Facile, efficient synthesis of polysubstituted thiazoles via α-nitroepoxides and thioureas

Article abstract of DOI:10.1016/j.tet.2016.05.010

An efficient synthesis of 2,4,5-trisubstituted thiazoles via the reaction of α-nitroepoxides and thioureas under mild conditions has been developed. This reaction proceeded well at room temperature, to afford products in excellent yields for a wide range

Full text of DOI:10.1016/j.tet.2016.05.010

Accepted Manuscript
Facile, efficient synthesis of polysubstituted thiazoles via α-nitroepoxides and
thioureas
Donghong Zhao, Shanshan Guo, Xiao Guo, Guolin Zhang, Yongping Yu
PII:
S0040-4020(16)30383-0
10.1016/j.tet.2016.05.010
TET 27737
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 16 March 2016
Revised Date: 29 April 2016
Accepted Date: 3 May 2016
Please cite this article as: Zhao D, Guo S, Guo X, Zhang G, Yu Y, Facile, efficient synthesis of
polysubstituted thiazoles via α-nitroepoxides and thioureas, Tetrahedron (2016), doi: 10.1016/
j.tet.2016.05.010.
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Facile, efficient synthesis of polysubstituted
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thiazoles via α-nitroepoxides and thioureas
Donghong Zhao, Shanshan Guo, Xiao Guo, Guolin Zhang* and Yongping Yu*
Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences,
Zhejiang University, Hangzhou 310058, P. R. China

1
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Tetrahedron
journal homepage: www.elsevier.com
Facile, efficient synthesis of polysubstituted thiazoles via α-nitroepoxides and
thioureas
Donghong Zhao, Shanshan Guo, Xiao Guo, Guolin Zhang* and Yongping Yu*
Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, P. R. China
ARTICLE INFO
ABSTRACT
An efficient synthesis of 2,4,5-trisubstituted thiazoles via the reaction of α-nitroepoxides and thioureas
under mild conditions has been developed. This reaction proceeded well at room temperature, to
afford products in excellent yields for a wide range of substrate, and a possible mechanism has also
been proposed.
Article history:
Received
Received in revised form
Accepted
Available online
2013 Elsevier Ltd. All rights reserved
.
Keywords:
2,4,5-trisubstituted thiazoles
α-nitroepoxides
thioureas
facile synthesis
1. Introduction
The substituted thiazole fragment is a structural motif in a
huge number of natural and synthetic products. Most of these
compounds show significant biological activities, such as
antineoplastic agents,1 anti-HIV drugs,2 anti-fungal agents,3
antiparasitic agents,4 anti-inflammatory agents,5 antiulcer agents6
and insecticide.7 Therefore, a great deal of attention has been
given to its organic synthesis, such as the Hantzsch method or
modified Hantzsch methodologies which consist of the
condensation of α-haloketones or haloacetaldehydes with
thioureas (Scheme 1-A, Eq. (1)),8 the synthesis method using
KSCN/SiO2–RNH3OAc/Al2O3 as the supported reagents (Scheme
1-A, Eq. (2)),9 the reaction of α-aminonitriles with carbon
disulfide (Scheme 1-A, Eq. (3)),10 the reaction performed under
microwave irradiation (Scheme 1-A, Eq. (4)).11 Despite these
procedures, the established method for the construction of 2,4,5-
trisubstituted thiazoles remains in demand. Therefore, we
developed a facile and more general method to provide 2,4,5-
trisubstituted thiazoles via α-nitroepoxides and thioureas
(Scheme 1-B).
2. Results and discussion
In our initial studies on the synthesis of 2,4,5-trisubstituted
thiazoles, 2-methyl-2-nitro-3-phenyloxirane 1a and thiourea 2a
Scheme 1. The synthesis of polysubstituted thiazoles
* 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).

