, potassium thiocyanate
and 3% PEG-400 in acetonitrile can obtain acyl isothiocyanates in good yields. In this
123

Substituted-nicotinyl thiourea derivatives bearing pyrimidine moiety
629
Table 1 Physical constants of compounds 4a–l
Compound Molecular
formula
Appearance M.P.
(°C)
Yield Analytical data calculated (%) (found)
(%)
C
H
N
Formula weight
4a
C13H12ClN5O3S Light
260–262 90
44.13 (44.02) 3.39 (3.47) 19.80 (19.92)
yellow
powder
353.5
4b
4c
C
13H12ClN5OS Yellow
258–259 84
48.52 (48.61) 3.73 (3.65) 21.77 (21.63)
47.18 (47.26) 4.19 (4.25) 18.35 (18.24)
powder
321.5
C15H16ClN5O3S Light
yellow
crystal
172–174 86
265–267 88
205–207 82
381.5
4d
4e
C
12H9Cl2N5O2S Light
40.22 (40.16) 2.51 (2.59) 19.55 (19.63)
41.94 (41.86) 2.96 (2.82) 18.82 (18.91)
yellow
powder
358
C
13H11Cl2N5O2S Light
yellow
powder
372
4f
C
11H6Cl3N5OS Yellow
[270
78
36.41 (36.35) 1.66 (1.72) 19.31 (19.24)
44.13 (44.21) 3.39 (3.42) 19.80 (19.71)
powder
362.5
4g
C13H12ClN5O3S Light
yellow
powder
254–256 88
176–178 87
353.5
4h
C
15H16ClN5O3S Light
47.18 (47.26) 4.19 (4.12) 18.35 (18.46)
yellow
powder
381.5
4i
C
12H9Cl2N5O2S Yellow
[260
[260
82
85
40.22 (40.28) 2.51 (2.60) 19.55 (19.43)
40.21 (40.27) 2.84 (2.75) 18.04 (17.96)
43.27 (43.35) 3.61 (3.68) 16.83 (16.75)
powder
358
4j
4k
C13H11Cl2N5O3S Yellow
powder
388
C15H15Cl2N5O3S Light
173–174 86
yellow
powder
416
4l
C
12H8Cl3N5O2S Light
[260
80
36.69 (36.58) 2.04 (2.12) 17.83 (17.76)
yellow
powder
392.5
paper, we have conducted our reaction using PEG-400 as the solid–liquid phase transfer
catalyst under ultrasonic irradiation, which is an easy and convenient method for the
synthesis of nicotinyl thiourea derivatives, with the advantages of simple operation,
short reaction times and high yields over the typical method.
General spectroscopy for substituted-nicotinylthiourea derivatives 4a–l
All the structures of the newly synthesized compounds 4 were assigned on the basis
of their elemental analyses (Table 1) and spectroscopic data, IR and 1H NMR
(Table 2). The IR (KBr) spectrum displayed absorptions at about 3,280, 1,635 and
1,280 cm-1, which are assigned to N–H, C=O and C=S functions, respectively. The
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S. Ke, X. Cao
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Substituted-nicotinyl thiourea derivatives bearing pyrimidine moiety
631
Table 3 The inhibition percentage of some target compounds to kinds of plants
Compound Concentration Inhibition (%) Digitaria
(lg/mL)
E. crusgallis L. Chenopodium Amaranthus
serotinum L. retroflexus L.
sanguinalis
(L) Scop
4b
4f
100
50
Stalk
Root
Stalk
Root
Stalk
Root
Stalk
Root
Stalk
Root
Stalk
Root
Stalk
Root
Stalk
Root
90
90
80
90
20
20
20
20
0
90
10
0
100
100
80
90
90
85
90
90
100
0
80
80
30
50
30
10
0
80
100
50
20
30
20
30
0
4g
4k
100
50
90
90
80
90
30
20
20
20
20
0
90
0
10
0
90
0
90
100
50
70
80
60
70
30
80
0
100
100
20
20
20
medium-strong vC=O band in the IR spectra of all the compounds appears at about
1,635 cm-1, apparently decreasing in wave-number compared with the ordinary
carbonyl absorption (1,710 cm-1), which is due to interaction and hydrogen
1
bonding between the N–H and C=O groups. The H NMR (DMSO-d6) spectrum
exhibited two broad absorption bands in the low-field region that were attributed to
the protons of N–H. In addition, the singlet and multiplet signals at about d
6.00–6.60 and d 7.20–9.00 were assigned to pyrimidine–CH and pyridine–CH
protons, respectively. All the compounds can be dissolved in DMF, DMSO and
other nonprotonic solvents, but were insoluble in chloroform and dichloromethane.
