Facile synthesis of substituted arylthioureas in the presence of sodium hydride

Article abstract of DOI:10.3184/174751917X14931424175476

A series of 11 1,1-dimethyl-3-aryl-thioureas were synthesised in good yields (70-92%) by reacting arylamines with S-aryl-N,Ndimethylthiocarbamate in DMSO in the presence of NaH at 90 °C. It is noteworthy that this method can also be used for arylamines containing a halogen atom at the ortho position.

Full text of DOI:10.3184/174751917X14931424175476

JOURNAL OF CHEMICAL RESEARCH 2017
VOL. 41 MAY, 301–303
RESEARCH PAPER 301
Facile synthesis of substituted arylthioureas in the presence of sodium
hydride
Qiang Caoa, Fang Liua, Min Wanga, Wan Xua, Meng-Tian Zenga, Min Liua, Yue-Sheng Lic and
Zhi-Bing Donga*,b
ªSchool of Chemistry and Environmental Engineering, Wuhan Institute of Technology, Wuhan 430074, P.R. China
bKey Laboratory of Green Chemical Process, Ministry of Education, Wuhan Institute of Technology, Wuhan 430074, P.R. China
cNonpower Nuclear Technology Collaborative Innovation Center, Hubei University of Science and Technology, Xianning 437100, P. R. China
A series of 11 1,1-dimethyl-3-aryl-thioureas were synthesised in good yields (70–92%) by reacting arylamines with S-aryl-N,N-
dimethylthiocarbamate in DMSO in the presence of NaH at 90 °C. It is noteworthy that this method can also be used for arylamines
containing a halogen atom at the ortho position.
Keywords: synthesis, substituted thioureas, dithiocarbamate, sodium hydride, arylamines
Arylthiourea derivatives represent an emerging class of
anticancer chemotherapeutics that show good inhibitory activity
against receptor tyrosine kinases (RTKs),1–2 protein tyrosine
kinases (PTKs),3–7 and DNA topoisomerases (e.g. A and B, Fig.
1), and some of them can serve as plant protection agents and
pesticides (e.g. C and D, Fig. 2).8–10
excess)16–17 or suffers from mixtures of products.17 Moreover,
the method cannot be used for an aniline substrate bearing an
ortho halogen atom, which limits its further applications.18
Some arylthiourea derivatives can also serve as catalysts or
ligands in synthetic chemistry (E, Fig. 3), in large part due to
their hydrogen-bonding interactions with partially developing
negatively charged atoms in the substrates as well as in the
transition state.11–14 Consequently, arylthiourea derivatives have
attracted the attention of synthetic chemists for the development
of synthetic methods for their preparation. Among these
methods, using isothiocyanates reacting with anilines suffers
from long reaction times (12–48 h)15 and reacting disulfides
with amines requires large excesses of amines (4–10-fold
Fig. 3 Substituted arylthioureas as ligands in bis(methoxycarbonylation)
of styrene.
Fig. 1 Substituted arylthioureas as potential DNA-topoisomerase inhibitors.
Fig. 2 Substituted arylthioureas as plant protection agents and pesticides.
* Correspondent. E-mail: mail: dzb04982@wit.edu.cn