2
Tetrahedron
ACCEPTED MANUSCRIPT
bIsolated yields.
were selected as reagents in order to optimize the reaction
condition. Firstly, a range of bases were screened (Table 1,
entries 1-8). As a result, a good yield could be achieved in the
presence of base, especially MeONa and K2CO3 (Table 1, entry
8, 5). Then, in order to identify the optimal reaction solvent, a
range of solvents were tested (Table 1, entries 9-15). It turns out
that MeOH (Table 1, entry 8) was superior to other aprotic and
protic solvents. In addition, when the reaction was tested at
different temperatures (Table 1, entries 16-17), the yields
decreased. Furthermore, after changing the amount of MeONa to
1.0 or 3.0 equiv., the yield of the desired product changed to 49%
or 88%, respectively (Table 1, entries 18-19). When reducing the
amount of thiourea 2a (Table1, entry 20), the yield were
maintained. According to the results, the optimal reaction
conditions occurred when 2-methyl-2-nitro-3-phenyloxirane 1a
(1.0 equiv.), thiourea 2a (1.0 equiv.), and MeONa (2.0 equiv.)
showed good reactivity to give the corresponding products in
good yields (3a-3l). However, when 2-methyl-2-nitro-3-
propyloxirane was used as the reagent, the desired product 3l was
obtained in relatively lower yield (77%). Moreover, thioureas 2
bearing electron-donating groups afforded the desired products in
a higher yield than that with electron-withdrawing groups (3m
compared to 3k, 3p compared to 3o, 3r compared to 3s). In our
tests, the highest yield was obtained, when 3-(4-chlorophenyl)-2-
methyl-2-nitrooxirane and 1-methylthiourea was used as the
reagents (3r).
Table 2. Scope of the reaction of α-nitroepoxides and
thioureas under optimal conditionsa
o
were conducted in MeOH(3mL) at 25 C for 6 h (Table1, entry
20).
Subsequently, the scope of the reaction for different α-
nitroepoxides and thioureas was studied using the optimized
reaction conditions. The α-nitroepoxides were prepared through
the straigthforward epoxidation of nitroalkenes,12-13 which are
readily accessed from a standard nitroaldol/Henry reaction.13-14
And a set of thioureas were readily prepared.15
The results were summarized in Table 2. To our delight, all
reactions investigated gave good yields (72–96%). No matter aryl
or alkyl substitution at the R1 and R2 positions of nitroepoxides 1,
Table 1. Optimization of reaction conditionsa
Entry Additive (equiv.)
Solvent
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
2a (equiv.) T(oC) Yieldb(%)
1
—
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.0
1.2
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
0
33
79
83
78
89
78
85
90
73
60
n.r.
20
59
30
n.r.
25
62
49
88
90
90
2
Et3N (2.0)
3
DIEA (2.0)
DBU (2.0)
4
5
K2CO3 (2.0)
NaOH (2.0)
Cs2CO3 (2.0)
MeONa (2.0)
MeONa (2.0)
MeONa (2.0)
MeONa (2.0)
MeONa (2.0)
MeONa (2.0)
MeONa (2.0)
MeONa (2.0)
MeONa (2.0)
MeONa (2.0)
MeONa (1.0)
MeONa (3.0)
MeONa (2.0)
MeONa (2.0)
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
t-BuOH
CH3CN
dioxane
THF
DMF
Toluene
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
50
25
25
25
25
aReaction conditions: 3a-3s were obtained under the conditions from Table 1,
entry 20. Isolated yields.
aReaction conditions: 2-methyl-2-nitro-3-phenyloxirane (0.5 mmol, 1.0
equiv.), thiourea, additive, 3mL of solvent, 6h. n.r. = no reaction.

3
Based on the observed results, a possible reaction mechanism
is proposed as shown in Scheme 2. In the presence of base,
thioureas 2 transfroms into intermediate I with a powerful
4.2.1
4-methyl-5-phenylthiazol-2-amine (3a). Yield: 90%,
ACCEPTED MANUSCRIPT
pale yellow solid, mp: 167.4-168.0°C; 1H NMR (500 MHz,
CDCl3) δ 7.39 – 7.35 (m, 4H), 7.28 – 7.24 (m, 1H), 5.06 (s, 2H),
2.31 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 165.18, 143.41,
132.77, 128.79, 128.58, 126.83, 121.27, 16.07. HRMS (ESI): m/z
calcd for C10H11N2S [M+H]+: 191.0637, found: 191.0643.
nucleophilic center. The nitroepoxide
1 is attacked by
intermediate I and undergos a ring opening to give the
intermediate II. Then, intermediate II affords the intermediate III
driven by the excellent leaving ability of nitro. Subsequently,
4.2.2
4-ethyl-5-phenylthiazol-2-amine (3b). Yield: 88%,
1
intermediate III transforms into final product
3 via an
white solid, mp: 128.3-129.0°C; H NMR (500 MHz, CDCl3) δ
7.41 – 7.31 (m, 4H), 7.28 (dd, J = 10.5, 3.9 Hz, 1H), 5.12 (s, 2H),
2.62 (q, J = 7.5 Hz, 2H), 1.25 (t, J = 7.5 Hz, 3H).13C NMR (125
MHz, CDCl3) δ 165.51, 149.39, 132.68, 129.05, 128.58, 126.99,
120.93, 22.94, 14.19. HRMS (ESI): m/z calcd for C11H13N2S
[M+H]+: 205.0794, found: 205.0797.
intramolecular nucleophilic addition and the elimination of one
molecule of H2O.
