Efficient and facile strategy to substituted 2-aminothiazoles via ring opening of α-nitroepoxides

Article abstract of DOI:10.1016/j.tet.2018.09.005

A novel and efficient reaction has been developed to synthesize a set of substituted 2-aminothiazoles from α-nitroepoxides and ammonium thiocyanate. This reaction could proceed smoothly at mild condition, to afford products for a wide range of substrates with good to excellent yields. A possible mechanism has also been proposed.

Full text of DOI:10.1016/j.tet.2018.09.005

Accepted Manuscript
Efficient and facile strategy to substituted 2-aminothiazoles via ring opening of α-
nitroepoxides
Yue Zhu, Qilin Wang, Haofan Luo, Guolin Zhang, Yongping Yu
PII:
S0040-4020(18)31058-5
10.1016/j.tet.2018.09.005
TET 29777
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 3 August 2018
Revised Date: 31 August 2018
Accepted Date: 3 September 2018
Please cite this article as: Zhu Y, Wang Q, Luo H, Zhang G, Yu Y, Efficient and facile strategy to
substituted 2-aminothiazoles via ring opening of α-nitroepoxides, Tetrahedron (2018), doi: 10.1016/
j.tet.2018.09.005.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Efficient and facile strategy to substituted
2-aminothiazoles via ring opening of
α-nitroepoxides
Leave this area blank for abstract info.
†
†
Yue Zhu a, , Qilin Wang b, , Haofan Luo a, Guolin Zhang a, * and Yongping Yu a, *
a Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences,
Zhejiang University, Hangzhou 310058, P. R. China
b School of Biological and Pharmaceutical Engineering, Wuhan Polytechnic University, Wuhan 430000, P. R.
China

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Efficient and facile strategy to substituted 2-aminothiazoles via ring opening of α-
nitroepoxides
Yue Zhu a, †, Qilin Wang b, †, Haofan Luo a, Guolin Zhang a, * and Yongping Yu a, *
a Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, P. R. China
b School of Biological and Pharmaceutical Engineering, Wuhan Polytechnic University, Wuhan 430000, P. R. China
ARTICLE INFO
ABSTRACT
A novel and efficient reaction has been developed to synthesize a set of substituted 2-aminothiazoles
from α-nitroepoxides and ammonium thiocyanate. This reaction could proceed smoothly at mild
condition, to afford products for a wide range of substrates with good to excellent yields. A possible
mechanism has also been proposed.
Article history:
Received
Received in revised form
Accepted
Available online
Keywords:
2-Aminothiazoles
α-Nitroepoxides
Ammonium thiocyanate
Facile synthesis
1. Introduction
improved the construction of 2-aminothiazoles, a method of
synthesizing 2-aminothiazoles from readily available starting
materials under mild condition remains in demand. Herein we
developed a facile and eco-friendly protocol for the synthesis of
2-aminothiazoles via α-nitroepoxides and ammonium thiocyanate
(Scheme 1-B).
2-Aminothiazole is one of the most important and versatile
scaffolds, which are frequently found in a plethora of natural
products and synthetic drugs, such as Famotidine (a histamine H2
receptor antagonist), Abafungin (a broad-spectrum antifungal
agent), Cefdinir (a semi-synthetic third generation broad
spectrum cephalosporin antibiotic)(Fig. 1). In pharmaceutical
field, functionalized 2-aminothiazoles are privileged core
structures used in medicinal chemistry because of their broad
bioactivities, such as anticancer,1 antihypertensive,2 anti-
inflammatory,3 antiviral,4 antimicrobial,5 and so on.
