A three-component one-pot synthesis of 2-alkoxy-4-amino-N-arylthiazole-5- carboxamides

Article abstract of DOI:10.1016/j.cclet.2013.12.005

A facile and efficient protocol was developed to access 2-alkoxy-4-amino-N-arylthiazole-5-carboxamides through a three-component one-pot reaction, which involved potassium methyl cyanimidodithiocarbonate, 2-halo-N-arylacetamides and alcohols. The easy availability and the broad structural diversity of substrates make the reaction useful for the construction of libraries in drug discovery.

Full text of DOI:10.1016/j.cclet.2013.12.005

Chinese Chemical Letters 25 (2014) 411–414
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
A three-component one-pot synthesis of 2-alkoxy-4-amino-N-
arylthiazole-5-carboxamides
Hai-Long Zhao a,b, Jie Zhou a, Hong-Rui Song b, Bai-Ling Xu a,
*
a Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia Medica Chinese Academy of Medical Sciences &
Peking Union Medical College, Beijing 100050, China
b Department of Pharmacy Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China
A R T I C L E I N F O
A B S T R A C T
Article history:
A facile and efficient protocol was developed to access 2-alkoxy-4-amino-N-arylthiazole-5-carbox-
amides through a three-component one-pot reaction, which involved potassium methyl cyanimido-
dithiocarbonate, 2-halo-N-arylacetamides and alcohols. The easy availability and the broad structural
diversity of substrates make the reaction useful for the construction of libraries in drug discovery.
ß 2013 Bai-Ling Xu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Received 4 September 2013
Received in revised form 18 November 2013
Accepted 25 November 2013
Available online 8 December 2013
Keywords:
4-Aminothiazole-5-carboxamide
Potassium methyl
cyanimidodithiocarbonate
Acetamide
1. Introduction
The general procedure of method A was given as follows: A mixture
of potassium methyl cyanimidodithiocarbonate 1 (1 equiv.) and 2-
The thiazole ring system as a privileged structure was often
explored in the drug discovery process [1–5], and a number of the
marketed drugs contained a thiazole fragment [2,6,7]. So far, a
great deal of diversified thiazole derivatives were produced and
demonstrated a variety of biological activities such as cytotoxic,
immunosuppressive and antifungal activities [1,8–10]. Pin1
(Protein interaction with NIMA1) is a peptidyl-prolyl cis/trans
isomerase and inhibition of Pin1 is a potential therapeutic strategy
for the treatment of cancer [11–15]. In our efforts to search for
novel thiazoles as Pin1 inhibitors, the desired intermediate 3 was
not obtained according to Scheme 1, while unexpectedly, 4-amino-
2-ethoxy-N-(naphthalene-2-yl)thiazole-5-carboxamide (4a) was
isolated in 54% yield. To our best knowledge, there were few 2-
alkoxy-4-amino-N-arylthiazole-5-carboxamides reported in the
literature [16,17]. Herein, we wish to present our detailed
investigations on the synthesis of the title thiazole derivatives
by a simple and efficient protocol.
halo-N-arylacetamides 2 [18–20] (1 equiv.) was heated for 2–4 h
using various alcohols (ROH) as reaction solvents. After that, 2
equivalents of triethylamine were added and the resulting reaction
mixture was refluxed for further 4–8 h to furnish the desired
molecules (4a–d and 4k–r) in 41–84% yields. Method B: A mixture
of compound
1 (1 equiv.) and 2-bromo-N-(naphthalen-2-yl)-
acetamide 2a (1 equiv.) in 2 mL of tert-butanol was loaded into
the sealed reaction tube and irradiated by microwave for 15 min
(power 60 W, temperature 120 8C, pressure 150 psi). And then, 10
equivalents of various alcohols as reactants and 2 equivalents of
triethylamine were added. The resulting reaction mixture was
irradiated by microwave at the same reaction conditions for 60–
90 min to afford the corresponding final products (4e–i) in 24–48%
yields.
3. Results and discussion
With an aim to explore the scope of this protocol, the
substituent variations on the 2-position and 5-position of thiazoles
were conducted by using a series of alcohols (Table 1, compounds
4a–j) and aryl amines (Table 2, compounds 4k–r), respectively. The
chemical structures, synthetic methods and yields of all the
obtained 2-alkoxy-4-amino-N-arylthiazole-5-carboxamides were
summarized in Tables 1 and 2 [21].
2. Experimental
In this work, two different methods were developed to access
the thiazole derivatives 4a–i and 4k–r as shown in Tables 1 and 2.
As shown in Table 1, when the unbranched primary alcohols
such as methanol, ethanol, n-propanol and n-butanol were tested
*
Corresponding author.
E-mail address: xubl@imm.ac.cn (B.-L. Xu).
1001-8417/$ – see front matter ß 2013 Bai-Ling Xu. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2013.12.005

