Chemistry of 3-hetarylcoumarins. 2. 3-(2-thiazolyl)coumarins

Article abstract of DOI:10.1007/s10593-005-0004-z

3-(2-Thiazolyl)coumarins were obtained by the reaction of substituted salicylaldehydes with 2-thiazolylacetonitriles. Methylation, acylation, and aminomethylation were studied for the 7-hydroxy-substituted products.

Full text of DOI:10.1007/s10593-005-0004-z

Chemistry of Heterocyclic Compounds, Vol. 40, No. 11, 2004
CHEMISTRY OF 3-HETARYLCOUMARINS.
2*. 3-(2-THIAZOLYL)COUMARINS
O. V. Khilya, O. V. Shablykina, M. S. Frasinyuk, A V. Turov,
V. V. Ishchenko, and V. P. Khilya
3-(2-Thiazolyl)coumarins were obtained by the reaction of substituted salicylaldehydes with
2-thiazolylacetonitriles. Methylation, acylation, and aminomethylation were studied for the 7-hydroxy-
substituted products.
Keywords: 8-aminomethyl-7-hydroxy-3-(2-thiazolyl)coumarins, 7-acyloxy-3-(2-thiazolyl)coumarins,
7-methoxy-3-(2-thiazolyl)coumarins, 3-(2-thiazolyl)coumarins.
Many synthetic coumarins have a wide spectrum of biological activity [2-5] and also fluorescence [2-5].
This makes it possible to use them as fluorescent probes, markers, and laser media [6, 7].
The heterocyclic analogs of coumarins are of particular interest with respect to the effect of the nature of
the heterocycle on their characteristics and the possibility of their practical application.
Earlier we obtained and studied 3-(2-benzimidazolyl)- and 3-(2-benzimidazolyl)coumarins [1]. The
subjects of the present work are 3-(2-thiazolyl)coumarins 1a-i with alkyl and aryl substituents at position 4 of the
thiazole ring. Such compounds are usually obtained by Knoevenagel condensation of salicylaldehydes and 2-
thiazolylacetonitriles followed by hydrolysis of the obtained 2-iminocoumarins (the most convenient and
frequently used method) [8, 9], by the reaction of 2-iminocoumarin-3-thiocarboxamides with α-halocarbonyl
compounds (in this case partial hydrolysis of the imino group occurs) [8-11], and by the reaction of
hetarylacetonitriles or the corresponding esters with Schiff base (azomethine) derivatives of salicylaldehydes
[12]. The spectral characteristics of some 3-(2-thiazolyl)coumarins [13, 14] and their potential pharmacological
activity [15] have been investigated.
The 3-(2-thiazolyl)coumarins 1a-i were synthesized by the condensation of 4-hydroxy-, 5-bromo-,
5-nitro-, and 5-chlorosalicylaldehydes with methyl- or aryl-substituted 2-thiazolylacetonitriles in the presence of
piperidine followed by hydrolysis of the obtained iminocoumarins with 3% sulfuric acid.
The products 1a-i are high-melting crystalline substances mostly yellow in color, insoluble in water, and
with the exception of 1a poorly soluble in organic solvents (Table 1). In their 1H NMR spectra in the downfield
region there is a singlet for H-5 of the thiazole ring (7.0-8.5 ppm) and also a full set of signals for the remaining
protons of the coumarin fragment and signals for the substituent R2 (Table 2).
_______
* For Communication 1, see [1].
__________________________________________________________________________________________
Taras Shevchenko Kiev University, Kiev, Ukraine; e-mail: shablykina@mail.univ.kiev.ua. Translated
from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1632-1644, November, 2004. Original article
submitted April 8, 2002. Revision received March 23, 2004.
1408
0009-3122/04/4011-1408©2004 Springer Science+Business Media, Inc.

NC
N
CHO
OH
H
N
R1
+
S
R2
R2
R2
N
N
+
S
S
H
R1
R1
O
NH
O
O
1a–i
1 a-d R1 = 7-OH, e, f R1 = 6-Br, g, h R1 = 6-NO2, i R1 = 6-Cl; a R2 = Me,
b, e, g R2 = C6H4Br-4, c, f, h, i R2 = C6H4NO2-3, d R2 = C6H3OCH2O-3,4
Methylation, acylation, and aminomethylation were studied for compounds 1a-d, which contain an
active hydroxyl group.
The methylation of the coumarins 1a-d by the action of dimethyl sulfate in acetone in the presence of
potassium carbonate led to 7-methoxycoumarins 2a-d, and acylation with acid chlorides in pyridine gave
1
7-acyloxycoumarins 3a-w (Table 1). The H NMR spectra of the synthesized derivatives show a slight
downfield shift of the signals for the protons of the coumarin fragment compared with the initial compounds and
also the presence of signals for the protons of the methoxy group (3.90-3.95 ppm) or the acyl substituent R3CO
(Table 2).
1
For the assignment of the complex multiplet signals in the H NMR spectra of compounds 3m and 3v
two-dimensional COSY spectroscopy was used (Fig. 1).
It is known that aminomethylation takes place readily in the isoflavone series, and the obtained Mannich
bases are biologically active [16, 17]. For the synthesis of such bases from 7-OH-3-thiazolylcoumarins 1a-d
(aminomethylation does not occur in the absence of a strong donating substituent – the hydroxy group) we used
aminals, since when the reaction is conducted under standard conditions (by the action of amine hydrochlorides
in alcohol) the nitrogen of the thiazole ring is protonated, and this deactivates the coumarin system in
Compound 3m Compound 3v
Fig. 1.
1409

