Thiazole analogs of chalcones, capable of functionalization at the heterocyclic nucleus

Article abstract of DOI:10.1007/s10593-010-0509-y

The synthesis of new amino and alkoxy derivatives of thiazole-5- carbaldehyde, on the basis of which a,β-unsaturated ketones of the thiazole series were synthesized, are described in this paper. The possibility of obtaining chalcones and variation of substitution reactions in the thiazole ring has been shown. 2010 Springer Science+Business Media, Inc.

Full text of DOI:10.1007/s10593-010-0509-y

Chemistry of Heterocyclic Compounds, Vol. 46, No. 3, 2010
THIAZOLE ANALOGS OF CHALCONES,
CAPABLE OF FUNCTIONALIZATION AT
THE HETEROCYCLIC NUCLEUS
V. N. Kotlyar1, P. A. Pushkarev1, V. D. Orlov1*,
V. N. Chernenko2, and S. M. Desenko2
The synthesis of new amino and alkoxy derivatives of thiazole-5-carbaldehyde, on the basis of which
α,β-unsaturated ketones of the thiazole series were synthesized, are described in this paper. The possibility
of obtaining chalcones and variation of substitution reactions in the thiazole ring has been shown.
Keywords: 2,4-dichoro-5-formylthiazole, chalcone, substitution of a chlorine atom, crotonic condensation.
At the time of its discovery in 1896, chalcone (1,3-diphenylpropen-1-one) [1] interest in the chemistry of
its substituted and heterocyclic analogs did not decrease. A retrospective review in Dhar’s monograph [2] showed
that most attention was concentrated on investigation of the reactivity of the propenone fragment of chalcone. In the
reviews [3, 4] this was illustrated in examples of the cyclocondensations with 1,2-, 1,3-, and 1,4-dinucleophiles. At
the same time reactions with the participation of the aromatic or heterocyclic nuclei were less studied.
In the present work we have studied the problem of synthesis of heterocyclic analogs of chalcone with
substituents in the heteroaromatic nucleus capable of further transformations not involving the propenone unit. It
is known [2, 3] that the most useful method for the synthesis of chalcones is the crotonic condensation with
compounds containing formyl and acetyl groups.
Starting with this problem we turned our attention to papers [5, 6], in which is proposed an original and
accessible method for the synthesis of 2,4-dichloro-5-formylthiazole 1. Compound 1 contains at least three reactive
centers: two chorine atoms and a formyl group, which is suggested by a series of reactions occurring either at the
aldehyde group (reduction, formation of oximes and acetals) [7-9], or with participation of the chlorine atoms
(substitution reactions with amines and thiols, dehalogenation) [9]. On the other hand, the chemistry of thiazole
arouses interest because among its derivatives there are a large number of compounds which possess physiological
activity (among natural compounds, for example, the triazole ring is the active center of thiamine, vitamin B1).
_______
* To whom correspondence should be addressed, e-mail: orlov@univer.kharkov.ua, kotlyar.v.n@mail.ru.
1V. N. Karazin Kharkiv National University, Kharkiv 61077, Ukraine.
2State Scientific Institution "Institute of Monocrystals", National Academy of Sciences of Ukraine, Kharkiv
61001, Ukraine; e-mail: desenko@isc.kharkov.com.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, 425-434, March, 2010. Original article
submitted June 5, 2009.
334
0009-3122/10/4603-0334©2010 Springer Science+Business Media, Inc.

We reproduced the synthesis of aldehyde 1, starting from 1,3-thiazolidine-2,4-dione, and carried out a
number of its chemical transformations with participation of the chlorine atoms. To begin with it should be
noted that there is a difference in chemical reactivity between the chlorine atoms. The chlorine atom in the meso
position is considerably more prone to nucleophilic substitution; even at room temperature in CCl4 solution it is
substituted by secondary amino groups in high yield: Dimethyl- and diethylamino-, piperidino-, morpholino-
and piperazinyl-, to form compounds 2- 6.
O
MeO
Cl
1
NaOH, MeOH
R
Me
N
N

