Solution-phase Synthesis of a Combinatorial Library of 3-[4-(Coumarin3-yl)-1,3-thiazol-2-ylcarbamoyl]propanoic acid Amides

Abstract

The parallel solution-phase synthesis of a new combinatorial library of 3-[4-(R1-coumarin-3-yl)-1,3-thiazol-2-ylcarbamoyl]propanoic acid amides 9 has been developed. The synthesis involves two steps: 1) the synthesis of core building blocks - 3- [4-(coumarin-3-yl)-1,3-thiazol-2-ylcarbamoyl]propanoic acids, 6 - by the reaction of 3-(omega-bromacetyl)coumarins 1 with 3-amino(thioxo)methylcarbamoylpropanoic acid (5); 2) the synthesis of the corresponding 3-[4-(coumarin-3-yl)-1,3-thiazol-2-yl- carbamoyl]propanoic acids amides 9 using 1,1'-carbonyldimidazole as a coupling reagent. The advantages of the method compared to existing ones are discussed.

Full text

Molecules 2005, 10, 444–456
molecules
ISSN 1420-3049
http://www.mdpi.org
Solution-phase Synthesis of a Combinatorial Library of 3-[4-
(Coumarin-3-yl)-1,3-thiazol-2-ylcarbamoyl]propanoic acid
Amides
Irina O. Zhuravel *, Sergiy M. Kovalenko, Sergiy V. Vlasov and Valentin P. Chernykh
National Pharmaceutical University, Kharkiv, Ukraine
* Author to whom correspondence should be addressed; E-mail: kosn@ic.kharkov.ua
Received: 27 August 2004; in revised form: 23 December 2004 / Accepted: 24 December 2004 /
Published: 28 February 2005
Abstract: The parallel solution-phase synthesis of a new combinatorial library of
3-[4-(R1-coumarin-3-yl)-1,3-thiazol-2-ylcarbamoyl]propanoic acid amides 9 has been
developed. The synthesis involves two steps: 1) the synthesis of core building blocks – 3-
[4-(coumarin-3-yl)-1,3-thiazol-2-ylcarbamoyl]propanoic acids, 6 – by the reaction of
3-(ω-bromacetyl)coumarins 1 with 3-amino(thioxo)methylcarbamoylpropanoic acid (5);
2) the synthesis of the corresponding 3-[4-(coumarin-3-yl)-1,3-thiazol-2-yl-
carbamoyl]propanoic acids amides 9 using 1,1’-carbonyldimidazole as a coupling reagent.
The advantages of the method compared to existing ones are discussed.
Keywords: Coumarin derivatives, 2-aminothiazole derivatives, dicarboxylic acids,
combinatorial synthesis.
Introduction
2-Aminothiazole derivatives are widely used as pharmaceuticals. For example, Talipexol [1] and
Pramipexole [2] with a 2-aminothiazole moiety are used as antiparkinsonian drugs and dopamine
agonists; Tigemonam [3] is an antibacterial drug and Amthamine [4] is known as an antiasthmatic one.
It is also known that heterocyclic compounds with free amino groups may exhibit teratogenic and
mutagenic properties because of their ability to form non-covalent complexes with DNA [5,6]. That is

Molecules 2005, 10
445
why 2-aminothiazole derivatives with an acylated amino group may be of interest as potentially less
toxic drugs with a wide variety of pharmacological activities.
A number of publications have described the synthesis of 2-aminothiazoles, N-acylated with
aliphatic [7 – 11], aromatic [7, 8, 10] and dicarboxylic acids [10, 12 – 17]. The importance of such
derivatives is due to their biological properties; for example, some of them show significant
bacteriostatic [7], tuberculostatic [8], hypoglycemic, anti-inflammatory, diuretic and fungicidal
activities [10], and some of them are useful for treating of asthma [14].
However, there are only a few publications describing syntheses of 3-(N-acyl-2-amino-1,3-thiazol-
4-yl)coumarin derivatives. These papers described syntheses of N-acetyl-N-allylamino-4-thiazolyl-
coumarins [18], N-chloroacetamido derivatives [19], and N-benzoyl derivatives, which displayed
significant analgesic and anti-inflammatory activity [20]. Some derivatives of N-[4-(R-coumarin-3-yl)-
2-thiazolyl]oxamates possess antiallergic, antianaphylactic and antiarthritic activity [21]. 2-Amino-4-
(coumarin-3-yl)thiazoles were also acylated with the cycloaddition product of methacrilic acid and
anthracene [22]. These compounds are glucocorticoid receptor modulators which are useful in treating
diabetes, inflammatory and immune diseases.
In spite of the above mentioned activities of the corresponding oxamates, their succinic analogues
have not been synthesized, though they may possess a great pharmacological potential. The aim of this
work was to develop a method and detailed procedures suitable for solution-phase parallel synthesis of
a library of 3-[4-(R
1
-coumarin-3-yl)-1,3-thiazol-2-ylcarbamoyl]propanoic acid amides.
Results and Discussion
Different substituted 3-(ω-bromoacetyl)-R
1
-coumarins 1{1-5} [23] were used as starting
compounds for the library synthesis. The synthesis of the core building blocks, 3-[4-(R
1
-coumarin-3-
yl)-1,3-thiazol-2-ylcarbamoyl]propanoic acids 6{1-5}, has been carried out by two methods (Scheme
1).
Scheme 1. The synthesis of 3-[4-(R
1
-coumarin-3-yl)-1,3-thiazol-2-ylcarbamoyl]-
propanoic acids 6{1-5}.
O
O
N
S
NH
2
O
O
N
S
N
H
O
O
OH
O
O
O
O
O
CH
2
Br
O
NH
2
N
H
S O
O
OH
R
1
R
1
NH
2
NH
2
S
4
2
6{1-5}
1{1-5}
5
route i
route ii
3{1}
According to the first pathway (route i, Scheme 1), 2-amino-4-(coumarin-3-yl)thiazole 3{1} was
obtained by reaction of 3-(ω-bromoacetyl)coumarine 1{1} with thiourea (2), then it was directly

