Base-promoted synthesis of N-arylbenzamides by N-benzoylation of dimethylphenylthioureas

Article abstract of DOI:10.3184/174751917X15016635672213

An efficient synthesis of 10 N-arylbenzamides was achieved by N-benzoylation of N,N-dimethyl-(N'-phenyl)thioureas with 4-substituted benzoyl chlorides in dimethylacetamide in the presence of K₂CO₃. The features of this method include

Full text of DOI:10.3184/174751917X15016635672213

484 RESEARCH PAPER
VOL. 41 AUGUST, 484–486
JOURNAL OF CHEMICAL RESEARCH 2017
Base-promoted synthesis of N-arylbenzamides by N-benzoylation of
dimethylphenylthioureas
Xing Liu, Wan Xu, Meng-Tian Zeng, Min Liu, Cai-Zhu Chang, Hui Zhu and Zhi-Bing Dong*
School of Chemistry and Environmental Engineering, Wuhan Institute of Technology, Wuhan 430205, P.R. China
An efficient synthesis of 10 N-arylbenzamides was achieved by N-benzoylation of N,N-dimethyl-(N'-phenyl)thioureas with 4-substituted
benzoyl chlorides in dimethylacetamide in the presence of K2CO3. The features of this method include good yields, short reaction times and
broad substrate scope. This work showed that arylthiourea derivatives can be alternative and useful starting materials for the preparation
of N-arylbenzamides.
Keywords: dimethylphenylthiourea, benzoyl chloride, benzanilide, N-benzoylation
The formation of C–N bonds, fundamental to the art of organic
synthesis, represents a key step in the synthesis of a broad range
of biologically important molecules and functional materials.1
As significant materials and building blocks in the synthesis
of fine chemicals, amides have a wide range of applications in
many areas such as pharmaceuticals,2 agrochemicals,3 polymers,4
natural products5 and colour pigments.6 Therefore, synthesis of
an amide is one of the most important processes in synthetic
chemistry.
It is estimated that more than 25% of known drugs contain
an amide group.7 Many pharmacophores possessing this
unit have shown great potential in the development of novel
pharmaceuticals. Among them, N-phenylbenzamides are
reported as essential building blocks that are found in a large
number of pharmaceutically active molecules. These molecules
include an inhibitor for treatment of cardiovascular diseases
(A), an inhibitor of microsomal triglyceride transfer protein (B),
imatinib (Gleevec) (C), and a cathepsin-D inhibitor (D) (Fig. 1).8
Owing to the pharmaceutical potential of amides, efforts towards
the identification and development of novel methods for
N-phenylbenzamide synthesis are encouraged. Traditionally,
amides are prepared from carboxylic acid derivatives (such as
acids, anhydrides, acyl chlorides, or esters) and amines,9 but there
are some disadvantages such as stoichiometric amount of wastes,
poor atom efficiency, harsh reaction condition and difficulties
in purification. Recently, several new methods have been
reported for the synthesis of N-phenylbenzamides. For example,
N-benzoylation reactions using microwave heating,10 N-arylation
of benzylamines,11 amidation of aldehydes and amines,12 silver-
promoted decarboxylative amidation of α-keto acids with
amines,13 amidation of phenylmethanols with anilines,14 N-
arylation of benzamides with iodobenzenes,15 and N-arylation
of benzamides with phenylboronic acids.16 These methods are
commonly efficient, but also suffer from disadvantages such as
using metal catalysts or harsh reaction conditions. As part of
our longstanding interest in developing dimethylphenylthioureas
and the relevant applications,17–19 we hereby report a convenient
method for the synthesis of N-phenylbenzamides through
N-benzoylation of dimethylphenylthioureas with benzoyl
chlorides. This could be an alternative way for the construction of
these important compounds.
Results and discussion
Our investigation started by treating N,N-dimethyl-N´-
phenylthiourea with benzoyl chloride (2a) in dimethyl
formamide at 80 °C in the presence of K2CO3 which was
O
N
OMe
H
O
N
O
CN
COOH
COOH
B: Inhibitor of microsomal
A: Inhibitor for treatment of
cardiovascular diseases
triglyceride transfer protein
S
N
N
O
OH
Cl
S
Cl
N
N
N
N
H
H
HN
N
N
O
CF
3
O
C: imatinib (Gleevec)
D: cathepsin-D inhibitor
Fig. 1 Biologically important molecules containing benzanilides.
* Correspondent. E-mail: dzb04982@wit.edu.cn

