Synthesis of 2-Aminothiazole Derivatives in Easy Two-Step,
Błażej Dziuk, Janusz B. Kyzioł, Jacek Zaleski, Krzysztof Ejsmont, and Bartosz Zarychta
Institute of Chemistry, University of Opole, 45-052 Opole, ul. Oleska 48, Poland
Received July 24, 2017
Published online 12 January 2018 in Wiley Online Library (wileyonlinelibrary.com).
Condensation of brominated ethyl acetoacetate with thiourea gives 2-amino-5-ethoxycarbonyl-4-
methylthiazole (1) and ethyl α-(2-amino-4-thiazolyl)acetate (2), indicating that bromination of the substrate
occurs on both sides of the carbonyl group. X-ray diffraction studies indicate weak hydrogen bonds of the
amino groups, which are not observed in the IR spectra. The 1 molecule adopts planar S,O-anti conformation
in the crystal lattice, whereas the methylene group, insulating thiazole ring and the ester group in 2 molecule,
makes it more ﬂexible and makes the ester group nearly perpendicular to the thiazole ring. The small devi-
ations of the bond lengths and angles indicate mesomeric interaction between complementary substituents
across the thiazole ring.
J. Heterocyclic Chem., 55, 763 (2018).
Thiazoles play an important role in designing new
compounds of medical importance with their great
usefulness owing to a very wide variety of applications
ranging from bacteriostatic agents, antibiotics, and
cytotoxic, antifungal, and inhibitory activities  to
central nervous systems active agents . In view of the
importance of thiazoles and their derivatives, several
methods for the synthesis of thiazole derivatives were
developed by Hantzsch , Zoltewicz and Deady ,
Sammes , Elederﬁeld , and Pola . The most
wildly used method is Hantzsch’s synthesis , who
originated it in 1887, involving the reaction of α-halo
carbonyl compounds with thioureas or thioamides .
Condensation of α-halo carbonyl compounds with
thiourea is the most general method of preparation of 2-
aminothiazole derivatives [9,10]. In such a way, 2-amino-
5-ethoxycarbonyl-4-methylthiazole (1) was obtained for
the ﬁrst time by Hantzsch  (Scheme 1).
Another method of 1 preparation involves condensation
of rhodanamine (H
N–SCN) with the 10-fold excess of
ethyl acetoacetate in a melt at 100–120°C .
Condensation of ethyl acetoacetate with formamidine
disulﬁde hydrobromide was performed analogously,
providing 1 in 57–62% yield . Carbonyl compounds
and thiourea can be combined directly into the thiazole
ring using bromine as the condensing agent .
We have prepared 1 in a simple two-step, one-pot
reaction. Ethyl acetoacetate was brominated in the carbon
tetrachloride solution. The ketoester forms its enol
tautomer in a signiﬁcant amount ; hence, the addition–
elimination process occurs smoothly at room temperature.
The solvent and hydrogen bromide were removed by
distillation under reduced pressure, and the condensation
with thiourea was carried out in an aqueous solution. The
crude product was isolated by neutralization of the cooled
reaction mixture and puriﬁed by crystallization from
toluene. The pure 1 was obtained in a moderate yield only
owing to the formation of some side products. The gas
chromatography–mass spectrometry (MS) analysis of the
mother liquors indicated the presence of the signiﬁcant
amount of another compound, which was probably
the isomer of 1, namely, 2-amino-4-ethoxycarbonyl-5-
methylthiazole. Its formation can be rationalized,
assuming that the amino groups of thiourea display also
some nucleophilic properties and may substitute labile
bromine atom. However, the spectral data did not agree
with the hypothesis of the structure. Our aim was to isolate
both products and compare their structure using
spectroscopic methods and X-ray diffraction studies.
RESULTS AND DISCUSSION
Condensation of brominated ethyl acetoacetate with
thiourea gave expected 2-amino-5-ethoxycarbonyl-4-
methylthiazole (1) and small amount of its isomer,
namely, ethyl (2-amino-4-thiazolyl)acetate (2) (Scheme 2).
Obviously, enolization of the keto group facilitates
bromination of the substrate, but the C–C double bond
may be formed on both sides of the enol hydroxyl.
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