In light of the importance of the 2-aminothiazoles, a variety of
synthetic strategies have been developed. The most traditional
method is Hantzsch method and its various modified
methodologies, which consist of the condensation of α-
haloketones or α-halogenated aldehydes with thioureas (Scheme
1-A, Eq. (1)),6 the synthesis method of ketones with thioureas
using SiO2–Cl as the supported reagents (Scheme 1-A, Eq. (2)).7
Also, 2-aminothiazoles could also be prepared through the
reaction between isothiocyanates and oxime acetates (Scheme 1-
A, Eq. (3)).8 Moreover, 2-aminothiazoles could be produced by
treating (Z)-(2-acetoxyvinyl)phenyl-λ3-iodanes with thioureas in
methol (Scheme 1-A, Eq. (4)).9 Although these strategies have
* Corresponding authors. Tel./fax: +86-571-8820-8450, +86-571-
8820-8452; e-mail addresses: guolinzhang@zju.edu.cn (G. Zhang),
yyu@zju.edu.cn (Y. Yu).
Figure 1. Drugs in the market with 2-aminothiazole scaffold.
Nitroepoxides are an interesting class of building blocks and
have unique chemical properties with two adjacent electrophilic
† Yue Zhu and Qilin Wang contributed equally to this work.

2
Tetrahedron
centers.10 Nitroepoxides have been reported as particularly
equiv) and K2CO3 (2 equiv) were conducted at 40
for 14 h
ACCEPTED MANUSCRIPT
attractive building blocks in organic synthesis.11 Our group have
reported some reactions with nitroepoxides to generate
substituted 2-aminothiazoles such as the condensation of α-
nitroepoxides with thioureas12 and one-pot three-component
protocol of α-nitroepoxides, cyanamide and sodium sulfide.13
with n-propanol as solvent (Table 1, entry 8).
With the optimized reaction conditions in hand, the scope and
generality of the methodology for the synthesis of 2-
aminothiazoles using a set of α-nitroepoxides was studied. The α-
nitroepoxides were readily prepared according to the literature14.
The results of substrate scope were summarized in Table 2.
Table 1. Optimization of reaction conditionsa
Entry Base
(equiv.)
Solvent
2(equiv.)
T(oC)
Conversionb
(%)
1
—
n-propanol
n-propanol
n-propanol
n-propanol
n-propanol
n-propanol
n-propanol
n-propanol
CH3CN
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
2
4
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
30
50
40
40
40
40
40
32
2
Et3N (2)
80
3
DIEA (2)
DBU (2)
79
4
56
5
MeONa (2)
NaOH (2)
Cs2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (1)
K2CO3 (1.5)
K2CO3 (3)
K2CO3 (2)
K2CO3 (2)
90
6
87
7
57
95(91)c
8
9
65
10
11
12
13
14
15
16
17
18
19
20
21
22
Dioxane
62
Toluene
n.r.
47
DMF
EtOH
87
MeOH
84
H2O
n.r.
88
n-propanol
n-propanol
n-propanol
n-propanol
n-propanol
n-propanol
n-propanol
92
Scheme 1. Previous and new synthesis of 2-aminothiazoles
.
92
93
86
2. Results and discussion
92
95(90)c
Initially, 2-methyl-2-nitro-3-phenyloxirane 1a and ammonium
thiocyanate 2 were selected as model reactants to optimize the
reaction condition. Firstly, it was pleased to see that the reaction
afforded the desired 2-aminothiazole 3a in 32% conversion rate
without any base (Table 1, entry 1). When a range of bases were
added, the conversion of 3a was increased (Table 1, entries 2-8).
It was revealed that K2CO3 was the most efficient one (Table 1,
entries 8). Replacing n-propanol with other organic solvents
caused either a decrease in the conversion (Table 1, entries 9, 10,
12, and 13) or failure to obtain the corresponding product (Table
1, entries 11 and 14). In addition, when the reaction was tested at
different temperatures (Table 1, entries 15 and 16), the
conversion decreased. Furthermore, when changing the ratio of
K2CO3 to 1.0 or 3.0 equiv, the conversion of the reaction slightly
decreased to 92% or 86%, respectively (Table 1, entries 17 and
18). Finally, after reducing the amount of ammonium thiocyanate
2 to 2 equiv (Table 1, entry 19), the conversion of 2-
aminothiazole 3a decreased not obviously. When increasing the
amount of ammonium thiocyanate 2 (Table 1, entry 20), the
conversion rate was maintained. On the basis of the initial study,
the optimal reaction condition was obtained, that is, 2-methyl-2-
nitro-3-phenyloxirane 1a (1 equiv), ammonium thiocyanate 2 (3
aReaction conditions: 2-methyl-2-nitro-3-phenyloxirane (0.2 mmol, 1 equiv.),
ammonium thiocyanate, base, 1mL of solvent, 14h. n.r. = no reaction.
bDetermined by LC–MS based on the disappearance of the starting α-
nitroepoxide. The most successful entry is highlighted in bold.
cIsolated yields.