electrophilic substitution reactions [1]. If the coumarin is boiled with a small excess of the aminal (10-20%) in
dioxane for 1 h 30 min to 2 h, the respective 8-aminomethyl derivative 4a-o is formed exclusively with a fairly
high yield. The reaction had the longest duration (3 h) during the synthesis of compound 4h, which has the
largest substituent at the nitrogen atom, and the yield was the lowest (51%) (Table 1).
R2
N
Me2SO4;
X2CH2;
dioxane
acetone; K2CO3
S
HO
O
O
R2
1a–d
R2
N
N
S
S
HO
O
O
R3COCl;
Py
MeO
O
O
4a–p
X
2a–d
HCl, CHCl3
R2
R2
+
N
N
H
S
S
R3 COO
O
3a–w
O
HO
O
O
_
+
2Cl
XH
5a–k
2a, 3 a,b R2 = Me, 2b, 3c-i R2 = C6H4Br-4, 2c, 3 j-p R2 = C6H4NO2-3,
2d, 3q-w R2 = C6H3OCH2O-3,4; 3 a,c,j,q R3 = Me, b,i,p,w R3 = 2-furyl, d,k,r R3 = Et, e,l,s R3 = CMe3,
f,m,t R3 = C6H4Me-2, g,n,u R3 = C6H4OMe-4, h,o,v R3 = C6H3(OMe)2-3,4, 4 a-c R2 = Me, d-h R2 = C6H4Br-4,
i-l R2 = C6H4NO2-3, m-p R2 = C6H3OCH2O-3,4; a X = N(CH2)4, b X = N(CH2)2CHMe(CH2)2, c X = N(CH2)4CHEt;
d,i,m X = NMe2, e,j,n X = N(CH2)4, f,k,o X = N(CH2)5, g,l,p X = N(CH2)2NMe(CH2)2, h X = NCHMe(CH2)3CHMe;
5a-c R2 = C6H4Br-4; d-g R2 = C6H4NO2-3, h-k R2 = C6H3OCH2O-3,4, a,d,h X = NMe2,
b,e,i X = N(CH2)4, c,f,j X = N(CH2)5, g,k X = N(CH2)2NMe(CH2)2
The aminomethyl derivatives dissolve better in organic solvents than the initial compounds, many are
moderately soluble in dilute mineral acids, and some are soluble in water. Solutions of compounds 4a-c,d-g,m-p
in organic solvents (ethanol, acetone), like the corresponding initial coumarins and their methyl and acyl
derivatives, fluoresce during excitation by visible light. In the 1H NMR spectra of the synthesized Mannich bases
there are signals for the protons of the aminoalkyl groups; the signals of the H-5 and H-6 protons (doublets with
3J = 8.5-9.0 Hz) are shifted upfield compared with the analogous signals of the initial coumarins (Table 3); the
signal of the H-8 proton is absent.
If the solutions of the Mannich bases 4d-f,i-l,m-p are saturated with HCl the corresponding
hydrochlorides 5a-k are precipitated. Protonation takes place at the two nitrogen atoms, as shown by the data
from elemental analysis of the obtained salts (see Experimental). The salts 5a-k are hygroscopic compounds,
which decompose to the initial base with the release of HCl when heated above ~60°C. They are very poorly
soluble in organic solvents but dissolve readily in water; the aqueous solutions of the hydrochlorides 5a-k
fluoresce strongly. In the 1H NMR spectra of the salts 5a-k there is a significant downfield shift of the signals for
the protons of the aminoalkyl groups compared with the analogous signals of the bases 4d-f,i-l,m-p (Table 3).
1410

TABLE 1. The Characteristics of the Synthesized Compounds 1-4
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Yield,
%
mp, °С
Hal
3
N
4
S
5
1
2
6
7
1a
1b
C13H9NO3S
5.47
5.40
—
12.39
12.36
8.19
8.01
295-296
98
78
C18H10BrNO3S
20.12
19.96
>330
1c
C18H10N2O5S
C19H11NO5S
7.38
7.65
4.14
3.83
9.10
8.75
8.99
8.78
321-325
93
79
1d
305
(dec.)
1e
1f
C18H9Br2NO2S
C18H9BrN2O4S
C18H9BrN2O4S
C18H9N3O6S
34.94
34.51
18.17
18.62
18.83
18.62
3.14
3.02
6.11
6.53
6.30
6.53
10.14
10.63
6.72
6.92
7.27
7.27
7.07
7.27
7.70
8.11
246-247
262-264
232-233
308-309
76
79
81
71
86
1g
1h
1i
C18H9ClN2O4S
8.90
9.21
6.92
7.28
8.06
8.33
300
(dec.)
2a
2b
2c
2d
3a
3b
3c
3d
3e
3f
C14H11NO3S
5.34
5.13
11.65
11.73
7.89
7.74
8.31
8.43
8.36
8.45
10.40
10.64
8.76
9.07
7.41
7.25
6.91
7.03
6.49
6.62
6.28
6.19
5.97
6.00
5.89
5.68
6.61
6.43
8.04
7.85
7.86
7.69
7.16
7.12
208-211
285-286
259-261
242-245
179-184
201-203
238-239
213-215
217-219
220-223
241-243
237-237.5
252-254
230-232
222-222.5
227-229
232-233
243-243.5
258-260
78
85
79
91
92
91
88
55
75
90
88
90
82
82
76
76
51
68
75
C19H12BrNO3S
C19H12N2O5S
C20H13NO5S
19.66
19.29
7.23
7.37
4.02
3.69
4.51
4.65
C15H11NO4S
C18H11NO5S
C20H12BrNO4S
C21H14BrNO4S
C23H18BrNO4S
C26H16BrNO4S
C26H16BrNO5S
C27H18BrNO6S
C23H12BrNO5S
C20H12N2O6S
C21H14N2O6S
C23H18N2O6S
C26H16N2O6S
C26H16N2O7S
C27H18N2O8S
18.30
18.07
17.89
17.51
16.86
16.50
15.74
15.42
15.06
14.95
14.50
14.16
16.42
16.17
3g
3h
3i
3j
7.07
6.85
6.91
6.63
5.98
6.22
5.72
5.78
5.57
5.60
5.39
5.28
3k
3l
3m
3n
3o
6.58
6.62
6.43
6.41
6.38
6.04
1411

