Solution-phase synthesis of a combinatorial library of 3-[4-(coumarin-3-yl) -1,3-thiazol-2-ylcarbamoyl]propanoic acid amides

Article abstract of DOI:10.3390/10020444

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-(coumar

Full text of DOI:10.3390/10020444

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
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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-(R1-coumarin-3-yl)-1,3-thiazol-2-ylcarbamoyl]propanoic acid amides.
Results and Discussion
Different substituted 3-(ω-bromoacetyl)-R1-coumarins 1{1-5} [23] were used as starting
compounds for the library synthesis. The synthesis of the core building blocks, 3-[4-(R1-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-(R1-coumarin-3-yl)-1,3-thiazol-2-ylcarbamoyl]-
propanoic acids 6{1-5}.
S
S
NH2
N
2
H2N
NH2
route i
O
O
3{1}
O
O
O
CH2Br
R1
O
O
4
O
O
O
S
O
1{1-5}
S
OH
OH
H2N
N
H
N
5
O
H
N
R1
route ii
O
O
6{1-5}
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)-R1-
coumarins 1{1-5} yielded 3-[4-(R1-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}
1
obtained by both methods found to be identical by m.p. and 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-(R1-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-(R1-coumarin-3-yl)-1,3-thiazol-2-yl-
carbamoyl]propanoic acids
Code
R1
H
Yield, % (route ii)
Time of reaction
10 min
M.p. °C
260-61
>300
6{1}
6{2}
6{3}
6{4}
6{5}
72
83
85
78
76
8-OCH3
6-Cl
15 min
25 min
276-78
215-16
255-56
7-OCH3
8-OCH2CH3
15 min
15 min
1
Table 2. IR and H-NMR spectra of 3-[4-(R1-coumarin-3-yl)-1,3-thiazol-2-ylcar-
bamoyl]propanoic acids
IR-spectra
1H-NMR -spectra
ν C=O
ν C=N
ν C=C
1721,
1684,
1608,
1574
1723,
1686
1579
s, 1H,
H-5-
thiazole
ν N-H
ν С-H
s, 1H,
H-4
Code
6{1}
Coumarin ring, R1
-CH2CH2-
NH, OH
3455,
3412,
3142,
2980
3445,
3140,
2966
3447,
3134,
3050,
2828
3420,
3300,
3063,
2891
3441,
3151,
2985,
2893
7.37 (t, 1Н, Н-6),
7.45 (d, 1Н, Н-8),
7.63 (t, 1Н, Н-7),
7.82 (d, 1H, Н-5)
3.92 (s, 3Н, OCH3),
7.33 (m, 3H, Ar)
8.56
7.95
2.52 (t,
2Н), 2.64
(t, 2Н)
12.17 (s, 1H),
12.34 (s, 1H)
6{2}
6{3}
8.54
7.96
7.94
2.50 (t,
2Н), 2.67
(t, 2Н)
12.15 (s, 1H),
12.33 (s, 1H)
1706,
1688
1560
7.45 (d, 1Н, H-8),
7.63 (dd, 1Н, H-7),
7.95 (d, 1H, H-5)
2.57 (t,
12.22 (s, 1H),
12.33 (s, 1H)
8.47
2Н), 2.69
(t, 2Н)
6{4}
6{5}
1708,
1671,
1612,
1555
1726,
1687,
1578
3.87 (s, 3Н, OCH3),
6.97 (dd, 1Н, H-6),
7.06 (s, 1Н, H-8),
7.72 (d, 1H, H-5)
8.51
7.87
7.97
2.50 (t,
2Н), 2.64
(t, 2Н)
12.15 (s, 1H),
12.33 (s, 1H)
1.33 (t, 3H, OСН2СН3), 8.54
4.15 (q, 2H,
2.53 (t,
2Н), 2.64
(t, 2Н)
12.15 (s, 1H),
12.33 (s, 1H)
OСН2СН3),
7.32 (m, 3H, Ar)

Molecules 2005, 10
447
For the synthesis of amides of 3-[4-(R1-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-(R1-coumarin-3-yl)-1,3-thiazol-2-ylcarbamoyl]-
propanoic acid amides 12
O
S
N
N
R1
O
R2
Ac2O, AcONa
O
O
O
HNR2R3
R3
7{1-4}
N
route i
OH
O
8{1-5}
S
O
N
S
H
O
N
N
R1
H
N
R1
O
O
9{1-108}
O
O
O
N
6{1-5}
N
N
HNR2R3
N
N
N
O
8{1-24}
route ii
S
O
N
H
N
R1
O
O
10{1-5}
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-(R1-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-(R1-
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 N1-[4-(R1-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-(R1-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, 1H-NMR and
IR spectra. (Tables 2, 3 and 4). The 1H-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-(R1-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-(R1-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-(R1-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-(R1-coumarin-3-yl)-
1,3-thiazol-2-ylcarbamoyl]propanoic acid 9 has been accomplished.
