I2/CuO-catalyzed tandem cyclization strategy for one-pot synthesis of substituted 2-aminothiozole from easily available aromatic ketones/α,β-unsaturated ketones and thiourea

Article abstract of DOI:10.1016/j.tet.2011.10.074

A concise and efficient one-pot process from easily available methyl ketones/unsaturated methyl ketones and thiourea was developed for the synthesis of 2-aminothiazoles under the media of I₂/CuO. The method can highly stereoselectivity obtain the E-isomers of 4-ethenyl-2-aminothiazoles (5a-f). All these target molecules were characterized by NMR, HRMS and IR spectra. Furthermore, the target compounds 3c and 5b were further determined by X-ray crystallographic analysis.

Full text of DOI:10.1016/j.tet.2011.10.074

Tetrahedron 68 (2012) 173e178
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
I2/CuO-catalyzed tandem cyclization strategy for one-pot synthesis of substituted
2-aminothiozole from easily available aromatic ketones/
and thiourea
a,
b-unsaturated ketones
*
Yan-Ping Zhu, Jing-Jing Yuan, Qin Zhao, Mi Lian, Qing-He Gao, Mei-Cai Liu, Yan Yang, An-Xin Wu
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, Central China Normal University, Wuhan 430079, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 July 2011
Received in revised form 15 October 2011
Accepted 21 October 2011
Available online 28 October 2011
A concise and efficient one-pot process from easily available methyl ketones/unsaturated methyl ketones
and thiourea was developed for the synthesis of 2-aminothiazoles under the media of I2/CuO. The
method can highly stereoselectivity obtain the E-isomers of 4-ethenyl-2-aminothiazoles (5aef). All these
target molecules were characterized by NMR, HRMS and IR spectra. Furthermore, the target compounds
3c and 5b were further determined by X-ray crystallographic analysis.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
2-Aminothiazole
One-pot reaction
Tandem cyclization
a
-Halogenation ketones
I2/CuO
1. Introduction
operations, and saving reagents, energy, time, and labour, have
been used in many chemical transformations.7
Thiazole as useful structural element plays an important role in
nature and has broad applications in the field of agriculture and
medicinal chemistry.1 Thiazole ring is a main structural motif of
many natural compounds such as vitamin B1 (thiamine), penicillin
and carboxylase.
Moreover 2-aminothiazoles as important precursors have
been employed in the preparation of different important drugs
required for the treatment of allergies, hypertension, inflammation,
schizophrenia, bacterial, and HIV infections.2 Therefore, much at-
tention has been paid to the synthesis of 2-aminothiazoles,
In our previous studies, we proposed a novel method for the
synthesis of -iodo ketones and -unsaturated
0-iodo ketones
-unsaturated
-halogenation
a
a
,
b
a
a,b
a
(Scheme 1) on the basis of aromatic ketones and
ketones under the media of I2/CuO.8 Moreover,
ketones as important precursors have been employed in the
preparation of various heterocycles.9 Therefore, we considered the
possibility of catalyzing aromatic ketones in situ obtained a-iodo
ketones, which can react with thiourea in one-pot to afford 2-
aminothiazole under the media of I2/CuO. If successful, this
would simplify the synthetic steps, and develop a novel synthetic
method for the synthesis of 2-amino-4-arylthiazole and 2-amino-
4-ethenylthiazole derivatives.
for which the general approaches include condensation of
a
-bro-
moketone with thiourea,3 the reaction of
a-thiocyanato carbonyl
compounds with aromatic or aliphatic aminehydrochlorides,4
treatment of stylene and thiourea with NBS5 and condensation of
aromatic ketone and thiourea with solid supported catalyst or
heterogeneous catalyst.6
In recent years, tandem, multicomponent, and one-pot re-
actions have attracted much attention as powerful and useful
synthetic tools in synthetic chemistry and drug discovery. These
reactions, by virtue of their atom-economy, reducing the number of
Scheme 1. Synthesis of
basis of aromatic ketones and
a
-iodo ketones and
-unsaturated ketones under the media of I2/CuO.
a,b-unsaturated a
0-iodo ketones on the
a,b
Herein, we present a concise, rapid and efficient method for
preparation of substituted 2-aminothiazole from easily available
aromatic ketones and thiourea. In addition, this method can also
synthesize 2-amino-4-ethenylthiazole derivatives efficiently.
* Corresponding author. Tel./fax: þ86 (0)27 67867773; e-mail address: chwuax@
mail.ccnu.edu.cn (A.-X. Wu).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.10.074

174
Y.-P. Zhu et al. / Tetrahedron 68 (2012) 173e178
Table 2
2. Results and discussion
Formation of 2-amino-4-arylthiazole via the tandem reaction of methyl ketones and
thiourea under the media of I2/CuOa
To initiate our study, we first tested the reaction of a-iodo ke-
tone with thiourea in MeOH at reflux. To our delight, the product
was obtained in 95% yield (Scheme 2).
Entry
Substrates (R¼)
Product
Yieldb (%)
1
2
3
4
5
6
7
8
C6H5 (1a)
3a
3b
3c
3d
3e
3f
3g
3h
3i
90
88
92
85
86
80
72
48
68
65
50
75
72
4-MeeC6H5 (1b)
4-MeeOC6H5 (1c)
3,4-OCH2OeC6H5 (1d)
2,4-OMe2eC6H5 (1e)
4-CleC6H5 (1f)
4-BreC6H5 (1g)
3-O2NeC6H5 (1h)
4-PheC6H5 (1i)
2-NapheC6H5 (1j)
4-HOeC6H5 (1k)
2-FuraneC6H5 (1l)
2-ThinyleC6H5 (1m)
Scheme 2. Formation of 2-amino-4-arylthiazole via the condensation of
with thiourea in MeOH at reflux.