[
H.-L. Zhao et al. / Chinese Chemical Letters 25 (2014) 411–414
NH
2
N
H
H CS
3
N
S
H
N
O
3
NC
SCH
SK
3
Br
N
+
O
NH
2
N
1
2a
H
C H O
2
5
N
S
O
4a
Scheme 1. Reagents and conditions: (i) ethanol, reflux, 1.5 h; (ii) Et3N/ethanol, reflux, 4 h.
by functioning as both substrates and solvents in method A, the
desired 2-alkoxy substituted thiazoles were obtained in moderate
yields (46–62%). However, when the branched iso-propanol or tert-
butanol were selected as a substrate, the desired compounds 4e or
4j was not found; on the contrary, N-(3-(naphthalen-2-yl)-4-
oxothiazolidin-2-ylidene)cyanamide 6 as shown in Scheme 2 was
isolated, probably due to the steric hindrance of iso-propanol and
tert-butanol. To our delight, compound 4e was obtained in 24%
yield under microwave irradiation, although compound 4j
remained elusive in the reaction. Moreover, the initial attempt
to introduce propargyloxy substituent onto the 2-position of
thiazole scaffold via method A resulted in a sluggish reaction; but
the desired product was generated in 42% yield when the reaction
was promoted by microwave. In order to further diversify the
alkoxy groups on the 2-poistion of thiazoles with different
alcohols, method B was developed. In this method, 10 equivalents
of various alcohols were used as substrates together with starting
materials 1 and 2a, and the reactions were carried out in tert-
butanol as the reaction medium under microwave irradiation.
According to this strategy, compounds 4f–i bearing structural
diversities were produced in moderate yields (42–48%).
base, the three-component one-pot reaction of potassium methyl
cyanimidodithiocarbonate 1, 2-halo-N-arylacetamides and
2
ethanol underwent readily, and thus producing the desired
trisubstituted thiazoles in moderate to good yields (41–84%). It
was indicated that the reaction could well tolerate the variations of
electron-poor (compounds 4l–n) and electron-rich (compounds
4o–r) aromatic groups (Ar).
Preliminarily, the reaction mechanism for the formation of 2-
alkoxy-4-amino-N-arylthiazole-5-carboxamides 4 was hypothe-
sized using compound 4a as an example as shown in Scheme 2. It
was reported that the reaction of potassium methyl cyanimido-
dithiocarbonate 1 with 2-chloro-N-(naphthalen-2-yl)-acetamide
2a could give rise to thiazolidone 6 [20] in ethanol in the absence of
bases. And in this work, we isolated the intermediate 6 in 80% yield
in ethanol and the intermediate 6 was heated at reflux in ethanol in
the presence of triethylamine or NaH, and the desired compound
4a was obtained in 60% and 65% yield, respectively. In order to
further improve the yield of this reaction, the following attempts
were conducted. When sodium ethoxide was used as the base for
the preparation of 4a with method A, the product 4a was isolated
in only 36% yield. While when KI (1 equiv.) was used with 2-
Subsequently, a number of 2-halo-N-arylacetamides 2 as
shown in Table 2 were examined to broaden the scope of this
protocol. In the presence of 2 equivalents of triethylamine as a
bromo-N-b-naphthylacetamide 2a or 2-iodo-N-b-naphthylaceta-
mide 2j was utilized to promote this reaction, the desired
compound 4a was obtained in comparable yield (57% and 52%
Table 1
Synthesis of 2-alkoxy-4-amino-N-(naphthalene-2-yl)thiazole-5-carboxamide derivatives.
NH2
H
N
N
H
N
R
ROH
NC
SCH3
SK
O
Br
S
[
N
+
Method A or B
O
O
1
2a
4
Product
R
Solvent
Method
Yield (%)a
Mp (8C)
4a
4b
4c
4d
4e
4e
4f
Et
Ethanol
Method Ab
Method A
Method A
Method A
Method A
Method Bc
Method A
Method B
Method B
Method B
Method B
Method A
Method B
54
62
46
55
179–181
216–218
95–97
Me
Methanol
n-Propanol
n-Butanol
n-Pr
n-Bu
93–94
e
i-Pr
iso-Propanol
iso-Propanol
tert-Butanol
tert-Butanol
tert-Butanol
tert-Butanol
tert-Butanol
tert-Butanol
tert-Butanol
–
i-Pr
24
109–112
d
Propargyl
Propargyl
Bn
–
4f
42
45
48
45
161–163
145–147
104–106
187–189
4g
4h
4i
i-Bu
CH3OCH2CH2
t-Bu
e
4j
–
e
4j
t-Bu
–
a
Isolated yields after silica gel column chromatography.
b
c
Method A: (i) 1 (1 equiv.), 2a (1 equiv.), refluxing 2–4 h; (ii) Et3N (2 equiv.), refluxing 4–8 h; alcohols (ROH) as both substrates and solvents.
Method B: (i) 1 (1 equiv.), 2a (1 equiv.), microwave 15 min; (ii) Et3N (2 equiv.), ROH (10 equiv.), microwave 60–90 min; t-BuOH as the solvent.
The reaction was sluggish, and only a small amount of desired product was detected.
d
e
Only compound 6 was formed, and no desired product was observed.