JOURNAL OF CHEMICAL RESEARCH 2017 485
O
N
N
S
O
H
K CO
2
3
N
N
Cl
o
+
DMF, 80 C
S
O
N
H
Scheme 1
Table 1 Yields of substituted benzanilide 3a–j prepared from the
reaction of various dimethylphenylthioureas 1a and 1b and benzoyl
chlorides 2a–ea
with water. We checked for the presence of the expected product
by analysing the reaction mixture after 20 min and 3 h by LC–
MS and were able to confirm its presence. However, the actual
product, N-phenylbenzamide was also detectable. This could
have been formed by hydrolysis in situ by a small amount of
water present in the ‘anhydrous’ dimethylacetamide.
R1
O
O
K2CO
H
N
3 (1 equiv.)
N
Cl
N
H
−
+
DMAC, 80 °C, 5 7 h
R2
S
R2
R1
1
2
3
Conclusion
Entry Products
R1
H
Me
H
Me
H
Me
H
Me
H
R2
H
H
Me
Me
Cl
Time (h)
5
5.5
5.5
6
5
5
5
5
Yield (%)b
86
82
81
76
82
77
80
75
In conclusion, we report a mild and efficient method for the
synthesis of N-arylbenzamides. A variety of substituted benzoyl
chlorides coupled with dimethylphenylthioureas smoothly to give
N-phenyl-benzamides in good yields. Compared with previously
known approaches which use metal catalysts, the simplicity of
this procedure and the generally satisfactory yields make this
method attractive. Further details and related applications are
still under research in our laboratory.
1
2
3
4
5
6
7
8
9
10
3a
3b
3c
3d
3e
3f
3g
3h
3i
Cl
NO2
NO2
OMe
OMe
Experimental
7
7
76
70
3j
Me
All starting materials were purchased from commercial suppliers and
used without further purification unless otherwise stated. Yields refer
to isolated compounds estimated to be >95% pure as determined by
1H NMR and capillary GC analysis. NMR spectra were recorded on a
Bruker AM400 NMR instrument in CDCl3 or DMSO-d6 using TMS
as an internal standard. Chemical shifts are given in ppm and coupling
constants (J) are given in Hz. All melting points were determined on a
RY-1G melting point instrument without correction. High-resolution
mass spectra (HRMS) were recorded on a Finnigan MAT 95Q or
a Finnigan 90 mass instrument (ESI). TLC was performed using
aluminum plates coated with SiO2 (Merck 60, F-254) and visualised with
UV light at 254 nm. Column chromatography was performed on silica
gel with petroleum ether–EtOAc as the eluent.
aReaction conditions: dimethylphenylthiourea 1 (1 mmol) was stirred with benzoyl
chloride 2(1.1 mmol) in the presence of K2CO3 (2 mmol) in dry DMAC (dimethylacetamide)
(2 mL) at 80 °C for 5–7 h; bIsolated yields of analytically pure product.
expected to furnish 1-benzoyl-3,3-dimethyl-1-phenyl-thiourea.
However, an unexpected compound N-phenylbenzamide was
obtained instead of the desired product (Scheme 1). Therefore,
a series of experiments were carried out to check the reaction
parameters such as base, solvent, and temperature. As a result, the
optimal reaction conditions were obtained and summarised as:
dimethylphenylthiourea (1.0 mmol), benzoyl chloride (1.1 mmol),
K2CO3 (1mmol) in DMAC (dimethylacetamide) (2 mL) at 80 °C
for 5–7 h.
Synthesis of benzanilides (3a–j); general procedure
Dimethylphenylthiourea (1.0 mml), the appropriate benzoyl chloride
(1.1 mmol) and K2CO3 (1 mmol) were added to a dried tube equipped
with a septum and a magnetic stirring bar. DMAC (dimethylacetamide)
(2 mL) was then added. The mixture was stirred at 80 °C and monitored
by TLC until the starting material was absent (about 5–7 h). The reaction
was cooled to room temperature, quenched with sat. NH4Cl solution
(5 mL) and then extracted with ethyl acetate. The crude solution was
dried over anhydrous Na2SO4 and evaporated under vacuum. The residue
was purified by flash column chromatography to afford the desired
product.
With the optimised reaction conditions in hand, we investigated
the substrate scope. By varying the substituent of benzoyl chloride
(2; R2 = various) and reacting them with dimethylphenylthiourea
(1; R1 = H) or dimethyl-(4-methylphenyl)thiourea (1; R1 = Me),
a series of N-arylbenzamides was prepared and the results are
shown in Table 1. It is clear that benzoyl chlorides with an
electron-withdrawing or an electron-donating group were well
tolerated and provided the corresponding amides in good yields
(70–86%), which indicates that the electronic properties of the
benzoyl chloride play either little or no effect on the reaction,
which reveals the versatility of this method.
As for the reaction mechanism, we presumed that the
expected product, the benzoylated thiourea (Scheme 1) was
formed under the anhydrous reaction conditions, but that it was
hydrolysed to the actual product, N-phenylbenzamide (Table 1;
3), trimethylamine and COS when the reaction was quenched
N-Phenylbenzamide (3a): The residue was purified by flash
chromatography on silica gel (ethyl acetate/petroleum ether = 1:3) to
give compound 3a: White solid; yield 169.4 mg, 86%; m.p. 163–164 °C
1
(lit.10 162–166 °C); H NMR (400 MHz, CDCl3) δ 8.11 (s, H), 7.84 (s,
2H), 7.64 (s, 2H), 7.24–7.49 (m, 5H), 7.12 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ 165.9, 137.9, 134.9, 131.8, 129.1, 128.7, 127.1, 124.6, 120.3;
HRMS (ESI) calcd for C13H11NO: 197.0841; found: 197.0835.