a-iodo ketone
With the success in obtaining substituted 2-aminothiazole from
phenacyl iodine with thiourea, we wondered whether it would be
possible to integrate the two processes (Schemes 1 and 2) in a one-
pot reaction. Therefore, we optimized the reaction conditions for
the formation of 2-aminothiazole with aryl methyl ketones (1a)
and thiourea (2) as substrates (Table 1). Various solvents were first
examined. The product was not obtained when acetonitrile
(MeCN), tetrahydrofuran (THF), toluene or dimethylformamide
(DMF) was used as solvent. It was notable, however, that this
transformation occurred smoothly in MeOH, with 88% yield. And
product 3a was obtained in moderate to good yields using meth-
anol, propanol and butanol as solvents. However, no reaction oc-
curred in tert-butanol in the conditions. It was obvious that ethanol
was the optimal solvent in the reaction. Next, the molar ratio of
substrate, I2 and CuO was also optimized. When the molar ratio of
n(1a)/n(2)/n(CuO)/n(I2) was varied from 1:1:1:1 to 1:1.1:1.1:1.1
(entries 6, 10e12), the reaction afforded the product 3a in 86e90%
yield in ethanol at reflux. It was obvious that n(1a)/n(2)/n(I2)/
n(CuO)¼1:1:1.1:1.1 is the optimal condition. Finally, the effect of
reaction temperature on the yield of the product 3a was also ex-
amined. The experiment result indicates that 78 ꢀC is the optimal
temperature.
9
10
11
12
13
3j
3k
3l
3m
a
Standard conditions: n(1)/n(2)/n(I2)/n(CuO)¼1:1:1.1:1.1, T¼78 ꢀC.
b
Isolated yield.
donating groups (e.g., 4-Me, 4-OMe, 2,4-OMe2), the correspond-
ing products 3bee were obtained in good yields (85e92%, entries
2e5, Table 2). And when the benzene rings substituted with
electron-withdrawing groups (e.g., 4-Cl, 4-Br, 3-NO2, 4-Ph), the
corresponding products 3bek were obtained in moderate to good
yields (48e80%, entries 6e9, Table 2). It should be noted that an
electron-donating substituent on the benzene ring caused a con-
siderable increase in the yield. 2-Naphthyl methyl ketone (1k) also
gave satisfying result. To our great satisfaction, sensitive hydroxy
group (OH) was not affected under these mild reaction conditions,
and the expected product 3k was obtained in 50% yield. Encour-
aged by the results obtained with aryl methyl ketones, we turned
our attention to the heteroaryl ketones. The heterocycle, including
furan (1l) and thiophen (1m), did not affect the overall efficiency,
and the corresponding products 3l and 3m were obtained in 75%
and 72% yields, respectively.
To assess the generality of this method and to evaluate the
electronic influence of the aromatic ring substituents, a series of
other aromatic ketones 1bem were examined under the optimal
conditions (Table 2). While the benzene rings bore electron-
To further expand scope of the ketone, unsaturated methyl ke-
tones such as 4aef were also investigated.10 Under the optimal
conditions, the corresponding ethenyl 2-aminothiazoles could be
obtained with a slightly lower yield of 45e63%. The possible reason
for the low yield was that C]C bond reduced the conjugate effect of
Table 1
Effect of solvent, temperature and molar ratio of n(1a)/n(2)/n(I2)/n(CuO) on the yield
of 3a
aromatic cycles and acetyl group. So, the a-iodination was not easy
to achieve in the first step. For further investigation, the reactions
with unsaturated methyl ketones such as benzalacetone (4g) and 4-
phenylbut-3-yn-2-one (4h) could not afford the desired product. It
should be noted that an electron-donating substituent on the
benzene ring caused a considerable increase in the yield than an
electron-withdrawing substituent, which was consistent with aryl
methyl ketones. In all cases, only the thermodynamically stable E-
isomers were obtained. It has a high stereoselectivity (Table 3).
After successful exploration of the scope of the reaction towards
Entry
Solvent/(ꢀC)
n(1a)/n(2)/n(I2)/n(CuO)
Yielda (%)
1
2
3
4
5
6
7
8
MeCN/82
THF/66
DMF/90
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
0b
0b
0b
Toluene/111
MeOH/65
EtOH/78
PrOH/97
BuOH/118
t-BuOH/83
EtOH/78
EtOH78
0b
reactants, the aromatic ketones/a,b-unsaturated ketones and
85
88
75
70
0b
90
88
86
75
50
thiourea, we turned our attention to other types of ketones and
thioureas. Accordingly, the substituted N-methylthiourea was in-
vestigated; all the aromatic ketones smoothly underwent the
transformation with N-methylthiourea to provide the N-methyl
aminothiazoles (7aec) in good yields (70e78% yields, Table 4).
Next, 1,3-diketone (1,3-bis(4-methoxyphenyl)propane-1,3-dione)
was also investigated, the desired product was obtained in 72%
yield. In addition, the scope of the reaction was further demon-
9
1:1:1:1
10
11
12
13
14
1:1:1.1:1
1:1:1.5:1.5
1:1.1:1.1:1.1
1:1:1.1:1.1
1:1:1.1:1.1
EtOH/78
EtOH/65
EtOH/55
a
strated by reacting
b-ketoesters (6eej) under the optimized con-
Isolated yield.
No reaction.
b
ditions. The results collected (Table 4) point out the facts that both

Y.-P. Zhu et al. / Tetrahedron 68 (2012) 173e178
175
Supplementary data page 7) and 5b 11 were further determined by
X-ray crystallographic analysis. In the crystal structure of com-
pound 5b, the bond distance of C8eC9 and the torsion angle of
Table 3
Formation of 2-amino-4-ethenylthiazoles via the tandem reaction of
a,b-un-
saturated methyl ketonesa
C(5)eC(8)eC(9)eC(10) are 1.32 A and ꢁ179.69ꢀ, respectively,
ꢀ
which supports the E-configuration of the olefin 5b (Fig. 1).