Gratifyingly, the groups at the R1 and R2 positions of
nitroepoxides 1, either aryl or alkyl substitutions, were
compatible in the reaction condition within good to excellent
yields (77-95%). The α-nitroepoxides with electron-withdrawing
groups at the aromatic ring (R1) gave relatively better results than
electron-donating groups (Table 2, 3b, 3d, 3e vs 3h). The steric
hindrance has a slightly effect on the reaction yields (Table 2, 3b
vs 3c; 3e, 3f vs 3g; 3a vs 3i). In addition, when a heteroaryl
group (Table 2, 3j) was at the R1 position, the desired product
was obtained in 89% yield. However, when 2-methyl-2-nitro-3-
propyloxirane was used as the reagent, the yield of this reaction
decreased (Table 2, 3k). Moreover, insteading the methyl group
at the R2 position with ethyl group or aryl group resulted in a
decrease of yields (Table 2, 3a vs 3l, 3o; 3d vs 3m; 3e vs 3n).

3
The structures of 2-aminothiazoles were characterized by 1H
3. Conclusion
ACCEPTED MANUSCRIPT
NMR, 13C NMR, and HRMS (ESI).
In conclusion, we have developed a novel and facile strategy
to construct functionalized 2-aminothiazoles from α-
nitroepoxides and ammonium thiocyanate with good to excellent
yields. This reaction has the advantages of easily available
starting materials, mild reaction condition, operational simplicity
and a satisfactory substrate scope. These features make it a highly
practical approach in medicinal chemistry.
Based on the results presented above, a possible reaction
mechanism is proposed as shown in Scheme 2. The nitroepoxide
1 is attacked by thiocyanate ion and undergoes a ring opening to
give the intermediate I. The intermediate
I affords the
intermediate II driven by the excellent leaving ability of nitro.15
Furthermore, the reaction of intermediate II and ammonia gives
rise to intermediate III followed by an intramolecular
nucleophilic addition. Finally, intermediate IV transforms into
the final product 3 by eliminating one molecule of H2O.12, 16
4. Experimental section
4.1 General
Table 2. Scope of the reaction of α-nitroepoxides and
All solvents were purified according to standard methods prior
to use. Melting points were recorded on a BÜCHI B-540 melting
point apparatus. NMR spectra were recorded for 1H NMR at 500
MHz and 13C NMR at 125 MHz. For 1H NMR, tetramethylsilane
(TMS) served as internal standard (δ=0) and data are reported as
follows: chemical shift, integration, multiplicity (s=singlet,
d=doublet, t=triplet, q=quartet, m=multiplet), and coupling
constant(s) in Hertz. For 13C NMR, TMS (δ=0) or DMSO
(δ=40.45) was used as internal standard and spectra were
obtained with complete proton decoupling. LC-MS and HRMS
data was obtained using Agilent Technologies 6224 TOF
LC/MS. The starting material α-nitroepoxides were prepared
according to literature methods.10
ammonium thiocyanate under optimal conditiona
4.2
General procedure for the synthesis of 2-
aminothiazoles 3
A mixture of α-nitroepoxides 1 (1 mmol), ammonium
thiocyanate 2 (3 mmol), K2CO3 (2 mmol) was stirred in n-
propanol 5mL at 40 for 14 hours. After the completeness of the
reaction, the reaction was diluted with water and extracted thrice
with ethyl acetate. The combined organic extracts were washed
with brine, dried over Na2SO4, concentrated, and purified by
column chromatography (Petroleum ether/EtOAc) on silica gel to
afford the desired product 3.
