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. 2005 Feb 28;10(2):444–456. doi: 10.3390/10020444

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

Irina O Zhuravel 1,*, Sergiy M Kovalenko 1, Sergiy V Vlasov 1, Valentin P Chernykh 1
PMCID: PMC6147696  PMID: 18007316

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 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 [7,8,9,10,11], aromatic [7,8,10] and dicarboxylic acids [10,12,13,14,15,16,17]. 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.

Scheme 1

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The synthesis of 3-[4-(R1-coumarin-3-yl)-1,3-thiazol-2-ylcarbamoyl]- propanoic acids 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 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} obtained by both methods found to be identical by m.p. and 1H-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} (Table 1 and Table 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 Yield, % (route ii) Time of reaction M.p. °C
6{1} H 72 10 min 260-61
6{2} 8-OCH3 83 15 min >300
6{3} 6-Cl 85 25 min 276-78
6{4} 7-OCH3 78 15 min 215-16
6{5} 8-OCH2CH3 76 15 min 255-56
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Table 2.

IR and 1H-NMR spectra of 3-[4-(R1-coumarin-3-yl)-1,3-thiazol-2-ylcar-bamoyl]propanoic acids

IR-spectra 1H-NMR -spectra
Code ν N-H
ν C-H		 ν C=O
ν C=N
ν C=C		 Coumarin ring, R1 s, 1H, H-4 s, 1H, H-5-thiazole -CH2CH2- NH, OH
6{1} 3455, 1721, 7.37 (t, 1Н, Н-6), 8.56 7.95 2.52 (t, 2Н), 2.64 (t, 2Н) 12.17 (s, 1H),
12.34 (s, 1H)
3412, 1684, 7.45 (d, 1Н, Н-8),
3142, 1608, 7.63 (t, 1Н, Н-7),
2980 1574 7.82 (d, 1H, Н-5)
6{2} 3445, 1723, 3.92 (s, 3Н, OCH3), 8.54 7.96 2.50 (t, 2Н), 2.67 (t, 2Н) 12.15 (s, 1H),
12.33 (s, 1H)
3140, 1686 7.33 (m, 3H, Ar)
2966 1579
6{3} 3447, 1706, 7.45 (d, 1Н, H-8), 8.47 7.94 2.57 (t, 2Н), 2.69 (t, 2Н) 12.22 (s, 1H),
12.33 (s, 1H)
3134, 1688 7.63 (dd, 1Н, H-7),
3050, 1560 7.95 (d, 1H, H-5)
2828
6{4} 3420, 1708, 3.87 (s, 3Н, OCH3), 8.51 7.87 2.50 (t, 2Н), 2.64 (t, 2Н) 12.15 (s, 1H),
12.33 (s, 1H)
3300, 1671, 6.97 (dd, 1Н, H-6),
3063, 1612, 7.06 (s, 1Н, H-8),
2891 1555 7.72 (d, 1H, H-5)
6{5} 3441, 1726, 1.33 (t, 3H, OСН2СН3), 8.54 7.95 2.53 (t, 2Н), 2.64 (t, 2Н) 12.15 (s, 1H),
12.33 (s, 1H)
3151, 1687, 4.15 (q, 2H, OСН2СН3),
2985, 1578
2893 7.32 (m, 3H, Ar)
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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.

Scheme 2

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The synthesis of 3-[4-(R1-coumarin-3-yl)-1,3-thiazol-2-ylcarbamoyl]-propanoic acid amides 12

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.

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.

Table 3.

Physico-chemical data of 3-[4-(R1-coumarin-3-yl)-1,3-thiazol-2-ylcarbamo- yl]propanoic acids amides