Entry
Substrates (R¼)
Product
Isolated yieldb (%)
transc (%)
1
2
3
4
5
6
7
8
C6H5 (4a)
5a
5b
5c
5d
5e
5f
60
58
62
63
45
48
0d
0d
>99
>99
>99
>99
>99
>99
d
4-MeeC6H5 (4b)
4-MeOeC6H5 (4c)
3,4-(MeO)2eC6H5(4d)
4-NO2eC6H5 (4e)
3-NO2eC6H5 (4f)
(E)-C6H5eCH]CHe (4g)
C6H5eCH^CHe (4h)
5g
5h
d
a
Standard conditions: n(1)/n(2)/n(I2)/n(CuO)¼1:1:1.1:1.1, T¼78 ꢀC.
Isolated yield.
b
c
Determined by 1H NMR of the crude product.
No reaction occurred.
Fig. 1. The X-ray crystal structure of compound 5b.
d
Table 4
,b
Scope of ketones and thioureasa
a
Standard conditions: n(6)/n(2)/n(I2)/n(CuO)¼1:1:1.1:1.1, T¼78 ꢀC.
b
Isolated yield.
electron-withdrawing and electron-donating groups at aromatic
cycles are tolerated. To our great satisfaction, the heterocycle (fu-
ran) was not affected under these mild reaction conditions, and the
expected product 7j was obtained in 50% yield. Other aliphatic
ketones (3,3-dimethylbutan-2-one, 3-methylbutan-2-one and
butan-2-one), hexamethylketone and hexamethyldiketone were
also investigated under the optimal conditions. Unfortunately, the
reaction could not be performed.
A possible mechanism of the present reaction could be described
as follows using acetophenone (1a) as an example (Scheme 3): Ini-
tially, the acetophenone 1a undergoes the formation of enolate ion A
under basic conditions, and A converts to B or its enolizational isomer
C in the media of I2 and CuO. Subsequently, CuO catalyses B con-
verting to D, CuI, H2O and regenerated I2. Then, G is obtained un-
dergoing intermolecular nucleophilic substitute of
D
with
thiourea enolizational isomer F. G undergoing an intramolecular
nucleophilic addition transforms into H, which converts to I via de-
hydration. Finally, intermediate I undergoes neutralization reaction
All these target molecules were characterized by NMR, MS and
IR spectra. Furthermore, the target compounds 3c (See

176
Y.-P. Zhu et al. / Tetrahedron 68 (2012) 173e178
Scheme 3. The proposed mechanism for the transformation.
to furnish the desired product in the presence of CuO. In addition,
regenerated I2 can catalyse the transformation of A to B again.
concentrated in vacuo. The residue was purified by column chro-
matography on silica gel using petroleum ether/EtOAc as the eluent
to give the expected products 3a in 90% yield.
3. Conculsion
In conclusion, a concise and efficient one-pot process from
easily available methyl ketones/unsaturated methyl ketones, 1,3-
4.3. Spectroscopic data
diketone, b-ketoesters and thioureas was developed for the syn-
4.3.1. 4-Phenylthiazol-2-amine (3a). IR (KBr): 3434, 3248, 3113,
1598, 1516, 1481, 1440, 1330, 1306, 1199, 1070, 1038, 1021 cmꢁ1; 1H
thesis of 2-aminothiazoles under the media of I2/CuO. In addition,
the method can highly stereoselectivity obtain the E-isomers of
4-ethenyl-2-aminothiazoles (5aef). Further application of this
methodology for the synthesis of various heterocyclic compounds
is under way in our laboratory.
NMR (600 MHz, CDCl3):
d
¼7.75 (d, J¼7.8 Hz, 2H), 7.36e7.38 (t,
J¼7.8 Hz, 2H), 7.27e7.29 (t, J¼7.8 Hz, 1H), 5.49 (s, 1H); 13C NMR
(150 MHz, CDCl3):
d¼167.5, 151.1, 134.6, 128.6, 127.7, 126.0, 102.7;
HRMS (ESI): m/z [MþH]þ calcd for C9H9N2S: 177.0418; found:
177.0477.
4. Experimental
4.3.2. 4-p-Tolylthiazol-2-amine (3b). IR (KBr): 3453, 3298, 3117,
1637, 1538, 1521, 1489, 1333, 1037 cmꢁ1; 1H NMR (600 MHz, CDCl3):
4.1. General method
d
¼7.64 (d, J¼8.4 Hz, 2H), 7.17 (d, J¼8.4 Hz, 2H), 6.62 (s, 1H), 5.54 (s,
2H); 13C NMR (150 MHz, CDCl3):
d
¼167.7, 151.2, 137.4, 131.9, 129.2,
All aryl methyl ketones (1aem), thiourea (2) and other reagents
were obtained from commercial suppliers and used without further
purification. TLC analysis was performed using pre-coated glass
plates. Column chromatography was performed using silica gel
(200e300 mesh). IR spectra were recorded on a PerkineElmer PE-
125.8, 101.7, 21.2; HRMS (ESI): m/z [MþH]þ calcd for C10H11N2S:
191.0637; found: 191.0632.
4.3.3. 4-(4-Methoxyphenyl)thiazol-2-amine (3c). IR (KBr): 3438,
983 infrared spectrometer as KBr pellets with absorption in cmꢁ1
.
3267, 3117, 2964, 2934, 2834, 1626, 1606, 1537, 1519, 1492, 1290,
1245, 1177, 1035 cmꢁ1
;
1H NMR (600 MHz, DMSO-d6):
d
¼7.73 (d,
NMR spectra were recorded on a Varian Mercury 400 or 600 MHz
spectrometer. Chemical shifts are reported in ppm, relative to the
internal standard of tetramethylsilane (TMS). HRMS were obtained
on a Bruker 7-tesla FT-ICR MS equipped with an electrospray
source. The X-ray crystal structure determinations of 1a and 5a
were obtained on a Bruker SMART APEX CCD system.
J¼9.0 Hz, 2H), 7.01 (s, 2H), 6.93 (d, J¼9.0 Hz, 2H), 3.78 (s, 3H); 13C
NMR (150 MHz, CDCl3):
d¼168.2, 158.7, 149.9, 128.0, 127.0, 114.0,
100.0, 55.2; HRMS (ESI): m/z [MþH]þ calcd for C10H11N2SO:
207.0587; found: 207.0581.