TABLE 1 (continued)
1
2
3
4
5
6
7
3p
3q
3r
3s
C23H12N2O7S
C21H13NO6S
C22H15NO6S
C24H19NO6S
C27H17NO6S
C27H17NO7S
C28H19NO8S
C24H13NO7S
C18H18N2O3S
C20H22N2O3S
C21H24N2O3S
C21H17BrN2O3S
C23H19BrN2O3S
C24H21BrN2O3S
C24H22BrN3O3S
C26H25BrN2O3S
6.04
6.08
7.24
6.96
7.99
7.86
7.32
7.61
6.92
7.13
6.56
6.63
6.41
6.42
6.06
(5.86)
7.11
6.98
9.54
9.36
8.49
8.66
8.51
8.34
7.01
(7.26)
6.63
6.63
6.70
6.45
246-250
232-232.5
251-252
255-258
237-238
215-218
242-243
224-226
175-178
202-209
78-81
58
90
86
78
85
89
77
71
95
87
82
92
85
87
86
51
3t
3u
3v
3w
4a
4b
4c
4d
4e
4f
3.21
3.05
8.38
8.18
7.44
7.56
7.50
7.28
6.11
6.13
6.01
5.80
5.48
5.63
8.38
8.20
17.87
17.47
16.24
16.63
16.47
16.07
15.82
15.59
214-215
228-230
238-240
206-208
4g
4h
6.38
6.25
6.68
6.45
16.41
16.06
5.89
5.63
220
(dec.)
4i
4j
C21H17N3O5S
C23H19N3O5S
C24H21N3O5S
C24H22N4O5S
C22H18N2O5S
C24H20N2O5S
C25H22N2O5S
C25H23N3O5S
10.18
9.92
9.66
9.35
9.23
9.07
12.38
11.71
6.69
6.63
6.47
6.25
5.80
6.06
8.83
8.80
7.84
7.57
6.96
7.13
6.81
6.92
6.91
6.70
7.71
7.59
7.19
7.15
7.14
6.93
6.96
6.71
225-226
212-213
235-237
240-243
198-199
213-215
228-230
212-213
71
84
73
76
93
89
88
83
4k
4l
4m
4n
4o
4p
Thus, the condensation of salicylaldehydes with 2-thiazolylacetonitriles provides a preparative method
for the synthesis of 3-(2-thiazolyl)coumarins. The presence of the hydroxyl group in the latter makes it possible
to obtain their alkyl and acyl derivatives and to realize aminomethylation by the action of formaldehyde aminals.
1412

TABLE 2. The 1H NMR Spectra of Substituted 7-Hydroxy-, 6-Halo-, 6-Nitro-, 7-Methoxy-, and 7-Acyloxycoumarins 1-3
Chemical shifts, δ, ppm (SSCC, J, Hz)
Com-
pound
H-5
of thiazole
(1Н, s)
Coumarin residue
R2
8
H-4
(1Н, s)
H-5 (1Н)
Н-6 (1Н)
H-7 / R3
5
H-8
6
1
2
3
4
7
1a
8.85
7.81
6.64
10.91 (1H, br. s, ОН)
10.9 (1H, br. s, ОН)
10.80 (1H, br. s, ОН)
10.89 (1H, br. s, ОН)
6.83
7.36
2.44 (3H, s, CH3)
(d, 3J = 8.0)
(dd, 3J = 8.0,
4J = 2.5)
(d, 4J = 2.5)
1b
1c
1d
9.00
8.99
8.99
7.80
6.8
6.70
8.24
8.44
8.03
7.65 (2H, d, 3J = 8.0, H-2,6); 8.20 (2Н, d, 3J = 8.0,
H-3,5)
(d, 3J = 8.5)
(dd, 3J = 8.5,
4J = 1.5)
(d, 4J = 1.5)
7.88
(d, 3J = 8.5)
6.88
6.81
8.92 (1Н, br. s, H-2); 8.48 (1H, d, 3J = 8.0, H-4);
7.75 (1H, t, 3J = 8.0, H-5); 8.26 (1H, br. d,
3J = 8.0, H-6)
(dd, 3J = 8.5,
4J = 1.5)
(d, 4J = 1.5)
7.82
(d, 3J = 8.5)
6.89
6.82
7.62 (1H, d, 4J = 1.0, H-2); 6.99 (1H, d, 3J = 8.0,
H-5); 7.61 (1H, dd, 3J = 8.0, 4J = 1.0, H-6);
6.07 (2H, s, OCH2O)
(dd, 3J = 8.5,
4J = 1.5)
(d, 4J = 1.5)
1e
1f
8.96
9.03
8.21
—
7.80 (1H, dd, 3J = 8.5, 4J = 2.0)
7.81 (1H, dd, 3J = 8.5, 4J = 2.0)
7.4
8.21
8.56
7.65 (2H, d, 3J = 8.0, H-2,6); 8.00 (2Н, d,
(d, 4J = 2.0)
(d, 3J = 8.5)
3J = 8.0, H-3,5)
8.03
—
7.44
8.92 (1Н, br. s, H-2); 8.48 (1H, d, 3J = 8.0, H-4);
7.75 (1H, t, 3J = 8.0, H-5); 8.26 (1H, br. d,
3J = 8.0, H-6)
(d, 4J = 2.0)
(d, 3J = 8.5)
1g
1h
9.22
9.28
8.94
—
—
8.45 (1H, dd, 3J = 8.5, 4J = 2.0)
8.43 (1H, dd, 3J = 8.5, 4J = 2.0)
7.68
8.28
8.64
7.67 (2H, d, 3J = 8.0, H-2,6); 8.03 (2Н, d,
(d, 4J = 2.0)
(d, 3J = 8.5)
3J = 8.0, H-3,5)
9.05
7.69
8.84 (1Н, br. s, H-2); 8.49 (1H, d, 3J = 8.0, H-4);
7.78 (1H, t, 3J = 8.0, H-5); 8.22 (1H, br. d,
3J = 8.0, H-6)
(d, 4J = 2.0)
(d, 3J = 8.5)