Table 3. Physico-chemical data of 3-[4-(R1-coumarin-3-yl)-1,3-thiazol-2-ylcarbamo-
yl]propanoic acids amides
Structure
R1= H
IR-spectral data
N, %,
calc/
found
Molecular
formula, M.w.
M.p.,
°C
Yield,
%
Code
9{1}
ν C=N
ν C=C
1642
ν N-H
ν C=O
*
C23H25N3O4S
439.54
262-63
77
9.56
9.60
3320
1696
HN
1604
1538
*
9{2}
9{3}
C22H23N3O4S
425.51
278-80
244-46
85
65
9.88
9.85
3316
3292
1696
1696
1644
1604
1537
1643
1604
1538
HN
C23H18ClN3O4S
467.93
8.98
9.01
3317
3292
HN
Cl
*
*
9{4}
O
CH3
O
C26H25N3O6S
507.57
228-30
73
8.28
8.30
3344
1719
1686
1641
1605
1547
HN
CH3

Molecules 2005, 10
449
Table 3. Cont.
Structure
IR-spectral data
N, %,
calc/
found
Molecular
formula, M.w.
M.p.,
°C
Yield,
%
Code
ν C=N
ν C=C
1627
1648
1527
R1= H
ν N-H
ν C=O
9{5}
C20H19N3O5S
413.46
273-75
259-61
243-45
60
10.16
10.15
3176
1719
*
N
O
9{6}
9{7}
C25H21N3O4S
459.53
78
92
9.14
9.15
3423
3256
1711
1695
1616
1546
*
N
C28H28N4O4S
516.62
11.15
11.14
3407
3314
3295
1641
1544
*
N
N
*
9{8}
9{9}
C23H26N4O5S
470.55
239-41
182-84
90
65
11.91
11.88
3407
3340
3244
1699
1728
1656
1553
HN
N
O
*
C26H32N4O5S
512.63
10.93
10.94
3254
1640
1605
1549
HN
N
CH3
R1= 8-OCH3
O
9{10}
9{11}
C25H21N3O7S
507.53
253-55
252-53
73
89
8.28
8.31
3255
3344
1720
1647
1604
1577
O
HN
*
*
C23H25N3O4S
439.54
7.82
7.82
1710
1688
1634
1607
1577
O
O
CH3
O
HN
CH3
9{12}
9{13}
C21H21N3O6S
443.48
272-73
252-54
63
76
9.48
9.50
3245
1720
1691
1628
1573
*
N
*
C26H25N3O5S
491.57
8.55
8.54
3408
3294
1700
1700
1688
1642
1545
HN
*
CH3
9{14}
C25H22ClN3O5S
511.99
275-77
72
8.21
8.23
3292
1647
1572
1548
Cl
HN
*
9{15}
9{16}
C24H27N3O5S
469.56
257-59
306-08
58
47
8.95
8.97
3430
3301
1637
1545
HN
CH3
*
C23H24N4O6S
484.53
11.24
11.27
3448
3252
3223
1726
1694
1656
1624
1550
O
HN
NH2
O
9{17}
9{18}
9{19}
C22H19N3O6S
453.48
281-82
282-83
259-60
63
68
73
9.27
8.28
3355
3236
1719
1686
1650
1571
1547
HN
*
C24H20ClN3O5S
497.96
8.44
8.43
3426
3293
1700
1639
1575
1545
HN
*
*
Cl
C26H23N3O5S
489.55
8.58
8.58
3408
3236
1721
1688
1627
1544
N

Molecules 2005, 10
450
Table 3. Cont.