4.3.4. 4-(1,3-Dihydroisobenzofuran-5-yl)thiazol-2-amine
(KBr): 3431, 3298, 3122, 2900, 1639, 1539, 1498, 1481, 1449, 1331,
1291, 1242, 1195, 1122, 1039 cmꢁ1 1H NMR (600 MHz, DMSO-d6):
¼7.38 (s, 2H), 7.08 (s, 2H), 6.91e6.95 (m, 2H), 6.07 (s, 2H), 3.48 (s,
(3d). IR
4.2. General procedure for preparation of 3 and 5 (3a as an
example)
;
d
A
mixture of acetophenone 1a (120 mg, 1 mmol), iodine
2H); 13C NMR (150 MHz, DMSO-d6):
d
¼168.1, 149.5, 147.5, 146.4,
(279.2 mg, 1.1 mmol), and CuO (88 mg, 1.1 mmol) in anhydrous
ethanol (30 mL) was heated at reflux, after disappearance of the
reactant (1e12 h, monitored by TLC), thiourea 2 (76 mg, 1 mmol)
was added and the mixture was refluxed for 1 h. After that, the
solvent was removed under reduce pressure, and added 50 mL
water to the residue, then extracted with EtOAc three times
(3ꢂ50 mL). The extract was washed with 10% Na2S2O3 then a small
amount 5% NaOH solution, dried over anhydrous Na2SO4 and
129.5, 119.4, 108.3, 105.9, 101.0, 100.1; HRMS (ESI): m/z [MþH]þ
calcd for C11H13N2O2S: 237.0692; found: 237.0690.
4.3.5. 4-(2,4-Dimethoxyphenyl)thiazol-2-amine
3382, 3287, 3113, 2924, 1609, 1579, 1533, 1463, 1434, 1291, 1211,
1160, 1127, 1069, 1050 cmꢁ1; 1H NMR (600 MHz, CDCl3):
¼7.94 (d,
J¼8.4 Hz, 1H), 7.25 (s, 1H), 6.51e6.54 (m, 2H), 5.31 (s, 2H), 3.87 (s,
3H), 3.82 (s, 3H); 13C NMR (150 MHz, CDCl3):
¼165.8, 160.0, 157.8,
(3e). IR
(KBr):
d
d

Y.-P. Zhu et al. / Tetrahedron 68 (2012) 173e178
177
146.5, 130.5, 116.6, 105.2, 104.4, 98.7, 55.3; HRMS (ESI): m/z [MþH]þ
960 cmꢁ1; 1H NMR (600 MHz, DMSO-d6):
d
¼7.48 (d, J¼7.2 Hz, 2H),
calcd for C11H13N2O2S: 237.0692; found: 237.0690.
7.32e7.34 (t, J¼7.8 Hz, 2H), 7.24 (d, J¼16.2 Hz, 1H), 8.86 (d,
J¼16.2 Hz, 1H), 5.24 (s, 2H); 13C NMR (150 MHz, CDCl3):
¼167.3,
d
4.3.6. 4-(4-Chlorophenyl)thiazol-2-amine (3f). IR (KBr): 3438, 3283,
150.2, 137.1, 130.3, 128.6, 127.6, 126.5, 121.4, 106.6; HRMS (ESI): m/z
[MþH]þ calcd for C11H11N2S: 203.0637; found: 203.0634.
3112, 1633, 1534, 1476, 1401, 1338, 1088 cmꢁ1 1H NMR (600 MHz,
;
DMSO-d6):
d
¼7.83 (d, J¼9.0 Hz, 2H), 7.43 (d, J¼9.0 Hz, 2H), 6.90 (s,
2H), 7.06 (s, 1H); 13C NMR (150 MHz, CDCl3):
d
¼168.6, 148.6, 133.7,
4.3.15. (E)-4-(4-Methylstyryl)thiazol-2-amine (5b). IR (KBr): 3410,
3282, 3112, 3019, 2918, 1616, 1533, 1512, 1352, 1295, 1124,
131.8, 128.7, 127.4, 102.5; HRMS (ESI): m/z [MþH]þ calcd for
C9H8N2SCl: 211.0091; found: 211.0086.
967 cmꢁ1
;
1H NMR (600 MHz, CDCl3):
d
¼7.36e7.37 (d, J¼6.6 Hz,
2H), 7.19e7.22 (d, J¼15.6 Hz, 1H), 7.13e7.14 (d, J¼6.6 Hz, 2H),
4.3.7. 4-(4-Bromophenyl)thiazol-2-amine (3g). IR (KBr): 3428,
6.80e6.83 (d, J¼15.6 Hz, 1H), 5.31 (s, 2H), 2.34 (s, 3H); 13C NMR
3282, 3111, 2926, 1633, 1534, 1472, 1396, 1336, 1198, 1068, 1037,
(150 MHz, CDCl3):
d¼167.4, 150.3, 137.4, 134.3, 130.2, 129.3, 126.4,
1006 cmꢁ1; 1H NMR (600 MHz, DMSO-d6):
d
¼7.76 (d, J¼8.4 Hz, 2H),
120.5, 106.1, 21.2; HRMS (ESI): m/z [MþH]þ calcd for C12H13N2OS:
7.56 (d, J¼8.4 Hz, 2H), 7.16 (s, 2H), 7.07 (s, 2H); 13C NMR (150 MHz,
233.0743; found: 233.0743.
CDCl3):
d
¼168.5, 148.8, 134.2, 131.5, 127.7, 120.3, 102.6; HRMS (ESI):
m/z [MþH]þ calcd for C9H8N2SBr: 254.9586; found: 254.9583.
