Unexpected synthesis of 3-(2-aminothiazol-5-yl)-3-arylpropanoates through a one-pot four-component procedure

Article abstract of DOI:10.3184/174751911X13220659039518

The novel one-pot four-component reactions of 2-aminothiazole, aldehydes, Meldrum's acid and aliphatic alcohols were investigated, and a series of unexpected compounds, 3-(2-aminothiazol-5-yl)-3-arylpropanoates, were synthesised under catalyst-free conditions. The protocol has advantages of mild conditions, high yield and simple work-up procedure. Thiazoles are important in the field of organic and medicinal chemistry.

Full text of DOI:10.3184/174751911X13220659039518

JOURNAL OF CHEMICAL RESEARCH 2011
RESEARCH PAPER 689
DECEMBER, 689–691
Unexpected synthesis of 3-(2-aminothiazol-5-yl)-3-arylpropanoates
through a one-pot four-component procedure
Zheng Li* and Yanbo Li
College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou, Gansu, 730070, P. R. China
The novel one-pot four-component reactions of 2-aminothiazole, aldehydes, Meldrum’s acid and aliphatic alcohols
were investigated, and a series of unexpected compounds, 3-(2-aminothiazol-5-yl)-3-arylpropanoates, were synthe-
sised under catalyst-free conditions. The protocol has advantages of mild conditions, high yield and simple work-up
procedure. Thiazoles are important in the field of organic and medicinal chemistry.
Keywords: 2-aminothiazole, 3-(2-aminothiazol-5-yl)-3-arylpropanoate, heterocycles, Meldrum’s acid, multi-component synthesis,
organic and medicinal chemistry
Aminothiazoles are known to be ligands of estrogen receptors1
as well as a novel class of adenosine receptor antagonists.2
Compounds including an aminothiazole moiety have been
found to possess antidegenerative,3 hypolipidemic4 and hypo-
glycemic5 activities. Metal complexes bearing aminothiazole
ligands have antitumour activity.6–7 In addition, thiazoles are
also synthetic intermediates and common substructures in
numerous biologically active compounds. Thus, the thiazole
nucleus is of importance in the field of organic and medicinal
chemistry.
Multi-component reactions (MCRs) are more and more
popular and effective. Recently MCRs have emerged as a
highly valuable synthetic tool in the context of modern drug
discovery. The atom economical and convergent character, the
simplicity of a one-pot procedure, the possible structural varia-
tions, the accessible complexity of the molecules, as well as
the very large number of accessible compounds are among the
advantages of MCRs.8,9 Thus, they are perfectly amenable to
automation for combinatorial synthesis.10,11
using 2-aminothiazole instead of 2-amino-1,3,4-thiadiazole as
a substrate under similar conditions, a series of unexpected
novel compounds were obtained, in which the amino group
of thiazole was compatible to the reaction systems, and the
formation of C–N bonds was not observed. Instead, the
reactions took place at the 5-position of the thiazole ring, and
very different compounds, 3-(2-aminothiazol-5-yl)-3-arylpro-
panoates 2a–i, were readily formed in high yield (Scheme 1).
Although the reactions could, potentially, proceed at the
4-position of the thiazole ring, the 1H NMR data (δH-4 = 6.64–
6.87) of compounds 2a–i are in full accord with the C-5 substi-
tution products. For example, in 2-amino-5-methylthiazole
δH-4 = 6.68 whereas in 2-amino-4-methylthiazole H-5 is much
less deshielded δH-5 = 6.01.17
In order to explore the generality and scope of these promis-
ing findings, 2-aminothiazole, various aldehydes, Meldrum’s
acid and aliphatic alcohols were selected as model substrates
to carry out the reactions by a one-pot procedure under
catalyst-free conditions. It was found that all of these four-
component reactions proceeded smoothly to give 3-(2-amino-
thiazol-5-yl)-3-arylpropanoates 2a–i in high yield under reflux
conditions and none of the expected 3-aryl-3-(thiazol-
2-ylamino)propanoates 1 were observed. In these reactions,
various aromatic aldehydes were all suitable substrates, and
the different substituents on aromatic rings have no obvious
effect on the yield of the reactions. Aliphatic alcohols, such as
ethanol and methanol, acted both as reactants and solvents.
The influence of catalytic systems, such as Lewis acids and
Lewis bases, were investigated for the reactions, however, no
significant effects were observed (Table 1).