OMe
OMe
S
S
O
O
9
16
NaOH, MeOH
AlkO
Cl
Cl
N
R2H
N
N
AlkONa
R2
O
S
R2
S
Cl
S
O
O
O
10–15
2–8
1
O
1
O
1
R
Me
R
Me
N
O
1
AcOH, H2SO4
R
Me
1
R
Me
Cl
NaOH,
MeOH
R1
S
R2
O
MeONa
R1
21–27
MeO
Cl
N
N
R2
Cl
S
R1
S
R2H
O
O
17–20
30, 31
MeONa

MeONa,
MeO
Cl
N

MeONa,
N
R1
R1
OMe
S
OMe
S
O
O
29
28
2 R2 = NMe2; 3 R2 = NEt2; 4 R2 = piperidino; 5 R2 = morpholino; 6 R2 = 4-(1-formylpiperazinyl);
7 R2 = OPh; 8 R2 = SPh; 10 R2 = NMe2, Alk = Me; 11 R2 = NMe2, Alk = Et; 12 R2 = piperidino,
Alk = Me; 13 R2 = piperidino, Alk=Et; 14 R2 = morpholino, Alk = Me; 15 R2 = morpholino, Alk = Et;
17 R1 = Ph; 18 R1 = 4-ClC6H4; 19 R1 = 4-BrC6H4; 20 R1 = 4-MeOC6H4; 21 R1 = Ph, R2 = NMe2;
22 R1 =Ph, R2 = NEt2; 23 R1 = Ph, R2 = piperidino; 24 R1 = 4-ClC6H4, R2 = piperidino; 25 R1=Ph,
R2= morpholino; 26 R1 = 4-ClC6H4, R2= morpholino; 27 R1 = 4-MeOC6H4, R2 = morpholino;
28 R1 = Ph; 29 R1 = Ph; 30 R1 = Ph, R2= piperidino; 31 R1 = Ph, R2= morpholino
335

We varied the conditions for carrying out the syntheses: the best results were obtained with using a two-
fold excess of the amine (the second equivalent of the amine was bound to the HCl) or by using potassium
carbonate as a catalyst [9]. It should be noted that substitution of the chlorine at position 4 was not observed,
even prolonged maintenance at room temperature of a reaction mixture containing a 10-fold excess of the
secondary amine, which indicates its low nucleophilicity.
The chlorine atom in position 2 is also readily substituted by phenoxy and phenylsulfanyl groups (to
form compounds 7 and 8), in this case only potassium carbonate permits the production of the required products
1
in excellent yields (~ 80%). In addition, in the H NMR spectrum of unpurified product 8 additional signals of
aromatic protons and the proton of an aldehyde group were obserwed which, in our view, is explained by partial
substitution of the chlorine atom in position 4 by a phenylsulfanyl group. This agrees with the mass spectrum of
the unpurified product in which, along with signal of the molecular ion peak of compound 8, a peak of the
impurity with m/z = 329 was observed, which disappeared on recrystallization. Phenol did not undergo this side
reaction which is probably a result of its lower nucleophilicity. As expected, introduction of an alkoxy group in
position 2 of compound 1 occurs considerably more easily. 4-Chloro-2-methoxy-1,3-thiazole-5-carbaldehyde (9)
was formed in the presence of 1 equivalent of sodium hydroxide in methanol at room temperature. Substitution
of the chlorine atom at position 4 proceeds with a twofold excess of alkali on mild (~50°C) heating to give the
dimethoxy-substituted product 16.
It should be noted the difference in mobility of the chlorine atoms in positions 2 and 4 of the thiazole
ring even appears in that the 2,4-dichloro derivative 1 is a strong lachrymator, while this property is lost in 2-R-
substituted 4-chloro-5-formylthiazole.
TABLE 1. Physicochemical Characteristics of Aldehydes of the Thiazole Series
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
mp, °C
Yield, %
N
S
1
C4HCl2NOS
7.67
7.69
14.71
14.69
12.83
12.81
12.17
12.14
12.07
12.04
16.19
16.18
5.87
5.84
5.52
5.48
7.72
7.69
15.08
15.04
14.03
13.99
12.42
12.38
11.69
11.66
12.29
12.27
11.59
11.56
8.11
8.09
17.63
17.61
16.84
16.82
14.69
14.66
13.93
13.90
13.79
13.78
12.39
12.35
13.41
13.38
25.10
25.07
18.09
18.05
17.24
17.22
16.03
16.01
14.20
14.17
13.37
13.34
14.08
14.05
13.25
13.23
18.54
18.51
40
91
50
85
85
90
95
95
70
75
75
85
80
85
80
85
80
80
2
C6H7ClN2OS
C8H11ClN2OS
C9H11ClN2OS
C8H9ClN2O2S
C9H10ClN3O2S
C10H6ClNO2S
C10H6ClNOS2
C5H4ClNO2S
C7H10N2O2S
C8H12N2O2S
C10H14N2O2S
C11H16N2O2S
C9H12N2O3S
C10H14N2O3S
C6H7NO3S
3
112
96
4
5
195
165
50
6
7
8
78
9
35
10
11
12
13
14
15
16
112
131
74
134
220
205
40
336

