Synthesis of 5-arylsubstituted thiazol-4-one acetyl and amino derivatives by the heterocyclization of the products of acrylamide thiocyanatoarylation

Article abstract of DOI:10.1134/S1070363211090271

The heterocyclization of 2-thiocyanato-3-arylpropionamides in acetic anhydride followed by the deacylation of the intermediates formed in an alkaline medium afforded the otherwise difficultly accessible 2- amino-5-benzylthiazol- 4-ones.

Full text of DOI:10.1134/S1070363211090271

ISSN 1070-3632, Russian Journal of General Chemistry, 2011, Vol. 81, No. 9, pp. 1896–1899. © Pleiades Publishing, Ltd., 2011.
Original Russian Text © B.D. Grishchuk, V.S. Baranovskii, 2011, published in Zhurnal Obshchei Khimii, 2011, Vol. 81, No. 9, pp. 1559–1562.
Synthesis of 5-Arylsubstituted Thiazol-4-one Acetyl
and Amino Derivatives by the Heterocyclization
of the Products of Acrylamide Thiocyanatoarylation
B. D. Grishchuk and V. S. Baranovskii
Gnatyuk National Pedagogical University, ul. M. Krivonosa 2, Ternopol’, 46027 Ukraine
e-mail: baranovsky@tnpu.edu.ua
Received September 16, 2010
Abstract—The heterocyclization of 2-thiocyanato-3-arylpropionamides in acetic anhydride followed by the
deacylation of the intermediates formed in an alkaline medium afforded the otherwise difficultly accessible 2-
amino-5-benzylthiazol-4-ones.
DOI: 10.1134/S1070363211090271
Owing to the presence of the sulfur atom in
combination with a nitrile group in the molecule, the
organic thiocyanates are widely used in the synthesis
of heterocyclic compounds [1]. A convenient method
of obtaining such thiocyanates is the anion-arylation of
unsaturated compounds with aromatic diazonium salts
[2, 3].
thiazol-2-yl)acetamides. The latter are easily converted
into 2-amino-5-benzyl-5-methylthiazol-4-ones in an
alkaline medium [6].
Continuing these investigations, in the present work
we examined the heterocyclization of acrylamide
thiocyanatoarylation products [7] into the thiazol-4-
one acetyl and amino derivatives, which are of interest
as potential biologically active substances [8, 9].
Recently the products of acrylonitrile thiocyanato-
arylation and allylisothiocyanate chloroarylation were
used to obtain some substituted thiazoles [4, 5]. By the
example of 2-thiocyanato-2-methyl-3-arylpropan-
amides, the methacrylamide thiocyanatoarylating pro-
ducts, a possibility was demonstrated of their cycliza-
tion to form N-(5-benzyl-5-methyl-4-oxo-4,5-dihydro-
We found that boiling 2-thiocyanato-3-arylpropan-
amides in acetic anhydride yielded 2-acetamido-5-
benzylthiazol-yl acetates I–VIII, which transformed
readily in an alkaline medium into the 2-amino-5-
benzylthiazol-4-ones IX–XVI as follows:
O
O
O
O
CH3
OH _
_Ac_, Δ
Ac2O
NH2
N
N
Δ
S
S
S
N
C
R
R
R
NH2
NH
O
CH3
IХ_ХVI
I_VIII
R = H (I, IX), 2-CH3 (II, X), 3-CH3 (III, XI), 4-CH3 (IV, XII), 2-CH3О (V, XIII), 4-CH3О (VI, XIV), 4-Br (VII, XV), 2,5-
Cl2 (VIII, XVI).
1896

