Novel one-pot process for the synthesis of ethyl 2-imino-4-methyl-2,3-dihydrothiazole-5-carboxylates

Article abstract of DOI:10.2298/JSC141021124B

A facile one-pot, two-step process for the synthesis of ethyl 2-imino-4-methyl-2,3-dihydrothiazole-5-carboxylates via the cyclocondensation of ethyl 3-oxo-2-thiocyanatobutanoate with a variety of hydrazine and hydrazide derivatives was developed. Ethyl 3-

Full text of DOI:10.2298/JSC141021124B

J. Serb. Chem. Soc. 80 (4) 453–458 (2015)
JSCS–4728
UDC 547–304.2+547.556.5+547.298.61+
+661.8’038+66.095.3.095.252
Short communication
SHORT COMMUNICATION
Novel one-pot process for the synthesis of ethyl 2-imino-4-
methyl-2,3-dihydrothiazole-5-carboxylates
-
HAMID BEYZAEI*, REZA ARYAN and HADI MOGHADAS
Department of Chemistry, Faculty of Science, University of Zabol, Zabol 9861335856, Iran
(
Received 21 October, revised 13 December, accepted 17 December 2014)
Abstract: A facile one-pot, two-step process for the synthesis of ethyl 2-imino-
-
4-methyl-2,3-dihydrothiazole-5-carboxylates via the cyclocondensation of
ethyl 3-oxo-2-thiocyanatobutanoate with a variety of hydrazine and hydrazide
derivatives was developed. Ethyl 3-oxo-2-thiocyanatobutanoate itself was syn-
thesized as an intermediate from the reaction of ethyl 2-chloroacetoacetate with
potassium thiocyanate (KSCN). The molecular structures of these newly syn-
thesized compounds were elucidated based on elemental analysis and spectral
data.
Keywords: three-component reaction; thiocyanation; thiazole derivatives; cyc-
locondensation; hydrazines; hydrazides.
INTRODUCTION
Thiazoles are of eminent importance because of their potential as bioactive
1,2
compounds and versatile building blocks for natural products and pharma-
3
,4
ceuticals. Thiazole heterocycles are important subunits in many complex nat-
ural compounds and drugs, e.g., vitamin B , epothilones, thiostrepton, nizatidine
1
(
ulcer therapeutic), ritonavir (a potent inhibitor of HIV protease, Fig. 1) and
thiamine pyrophosphate (TPP, a coenzyme that is part of the Krebs cycle in the
3
–6
process of cellular respiration).
A tetrahydrothiazole also appears in the
skeleton of penicillin, which is one of the first and most important broad spec-
trum antibiotics. Thiazole derivatives display a wide range of biological acti-
vities, such as cardiotonic, fungicidal, sedative, anesthetic, bactericidal and anti-
7
–12
-
inflammatory.
Furthermore, there are many other applications of thiazole
1
3,14
derivatives, for example in liquid crystals or cosmetics (sunscreens).
The synthesis of thiazole derivatives is important because of their wide range
of pharmaceutical and biological properties. Many methods have been developed
*
Corresponding author. E-mail: hbeyzaei@yahoo.com
doi: 10.2298/JSC141021124B
4
53
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4
54
BEYZAEI, ARYAN and MOGHADAS
for the construction of thiazole ring systems. One classical and widely used
method is the condensation of α-haloketones with thioamide derivatives, which is
1
5–17
known as the Hantzsch reaction.
Another efficient method is the intro-
duction of substituents onto a thiazole core structure through Stille coupling,
1
8
which involves the use of organostannane intermediates. In recent years, a new
and frequently encountered method for thiazole synthesis is the conversion of
thiazoline derivatives through the use of dehydrogenating reagents, such as sul-
1
9–26
fur, KMnO , Cu(I)/Cu(II)/peroxide oxidation, MnO , NaH/DBU, etc.
4
2
Fig. 1. Thiazoles as part of some natural compounds and drugs.
These findings prompted the present synthesis of new ethyl 2-imino-4-
methyl-2,3-dihydrothiazole-5-carboxylates. These synthesized compounds were
-
characterized by NMR and IR spectral data, and elemental analysis data.