It should also be noted that in the case of aldehydes 2, 4, and 5, which contain a secondary amino group
in position 2, substitution of the remaining chlorine in position 4 is effected by the sodium alkoxide in the
corresponding alcohol at room temperature. The methoxy- and ethoxy-substituted thiazolecarbaldehydes 10-15
were obtained in this way. In contrast, all attempts at hydrolysis in the presence of aqueous solutions of alkali
resulted in resinification.
The composition and structures of the first synthesized aldehydes were confirmed by elemental and
spectroscopic analyses (Tables 1 and 2).
Formylthiazoles we obtained were subjected to the Claisen-Schmidt reaction with acetophenone with the
objective of obtaining the corresponding α,β-unsaturated ketones. It appeared that a direct reaction of 2,4-di-
chlorothiazole-5-carbaldehyde 1 with acetophenone in methanol in conditions of alkaline catalysis gave 3-(4-
chloro-2-methoxy-1,3-thiazol-5-yl)-1-phenyl-2-propenone (28) in comparatively low yield (25%).
Taking into account the high mobility of the chlorine atoms in the 2,4-dichloro-5-formylthiazole we
used acid catalysis for the condensation. The best results were obtained by using acetic and sulfuric acids, the
optimum results were obtained with an equivalent amount of sulfuric acid relative to the aldehyde. As a result
we obtained the corresponding 1-aryl-3-(2,4-dichloro-1,3-thiazol-5-yl)-2-propen-1-ones 17-20. With the
objective of increasing the rate of the reaction we used ultrasonic oscillation, which decreased the reaction time
to 24 h.
In contrast 2-amino-substituted 4-chloro-1,3-thiazole-5-carbaldehydes 2-4 readily underwent
condensation with aromatic ketones with alkaline catalysis to give the chalcones 21-23 in good yields
(48-52%). 4-Chloro-2-morpholino-1,3-thiazole-5-carbaldehyde (5) was the exception. It did not give the desired
products in these conditions with acetophenone. The thiazole-5-carbaldehydes 10-16, with an alkoxy substituent
at position 4, did not undergo analogous reactions. This is possibly explained by the electronic and steric effects
of the alkoxy groups on the reactivity of the formyl groups.
TABLE 2. Spectroscopic Characteristics of Aldehydes of the Thiazole Series
IR spectrum,
Com-
pound
1H NMR spectrum, δ, ppm (J, Hz)
9.60 (1H, s, СНО)
νС=О, cm1
1
2
3
1625
1620
1628
3.15 (6Н, s, N(CH3)2); 9.65 (1H, s, СНО)
1.27 (6Н, t J = 7.0, N(CH2CH3)2); 3.56 (4Н, q, J = 7.0, N(CH2CH3)2);
9.45 (1H, s, СНО)
4
5
1625
1635
1.61 (6Н, s, piperidine); 3.50 (4Н, s, piperidine); 9.45 (1H, s, СНО)
3.54-3.87 (4Н, m, morpholine); 3.67-3.72 (4Н, m, morpholine);
9.68 (1H, s, СНО)
6
1660,
1670
1663
1665
1610
1620
1619
3.28-3.33 (2Н, m, piperazine); 3.55-3.70 (6Н, m, piperazine);
8.10 (1H, s, СНО); 9.65 (1H, s, СНО)
7
7.35-7.55 (5Н, m, Н Ar); 9.85 (1H, s, СНО)
7.60-7.85 (5Н, m, Н Ar); 9.78 (1H, s, СНО)
4.07 (3Н, s, ОСН3); 9.51 (1H, s, СНО)
8
9
10
11
3.1 (6Н, s, N(CH3)2); 3.99 (3Н, s, ОСН3); 9.43 (1H, s, СНО)
1.31 (3Н, t, J = 7.0, ОСН2СН3); 3.1 (6Н, s, N(CH3)2);
4.39 (2Н, q, J = 7.0, ОСН2СН3); 9.45 (1H, s, СНО)
12
13
1615
1615
1.59 (6Н, s, piperidine); 3.53 (4Н, s, piperidine); 3.97 (3Н, s, ОСН3);
9.47 (1H, s, СНО)
1.30 (3Н, t, J = 7.0, ОСН2СН3); 1.57 (6Н, s, piperidine);
3.55 (4Н, s, piperidine); 4.40 (2Н, q, J = 7.0, ОСН2СН3);
9.48 (1H, s, СНО)
14
15
1627
1632
3.53-3.60 (4Н, m, morpholine); 3.63-3.66 (4Н, m, morpholine);
3.98 (3Н, s, ОСН3); 9.5 (1H, s, СНО)
1.3 (3Н, t, J = 7.0, ОСН2СН3); 3.45-3.48 (4Н, m, morpholine);
3.63-3.65 (4Н, m, morpholine); 4.42 (2Н, q, J = 7.0, ОСН2СН3);
9.5 (1H, s, СНО)
16
1617
3.95 (3Н, s, ОСН3); 4.17 (3Н, s, ОСН3); 9.51 (1H, s, СНО)
337