Biological activity evaluation
The preliminary biological activities of compounds 4a–l have been determined by
the flat-utensil method according to the standard bioactivity test procedures.
Compounds 4b, 4f, 4g, 4k, etc. showed inhibitory activities against the root and
stalk of dicotyledon plants (such as Chenopodium Serotinum L.) and monoctyledon
plants (such as Echinochloa crusgallis L.). The inhibition percentages of some
active compounds are shown in Table 3.
Conclusions
In conclusion, we have described a molecular diversity-oriented convenient process
for the assembly of substituted-nicotinic core and acylthiourea scaffold that are
123

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S. Ke, X. Cao
potential agrochemical agents. In the above-described experimental conditions, the
reaction reached completion with a very simple disposal, good yield and mild
reaction conditions compared to the conventional methods. The preliminary
biological tests show that some of the target compounds have better inhibitory
activities against root and stalk of dicotyledons and are safe for monocotyledon
plants.
Experimental
Instrumentation and chemicals
The melting points were determined on an XT4A micro digital melting point
apparatus and are uncorrected. The isolated compounds 4 were characterized by
elemental microanalyses. The C, H and N analyses were repeated twice. IR spectra
were obtained on a Nicolet5DX FT-IR spectrophotometer in the region
1
4,000–400 cm-1 KBr discs. H NMR spectra were recorded on a Varian-300-54
spectrometer with DMSO-d6 as the solvent. Chemical shift values are reported in
ppm (d) relative to TMS as internal standard. Thin layer chromatography (TLC)
analyses were carried out on 5 9 20 cm plates coated with silica gel GF254 type 60
(50–250 mesh) using a ethyl acetate–petroleum ether mixture as solvent. Ultrasonic
irradiation was performed within a CQ-250S ultrasonic cleaner (35 5% kHz,
250 W, made in Shanghai J and L ultrasonic Ltd., Shanghai, P. R. China). All
starting materials are commercial products of chemical or analytic grade purity.
Sulfuric chloride was distillated before use and potassium thiocyanate was baked
before use. All the substituted-pyrimidine intermediates were prepared by the
literature method [29].
General synthetic procedures for the target compounds 4a–l
Substituted-nicotinic acid (0.05 mol), 10 mL of toluene and sulfuric chloride
(15 mL) were placed in a dried round-bottomed flask containing a magnetic stirrer
bar and stirred at about 50 °C for 2 h. Then the excessive sulfuric chloride was
removed under reduced pressure to give a clear solution of substituted-nicotinyl
chloride 1.
To a solution of potassium thiocyanate (0.15 mol) in 10 mL of acetonitrile, the
clear solution of substituted-nicotinyl chloride 1 and 3% PEG-400 were added. The
flask with the reaction mixture was immersed into the water bath of an ultrasonic
cleaner at refluxed temperature for about 0.5 h and then the reaction mixture was
filtered off to yield an orange-red solution 2. Then equimolar quantity of 4,6-
disubstituted-2-amino pyrimidine 3 was added and under ultrasonic irradiation for
about 15–20 min and the reaction was monitored by TLC. At the end of the
reaction, the resulting precipitate was collected by filtration and recrystallized from
EtOH to yield compound 4. All the physico-chemical properties for the target
compounds are given in Tables 2 and 3, respectively.
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Substituted-nicotinyl thiourea derivatives bearing pyrimidine moiety
633
Acknowledgments This work was financially supported by the Projects in the National Science and
Technology Pillar Program during the Eleventh Five-Year Plan Period (2008BADA5B03) and Special
Fund for Agro-Scientific Research in the Public Interest (200903052).