Structure
IR-spectral data
N, %,
calc/
found
Molecular
formula, M.w.
M.p.,
°C
Yield,
%
Code
ν C=N
ν C=C
1649
R1= H
ν N-H
ν C=O
CH3
O
9{20}
C22H18ClN3O5S
471.92
274-75
83
8.90
8.94
3407
3334
3244
1704
1547
HN
*
*
9{21}
C28H27ClN4O4S
551.07
259-60
87
10.17
10.18
3448
3255
1736
1666
1556
HN
N
*
9{22}
9{23}
9{24}
C24H19Cl2N3O4S
516.41
246-47
255-56
229-30
76
69
56
8.14
8.15
3360
3252
1726
1734
1704
1657
1640
1557
1534
1657
1632
1556
1547
1659
1552
Cl
HN
*
C23H24ClN3O4S
473.98
8.87
8.91
HN
*
C23H25ClN4O4S
489.00
11.46
11.45
3366
3348
3238
HN
N
*
9{25}
9{26}
O
CH3
C26H24ClN3O6S
542.01
243-45
270-72
74
66
7.75
7.74
3360
3179
1729
1655
1547
HN
O
CH3
R1= 7-OCH3
*
C23H25N3O5S
455.54
9.22
9.22
3292
3228
1708
1684
1644
1612
1564
1540
1664
1648
1552
HN
*
9{27}
9{28}
9{29}
C25H22ClN3O5S
511.99
249-50
196-98
307-08
72
56
63
8.21
8.25
3324
3288
3256
1716
Cl
HN
HN
*
C25H30N4O5S
498.61
11.24
11.21
3360
3248
1716
1688
1648
1620
1560
H3C
N
O
C22H19N3O6S
453.48
9.27
9.31
3360
3232
1716
1688
1648
1616
1548
1540
1648
1616
1548
HN
*
CH3
O
9{30}
9{31}
C23H21N3O6S
467.50
277-79
267-68
82
66
8.99
8.98
3364
3236
1724
1712
1688
HN
*
*
C22H23N3O5S
441.51
9.52
9.50
3228
1708
1696
1684
1648
1620
1540
HN
R1=8-OCH2CH3
*
HN
C28H27N3O5S
517.61
8.12
8.16
1616
1604
1540
1720
1696
301-02
79
9{32}
3308

Molecules 2005, 10
451
Table 3. Cont.
Structure
IR-spectral data
N, %,
calc/
found
Molecular
formula, M.w.
M.p.,
°C
Yield,
%
Code
ν C=N
ν C=C
R1= H
ν N-H
ν C=O
*
HN
C27H34N4O5S
526.66
10.64
10.65
1616
1604
1544
1708
1684
N
210-12
208-10
71
53
9{33}
3280
CH3
*
9{34}
C25H30N4O5S
498.61
11.24
11.28
3332
3280
1708
1684
1648
1616
1604
1572
1544
HN
N
*
9{35}
C29H32N4O5S
548.67
230-32
87
10.21
10.23
3356
3304
1720
1688
1644
1604
1552
HN
N
H3C
*
9{36}
C26H32N4O5S
512.63
213-15
259-61
62
56
10.93
10.95
1720
1700
1652
1604
1572
1544
1624
1557
H3C
HN
N
9{37}
C23H26N4O5S
470.55
11.91
11.96
3439
3258
1718
1695
*
N
N CH3
Experimental
General
The melting points were measured with a Buchi В-520 melting point apparatus and are not
1
corrected. IR spectra were recorded on Specord M80 spectrometers in KBr. H-NMR spectra were
recorded on Varian WXR-400 (200 MHz) and Bruker DRX-500 (500 MHz) spectrometers in DMSO-