302 JOURNAL OF CHEMICAL RESEARCH 2017
Scheme 1
Table
1
Yields of 1-aryl-3,3-dimethylthioureas 3a–k prepared
was then heated at 90 °C and checked by TLC until the starting
material was exhausted. The reaction was cooled to room temperature,
quenched with sat. NH4Cl solution (5 mL), extracted with ethyl acetate,
dried over anhydrous MgSO4 and evaporated under vacuum.
from the reaction of various arylamines 2a–k with S-aryl-N,N-
dimethylthiocarbamate 1 (Scheme 1)a
Entry Products
1
2
3
4
5
6
7
8
9
10
11
R
H
Time (h)
4
Yield (%)b
90
3a
3b
3c
3d
3e
3f
3g
3h
3i
CAUTION! The whole workup should be performed in a fume hood
to minimise the smell of the by-product thiophenol.
4-Me
3.5
4
5
92
81
75
73
2,4,6-Trimethyl
2-I, 4-Br
2-Br
The residue was purified by flash column chromatography to afford
the desired product.
4
1,1-Dimethyl-3-phenylthiourea (3a): The crude product was purified
by flash chromatography on silica gel (petroleum ether/ethyl acetate
= 3:1) to give 3a: White solid; yield 162 mg (90%); m.p. 127–129 °C;
1H NMR (400 MHz, DMSO-d6): δ 9.12 (s, 1H), 7.41–7.45 (m, 4H),
7.23–7.26 m, 1H), 3.41 (s, 6H); 13C NMR (100 MHz, CDCl3): δ 181.8,
139.9, 128.5, 125.5, 125.4, 41.4; Anal. calcd for C9H12N2S: C, 59.96; H,
6.71; N, 15.54; found: C, 59.89; H, 6.66; N, 15.52%.
2-Br, 5-NO2
2-NO2, 5-Me
2-Br, 4-Me, 6-Br
3,4,5-Trimethoxyl
2-SMe
5
4
5
4
70
84
70
85
3j
3k
4
89
2-OMe
4
91
aReaction conditions: an arylamine
2 (1 mmol) was reacted with S-aryl-N,N-
dimethylthiocarbamate 1 (1.2 mmol) in the presence of NaH (2 mmol) in dry DMSO (3 mL)
at 90 °C for 3–5 h.
1,1-Dimethyl-3-p-tolylthiourea (3b): The crude product was purified
by flash chromatography on silica gel (petroleum ether/ethyl acetate
= 3:1) to give 3b: White solid; yield 178 mg (92%); m.p. 166–169 °C;
1H NMR (400 MHz, DMSO-d6): δ 8.81 (s, 1H), 7.11 (d, J = 8 Hz, 2H),
6.81 (d, J = 8 Hz, 2H), 3.68 (s, 3H), 3.21 (s, 6H); 13C NMR (100 MHz,
CDCl3): δ 182.6, 157.7, 132.7, 127.6, 113.9, 55.4, 41.3; Anal. calcd for
C10H14N2S: C, 61.82; H, 7.26; N, 14.42; found: C, 61.70; H, 7.22; N,
14.39%.
b Isolated yields of analytically pure product.
Herein, we wish to report a facile preparation of 1-substituted
aryl-3,3-dimethylthioureas.
Results and discussion
Our plan was to treat arylamines with NaH/DMSO to form
the corresponding nitranions and then react them with S-aryl-
N,N-dimethyldithiocarbamates at 90 °C for 3–5 h to displace
thiophenolate (Scheme 1). The reaction worked well, and a
series of 1-aryl-3,3-dimethylthioureas 3a-k were synthesised
smoothly in good yield (70–92%), as shown in Table 1. In
general, arylamines containing electron-donating groups
(entries 3, 9–11) gave higher yields than those with electron-
withdrawing groups (entries 4–7). It is noteworthy that this
method can be used for an aniline substrate bearing an ortho
halogen atom (entries 4–6), which broadens the methods of
preparation of arylthioureas.
1,1-Dimethyl-3-(2,4,6-trimethylphenyl)-thiourea (3c): The crude
product was purified by flash chromatography on silica gel (petroleum
ether/ethyl acetate = 3:1) to give 3c: White solid; yield 179 mg (81%);
1
m.p. 126–128 °C; H NMR (400 MHz, CDCl3): δ 6.89 (s, 2H), 6.62
(s, 1H), 3.35 (s, 6H), 2.26 (s, 3H), 2.19 (s, 6H); 13C NMR (100 MHz,
CDCl3): δ 181.9, 141.9, 136.7, 136.7, 128.1, 127.8, 126.1, 41.09, 24.6,
18.6, 14.2; Anal. calcd for C12H18N2S: C, 64.82; H, 8.16; N, 12.60;
found: C, 64.72; H, 8.12; N, 12.56%.
3-(4-Bromo-2-iodophenyl)-1,1-dimethyl-thiourea (3d): The crude
product was purified by flash chromatography on silica gel (petroleum
ether/ethyl acetate = 7:1) to give 3b: Pale red solid; yield 288 mg (75%);
m.p. 128–132 °C; 1H NMR (400 MHz, CDCl3 ): δ 7.68 (s, 1H), 7.40–7.38
(m, 2H), 3.17 (s, 6s); 13C NMR (100 MHz, CDCl3): δ 168.8, 152.2, 132.8,
129.1, 123.1, 119.8, 113.1, 40.2; Anal. calcd for C9H10BrIN2S: C, 28.07; H,
2.62; N, 7.28; found: C, 28.16; H, 2.66; N, 7.25%.
Experimental
All reactions were carried out in dried glassware with septums. All
starting materials were purchased from commercial suppliers and
used without further purification unless otherwise stated. DMSO
was dried over molecular sieves. Yields refer to isolated compounds
3-(2-Bromophenyl)-1,1-dimethyl-thiourea (3e): The crude product
was purified by flash chromatography on silica gel (petroleum ether/
ethyl acetate = 4:1) to give 3e: White solid; yield 189 mg (73%); m.p.
148–152 °C; 1H NMR (400 MHz, DMSO-d6): δ 8.92 (s, 1H), 7.13–7.61
(m, 4H), 3.25 (s, 6H); 13C NMR (100 MHz, CDCl3): δ 181.3, 137.8,
132.4, 127.6, 126.9, 126.5, 118.0, 41.4; Anal. calcd for C9H11BrN2S: C,
41.71; H, 4.28; N, 10.81; found: C, 41.65; H, 4.25; N, 10.86%.
1
estimated to be >95% pure as determined by H NMR and capillary
GC analysis. NMR spectra were measured on a Bruker 400 MHz
spectrometer. Elemental analyses were carried out on an Elementar
Vario EL III spectrometer. Column chromatography was performed
using SiO2 (0.040–0.063 mm, 230–400 mesh ASTM) from Merck if
not indicated.
3-(2-Bromo-5-nitrophenyl)-1,1-dimethyl-thiourea (3f): The crude
product was purified by flash chromatography on silica gel (petroleum
ether/ethyl acetate = 6:1) to give 3f: Yellow solid; yield 213 mg (70%);
Preparation of arylthiourea in the presence of sodium hydride;
general procedure
1
m.p. 187–191 °C; H NMR (400 MHz, DMSO-d6): δ 7.83–8.08 (m,
In a dried tube equipped with a magnetic stirrer and a septum,
an aniline (1.0 mmol) was dissolved in DMSO (3 mL) and NaH
(2 mmol) was added. The mixture was stirred for 5 min and then
dimethyldithiocarbamate (1.2 mmol) was added. The reaction mixture
3H), 3.15 (s, 6H); 13C NMR (100 MHz, CDCl3): δ 170.2, 153.7, 146.9,
138.6, 120.7, 115.8, 113.5, 40.4; Anal. calcd for C9H10BrN3O2S: C,
35.54; H, 3.31; N, 13.81; found: C, 35.50; H, 3.22; N, 13.78%.