4.3.16. (E)-4-(4-Methoxystyryl)thiazol-2-amine
3428, 3267, 3118, 2962, 2931, 2836, 1624, 1603, 1535, 1514, 1417,
1347, 1304, 1266, 1239, 1176, 1110, 1024, 963 cmꢁ1 1H NMR
(600 MHz, CDCl3):
(5c). IR
(KBr):
4.3.8. 4-(3-Nitrophenyl)thiazol-2-amine (3h). IR (KBr): 3423, 3291,
;
3110, 1636, 1537, 1514, 1473, 1344, 1259, 1205, 1050 cmꢁ1; 1H NMR
d
¼7.41 (d, J¼8.4 Hz, 2H), 7.12e7.20 (d,
(600 MHz, DMSO-d6):
d
¼8.63 (s, 1H), 8.25 (d, J¼7.8 Hz, 1H), 8.12 (d,
J¼15.6 Hz, 1H), 6.86e6.88 (d, J¼7.8 Hz, 2H), 6.72e6.75 (d,
J¼7.8 Hz, 1H), 7.67e7.69 (t, J¼7.8 Hz, 1H), 7.35 (s, 1H), 7.25 (s, 2H);
J¼15.6 Hz, 1H), 5.25 (s, 2H), 3.81 (s, 3H); 13C NMR (150 MHz,
13C NMR (150 MHz, CDCl3):
d
¼168.6, 148.3, 147.5, 136.4, 131.6, 130.1,
CDCl3):
d
¼167.3, 159.2, 150.2, 129.8, 128.8, 127.7, 119.3, 114.0, 105.5,
121.8, 120.0, 104.3; HRMS (ESI): m/z [MþH]þ calcd for C7H7N2OS:
89.6, 55.2; HRMS (ESI): m/z [MþH]þ calcd for C12H13N2OS:
222.0332; found: 222.0332.
233.0743; found: 233.0743.
4.3.9. 4-([1,10-Biphenyl]-4-yl)thiazol-2-amine (3i). IR (KBr): 3438,
4.3.17. (E)-4-(3,4-Dimethoxystyryl)thiazol-2-amine (5d). IR (KBr):
3289, 3109, 1631, 1524, 1480, 1405, 1332, 1306, 1198, 1041 cmꢁ1; 1H
3415, 3292, 3146, 3109, 2967, 2932, 2833, 1631, 1538, 1514, 1495,
NMR (600 MHz, DMSO-d6):
d
¼7.91 (d, J¼8.4 Hz, 2H), 7.68e7.73 (m,
1462, 1417, 1349, 1260, 1221, 1156, 1135, 1026 cmꢁ1 1H NMR
;
4H), 7.46e7.48 (t, J¼7.8 Hz, 2H), 7.35e7.39 (t, J¼7.8 Hz, 1H), 7.12 (s,
(600 MHz, CDCl3):
d
¼7.17e7.19 (d, J¼16.8 Hz, 1H), 7.02e7.03 (d,
2H); 13C NMR (150 MHz, CDCl3):
d¼168.3, 149.6, 139.8, 138.8, 134.1,
J¼6.6, Hz, 2H), 6.83e6.84 (d, J¼8.4 Hz, 1H), 6.74e6.76 (d, J¼16.8 Hz,
129.0, 127.5, 126.8, 126.5, 126.2, 101.9; HRMS (ESI): m/z [MþH]þ
1H), 6.39 (s, 1H), 5.29 (s, 2H), 3.91 (s, 3H), 3.89 (s, 3H); 13C NMR
calcd for C15H13N2S: 253.0794; found: 253.0790.
(150 MHz, CDCl3):
d
¼167.4, 150.3, 148.9, 148.8, 130.0, 119.9, 119.7,
111.0, 108.5, 105.7, 55.8; HRMS (ESI): m/z [MþH]þ calcd for
4.3.10. 4-(Naphthalen-2-yl)thiazol-2-amine (3j). IR (KBr): 3423,
C12H13N2OS: 233.0743; found: 233.0743.
3248, 3111, 2925, 2856, 1599, 1525, 1494, 1361, 1321, 1182,
1037 cmꢁ1
;
1H NMR (600 MHz, DMSO-d6):
d
¼8.36 (s, 1H),
4.3.18. (E)-4-(4-Nitrostyryl)thiazol-2-amine (5e). IR (KBr): 3418,
2959, 2925, 2854, 1726, 1628, 1589, 1514, 1340, 1288, 1106,
7.89e7.98 (m, 5H), 7.49e7.53 (m, 2H), 7.18 (s, 2H); 13C NMR
(150 MHz, CDCl3):
d
¼168.3, 149.8, 133.3, 132.3, 128.2, 128.0, 127.6,
1075 cmꢁ1
;
1H NMR (600 MHz, CDCl3):
d
¼8.18e8.20 (d, J¼8.4 Hz,
126.4, 126.0, 124.1, 102.5; HRMS (ESI): m/z [MþH]þ calcd for
2H), 7.77e7.78 (d, J¼8.4 Hz, 2H), 7.23e7.26 (d, J¼15.6 Hz, 1H),
C13H11N2S: 227.0637; found: 222.0632.
7.15e7.18 (d, J¼15.6 Hz, 1H), 6.82 (s, 1H); 13C NMR (150 MHz,
CDCl3):
d
¼168.2, 149.3, 145.9, 144.3, 129.5, 127.0, 126.3, 124.1, 109.6;
4.3.11. 4-(2-Aminothiazol-4-yl)phenol (3k). IR (KBr): 3449, 3304,
HRMS (ESI): m/z [MþH]þ calcd for C12H13N2OS: 233.0743; found:
3199, 3120, 2654, 2588, 1622, 1539, 1515, 1436, 1339, 1265, 1245,
233.0743.