TABLE 3. Physicochemical Characteristics of Chalkones of the Thiazole Series
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
mp, °С
Yield, %
N
S
17
18
19
20
21
C12H7Cl2NOS
C12H6Cl3NOS
C12H6BrCl2NOS
C13H9Cl2NO2S
C14H13ClN2OS
4.97
4.93
4.45
4.40
3.94
3.86
4.51
4.46
11.33
11.28
10.11
10.06
8.90
8.83
10.25
10.21
95
55
50
40
53
48
105
124
116
185
9.59
9.57
10.97
10.95
22
23
24
25
26
27
28
29
30
31
C16H17ClN2OS
C17H17ClNO2S
C17H16Cl2N2OS
C16H15ClN2O2S
C16H14Cl2N2O2S
C17H17ClN2O3S
C13H10ClNO2S
C14H13NO3S
8.78
8.73
8.47
8.42
7.69
7.63
8.49
8.37
7.65
7.59
7.73
7.68
5.15
5.01
5.15
5.09
10.15
9.99
9.69
9.63
8.77
8.73
9.70
9.58
8.78
8.68
8.88
8.79
11.58
11.46
11.73
11.65
112
181
155
190
193
184
122
134
175
168
50
(80)*
52
(85)*
90
87
90
85
80
80
75
70
C18H20N2O2S
8.62
8.53
8.56
8.48
9.81
9.76
9.78
9.70
C17H18N2O3S
_______
* From compound 17
We attempted to solve this problem by substituting the chlorine atoms in the alredy created molecule
3-(2,4-dichloro-1,3-thiazol-5-yl)-1-phenyl-2-propen-1-one (17) under conditions previously used for 2,4-di-
chloro-1,3-thiazole-5-carbaldehyde (1). It was shown that the chlorine atom in position 2 was readily replaced
by amino (including morpholino) and methoxy groups under the influence of the corresponding amines or
sodium methoxide.
Analogously to the reactions of derivatives of thiazole-5-carbaldehydes, the chlorine atom at position 4
in the thiazole ring of chalcones 23 and 25 is capable of nucleophilic substitution by the methoxy group to give
compounds 30 and 31.
EXPERIMENTAL
1
IR spectra (KBr) were measured with a Specord IR-75 spectrophotometer and H NMR spectra of
DMSO-d6 solutions with TMS as internal standard were measured with Varian VX-200 instrument (200 MHz).
Monitoring of the course of reactions and purity of the compounds obtained was carried out by TLC on Silufol-
254 plates, using the following eluents: 1:1 acetone–hexane (compounds 1-8), 1:1 ethyl acetate–toluene
(compounds 9-15), 1:1 chloroform–hexane (compounds 16, 28-31), and pure chloroform (compounds 17-27).
338