Molecules 2005, 10
446
acylated with succinic anhydride (4). Generally heterocyclic amines are acylated by succinic anhydride
in ethyl acetate [16], acetone [13], benzene [13] or glacial acetic acid media. We performed this
synthesis both in benzene and glacial acetic acid, obtaining 6{1} in yields of 48 and 52 %, respectively.
The second pathway (route ii, Scheme 1) involves synthesis of the intermediate 3-amino(thioxo)-
methylcarbamoylpropanoic acid (5), by the acylation of thiourea (2) with succinic anhydride (4) [24].
Then the reaction of 5 in boiling ethanol or acetic acid for 10 – 25 minutes with 3-(ω-bromoacetyl)-R
1
-
coumarins 1{1-5} yielded 3-[4-(R
1
-coumarin-3-yl)-1,3-thiazol-2-ylcarbamoyl]propanoic acids 6{1-5}.
In this case the reaction was carried out in solution to facilitate the interaction. The product 6{1}
obtained by both methods found to be identical by m.p. and
1
H-NMR. However, the second route
afforded compound 6{1} in better yield and purity, and it was thus used to prepare compounds 6{2-5}
(Tables 1 and 2). Consequently the use of 3-amino(thioxo)methylcarbamoylpropanoic acid (5) (route ii,
Scheme 1) for the synthesis of core building blocks, 3-[4-(R
1
-coumarin-3-yl)-1,3-thiazol-2-
ylcarbamoyl]propanoic acids 6, has been found to be the preferable approach.
Table 1. Physico-chemical data of 3-[4-(R
1
-coumarin-3-yl)-1,3-thiazol-2-yl-
carbamoyl]propanoic acids
Code R
1
Yield, % (route ii) Time of reaction M.p. °C
6{1}
H 72 10 min 260-61
6{2}
8-OCH
3
83 15 min >300
6{3}
6-Cl 85 25 min 276-78
6{4}
7-OCH
3
78 15 min 215-16
6{5}
8-OCH
2
CH
3
76 15 min 255-56
Table 2. IR and
1
H-NMR spectra of 3-[4-(R
1
-coumarin-3-yl)-1,3-thiazol-2-ylcar-
bamoyl]propanoic acids
IR-spectra
1
H-NMR -spectra
Code
ν N-H
ν С-H
ν C=O
ν C=N
ν C=C
Coumarin ring, R
1
s, 1H,
H-4
s, 1H,
H-5-
thiazole
-CH
2
CH
2
- NH, OH
6{1}
3455,
3412,
3142,
2980
1721,
1684,
1608,
1574
7.37 (t, 1Н, Н-6),
7.45 (d, 1Н, Н-8),
7.63 (t, 1Н, Н-7),
7.82 (d, 1H, Н-5)
8.56 7.95 2.52 (t,
2Н), 2.64
(t, 2Н)
12.17 (s, 1H),
12.34 (s, 1H)
6{2}
3445,
3140,
2966
1723,
1686
1579
3.92 (s, 3Н, OCH
3
),
7.33 (m, 3H, Ar)
8.54 7.96 2.50 (t,
2Н), 2.67
(t, 2Н)
12.15 (s, 1H),
12.33 (s, 1H)
6{3}
3447,
3134,
3050,
2828
1706,
1688
1560
7.45 (d, 1Н, H-8),
7.63 (dd, 1Н, H-7),
7.95 (d, 1H, H-5)
8.47
7.94 2.57 (t,
2Н), 2.69
(t, 2Н)
12.22 (s, 1H),
12.33 (s, 1H)
6{4}
3420,
3300,
3063,
2891
1708,
1671,
1612,
1555
3.87 (s, 3Н, OCH
3
),
6.97 (dd, 1Н, H-6),
7.06 (s, 1Н, H-8),
7.72 (d, 1H, H-5)
8.51 7.87 2.50 (t,
2Н), 2.64
(t, 2Н)
12.15 (s, 1H),
12.33 (s, 1H)
6{5}
3441,
3151,
2985,
2893
1726,
1687,
1578
1.33 (t, 3H, OСН
2
СН
3
),
4.15 (q, 2H,
OСН
2
СН
3
),
7.32 (m, 3H, Ar)
8.54 7.97 2.53 (t,
2Н), 2.64
(t, 2Н)
12.15 (s, 1H),
12.33 (s, 1H)