D6 or CDCl3 using TMS as an internal standard (chemical shifts are reported in ppm). 3-(ω-
Bromacetyl)-R1-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-(R1-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)-R1-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-(R1-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-(R1-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-(R1-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-(R1-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-(R1-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. 1H-NMR -spectra of 3-[4-(R1-coumarin-3-yl)-1,3-thiazol-2-ylcarbamoyl]propanoic acids amides
s, 1H,
s, 1H,
H-4
Code
Coumarin ring, R1
H-5-
thiazole
7.65
-CH2CH2-
NH
R2, R3
9{1}
9{2}
9{3}
9{4}
9{5}
9{6}
9{7}
7.37 (t, 1Н, Н-6), 7.47 (d, 1Н, Н-8),
7.63 (t, 1Н, Н-7), 7.83 (d, 1H, Н-5)
7.38 (t, 1Н, H-6), 7.44 (d, 1Н, H-8),
7.63 (t, 1Н, H-7), 7.83 (d, 1H, H-5)
7.35 (t, 1Н, H-6), 7.43 (d, 1Н, H-8),
7.63 (t, 1Н, H-7), 7.83 (d, 1H, H-5)
7.35 (t, 1Н, H-6), 7.46 (d, 1Н, H-8),
7.62 (t, 1Н, H-7), 7.82 (d, 1H, H-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)
7.39 (t, 1Н, H-6), 7.46 (d, 1Н, H-8),
7.64 (t, 1Н, H-7), 7.83 (d, 1H, H-5)
7.37 (t, 1Н, H-6), 7.44 (d, 1Н, H-8),
7.63 (t, 1Н, H-7), 7.82 (d, 1H, H-5)
8.55
2.38 (t, 2Н),
2.65 (t, 2Н)
2.38 (t, 2Н),
2.65 (t, 2Н)
2.38 (t, 2Н),
2.65 (t, 2Н)
2.52 (t, 2Н),
2.78 (t, 2Н)
2.65 (s, 4H)
7.81 (br.d, 1H),
12.30 (s, 1H)
7.73 (br.d, 1H),
12.41 (s, 1H)
8.44 (br.d, 1H),
12.18 (s, 1H)
7.99 (br.t, 1H),
12.30 (s, 1H)
12.1 (s, 1H)
1.30 – 1.65 (m, 12Н), 3.68 (s, 1Н)
1.10 (m, 5Н), 1.60 (m, 5Н), 3.48 (s, 1Н)
4.32 (d, 2Н, CH2), 7.30 (m, 4Н, Ar)
8.52
8.56
8.51
8.55
8.58
8.62
7.96
7.77
7.99
7.95
7.98
7.96
2.60 (t, 2Н, CH2CH2), 3.20 (q, 2Н, CH2CH2),
3.70 (s, 6Н, 2OCH3), 6.40 (d, 1Н), 6.65 (d, 2Н)
3.47 (br.d, 8Н, 4CH2)
2.72 (m, 4Н)
12.18 (s, 1H)
2.89 (d, 2H, CH2), 3.69 (d, 2H, CH2),
4.62 (d, 2H, CH2),7.18 (m, 4H, Ar)
1.33 (t, 2H, СН2), 1.62 (d, 2H, СН2),
1.95 (t, 2H, СН2), 2.65 (m, 2H, СН2),
3.37 (s, 2H, CH2Ar), 3.50 (m, 1Н, СH),
7.25 (m, 5Н Ar)
2.40 (t, 2Н),
2.65 (m, 2Н)
7.25 (m, 1Н),
12.23 (s, 1H)
9{8}
9{9}
7.37 (t, 1Н, H-6), 7.43 (d, 1Н, H-8),
7.63 (t, 1Н, H-7), 7.79 (d, 1H, H-5),
3.80 (s, 3Н, OCH3), 7.65 (m, 3H)
8.54
8.55
7.94
7.99
2.43 (t, 2Н),