486 JOURNAL OF CHEMICAL RESEARCH 2017
N-p-tolylbenzamide (3b): The residue was purified by flash
chromatography on silica gel (ethyl acetate/petroleum ether = 1:7)
to give the compound 3b: White solid; yield 173.0 mg, 82%; m.p.
156–157 °C (lit.20 156–157 °C); 1H NMR (400 MHz, CDCl3) δ 7.79 (s,
1H), 7.84 (d, J = 7.7 Hz, 2H), 7.41–7.53 (m, 5H), 7.17 (d, J = 8.1 Hz,
2H), 2.33 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.9, 135.4, 135.0,
134.2, 131.6, 129.5, 128.6, 127.1, 120.5, 20.9; HRMS (ESI) calcd for
C14H13NO: 211.0997; found: 211.0105.
4-Methyl-N-phenylbenzamide (3c): The residue was purified by
flash chromatography on silica gel (ethyl acetate/petroleum ether
= 1:7) to give compound 3c: White solid; yield 171.0 mg, 81%; m.p.
145–146 °C (lit.20 145–146 °C); 1H NMR (400 MHz, CDCl3 ) δ
7.87 (s, 1H), 7.75 (d, J = 8.2 Hz, 2H), 7.62 (d，J = 7.9 Hz, 2H), 7.34
(t, J = 7.4 Hz, 2H), 7.25 (d, J = 7.2 Hz, 2H), 7.12 (t, J = 7.4 Hz, 1H),
2.40 (s，3H); 13C NMR (100 MHz, CDCl3) δ 165.7, 142.4, 138.0,
132.1, 129.4, 129.0, 127.0, 124.4, 120.1, 21.5; HRMS (ESI) calcd for
C14H13NO: 211.0997; found: 211.0100.
114.0, 55.5; HRMS (ESI) calcd for C13H10N2O3: 227.0946; found:
227.0954.
4-Methoxy-N-p-tolylbenzamide (3j): The residue was purified by
flash chromatography on silica gel (ethyl acetate/petroleum ether
= 1:5) to give compound 3j: White solid; yield 168.7 mg, 70%; m.p.
155–157°C (lit.22 152–154 °C); 1H NMR (400 MHz, CDCl3) δ 7.82 (d,
J = 8.8 Hz, 2H), 7.66 (s, 1H), 7.49 (d, J = 8.1 Hz, 2H), 7.16 (d, J = 8.2
Hz, 2H), 6.96 (d, J = 8.9 Hz, 2H), 3.86 (s, 3H), 2.32 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 165.1, 162.4, 135.5, 134.0, 129.5, 128.8, 127.2,
120.2, 113.9, 55.4, 20.9; HRMS (ESI) calcd for C15H15NO2: 241.1103;
found: 241.1112.
Acknowledgements
We thank the foundation support from National Natural Science
Foundation of China (21302150), Hubei Provincial Department
of Education (D20131501), Scientific Research Foundation
for the Returned Overseas Chinese Scholars, State Education
Ministry [2012]1707. We also thank Prof. Aiwen Lei at Wuhan
University for his generous NMR analysis support.
4-Methyl-N-p-tolylbenzamide (3d): The residue was purified by
flash chromatography on silica gel (ethyl acetate/petroleum ether =
1:10) to give compound 3d: White solid; yield 171.0 mg, 76%; m.p.
1
230–232 °C (lit.23 230–231 °C); H NMR (400 MHz, CDCl3 ) δ 7.96
(s, 1H), 7.73 (d, J = 8.1 Hz, 2H), 7.50 (d, J = 8.3 Hz, 2H), 7.21 (d, J = 7.9
Hz, 2H), 7.12 (d, J = 8.3 Hz, 2H), 2.38 (s, 3H), 2.31 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 165.8, 142.1, 135.5, 134.0, 132.1, 129.5, 129.3,
127.1, 120.5, 21.5, 20.9; HRMS (ESI) calcd for C15H15NO: 225.1154;
found: 225.1162.
Electronic Supplementary Information
The ESI is available through: http://ingentaconnect.com/
content/stl/jcr/2017/00000041/00000008
Received 8 June 2017; accepted 25 July 2017
Paper 1704816
https://doi.org/10.3184/174751917X15016635672213
Published online: 4 August 2017
4-Chloro-N-phenylbenzamide (3e): The residue was purified by
flash chromatography on silica gel (ethyl acetate/petroleum ether
= 1:7) to give compound 3e: White solid; yield 189.4 mg, 82%; m.p.
1
199–200 °C (lit.20 199–200 °C); H NMR (400 MHz, DMSO-d6) δ
10.21 (s, 1H), 7.88 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 8.0 Hz, 2H), 7.49
(d, J = 8.0 Hz, 2H), 7.24 (t, J = 8.0 Hz, 2H), 6.99 (t, J = 8.0 Hz, 1H);
13C NMR (100 MHz, DMSO-d6) δ 164.9, 139.4, 136.8, 134.1, 130.1,
129.1, 128.9, 124.3, 120.9; HRMS (ESI) calcd for C13H10ClNO:
231.0451; found: 231.046.
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