Phase transfer-catalyzed, one-pot synthesis of some novel N-pyrimidinyl-N'-nicotinyl thiourea derivatives

Article abstract of DOI:10.1080/10426507.2010.508059

A new series of acyl thiourea derivatives were synthesized in one-pot using PEG-600 as the phase transfer catalyst (PTC). The structures of title compounds were characterized by ¹H NMR, IR, MS, and elemental analysis. In addition, the fungicidal activity of the acyl thiourea derivatives were tested, which showed that most of them exhibit moderate activity. Supplemental materials are available for this article. Go to the publisher's online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426507.2010.508059

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Phase Transfer–Catalyzed, One-Pot
Synthesis of Some Novel N-Pyrimidinyl-
N′-nicotinyl Thiourea Derivatives
a
a
a
Xing-Hai Liu , Cheng-Xia Tan & Jian-Quan Weng
a
College of Chemical Engineering and Materials Science , Zhejiang
University of Technology , Hangzhou, Zhejiang, China
Published online: 07 Mar 2011.
To cite this article: Xing-Hai Liu , Cheng-Xia Tan & Jian-Quan Weng (2011) Phase Transfer–Catalyzed,
One-Pot Synthesis of Some Novel N-Pyrimidinyl-N′-nicotinyl Thiourea Derivatives, Phosphorus, Sulfur,
and Silicon and the Related Elements, 186:3, 552-557, DOI: 10.1080/10426507.2010.508059
To link to this article: http://dx.doi.org/10.1080/10426507.2010.508059
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Phosphorus, Sulfur, and Silicon, 186:552–557, 2011
Copyright ꢀ
Taylor & Francis Group, LLC
C
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2010.508059
PHASE TRANSFER–CATALYZED, ONE-POT SYNTHESIS
ꢀ
OF SOME NOVEL N-PYRIMIDINYL-N -NICOTINYL
THIOUREA DERIVATIVES
Xing-Hai Liu, Cheng-Xia Tan, and Jian-Quan Weng
College of Chemical Engineering and Materials Science, Zhejiang University
of Technology, Hangzhou, Zhejiang, China
GRAPHICAL ABSTRACT
Abstract A new series of acyl thiourea derivatives were synthesized in one-pot using PEG-
6
00 as the phase transfer catalyst (PTC). The structures of title compounds were characterized
1
by H NMR, IR, MS, and elemental analysis. In addition, the fungicidal activity of the acyl
thiourea derivatives were tested, which showed that most of them exhibit moderate activity.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file.
Keywords Acyl thiourea; fungicidal activity; one-pot synthesis; phase transfer catalysis
INTRODUCTION
The synthesisand bioactivity study of heterocyclic compounds is an important re-
1
–5
search area in pesticidal and medicinal chemistry. Nicotinic acid, pyrimidine, and their
derivatives are well-known heterocyclic compounds due to their excellent biological activ-
ities. Thus, numerous pyridine and pyrimidine derivatives have been used in the synthesis
6
of natural compounds, drugs, and agrochemicals. For example, milirinone is a phospho-
diesterase 3 inhibitor, which is useful in the treatment of heart diseases. Sulfonylurea her-
7
8
bicides containing a pyrimidine ring have been wildly used in agriculture. Imidacloprid,
developed by Bayer Company, is a neonieotinoid insecticide. In the bioactive compounds
Received 12 May 2010; accepted 9 July 2010.
This work was funded by National Natural Science Foundation of China (No. 21002090, 31000008,
30900959); the Key Laboratory of Pesticide Chemistry and Application, Ministry of Agriculture (MOA), Beijing,
PR China (No. MOAPCA201005); Zhejiang Provincial Natural Science Foundation of China (Y3080096); and
Scientific Research Fund of Zhejiang Education Department (Y201018479).
Address correspondence to Xing-Hai Liu, College of Chemical Engineering and Materials Science, Zhejiang
University of Technology, Hangzhou 310014, Zhejiang, China. E-mail: xhliu@zjut.edu.cn
5
52

