Synthesis of functionalized 1,3-thiazoles from acid chlorides, primary amines, ethyl bromopyruvate, and ammonium thiocyanate

Article abstract of DOI:10.1055/s-2008-1077871

An efficient synthesis of l,3-thiazole-4(3H)-carboxylates is described via a four-component reaction between acid chlorides, primary amines, ethyl bromopyruvate, and ammonium thiocyanate. Thieme Stuttgart.

Full text of DOI:10.1055/s-2008-1077871

LETTER
1631
Synthesis of Functionalized 1,3-Thiazoles from Acid Chlorides, Primary
Amines, Ethyl Bromopyruvate, and Ammonium Thiocyanate
S
ynthesi
s
s
of Funct
sionalized
a1,3-Thiazoles Yavari,* Zinatossadat Hossaini, Faezeh Shirgahi-Talari, Samereh Seyfi
Chemistry Department, Tarbiat Modares University, P.O. Box 14115-175, Tehran 18716, Iran
Fax +98(21)88006544; E-mail: yavarisa@modares.ac.ir
Received 17 March 2008
As part of our current studies on the development of new
routes in heterocyclic synthesis,10–13 we report an efficient
procedure for direct synthesis of 1,3-thiazole-4(3H)-car-
boxylates 5 from ammonium thiocyanate (1) acid chlo-
rides 2, ethyl bromopyruvate (3), and primary amines 4 at
room temperature14 (Scheme 1).
Abstract: An efficient synthesis of 1,3-thiazole-4(3H)-carboxy-
lates is described via a four-component reaction between acid chlo-
rides, primary amines, ethyl bromopyruvate, and ammonium
thiocyanate.
Key word: 1,3-thiazole, benzylamine, ethyl bromopyruvate, benzoyl
isothiocyanate
The structures of compounds 5a–j were assigned by IR,
1H NMR, 13C NMR, and mass spectral data. For example,
the 1H NMR spectrum of 5a exhibited a triplet at d = 1.33
ppm (3J = 7.2 Hz) for the methyl protons, a quartet at d =
4.42 ppm (3J = 7.2 Hz) for the OCH2 moiety, and a singlet
at d = 6.07 ppm for the NCH2 groups. The carbonyl and
C=N group resonances in the 13C NMR spectra of 5a ap-
pear at d = 158.3 (C=O), 169.3 (C=N), and 174.8 (C=O)
ppm. The mass spectrum of 5a displayed the molecular
ion peak at m/z = 366.
Thiazoles play a prominent role in nature. For example,
the thiazolium ring present in vitamin B1 serves as an elec-
tron sink and its coenzyme form is important for the de-
carboxylation of a-keto acids.1 Large numbers of thiazole
derivatives have emerged as active pharmaceutical ingre-
dients in several drugs for their potential anti-inflammato-
ry,2,3 antitumour,4,5 antihyperlipidemic,5 and anti-
hypertensive6 properties. Thiazoles are also synthetic in-
termediates and common substructures in numerous bio-
logically active compounds. Several methods7 for the
synthesis of thiazoles have been developed amongst
which the most widely used method is Hantzsch’s
synthesis7–9 (reaction between a-halocarbonyl com-
pounds and thioamides, thioureas, thiocarbamic acids, or
dithiocarbamic acids).
A tentative mechanism for this transformation is proposed
in Scheme 2. The reaction starts with formation of isothio-
cyanate 6 followed by addition of amine 4 to generate 7.
Subsequent nucleophilic attack of 7 on 3 yields the 1:1 ad-
duct 8. Intermediate 8 undergoes cyclization reaction to
generate 9, which is converted into 5 by elimination of
water.
O
R1
N
R2
O
acetone
r.t.
N
S
CO2Et
+ R2NH2
NH4SCN
+
Br
+
R1
Cl
O
EtO2C
1
2
3
4
5
R2
Bn
R1
Yield (%)
2, 4, 5
a
b
c
Ph
Ph
85
87
4-Me-Bn
4-MeO-Bn
4-Cl-Bn
2-Cl-Bn
2-naphthylmethyl
n-Bu
78
Ph
Ph
Ph
Ph
d
e
f
82
80
75
80
g
Ph
h
Bn
4-BrC6H4
78
74
76
i
j
Bn
Bn
t-Bu
Et
Scheme 1
SYNLETT 2008, No. 11, pp 1631–1632
x
x
.x
x
.2
0
0
8
Advanced online publication: 11.06.2008
DOI: 10.1055/s-2008-1077871; Art ID: D08508ST
© Georg Thieme Verlag Stuttgart · New York