TABLE 2 (continued)
1
2
3
4
5
6
7
8
1i
9.06
8.17
—
8.48 (1H, dd, 3J = 8.0, 4J = 1.5)
7.51
8.55
8.83 (1Н, br. s, H-2); 8.64 (1H, d, 3J = 8.0, H-4);
7.71 (1H, t, 3J = 8.0, H-5); 8.24 (1H, br. d,
3J = 8.0, H-6)
(d, 4J = 1.5)
(d, 3J = 8.0)
2a
2b
2c
2d
3a
8.85
9.03
9.00
9.00
8.81
7.81
6.96
3.90 (3H, s, CH3O)
3.95 (3H, s, CH3O)
3.95 (3H, s, CH3O)
3.91 (3H, s, CH3O)
2.36 (3H, s, CH3CO)
7.04
7.22
8.23
8.48
8.01
7.10
2.47 (3H, s, CH3)
(d, 3J = 8.0)
(dd, 3J = 8.0,
4J = 2.5)
(d, 4J = 2.5)
7.95
7.07
7.13
7.68 (2H, d, 3J = 8.0, H-2,6); 8.05 (2Н, d,
3J = 8.0, H-3,5)
(d, 3J = 8.5)
(dd, 3J = 8.5,
4J = 1.5)
(d, 4J = 1.5)
7.94
7.02
7.06
8.72 (1Н, br. s, H-2); 8.48 (1H, d, 3J = 8.0, H-4);
7.74 (1H, t, 3J = 8.0, H-5); 8.18 (1H, br. d,
3J = 8.0, H-6)
7.61 (1H, d, 4J = 1, H-2); 6.97 (1H, d,
3J = 8.0, H-5); 7.62 (1H, dd, 3J = 8.0,
4J = 1.0, H-6); 6.07 (2H, s, OCH2O)
(d, 3J = 8.5)
(dd, 3J = 8.5,
4J = 1.5)
(d, 4J = 1.5)
7.91
7.07
7.08
(d, 3J = 8.0)
(dd, 3J = 8.0,
4J = 1.5)
(d, 4J = 1.5)
7.67
7.31
7.22
2.54 (3H, s, CH3)
(d, 3J = 8.0)
(dd, 3J = 8.0,
4J = 2.5)
(d, 4J = 2.5)
3b
3c
8.84
9.08
7.72
7.26 (dd, 3J = 8.0, 7.45 (1Н, br. s, H-3); 6.64 (1Н, m,
7.36
7.11
8.32
2.50 (3H, s, CH3)
(d, 3J = 8.0)
4J = 2.5)
H-4); 7.73 (1Н, br. s, H-5)
(d, 4J = 2.5)
8.07
7.26
2.32 (3H, s, CH3CO)
7.39
7.67 (2H, d, 3J = 8.0, H-2,6); 8.06 (2Н, d,
3J = 8.0, H-3,5)
(d, 3J = 8.5)
(dd, 3J = 8.5,
4J = 1.5)
(d, 4J = 1.5)
3d
3e
8.94
9.04
7.72
7.26
1.29 (3Н, t, 3J = 8.0, CH3);
2.63 (2Н, q, 3J = 8.0, СН2)
7.21
7.68
8.29
7.58 (2H, d, 3J = 8.0, H-2, H-6); 7.89 (2Н, d,
3J = 8.0, H-3,5)
(d, 3J = 8.5)
(dd, 3J = 8.5,
4J = 1.5)
(d, 4J = 1.5)
8.07
7.22
1.35 (9Н, s, (CH3)3C)
7.35
7.66 (2H, d, 3J = 8.0, H-2,6); 8.04 (2Н, d,
3J = 8.0, H-3,5)
(d, 3J = 8.5)
(dd, 3J = 8.5,
4J = 1.5)
(d, 4J = 1.5)