1180, 1033 cmꢁ1
;
1H NMR (600 MHz, DMSO-d6):
d¼9.58 (s, 1H),
7.64 (s, 2H), 7.07 (s, 2H), 6.81 (s, 2H), 6.73 (s, 1H); 13C NMR
4.3.19. (E)-4-(3-Nitrostyryl)thiazol-2-amine (5f). IR (KBr): 3407,
(150 MHz, CDCl3):
d¼168.3, 156.9, 149.9, 127.1, 126.3, 115.4, 98.8;
3103, 2926, 1725, 1633, 1536, 1519, 1350, 1125 cmꢁ1 1H NMR
;
HRMS (ESI): m/z [MþH]þ calcd for C9H9N2OS: 193.0430; found:
(600 MHz, CDCl3):
d
¼8.33 (s, 1H), 8.07e8.08 (q, J¼7.8 Hz, 1H),
193.0427.
7.96e7.97 (d, J¼7.8 Hz,1H), 7.63e7.65 (t, J¼7.8 Hz,1H), 7.20e7.23 (d,
J¼15.6 Hz, 1H), 7.15e7.18 (d, J¼15.6 Hz, 1H), 7.10 (s, 2H), 6.76 (s, 1H);
4.3.12. 4-(Furan-2-yl)thiazol-2-amine (3l). IR (KBr): 3436, 3271,
13C NMR (150 MHz, CDCl3):
d¼168.3, 149.3, 148.5, 139.3, 132.8,
3106, 2960, 1627, 1527, 1453, 1389, 1333, 1204, 1150, 1047,
130.4, 126.3, 125.5, 121.8, 120.3, 108.5; HRMS (ESI): m/z [MþH]þ
1008 cmꢁ1
;
1H NMR (600 MHz, DMSO-d6):
d
¼7.64 (s, 1H), 7.14 (s,
calcd for C12H13N2OS: 233.0743; found: 233.0743.
2H), 6.74 (s, 1H), 6.54 (d, J¼4.8 Hz, 2H); 13C NMR (150 MHz, CDCl3):
d
¼168.7, 150.6, 142.2, 141.8, 111.6, 106.0, 100.6; HRMS (ESI): m/z
4.3.20. N-Methyl-4-phenylthiazol-2-amine (7a). IR (KBr): 3444,
[MþH]þ calcd for C7H7N2OS: 167.0274; found: 167.0270.
3225, 3116, 2918, 1588, 1482, 1403, 1330, 1072, 1059 cmꢁ1; 1H NMR
(400 MHz, CDCl3):
d
¼7.78 (d, J¼7.2 Hz, 2H), 7.35e7.39 (t, J¼7.2 Hz,
4.3.13. 4-(Thiophen-2-yl)thiazol-2-amine (3m). IR (KBr): 3425,
2H), 7.29 (s, 1H), 6.92 (s, 2H), 6.66 (s, 1H), 2.87 (s, 3H); 13C NMR
3269, 3100, 2928, 1622, 1551, 1520, 1364, 1317, 1285, 1186, 1079,
(100 MHz, CDCl3):
d
¼171.5, 151.6, 135.1, 128.5, 127.6, 126.0, 100.4,
1050 cmꢁ1
;
1H NMR (600 MHz, CDCl3):
d
¼7.31 (d, J¼3.0 Hz, 1H),
32.2; HRMS (ESI): m/z [MþH]þ calcd for C10H11N2S: 191.06375;
7.21 (d, J¼4.8 Hz, 1H), 7.01e7.02 (t, J¼4.2 Hz, 1H), 5.54 (s, 2H); 13C
found: 191.06313.
NMR (150 MHz, CDCl3):
d
¼167.7, 145.4, 138.6, 127.6, 124.5, 123.4,
123.3, 101.3; HRMS (ESI): m/z [MþH]þ calcd for C7H7N2S2:
4.3.21. 4-(4-Methoxyphenyl)-N-methylthiazol-2-amine
(7b). IR
183.0045; found: 183.0042.
(KBr): 3275, 3111, 2923, 1715, 1578, 1534, 1492, 1463, 1396, 1330,
1303, 1251, 1182, 1108, 1055, 1029 cmꢁ1; 1H NMR (400 MHz, CDCl3):
4.3.14. (E)-4-Styrylthiazol-2-amine (5a). IR (KBr): 3478, 3377, 3287,
3092, 3024, 1636, 1599, 1538, 1522, 1444, 1343, 1292, 1124, 1072,
d
¼7.68 (d, J¼8.8 Hz, 2H), 6.90 (d, J¼8.4 Hz, 2H), 6.83 (s, 1H), 6.53 (s,
1H), 3.82 (s, 3H), 2.77 (s, 3H); 13C NMR (100 MHz, CDCl3):
d¼159.3,

178
Y.-P. Zhu et al. / Tetrahedron 68 (2012) 173e178
127.6, 127.3, 113.9, 98.6, 55.2, 32.2; HRMS (ESI): m/z [MþH]þ calcd
60.6, 13.8; HRMS (ESI): m/z [MþH]þ calcd for C14H11F6O2N2S:
for C11H13N2OS: 221.07431; found: 211.0738.
385.04399; found: 385.04359.
4.3.22. 4-(4-Bromophenyl)-N-methylthiazol-2-amine (7c). IR (KBr):
4.3.29. Ethyl 2-amino-4-(furan-2-yl)thiazole-5-carboxylate (7j). IR
3443, 3265, 1581, 1567, 1474, 1451, 1394, 1325, 1268, 1121, 1071,
(KBr): 3452, 3270, 3115, 1699, 1631, 1511, 1478, 1302, 1273, 1170,
1008 cmꢁ1
;
1H NMR (400 MHz, CDCl3):
d
¼7.65 (d, J¼8.8 Hz, 2H),
1145, 1119, 107.3, 1020 cmꢁ1; 1H NMR (400 MHz, DMSO):
d¼7.75 (s,
7.49 (d, J¼8.4 Hz, 2H), 6.68 (s, 1H), 6.35 (s,1H), 2.91 (s, 3H); 13C NMR
1H), 7.53 (s, 1H), 6.53 (s, 1H), 6.04 (s, 2H), 4.29 (br, 2H), 1.33e1.36
(100 MHz, CDCl3):
d
¼171.3, 150.3, 133.8, 131.6, 127.6, 121.5, 101.1,
(br, 3H); 13C NMR (100 MHz, DMSO):
d
¼169.2, 147.9, 143.1, 115.2,
32.2; HRMS (ESI): m/z [MþH]þ calcd for C10H10BrN2S: 268.97426;
111.9, 60.9, 29.5, 14.4; HRMS (ESI): m/z [MþH]þ calcd for
found: 268.97392.