SYNTHESIS OF 5-ARYLSUBSTITUTED THIAZOL-4-ONE ACETYL
1897
Table 1. Yields, melting points, and elemental analysis data of compounds I–XVI
Found, %
Calculated, %
mp, °С
Comp. no. Yield, %a
Formula
(methanol)
N
S
N
S
77
70
74
85
65
74
77
82
–
173
154
114
168
129
156
94
9.74
9.01
11.22
10.43
10.65
10.49
9.90
С14H14N2O3S
С15H16N2O3S
С15H16N2O3S
С15H16N2O3S
С15H16N2O4S
С15H16N2O4S
С14H13BrN2O3S
С14H12Cl2N2O3S
С10H10N2OS
С11H12N2OS
С11H12N2OS
С11H12N2OS
С11H12N2O2S
С11H12N2O2S
С10H9BrN2OS
С10H8Cl2N2OS
9.65
9.20
11.04
10.54
10.54
10.54
10.01
10.01
8.68
I
II
9.27
9.20
III
IV
9.09
9.20
8.59
8.74
V
8.68
10.07
8.80
8.74
VI
7.41
7.59
VII
VIII
IX
204
192
218
244
215
226
245
231
251
7.86
8.88
7.80
8.93
13.64
12.64
12.81
12.79
11.99
11.77
9.72
15.41
14.39
14.69
14.45
13.70
13.61
11.06
11.84
13.58
12.72
12.72
12.72
11.86
11.86
9.82
15.55
14.56
14.56
14.56
13.57
13.57
11.24
11.65
–
X
–
XI
–
XII
XIII
XIV
XV
XVI
–
–
–
–
10.23
10.18
a Yields are quantitative for compounds IX–XVI.
The yields of derivatives I–VIII are 65–85%, and
they convert into the 2-aminothiazol-4-ones IX–XVI
quantitatively. Tables 1, 2 list the yields, melting
points, elemental analysis, and H NMR spectral data
of the synthesized compounds I–XVI.
signals of the methyl protons of acetyl fragments. The
amino protons resonate upfield at 8.85 ppm.
1
1
The presence in the H NMR spectrum of the
cyclization product I of a double number of the signals
of methyl protons in comparison with the heterocycles
based on methacrylamide [7] is due to the fact that it
includes two acetyl fragments, one of which forms the
acetamide moiety.
1
The H NMR spectrum of acetamide I contains the
multiplet signals of phenyl protons at 7.33–7.20 ppm
and the singlet signals of the methylene protons of
benzyl fragment at 3.88 ppm and the methyl protons of
acetyl fragments at 2.27 and 2.09 ppm. The NH-proton
of acetamide moiety is shifted downfield to 7.12 ppm.
In the spectrum of aminothiazole IX there are no
Thus, the cyclization of 2-thiocyanato-3-
arylpropanamides can results in the products of
different structures containing two acetyl fragments.
Me
Me
O
O
O
O
O
N
N
N
S
S
S
Me
O
R
R
R
N
NH
Me
NH
Me
O
O
O
Me
B
C
A
To determine the structure of the heterocyclization
products we recorded the 13C NMR spectrum of
compound IV whose analysis allowed us to exclude
structure A. To choose between structures B and C we
performed a comprehensive analysis of the hetero-
nuclear correlation (HMBC and HMQC) spectra. The
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 81 No. 9 2011