In continuation of our ongoing program to synthesise bio-
logically active compounds and develop one-pot multi-compo-
nent synthetic strategies for important organic compounds,12–15
we now report an efficient, unexpected route to prepare
3-(2-aminothiazol-5-yl)-3-arylpropanoates by condensation of
2-aminothiazoles, aldehydes, Meldrum’s acid and aliphatic
alcohols under catalyst-free conditions.
Results and discussion
In our previous work,16 2-amino-1,3,4-thiadiazoles, aldehydes,
Meldrum’s acid and aliphatic alcohols underwent a one-
pot four-component reaction to give 3-(1,3,4-thiadiazol-2-
ylamino)-3-arylpropanoates. In these reactions, the amino
groups of the heteroaryl amine participated in the four-compo-
nent reaction to form a C–N bond in the final products.
However, in later research to extend this synthetic method
A plausible mechanism for these four-component reactions
is shown in Scheme 2. The Knoevenagel condensation of alde-
hydes with Meldrum’s acid first gives the α,β-unsaturated
intermediate A. The latter undergoes Michael addition with
2-aminothiazole to yield intermediates B. One carbonyl group
Scheme 1 Synthesis of 3-(2-aminothiazol-5-yl)-3-arylpropanoates.
* Correspondent. E-mail: lizheng@nwnu.edu.cn

690 JOURNAL OF CHEMICAL RESEARCH 2011
Scheme 2 The proposed mechanism for four-component synthesis of 3-(2-aminothiazol-5-yl)-3-arylpropanoates.
Ethyl 3-(2-aminothiazol-4-yl)-3-(4-chlorophenyl)propanoate (2c):
White solid, m.p. 113–115 °C; 1H NMR (400 MHz, CDCl3): δ 7.29–
7.18 (m, 4H, Ph-H), 6.76 (s, 1H, Th-H), 5.13 (brs, 2H, NH2), 4.55–
4.51 (t, J = 7.8 Hz, 1H, CH), 4.10–4.04 (q, J = 7.2 Hz, 2H, CH2),
3.02–2.86 (m, 2H, CH2), 1.18–1.14 (t, J = 7.2 Hz, 3H, CH3). 13C NMR
(100 MHz, CDCl3): δ 170.83, 167.62, 140.83, 134.64, 132.89, 130.82,
128.78, 128.75, 60.76, 41.28, 39.93, 14.04. IR (KBr, v, cm−1): 3366
of B is then subjected to nucleophilic attack by the aliphatic
alcohol and this is followed by elimination of acetone and
decarboxylation to afford 3-(2-aminothiazol-5-yl)-3-arylpro-
panoates 2a–i as the final products.
Conclusion
(NH), 3296 (NH), 1714 (C=O). Anal. Calcd for C
54.10; H, 4.86; N, 9.01. Found: C, 54.04; H, 4.86; N, 8.98%.
H
S: C,
In summary, an efficient synthetic method to access 3-(2-
aminothiazol-5-yl)-3-arylpropanoates by a catalyst-free, one-
pot four-component reaction of 2-aminothiazole, aldehydes,
Meldrum’s acid and aliphatic alcohols has developed. This
protocol has the advantages of mild conditions, high yield and
a simple work-up procedure.
14 15C1N2O2
Ethyl 3-(2-aminothiazol-4-yl)-3-(2,4-dichlorophenyl)propanoate
(2d): White solid, m.p. 86–88 °C; 1H NMR (400 MHz, CDCl3): δ 7.38
(s, 1H, Ph-H), 7.20–7.18 (d, J = 8.4 Hz, 2H, Ph-H), 6.78 (s, 1H,
Th-H), 5.39 (brs, 2H, NH2), 5.05–5.01 (t, J = 7.8 Hz, 1H, CH), 4.11–
4.06 (q, J = 7.2 Hz, 2H, CH2), 2.97–2.95 (d, J = 8.0 Hz, 2H, CH2),
1.19–1.15 (t, J = 7.2 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3):
δ 170.45, 167.86, 138.30, 135.15, 134.11, 133.30, 129.57, 128.88,
128.62, 127.41, 60.82, 40.16, 36.16, 13.97. IR (KBr, v, cm−1): 3355
(NH), 3199 (NH), 1726 (C=O). Anal. Calcd for C14H14C N O S: C,
Experimental
IR spectra were recorded using KBr pellets on a Digilab FTS 3000
FTIR spectrophotometer, and 1H NMR, 13C NMR spectra on a Varian
Mercury Plus-400 instrument using CDCl3 or DMSO-d6 as solvent
and Me4Si as internal standard. Elemental analyses were performed
on a Vario E1 Elemental Analysis instrument. Melting points were
determined using an Electrothermal apparatus.