C10H11O3N2S: 239.04849; found: 239.04811.
4.3.23. (2-Amino-4-(4-methoxyphenyl)thiazol-5-yl)(4-
methoxyphenyl)methanone (7d). IR (KBr): 3310, 3071, 2961, 2833,
1709, 1643, 1606, 1585, 1568, 1510, 1471, 1433, 1330, 1299, 1248,
Acknowledgements
We thank the National Natural Science Foundation of China
(Grants 20872042, and 201032001) and PCSIRT (No. IRT0953). We
are also grateful to Xianggao Meng for his help with X-ray diffrac-
tion analysis.
1172, 1124, 1071, 1033 cmꢁ1; 1H NMR (400 MHz, DMSO):
d¼7.90 (s,
2H), 7.42 (d, J¼7.6 Hz, 2H), 7.24 (d, J¼7.6 Hz, 2H), 6.72 (d, J¼7.6 Hz,
2H), 6.68 (d, J¼7.6 Hz, 2H), 3.72 (s, 3H), 3.68 (s, 3H); 13C NMR
(100 MHz, DMSO):
d
¼186.4, 170.2, 161.8, 159.3, 131.0, 113.1, 112.9,
55.3, 55.1; HRMS (ESI): m/z [MþH]þ calcd for C18H17N2O3S:
Supplementary data
341.09544; found: 341.09510.
Supplementary data associated with this article can be found in
online version, at doi:10.1016/j.tet.2011.10.074. These data include
MOL files and InChiKeys of the most important compounds de-
scribed in this article.
4.3.24. Ethyl
(KBr): 3396, 3285, 3095, 2979, 1658, 1635, 1516, 1481, 1448, 1369,
1340, 1303, 1170, 1091 cmꢁ1; 1H NMR (400 MHz, DMSO):
¼7.89 (s,
2-amino-4-phenylthiazole-5-carboxylate
(7e). IR
d
2H), 7.66e7.69 (m, 2H), 7.37e7.39 (m, 2H), 4.09e4.13 (m, 2H),
1.13e1.17 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, DMSO):
¼170.0,
d
References and notes
161.2, 158.8, 134.7, 129.7, 128.7, 127.3, 108.5, 60.1, 14.1; HRMS (ESI):
m/z [MþH]þ calcd for C12H13O2N2S: 249.06922; found: 249.06878.
1. (a) Metzger, J. V. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees, C.
W., Eds.; Pergamon:New York, NY,1984; Vol. 6, pp 235e332;(b) Wang, W.-L.; Yao,
D.-Y.; Gu, M.; Fan, M.-Z.; Li, J.-Y.; Xing, Y.-C.; Nan, F.-J. Bioorg. Med. Chem. Lett. 2005,
15, 5284; (c) Lewis, J. R. Nat. Prod. Rep.1999, 16, 389; (d) Fink, B. A.; Mortensen, D.
S.; Stauffer, S. R.; Aron, Z. D.; Katzenellenbogen, J. A. Chem. Biol. 1999, 6, 205.
2. (a) Haviv, F.; Ratajczyk, J. D.; DeNet, R. W.; Kerdesky, F. A.; Walters, R. L.;
Schmidt, S. P.; Holms, J. H.; Young, P. R.; Carter, G. W. J. Med. Chem. 1988, 31,
1719; (b) Clemence, F.; Martret, O. L.; Delevallee, F.; Benzoni, J.; Jouanen, A.;
Jouquey, S.; Mouren, M.; Deraedt, R. J. Med. Chem. 1988, 31, 1453; (c) Jaen, J. C.;
Wise, L. D.; Caprathe, B. W.; Tecle, H.; Bergmeier, S.; Humblet, C. C.; Heffner, T.
G.; Meltzner, L. T.; Pugsley, T. A. J. Med. Chem. 1990, 33, 311; (d) Tsuji, K.; Ishi-
kawa, H. Bioorg. Med. Chem. Lett. 1994, 4, 1601.
3. (a) Kearney, P. C.; Fernandez, M.; Flygare, J. A. J. Org. Chem. 1998, 63, 196; (b)
Potewar, T. M.; Ingale, S. A.; Srinivasan, K. V. Tetrahedron 2008, 64, 5019.
4. (a) Aoyama, T.; Murata, S.; Nagata, Y.; Takidoa, T.; Kodomari, M. Tetrahedron Lett.
2005, 46, 4875; (b) Aoyama, T.; Murata, S.; Arai, I.; Araki, N.; Takidoa, T.; Suzuki,
Y.; Kodomari, M. Tetrahedron 2006, 62, 3201.
4.3.25. Ethyl 2-amino-4-(3,4-dimethoxyphenyl)thiazole-5-
carboxylate (7f). IR (KBr): 3366, 3112, 2971, 2939, 1705, 1639,
1520, 1302, 1255, 1228, 1183, 1138, 1076, 1025 cmꢁ1 1H NMR
;
(400 MHz, CDCl3):
d
¼7.35 (d, J¼8.8 Hz, 1H), 7.31 (s, 1H), 6.90 (d,
J¼8.0 Hz,1H), 5.85 (s, 2H), 4.19e4.24 (q, J¼14.0 Hz, 2H), 3.92 (s, 6H),
1.25e1.28 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, DMSO):
¼168.82,
d
161.71, 158.45, 149.74, 126.61, 122.96, 112.89, 110.84, 110.11, 60.79,
55.90, 55.85, 14.28; HRMS (ESI): m/z [MþH]þ calcd for
C14H17O4N2S: 309.09035; found: 309.09021.
