A new facile synthesis of 2-aminothiazole-5-carboxylates

Article abstract of DOI:10.1016/S0040-4039(01)00161-7

A new facile method has been developed for the synthesis of 2-aminothiazole-5-carboxylates. The new method involves reaction of ethyl β-ethoxyacrylate with N-bromosuccinimide (NBS) to give a novel intermediate, α-bromo-α-formylacetate hemiacetal. Cyclization of the in situ formed hemiacetal with thioureas afforded 2-aminothiazole-5-carboxylates in 60-98% yields.

Full text of DOI:10.1016/S0040-4039(01)00161-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2101–2102
A new facile synthesis of 2-aminothiazole-5-carboxylates
Rulin Zhao,* Stacey Gove, Joseph E. Sundeen and Bang-Chi Chen
Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543, USA
Received 1 December 2000; revised 23 January 2001; accepted 24 January 2001
Abstract—A new facile method has been developed for the synthesis of 2-aminothiazole-5-carboxylates. The new method involves
reaction of ethyl b-ethoxyacrylate with N-bromosuccinimide (NBS) to give a novel intermediate, a-bromo-a-formylacetate
hemiacetal. Cyclization of the in situ formed hemiacetal with thioureas afforded 2-aminothiazole-5-carboxylates in 60–98% yields.
© 2001 Elsevier Science Ltd. All rights reserved.
2-Aminothiazole-5-carboxylates are an important class
of heterocycles in organic synthesis especially in the
preparation of biologically important and medicinally
useful agents such as angiotensin II antagonists,1 DNA
minor groove binding analogs of netropsin,2 in addition
to many others.3 Previously, 2-aminothiazole-5-car-
boxylates were prepared in two steps from a-chloro-
acetates through a-formyl-a-chloroacetate inter-
mediates.2,4 For example, treatment of ethyl a-
chloroacetate and ethyl formate using potassium ethox-
ide generated from potassium metal and absolute
ethanol gave ethyl a-formyl-a-chloroacetate in 25% iso-
lated yield which after reaction with thiourea in water
afforded ethyl 2-aminothiazole-5-carboxylate in 67%.2
Although this procedure can be carried out in gram
scale, it is limited by its low overall yield (17%). Alter-
natively, a-formyl-a-bromoacetate has been used for
the synthesis of 2-aminothiazole-5-carboxylates.5 The
second method however suffered from similar prob-
lems, i.e. the preparation and isolation of the generally
unstable a-formyl-a-haloacetates.6 In a project of our
drug discovery programs, we required a rapid access to
various 2-aminothiazole-5-carboxylates. Herein, we
report a new facile synthesis of the titled compounds.
Our synthesis of 2-aminothiazole-5-carboxylates entails
the use of the readily available ethyl b-ethoxy acrylate 1
(Scheme 1). Thus, treatment of 1 with N-bromosuccin-
imide (NBS) in a mixture of water and dioxane gave
a-formyl-a-bromoacetate hemiacetal 2 which was confi-
rmed by LC/MS analysis of the reaction mixture (M+
H=240). Addition of thiourea 3a in situ to hemiacetal
2 and heating the resulting mixture at 80°C for 1 h
cleanly afforded ethyl 2-aminothiazole-5-carboxylate 4a
which was isolated in 90% yield.7
The new one-pot method worked well also for the
preparation of N-substituted 2-aminothiazole-5-car-
S
H2O/NBS
O
R
O
OH
O
N
H
NH2
dioxane
N
3
OEt
EtO
OEt
-10oC to rt
0.5h
EtO
OEt
S
80oC
Br
R
NH
1
4
2
3/4
Time (h) Yield % (4)
Entry
a, R=H
b, R=Pr-i
c, R=Bu-t
d, R=Bn
a
b
c
d
e
1
2
3
4
5
1h
90%
60%
75%
70%
98%
16h
16h
16h
16h
e, R=C6H4OMe-p
Scheme 1.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00161-7