[
H.-L. Zhao et al. / Chinese Chemical Letters 25 (2014) 411–414
413
NC
SCH3
N
H
N
NC
SCH3
SK
S
O
C2H5OH
CN
N
S
Br
N
NH
+
O
N
N
S
OC2H5
NH
O
O
C2H5OH
NC
1
2a
6
7
5
N
N
NEt3
N
N
H
H
N
Et3N
deprotonation
protonation
H
N
C2H5O
S
C2H5O
S
enolization
O
O
9
8
NH2
NH
O
N
N
H
tautomerization
H
C2H5O
C2H5O
N
nucleophilic attack
protonation
N
S
S
O
4a
10
Scheme 2. A plausible mechanism proposed for the formation of 4-amino-2-ethoxy-N-(naphthalene-2-yl)thiazole-5-carboxamide (4a).
Table 2
4. Conclusion
Synthesis of 4-amino-2-ethoxy-N-arylthiazole-5-carboxamide derivatives via
method A.a
An efficient and straightforward approach was developed for
the construction of novel 2-alkoxy-4-amino-N-arylthiazole-5-
carboxamide derivatives. It has been demonstrated that structur-
ally diverse alcohols and 2-halo-N-arylacetamides, which were
easily accessed by the reaction of 2-chloroacetyl chloride and
arylamines, were well tolerated. Therefore, this three-component
H
N
NH2
SCH3
SK
N
NC
X
Ar
EtOH
H
N
+
EtO
N
O
]
S
Ar
X = Cl or Br
O
1
4
2
one-pot protocol could be used to build up
diversified thiazole library for the drug discovery and develop-
ment.
a structurally
Product
Ar
Yield (%)b
Mp (8C)
4k
4l
Ph
84
41
60
58
44
58
54
45
137–139
186–188
182–185
240–242
210–212
141–143
179–181
190–193
4-CF3C6H4
4-FC6H4
4m
4n
4o
4p
4q
4r
Acknowledgments
4-NO2C6H4
4-CH3OC6H4
3-CH3C6H4
This work is supported by the National Natural Science
Foundation of China (No. 81273380) and ‘‘863’’ Program of China
(No. 2012AA020302).
3,4-(CH3O)2C6H3
4-Phenoxyphenyl
a
Method A: (i) 1 (1 equiv.), 2 (1 equiv.), refluxing 2–4 h; (ii) Et3N (2 equiv.),
refluxing 4–8 h; ethanol as the substrate and solvent.
b
Isolated yields after silica gel column chromatography.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.cclet.2013.12.005.
yield, respectively), compared with the case where 2-bromo-N-b-
naphthylacetamide 2a was treated as a reactant. Based on these
experimental results, a plausible mechanism for this three-
component one-pot synthesis of trisubstituted thiazoles was
suggested as illustrated in Scheme 2. The initial SN2 substitution
of thiolate 1 with 2-bromo-N-(naphthalen-2-yl)-acetamide and
the subsequent intramolecular cyclization of intermediate 5
yielded thiazolidone 6. Next, in the presence of triethylamine,
ethanol attacks on the electrophilic carbon of N-cyanamide 6,
followed by the intramolecular ring opening of 7 to provide the key
intermediate 8. After deprotonation of 8 with Et3N, the generated 9
underwent an intramolecular cyclization by attacking the present
cyano group to afford 10, which was tautomerized into the desired
compound 4a with the assistance of Et3N.
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[21] The synthetic procedure and structure identification for compounds 2a–j, 4a–i
and 4k–r are available in Supporting information. All synthesized final products
were characterized by 1H NMR, 13C NMR and ESI-HRMS. For example, compound
4a: light yellow solid; mp 179–182 8C; 1H NMR (300 MHz, DMSO-d6): d 10.77 (s,
1H), 8.27 (s, 1H), 7.79–7.89 (m, 3H), 7.58 (dd, 1H, J1 = 8.7 Hz, J2 = 2.1 Hz), 7.48 (t,
1H, J = 6.9 Hz), 7.38 (t, 1H, J = 7.2 Hz), 6.95 (brs, 2H), 4.14 (q, 2H, J = 6.9 Hz), 1.22 (t,
3H, J = 6.9 Hz); 13C NMR (100 MHz, DMSO-d6): d 165.04, 163.47, 137.56, 133.60,
129.41, 128.73, 127.53, 127.02, 126.61, 124.44, 119.59, 113.80, 58.97, 14.65;
HRMS (ESI) Calcd. for C16H16N3O2S [M+H+]: 314.0958; found: 314.0957.