4.2.1
4-methyl-5-phenylthiazol-2-amine (3a). Yield: 91%,
1
white powder, mp: 167.3~167.7°C; H NMR (500 MHz, CDCl3)
δ 7.37 – 7.36 (m, 4H), 7.28 – 7.26 (m, 1H), 5.00 (s, 2H), 2.31 (s,
3H). 13C NMR (125 MHz, CDCl3) δ 165.06, 143.46, 132.77,
128.82, 128.61, 126.87, 121.40, 16.11. HRMS (ESI): m/z calcd
for C10H11N2S [M+H]+: 191.0637, found: 191.0638.
4.2.2
5-(4-fluorophenyl)-4-methylthiazol-2-amine (3b). Yield:
1
95%, pale yellow powder, mp: 163.8~165.2°C; H NMR (500
MHz, CDCl3) δ 7.33 – 7.29 (m, 2H), 7.08 – 7.04 (m, 2H), 5.07 (s,
2H), 2.26 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 165.13, 161.79
(d, J = 245.5 Hz), 143.42, 130.56 (d, J = 7.9 Hz), 128.71 (d, J =
3.3 Hz), 120.08, 115.57 (d, J = 21.5 Hz), 15.87. HRMS (ESI):
m/z calcd for C10H10FN2S [M+H]+: 209.0543, found: 209.0545.
aReaction condition: α-nitroepoxides (1 mmol, 1.0 equiv.), ammonium
thiocyanate (3 mmol, 3.0 equiv.), K2CO3 (2 mmol, 2.0 equiv.), 5 mL of n-
propanol, 14 h, 40oC. Isolated yield.
4.2.3
5-(3-fluorophenyl)-4-methylthiazol-2-amine (3c). Yield:
89%, tan powder, mp: 117.7~118.6°C; 1H NMR (500 MHz,
CDCl3) δ 7.32 (dd, J = 14.0, 8.0 Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H),
7.06 (d, J = 10.0 Hz, 1H), 6.97 – 6.93 (m, 1H), 5.13 (s, 2H), 2.31
(s, 3H). 13C NMR (125 MHz, CDCl3) δ 165.37, 162.80 (d, J =
244.8 Hz), 144.35, 134.94 (d, J = 8.3 Hz), 130.09 (d, J = 8.6 Hz),
124.43 (d, J = 2.8 Hz), 120.06, 115.51 (d, J = 22.1 Hz), 113.67 (d,
J = 21.1 Hz), 16.21. HRMS (ESI): m/z calcd for C10H10FN2S
[M+H]+: 209.0543, found: 209.0546.
4.2.4
5-(4-chlorophenyl)-4-methylthiazol-2-amine
(3d).
Yield: 92%, tan powder, mp: 180.1~181.6°C; 1H NMR (500
MHz, CDCl3) δ 7.34 – 7.32 (m, 2H), 7.29 – 7.26 (m, 2H), 5.06 (s,
2H), 2.28 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 165.24, 143.95,
132.71, 131.25, 129.99, 128.79, 120.04, 16.08. HRMS (ESI): m/z
Scheme 2. Proposed mechanism for the synthesis of 2-
aminothiazoles.

4
Tetrahedron
calcd for C10H10ClN2S [M+H]+: 225.0248, found: 225.0248.
130.25, 128.79, 119.59, 22.94, 14.14. HRMS (ESI): m/z calcd for
ACCEPTED MANUSCRIPT
C11H12ClN2S [M+H]+: 239.0404, found: 239.0407.
4.2.5
5-(4-bromophenyl)-4-methylthiazol-2-amine (3e). Yield:
1
90%, pale yellow powder, mp: 200.2~200.7°C; H NMR (500
MHz, CDCl3) δ 7.50-7.46 (m, 2H), 7.23-7.20 (m, 2H), 5.08 (s,
2H), 2.28 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 165.16, 144.03,
131.75, 131.73, 130.29, 120.78, 120.14, 16.11. HRMS (ESI): m/z
calcd for C10H10BrN2S [M+H]+: 268.9743, found: 268.9745.