2102
R. Zhao et al. / Tetrahedron Letters 42 (2001) 2101–2102
boxylates as shown in Scheme 1. N-Alkyl, N-benzyl
and N-aryl 2-aminothiazole-5-carboxylates 4b–e were
all readily prepared in good to excellent yields.8
4. Noto, R.; Ciofalo, M.; Buccheri, F.; Werber, G.; Spinelli,
D. J. Chem. Soc., Perkin Trans. 2 1991, 349.
5. Kaye, P. T.; Meakins, G. D.; Smith, A. K.; Tirel, M. D. J.
Chem. Soc., Perkin Trans. 1 1983, 1677.
In summary, a new facile synthesis of 2-aminothiazole-
5-carboxylates has been developed. Compared to the
previous two-step syntheses, the new one-pot method
not only is manipulatively simpler, but also affords
higher overall yields (60–98% versus <25%). In addi-
tion, the new intermediate, a-formyl-a-bromoacetate
hemiacetal 2, is expected to be useful for the synthesis
of a variety of heterocycles other than 2-aminothiazole-
5-carboxylates 4.
6. Ethyl a-formyl-a-bromoacetate was prepared similarly by
formylation of ethyl bromoacetate in 26% yield, see:
Yoffe, S. T.; Petrovsky, P. V.; Goryunov, Y. I.; Yershova,
T. V.; Kabachnik, M. I. Tetrahedron 1972, 28, 2783.
7. Typical procedure: To a mixture of ethyl b-ethoxyacrylate
1 (144.2 g, 1.0 mol) in water (500 mL) and dioxane (500
mL) at −10°C was added NBS (195.7 g, 1.1 mol, 1.1
equiv.). The reaction mixture was stirred at rt for 1 h and
HPLC showed disappearance of 1. Thiourea 3a (76.0 g,
1.0 mol, 1.0 equiv.) was added and the reaction mixture
was heated to 80°C for 1 h. After cooling to rt, conc.
NH4OH (200 mL) was added. The resulting slurry was
stirred at rt for 10 min and filtered. The cake was washed
with water (3×500 mL) and dried to give 2-aminothiazole-
5-carboxylate 4a (155.1 g, 90% yield), mp 159°C, lit.2
156–158°C. The NMR spectrum data were consistent with
those reported for this compound.2
References
1. Pratt, J.; Jae, H.-S.; Rosenberg, S.; Spina, K.; Winn, M.;
Buchner, S.; Novosad, E.; Kerkman, D.; Shiosaki, K.;
Opgenorth, T.; DeBernardis, J. Bioorg. Med. Chem. Lett.
1994, 4, 169.
2. Plouvier, B.; Bailly, C.; Houssin, R.; Henichart, J.-P.
8. 1H NMR (CDCl3) spectrum data for new compounds: 4b,
l 7.72 (s, 1H), 6.72 (br s, 1H), 4.24 (q, J=7.1 Hz, 2H),
3.55 (m, 1H), 1.29 (t, J=7.1 Hz, 3H), 1.27 (d, J=6.3 Hz,
3H); 4c, l 7.82 (s, 1H), 5.90 (br s, 1H), 4.29 (q, J=7.1 Hz,
2H), 1.45 (s, 9H), 1.34 (t, J=7.1 Hz, 3H); 4d, l 10.50 (br
s, 1H), 7.87 (s, 1H), 7.52 (m, 5H), 4.67 (s, 2H), 4.46 (q,
J=7.1 Hz, 2H), 1.47 (t, J=7.1 Hz, 3H); 4e, l 8.18 (br s,
1H), 7.91 (s, 1H), 7.29 (d, J=8.9 Hz, 2H), 6.95 (d, J=8.9
Hz, 2H), 4.29 (q, J=7.1 Hz, 2H), 3.83 (s, 3H), 1.33 (t,
J=7.1 Hz, 3H).
Heterocycles 1991, 32, 693.
3. (a) Lehmann, T. E.; Greenberg, W. A.; Liberles, D. A.;
Wada, C. K.; Dervan, P. B. Helv. Chim. Acta 1997, 80,
2002; (b) Roberts, E. C.; Shealy, Y. F. J. Med. Chem.
1972, 15, 1310; (c) Knauf, W.; Strehlke, P.; Woelk, E. Eur.
J. Med. Chem. Chim. Ther. 1975, 10, 533; (d) Plazzi, P. V.;
Bordi, F.; Silva, C.; Morini, G.; Catellani, P. L.; Vaona,
G.; Impicciatore, M. Farmaco 1989, 44, 1011; (e) Islip, P.
J.; Closier, M. D.; Johnson, M. R.; Neville, M. C. J. Med.
Chem. 1972, 15, 101.
.