TABLE 4. Spectroscopic Characteristics of Chalcones of the Thiazole Series
Com-
pound
IR spectrum,
1H NMR spectrum, δ, ppm (J, Hz)
νС=О,cm–1
17
18
19
20
21
22
1662
1665
1675
1658
1642
1638
7.64 (1Н, d, J = 15.4, HC=CH); 7.73 (1Н, d, J = 15.4, HC=CH);
7.55-8.12 (5Н, m, Н Ar)
7.63 (1Н, d, J = 15.4, HC=CH); 7.71 (1Н, d, J = 15.4, HC=CH);
7.61-8.13 (4Н, m, Н Ar)
7.62 (1Н, d, J = 15.4, HC=CH); 7.68 (1Н, d, J = 15.4, HC=CH);
7.75-8.04 (4Н, m, Н Ar)
3.86 (3Н, s, OCH3); 7.63 (1Н, d, J = 15.4, HC=CH);
7.73 (1Н, d, J = 15.4, HC=CH); 7.07-8.13 (4Н, m, Н Ar)
3.10 (6Н, s, N(CH3)2); 7.09 (1Н, d, J = 14.7, HC=CH);
7.65 (1Н, d, J = 14.7, HC=CH); 7.48-8.05 (5Н, m, Н Ar)
1.18 (6Н, t, J = 6.9, N(CH2CH3)2); 3.49 (4Н, q, J = 6.9, N(CH2CH3)2);
7.04 (1Н, d, J = 14.7, HC=CH); 7.72 (1Н, d, J = 14.7, HC=CH);
7.49-8.03 (5Н, m, Н Ar)
23
24
25
26
27
1640
1639
1648
1650
1655
1.62 (6Н, s, piperidine); 3.54 (4Н, s, piperidine);
7.02 (1Н, d, J = 14.7, HC=CH); 7.72 (1Н, d, J = 14.7, HC=CH);
7.50-8.02 (5Н, m, Н Ar)
1.61 (6Н, s, piperidine); 3.53 (4Н, s, piperidine);
7.03 (1Н, d, J = 14.6, HC=CH); 7.71 (1Н, d, J = 14.6, HC=CH);
7.56-8.05 (4Н, m, Н Ar)
3.48-3.53 (4Н, m, morpholine); 3.66-3.71 (4Н, m, morpholine);
7.09 (1Н, d, J = 14.6, HC=CH); 7.72 (1Н, d, J = 14.6, HC=CH);
7.48-8.05 (5Н, m, Н Ar)
3.52-3.57 (4Н, m, morpholine); 3.70-3.75 (4Н, m, morpholine);
7.08 (1Н, d, J = 14.6, HC=CH); 7.72 (1Н, d, J = 14.6, HC=CH);
7.54-8.06 (4Н, m, Н Ar)
3.48-3.53 (4Н, m, morpholine); 3.61-3.66 (4Н, m, morpholine);
3.82 (3Н, s, OCH3); 7.12 (1Н, d, J = 14.6, HC=CH);
7.68 (1Н, d, J = 14.6, HC=CH); 7.01-8.05 (4Н, m, Н Ar)
28
29
30
1645
1620
1635
4.10 (3Н, s, OCH3); 7.41 (1Н, d, J = 15.3, HC=CH);
7.68 (1Н, d, J = 15.3, HC=CH); 7.50-8.10 (5Н, m, Н Ar)
3.99 (3Н, s, OCH3); 4.12 (3Н, s, OCH3); 7.41 (1Н, d, J = 15.1, HC=CH);
7.75 (1Н, d, J = 15.1, HC=CH); 7.50-7.80 (5Н, m, Н Ar)
1.61 (6Н, s, piperidine); 3.54 (4Н, s, piperidine); 3.97 (3Н, s, OCH3);
6.54 (1Н, d, J = 14.7, HC=CH); 7.80 (1Н, d, J = 14.7, HC=CH);
7.46-7.93 (5Н, m, Н Ar)
31
1627
3.51-3.55 (4Н, m, morpholine); 3.67-3.72 (4Н, m, morpholine);
3.98 (3Н, s, OCH3); 6.61 (1Н, d, J = 14.6, HC=CH);
7.81 (1Н, d, J = 14.6, HC=CH); 7.43-7.94 (5Н, m, Н Ar)
2,4-Dichloro-1,3-thiazole-5-carbaldehyde (1). DMF (24 g, 0.33 mol) was added dropwise to a
suspension of 1,3-thiazolidine-2,4-dione (35.1 g, 0.3 mol) in phosphorus oxytrichloride (180 ml, 1.8 mol). The
mixture was stirred for 1 h at room temperature, then for 1 h at 80-90°C, after which the mixture was raised to
boiling point and heated for another 4 h. The reaction mixture was poured onto ice (1.5 kg), the aldehyde 1 was
separated by steam distillation. It crystallized on cooling, yield 272.3 g (50%); mp 40°C.
4-Chloro-2-dimethylamino-1,3-thiazole-5-carbaldehyde (2). A solution of dimethylamine (9 g,
0.2 mol) in carbon tetrachloride (50 ml) was added dropwise with stirring and cooling to a solution of
2,3-dichloro-5-formyl-1,3-thiazole (18.2 g, 0.1 mol) in CCl4 (100 ml) and kept at room temperature for 24 h.
The solvent was removed under reduced pressure, the residue was diluted with water, and the precipitate of
aldehyde 2 was filtered off to give a yield of 16.2 g (85%); mp 91°C.
4-Chloro-2-diethylamino-1,3-thiazole-5-carbaldehyde (3). A solution of diethylamine (14.6 g,
0.2 mol) in carbon tetrachloride (50 ml) was added dropwise with stirring and cooling to a solution of
2,3-dichloro-5-formyl-1,3-thiazole (18.2 g, 0.1 mol) in CCl4 (100 ml). The mixture was stirred for a further 2 h
and then kept overnight. The solvent was evaporated, the residue was diluted with water, and the precipitate of
aldehyde 3 was filtered off to give a yield of 18.6 g (85%); mp 112°C.
339