4.2.14 5-(4-bromophenyl)-4-ethylthiazol-2-amine (3n). Yield:
85%, pale yellow powder, mp:171.5~171.6℃; 1H NMR (500
MHz, CDCl3) δ 7.50 – 7.46 (m, 2H), 7.21 – 7.18 (m, 2H), 5.12 (s,
2H), 2.58 (q, J = 7.5 Hz, 2H), 1.23 (t, J = 7.5 Hz, 3H). 13C NMR
(125 MHz, CDCl3) δ 165.67, 149.97, 131.75, 131.68, 130.55,
120.96, 119.62, 22.97, 14.11. HRMS (ESI): m/z calcd for
C11H12BrN2S [M+H]+: 282.9899, found: 282.9905.
4.2.6
5-(3-bromophenyl)-4-methylthiazol-2-amine (3f). Yield:
1
90%, white powder, mp: 142.5~143.6°C; H NMR (500 MHz,
CDCl3) δ 7.50 (t, J = 1.7 Hz, 1H), 7.39 – 7.37 (m, 1H), 7.29 –
7.27 (m, 1H), 7.23 (t, J = 7.8 Hz, 1H), 5.10 (s, 2H), 2.30 (s, 3H).
13C NMR (125 MHz, CDCl3) δ 165.42, 144.48, 134.91, 131.54,
130.07, 129.81, 127.36, 122.64, 119.69, 16.14. HRMS (ESI): m/z
calcd for C10H10BrN2S [M+H]+: 268.9743, found: 268.9742.
4.2.15 4,5-diphenylthiazol-2-amine (3o). Yield: 80%, white
solid, mp: 189.5-189.9°C; 1H NMR (500 MHz, DMSO-d6) δ 7.38
– 7.35 (m, 2H), 7.31 – 7.19 (m, 8H), 7.12 (s, 2H). 13C NMR (125
MHz, DMSO-d6) δ 166.11, 144.96, 135.44, 132.83, 128.96,
128.73, 128.47, 128.06, 127.32, 127.05, 119.05. HRMS (ESI):
m/z calcd for C15H13N2S [M+H]+: 253.0794, found: 253.0792.
4.2.7
5-(2-bromophenyl)-4-methylthiazol-2-amine (3g). Yield:
1
86%, pale yellow powder, mp: 150.1~151.9°C; H NMR (500
MHz, CDCl3) δ 7.65 (dd, J = 8.0, 1 Hz, 1H), 7.37 – 7.29 (m, 2H),
7.22 – 7.18 (m, 1H), 5.02 (s, 2H), 2.07 (s, 3H). 13C NMR (125
MHz, CDCl3) δ 166.26, 145.60, 133.26, 133.13, 133.10, 129.68,
127.25, 125.73, 119.12, 15.73. HRMS (ESI): m/z calcd for
C10H10BrN2S [M+H]+: 268.9743, found: 268.9742.
Acknowledgements
This project was supported from Zhejiang Provincial Natural
Science Foundation of China (LY16H300001) to G. Zhang,
National Natural Science Foundation of China (81473074 and
81673291) and Osteoporosis & Breast Cancer Research Center,
USA, to Y. Yu.
4.2.8
4-methyl-5-(p-tolyl)thiazol-2-amine (3h). Yield: 88%,
1
white powder, mp:147.8~149.0 ; H NMR (500 MHz, DMSO-
d6) δ 7.22 – 7.16 (m, 4H), 6.89 (s, 2H), 2.29 (s, 3H) , 2.16 (s, 3H).
13C NMR (125MHz, DMSO-d6) δ 165.52, 142.69, 135.47, 130.17,
129.33, 127.92, 117.61, 20.72, 16.22. HRMS (ESI): m/z calcd for
C11H12N2S [M+H]+: 205.0799, found: 205.0795.