Molecules 2005, 10
447
For the synthesis of amides of 3-[4-(R
1
-coumarin-3-yl)-1,3-thiazol-2-ylcarbamoyl]propanoic acids
9 several approaches were also developed (Scheme 2).
Scheme 2. The synthesis of 3-[4-(R
1
-coumarin-3-yl)-1,3-thiazol-2-ylcarbamoyl]-
propanoic acid amides 12
O O
N
S
N
O
O
O O
N
S
N
H
O
O
OH
O O
N
S
N
H
O
O
N
R
2
R
3
N N
O
N
N
O O
N
S
N
H
O
O
N
N
R
1
R
1
R
1
R
1
Ac
2
O, AcONa
HNR
2
R
3
HNR
2
R
3
route i
route ii
6{1-5}
7{1-4}
10{1-5}
8{1-5}
9{1-108}
8{1-24}
Earlier we had reported the synthesis of some amides of 3-[4-(coumarin-3-yl)-1,3-thiazol-2-
ylcarbamoyl]propanoic acid starting from the methyl ester of 6{1} [25]. However, this method gave
poor yields of the products (27 – 42%), due to the possibility of re-amidation as a side reaction and
formation of succinic acid diamide as a by-product.
We have more succesfully applied another two methods: one of them (route i, Scheme 2) involves
utilization of 3-[4-(R
1
-coumarin-3-yl)-1,3-thiazolyl-2-N-pyrrolidin-2,5-diones 7 as key intermediates
for synthesis of 9{1-3} [26] and the other one is the method using 1,1’-carbonyldimidazole as a
coupling reagent (route ii, Scheme 2).
In accordance with the first method (route i, Scheme 2) the initial step is the synthesis of 3-[4-(R
1
-
coumarin-3-yl)-1,3-thiazolyl-2-N-pyrrolidin-2,5-diones 7{1-4} (59 – 96%), which was performed by
heating the corresponding acids 6 in acetic anhydride in the presence of sodium acetate. The
pyrrolidindiones 7 were then treated in dioxane for 1-3 hours with a series of primary amines to form
the corresponding amides 9{2, 3, 10, 14, 18, 22, 23, 26}. However, the heterogeneous conditions of
this procedure and steric difficulties make this method unsuitable for the synthesis of the combinatorial
library.
According to the second method N
1
-[4-(R
1
-coumarin-3-yl)-1,3-thiazol-2-yl]-4-(1H-1-imidazol-
yl)oxobutanamides 10{1-5}, which were generated in situ using 1,1’-carbonyldimidazole, were directly
treated with corresponding amines 8{1-24}. The reaction was carried out at 80°C using a 10% excess
of amine. This method provided high yields of amides 9 and appeared to be suitable for application to
solution-phase parallel synthesis methods.

Molecules 2005, 10
448
Using this method the combinatorial library of 108 amides of 3-[4-(R
1
-coumarin-3-yl)-1,3-thiazol-
2-ylcarbamoyl]propanoic acid 9 has been accomplished. For illustration purposes 37 arbitrary
compounds synthesized 9{1-37} and their physico-chemical data are listed in the Table 3.
The structures of the compounds 6 and 9 have been confirmed by elemental analysis,
1
H-NMR and
IR spectra. (Tables 2, 3 and 4). The
1
H-NMR spectra of the compounds 6{1-5} showed a broad signal
for the OH proton at δ 12.33 – 12.34 ppm and a NH signal at 12.15 – 12.22 ppm, whereas the
corresponding amides 9 were characterised by two broad NH signals at 7.53 – 8.47 ppm and 12.30 –
12.41 ppm in the case of primary amides and only one signal at 11.95 – 12.25 ppm in the case of
secondary amides. The protons of the succinic acid moiety showed two triplets at 2.52 (2H) and 2.64
(2H) for the most of compounds 9 but in the case of the morpholinyl and N-methylpiperazinyl amides
(9{5}, 9{12} and 9{37}) their signals are observed as singlet (4H) protons at 2.59 for 9{5}, 9{12} and
at 2.65 ppm for 9{37}. The IR spectra of all compounds exhibited strong absorption bands 1726 – 1684
сm
-1
(νC=O) and a broad band at 3445 – 3420 сm
-1
(νO–H) in the case of 3-[4-(R
1
-coumarin-3-yl)-1,3-
thiazol-2-ylcarbamoyl]propanoic acids 6; amides 9 have NH bands at 3448 – 3176 сm
-1
.
Conclusions
Two alternative approaches for synthesis of 3-[4-(R
1
-coumarin-3-yl)-1,3-thiazol-2-
ylcarbamoyl]propanoic acids 6 have been compared. In the first pathway (route i) 3-(2-amino-1,3-thi-
azol-4-yl)-coumarine 3{1} was directly acylated with succinic anhydride (4) in benzene or in glacial
acetic acid medium, in the second method (route ii) we used the Hantsch reaction between 3-(ω-
bromacetyl)oumarins 1{1-5} and 3-amino(thioxo)methylcarbamoylpropanoic acid (5). However, the
second route has been found to afford the targets 6 in better yields and purity. The choice of the
synthetic method for a new combinatorial library of 3-[4-(R
1
-coumarin-3-yl)-1,3-thiazol-2-yl-
carbamoyl]propanoic acid amides 9 by the solution-phase parallel synthesis method has been
established. Using this method the combinatorial library of 108 amides of 3-[4-(R
1
-coumarin-3-yl)-
1,3-thiazol-2-ylcarbamoyl]propanoic acid 9 has been accomplished.
Table 3. Physico-chemical data of 3-[4-(R
1
-coumarin-3-yl)-1,3-thiazol-2-ylcarbamo-
yl]propanoic acids amides
Structure IR-spectral data
Code
R
1
= H
Molecular
formula, M.w.
M.p.,
°C
Yield,
%
N, %,
calc/
found
ν N-H ν C=O
ν C=N
ν C=C
9{1}
NH
*
C
23
H
25
N
3
O
4
S
439.54
262-63 77 9.56
9.60
3320 1696 1642
1604
1538
9{2}
NH
*
C
22
H
23
N
3
O
4
S
425.51
278-80 85 9.88
9.85
3316
3292
1696 1644
1604
1537
9{3}
NH
*
Cl
C
23
H
18
ClN
3
O
4
S
467.93
244-46 65 8.98
9.01
3317
3292
1696 1643
1604
1538
9{4}
NH
*
O
CH
3
O CH
3
C
26
H
25
N
3
O
6
S
507.57
228-30 73 8.28
8.30
3344 1719
1686
1641
1605
1547