TABLE 2 (continued)
1
2
3
4
5
6
7
8
3f
9.19
8.14-8.18
(m)
7.45-7.47
(m)
2.63 (3H, s, 2-CH3); 7.45-7.47 (2Н, m, 7.61-7.65 (m)
H-3,5); 7.61-7.65 (1Н, m, H-4);
8.42
7.72 (2H, d, 3J = 8.0, H-2,6); 8.05 (2Н, d,
3J = 8.0, H-3,5)
8.14-8.18 (1Н, m, H-6)
3g
3h
8.99
9.15
7.81
7.29
3.92 (3Н, s, 4-CH3О); 7.03 (2Н, d,
3J = 8.0, Н-3,5); 8.17 (2Н, d,
3J = 8.0, Н-2,6)
7.34
7.73
8.39
7.59 (2H, d, 3J = 8.0, H-2,6); 7.92 (2Н, d,
3J = 8.0, H-3,5)
(d, 3J = 8.5)
(dd, 3J = 8.5,
4J = 1.5)
(d, 4J = 1.5)
8.13
7.42
3.89 (3H, s, 3-CH3O); 3.87 (3H, s,
4-CH3O); 7.60 (1Н, d, 4J = 1.5, Н-2);
7.17 (1Н, d, 3J = 8.5, Н-5); 7.81 (1Н,
dd, 3J = 8.5, 4J = 1.5, Н-6)
7.61 (1Н, br. s, H-3); 6.85 (1Н, m,
H-4); 8.17 (1Н, br. s, H-5)
7.58
7.70 (2H, d, 3J = 8.0, H-2,6); 8.07 (2Н, d,
3J = 8.0, H-3,5)
(d, 3J = 8.0)
(dd, 3J = 8.0,
4J = 2.0)
(d, 4J = 2.0)
3i
3j
9.15
9.12
8.14
7.43
7.65
8.32
8.57
7.67 (2H, d, 3J = 8.5, H-2,6); 8.06 (2Н, d,
3J = 8.5, H-3,5)
(d, 3J = 9.0)
(dd, 3J = 8.0,
4J = 1.5)
(d, 4J = 1.5)
8.11
7.56
2.32 (3H, s, CH3CO)
7.39
8.85 (1Н, br. s, H-2); 8.51 (1H, d, J = 8.0, H-4);
7.77 (1H, t, 3J = 8.0, H-5); 8.21 (1H, br. d,
3J = 8.0, H-6)
(d, 3J = 8.5)
(dd, 3J = 8.5,
(d, 4J = 2.0)
4J = 2.0)
3k
3l
9.02
9.01
9.20
9.08
7.80
7.20
1.31 (3Н, t, 3J = 8.0, CH3); 2.66 (2Н,
q, 3J = 8.0, СН2)
7.26
7.84
8.48
8.63
7.96
8.92 (1Н, br. s, H-2); 8.31 (1H, d, J = 8.0, H-4);
7.64 (1H, t, 3J = 8.0, H-5); 8.23 (1H, br. d,
3J = 8.0, H-6)
8.77 (1Н, br. s, H-2); 8.44 (1H, d, 3J = 8.0, H-4);
7.72 (1H, t, 3J = 8.0, H-5); 8.18 (1H, br. d,
3J = 8.0, H-6)
8.90 (1Н, br. s, H-2); 8.55 (1H, d, 3J = 8.0, H-4);
7.81 (1H, t, 3J = 8.0, H-5); 8.25 (1H, br. d,
3J = 8.0, H-6)
8.93 (1Н, br. s, H-2); 8.38 (1H, d, 3J = 8.0, H-4);
7.68 (1H, t, 3J = 8.0, H-5); 8.24 (1H, br. d,
3J = 8.0, H-6)
(d, 3J = 8.5)
(dd, 3J = 8.5,
4J = 2.0)
(d, 4J = 2.0)
8.05
7.18
1.35 (9Н, s, (CH3)3СО)
7.30
(d, 3J = 8.5)
(dd, 3J = 8.5,
4J = 2.0)
(d, 4J = 2.0)
3m
3n
8.14
7.43-7.46
(3Н, m)
2.63 (3H, s, 2-CH3); 7.43-7.46 (2Н, m,
Н-3,5); 7.60-7.64 (1Н, m, Н-4);
8.19 (1Н, d, 3J = 8.0, H-6)
7.60-7.64
(m)
(d, 3J = 8.0)
7.90
7.35
3.93 (3Н, s, 4-CH3О); 7.04 (2Н, d,
3J = 8.0, Н-3,5); 8.18 (2Н, d,
3J = 8.0, Н-2,6)
7.45
(d, 3J = 8.5)
(dd, 3J = 8.5,
4J = 2.0)
(d, 4J = 2.0)

