Efficient synthesis of functionalized thiazoles from acid chlorides, tetramethylthiourea, ethyl bromopyruvate, and ammonium thiocyanate

Article abstract of DOI:10.1002/hlca.200890127

An efficient synthesis of ethyl 2-(dimethylamino)-1,3-thiazole-4- carboxylates is described via a four-component reaction between acid chlorides, tetramethylthiourea, ethyl bromopyruvate, and ammonium thiocyanate.

Full text of DOI:10.1002/hlca.200890127

Helvetica Chimica Acta – Vol. 91 (2008)
1177
Efficient Synthesis of Functionalized Thiazoles from Acid Chlorides,
Tetramethylthiourea, Ethyl Bromopyruvate, and Ammonium Thiocyanate
by Issa Yavari*, Zinatossadat Hossaini, Samereh Seyfi, and Faezeh Shirgahi-Talari
Chemistry Department, Tarbiat Modares University, P.O. Box 14115-175, Tehran, Iran
(phone: þ 98-21-82883465; fax: þ 98-21-82886544; e-mail: yavarisa@modares.ac.ir)
An efficient synthesis of ethyl 2-(dimethylamino)-1,3-thiazole-4-carboxylates is described via a four-
component reaction between acid chlorides, tetramethylthiourea, ethyl bromopyruvate, and ammonium
thiocyanate.
Introduction. – Thiazoles occupy a prominent position among heterocycles. In
nature, the thiazolium ring is the chemically active center in the coenzyme derived from
vitamin B1 (thiamin). A large number of thiazoles obtained from microbial and marine
origins exhibit important biological effects such as antitumor, antifungal, antibiotic, and
antiviral activities [1]. Synthetic thiazoles also show a wide variety of biological activity
[2], while others have found application as liquid crystals [3] and cosmetic sunscreens
[4]. The classical method for the synthesis of thiazoles is the Hantzsch process, in which
an a-haloketone is condensed with a thioamide [5]. This method gives excellent yields
for simple thiazoles; however, for some substituted examples, low yields have been
reported as a result of dehalogenation of the a-haloketone during the reaction [4][6].
As part of our current studies on the development of new routes in heterocycle
synthesis [7 – 10], we report an efficient synthetic route to functionalized thiazoles.
Results and Discussion. – The reaction of ammonium thiocyanate (1), acid
chlorides 2, ethyl bromopyruvate (3), and tetramethylthiourea (4) gave ethyl 2-
(dimethylamino)-5-(methylcarbamothioyl)-1,3-thiazole-4-carboxylates 5 in 78 – 90%
yields (Scheme 1).
The structures of compounds 5a – 5g were apparent from their MS spectra, which in
each case displayed the molecular-ion peak at the appropriate m/z values. The IR, 1H-
and 13C-NMR spectra are in agreement with the proposed structures. For example, the
1H-NMR spectrum of 5a exhibited a triplet at 1.32 (J ¼ 7.2) and a quartet at 4.23 (J ¼
7.2) for the ethoxycarbonyl group, and three singlets for MeN groups at 3.27, 3.32, and
3.46 ppm. The C¼O and C¼S group resonances in the 13C-NMR spectrum of 5a
appeared at 167.1 (C¼O), 177.4 (C¼O), and 208.2 (C¼S) ppm. The mass spectrum of
5a displayed the molecular-ion peak at m/z 377.
Mechanistically, it is conceivable that the reaction involves the initial formation of
intermediate 6 from 3 and 4. The elimination of HBr generates 7, which undergoes a
nucleophilic attack at 8 to give 9. Finally, H2O elimination of 10 produces 5 (Scheme 2).
ꢀ 2008 Verlag Helvetica Chimica Acta AG, Zürich

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Helvetica Chimica Acta – Vol. 91 (2008)
Scheme 1
Scheme 2
In conclusion, we have described a convenient route to functionalized 1,3-thiazoles
from ammonium thiocyanate, acid chlorides, tetramethyl thiourea, and ethyl bromo-
pyruvate. The advantage of the present procedure is that the reaction is performed