EXPERIMENTAL
All chemicals and solvents were purchased from Merck and TCI Chemical Companies
and were used without purification. All yields refer to isolated products and are expressed in
%
. Melting points were recorded on a Kruss type KSP1N melting point meter and are
-
1
uncorrected. The IR spectra of the products in the range 400–4,000 cm were recorded on a
Bruker Tensor-27 FT-IR spectrometer and only noteworthy absorptions are listed. The H-
and 13C-NMR spectra of DMSO-d solutions were recorded on a Bruker FT-NMR Ultra
1
6
Shield-400 spectrometer with residual protons of the solvent as internal standard (2.50 ppm
1
13
for H and 39.48 ppm for C). Elemental analyses were performed for C, H, N and S on a
Thermo Finnigan Flash EA microanalyzer. Monitoring of the progress of the reactions and the
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SYNTHESIS OF SUBSTITUTED 2,3-DIHYDROTHIAZOLE-5-CARBOXYLATES
455
purity of the products were affected by TLC on alufoil plates pre-coated with silica gel (60,
Merck); the eluent was CHCl :CH OH, 9:1 and visualization was with I vapor.
3
3
2
Physical, analytical and spectral data of the synthesized compounds are given in Sup-
plementary material to this paper.
General procedure for the synthesis of ethyl 2-imino-4-methyl-2,3-dihydrothiazole-5-
carboxylates (4a–f)
A suspension of ethyl 2-chloroacetoacetate (1, 1.65 g, 10 mmol) and potassium thio-
cyanate (KSCN) (0.97 g, 10 mmol) in acetonitrile (10 mL) was stirred at room temperature for
2
h. Then, hydrazine or hydrazide derivatives 3a–f were added dropwise to the reaction
mixture and the mixture was stirred for a further 1 h at the same temperature before it was
heated under reflux for 2.5–5 h (2.5 h for 4a and b; 4 h for 4c and 5h for 4d–f). The reaction
mixture was cooled to room temperature, the precipitate was filtered off, and washed with
water (10 mL) and ethanol (10 mL), dried in air, and recrystallized from methanol, to give the
pure products 4a–f as white, yellow or red crystals.
RESULTS AND DISCUSSION
Ethyl 2-imino-4-methyl-2,3-dihydrothiazole-5-carboxylates 4a–f were pre-
pared in a simple and facile one-pot, two-step procedure. First, ethyl 2-chloro-
acetoacetate (1) was reacted with potassium thiocyanate (KSCN) in acetonitrile
as a solvent at room temperature for 2 h to give ethyl 3-oxo-2-thiocyanatobuta-
noate (2) as an intermediate. Then, treatment of this compound with various hyd-
razine or hydrazide derivatives (3a–f) under reflux for 2.5–5 h gave new thia-
zoles 4a–f in 48–83 % yields after recrystallization from methanol (Scheme 1).
The structures of all products are presented in Table I.
Scheme 1. Total synthesis of thiazole derivatives 4a–f.
A plausible mechanism is depicted in Scheme 2 for the formation of these
compounds. As shown, first, ethyl 3-oxo-2-thiocyanatobutanoate (2) as an inter-
mediate was probably produced from the substitution reaction between ethyl
2
-chloroacetoacetate (1) and potassium thiocyanate (KSCN). Then, condensation
of compound 2 with hydrazine and hydrazide derivatives 3a–f generated inter-
mediates 3′a–f or 3″a–f. Finally, ethyl 2-imino-4-methyl-2,3-dihydrothiazole-5-
-carboxylates 4a–f were afforded from intramolecular addition reactions of inter-
mediates 3″a–f by attack of the NH group to the carbon atom of the C≡N bond.
Note that in this multistep synthesis, none of the likely key intermediates was
isolated.
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4
56
BEYZAEI, ARYAN and MOGHADAS
TABLE I. Synthesis of thiazole derivatives 4a–f
No.
Product
R
H
Reagent 3a–f
Hydrazine
Yield, % M.p., °C
4a
50
285–286
4
b
c
C H
Phenylhydrazine
55
83
280–281
Decomp.)
6
5
(
4
2,4-[NO ] -C H 2,4-Dinitrophe-
218–219
2
2
6 3
nylhydrazine
(Decomp.)
4
d
e
C H CO
Benzhydrazide
68
48
200–201
6
5
4
4-OH-C H CO 4-Hydroxybenz-
185–186
179–180
6
4
hydrazide
4
f
CH CO
Acetohydrazide
60
3
The structural assignments of compounds 4a–f were based on their anal-
1
ytical and spectral data. The H-NMR spectra of compounds 4a–f showed triplet
and quartet signals due to methyl and methylene protons included in the ethoxy
group within δ 1.23–1.30 and 4.15–4.27 ppm (J ≈ 7.1 Hz), signals due to the
methyl and –NH– groups of the thiazole ring within δ 1.91–2.55 and 10.02–11.44
Scheme 2. The proposed mechanism of formation of products 4a–f.