Molecules 2005, 10
449
Table 3. Cont.
Structure IR-spectral data
Code
R
1
= H
Molecular
formula, M.w.
M.p.,
°C
Yield,
%
N, %,
calc/
found
ν N-H ν C=O
ν C=N
ν C=C
9{5}
O
N
*
C
20
H
19
N
3
O
5
S
413.46
273-75 60 10.16
10.15
3176 1719 1627
1648
1527
9{6}
N
*
C
25
H
21
N
3
O
4
S
459.53
259-61 78 9.14
9.15
3423
3256
1711 1616
1546
9{7}
N
N
*
C
28
H
28
N
4
O
4
S
516.62
243-45 92 11.15
11.14
3407
3314
3295
1695 1641
1544
9{8}
NH
*
N
O
C
23
H
26
N
4
O
5
S
470.55
239-41 90 11.91
11.88
3407
3340
3244
1699 1656
1553
9{9}
NH
*
N
CH
3
C
26
H
32
N
4
O
5
S
512.63
182-84 65 10.93
10.94
3254 1728 1640
1605
1549
R1= 8-OCH
3
9{10}
NH
*
O
O
C
25
H
21
N
3
O
7
S
507.53
253-55 73 8.28
8.31
3255 1720 1647
1604
1577
9{11}
NH
*
O
CH
3
O CH
3
C
23
H
25
N
3
O
4
S
439.54
252-53 89 7.82
7.82
3344 1710
1688
1634
1607
1577
9{12}
O
N
*
C
21
H
21
N
3
O
6
S
443.48
272-73 63 9.48
9.50
3245 1720
1691
1628
1573
9{13}
NH
*
CH
3
C
26
H
25
N
3
O
5
S
491.57
252-54 76 8.55
8.54
3408
3294
1700 1642
1545
9{14}
NH
*
Cl
C
25
H
22
ClN
3
O
5
S
511.99
275-77 72 8.21
8.23
3292 1700 1647
1572
1548
9{15}
NH
*
CH
3
C
24
H
27
N
3
O
5
S
469.56
257-59 58 8.95
8.97
3430
3301
1688 1637
1545
9{16}
NH
*
NH
2
O
C
23
H
24
N
4
O
6
S
484.53
306-08 47 11.24
11.27
3448
3252
3223
1726
1694
1656
1624
1550
9{17}
NH
*
O
C
22
H
19
N
3
O
6
S
453.48
281-82 63 9.27
8.28
3355
3236
1719
1686
1650
1571
1547
9{18}
NH
*
Cl
C
24
H
20
ClN
3
O
5
S
497.96
282-83 68 8.44
8.43
3426
3293
1700 1639
1575
1545
9{19}
N
*
C
26
H
23
N
3
O
5
S
489.55
259-60 73 8.58
8.58
3408
3236
1721
1688
1627
1544

Molecules 2005, 10
450
Table 3. Cont.
Structure IR-spectral data
Code
R
1
= H
Molecular
formula, M.w.
M.p.,
°C
Yield,
%
N, %,
calc/
found
ν N-H ν C=O
ν C=N
ν C=C
9{20}
NH
*
O
CH
3
C
22
H
18
ClN
3
O
5
S
471.92
274-75 83 8.90
8.94
3407
3334
3244
1704 1649
1547
9{21}
NH
*
N
C
28
H
27
ClN
4
O
4
S
551.07
259-60 87 10.17
10.18
3448
3255
1736 1666
1556
9{22}
NH
*
Cl
C
24
H
19
Cl
2
N
3
O
4
S
516.41
246-47 76 8.14
8.15
3360 1726 1657
1640
1557
1534
9{23}
NH
*
C
23
H
24
ClN
3
O
4
S
473.98
255-56 69 8.87
8.91
3252 1734 1657
1632
1556
1547
9{24}
NH
*
N
C
23
H
25
ClN
4
O
4
S
489.00
229-30 56 11.46
11.45
3366
3348
3238
1704 1659
1552
9{25}
NH
*
O
CH
3
O CH
3
C
26
H
24
ClN
3
O
6
S
542.01
243-45 74 7.75
7.74
3360
3179
1729
1655
1547
R1= 7-OCH
3
9{26}
NH
*
C
23
H
25
N
3
O
5
S
455.54
270-72 66 9.22
9.22
3292
3228
1708
1684
1644
1612
1564
1540
9{27}
NH
*
Cl
C
25
H
22
ClN
3
O
5
S
511.99
249-50 72 8.21
8.25
3324
3288
3256
1716 1664
1648
1552
9{28}
NH
*
N
CH
3
C
25
H
30
N
4
O
5
S
498.61
196-98 56 11.24
11.21
3360
3248
1716
1688
1648
1620
1560
9{29}
NH
*
O
C
22
H
19
N
3
O
6
S
453.48
307-08 63 9.27
9.31
3360
3232
1716
1688
1648
1616
1548
1540
9{30}
NH
*
O
CH
3
C
23
H
21
N
3
O
6
S
467.50
277-79 82 8.99
8.98
3364
3236
1724
1712
1688
1648
1616
1548
9{31}
NH
*
C
22
H
23
N
3
O
5
S
441.51
267-68 66 9.52
9.50
3228 1708
1696
1684
1648
1620
1540
R1=8-OCH
2
CH
3
9{32}
NH
*
C
28
H
27
N
3
O
5
S
517.61
301-02 79
8.12
8.16
3308
1720
1696
1616
1604
1540