12
2
2
48.70; H, 4.09; N, 8.11. Found: C, 48.65; H, 4.08; N, 8.13%.
Ethyl 3-(2-aminothiazol-4-yl)-3-(2-nitrophenyl)propanoate (2e):
White solid, m.p. 116–118 °C; 1H NMR (400 MHz, CDCl3): δ 7.84–
7.36 (m, 4H, Ph-H), 6.87 (s, 1H, Th-H), 5.24–5.20 (t, J = 8.0 Hz, 1H,
CH), 5.13 (brs, 2H, NH2), 4.06–4.03 (q, J = 7.0 Hz, 2H, CH2),
3.08–3.06 (d, J = 8.8 Hz, 2H, CH2), 1.15–1.12 (t, J = 7.0 Hz, 3H,
CH3). 13C NMR (100 MHz, CDCl3): δ 170.11, 167.96, 149.30, 136.76,
135.01, 133.01, 129.14, 129.04, 127.95, 124.52, 60.97, 40.84, 34.50,
13.94. IR (KBr, v, cm−1): 3383 (NH), 3274 (NH), 1715 (C=O). Anal.
Synthesis of 3-(2-aminothiazol-5-yl)-3-arylpropanoates; general
procedure
A mixture of 2-aminothiazole (2.0 mmol), an appropriate aldehyde
(2.2 mmol) and Meldrum’s acid (2.0 mmol) in ethanol or methanol
(5 mL) was stirred under reflux for the time indicated in Table 1. After
completion of reaction (TLC), the solvent was removed under reduced
pressure, and the residue was subjected to column chromatography
using petroleum ether (b.p. 60–90 °C) and ethyl acetate (1:1) as eluent
to give pure product. The analytical data for the products are given
below.
Calcd for C14H15N O S: C, 52.33; H, 4.70; N, 13.08. Found: C, 52.40; H,
4
4.71; N, 13.05%.3
Ethyl 3-(2-aminothiazol-4-yl)-3-(4-nitrophenyl)propanoate (2f):
White solid, m.p. 114–116 °C; 1H NMR (400 MHz, CDCl3): δ 8.19–
8.16 (m, 2H, Ph-H), 7.46–7.42 (m, 2H, Ph-H), 6.82 (s, 1H, Th-H),
5.05 (brs, 2H, NH2), 4.70–4.66 (t, J = 7.6 Hz, 1H, CH), 4.12–4.04
(q, J = 8.0 Hz, 2H, CH2), 3.09–2.93 (m, 2H, CH2), 1.20–1.16 (t, J =
8.0 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3): δ 170.41, 167.68,
149.70, 147.04, 135.22, 129.53, 128.40, 123.98, 60.00, 40.90, 40.28,
14.06. IR (KBr, v, cm−1): 3363 (NH), 3299 (NH), 1712 (C=O). Anal.
Ethyl 3-(2-aminothiazol-5-yl)-3-phenylpropanoate (2a): White
1
solid, m.p. 110–112 °C; H NMR (400 MHz, CDCl3): δ 7.32–7.20
(m, 5H, Ph-H), 6.77 (s, 1H, Th-H), 5.20 (brs, 2H, NH2), 4.57–4.53
(t, J = 8.0 Hz, 1H, CH), 4.09–4.03 (q, J = 7.2 Hz, 2H, CH2), 3.03–2.89
(m, 2H, CH2), 1.16–1.13 (t, J = 7.2 Hz, 3H, CH3). 13C NMR
(100 MHz, CDCl3): δ 171.09, 167.73, 142.30, 134.31, 131.15, 128.58,
127.28, 127.07, 60.61, 41.39, 40.52, 13.98. IR (KBr, v, cm−1): 3368
Table 1 Synthesis of 3-(2-aminothiazol-5-yl)-3-arylpropanoates
(NH), 3295 (NH), 1714 (C=O). Anal. Calcd for C
60.85; H, 5.84; N, 10.14. Found: C, 60.77; H, 5.83; N, 10.11%.