2.68 (t, 2Н)
2,38 (t, 2Н),
2,65 (t, 2Н)
7.69 (m, 1Н),
12.12 (s, 1H)
7.87 (t, 1H)
1.53 (m, 2H, CH2), 2.26 (m, 6H, 3CH2),
3.07 (q, 2H, CH2), 3.55 (m, 4H, 2CH2)
0.60 (t, 3H, CH3), 1.07 (dt, 2H, CH2),
1.40 (m, 1Н, CH), 1.45 (m, 4H, 2CH2),
1.75 (t, 2H, CH2), 2.70 (m, 4H 2CH2),
3.05 (q, 2H, CH2)
9{10}
9{11}
3.85 (s, 3Н, OCH3), 7.32 (m, 3H)
3.91 (s, 3Н, OCH3), 7.32 (m, 3H)
8.52
8.52
7.99
7.95
2.40 (t, 2Н),
2.60 (t, 2Н)
2.40 (t, 2Н),
2.63 (t, 2Н)
8.35 (t, 1H),
12.32 (s, 1H)
7.90 (br.t, 1H),
12.24 (s, 1H)
4.15 (d, 2Н, CH2), 5.95 (s, 1Н, OCH2O),
6.37 (d, 1Н), 6.51 (d, 2Н)
2.65 (t, 2Н, CH2), 3.15 (q, 2Н, CH2),
3.66 (s, 3H, OCH3), 3.71 (s, 3Н, OCH3),
6.20 (d, 1Н), 6.78 (d, 2Н)
9{12}
9{13}
3.89 (s, 3Н, OCH3), 7.28 (m, 3H)
3.94 (s, 3Н, OCH3), 7.31 (m, 3H)
8.49
8.54
7.92
7.96
2.65 (s, 4Н)
2.39 (t, 2Н),
2.65 (t, 2Н)
2.35 (t, 2Н),
2.62 (t, 2Н)
2.39 (t, 2Н),
2.65 (m, 2Н),
12.20 (s, 1H)
7.89 (m, 1H),
12.22 (s, 1H)
7.97 (br.t, 1H),
12.19 (s, 1H)
7.53 (br.d, 1H),
12.25 (s, 1H)
3.45 (br.d, 8Н, 4CH2)
2.65 (m, 2H, СН2), 3.15 (s, 2H, CH2),
7.06 (s, 4H)
2.78 (t, 2Н, CH2), 3.20 (s, 2H, CH2),
7.27 (m, 4Н)
0.80 (d, 3Н, СН3), 1.40 (m, 8H, 4СН2),
1.73 (m, 2Н, 2СН)
9{14}
9{15}
3.92 (s, 3Н, OCH3), 7.27 (m, 3Н)
3.94 (s, 3Н, OCH3), 7.30 (m, 3H)
8.52
8.53
7.94
7.96

Molecules 2005, 10
454
Table 4. Cont.
s, 1H,
H-5-
thiazole
s, 1H,
H-4
Code
Coumarin ring, R1
-CH2CH2-
NH
R2, R3
9{16}
3.87 (s, 3Н, OCH3), 7.25 (m, 3H)
8.49
7.93
2.59 (s, 4Н)
12.12 (s, 1H)
1.40 (m, 4H, 2CH2), 2.23 (t, 2Н, CH2),
2.99 (t, 2Н, CH2), 4.23 (d, 1H, CH),
6.72 (s, 1Н, NH), 7.20 (s, 1Н, NH)
4.23 (d, 2H, CH2), 6.22 (d, 1H), 6.39 (t, 1H),
7.52 (d, 1Н)
9{17}
9{18}
3.87 (s, 3Н, OCH3), 7.27 (m, 3H)
3.88 (s, 3Н, OCH3), 7.30 (m, 3H)
8.49
8.49
8.53
8.49
8.52
7.93
7.97
7.94
7.99
7.99
2.46 (t, 2Н),
2.67 (t, 2Н)
2.55 (t, 2Н),
2.73 (t, 2Н)
2.63 (m, 4Н)
8.34 (br.t, 1H),
12.18 (s, 1H)
8.47 (br.t, 1H),
12.42 (s, 1H)
12.18 (s, 1H)
4.29 (d, 2H, СН2), 7.30 (m, 4H)
2.87 (d, 2H, CH2), 3.68 (d, 2H, CH2),
4.62 (d, 2H, CH2), 7.12 (m, 4H)
2.12 (s, 3H, CH3), 4.15 (d, 2H, CH2),
5.93 (d, 1H), 6.07 (d, 1H)
1.44 (m, 2H, CH2), 1.72 (m, 2H, CH2),
2.04 (m, 2H, CH2), 2.75 (m, 2H, CH2),
3.55 (m, 1Н, CH), 7.18 (q, 1Н), 7.26 (d, 4H)
2.79 (t, 2Н, CH2), 3.20 (s, 2H CH2),
7.28 (m, 4Н)