Supplementary data
Supplementary
data
(Experimental
procedures,
characterization data, and copies of H and 13C NMR spectra for
all products.) associated with this article can be found in online
version at http://dx.doi.org/
1
4.2.9
4-methyl-5-(naphthalen-1-yl)thiazol-2-amine (3i). Yield:
77%, pale brown solid, mp: 147.7~149.1°C; 1H NMR (500 MHz,
CDCl3) δ 7.93 – 7.85 (m, 3H), 7.51 – 7.48 (m, 4H), 5.06 (s, 2H),
2.05 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 166.42, 145.28,
133.77, 132.89, 129.59, 129.42, 128.72, 128.37, 126.47, 126.07,
125.93, 125.26, 118.06, 15.70. HRMS (ESI): m/z calcd for
C14H13N2S [M+H]+: 241.0794, found: 241.0800.
References and notes
1
(a) Kim, K. S.; Kimball, S. D.; Misra, R. N.; Rawlins, D.
B.; Hunt, J. T.; Xiao, H. Y.; et al. J. Med. Chem 2002, 45,
3905-3927. (b) Misra, R. N.; Xiao, H. Y.; Kim, K. S.; Lu,
S.; Han, W. C.; Barbosa, S. A.; et al. J. Med. Chem 2004
.
.
,
4.2.10 4-methyl-5-(pyridin-3-yl)thiazol-2-amine (3j). Yield:
75%, tan powder, mp:176.8~178.2ꢀ; 1H NMR (500 MHz,
CDCl3) δ 8.63 (d, J = 2.0 Hz, 1H), 8.49 (dd, J = 4.5, 1.3 Hz,
1H), 7.66 ꢁ 7.64 (m, 1H), 7.30 (dd, J =7.8, 4.8 Hz, 1H), 5.20 (s,
2H), 2.30 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 165.95,
149.38, 147.76, 145.06, 135.80, 129.11, 123.40, 117.15, 16.04.
HRMS (ESI): m/z calcd for C9H10N3S [M+H]+:192.0590, found:
192.0588.
47, 1719-1728. (c) Bischof, J.; Leban, J.; Zaja, M.;
Grothey, A.; Radunsky, B.; Othersen, O.; Strobl, S. Amino
Acids. 2012, 43, 1577-1591. (d) Lee, Y. S. E.; Chuang, S.
H.; Huang, L. Y. L.; Lai, C. L.; Lin, Y. H.; Yang, J. Y.; et
al. J. Med. Chem
(a) Turanzitouni, G.; Chevallet, P.; Kilic, F. S.; Erol, K.
Eur. J. Med. Chem 2000, 35, 635-641. (b) Abdel-Wahab,
B. F.; Mohamed, S. F.; Amr, A. E. G. E.; Abdalla, M. M.
Monatsh. Chem. 2008, 139, 1083-1090.
. 2014, 57, 4098-4110.
2
3
.
4.2.11 4-methyl-5-propylthiazol-2-amine (3k). Yield: 78%, tan
1
liquid; H NMR (500 MHz, CDCl3) δ 4.96 (s, 1H), 2.51 (t, J =
(a) Kalkhambkar, R. G.; Kulkarni, G. M.; Shivkumar, H.;
Rao, R. N. Eur. J. Med. Chem. 2007, 42, 1272-1276. (b)
7.5 Hz, 2H), 2.09 (s, 3H), 1.57 – 1.49 (m, 2H), 0.92 (t, J = 7.3 Hz,
3H). 13C NMR (125 MHz, CDCl3) δ 164.12, 142.44, 121.55,
28.23, 24.87, 14.61, 13.53. HRMS (ESI): m/z calcd for C7H13N2S
[M+H]+: 157.0794, found: 157.0795.
Singh, N.; Bhati, S. K.; Kumar, A. Eur. J. Med. Chem
2008, 43, 2597-2609.
.
4
5
Venkatachalam, T. K.; Sudbeck, E. A.; Mao, C.; Uckun, F.
M. Bio. Med. Chem 2001, 11, 523-528.
(a) Chimenti, F.; Bizzarri, B.; Maccioni, E.; Secci, D.;
Bolasco, A.; et al. Bioorg. Med. Chem. Lett 2007, 17,
4635-4640. (b) Bharti, S. K.; Nath, G.; Tilak, R.; Singh, S.
K. Eur. J. Med. Chem 2010, 45, 651-660.
.