O
NO2
R2
HN
NH
R1
R2
NO2
S
SH
S
S
Base
1
R3
R3
R3
R3
HN
HN
N
N
4.2.3
4,5-diphenylthiazol-2-amine(3c). Yield: 91%, white
H2
N
N
R1
H
H
H
O
solid, mp: 189.2-189.6°C; 1H NMR (500 MHz, DMSO-d6) δ 7.37
(d, J = 6.5 Hz, 2H), 7.31 – 7.19 (m, 8H), 7.16 (s, 2H). 13C NMR
(125 MHz, DMSO-d6) δ 166.56, 145.43, 135.91, 133.30, 129.42,
129.17, 128.93, 128.50, 127.75, 127.49, 119.53. HRMS (ESI):
m/z calcd for C15H13N2S [M+H]+: 253.0794, found: 253.0794.
Base+H
I
II
2
- NO2
R3
N
R3
N
HN
HN
HN
R3 NH
-H2
O
S
R2
O
S
S
R1
III
R2
OH
R1
R2
H
R1
4.2.4
5-(4-fluorophenyl)-4-methylthiazol-2-amine (3d). Yield:
IV
95%, white solid, mp: 165.5-167.0°C; 1H NMR (500 MHz,
CDCl3) δ 7.35 – 7.28 (m, 2H), 7.10 – 7.02 (m, 2H), 5.18 (s, 2H),
2.26 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 165.19,162.75,
160.79, 143.41, 130.56, 130.50, 128.73, 120.01, 115.63, 115.46,
15.85. HRMS (ESI): m/z calcd for C10H10FN2S [M+H]+:
209.0543, found: 209.0544.
3
Scheme 2. Proposed mechanism for the synthesis of 2,4,5-
trisubstituted thiazoles.
3. Conclusion
In conclusion, we report that 2,4,5-trisubstituted thiazoles can
be prepared by treating easily available α-nitroepoxides with
thioureas. The reaction provides products in good yields at room
temperature with the advantage of operational simplicity and a
satisfactory substrate scope. The structures of the 2,4,5-
4.2.5
5-(4-chlorophenyl)-4-methylthiazol-2-amine (3e). Yield:
93%, white solid, mp: 219.8-220.8°C; 1H NMR (500 MHz,
CDCl3) δ 7.38 – 7.34 (m, 2H), 7.33 – 7.29 (m, 2H), 5.07 (s, 2H),
2.31 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 165.19, 143.98,
132.69, 131.25, 129.98, 128.77, 120.04, 16.04. HRMS (ESI): m/z
calcd for C10H10ClN2S [M+H]+: 225.0248, found: 225.0249.
1
trisubstituted thiazoles 3 were characterized by H NMR, 13C
NMR, and HRMS.
4.2.6
5-(4-bromophenyl)-4-methylthiazol-2-amine (3f). Yield:
4. Experimental section
89%, pale yellow solid, mp: 194.7-195.6°C; 1H NMR (500 MHz,
DMSO-d6) δ 7.55 (d, J = 8.2 Hz, 2H), 7.27 (d, J = 8.5 Hz, 2H),
7.04 (s, 2H), 2.18 (s, 3H). 13C NMR (125 MHz, DMSO-d6) δ
166.43, 144.56, 132.86, 132.03, 130.18, 119.31, 116.63, 16.78.
HRMS (ESI): m/z calcd for C10H10BrN2S [M+H]+: 268.9743,
found: 268.9743.