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SYNTHESIS OF SUBSTITUTED 2,3-DIHYDROTHIAZOLE-5-CARBOXYLATES
457
ppm, respectively, and signals within δ 7.81–11.00 ppm belonging to the –NNH–
1
3
groups of compounds 4b–f. The C-NMR spectra of the products exhibited
signals within δ 14.00–14.44, 59.67–62.81 and 162.44–169.91 ppm attributed to
methyl, methylene and carbonyl carbons, respectively, included in the –CO Et
2
group, signals within δ 11.31–22.41, 106.08–107.95, 161.35–163.03 and 157.06–
–
161.58 ppm, attributed to the –C=CCH , –C=CCH , –C=CCH and –C=NH
3 3 3
carbons, respectively, signals within δ 165.11–167.73 ppm belonging to the car-
bonyl carbons adjacent to the –NH– groups of compounds 4d–f. The FT-IR spec-
–
1
tra of 4a–f in KBr disks showed absorption bands within ν 3305–3467 cm
–
1
corresponding to –NH– groups, 1647–1715 cm belonging to carbonyl groups,
601–1666 cm belonging to imine groups and 1406–1611 cm–1 attributed to
–
1
1
the –C=C– bonds. All this evidence plus microanalytical data strongly supports
the formation of all products.
CONCLUSIONS
In summary, several new ethyl 2-imino-4-methyl-2,3-dihydrothiazole-5-car-
boxylates were synthesized in a one-pot, two-step process from the cyclo-
condensation of ethyl 3-oxo-2-thiocyanatobutanoate as an intermediate with
various hydrazines and hydrazides, which constitute potential precursors for the
synthesis of various biological and pharmaceutical compounds.
SUPPLEMENTARY MATERIAL
Physical, analytical and spectral data of the synthesized compounds are available electro-
nically from http://www.shd.org.rs/JSCS/, or from the corresponding author on request.
Acknowledgments. The authors would like to thank Mrs. Marzieh Akbari for recording
the NMR spectra.
И З В О Д
НОВ ПОСТУПАК СИНТЕЗЕ ЕТИЛ-2-ИМИНО-4-МЕТИЛ-2,3-ДИХИДРОТИАЗОЛ-5-
-КАРБОКСИЛАТА У ЈЕДНОМ РЕАКЦИОНОМ КОРАКУ
HAMID BEYZAEI, REZA ARYAN и HADI MOGHADAS
Department of Chemistry, Faculty of Science, University of Zabol, Zabol 9861335856, Iran
Развијен је нов поступак синтезе етил-2-имино-4-метил-2,3-дихидротиазол-5-кар-
боксилата, у једном реакционом кораку циклокондензације етил-3-оксо-2-тиоцијанато-
бутаноата и хидразина или хидразинских деривата. Полазно једињење етил-3-оксо-2-
-
(
тиоцијанатобутаноат синтетисан је из етил-2-хлорацетата и калијум-тиоцијаната
KSCN). Структура добијених једињења одређена је на основу резултата спектроскопске
и елементалне анализе.
(
Примљено 21. октобра, ревидирано 13. децембра, прихваћено 17. децембра 2014)
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4
58
BEYZAEI, ARYAN and MOGHADAS
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A. Kiryanov, P. Sampson, A. J. Seed, J. Org. Chem. 66 (2001) 7925; c) A. Mori, A.
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J. Serb. Chem. Soc. 80 (4) S119–S121 (2015)
Supplementary material
SUPPLEMENTARY MATERIAL TO
Novel one-pot process for the synthesis of ethyl 2-imino-4-
methyl-2,3-dihydrothiazole-5-carboxylates
-
HAMID BEYZAEI*, REZA ARYAN and HADI MOGHADAS
Department of Chemistry, Faculty of Science, University of Zabol, Zabol 9861335856, Iran
J. Serb. Chem. Soc. 80 (4) (2015) 453–458
PHYSICAL, ANALYTICAL AND SPECTRAL DATA OF THE SYNTHESIZED
COMPOUNDS
Ethyl 3-amino-2-imino-4-methyl-2,3-dihydrothiazole-5-carboxylate (4a).