2-Piperidino- (4), 2-Morpholino- (5) and 2-(Formylpiperazin-4-yl)-substituted (6) 4-Chloro-
1,3-thiazole-5-carbaldehydes were prepared analogously (Table 1).
4-Chloro-2-phenoxy-1,3-thiazol-5-carbaldehyde (7). Anhydrous potassium carbonate (13.8 g,
0.1 mol) was added to a solution of aldehyde 1 (9.1 g, 0.05 mol) in acetonitrile (200 ml), then at room
temperature with stirring a solution of phenol (4.7 g, 0.05 mol) in acetonitrile (20 ml) was added. The mixture
was stirred for 16 h, the inorganic precipitate was filtered off and the filtrate evaporated. The residue was
recrystallized from hexane. Yield 8.4 g (70%); mp 50°C.
4-Chloro-2-phenylsulfanyl)- 1,3-thiazole-5-carbaldehyde (8) was prepared analogously (Table 1).
4-Chloro-2-methoxy-1,3-thiazole-5-carbaldehyde (9). NaOH (1 g) was added to a stirred solution of
aldehyde 1 (5 g, 0.027 mol) in methanol (100 ml) at room temperature, stirring was continued for 8 h, after
which the solvent was evaporated. The residue was dissolved in dichloromethane, washed with a small quantity
of water, the organic layer was separated and dried over sodium sulfate. The solvent was evaporated and the
residue – compound 9 as a brownish oily liquid – crystallized on standing to solid with mp 35°C.
4-Methoxy-2-morpholino-1,3-thiazole-5-carbaldehyde (14). A solution of MeONa (5.4 g, 0.1 mol) in
methanol (50 ml) was added dropwise with stirring to a solution 4-chloro-2-morpholino-1,3-thiazole-
5-carbaldehyde (23.25 g, 0.1 mol) in methanol (200 ml). The reaction mixture was kept for 10 h, the solvent was
removed under reduced pressure, and the residue was washed with a small amount of water. The precipitated
product was filtered off and recrystallized from heptane. Yield 19.4 g (85%); mp 74°C.
4-Methoxy-2-dimethylamino- and 4-Methoxy-2-piperidino-1,3-thiazole-5-carbaldehydes (10 and
12, Table 1) and also (with ethanol and sodium ethoxide) the 4-ethoxy analogs 11, 13, and 15 were made
analogously.
2,4-Dimethoxy-1,3-thiazole-5-carbaldehyde (16). A. Sodium hydroxide (0.68 g, 0.0175 mol) was
added at 50°C to a stirred solution of 4-chloro-2-methoxy-1,3-thiazole-5-carbaldehyde (3 g, 0.017 mol) in
methanol (100 ml) and the reaction was continued for another 6 h. The solvent was evaporated, the residue was
dissolved in dichloromethane and washed with a small amount of water. The organic layer was separated, dried
over sodium sulfate, and the solvent evaporated at reduced pressure to give compound 16 as a deep-brown oily
liquid which crystallized on standing to give a solid with mp 40°C. Yield 2.35 g (80%).
B. Sodium hydroxide (2.4 g, 0.06 ml) was added at 50°C with stirring to a solution of 2,4-dichloro-
1,3-thiazol-5-carbaldehyde (5 g, 0.027 mol) in methanol (100 ml) and kept under these conditions for another 6