4.2.12 4-ethyl-5-phenylthiazol-2-amine (3l). Yield: 87%, white
powder, mp: 125.8~126.7°C; 1H NMR (500 MHz, CDCl3) δ 7.38
– 7.33 (m, 4H), 7.29 – 7.26 (m, 1H), 5.01 (s, 2H), 2.62 (q, J = 7.5
Hz, 2H), 1.25 (t, J = 7.5 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ
165.49, 149.24, 132.64, 129.09, 128.62, 127.08, 121.01, 22.94,
14.19. HRMS (ESI): m/z calcd for C11H13N2S [M+H]+: 205.0794,
found: 205.0797.
.
.
6
7
8
9
Hantzsch, A.; Weber, J. H. Ber. Dtsch. Chem. Ges. 1887,
20, 3118-3132.
Hitendra, K.; Manisha, S. Catal. Commun. 2007, 8, 741-
746.
Tang, X.; Zhu, Z.; Qi, C.; Wu, W.; Jiang, H. Org. Lett
2016, 18, 180-183.
Masahito, O.; Yoshio, N. J. Org. Chem. 2003, 68, 7887.
4.2.13 5-(4-chlorophenyl)-4-ethylthiazol-2-amine (3m). Yield:
88%, pale yellow powder, mp:169.4~170.9ꢀ; 1H NMR (500
MHz, CDCl3) δ 7.35 ꢁ 7.31 (m, 2H), 7.28 ꢁ 7.24 (m, 2H),
5.15 (s, 2H), 2.58 (q, J = 7.5 Hz, 2H), 1.24 (t, J = 7.5 Hz, 3H).
13C NMR (125 MHz, CDCl3) δ 165.66, 149.89, 132.89, 131.17,
.

5
10 Vidal-Albalat, A.; Rodriguez, S.; Gonzalez, F. V. Org.
ACCEPTED MANUSCRIPT
Lett
11 (a) Nosood, Y. L.; Halimehjani, A. Z.; González, F. V. J.
Org. Chem 2018, 83, 1253-1258. (b) Ibrahim, M. M.;
Grau, D.; Hampel, F. Eur. J. Org. Chem 2014, 7, 1401-
. 2014, 16, 1752-1755.
.
.
1405. (c) Weiß, K. M.; Wei, S.; Tsogoeva, S. B. Org.
Biomol. Chem. 2011, 9, 3457-3461.
12 Zhao, D.; Guo, S.; Guo, X.; Zhang, G.; Yu, Y.
Tetrahedron. 2016, 72, 5285-5289.
13 Guo, S.; Zhao, D.; Zhu, Y.; Yu, Y.; Chen, W.; Zhang, G.
Synth. Commun. 2017, 47, 1758-1764.
14 (a) Vidal-Albalat, A.; Rodriguez, S.; Gonzalez, F. V. Org.
Lett 2014, 16, 1752-1755. (b) Sprang, C. A.; Degering, E.
F. J. Am. Chem. Soc 1942, 64, 1063-1064. (c) Anderson,
J. C.; Blake, A. J.; Mills, M.; Ratcliffe, P. D. Org. Lett
.
.
.
2008, 10, 4141-4143. (d) Zhao, D.; Guo, S.; Guo, X.;
Zhang, G.; Yu, Y. Tetrahedron. 2016, 72, 5285-5289. (e)
Nosood, Y. L.; Halimehjani, A. Z.; González, F. V. J. Org.
Chem
15 (a) Guo, X.; Chen, W.; Chen, B. Org. Lett
(b) Ibrahim, M. M.; Grau, D.; Hampel, F. Eur. J. Org.
Chem 2014, 7, 1401-1405. (c) Agut, J.; Vidal, A.;
Rodríguez, S. J. Org. Chem 2013, 78, 5717. (d) Vidal-
. 2018, 83, 1253-1258.
.
2015, 17, 1157.
.
.
Albalat, A.; Rodriguez, S.; Gonzalez, F. V. Org. Lett
2014, 16, 1752-1755.
.
16 Guo, X.; Shao, J.; Liu, H.; Chen, B.; Chen, W.; Yu, Y.
RSC Adv 2015, 5, 51559-51562.
.