Molecules 2005, 10
451
Table 3. Cont.
Structure IR-spectral data
Code
R
1
= H
Molecular
formula, M.w.
M.p.,
°C
Yield,
%
N, %,
calc/
found
ν N-H ν C=O
ν C=N
ν C=C
9{33}
NH
*
N
CH
3
C
27
H
34
N
4
O
5
S
526.66
210-12 71
10.64
10.65
3280
1708
1684
1616
1604
1544
9{34}
NH
*
N
C
25
H
30
N
4
O
5
S
498.61
208-10 53 11.24
11.28
3332
3280
1708
1684
1648
1616
1604
1572
1544
9{35}
NH
*
N
CH
3
C
29
H
32
N
4
O
5
S
548.67
230-32 87 10.21
10.23
3356 1720
1688
1644
1604
1552
9{36}
NH
*
N
CH
3
C
26
H
32
N
4
O
5
S
512.63
213-15 62 10.93
10.95
3304 1720
1700
1652
1604
1572
1544
9{37}
N
N
*
CH
3
C
23
H
26
N
4
O
5
S
470.55
259-61 56 11.91
11.96
3439
3258
1718
1695
1624
1557
Experimental
General
The melting points were measured with a Buchi В-520 melting point apparatus and are not
corrected. IR spectra were recorded on Specord M80 spectrometers in KBr.
1
H-NMR spectra were
recorded on Varian WXR-400 (200 MHz) and Bruker DRX-500 (500 MHz) spectrometers in DMSO-
D
6
or CDCl
3
using TMS as an internal standard (chemical shifts are reported in ppm). 3-(ω-
Bromacetyl)-R
1
-coumarins 1{1-5} were prepared according to a reported method [23].
3-(2-Amino-1,3-thiazol-4-yl)coumarin (3{1}). Thiourea (2, 0.38 g, 5 mmol) was added to the solution
of 3-(ω-bromacetyl)coumarin (1, 1.34 g, 5 mmol) in boiling ethanol (20 mL). The mixture was
refluxed for 1 hour, then cooled and neutralized with aqueous ammonia. The precipitate was filtered
off, washed with ethanol and used directly without crystallization or other purification. Yield 84%, m.p.
225-226°C.
3-Amino(thioxo)methylcarbamoylpropanoic acid (5). Thiourea (2, 3.8 g, 50 mmol) and succinic
anhydride (4, 5.0 g, 50 mmol) were well mixed, then this mixture was placed in a 25 mL round-
bottomed flask equipped with a magnetic stirrer and heated in an oil bath at 150°C for 10 minutes;
without any other additional solvent. Then the reaction mixture had cooled, the flask was broken and

Molecules 2005, 10
452
the resulting product was crystallized from 10 % acetic acid to form yellow crystals of the title
compound. Yield 80%, m.p.210-211°С [24].
General method for synthesis of 3-[4-(R
1
-coumarin-3-yl)-1,3-thiazol-2-ylcarbamoyl]propanoic acids
(6{1-5}).
Route i
A mixture of 3-(2-amino-1,3-thiazol-4-yl)coumarin (3{1}, 2.44 g, 10 mmol) and dihydrofuran-2,5-
dione (4, 1.0 g, 10 mmol) was heated in benzene (25 mL) with the addition of glacial acetic acid (1.5
mL) (Method A) or in glacial acetic acid (30 mL) (Method B). The reaction mixture was refluxed for 2
– 3 h and then cooled. The solid formed was filtered off, dried and recrystallized from dioxane. Yield
48%, m.p. 260-261°С.
Route ii
3-Amino(thioxo)methylcarbamoylpropanoic acid (5, 1.76 g, 10 mmol) was added to the solution of
the corresponding 3-(ω-bromacetyl)-R
1
-coumarin 4 (10 mmol) in glacial acetic acid (30 mL) or
ethanol (30 mL). The reaction mixture was heated under a condenser for 15 – 20 minutes, then cooled
and diluted with water. The precipitate formed was filtered off, washed with water and crystallized
from glacial acetic acid. Yield 72%, m.p.=260-261°С.
3-[4-(R
1
-coumarin-3-yl)-1,3-thiazolyl-2-N-pyrrolidin-2,5-diones (7{1-4}) were prepared according to
the reported method [26].
Synthesis of 3-[4-(R
1
-coumarin-3-yl)-1,3-thiazol-2-ylcarbamoyl]propanoic acid amides 9{2, 3, 10, 14,
18, 22, 23, 26} (Route i)
To a suspension of the corresponding 3-[4-(R
1
-coumarin-3-yl)-1,3-thiazolyl-2-N-pyrrolidin-2,5-
dione 7 (10 mmol) in anhydrous dioxane (30 mL) an appropriate primary amine 8 (15 mmol) was
added. The reaction mixture was refluxed for 1 – 3 h. After cooling the mixture was poured into cold
water (50 mL) to form a precipitate of the corresponding amide. Solids were filtered off and purified
by crystallization from a DMF – ethanol mixture.
Synthesis of 3-[4-(R
1
-coumarin-3-yl)-1,3-thiazol-2-ylcarbamoyl]propanoic acid amides 9{1-108}
(Route ii)
A solution of 1,1’-carbonyldiimidazole (7, 27 mmol) in anhydrous dioxane (120 mL) was added to
the stirred suspension of the corresponding 3-[4-(R
1
-coumarin-3-yl)-1,3-thiazol-2-ylcarbamoyl]-
propanoic acid 6 (24 mmol) in anhydrous dioxane (240 mL) at 90°C. The mixture was stirred at reflux
for 2 h, then the solution was cooled and dispensed into 24 combinatorial vials (15 mL per vial). The
appropriate primary or secondary amine 8{1-24} (1.1 mmol) was then added to these aliquots by
injection and the resulting mixtures were heated at 80°C for 12 hours. After cooling each portion was
poured into cold water (50 mL) to form the precipitate of the corresponding amide. The solids
separated were filtered off and purified by crystallization from a DMF – 2-propanol mixture.