h. The solvent was evaporated, the residue was dissolved in dichloromethane and washed with a small amount
of water. The organic layer was separated and dried over sodium sulfate, the dichloromethane was evaporated
under reduced pressure to give compound 16 as dark-brown oily liquid, which crystallized on standing to a solid
with mp 40°C. Yield 3.74 g (80%).
3-(2,4-Dichloro-1,3-thiazol-5-yl)-1-phenyl-2-propen-1-one (17). A. Conc. H
2SO4 (0.3 ml) was added
to a solution of aldehyde 1 (1 g, 0.0054 mol) and acetophenone (0.66 g, 0.0054 mol) in acetic acid (20 ml) and
kept at room temperature for 3 d. The precipitate was filtered off and recrystallized from acetic acid. Yield
0.84 g (55%); mp 95°C.
Chalcones 18-20 were made analogously (Table 3).
3-(4-Chloro-2-dimethylamino-1,3-thiazol-5-yl)-1-phenyl-2-propen-1-one (21). B 3-5 Drops of (20%)
aqueous sodium hydroxide solution were added to a solution of aldehyde 2 (1 g, 0.0052 mol) and acetophenone
(0.63 g, 0.0052 mol) in ethanol (10 ml) and the solution was kept overnight. The precipitate which formed was
filtered off, washed with 5% aqueous acetic acid, and recrystallized from ethanol to give compound 21 (0.73 g,
48%); mp 185°C.
Chalcones 22 and 23 were made analogously (Table 3).
3-(4-Chloro-2-morpholino-1,3-thiazol-5-yl)-1-(4-chlorophenyl)-2-propen-1-one (26). C. Morpholine
(2.73 g, 0.0314 mol) in acetonitrile (10 ml) was added dropwise with stirring to a solution of
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3-(2,4-dichloro-1,3-thazol-5-yl)-1-(4-chlorophenyl)-2-propen-1-one (18) (5 g, 0.0157 mol) in acetonitrile
(50 ml). The mixture was stirred for 3 h and kept overnight. The solvent was evaporated , the residue washed
with water, the precipitate filtered off and recrystallized from ethanol. Yield 4.92 g (85%); mp 182°C.
Chalcones 22-25 and 27 were obtained analogously (Tables 3 and 4).
3-(4-Chloro-2-methoxy-1,3-thaizol-5-yl)-1-phenyl-2-propen-1-one (28). D. A solution of sodium
methoxide (0.19 g, 0.0035 mol) in methanol (10 ml) was added to a solution of chalcone 17 (1 g, 0.0035 mol) in
methanol (20 ml) at room temperature with stirring and kept for 4 h. The solvent was evaporated and the residue
was recrystallized from ethanol. Yield 0.49 g (50%); mp 122°C.
3-(2,4-Dimethoxy-1,3-thiazol-5-yl)-1-phenyl-2-propen-1-one (29). E. A solution of sodium methoxide
(0.4 g, 0.0074 mol) in methanol (10 ml) was added to a solution of chalcone 17 (1 g, 0.0035 mol) in methanol
(20 mol) and the mixture was heated at 50°C for 5 h. The solvent was evaporated and the residue was
recrystallized from ethanol. Yield 0.43 g (45%); mp 134°C.
Chalcones 30 and 31 were obtained analogously from chalcones 23 and 25 (Tables 3 and 4).
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