1.39 (m, 10Н, 5СН2), 1.72 (m, 2Н, СН2),
3.68 (m, 1Н, СH)
1.25 (m, 2H, CH2), 1.49 (m, 2Н, CH2),
1.63 (m, 4Н, 2СН2), 2.32 (m, 6Н, 3CH2),
3.05 (q, 2Н, СH2)
9{19}
9{20}
3.92 (s, 3Н, OCH3), 7.23 (m, 3H)
7.44 (d, 1Н, H-8), 7.71 (dd, 1Н, H-7),
7.94 (d, 1H, H-5)
7.39 (d, 1Н, H-8), 7.53 (dd, 1Н, H-7),
7.89 (d, 1H, H-5)
2.42 (t, 2Н),
2.65 (t, 2Н)
2.45 (t, 2Н),
2.67 (t, 2Н)
8.24 (br.t, 1H),
12.21 (s, 1H)
7.62 (br.d, 1H),
12.18 (s, 1H)
9{21}
9{22}
9{23}
9{24}
7.45 (d, 1Н, H-8), 7.61 (dd, 1Н, H-7),
7.94 (d, 1H, H-5)
7.44 (d, 1Н, H-8), 7.62 (dd, 1Н, H-7),
7.93 (d, 1H, H-5)
7.45 (d, 1Н, H-8), 7.62 (dd, 1Н, H-7),
7.95 (d, 1H, H-5)
8.47
8.49
8.48
7.98
7.93
7.98
2.35 (t, 2Н),
2.63 (t, 2Н)
2.39 (t, 2Н),
2.65 (t, 2Н)
2.33 (m, 2Н),
2.67 (t, 2Н)
7.97 (m, 1H),
12.22 (s, 1H)
7.62 (d, 1Н),
12.05 (s, 1H),
7.30 (br.t, 1H),
9{25}
9{26}
9{27}
9{28}
9{29}
9{30}
7.46 (d, 1Н, H-8), 7.65 (dd, 1Н, H-7),
7.94 (d, 1H, H-5)
8.50
8.51
8.51
8.51
8.49
8.49
7.99
7.84
7.84
7.84
7.84
7.84
2.43 (m, 2Н),
2.63 (m, 2Н)
2.38 (m, 2Н),
2.65 (t, 2Н)
2.38 (m, 2Н),
2.65 (t, 2Н)
2.38 (m, 2Н),
2.65 (m, 2Н)
2.38 (m, 2Н),
2.65 (m, 2Н)
2.38 (m, 2Н),
2.65 (m, 2Н)
7.84 (br.t, 1H),
12.12 (s, 1H)
7.62 (br.d, 1H),
12.01 (s, 1H)
7.87 (br.t, 1H),
12.09 (s, 1H)
7.60 (br.t, 1H),
12.05 (s, 1H)
8.23 (br.t, 1H),
11.99 (s, 1H)
8.16 (br.t, 1H),
12.09 (s, 1H)
2.65 (m, 2Н, СН2), 3.22 (m, 2H, CH2),
3.71 (s, 6Н, 2OCH3), 6.70 (m, 3Н)
1.10 (m, 5Н), 3.48 (s, 1Н), 1.60 (m, 5Н)
3.92 (s, 3Н, OCH3), 6.97 (dd, 1Н, H-6),
7.03 (s, 1Н, H-8), 7.72 (d, 1H, H-5)
3.89 (s, 3Н, OCH3), 6.97 (dd, 1Н, H-6),
7.03 (s, 1Н, H-8), 7.72 (d, 1H, H-5)
3.87 (s, 3Н, OCH3), 6.97 (dd, 1Н, H-6),
7.03 (s, 1Н, H-8), 7.72 (d, 1H, H-5)
3.87 (s, 3Н, OCH3), 6.97 (dd, 1Н, H-6),
7.03 (s, 1Н, H-8), 7.72 (d, 1H, H-5)
3.85 (s, 3Н, OCH3), 6.97 (d, 1Н, H-
6Н),
2.83 (t, 2Н, CH2), 3.28 (q, 2H, CH2),
7.28 (m, 4Н)
0.96 (d, 3Н, СН3), 1.15 - 3.05 (m, 13Н)
4.24 (d, 2H, CH2), 6.21 (d, 1H), 6.39 (t, 1H),
7.49 (d, 1Н)
2.09 (s, 3H, CH3), 4.15 (d, 2H, CH2),
5.93 (d, 1H), 6.07 (d, 1H)
7.03 (s, 1Н, H-8), 7.72 (d, 1H, H-5)
3.87 (s, 3Н, OCH3), 6.97 (dd, 1Н, H-6),
7.03 (s, 1Н, H-8), 7.72 (d, 1H, H-5)
9{31}
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, 4СН2), 3.97 (m, 1Н, СН)

Molecules 2005, 10
455
Table 4. Cont.