1898
GRISHCHUK, BARANOVSKII
Table 2. 1Н NMR spectral parameters of compounds I–XVI
Chemical shift, δ, ppm
Comp.
no.
Ar
NН (NH2)
12.07s
СН
C(O)CH3
CH2Ar
3.88 s
R
–
7.33–7.20 m (5Н)
7.15 s (4Н)
–
2.27 s, 2.09 s
I
12.08 s
–
–
2.22 s, 2.08 s
3.86 s
2.23 s
2.22 s
2.27 s
3.75 s
3.73 s
–
II
7.21–6.99 m (4Н)
7.09 s (4Н)
12.06 s
2.24 s, 2.10 s
3.85 s
III
IV
12.09 s
–
2.25 s, 2.08 s
3.82 s
7.31–6.94 m (4Н)
7.13 d, 6.86 d (4Н)
7.87 d, 7.66 d (4Н)
7.56–7.27 m (3Н)
7.32–7.18 m (5Н)
7.28–7.00 m (4Н)
7.25–6.97 m (4Н)
7.21–6.99 m (4Н)
7.28–6.89 m (4Н)
7.11 d, 6.82 d (4Н)
7.47 d, 7.19 d (4Н)
7.67–7.31 m (3Н)
12.01 s
–
2.26 s, 2.08 s
3.81 s
V
12.00 s
–
2.27 s, 2.09 s
3.80 s
VI
12.11 s
–
2.26 s, 2.10 s
3.87 s
VII
VIII
IX
12.12 s
–
2.24 s, 2.10 s
4.00 s
–
8.85 br.s.
4.58 d.d
4.55 d.d
4.54 d.d
4.55 d.d
4.57 d.d
4.54 d.d
4.59 d.d
4.62 d.d
–
–
–
–
–
–
–
–
3.38 d.d, 2.88 d.d
3.46 d.d, 2.81 d.d
3.35 d.d, 2.81 d.d
3.32 d.d, 2.85 d.d
3.38 d.d, 2.84 d.d
3.37 d.d, 2.91 d.d
3.31 d.d, 2.93 d.d
3.48 d.d, 3.02 d.d
–
8.99 br.s, 8.75 br.s
8.91 br.s
2.30 s
2.27 s
2.26 s
3.75 s
3.74 s
–
X
XI
8.92 br.s, 8.70 br.s
8.94 br.s, 8.62 br.s
8.88 br.s, 8.65 br.s
8.92 br.s, 8.76 br.s
8.96 br.s
XII
XIII
XIV
XV
XVI
–
full assignment of the signals to the protons and carbon
atoms allowed us to exclude structure B. The found
correlations are listed in Table 3.
as biologically active substances of a broad activity
range.
EXPERIMENTAL
Thus, the heterocyclization of 2-thiocyanato-3-
arylpropanamides is accompanied by the acylation at
the position 4 of thiazole ring, which is possible due to
the migration of the hydrogen atom from the position 5
by the mechanism of keto-enol tautomerization. For
this reason the cyclization products I–VIII contain two
acetyl fragments. Their structures differ from those of
the heterocycles derived from 2-thiocyanato-2-methyl-
3-arylpropanamides [7] where the hydrogen migration
at their formation is impossible owing to the presence
of a methyl group in the position 5.
The IR spectra of compounds I–XXIV were
recorded on IKS-29 and Specord M80 instruments
1
from mulls in mineral oil. The H NMR spectra were
obtained on a Varian Mercury instrument (400 MHz)
from DMSO-d6 solutions with external reference TMS.
The individuality of the synthesized compounds was
established by the TLC on Silufol UV-254 plates
eluting with a methanol–acetone mixture (5:2). 2-
Thiocyanato-3-arylpropanamides were obtained by the
procedure [7].
These results confirm the usefulness of the fatty-
aromatic α-thiocyanatoamides as convenient synthons
for the preparation of difficultly accessible 5-aryl-
substituted 2-aminothiazol-4-ones. The latter are of
interest for the design of new heterocyclic systems and
2-Acetamido-5-benzylthiazol-4-yl acetate (I). A
solution of 1.5 g (7.3 mmol) of 2-thiocyanato-3-
phenylpropanamide in 20 ml of acetic anhydride was
boiled for 4 h, then evaporated in a vacuum to a
volume of 5 ml, and cooled. The reaction product was
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 81 No. 9 2011

SYNTHESIS OF 5-ARYLSUBSTITUTED THIAZOL-4-ONE ACETYL
1899
Table 3. HMBC and HMQC spectral analysis of 2-acetamido-
5-(4-methylbenzyl)thiazol-4-yl acetate IV
thiazol-4-yl acetate I in 15 ml of 96% ethanol was
added a solution of 1.8 g (30 mmol) of KOH in 3 ml of
water. The mixture was boiled for 2 h, then cooled to
room temperature and extracted with 15 ml of diethyl
ether. The organic extract was washed with water and
dried with CaCl2. The solvent was evaporated in a
vacuum, the solid residue was recrystallized from
methanol. Yield 0.67 g (95%), mp 192°C.
7.09
7.09
H
H
H
3.82
H
2.25
H
H
2.27 H
21.30
H
H
21.00
29.75
O
169.49
137.18
136.24
114.56
H
146.03
O
128.92
129.77
S
N
154.24
Compounds X–XVI were obtained similarly.
O
N
H
169.49
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12.09
23.08
H
H
2.08
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Chemical shift, δ, ppm
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1H
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HMBC
129.77
2.27
7.09
7.09
3.82
2.25
12.09
2.08
21.00
129.77
128.92
29.75
136.24
137.18
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tion of 1 g (3.4 mmol) of 2-acetamido-5-benzyl-
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RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 81 No. 9 2011