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N-PYRIMIDINYL-N -NICOTINYL THIOUREA DERIVATIVES
553
research area, there is another type of molecules, namely thioureas, which are also ex-
tensively used in medicinal chemistry and agrochemistry due to their superior biological
activities. As far as their applications in the agrotechnology area are concerned, thiourea
9
and its derivatives, especially acyl-thiourea compounds, exhibit a variety of herbicidal,
10
11
fungicidal, and insecticidal activities. In view of their superior features, we believe that
the rational combination of pyridine/pyrimidine and thiourea should be promising in the
development of novel bioactive compounds. In this article, we report the design and synthe-
sis of a new group of thiourea compounds (3a–j) incorporated with pyrimidine rings. Their
1
structures were characterized by H NMR, IR, MS, and elemental analysis. The preliminary
biological tests showed that these compounds have moderate fungicidal activities.
Regarding the synthesis of the title compounds, phase transfer catalysis (PTC) proved
to be an effective tool. In recent years, this method has been widely used in numerous organic
syntheses, and has become a powerful and efficient technique that can promote a variety
of reactions under mild conditions.1
2–14
Harrison and Hodge reported the successful
15
preparation of benzoyl isothiocyanate by treating benzoyl chloride and polymer-supported
thiocyanate in benzene. However, the preparation of such polymer-supported reagents
requires long reaction time and vacuum conditions. Later, as shown in Scheme 1, Wei
16
et al. proposed the reaction mechanism of a PEG-catalyzed procedure.
Scheme 1 The proposed mechanism by PEG catalysis.
RESULTS AND DISCUSSION
The preferable reaction temperature for preparing 4-chloropyrimidin-2-amine should
◦
be below 90 C, because the higher temperature will lower the yield. When treating 4-
chloropyrimidin-2-amine with NaOMe in MeOH to synthesize 4-methoxypyrimidin-2-
amine, a large amount of inorganic salt NaCl was formed, which resulted in a highly
viscous suspension. Thus, in order to get a better yield, the reaction mixture was filtered
while hot when working up.
In this article, we report the successful synthesis of the title acyl thiourea derivatives
using PEG-600 as solid–liquid phase transfer catalyst (Scheme 2). The catalyst PEG-600
is indispensable for these reactions. This procedure is facile and convenient. In addition,
PEG-600 is inexpensive, relatively nontoxic, highly stable, and ready available.
In the infrared spectrum (FT-IR) of compound 3, N H stretching absorption signal
−
1
appears at 3436–3125 cm , and the characteristic stretching vibration signals of ν(C O)
−1
−1
1
and ν(C S) appears at 1700–1720 cm and 1258–1264 cm , respectively. In the H
NMR spectrum of 3, the -NH proton signals were observed at δ 8.13∼13.98 ppm as a
singlet.

5
54
X.-H. LIU ET AL.
Scheme 2 Synthetic route for the title compounds.
EXPERIMENTAL
Nicotinic acid, iso-nicotinic acid, 2-chloro nicotinic acid, and PEG-600 were com-
mercially available. The mono-substituted pyrimidines were synthesized according to the
17
procedure reported in the literature. Melting points were determined using an X-4 appa-
ratus without calibration. Infrared spectra (FT-IR) were recorded on a Bruker Equinox 55
1
spectrophotometer using potassium bromide tablets. H NMR spectra were measured on a
Bruker AC-P500 instrument (300 MHz) using TMS as the internal standard and DMSO-d6
as solvent. Mass spectra (ESI-MS) were recorded on a Thermo Finnigan LCQ Advantage
LC/mass detector instrument. Elemental analyses were performed on a Vario EL elemental
analyzer.
General Procedure for the Preparation of Acyl Thiourea
Thionyl chloride (15 mL) was added into nicotinic acid (5 g, 40 mmol), and the
mixture was refluxed for 3 h. Next, the excessive thionyl chloride was distilled off under
reduced pressure. Then, the resulting residue was re-dissolved in toluene (20 mL) and
again concentrated using a rotary evaporator to afford nicotinic acid chloride hydrochloride
(6.81 g, 95%) as a solid. Nicotinic acid chloride hydrochloride (6.81g, 38 mmol) was added
into a solution of triethylamine (28 mL, 38 mmol) in THF (30 mL) and then stirred at
room temperature for 2 h. Afterward, the reaction was quenched with water (50 mL) and
extracted with CH2Cl2. The combined organic layer was dried over sodium sulfate, filtered,
and concentrated on a rotary evaporator to give the desired acid chloride.
Powdered ammonium thiocyanate (1.14 g, 15 mmol), acid chloride (1.04 g,
10 mmol), PEG-600 (0.18 g, 3% with respect to ammonium thiocyanate), methylene