Yield: 50 %; white crystals; m.p.: 285–286 °C; Anal. Calcd. for C H N O S: C,
7
11 3 2
4
1
1.78; H, 5.51; N, 20.88; S, 15.93 %. Found: C, 41.82; H, 5.56; N, 20.86, S,
5.85 %; IR (KBr, cm ): 1585 (C=C stretching of thiazole ring), 1623 (C=N
–
1
stretching of imine group), 1693 (C=O stretching of CO Et group), 3467, 3434
2
1
(
NH stretching of imine and primary amine groups); H-NMR (400 MHz,
DMSO-d , δ / ppm): 1.24 (3H, t, J = 7.1 Hz, CH ), 2.07 (3H, s, =CCH ), 4.16
6
3
3
(
2H, q, J = 7.1 Hz, OCH ), 7.91 (2H, s, NH , D O exchangeable), 10.16 (1H, s,
2 2 2
1
3
NH, D O exchangeable); C-NMR (100 MHz, DMSO-d , δ / ppm): 169.91
2
6
(
C=O), 161.32 (=CCH ), 159.99 (C=NH), 106.65 (C=CCH ), 59.73 (OCH ),
3 3 2
1
9.91 (C=CCH ), 14.44 (CH CH ).
3 2 3
Ethyl 2-imino-4-methyl-3-(phenylamino)-2,3-dihydrothiazole-5-carboxylate
4b). Yield: 55 %; white crystals; Decomp. 280–281 °C; Anal. Calcd. for
C H N O S: C, 56.30; H, 5.45; N, 15.15; S, 11.56 %. Found: C, 56.24; H,
(
1
3 15 3 2
–
1
5
.52; N, 15.18, S, 11.48 %; IR (KBr, cm ): 1406, 1545 (C=C stretching of
aromatic ring), 1611 (C=C– stretching of thiazole ring), 1666 (C=N stretching of
imine group), 1709 (C=O stretching of CO Et group), 3349 (NH stretching of
2
1
imine and secondary amine); H-NMR (400 MHz, DMSO-d , δ / ppm): 1.30
6
(
3H, t, J = 7.1 Hz, CH ), 2.09 (3H, s, =CCH ), 4.27 (2H, q, J = 7.1 Hz, OCH ),
3 3 2
7
.43, 7.72 (3H, m, 2H, d, J = 10.1 Hz, aromatic), 7.81 (1H, s, NHPh, D O
2
1
3
exchangeable), 10.06 (1H, s, C=NH, D O exchangeable); C-NMR (100 MHz,
2
DMSO-d , δ / ppm): 162.44 (C=O), 161.44 (=CCH ), 157.06 (C=NH), 145.85,
6
3
1
30.72, 123.05, 115.79 (aromatic), 106.93 (C=CCH ), 60.96 (OCH ), 17.31
3 2
(
=CCH ), 14.13 (CH CH ).
3 2 3
*
Corresponding author. E-mail: hbeyzaei@yahoo.com
S119
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S120
BEYZAEI, ARYAN and MOGHADAS
Ethyl 3-((2,4-dinitrophenyl)amino)-2-imino-4-methyl-2,3-dihydrothiazole-5-
carboxylate (4c). Yield: 83 %; red crystals; Decomp. 218–219 °C; Anal. Calcd.
for C H N O S: C, 42.51; H, 3.57; N, 19.07; S, 8.73 %. Found: C, 42.55; H,
1
3 13 5 6
–
1
3
.53; N, 19.14, S, 8.67 %; IR (KBr, cm ): 1338, 1427 (N–O stretching of NO
2
group), 1498, 1594 (C=C stretching of aromatic and thiazole rings), 1613 (C=N
stretching of imine group), 1715 (C=O stretching of CO Et group), 3089, 3305
2
1
(
NH stretching of imine and secondary amine); H-NMR (400 MHz, DMSO-d ,
6
δ / ppm): 1.26 (3H, t, J = 7.1 Hz, CH ), 2.55 (3H, s, =CCH ), 4.26 (2H, q, J = 7.1
3
3
Hz, OCH ), 8.30, 8.33, 9.03 (1H, d, J = 2.6 Hz, 1H, d, J = 2.6 Hz, 1H, d, J = 9.3
2
Hz, aromatic), 8.95 (1H, s, NHPh, D O exchangeable), 11.44 (1H, s, C=NH,
2
1
3
D O exchangeable); C-NMR (100 MHz, DMSO-d , δ / ppm): 168.65 (C=O),
2
6
1
1
61.83 (C=CCH ), 159.11 (C=NH), 148.99, 143.07, 138.47, 130.25, 122.79,
3
16.27 (aromatic), 107.95 (C=CCH ), 62.81 (OCH ), 14.00 (CH CH ), 11.31
3
2
2
3
(
=CCH3).