s, 1H,
H-5-
thiazole
s, 1H,
H-4
Code
Coumarin ring, R1
-CH2CH2-
NH
R2, R3
9{32}
1.35 (t, 3H, OСН2СН3),
4.18 (q, 2H, OСН2СН3),
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, 2СН2), 2.60 (m, 2Н, СН2),
4.95 (s, 1Н, СН), 7.08 (m, 4Н)
7.28 (m, 3H, Ar)
9{33}
1.35 (t, 3H, OСН2СН3),
4.19 (q, 2H, OСН2СН3),
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, CH3), 1.07 (dt, 2H, CH2),
1.40 (m, 1Н, CH), 1.45 (m, 4H, 2CH2),
1.75 (t, 2H, CH2), 2.70 (m, 4H, 2CH2),
3.05 (q, 2H, CH2)
9{34}
9{35}
1.40 (t, 3H, OСН2СН3),
4.19 (q, 2H, OСН2СН3),
7.28 (m, 3H, Ar)
1.35 (t, 3H, OСН2СН3),
4.19 (q, 2H, OСН2СН3),
7.31 (m, 3H, Ar), 8.52 (s, 1H, H-4)
8.52
7.94
7.96
2.33 (m, 2Н),
2.65 (t, 2Н)
7.69 (br.t, 1H),
12.05 (s, 1H)
1.63 (m, 8Н, 4СН2), 2.32 (m, 4Н, 2CH2),
3.05 (q, 2Н, СH2)
2.39 (m, 2Н),
2.65 (t, 2Н)
7.64 (br.t, 1H),
12.11 (s, 1H)
1.02 (t, 3Н, CH3), 1.63 (m, 2H, CH2),
3.05 (d, 2Н, CH2), 3.20 (d, 2Н, CH2),
3.25 (q, 2Н, CH2), 6.53 (t, 2Н), 6.63 (d, 2Н),
7.11 (t, 2Н)
9{36}
9{37}
1.35 (t, 3H, OСН2СН3),
4.19 (q, 2H, OСН2СН3),
7.34 (m, 3H, Ar), 8.52 (s, 1H, H-4)
1.39 (t, 3H, OСН2СН3),
4.19 (q, 2H, OСН2СН3),
7.96
7.92
2.39 (m, 2Н),
2.65 (t, 2Н)
7.62 (br.t, 1H),
12.09 (s, 1H)
0.96 (d, 3Н, СН3), 1.15 (m, 2H, CH2),
1.50 (m, 4H, 2CH2), 2.22 (m, 2H, CH2),
2.68 (m, 2H, CH2), 3.05 (m, 3Н, CH2 + CH)
2.09 (s, 4Н, CH2), 2.25 (s, 4Н, 2CH2),
3.39 (s, 4Н, CH2)
2.65 (s, 4Н)
11.95 (s, 1H),
7.34 (m, 3H, Ar), 8.51 (s, 1H, H-4)

Molecules 2005, 10
456
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