Molecules 2005, 10
453
Table 4.
1
H-NMR -spectra of 3-[4-(R
1
-coumarin-3-yl)-1,3-thiazol-2-ylcarbamoyl]propanoic acids amides
Code Coumarin ring, R
1
s, 1H,
H-4
s, 1H,
H-5-
thiazole
-CH
2
CH
2
- NH R2, R3
9{1}
7.37 (t, 1Н, Н-6), 7.47 (d, 1Н, Н-8),
7.63 (t, 1Н, Н-7), 7.83 (d, 1H, Н-5)
8.55 7.65 2.38 (t, 2Н),
2.65 (t, 2Н)
7.81 (br.d, 1H),
12.30 (s, 1H)
1.30 – 1.65 (m, 12Н), 3.68 (s, 1Н)
9{2}
7.38 (t, 1Н, H-6), 7.44 (d, 1Н, H-8),
7.63 (t, 1Н, H-7), 7.83 (d, 1H, H-5)
8.52 7.96 2.38 (t, 2Н),
2.65 (t, 2Н)
7.73 (br.d, 1H),
12.41 (s, 1H)
1.10 (m, 5Н), 1.60 (m, 5Н), 3.48 (s, 1Н)
9{3}
7.35 (t, 1Н, H-6), 7.43 (d, 1Н, H-8),
7.63 (t, 1Н, H-7), 7.83 (d, 1H, H-5)
8.56 7.77 2.38 (t, 2Н),
2.65 (t, 2Н)
8.44 (br.d, 1H),
12.18 (s, 1H)
4.32 (d, 2Н, CH
2
), 7.30 (m, 4Н, Ar)
9{4}
7.35 (t, 1Н, H-6), 7.46 (d, 1Н, H-8),
7.62 (t, 1Н, H-7), 7.82 (d, 1H, H-5)
8.51 7.99 2.52 (t, 2Н),
2.78 (t, 2Н)
7.99 (br.t, 1H),
12.30 (s, 1H)
2.60 (t, 2Н, CH
2
CH
2
), 3.20 (q, 2Н, CH
2
CH
2
),
3.70 (s, 6Н, 2OCH
3
), 6.40 (d, 1Н), 6.65 (d, 2Н)
9{5}
7.36 (t, 1Н, H-6), 7.42 (d, 1Н, H-8),
7.60 (t, 1Н, H-7), 7.79 (d, 1H, H-5)
8.55 7.95 2.65 (s, 4H) 12.1 (s, 1H)
3.47 (br.d, 8Н, 4CH
2
)
9{6}
7.39 (t, 1Н, H-6), 7.46 (d, 1Н, H-8),
7.64 (t, 1Н, H-7), 7.83 (d, 1H, H-5)
8.58 7.98 2.72 (m, 4Н) 12.18 (s, 1H) 2.89 (d, 2H, CH
2
), 3.69 (d, 2H, CH
2
),
4.62 (d, 2H, CH
2
),7.18 (m, 4H, Ar)
9{7}
7.37 (t, 1Н, H-6), 7.44 (d, 1Н, H-8),
7.63 (t, 1Н, H-7), 7.82 (d, 1H, H-5)
8.62 7.96 2.40 (t, 2Н),
2.65 (m, 2Н)
7.25 (m, 1Н),
12.23 (s, 1H)
1.33 (t, 2H, СН
2
), 1.62 (d, 2H, СН
2
),
1.95 (t, 2H, СН
2
), 2.65 (m, 2H, СН
2
),
3.37 (s, 2H, CH
2
Ar), 3.50 (m, 1Н, СH),
7.25 (m, 5Н Ar)
9{8}
7.37 (t, 1Н, H-6), 7.43 (d, 1Н, H-8),
7.63 (t, 1Н, H-7), 7.79 (d, 1H, H-5),
8.54 7.94 2.43 (t, 2Н),
2.68 (t, 2Н)
7.69 (m, 1Н),
12.12 (s, 1H)
1.53 (m, 2H, CH
2
), 2.26 (m, 6H, 3CH
2
),
3.07 (q, 2H, CH
2
), 3.55 (m, 4H, 2CH
2
)
9{9}
3.80 (s, 3Н, OCH
3
), 7.65 (m, 3H) 8.55 7.99 2,38 (t, 2Н),
2,65 (t, 2Н)
7.87 (t, 1H) 0.60 (t, 3H, CH
3
), 1.07 (dt, 2H, CH
2
),
1.40 (m, 1Н, CH), 1.45 (m, 4H, 2CH
2
),
1.75 (t, 2H, CH
2
), 2.70 (m, 4H 2CH
2
),
3.05 (q, 2H, CH
2
)
9{10}
3.85 (s, 3Н, OCH
3
), 7.32 (m, 3H) 8.52 7.99 2.40 (t, 2Н),
2.60 (t, 2Н)
8.35 (t, 1H),
12.32 (s, 1H)
4.15 (d, 2Н, CH
2
), 5.95 (s, 1Н, OCH
2
O),
6.37 (d, 1Н), 6.51 (d, 2Н)
9{11}
3.91 (s, 3Н, OCH
3
), 7.32 (m, 3H) 8.52 7.95 2.40 (t, 2Н),
2.63 (t, 2Н)
7.90 (br.t, 1H),
12.24 (s, 1H)
2.65 (t, 2Н, CH
2
), 3.15 (q, 2Н, CH
2
),
3.66 (s, 3H, OCH
3
), 3.71 (s, 3Н, OCH
3
),
6.20 (d, 1Н), 6.78 (d, 2Н)
9{12}
3.89 (s, 3Н, OCH
3
), 7.28 (m, 3H) 8.49 7.92 2.65 (s, 4Н) 12.20 (s, 1H) 3.45 (br.d, 8Н, 4CH
2
)
9{13}
3.94 (s, 3Н, OCH
3
), 7.31 (m, 3H) 8.54 7.96 2.39 (t, 2Н),
2.65 (t, 2Н)
7.89 (m, 1H),
12.22 (s, 1H)
2.65 (m, 2H, СН
2
), 3.15 (s, 2H, CH
2
),
7.06 (s, 4H)
9{14}
3.92 (s, 3Н, OCH
3
), 7.27 (m, 3Н) 8.52 7.94 2.35 (t, 2Н),
2.62 (t, 2Н)
7.97 (br.t, 1H),
12.19 (s, 1H)
2.78 (t, 2Н, CH
2
), 3.20 (s, 2H, CH
2
),
7.27 (m, 4Н)
9{15}
3.94 (s, 3Н, OCH
3
), 7.30 (m, 3H) 8.53 7.96 2.39 (t, 2Н),
2.65 (m, 2Н),
7.53 (br.d, 1H),
12.25 (s, 1H)
0.80 (d, 3Н, СН
3
), 1.40 (m, 8H, 4СН
2
),
1.73 (m, 2Н, 2СН)