Ethyl
4d). Yield: 68 %; white crystals; m.p.: 200–201 °C; Anal. Calcd. for
3-benzamido-2-imino-4-methyl-2,3-dihydrothiazole-5-carboxylate
(
C H N O S: C, 55.07; H, 4.95; N, 13.76; S, 10.50 %. Found: C, 55.00; H,
1
4 15 3 3
–
1
5
.01; N, 13.79, S, 10.45 %; IR (KBr, cm ): 1463, 1509 (C=C stretching of
aromatic and thiazole rings), 1601 (C=N stretching of imine group), 1647 (C=O
stretching of CONH group), 1669 (C=O stretching of CO Et group), 3442 (NH
2
1
stretching of imine and amide); H-NMR (400 MHz, DMSO-d , δ / ppm): 1.23
6
(
3H, t, J = 7.0 Hz, CH ), 2.12 (3H, s, =CCH ), 4.15 (2H, q, J = 7.0 Hz, OCH ),
3 3 2
7
.53–7.98 (5H, m, aromatic), 10.72 (1H, s, C=NH, D O exchangeable), 11.00
2
1
3
(
1H, s, CONH, D O exchangeable); C-NMR (100 MHz, DMSO-d , δ / ppm):
2
6
1
1
68.47 (CO Et), 165.11 (CONH), 161.35 (=CCH ), 159.72 (C=NH), 132.14,
2 3
31.92, 128.53, 127.60 (aromatic), 106.08 (C=CCH ), 59.67 (OCH ), 16.96
3
2
(
=CCH ), 14.44 (CH CH ).
3 2 3
Ethyl 3-(4-hydroxybenzamido)-2-imino-4-methyl-2,3-dihydrothiazole-5-car-
boxylate (4e). Yield: 48 %; yellow crystals; m.p.: 185–186 °C; Anal. Calcd. for
C H N O S: C, 52.33 %; H, 4.71; N, 13.08; S, 9.98 %. Found: C, 52.39; H,
1
4 15 3 4
–
1
4
.66; N, 13.15, S, 9.90 %; IR (KBr, cm ): 1472, 1506 (C=C– stretching of
aromatic and thiazole rings), 1609 (C=N stretching of imine group), 1674 (C=O
stretching of CONH group), 1702 (C=O stretching of CO Et group), 3419 (NH
2
1
stretching of imine and amide); H-NMR (400 MHz, DMSO-d , δ / ppm): 1.24
6
(
3H, t, J = 7.0 Hz, CH ), 2.16 (3H, s, =CCH ), 4.17 (2H, q, J = 7.0 Hz, OCH ),
3 3 2
6
.93, 7.80 (2H, d, J = 8.2 Hz, 2H, d, J = 8.2 Hz, aromatic), 8.15 (1H, s, OH, D O
2
exchangeable), 10.13 (1H, s, C=NH, D O exchangeable), 10.59 (1H, s, CONH,
2
1
3
D O exchangeable); C-NMR (100 MHz, DMSO-d , δ / ppm): 169.85 (CO Et),
2
6
2
1
1
67.73 (CONH), 163.03 (=CCH ), 161.58 (C=NH), 159.73, 132.32, 129.41,
3
14.93 (aromatic), 106.63 (C=CCH ), 60.40 (OCH ), 22.41 (=CCH ), 14.35
3
2
3
(
CH CH ).
2 3
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_
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SUPPLEMENTARY MATERIAL
S121
Ethyl 3-acetamido-2-imino-4-methyl-2,3-dihydrothiazole-5-carboxylate (4f).
Yield: 60 %; white crystals; m.p.: 179–180 °C; Anal. Calcd. for C H N O S: C,
9
13 3 3
4
1
1
1
4.43; H, 5.39; N, 17.27; S, 13.18 %. Found: C, 44.39; H, 5.37; N, 17.33, S,
3.14 %; IR (KBr, cm ): 1590 (C=C stretching of aromatic and thiazole rings),
616 (C=N stretching of imine group), 1673 (C=O stretching of CONH group),
–
1
703 (C=O stretching of CO Et group), 3253, 3382 (NH stretching of imine and
2
1
amide); H-NMR (400 MHz, DMSO-d , δ / ppm): 1.23 (3H, t, J = 7.1 Hz, CH ),
6
3
1
1
.91 (3H, s, =CCH ), 2.43 (3H, s, COCH ), 4.16 (2H, q, J = 7.1 Hz, OCH ),
3 3 2
0.02 (1H, s, C=NH, D O exchangeable), 10.39 (1H, s, CONH, D O exchange-
2
2
1
3
able); C-NMR (100 MHz, DMSO-d , δ / ppm): 168.99 (CO Et), 167.72
6
2
(
CONH), 161.79 (=CCH ), 161.49 (C=NH), 106.86 (C=CCH ), 60.03 (OCH ),
3 3 2
2
0.45 (=CCH ), 17.29 (COCH ), 14.24 (CH CH ).
3 3 2 3
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________________________________________________________________________________________________________________________
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