ꢀ
N-PYRIMIDINYL-N -NICOTINYL THIOUREA DERIVATIVES
555
chloride (25 mL), and pyridine(0.5 mL) were charged into a dry round-bottomed flask
equipped with a magnetic stirrer bar and stirred at room temperature for 1 h. Then the
solution of substituted 2-amino-pyrimidine (4.5 mmol) in methylene dichloride (10 mL)
was added dropwise into the flask over 0.5 h. During this course, the corresponding acyl
thiourea precipitated immediately. The reaction was stirred for a further 1∼2 h with TLC
monitoring. When the reaction was complete, the product was filtered, washed with water
to remove inorganic salts, dried, and recrystallized from DMF/EtOH/H2O. Finally, the
acyl thiourea was obtained as a light yellow solid.
N-(Pyrimidin-2-ylcarbamothioyl)nicotinamide 3a
◦
1
Yellow crystal, yield 42.3%, mp 185–186 C; H NMR (DMSO-d6) δ: 7.21–9.06 (m,
−1
6
1
H, Py and ph), 12.26 (s, 1H, NH),13.36(s, 1H, NH); IR/cm : 3420 (N H), 3167 (N H),
718 (C O), 1554, 1452 (Ar), 1263 (C S); ESI-MS: 258[M-1] ; Elemental analysis for
−
C11H9N5OS: found C 50.60, H 3.48, N 27.05; calc. C, 50.95; H, 3.50; N, 27.01.
N-(4-Methylpyrimidin-2-ylcarbamothioyl)nicotinamide 3b
◦
1
Yellow crystal, yield 55.83%, mp 192–194 C; H NMR (DMSO-d6) δ: 2.43 (s, 3H,
−1
CH3), 7.22–9.15 (m, 6H, Py and ph), 11.88 (s, 1H, NH),13.98 (s, 1H, NH); IR/cm : 3417
N H), 3125 (N H), 1703 (C O), 1550, 1450 (Ar), 1261 (C S); ESI-MS: 272[M-1] ;
−
(
Elemental analysis for C12H11N5OS: found C 52.64, H 4.08, N 25.31; calc. C, 52.73; H,
.06; N, 25.62.
4
2-Chloro-N-(pyrimidin-2-ylcarbamothioyl)nicotinamide 3c
◦
1
Yellow crystal, yield 65.87%, mp 190–191 C; H NMR (DMSO-d6) δ: 7.22–8.98
−1
(
3
m, 6H, Py H and ArH), 12.34 (s, 1H, NH),13.21 (s, 1H, NH); IR/cm : 3425 (N H),
157 (N H), 1720 (C O), 1548, 1450 (Ar), 1264 (C S); ESI-MS: 292[M-1] ; Elemental
−
analysis for C11H8ClN5OS: found C 44.95, H 2.84, N 23.76; calc. C, 44.98; H, 2.75; N,
1
2
3.84. The H NMR spectrum of 3c is shown as Figure S 1 (Supplemental Materials,
available online).
2
-Chloro-N-(4-methylpyrimidin-2-ylcarbamothioyl)nicotinamide 3d
◦
1
Yellow crystal, yield 65.44%, mp 195–196 C; H NMR (DMSO-d6) δ: 2.46 (s, 3H,
−1
CH3), 7.20–8.99 (m, 5H, Py H and Ar H), 12.01 (s, 1H, NH), 13.65 (s, 1H, NH); IR/cm :
3
423 (N H), 3168 (N H), 1717 (C O), 1550, 1452 (Ar), 1265 (C S); ESI-MS: 306[M-
−
1] ; Elemental analysis for C12H10ClN5OS: found C 46.95, H 3.08, N 22.61; calc. C, 46.83;
H, 3.28; N, 22.76.
N-(Pyrimidin-2-ylcarbamothioyl)isonicotinamide 3e
◦
1
Yellow crystal, yield 54.13%, mp 194–195 C; H NMR (DMSO-d6) δ: 7.31–8.98
−1
(
3
m, 7H, Py H and ArH,), 12.15 (s, 1H, NH),13.75 (s, 1H, NH); IR/cm : 3423 (N H),
166 (N H), 1714 (C O), 1550, 1452 (Ar), 1264 (C S); ESI-MS: 258[M-1] ; Elemental
−
analysis for C11H9N5OS: found C 51.01, H 3.55, N 27.15; calc. C, 50.95; H, 3.50; N, 27.01.