Molecules 2005, 10
454
Table 4. Cont.
Code Coumarin ring, R
1
s, 1H,
H-4
s, 1H,
H-5-
thiazole
-CH
2
CH
2
- NH R2, R3
9{16}
3.87 (s, 3Н, OCH
3
), 7.25 (m, 3H) 8.49 7.93 2.59 (s, 4Н) 12.12 (s, 1H) 1.40 (m, 4H, 2CH
2
), 2.23 (t, 2Н, CH
2
),
2.99 (t, 2Н, CH
2
), 4.23 (d, 1H, CH),
6.72 (s, 1Н, NH), 7.20 (s, 1Н, NH)
9{17}
3.87 (s, 3Н, OCH
3
), 7.27 (m, 3H) 8.49 7.93 2.46 (t, 2Н),
2.67 (t, 2Н)
8.34 (br.t, 1H),
12.18 (s, 1H)
4.23 (d, 2H, CH
2
), 6.22 (d, 1H), 6.39 (t, 1H),
7.52 (d, 1Н)
9{18}
3.88 (s, 3Н, OCH
3
), 7.30 (m, 3H) 8.49 7.97 2.55 (t, 2Н),
2.73 (t, 2Н)
8.47 (br.t, 1H),
12.42 (s, 1H)
4.29 (d, 2H, СН
2
), 7.30 (m, 4H)
9{19}
3.92 (s, 3Н, OCH
3
), 7.23 (m, 3H)
8.53 7.94 2.63 (m, 4Н) 12.18 (s, 1H) 2.87 (d, 2H, CH
2
), 3.68 (d, 2H, CH
2
),
4.62 (d, 2H, CH
2
), 7.12 (m, 4H)
9{20}
7.44 (d, 1Н, H-8), 7.71 (dd, 1Н, H-7),
7.94 (d, 1H, H-5)
8.49 7.99 2.42 (t, 2Н),
2.65 (t, 2Н)
8.24 (br.t, 1H),
12.21 (s, 1H)
2.12 (s, 3H, CH
3
), 4.15 (d, 2H, CH
2
),
5.93 (d, 1H), 6.07 (d, 1H)
9{21}
7.39 (d, 1Н, H-8), 7.53 (dd, 1Н, H-7),
7.89 (d, 1H, H-5)
8.52 7.99 2.45 (t, 2Н),
2.67 (t, 2Н)
7.62 (br.d, 1H),
12.18 (s, 1H)
1.44 (m, 2H, CH
2
), 1.72 (m, 2H, CH
2
),
2.04 (m, 2H, CH
2
), 2.75 (m, 2H, CH
2
),
3.55 (m, 1Н, CH), 7.18 (q, 1Н), 7.26 (d, 4H)
9{22}
7.45 (d, 1Н, H-8), 7.61 (dd, 1Н, H-7),
7.94 (d, 1H, H-5)
8.47 7.98 2.35 (t, 2Н),
2.63 (t, 2Н)
7.97 (m, 1H),
12.22 (s, 1H)
2.79 (t, 2Н, CH
2
), 3.20 (s, 2H CH
2
),
7.28 (m, 4Н)
9{23}
7.44 (d, 1Н, H-8), 7.62 (dd, 1Н, H-7),
7.93 (d, 1H, H-5)
8.49 7.93 2.39 (t, 2Н),
2.65 (t, 2Н)
7.62 (d, 1Н),
12.05 (s, 1H),
1.39 (m, 10Н, 5СН
2
), 1.72 (m, 2Н, СН
2
),
3.68 (m, 1Н, СH)
9{24}
7.45 (d, 1Н, H-8), 7.62 (dd, 1Н, H-7),
7.95 (d, 1H, H-5)
8.48 7.98 2.33 (m, 2Н),
2.67 (t, 2Н)
7.30 (br.t, 1H), 1.25 (m, 2H, CH
2
), 1.49 (m, 2Н, CH
2
),
1.63 (m, 4Н, 2СН
2
), 2.32 (m, 6Н, 3CH
2
),
3.05 (q, 2Н, СH
2
)
9{25}
7.46 (d, 1Н, H-8), 7.65 (dd, 1Н, H-7),
7.94 (d, 1H, H-5)
8.50 7.99 2.43 (m, 2Н),
2.63 (m, 2Н)
7.84 (br.t, 1H),
12.12 (s, 1H)
2.65 (m, 2Н, СН
2
), 3.22 (m, 2H, CH
2
),
3.71 (s, 6Н, 2OCH
3
), 6.70 (m, 3Н)
9{26}
3.92 (s, 3Н, OCH
3
), 6.97 (dd, 1Н, H-6),
7.03 (s, 1Н, H-8), 7.72 (d, 1H, H-5)
8.51 7.84 2.38 (m, 2Н),
2.65 (t, 2Н)
7.62 (br.d, 1H),
12.01 (s, 1H)
1.10 (m, 5Н), 3.48 (s, 1Н), 1.60 (m, 5Н)
9{27}
3.89 (s, 3Н, OCH
3
), 6.97 (dd, 1Н, H-6),
7.03 (s, 1Н, H-8), 7.72 (d, 1H, H-5)
8.51 7.84 2.38 (m, 2Н),
2.65 (t, 2Н)
7.87 (br.t, 1H),
12.09 (s, 1H)
2.83 (t, 2Н, CH
2
), 3.28 (q, 2H, CH
2
),
7.28 (m, 4Н)
9{28}
3.87 (s, 3Н, OCH
3
), 6.97 (dd, 1Н, H-6),
7.03 (s, 1Н, H-8), 7.72 (d, 1H, H-5)
8.51 7.84 2.38 (m, 2Н),
2.65 (m, 2Н)
7.60 (br.t, 1H),
12.05 (s, 1H)
0.96 (d, 3Н, СН
3
), 1.15 - 3.05 (m, 13Н)
9{29}
3.87 (s, 3Н, OCH
3
), 6.97 (dd, 1Н, H-6),
7.03 (s, 1Н, H-8), 7.72 (d, 1H, H-5)
8.49 7.84 2.38 (m, 2Н),
2.65 (m, 2Н)
8.23 (br.t, 1H),
11.99 (s, 1H)
4.24 (d, 2H, CH
2
), 6.21 (d, 1H), 6.39 (t, 1H),
7.49 (d, 1Н)
9{30}
3.85 (s, 3Н, OCH
3
), 6.97 (d, 1Н, H-
6Н),
7.03 (s, 1Н, H-8), 7.72 (d, 1H, H-5)
8.49 7.84 2.38 (m, 2Н),
2.65 (m, 2Н)
8.16 (br.t, 1H),
12.09 (s, 1H)
2.09 (s, 3H, CH
3
), 4.15 (d, 2H, CH
2
),
5.93 (d, 1H), 6.07 (d, 1H)
9{31}
3.87 (s, 3Н, OCH
3
), 6.97 (dd, 1Н, H-6),
7.03 (s, 1Н, H-8), 7.72 (d, 1H, H-5)
8.52 7.85 2.38 (t, 2Н),
2.65 (t, 2Н)
7.64 (br.d, 1H),
12.05 (s, 1H)
1.50 (m, 8Н, 4СН
2
), 3.97 (m, 1Н, СН)