TABLE 2 (continued)
1
2
3
4
5
6
7
8
3o
9.15
8.16
7.42
3.89 (3H, s, 3-CH3O); 3.87 (3H, s,
4-CH3O); 7.60 (1Н, d, 4J = 1.5, Н-2);
7.17 (1Н, d, 3J = 8.5, Н-5); 7.81 (1Н,
dd, 3J = 8.5, 4J = 1.5, Н-6)
7.56
8.60
8.86 (1Н, br. s, H-2); 8.52 (1H, d, 3J = 8.0, H-4);
7.79 (1H, t, 3J = 8.0, H-5); 8.23 (1H, br. d,
3J = 8.0, H-6)
(d, 3J = 8.5)
(dd, 3J = 8.5,
4J = 2.0)
(d, 4J = 2.0)
3p
3q
3r
3s
3t
9.19
9.07
8.95
9.08
9.15
8.97
9.17
8.19
7.44
7.62 (1Н, br. s, H-3); 6.86 (1Н, m,
H-4); 8.17 (1Н, br. s, H-5)
7.69
8.59
8.10
7.58
8.14
8.17
7.55
8.20
8.90 (1Н, br. s, H-2); 8.55 (1H, d, 3J = 8.0, H-4);
7.81 (1H, t, 3J = 8.0, H-5); 8.25 (1H, br. d,
3J = 8.0, H-6)
7.67 (1H, d, 4J = 1.0, H-2); 6.99 (1H, d, 3J = 8.0,
H-5); 7.67 (1H, dd, 3J = 8.0, 4J = 1.0, H-6);
6.09 (2H, s, OCH2O)
7.51 (1H, d, 4J = 1.0, H-2); 6.90 (1H, d, 3J = 8.0,
H-5); 7.45 (1H, dd, 3J = 8.0, 4J = 1.0, H-6);
6.09 (2H, s, OCH2O)
7.66 (1H, d, 4J = 1.0, H-2); 7.01 (1H, d, 3J = 8.0,
H-5); 7.65 (1H, dd, 3J = 8.0, 4J = 1.0, H-6);
6.09 (2H, s, OCH2O)
7.67 (1H, d, 4J = 1.0, H-2); 7.04 (1H, d, 3J = 8.0,
H-5); 7.65 (1H, dd, 3J = 8.0, 4J = 1.0, H-6);
6.09 (2H, s, OCH2O)
7.54 (1H, d, 4J = 1.0, H-2); 6.90 (1H, d, 3J = 8.0,
H-5); 7.54 (1H, dd, 3J = 8.0, 4J = 1.0, H-6);
6.09 (2H, s, OCH2O)
7.69 (1H, d, 4J = 1.0, H-2); 7.05 (1H, d, 3J = 8.0,
H-5); 7.68 (1H, dd, 3J = 8.0, 4J = 1.0, H-6);
6.10 (2H, s, OCH2O)
(dd, 3J = 8.0,
4J = 1.5)
(d, 4J = 1.5)
(d, 3J = 8.0)
8.05
7.25
2.32 (3H, s, CH3CO)
7.37
(d, 3J = 8.5)
(dd, 3J = 8.5,
4J = 1.5)
(d, 4J = 1.5)
7.77
7.17
1.30 (3Н, t, 3J = 8.0, CH3); 2.65 (2Н,
q, 3J = 8.0, СН2)
7.24
(d, 3J = 8.5)
(dd, 3J = 8.5,
4J = 1.5)
(d, 4J = 1.5)
8.08
7.23
1.34 (9Н, s, (CH3)3СО)
7.39
(d, 3J = 8.5)
(dd, 3J = 8.5,
4J = 1.5)
(d, 4J = 1.5)
8.13
(2Н, br. d,
H-2)
7.42-7.45
(3Н, m)
2.62 (3H, s, 2-CH3); 7.42-7.45 (2Н, m,
Н-3,5); 7.60-7.67 (1Н, m, Н-4);
8.13 (1Н, br. d, 3J = 8.0, H-6)
7.60-7.67
(m)
3u
3v
7.76
7.28
3.93 (3Н, s, 4-CH3O); 7.02 (2Н, d,
3J = 8.0, Н-3,5); 8.17 (2Н, d,
3J = 8.0, Н-2,6)
7.34
(d, 3J = 8.5)
(dd, 3J = 8.5,
4J = 1.5)
(d, 4J = 1.5)
8.13
7.43
3.89 (3H, s, CH3O); 3.87 (3H, s,
7.61
(d, 3J = 8.5)
(dd, 3J = 8.5,
4J = 1.5)
(d, 4J = 1.5)
CH3O); 7.60 (1H, d, 4J = 1.5, H-2);
7.18 (1H, d, 3J = 8.0, H-5); 7.83 (1H,
dd, 3J = 8.0, 4J = 1.0, H-6)
3w
9.17
8.13
7.43
7.62 (1Н, br. s, H-3); 6.85 (1Н, m,
H-4); 8.17 (1Н, br. s, H-5)
7.65
(d, 4J = 1.5)
8.20
7.62 (1H, d, 4J = 1.0, H-2); 6.99 (1H, d, 3J = 8.0,
H-5); 7.61 (1H, dd, 3J = 8.0, 4J = 1.0, H-6);
6.09 (2H, s, OCH2O)
(d, 3J = 9.5)
(dd, 3J = 9.5,
4J = 1.5)

TABLE 3. The 1H NMR Spectra of Mannich Bases 4a-p and Hydrochlorides 5a-k
Chemical shifts, δ, ppm (SSCC, J, Hz)*
Com-
pound
Н-5
Coumarin residue
8-СН2
R2
8
of thiazole
(1Н, s)
Н-4 (1H, s)
Н-5*2
Н-6*2
X
6
(2H, s)
1
4a
2
3
4
5
7
8.73
8.72
8.69
6.80
7.44
7.37
7.44
6.79
6.79
4.23
4.08
4.20
1.92 (4Н, m, 2СН2); 2.77 (4Н, m,
2СН2N)
7.01
7.00
6.97
2.52 (3Н, s, CH3)
2.51 (3Н, s, CH3)
2.49 (3Н, s, CH3)
4b
4c
1.7 (3Н, m, СН3); 2.29 (5Н, m,
CH2CHСН2); 3.03 (4Н, m, 2СН2N)
0.93 (5H, m, СН3, 4-СН2); 1.65 (6-Н, m,
3СН2); 2.9 (3Н, m, СH2NCH)
4d
4e
8.92
8.88
7.71
7.67
6.67
6.64
4.07
4.19
2.53 (6Н, s, 2CH3)
8.12
8.14
7.68 (2H, d, 3J = 8.0, H-2,6); 8.05 (2Н, d, 3J = 8.0, H-3,5)
7.67 (2H, d, 3J = 8.0, H-2,6); 8.03 (2Н, d, 3J = 8.0, H-3,5)
1.88 (4Н, m, 2СН2); 2.92 (4Н, m,
2СН2N)
4f
8.94
8.80
8.92
7.74
7.48
7.67
6.74
6.81
6.65
4.05
4.07
4.25
1.55 (6Н, m, 3СН2); 2.71 (4Н, m, 2СН2N)
2.31 (3Н, s, СН3); 2.71 (8Н, m, 4СН2)
8.21
7.38
8.19
7.66 (2H, d, 3J = 8.0, H-2,6); 8.05 (2Н, d, 3J = 8.0, H-3,5)
7.50 (2H, d, 3J = 8.0, H-2,6); 7.84 (2Н, d, 3J = 8.0, H-3,5)
7.65 (2H, d, 3J = 8.0, H-2,6); 8.04 (2Н, d, 3J = 8.0, H-3,5)
4g
4h
1.09 (6Н, m, 2СН3); 1.66 (6H, m,
3СН2); 2.80 (2Н, m, 2СНN)
4i
8.92
8.87
8.95
8.92
8.92
7.74
7.68
7.67
7.77
7.71
6.68
6.63
6.73
6.79
6.71
4.07
4.20
4.06
3.98
4.05
2.50 (6Н, s, 2CH3)
8.39
8.35
8.42
8.39
7.97
8.86 (1Н, br. s, H-2); 8.52 (1H, d, J = 8.0, H-4);
7.79 (1H, t, J = 8.0, H-5); 8.23 (1H, br. d, J = 8.0, H-6)
4j
1.88 (4Н, m, 2СН2); 2.92 (4Н, m,
2СН2N)
8.86 (1Н, br. s, H-2); 8.52 (1H, d, 3J = 8.0, H-4);
7.79 (1H, t, 3J = 8.0, H-5); 8.23 (1H, br. d, 3J = 8.0, H-6)
1.57 (6Н, m, 3СН2); 2.74 (4Н, m,
2СН2N)
8.83 (1Н, br. s, H-2); 8.51 (1H, d, 3J = 8.0, H-4);
4k
4l
7.77 (1H, t, 3J = 8.0, H-5); 8.21 (1H, br. d, 3J = 8.0, H-6)
2.20 (3Н, s, СН3); 2.65 (8Н, m, 4СН2)
8.80 (1Н, br. s, H-2); 8.48 (1H, d, 3J = 8.0, H-4);
7.73 (1H, t, 3J = 8.0, H-5); 8.17 (1H, br. d, 3J = 8.0, H-6)
4m
2.50 (6Н, s, CH3)
7.63 (1H, d, 4J = 1.0, H-2); 7.00 (1H, d, 3J = 8.0, H-5);
7.62 (1H, dd, 3J = 8.0, 4J = 1.0, H-6); 6.07 (2H, s, OCH2O)