4.1 General
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.12-13 The starting material
monosubstituted thioureas were prepared according to literature
methods.15
4.2.7
5-(3-bromophenyl)-4-methylthiazol-2-amine (3g). Yield:
90%, yellow solid, mp: 139.7-141.5°C; 1H NMR (500 MHz,
CDCl3) δ 7.50 (t, J = 1.8 Hz, 1H), 7.40 – 7.36 (m, 1H), 7.30 –
7.20 (m, 2H), 5.19 (s, 2H), 2.29 (s, 3H). 13C NMR (125 MHz,
CDCl3) δ 165.56, 144.41, 134.88, 131.47, 130.04, 129.73, 127.30,
122.60, 119.51, 16.12. HRMS (ESI): m/z calcd for C10H10BrN2S
[M+H]+: 268.9743, found: 268.9743.
4.2.8
5-(2-bromophenyl)-4-methylthiazol-2-amine (3h). Yield:
85%, yellow solid, mp: 147.9-150.2°C; 1H NMR (500 MHz,
CDCl3) δ 7.65 (dd, J = 8.0, 1.1 Hz, 1H), 7.37 – 7.30 (m, 2H),
7.23 – 7.18 (m, 1H), 5.09 (s, 2H), 2.08 (s, 3H). 13C NMR (125
MHz, CDCl3) δ 166.28, 145.64, 133.24, 133.16, 133.08, 129.64,
127.22, 125.71, 119.08, 15.72 HRMS (ESI): m/z calcd for
C10H10BrN2S [M+H]+: 268.9743, found: 268.9743.
4.2
General procedure for the synthesis of 2,4,5-
trisubstituted thiazoles
A mixture of α-nitroepoxides 1 (0.5 mmol), thioureas 2 (0.5
mmol), NaOMe (1.0 mmol) was stirred in MeOH 3mL at room
temperature for 6 hours. After the completenes of the reaction,
the MeOH was evaporated in vacuo. The residuum was dissolved
in water and ethyl acetate. The organic layer was isolated and the
aqueous layer was extracted with ethyl acetate. The combined
organic extracts were washed with brine, dried over Na2SO4,
concentrated and purified by flash chromaraography
(DCM/MeOH) on slica gel to afford 3a-3s.
4.2.9
4-methyl-5-(p-tolyl)thiazol-2-amine (3i). Yield: 86%,
1
white solid, mp: 148.8-149.2°C; H NMR (500 MHz, CDCl3) δ
7.27 – 7.24 (m, 2H), 7.18 (d, J = 7.9 Hz, 2H), 5.14 (s, 2H), 2.36
(s, 3H), 2.29 (s, 3H).13C NMR (125 MHz, CDCl3) δ 164.97,
142.99, 136.68, 129.79, 129.27, 128.72, 121.31, 21.15, 16.01.
HRMS (ESI): m/z calcd for C11H13N2S [M+H]+: 205.0794,
found:205.0794.

4
Tetrahedron
ACCEPTED MANUSCRIPT
4.2.10 4-methyl-5-(naphthalen-2-yl)thiazol-2-amine
(3j).
3H), 2.22 (s, 3H).13C NMR (125 MHz, DMSO-d6) δ 167.27,
1
Yield: 94%, light brown solid, mp:161.2-162.5°C; H NMR (500
MHz, CDCl3) δ 7.94 – 7.84 (m, 3H), 7.53 – 7.46 (m, 4H), 5.10 (s,
2H), 2.05 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 166.38, 145.40,
133.77, 132.89, 129.56, 129.47, 128.68, 128.35, 126.44, 126.04,
125.93, 125.24, 118.08, 15.71. HRMS (ESI): m/z calcd for
C14H13N2S [M+H]+: 241.0794, found: 241.0795.
144.88, 132.44, 130.95, 129.88, 129.15, 31.18, 16.96. HRMS
(ESI): m/z calcd for C11H12ClN2S [M+H]+: 239.0404, found:
239.0405.
4.2.19 5-(4-chlorophenyl)-4-methyl-N-phenylthiazol-2-amine
(3s) Yield: 82%, White solid, mp: 151.0-152.7°C; H NMR (500
1
MHz, CDCl3) δ 7.95 (s, 1H), 7.40 – 7.30 (m, 8H), 7.11 – 7.06 (m,
1H), 2.35 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 162.88, 143.88,
140.23, 132.77, 129.98, 129.55, 128.82, 123.34, 118.99, 118.67,
29.71, 16.21. HRMS (ESI): m/z calcd for C16H14ClN2S [M+H]+:
301.0561, found: 301.0563.