Molecules 2005, 10
455
Table 4. Cont.
Code Coumarin ring, R
1
s, 1H,
H-4
s, 1H,
H-5-
thiazole
-CH
2
CH
2
- NH R2, R3
9{32}
1.35 (t, 3H, OСН
2
СН
3
),
4.18 (q, 2H, OСН
2
СН
3
),
7.28 (m, 3H, Ar)
8.53 7.92 2.48 (m, 2Н),
2.72 (m, 2Н)
8.11 (br.d, 1H),
12.12 (s, 1H)
1.70 (m, 4H, 2СН
2
), 2.60 (m, 2Н, СН
2
),
4.95 (s, 1Н, СН), 7.08 (m, 4Н)
9{33} 1.35 (t, 3H, OСН
2
СН
3
),
4.19 (q, 2H, OСН
2
СН
3
),
7.28 (m, 3H, Ar),
8.52 7.96 2.38 (t, 2Н),
2.65 (t, 2Н)
7.72 (br.t, 1H),
12.04 (s, 1H),
0.64 (t, 3H, CH
3
), 1.07 (dt, 2H, CH
2
),
1.40 (m, 1Н, CH), 1.45 (m, 4H, 2CH
2
),
1.75 (t, 2H, CH
2
), 2.70 (m, 4H, 2CH
2
),
3.05 (q, 2H, CH
2
)
9{34} 1.40 (t, 3H, OСН
2
СН
3
),
4.19 (q, 2H, OСН
2
СН
3
),
7.28 (m, 3H, Ar)
8.52 7.94 2.33 (m, 2Н),
2.65 (t, 2Н)
7.69 (br.t, 1H),
12.05 (s, 1H)
1.63 (m, 8Н, 4СН
2
), 2.32 (m, 4Н, 2CH
2
),
3.05 (q, 2Н, СH
2
)
9{35} 1.35 (t, 3H, OСН
2
СН
3
),
4.19 (q, 2H, OСН
2
СН
3
),
7.31 (m, 3H, Ar), 8.52 (s, 1H, H-4)
7.96 2.39 (m, 2Н),
2.65 (t, 2Н)
7.64 (br.t, 1H),
12.11 (s, 1H)
1.02 (t, 3Н, CH
3
), 1.63 (m, 2H, CH
2
),
3.05 (d, 2Н, CH
2
), 3.20 (d, 2Н, CH
2
),
3.25 (q, 2Н, CH
2
), 6.53 (t, 2Н), 6.63 (d, 2Н),
7.11 (t, 2Н)
9{36} 1.35 (t, 3H, OСН
2
СН
3
),
4.19 (q, 2H, OСН
2
СН
3
),
7.34 (m, 3H, Ar), 8.52 (s, 1H, H-4)
7.96 2.39 (m, 2Н),
2.65 (t, 2Н)
7.62 (br.t, 1H),
12.09 (s, 1H)
0.96 (d, 3Н, СН
3
), 1.15 (m, 2H, CH
2
),
1.50 (m, 4H, 2CH
2
), 2.22 (m, 2H, CH
2
),
2.68 (m, 2H, CH
2
), 3.05 (m, 3Н, CH
2
+ CH)
9{37} 1.39 (t, 3H, OСН
2
СН
3
),
4.19 (q, 2H, OСН
2
СН
3
),
7.34 (m, 3H, Ar), 8.51 (s, 1H, H-4)
7.92 2.65 (s, 4Н) 11.95 (s, 1H), 2.09 (s, 4Н, CH
2
), 2.25 (s, 4Н, 2CH
2
),
3.39 (s, 4Н, CH
2
)

Molecules 2005, 10
456
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