TABLE 3 (continued)
1
2
3
4
5
6
7
8
4n
8.90
8.94
7.62
7.73
6.66
6.75
4.19
4.05
1.86 (4Н, m, 2СН2); 2.90 (4Н, m,
2СН2N)
7.95
7.99
7.63 (1H, d, 4J = 1.0, H-2); 7.00 (1H, d, 3J = 8.0, H-5);
7.63 (1H, dd, 3J = 8.0, 4J = 1.0, H-6); 6.07 (2H, s, OCH2O)
4o
4p
1.56 (6Н, m, 3СН2); 2.70 (4Н, m,
2СН2N)
7.63 (1H, d, 4J = 1.0, H-2); 7.00 (1H, d, 3J = 8.0, H-5);
7.63 (1H, dd, 3J = 8.0, 4J = 1.0, H-6); 6.08 (2H, s, OCH2O)
7.62 (1H, d, 4J = 1.0, H-2); 7.00 (1H, d, 3J = 8.0, H-5);
7.61 (1H, dd, 3J = 8.0, 4J = 1.0, H-6); 6.08 (2H, s, OCH2O)
8.95
7.78
6.73
3.99
2.18 (3Н, s, СН3); 2.64 (8Н, m, 4СН2)
8.02
5a
5b
5c
5d
8.99
9.04
9.02
9.08
7.95
7.99
7.98
8.03
7.31
7.28
7.30
7.29
4.40
4.50
4.36
4.42
2.83 (6Н, s, CH3)
8.25
8.31
8.28
8.54
7.65 (2H, d, 3J = 8.0, H-2,6); 8.03 (2Н, d, 3J = 8.0, H-3,5)
7.69 (2H, d, 3J = 8.0, H-2,6); 8.07 (2Н, d, 3J = 8.0, H-3,5)
7.67 (2H, d, 3J = 8.0, H-2,6); 8.06 (2Н, d, 3J = 8.0, H-3,5)
1.99 (4Н, m, 2СН2); 3.44 (4Н, m, 2СН2N)
1.81 (6Н, m, 3СН2); 3.38 (4Н, m, 2СН2N)
2.35 (6Н, s, CH3)
8.87 (1Н, br. s, H-2); 8.55 (1H, d, 3J = 8.0, H-4);
7.79 (1H, t, 3J = 8.0, H-5); 8.23 (1H, br. d, 3J = 8.0, H-6)
5e
5f
9.04
9.01
9.02
9.03
9.05
9.01
9.04
8.00
7.79
8.01
7.97
7.97
7.97
7.79
7.28
7.27
7.67
7.29
7.27
7.29
7.26
4.47
4.30
4.50
4.41
4.20
4.38
4.2
1.99 (4Н, m, 2СН2); 3.40 (4Н, m,
2СН2N)
8.50
8.48
8.49
8.07
8.10
8.07
8.10
8.85 (1Н, br. s, H-2); 8.51 (1H, d, J = 8.0, H-4);
7.77 (1H, t, J = 8.0, H-5); 8.22 (1H, br. d, J = 8.0, H-6)
1.83 (6Н, m, 3СН2); 3.39 (4Н, m,
2СН2N)
8.81 (1Н, br. s, H-2); 8.50 (1H, d, J = 8.0, H-4);
7.76 (1H, t, J = 8.0, H-5); 8.18 (1H, br. d, J = 8.0, H-6)
5g
5h
5i
2.83 (3Н, s, СН3); 3.66 (8Н, m, 4СН2)
8.83 (1Н, br. s, H-2); 8.51 (1H, d, J = 8.0, H-4);
7.77 (1H, t, J = 8.0, H-5); 8.20 (1H, br. d, J = 8.0, H-6)
2.82 (6Н, s, CH3)
7.64 (1H, d, 4J = 1.0, H-2); 7.00 (1H, d, 3J = 8.0, H-5);
7.64 (1H, dd, 3J = 8.0, 4J = 1.0, H-6); 6.08 (2H, s, OCH2O)
2.0 (4Н, m, 2СН2); 3.36 (4Н, m,
2СН2N)
7.66 (1H, d, 4J = 1.0, H-2); 7.02 (1H, d, 3J = 8.0, H-5);
7.67 (1H, dd, 3J = 8.0, 4J = 1.0, H-6); 6.07 (2H, s, OCH2O)
5j
1.84 (6Н, m, 3СН2); 3.82 (4Н, m,
2СН2N)
7.64 (1H, d, 4J = 1.0, H-2); 7.00 (1H, d, 3J = 8.0, H-5);
7.64 (1H, dd, 3J = 8.0, 4J = 1.0, H-6); 6.07 (2H, s, OCH2O)
5k
2.82 (3Н, s, СН3); 3.64 (8Н, m, 4СН2)
7.66 (1H, d, 4J = 1.0, H-2); 7.01 (1H, d, 3J = 8.0, H-5);
7.66 (1H, dd, 3J = 8.0, 4J = 1.0, H-6); 6.07 (2H, s, OCH2O)
_______
* It was not possible to determine the position of the signals for the 7-OH groups on account of their strong broadening.
*2 1H, d, 3J = 9.0-9.5 Hz.