1632
I. Yavari et al.
LETTER
(5) Pereira, R.; Gaudon, C.; Iglesias, B.; Germain, P.;
O
S
O
Gronemeyer, H.; de Lera, A. R. Bioorg. Med. Chem. Lett.
2006, 16, 49.
3
4
R2
1 + 2
N
C
S
N
H
N
H
R1
R1
– HBr
(6) Tsuruni, Y.; Ueda, H.; Hayashi, K.; Takase, S.; Nishikawa,
M.; Kiyoto, S.; Okuhara, M. J. Antibiot. 1995, 48, 1066.
(7) Aguilar, E.; Meyers, A. I. Tetrahedron Lett. 1994, 35, 2473.
(8) Varma, R. S. Pure Appl. Chem. 2001, 73, 193.
(9) Ochiai, M.; Nishi, Y.; Hashimoto, S.; Tsuchimoto, Y.; Chen,
D.-W. J. Org. Chem. 2003, 68, 7887.
(10) Yavari, I.; Djahaniani, H. Tetrahedron Lett. 2006, 47, 2953.
(11) Yavari, I.; Moradi, L. Helv. Chim. Acta 2006, 89, 1942.
(12) Yavari, I.; Sabbaghan, M.; Hossaini, Z. Synlett 2006, 2501.
(13) Yavari, I.; Souri, S. Synlett 2007, 2969.
6
7
O
O
S
R1
N
R1
N
R2
R2
– H2O
N
N
S
H
5
EtO2C
EtO2C
OH
O
(14) Ethyl 2-(Benzoylimino)-3-benzyl-1,3-thiazole-4(3H)-
carboxylate (5a); Typical Procedure
8
9
To a stirred solution of NH4SCN (0.15 g, 2 mmol) in acetone
(15 mL) was added benzoyl chloride (0.28 g, 2 mmol), the
mixture was refluxed for 5 min and a solution of ethyl
bromopyruvate (0.39 g, 2 mmol) in acetone (10 mL) acetone
was added dropwise. After addition of the primary amine (2
mmol) at r.t., the reaction mixture was then stirred for 24 h,
the solvent was removed under reduced pressure, and the
residue was purified by column chromatography (SiO2;
hexane–EtOAc, 9:1) to give 5a as colorless crystals; mp
119–121 °C, yield 0.62 g (85%). IR (KBr): nmax = 1716,
1658, 1587, 1477, 1429, 1369, 1369, 1304, 1231, 1105, 1054
cm–1. 1H NMR (500.1 MHz, CDCl3): d = 1.33 (3 H, t,
3J = 7.2 Hz, Me), 4.31 (2 H, q, 3J = 7.2 Hz, OCH2), 6.07 (2
H, s, NCH2), 7.24–7.32 (3 H, m, 3 CH), 7.38 (2 H, d, 3J = 7.4
Hz, 2 CH), 7.45 (2 H, t, 3J = 7.2 Hz, CH), 7.51 (1 H, d,
3J = 7.2 Hz, CH), 7.63 (1 H, s, CH), 8.34 (2 H, d, 3J = 7.2 Hz,
2 CH) ppm. 13C NMR (500.1 MHz, CDCl3): d = 14.0 (Me),
50.4 (CH2), 61.9 (OCH2), 120.8 (CH), 127.7 (2 CH), 128.1
(3 CH), 128.6 (2 CH), 129.5 (3 CH), 131.8 (C), 136.5 (C),
136.8 (C), 158.3 (C=O), 169.3 (C=N), 174.8 (C=O). MS:
m/z (%) = 366 (10) [M+], 293 (75), 261 (62), 105 (100), 91
(82), 45 (84). Anal. Calcd (%) for C20H18N2O3S (366.43): C,
65.56; H, 4.95; N, 7.64. Found: C, 65.63; H, 4.99; N, 7.68.
All other compounds 5b–j gave satisfactory analytical and
spectroscopic data.
Scheme 2
In conclusion, we have described a convenient route to
functionalized 1,3-thiazole-4(3H)-carboxylates through a
four-component reaction of ammonium thiocyanate, acid
chlorides, primary amines, and ethyl bromopyruvate. The
advantage of the present procedure is that the reaction is
performed by simple mixing of the starting materials. The
procedure described here provides an acceptable one-pot
method for the preparation of functionalized 1,3-thiazole-
4(3H)-carboxylates.
References and Notes
(1) Breslow, R. J. Am. Chem. Soc. 1958, 80, 3719.
(2) Miwatashi, S.; Arikawa, Y.; Kotani, E.; Miyamoto, M.;
Naruo, K.-I.; Kimura, H.; Tanaka, T.; Asahi, S.; Ohkawa, S.
J. Med. Chem. 2005, 48, 5966.
(3) Papadopoulou, C.; Geronikaki, A.; Hadjipavlou-Litina, D.
Farmaco 2005, 60, 969.
(4) Kumar, Y.; Green, R.; Borysko, K. Z.; Wise, D. S.; Wotring,
L. L.; Townsend, L. B. J. Med. Chem. 1993, 36, 3843.
Synlett 2008, No. 11, 1631–1632 © Thieme Stuttgart · New York