H
S: C,
R1
R2
Time/h
M.p./oC
Yield/%a
14 16N2O2
Compd
Ethyl 3-(2-aminothiazol-4-yl)-3-(2-chlorophenyl)propanoate (2b):
White solid, m.p. 110–111 °C; 1H NMR (400 MHz, CDCl3): δ 7.37–
7.15 (m, 4H, Ph-H), 6.79 (s, 1H, Th-H), 5.27 (brs, 2H, NH2), 5.11–
5.07 (t, J = 8.0 Hz, 1H, CH), 4.11–4.05 (q, J = 7.2 Hz, 2H, CH2),
3.30–2.97 (d, J = 8.4 Hz, 2H, CH2), 1.18–1.14 (t, J = 7.2 Hz, 3H,
CH3). 13C NMR (100 MHz, CDCl3): δ 170.69, 167.65, 139.62, 135.08,
133.45, 129.83, 129.38, 128.24, 127.97, 127.11, 60.72, 40.37, 36.57,
13.98. IR (KBr, v, cm−1): 3390 (NH), 3281 (NH), 1721(C=O). Anal.
2a
2b
2c
2d
2e
2f
2g
2h
2i
C6H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
CH3
10
15
11
14
12
9
15
13
11
110–112
110–111
113–115
86–88
116–118
114–116
84–86
80
82
72
73
77
83
85
75
79
2-ClC6H4
4-ClC6H4
2,4-Cl2C6H3
2-O2NC6H4
4-O2NC6H4
4-CH3OC6H4
4-HOC6H4
C6H5
180–181
108–110
Calcd for C
H
S: C, 54.10; H, 4.86; N, 9.01. Found: C, 54.21;
14 15C1N2O2
a Yields refer to the isolated products.
H, 4.87; N, 8.99%.

JOURNAL OF CHEMICAL RESEARCH 2011 691
The authors thank the National Natural Science Foundation of
China (21162024) for financial support of this work.
Calcd for C
H, 4.71; N, 13.04%.
H
S: C, 52.33; H, 4.70; N, 13.08. Found: C, 52.43;
14 15N3O4
Ethyl 3-(2-aminothiazol-4-yl)-3-(4-methoxyphenyl)propanoate (2g):
White solid, m.p. 84–86 °C; 1H NMR (400 MHz, CDCl3): δ 7.18–7.14
(m, 2H, Ph-H), 6.85–6.81 (m, 2H, Ph-H), 6.75 (s, 1H, Th-H),
5.14 (brs, 2H, NH2), 4.52–4.48 (t, J = 7.8 Hz, 1H, CH), 4.09–4.02
(q, J = 7.6 Hz, 2H, CH2), 3.76 (s, 3H, CH3), 3.00–2.86 (m, 2H, CH2),
1.17–1.14 (t, J=7.6 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3):
δ 171.15, 167.53, 158.51, 134.47, 134.22, 131.89, 128.33, 113.91,
60.58, 55.14, 41.59, 39.76, 14.02. IR (KBr, v, cm−1): 3369 (NH), 3295
(NH), 1714 (C=O). Anal. Calcd for C
N, 9.14. Found: C, 58.71; H, 5.93; N, 9.13%.
Ethyl 3-(2-aminothiazol-4-yl)-3-(4-hydroxyphenyl)propanoate (2h):
White solid, m.p. 180–181 °C; H NMR (400 MHz, DMSO–d6):
δ 9.29 (s, 1H, OH), 7.05 (s, 2H, NH2), 6.69–6.64 (m, 5H, Ph-H, Th-H),
4.32–4.28 (t, J = 7.8 Hz, 1H, CH), 4.02–3.94 (m, 2H, CH2), 2.97–2.81
(m, 2H, CH2), 1.09–1.06 (t, J = 7.2 Hz, 3H, CH3). 13C NMR
(100 MHz, DMSO-d6): δ 170.82, 167.04, 156.04, 133.95, 133.93,
133.37, 129.21, 128.21, 115.09, 59.86, 40.95, 14.01. IR (KBr, v, cm−1):
3449 (OH), 3331 (NH), 3201 (NH), 1723 (C=O). Anal. Calcd for
Received 20 October 2011; accepted 14 November 2011
Paper 1100944 doi: 10.3184/174751911X13220659039518
Published online: 27 December 2011
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15 18N2O3
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(m, 5H, Ph-H), 6.76 (s, 1H, Th-H), 5.17 (brs, 2H, NH2), 4.57–4.53
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H
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13 14N2O2
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