4.3.26. Ethyl 2-amino-4-(4-bromophenyl)thiazole-5-carboxylate
5. Donohoe, T. D.; Kabeshov, M. A.; Rathi, A. H.; Smith, I. E. D. Synlett 2010, 2956.
6. (a) Karade, H.; Sathe, M.; Kaushik, M. P. Catal. Commun. 2007, 8, 741; (b)
Dodson, R. M.; Carroll King, L. J. Am. Chem. Soc. 1945, 67, 2242.
(7g). IR (KBr): 3413, 3289, 3107, 1984, 1668, 1642, 1524, 1478,
1394, 1368, 1309, 1170, 1091, 1013 cmꢁ1
;
1H NMR (400 MHz,
DMSO):
d
¼7.90 (s, 2H), 7.60 (s, 4H), 4.08e4.12 (m, 2H), 1.15e1.18 (t,
7. For some recent reviews, see: (a) Tietze, L. F. Chem. Rev. 1996, 96, 115; (b) Ikeda,
J¼6.8 Hz, 3H); 13C NMR (100 MHz, DMSO):
d
¼175.16, 166.23,
S. Acc. Chem. Res. 2000, 33, 511; (c) Walji, A. M.; MacMillan, D. W. C. Synlett 2007,
ꢁ
1477; (d) Zhu; bienayme, H. Multicomponent reactions; Wiley-VCH: Eeinheim,
162.50, 138.90, 136.92, 135.51, 127.14, 113.8, 65.36, 19.28; HRMS
(ESI): m/z [MþH]þ calcd for C12H12BrF6O2N2S: 328.97974; found:
328.97726.
2005; (e) Domling, A. Chem. Rev. 2006, 106, 17; (f) Tejedor, D.; Garcia-Tellado, F.
Chem. Soc. Rev. 2007, 36, 484.
8. Yin, G. D.; Gao, M.; She, N. F.; Hu, S. L.; Wu, A. X.; Pan, Y. J. Synthesis 2007, 20,
3113; (b) Wang, Z. H.; Yin, G. D.; Qin, J.; Gao, M.; Cao, L. P.; Wu, A. X. Synthesis
2008, 22, 3675; (c) Yin, G. D.; Zhou, B. H.; Meng, X. G.; Wu, A. X.; Pan, Y. J. Org.
Lett. 2006, 8, 2245; (d) Gao, M.; Yin, G. D.; Wang, Z. H.; Wu, Y. D.; Guo, C.; Pan,
Y. J.; Wu, A. X. Tetrahedron 2009, 65, 6047.
9. (a) Erian, A. W.; Sherif, S. M.; Gaber, H. M. Molecules 2003, 8, 793; (b) Frie-
drichsen, W. In Furans and Their Benzo Derivatives; Katritzky, A. R., Rees, C. W.,
Scriven, E. F. V., Eds.; Comprehensive Heterocyclic Chemistry II; Pergamon,
Elsevier Science: Oxford, 1996; Vol. 2, p 359; (c) Li, B.; Chiu, C. K.-F.; Hank, R. F.;
Murry, J.; Roth, J.; Tobiassen, H. Org. Process Res. Dev. 2002, 6, 682.
10. Compounds 5ae5f were synthesized via condensation of aromatic aldehyde
and acetone in the presence of NaOH. See: Drake, N. L.; Allen, P., Jr. Org. Synth.
Coll.; John Wiley & Sons: London, 1941; Vol. 1, pp 77e78.
4.3.27. Ethyl 2-amino-4-(4-nitrophenyl)thiazole-5-carboxylate
(7h). IR (KBr): 3411, 3128, 1707, 1648, 1600, 1519, 1482, 1346,
1279, 1159, 1113, 1071 cmꢁ1; 1H NMR (400 MHz, DMSO):
d¼8.24 (s,
2H), 7.91 (s, 4H), 4.11 (s, 2H), 1.16 (s, 3H); 13C NMR (100 MHz,
DMSO):
d
¼170.2, 160.9, 155.7, 147.2, 140.9, 131.0, 122.6, 60.5, 14.0;
HRMS (ESI): m/z [MþH]þ calcd for C12H12N3O4S: 294.05430; found:
294.05400.
11. Crystal structure data for macrocycle 5b: CCDC 834646. C48H48N8S4, chemical
4.3.28. Ethyl 2-amino-4-(3,5-bis(trifluoromethyl)phenyl)thiazole-5-
carboxylate (7i). IR (KBr): 3368, 3139, 1662, 1645, 1516, 1464,
formula weight: 865.18, monoclinic, space group P2(1)/n, a¼14.3676(16), b¼17.
3
ꢀ
ꢀ
ꢀ
231(2), c¼18.422(2) A;
a
¼90.000ꢀ,
b
m
¼92.679(2)ꢀ,
g
¼90.00 , U¼4555.8(9) A ,
1380, 1308, 1278, 1168, 1130, 1080, 1017 cmꢁ1
;
1H NMR (400 MHz,
T¼200(2) K, Z¼4, DC¼1.261 Mg/M3,
¼0.252 mmꢁ1
¼0.71073 A, F(000) 1824,
,
l
ꢀ
crystal size 0.16ꢂ0.12ꢂ0.10 mm3, 8458 independent reflections[R(int)¼0.0380],
DMSO):
4.11e4.16 (m, 2H), 1.12e1.21 (m, 3H); 13C NMR (100 MHz, DMSO):
¼170.4, 160.9, 154.3, 136.7, 130.4, 129.7, 129.4, 124.7, 122.0, 110.6,
d¼8.37 (d, J¼6.8 Hz, 2H), 8.12 (s, 1H), 8.05 (d, J¼7.6 Hz, 2H),
reflections collected 24,747, refinement method: full-matrix least-squares on
F2: goodness-of-fit on F2 1.183, final R indices [I>2
1544, largest diff. peak and hole 0.321 A and ꢁ0.206 e A
s
(I)], R1¼0.0734, wR2¼0.
ꢀꢁ3
ꢀꢁ3
d
.