5
56
X.-H. LIU ET AL.
N-(4-Methylpyrimidin-2-ylcarbamothioyl)isonicotinamide 3f
◦
1
Yellow crystal, yield 45.66%, mp 202–204 C; H NMR (DMSO-d6) δ: 2.40 (s, 3H,
−1
CH3), 7.15–8.86 (m, 6H, Py H and Ar H), 11.92 (s, 1H, NH), 13.83 (s, 1H, NH); IR/cm :
3
424 (N H), 3159 (N H), 1701 (C O), 1549, 1450 (Ar), 1260 (C S); ESI-MS: 272[M-
−
1] ; Elemental analysis for C12H11N5OS: found C 52.84, H 4.18, N 25.55; calc. C, 52.73;
H, 4.06; N, 25.62.
N-(4-Methoxylpyrimidin-2-ylcarbamothioyl)nicotinamide 3g
◦
1
Yellow crystal, yield 55.15%, mp 203–204 C; H NMR (DMSO-d6) δ: 3.94 (s, 3H,
−1
OCH3), 7.16–7.41 (m, 6H, Py H), 8.13 (s, 1H, NH), 8.14 (s, 1H, NH); IR/cm : 3423
N H), 3156 (N H), 1703 (C O), 1545, 1451 (Ar), 1261 (C S); ESI-MS: 288[M-1] ;
−
(
Elemental analysis for C12H11N5O2S: found C 49.79, H 3.95, N 24.55; calc. C 49.82; H
.83; N 24.21.
3
N-(4-Chloropyrimidin-2-ylcarbamothioyl)nicotinamide 3h
◦
1
Yellow crystal, yield 54.38%, mp 200–201 C; H NMR (DMSO-d6) δ: 7.21–7.66
−1
(
3
m, 6H, Py H and Ar H), 9.08 (s, 1H, NH), 9.85 (s, 1H, NH); IR/cm : 3425 (N H),
149 (N H), 1698 (C O), 1550, 1450 (Ar), 1261 (C S); ESI-MS: 292[M-1] ; Elemental
−
analysis for C11H8ClN5OS: found C 52.84, H 4.18, N 25.55; calc. C 44.98, H 2.75, N
3.84.
2
N-(4-Methoxylpyrimidin-2-ylcarbamothioyl)isonicotinamide 3i
◦
1
Yellow crystal, yield 65.21%, mp 199–200 C; H NMR (DMSO-d6) δ: 7.15–8.86
−1
(
3
m, 5H, Py H and Ar H), 8.75 (s, 1H, NH), 10.33 (s, 1H, NH); IR/cm : 3434 (N H),
159 (N H), 1700 (C O), 1545, 1450 (Ar), 1259 (C S); ESI-MS: 288[M-1] ; Elemental
−
analysis for C12H11N5OS: found C 52.84, H 4.18, N 25.55; calc. C, 52.73; H, 4.06; N,
5.62.
2
N-(4-Chloropyrimidin-2-ylcarbamothioyl)isonicotinamide 3j
◦
1
Yellow crystal, yield 49.98%, mp 206–207 C; H NMR (DMSO-d6) δ: 7.15–8.86
−1
(
3
m, 6H, Py H and Ar H), 9.73 (s, 1H, NH), 12.17 (s, 1H, NH); IR/cm : 3436 (N H),
160 (N H), 1708 (C O), 1552, 1450 (Ar), 1258 (C S); ESI-MS: 292[M-1] ; Elemental
−
analysis for C11H8ClN5OS: found C 52.84, H 4.18, N 25.55; calc. C 52.77, H 4.33, N
5.45.
2
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