JOURNAL OF CHEMICAL RESEARCH 2017 303
1,1-Dimethyl-3-(5-methyl-2-nitrophenyl)-thiourea (3g): The crude
product was purified by flash chromatography on silica gel (petroleum
ether/ethyl acetate = 4:1) to give 3g: Yellow solid; yield 201 mg (84%);
Chinese Scholars, the State Education Ministry [2012] 1707,
the President of the Wuhan Institute of Technology (2014038),
Chutian Foundation Distinguished Fellow of Hubei Provincial
Department of Education, and the Foundation of High-end
Talent Cultivation Program of Wuhan Institute of Technology.
We also thank Professor Aiwen Lei of Wuhan University for his
generous NMR analysis support.
1
m.p. 108–110 °C; H NMR (400 MHz, DMSO-d6): δ 9.29 (s, 1H),
7.16–7.86 (m, 3H), 3.26 (s, 6H), 2.35 (s, 3H); 13C NMR (100 MHz,
CDCl3): δ 180.0, 146.1, 136.6, 136.0, 125.3, 124.9, 124.4, 29.7, 22.1;
Anal. calcd for C10H13N3O2S: C, 50.19; H, 5.48; N, 17.56; found: C,
50.13; H, 5.46; N, 17.54.
Electronic Supplementary Information
3-(2,6-Dibromo-4-methylphenyl)-1,1-dimethyl-thiourea (3h): The
crude product was purified by flash chromatography on silica gel
(petroleum ether/ethyl acetate = 6:1) to give 3h: Yellow solid; yield
246 mg (70%); m.p. 186–188 °C; 1H NMR (400 MHz, CDCl3): δ 7.27
(s, 2H), 3.16 (s, 6H), 2.32 (s, 3H); 13C NMR (100 MHz, CDCl3): δ
167.9, 149.2, 131.6, 131.6, 130.1, 119.9, 111.2, 40.1, 20.9; Anal. calcd for
C10H12Br2N2S: C, 34.11; H, 3.44; N, 7.96; found: C, 34.20; H, 3.51; N,
7.82%.
The ESI is available through:
stl.publisher.ingentaconnect.com/content/stl/jcr/supp-data
Received 10 February 2017; accepted 9 April 2017
Paper 1704593
https://doi.org/10.3184/174751917X14931424175476
Published online: 28 April 2017
1,1-Dimethyl-3-(3,4,5-trimethoxyphenyl)-thiourea (3i): The crude
product was purified by flash chromatography on silica gel (petroleum
ether/ethyl acetate = 1:1) to give 3i: White solid; yield 229 mg (85%);
m.p. 145–150 °C; 1H NMR (400 MHz, CDCl3): δ 7.02 (s, 1H), 6.50 (s,
2H), 3.77 (s, 9H), 3.30 (s, 6H); 13C NMR (100 MHz, CDCl3): δ 181.9,
153.1, 135.7, 135.6, 102.9, 60.9, 56.1, 41.4; Anal. calcd for C12H18N2O3S:
C, 53.31; H, 6.71; N, 10.36; found: C, 53.24; H, 6.68; N, 10.38%.
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Acknowledgements
We acknowledge financial support from the National Natural
Science Foundation of China (Nos. 21302150 and 11405050),
Hubei Provincial Department of Education (D20131501), the
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