References
1. Y. Bessard, R. Crettaz, Tetrahedron 56, 4739 (2000)
2. P. Jeschke, Pest Manag. Sci. 66, 10 (2010)
3. A. Upadhyay, M. Gopal, C. Srivastava, N.D. Pandey, J. Pestic. Sci. 35, 464 (2010)
4. A. Arnoldi, S. Dallavalle, L. Merlini, L. Musso, G. Farina, M. Moretti, L. Jayasinghe, J. Agric. Food
Chem. 55, 8171 (2007)
5. A.A. Geronikaki, A.A. Lagunin, D.I. Hadjipavlou-Litina, P.T. Eleftheriou, D.A. Filimonov, V.V.
Poroikov, I. Alam, A.K. Saxena, J. Med. Chem. 51, 1601 (2008)
6. B. Cosimelli, G. Greco, M. Ehlardo, E. Novellino, F.D. Settimo, S. Taliani, C.L. Motta, M. Bellandi,
T. Tuccinardi, A. Martinelli, O. Ciampi, M.L. Trincavelli, C. Martini, J. Med. Chem. 51, 1764 (2008)
7. I.T. Hwang, H.R. Kim, D.J. Jeon, K.S. Hong, J.H. Song, K.Y. Cho, J. Agric. Food Chem. 53, 8639
(2005)
8. T.Y. Zhang, J.R. Stout, J.G. Keay, Tetrahedron 51, 13177 (1995)
9. F. Wen, H. Zhang, Z. Yu, H. Jin, Q. Yang, T. Hou, Pestic. Biochem. Phys. 98, 248 (2010)
10. P. Jain, J.T. Slama, L.A. Perez-Haddock, T.F. Walseth, J. Med. Chem. 53, 7599 (2010)
11. B. Li, F.C. Bi, R.A. Buzon, M. Kang, R.M. Oliver, J.F. Sagal, L. Samp, D.P. Walker, Z. Zhang,
Synlett 14, 2133 (2010)
12. J. Sun, S. Cai, H. Mei, J. Li, N. Yan, Q. Wang, Z. Lin, D. Huo, Chem. Biol. Drug Des. 76, 245 (2010)
13. L. Xiao, C. Liu, Y. Li, Molecules 14, 1423 (2009)
14. V. Ravichandran, B.R.P. Kumar, S. Sankar, R.K. Agrawal, Med. Chem. Res. 17, 1 (2008)
15. A.R. Katritzky, N. Kirichenko, B.V. Rogovoy, J. Kister, H. Tao, Synthesis 11, 1799 (2004)
16. K. Amornraksa, A. Worachartcheewan, V. Prachayasittikul, Eur. J. Sci. Res. 31, 510 (2009)
17. A. Saeed, N. Abbas, H. Rafique, S. Rashid, A. Hameed, Chemistry 18, 152 (2009)
18. M. Soung, K. Park, N. Sung, Bull. Korean Chem. Soc. 31, 1469 (2010)
19. T. Hashimoto, K. Maruoka, in Asymmetric Phase Transfer Catalysis, ed. by K. Maruoka
(Wiley-VCH GmbH and Co. KGaA, Weinheim, 2008)
20. E. O’Reilly, E. Lestini, D. Balducci, F. Paradisi, Tetrahedron Lett. 50, 1748 (2009)
21. G. Keglevich, E. Balint, E. Karsai, J. Varga, A. Gruen, M. Balint, I. Greiner, Lett. Org. Chem. 6, 535
(2009)
22. Q. Wang, X. Zhang, L. Wang, Z. Mi, J. Mol. Catal. A Chem. 309, 89 (2009)
23. R. He, S. Shirakaw, K. Maruoka, J. Am. Chem. Soc. 131, 16620 (2009)
24. E. Ohayon, A. Gedanken, Ultrason. Sonochem. 17, 173 (2010)
25. R. Gupta, A. Jain, M. Jain, R. Joshi, Bull. Korean Chem. Soc. 31, 3180 (2010)
26. H. Jin, H. Zhao, F. Zhao, S. Li, W. Liu, G. Zhou, K. Tao, T. Hou, Ultrason. Sonochem. 16, 304
(2009)
27. S. Sadjadi, H. Sepehrian, Ultrason. Sonochem. 18, 480 (2011)
28. H. Jin, L. Xiang, F. Wen, K. Tao, Q. Liu, T. Hou, Ultrason. Sonochem. 15, 681 (2008)
29. Z. Li, Q. Wang, J. Huang, Preparation for the Organic Intermediates (Chemical Industry Press,
Beijing, 2001)
123