Helvetica Chimica Acta – Vol. 91 (2008)
1179
under neutral conditions, and the starting materials can be used without any activation
or modification. The simplicity of the present procedure makes it an interesting
alternative to other approaches. The procedure described here provides an acceptable
one-pot method for the preparation of functionalized thiazols.
Experimental Part
General. All starting materials were obtained from Fluka and were used without further purification.
M.p.: Electrothermal-9100 apparatus. IR Spectra: Shimadzu IR-460 spectrometer; in cmꢀ1 1H- and
.
13C-NMR Spectra: Bruker DRX-500 Avance instrument, in CDCl3 at 500.1 and 125.7 MHz, resp.; d in
ppm, J in Hz. EI-MS (70 eV): Finnigan MAT-8430 MS spectrometer; in m/z. Elemental analyses (C, H,
N): Heraeus CHN-O-Rapid analyzer.
General Procedure for the Preparation of Compounds 5. To a stirred soln. of 0.15 g of NH4SCN
(2 mmol) in 15 ml of acetone was added acid chloride (2 mmol), and the mixture was refluxed for 5 min.
Then, a soln. of 0.39 g of 3 (2 mmol) in acetone (10 ml) was added gently. Finally, 0.26 g of 4 (2 mmol)
was added slowly at r.t. The mixture was then stirred for 12 h. The solvent was removed under reduced
pressure, and the residue was purified by column chromatography (SiO2; hexane/AcOEt 10 :1) to afford
the pure title compounds.
Ethyl 5-[(Benzoylmethylamino)thioxomethyl]-2-(dimethylamino)-1,3-thiazole-4-carboxylate (5a).
Yield: 0.68 g (90%). Orange powder. M.p. 122 – 1248. IR (KBr): 1721, 1653, 1510, 1372, 1124.
1H-NMR: 1.32 (t, 3J ¼ 7.2, Me); 3.27 (s, MeN); 3.32 (s, MeN); 3.46 (s, MeN); 4.23 (q, 3J ¼ 7.2, CH2O); 7.43
(t, 3J ¼ 7.2, 2 arom. H); 7.53 (t, 3J ¼ 7.5, arom. H); 7.80 (d, 3J ¼ 7.5, 2 arom. H). 13C-NMR: 14.1 (MeN); 36.4
(MeN); 36.9 (MeN); 38.7 (MeN); 62.2 (CH2O); 128.4 (2 CH); 128.6 (2 CH); 129.5 (C); 130.1 (CH);
.
133.5 (C); 153.9 (C); 158.2 (C); 167.1 (C¼O); 177.4 (C¼O); 208.2 (C¼S). EI-MS: 377 (15, Mþ ), 272
(60), 243 (62), 223 (45), 134 (54), 105 (100), 45 (64). Anal. calc. for C17H19N3O3S2 (377.74): C 54.09, H
5.07, N 11.13; found: C 54.10, H 5.05, N 11.10.
Ethyl 2-(Dimethylamino)-5-{[methyl(4-methylbenzoyl)amino]thioxomethyl}-1,3-thiazole-4-carboxy-
late (5b). Yield: 0.66 g (85%). Yellow powder. M.p. 130 – 1328. IR (KBr): 1720, 1655, 1512, 1369,
1022. 1H-NMR: 1.41 (t, J ¼ 7.2, Me); 2.42 (s, Me); 3.13 (s, MeN); 3.26 (s, MeN); 3.53 (s, MeN); 4.42 (q,
J ¼ 7.2, CH2O); 7.30 (d, J ¼ 7.8, 2 arom. H); 7.52 (d, J ¼ 7.8, 2 arom. H). 13C-NMR: 13.9 (Me); 22.9 (Me);
36.4 (MeN); 38.8 (MeN); 43.1 (MeN); 62.2 (CH2O); 129.1 (2 CH); 129.5 (C); 130.1 (2 CH); 130.8 (C);
.
144.3 (C); 153.9 (C); 160.2 (C); 167.7 (C¼O); 177.4 (C¼O); 208.7 (C¼S). EI-MS: 391 (5, Mþ ), 272
(36), 243 (85), 192 (58), 148 (76), 119 (100), 45 (48). Anal. calc. for C18H21N3O3S2 (391.50): C 55.22, H
5.41, N 10.73; found: C 55.20, H 5.40, N 10.70.
Ethyl 2-(Dimethylamino)-5-{[methyl(4-nitrobenzoyl)amino]thioxomethyl}-1,3-thiazole-4-carboxy-
late (5c). Yield: 0.70 g (83%). Red powder. M.p. 155 – 1578. IR (KBr): 1715, 1679, 1599, 1369, 1176,
1116. 1H-NMR: 1.39 (t, J ¼ 7.2, Me); 3.13 (s, MeN); 3.28 (s, MeN); 3.51 (s, MeN); 4.43 (q, J ¼ 7.2, CH2O);
8.03 (d, J ¼ 8.1, 2 arom. H); 8.32 (d, J ¼ 8.1, 2 arom. H). 13C-NMR: 14.0 (Me); 35.9 (MeN); 37.0 (MeN);
38.8 (MeN); 62.2 (CH2O); 123.6 (C); 123.8 (2 CH); 129.3 (2 CH); 131.1 (C); 137.9 (C); 150.3 (C); 153.9
.
(C); 167.4 (C¼O); 177.4 (C¼O); 208.3 (C¼S). EI-MS: 422 (10, Mþ ), 272 (66), 223 (45), 199 (62), 179
(64), 150 (100); 45 (84). Anal. calc. for C17H18N4O5S2 (422.47): C 48.33, H 4.29, N 13.26; found: C 48.30, H
4.30, N 13.25.
Ethyl 5-{[(4-Bromobenzoyl)methylamino]thioxomethyl}-2-(dimethylamino)-1,3-thiazole-4-carboxy-
late (5d). Yield: 0.71 g (78%). Red powder. M.p. 152 – 1548. IR (KBr): 1762, 1724, 1664, 1579, 1369, 1101.
1H-NMR: 1.42 (t, J ¼ 7.2, Me); 3.05 (s, MeN); 3.14 (s, MeN); 3.47 (s, MeN); 4.38 (q, J ¼ 7.2, CH2O); 7.59
(d, J ¼ 7.8, 2 arom. H); 7.69 (d, J ¼ 7.8, 2 arom. H). 13C-NMR: 14.0 (Me); 36.4 (MeN); 36.9 (MeN); 38.8
(MeN); 62.2 (CH2O); 127.9 (C); 128.9 (2 CH); 129.1 (C); 129.4 (2 CH); 132.9 (C); 150.3 (C); 153.9 (C);
.
167.7 (C¼O); 177.4 (C¼O); 208.2 (C¼S). EI-MS: 456 (10, Mþ ), 454 (5), 272 (44), 257 (36), 243 (60),
213 (65), 184 (100), 45 (84). Anal. calc. for C17H18BrN3O3S2 (456.37): C 44.74, H 3.98, N 9.21; found: C
44.70, H 3.95, N 9.20.
Ethyl 5-{[(4-Chlorobenzoyl)methylamino]thioxomethyl}-2-(dimethylamino)-1,3-thiazole-4-carboxy-
late (5e). Yield: 0.67 g (82%). Yellow powder. M.p. 165 – 1678. IR (KBr): 1759, 1721, 1665, 1584, 1354,