4.2.11 4-methyl-5-(pyridin-3-yl)thiazol-2-amine (3k). Yield:
87%, white solid, mp: 172.9-173.2; 1H NMR (500 MHz, DMSO-
d6) δ 8.55 (d, J = 1.8 Hz, 1H), 8.41 (dd, J = 4.7, 1.3 Hz, 1H), 7.75
– 7.71 (m, 1H), 7.39 (dd, J = 7.8, 4.8 Hz, 1H), 7.14 (s, 2H), 2.20
(s, 3H).13C NMR (125 MHz, DMSO-d6) δ 166.95, 148.68, 147.31,
145.44, 135.33, 129.81, 124.09, 114.06, 16.66. HRMS (ESI): m/z
calcd for C9H10N3S [M+H]+:192.0590, found: 192.0592.
Acknowledgements
This project was supported from the Zhejiang Provincial
Natural Science Foundation of China under Grant No.
LY16H300001, National Natural Science Foundation of China
(No. 81273356), National Science & Technology Major Projects
for "Major New Drugs Innovation and Development" of China
(2014ZX09304002-007), the Program for Zhejiang Leading
Team of S&T Innovation Team (2011R50014) and Arthritis &
Chronic Pain Research Institute, USA to Y. Yu.
4.2.12 4-methyl-5-propylthiazol-2-amine (3l). Yield: 77%, tan
liquid; H NMR (500 MHz, CDCl3) δ 4.95 (s, 2H), 2.51 (t, J =
7.4 Hz, 2H), 2.09 (s, 3H), 1.58 – 1.48 (m, 2H), 0.92 (t, J = 7.3 Hz,
3H).13C NMR (125 MHz, CDCl3) δ 164.34, 142.27, 121.32,
28.18, 24.85, 14.56, 13.52. HRMS (ESI): m/z calcd for C7H13N2S
[M+H]+: 157.0794, found: 157.0796.
1
4.2.13 N,4-dimethyl-5-phenylthiazol-2-amine (3m). Yield:
89%, white solid, mp: 149.9-150.9°C; 1H NMR (500 MHz,
CDCl3) δ 7.40 – 7.34 (m, 4H), 7.26 – 7.22 (m, 1H), 6.07 (s, 1H),
2.97 (s, 3H), 2.33 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 168.95,
143.80, 133.23, 128.61, 128.55, 126.46, 119.07, 32.11, 16.32.
HRMS (ESI): m/z calcd for C11H13N2S [M+H]+: 205.0794, found:
205.0795.
Supplementary data
Supplementary
data
(Experimental
procedures,
1
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/
4.2.14 4-methyl-N,5-diphenylthiazol-2-amine (3n). Yield: 85%,
1
white solid, mp: 148.5-149.4°C; H NMR (500 MHz, CDCl3) δ
References and notes
8.02 (s, 1H), 7.46 – 7.35 (m, 8H), 7.34 – 7.29 (m, 1H), 7.10 (m,
1H), 2.42 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 162.84, 143.35,
140.45, 132.62, 129.51, 128.83, 128.64, 126.91, 123.12, 120.25,
118.60, 16.25. HRMS (ESI): m/z calcd for C16H15N2S [M+H]+:
267.0950, found: 267.0953.
1
(a) Das, J.; Chen, P.; Norris, D.; Padmanabha, R.; Lin, J.;
Moquin, R. V.; Shen, Z.; Cook, L. S.; Doweyko, A. M.;
Pitt, S.; Pang, S.; Shen, D. R.; Fang, Q. J. Med. Chem.
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Hulme, C. Bioorg. Med. Chem. Lett. 2012 22, 3567-3570.
, 49, 6819-6832. (b) Smith, B.; Chang, H.-H.; Medda,
4.2.15 4-methyl-N-(4-nitrophenyl)-5-phenylthiazol-2-amine
1
(3o). Yield: 72%, yellow solid, mp: 217.7-218.5°C; H NMR
,
(500 MHz, DMSO-d6) δ 11.01 (s, 1H), 8.23 (d, J = 9.1 Hz, 2H),
7.85 (d, J = 9.0 Hz, 2H), 7.46 (t, J = 6.1 Hz, 4H), 7.35 (m, 1H),
2.39 (s, 3H). 13C NMR (125 MHz, DMSO-d6) δ 159.52, 147.25,
144.08, 140.63, 132.06, 129.39, 129.04, 127.78, 125.98, 122.20,
116.61, 16.83. HRMS (ESI): m/z calcd for C16H14N3O2S [M+H]+:
312.0801, found: 312.0806.