EXPERIMENTAL
The reactions and the purity of the obtained compounds were monitored by TLC on Silufol UV-254
1
plates with 9:1 and 19:1 chloroform–methanol as eluents. The H NMR spectra were measured on Bruker WP
100SY and Varian Mercury 400 instruments (100 and 400 MHz respectively) in DMSO-d6 with TMS as internal
standard.
6- or 7-R1-Substituted 3-(4-R2-2-thiazolyl)coumarins 1a-i. In the smallest amount of ethanol or
2-propanol at 50-60°C we dissolved the substituted salicylaldehyde (100 mmol) and the respective
2-thiazolylacetonitrile (0.1 mol). (During the synthesis of compounds 1e-i a suspension of the indicated amounts
of the reagents in 50 ml of alcohol was prepared.) To the solution we added piperidine (3-5 drops). The reaction
mixture was kept at room temperature for 24 h. The precipitated 2-iminocoumarin was filtered off, washed with
alcohol, and hydrolyzed by boiling with a 3% aqueous solution of sulfuric acid (50 ml) for 6-48 h. The coumarin
that formed was filtered off, washed with water, dried, and crystallized from DMF.
7-Methoxy-3-(4-R2-2-thiazolyl)coumarins 2a-d. To a suspension of the coumarin 1a-d (2.5 mmol) and
freshly calcined potassium carbonate (1 g) in acetone (40 ml) we added dimethyl sulfate (3 mmol). The mixture
was boiled with stirring for 1 h 30 min to 2 h 30 min. The reaction mass was then poured into water (100 ml),
and the precipitated product 2a-d was filtered off, washed with water, dried, and crystallized from DMF.
7-Acyloxy-3-(4-R2-2-thiazolyl)coumarins 3a-w. To a solution or suspension of the 7-hydroxycoumarin
1a-d (2.5 mmol) in pyridine (5 ml) we added the acid anhydride or chloride (5.0 mmol). The mixture was kept at
room temperature for 24 h. The precipitated product 3a-w was filtered off, washed with 2-propanol, dried, and
crystallized from DMF.
8-Aminomethyl-7-hydroxy-3-(4-R2-2-thiazolyl)coumarins 4a-p. A mixture of the coumarin 1a-d
(2.5 mmol) and the respective formaldehyde aminal (3 mmol) was boiled in absolute dioxane (25 ml) until a
transparent solution had formed. The reaction mixture was cooled, and the separated crystals of the product 4a-p
were filtered off and crystallized from DMF.
The Hydrochlorides of the Mannich Bases 4a-p (5a-k). A solution of the aminomethyl derivative of
coumarin 4a-p (0.2 g) in the smallest amount of chloroform was saturated with hydrogen chloride and kept at
room temperature for 20-30 min. The crystals that separated were filtered off and washed with chloroform.
Compound 5b. Found, %: Cl 12.61. C23H21BrCl2N2O3S. Calculated, %: Cl 12.75.
Compound 5c. Found, %: Cl 12.17. C24H23BrCl2N2O3S. Calculated, %: Cl 12.43.
Compound 5d. Found, %: Cl 14.09. C21H19Cl2N3O5S. Calculated, %: Cl 14.27.
Compound 5e. Found, %: Cl 13.32. C23H21Cl2N3O5S. Calculated, %: Cl 13.57.
Compound 5f. Found, %: Cl 13.02. C24H23Cl2N3O5S. Calculated, %: Cl 13.22.
Compound 5g. Found, %: Cl 12.99. C24H24Cl2N4O5S. Calculated, %: Cl 12.86.
Compound 5h. Found, %: Cl 14.31. C21H20Cl2N2O5S. Calculated, %: Cl 14.31.
Compound 5i. Found, %: Cl 13.87. C24H22Cl2N2O5S. Calculated, %: Cl 13.60.
Compound 5j. Found, %: Cl 13.09. C25H24Cl2N2O5S. Calculated, %: Cl 13.24.
Compound 5k. Found, %: Cl 12.73. C25H25Cl2N3O5S. Calculated, %: Cl 12.88.
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