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Helvetica Chimica Acta – Vol. 91 (2008)
1027. 1H-NMR: 1.42 (t, J ¼ 7.2, Me); 3.05 (s, MeN); 3.14 (s, MeN); 3.47 (s, MeN); 4.38 (q, J ¼ 7.2, CH2O);
7.59 (d, J ¼ 7.5, 2 arom. H); 7.69 (d, J ¼ 7.5, 2 arom. H). 13C-NMR: 14.3 (MeN); 35.7 (MeN); 37.0 (MeN);
38.8 (MeN); 62.4 (CH2O); 128.4 (2 CH); 129.2 (C); 130.1 (2 CH); 132.5 (C); 136.4 (C); 150.4 (C); 154.0
.
(C); 168.2 (C¼O); 177.5 (C¼O); 208.4 (C¼S). EI-MS: 411 (15, Mþ ), 243 (34), 212 (80), 199 (46), 168
(86), 139 (100), 45 (36). Anal. calc. for C17H18ClN3O3S2 (411.92): C 49.57, H 4.40, N 10.20; found: C 49.55,
H 4.40, N 10.21.
Ethyl 2-(Dimethylamino)-5-{[(2,2-dimethyl-1-oxopropyl)methylamino]thioxomethyl}-1,3-thiazole-
4-carboxylate (5f). Yield: 0.59 g (83%). Red powder. M.p. 134 – 1368. IR (KBr): 1745, 1719, 1660,
1
1574, 1299, 1010. H-NMR: 1.27 (t, J ¼ 7.4, Me); 1.41 (s, 3 Me); 2.98 (s, MeN); 3.07 (s, MeN); 3.54 (s,
MeN); 4.39 (q, J ¼ 7.4, CH2O). 13C-NMR: 13.9 (Me); 27.0 (3 Me); 36.4 (Me); 38.7 (Me); 39.0 (Me); 39.7
(C); 62.2 (CH2O); 128.7 (C); 135.4 (C); 153.9 (C); 167.1 (C¼O); 177.4 (C¼O); 208.4 (C¼S). EI-MS: 357
.
(5, Mþ ), 313 (58), 300 (34), 283 (46), 57 (100), 44 (36). Anal. calc. for C15H23N3O3S2 (357.48): C 50.40, H
6.48, N 11.75; found: C 49.95, H 6.40, N 11.68.
Ethyl 2-(Dimethylamino)-5-{[methyl(1-oxopropyl)amino]thioxomethyl}-1,3-thiazole-4-carboxylate
(5g). Yield: 0.58 g (85%). Red powder. M.p. 138 – 1408. IR (KBr): 1758, 1715, 1659, 1581, 1255, 1009.
1H-NMR: 1.12 (t, J ¼ 7.6, Me); 1.43 (t, J ¼ 7.2, Me); 2.61 (q, J ¼ 7.6, CH2N); 3.08 (s, MeN); 3.12 (s, MeN);
3.52 (s, MeN); 4.42 (q, 3J ¼ 7.2, CH2O). 13C-NMR: 13.9 (Me); 14.0 (Me); 32.4 (CH2N); 35.8 (MeN); 36.4
(MeN); 37.0 (MeN); 62.2 (CH2O); 132.4 (C); 153.9 (C); 160.3 (C); 167.2 (C¼O); 177.4 (C¼O); 208.2
.
(C¼S). EI-MS: 343 (10, Mþ ), 299 (68), 272 (58), 57 (100), 44 (86). Anal. calc. for C13H19N3O3S2
(329.43): C 47.40, H 5.81, N 12.76; found: C 47.32, H 5.75, N 12.70.
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ReceivedFebruary 20, 2008