2
3
4
5
De Souza, M. V. N.; De Almeida M. V. Quim. Nova 2003
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(a) Siddiqui, H. L.; Zia-ur-Rehman, M.; Ahmad, N.;
Weaver, G. W. Chem. Pharm. Bull. 2007, 55, 1014-1017.
(b) Franklin, P. X.; Pillai, A. D.; Rathod, P. D.; Yerande,
S. G.; Nivsarkar, M.; Padh, H.; Sudarsanam, V.; Vasu, K.
K. Eur. J. Med. Chem. 2008, 43, 129-134. (c) Inamdar, G.
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4.2.16 N-(4-methoxyphenyl)-4-methyl-5-phenylthiazol-2-amine
1
(3p). Yield: 87%, white solid, mp: 121.6-123.5°C; H NMR (500
MHz, CDCl3) δ 7.84 (s, 1H), 7.39 – 7.33 (m, 4H), 7.32 – 7.27 (m,
2H), 7.27 – 7.23 (m, 2H), 6.94 – 6.89 (m, 2H), 3.81 (s, 3H), 2.34
(s, 3H). 13C NMR (125 MHz, CDCl3) δ 165.08, 156.58, 142.99,
133.60, 132.67, 128.72, 128.60, 126.80, 122.36, 119.45, 114.78,
55.56, 16.07. HRMS (ESI): m/z calcd for C17H17N2OS [M+H]+:
297.1056, found: 297.1059.
K. K. Eur. J. Med. Chem
(a)LaMattina, J. L.; McCarthy, P. A.; Reiter, L. A.; Holt,
W. F. J Med Chem. 1990 33, 543-552. (b) Mohareb, R.
M.; Zaki, M. Y.; Abbas, N. S. Steroids 2015 98, 80-91.
Nauen, R.; Ebbinghaus-Kintscher, U.; Salgado, V. L.;
Kaussmann, M.; Pest. Biochem. Physiol. 2003 76, 55-69.
(a) Hantzsch, A.; Weber, J. H. Ber. Dtsch. Chem. Ges.
1887 20, 3118. (b) Aguilar, E.; Meyers, A. I. Tetrahedron
Lett. 1994 35, 2473. (c) Ochiai, M.; Nishi, Y.; Hashimoto,
. 2013, 63, 924-934.
6
4.2.17 4-methyl-5-phenyl-N-(pyridin-2-yl)thiazol-2-amine (3q).
Yield: 83%, pale yellow solid, mp: 206.2-206.3°C; 1H NMR (500
MHz, DMSO-d6) δ 11.30 (s, 1H), 8.30 (dd, J = 4.9, 1.0 Hz, 1H),
7.69 (dd, J = 11.3, 4.2 Hz, 1H), 7.45 (dt, J = 15.1, 7.4 Hz, 4H),
7.30 (t, J = 7.1 Hz, 1H), 7.04 (d, J = 8.3 Hz, 1H), 6.91 (t, 1H),
2.36 (s, 3H). 13C NMR (125 MHz, DMSO-d6) δ 157.29, 152.08,
147.00, 142.24, 138.33, 133.36, 129.28, 128.71, 127.00, 122.29,
116.34, 111.26, 16.64. HRMS (ESI): m/z calcd for C15H14N3S
[M+H]+: 268.0903, found: 268.0909.
,
,
7
8
,
,
,
S.; Tsuchimoto, Y.; Chen, D. W. J. Org. Chem. 2003, 68,
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9
(a) Kodomari, M.; Aoyama, T.; Suzuki, Y. Tetrahedron
Lett. 2002 43, 1717. (b) Aoyama, T; Murata, S; Arai, I.
Tetrahedron 2006 62, 3201-3213.
4.2.18 5-(4-chlorophenyl)-N,4-dimethylthiazol-2-amine (3r).
Yield: 96%, white solid, mp: 219.8-220.8°C; 1H NMR (500 MHz,
DMSO-d6) δ 7.58 (s, 1H), 7.39 (dd, J = 39.8,7.1 Hz, 4H), 2.82 (s,
,
,
,

5
10 (a)Cook, A. H.; Heilbron, I.; MacDonald, S. F.;
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2093-2096. (b) Lingaraju, G. S.; Swaroop, T. R.;
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