code Structure Molecular formula, M.w. M.p., °C Yield, % N, %, calc/found IR-spectral data
R1=H ν N-H ν C=O ν C=N
ν C=C
9{1} graphic file with name molecules-10-00444-i001.jpg C23H25N3O4S 262-63 77 9.56 3320 1696 1642
439.54 9.60 1604
1538
9{2} graphic file with name molecules-10-00444-i002.jpg C23H23N3O4S 278-80 85 9.88 3316 1696 1644
425.51 9.85 3292 1604
1537
9{3} graphic file with name molecules-10-00444-i003.jpg C23H18ClN3O4S 244-46 65 8.98 3317 1696 1643
467.93 9.01 3292 1604
1538
9{4} graphic file with name molecules-10-00444-i004.jpg C26H25N3O6S 507.57 73 8.28 3344 1719 1641
507.57 8.30 1686 1605
1547
9{5} graphic file with name molecules-10-00444-i005.jpg C20H19N3O5S 273-75 60 10.16 3176 1719 1627
413.46 10.15 1648
1527
9{6} graphic file with name molecules-10-00444-i006.jpg C25H21N3O4S 259-61 78 9.14 3423 1711 1616
459.53 9.15 3256 1546
9{7} graphic file with name molecules-10-00444-i007.jpg C28H28N4O4S 243-45 92 11.15 3407 1695 1641
516.62 11.14 3314 1544
3295
9{8} graphic file with name molecules-10-00444-i008.jpg C23H26N4O5S 239-41 90 11.91 3407 1699 1656
470.55 11.88 3340 1553
3244
9{9} graphic file with name molecules-10-00444-i009.jpg C26H32N4O5S 182-84 65 10.93 3254 1728 1640
512.63 10.94 1605
1549
9{10} graphic file with name molecules-10-00444-i010.jpg C25H21N3O7S 253-55 73 8.28 3255 1720 1647
507.53 8.31 1604
1577
9{11} graphic file with name molecules-10-00444-i011.jpg C23H25N3O4S 252-53 89 7.82 3344 1710 1634
439.54 7.82 1688 1607
1577
9{12} graphic file with name molecules-10-00444-i012.jpg C21H21N3O6S 272-73 63 9.48 3245 1710 1628
443.48 9.50 1691 1573
9{13} graphic file with name molecules-10-00444-i013.jpg C26H25N3O5S 252-54 76 8.55 3408 1700 1642
491.57 8.54 3294 1545
9{14} graphic file with name molecules-10-00444-i014.jpg C25H22ClN3O5S 275-77 72 8.21 3292 1700 1647
511.99 8.23 1572
1548
9{15} graphic file with name molecules-10-00444-i015.jpg C24H27N3O5S 257-59 58 8.95 3430 1688 1637
469.56 8.97 3301 1545
9{16} graphic file with name molecules-10-00444-i016.jpg C23H24N4O6S 306-08 47 11.24 3448 1726 1656
484.53 11.27 3252 1694 1624
3223 1550
9{17} graphic file with name molecules-10-00444-i017.jpg C22H19N3O6S 281-82 63 9.27 3355 1719 1650
453.48 8.28 3236 1686 1571
1547
9{18} graphic file with name molecules-10-00444-i018.jpg C24H20ClN3O5S 282-83 68 8.44 3426 1700 1639
497.96 8.43 3293 1575
1545
9{19} graphic file with name molecules-10-00444-i019.jpg C26H23N3O5S 259-60 73 8.58 3408 1721 1627
489.55 8.58 3236 1688 1544
9{20} graphic file with name molecules-10-00444-i020.jpg C28H27ClN4O4S 274-75 83 8.90 3407 1704 1649
491.92 8.94 3334 1547
3244
9{21} graphic file with name molecules-10-00444-i021.jpg C28H27N4O4S 259-60 87 10.17 3448 1736 1666
551.07 10.18 3255 1556
9{22} graphic file with name molecules-10-00444-i022.jpg C24H19Cl2N3O4S 246-47 76 8.14 3360 1726 1657
516.41 8.15 1640
1557
1534
9{23} graphic file with name molecules-10-00444-i023.jpg C23H24ClN3O4S 255-56 69 8.87 3252 1734 1657
473.98 8.91 1632
1556
1547
9{24} graphic file with name molecules-10-00444-i024.jpg C23H25ClN4O4S 229-30 56 11.46 3366 1704 1659
489.00 11.45 3348 1552
3238
9{25} graphic file with name molecules-10-00444-i025.jpg C26H24ClN3O6S 243-45 74 7.75 3360 1729 1547
542.01 7.74 3179 1655
9{26} graphic file with name molecules-10-00444-i026.jpg C23H25N3O5S 270-72 66 9.22 3292 1708 1644
455.54 9.22 3228 1684 1612
1564
1540
9{27} graphic file with name molecules-10-00444-i027.jpg C25H22ClN3O5S 249-50 72 8.21 3324 1716 1664
511.99 8.25 3288 1648
3256 1552
9{28} graphic file with name molecules-10-00444-i028.jpg C25H30N4O5S 196-98 56 11.24 3360 1716 1648
498.61 11.21 3248 1688 1620
1560
9{29} graphic file with name molecules-10-00444-i029.jpg C22H19N3O6S 307-08 63 9.27 3360 1716 1648
453.48 9.31 3232 1688 1616
1548
1540
9{30} graphic file with name molecules-10-00444-i030.jpg C23H21N3O6S 277-79 82 8.99 3364 1724 1648
467.50 8.98 3236 1712 1616
1688 1548
9{31} graphic file with name molecules-10-00444-i031.jpg C22H31N3O5S 267-68 66 9.52 3228 1708 1648
441.51 9.50 1696 1620
1684 1540
9{32} graphic file with name molecules-10-00444-i032.jpg C28H27N3O5S 301-02 79 8.12 3308 1720 1616
517.61 8.16 1696 1604
1540
9{33} graphic file with name molecules-10-00444-i033.jpg C22H23N3O5S 210-12 71 10.64 3208 1708 1616
526.66 10.65 1684 1604
1544
9{34} graphic file with name molecules-10-00444-i034.jpg C25H30N4O5S 208-10 53 11.24 3332 1708 1648
498.61 11.28 3280 1684 1616
1604
1572
1544
9{35} graphic file with name molecules-10-00444-i035.jpg C29H32N4O5S 230-32 87 10.21 3356 1720 1644
548.67 10.23 1688 1604
1552
9{36} graphic file with name molecules-10-00444-i036.jpg C26H32N4O5S 213-15 62 10.93 3304 1720 1652
512.63 10.95 1700 1604
1572
9{37} graphic file with name molecules-10-00444-i037.jpg C23H26N4O5S 259-61 56 11.91 3439 1717 1624
470.55 11.96 3258 1695 1557
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The structures of the compounds 6 and 9 have been confirmed by elemental analysis, 1H-NMR and IR spectra. (Table 2, Table 3 and Table 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.

Table 4.

1H-NMR -spectra of 3-[4-(R1-coumarin-3-yl)-1,3-thiazol-2-ylcarbamoyl]propanoic acids amides

code Coumarin ring, R1 s, 1H, H-4 s, 1H, H-5-thiazole -CH2CH2- NH R2, R3
9{1} 7.37 (t, 1Н, Н-6), 7.47 (d, 1Н, Н-8), 8.55 7.65 2.38 (t, 2Н), 7.81 (br.d, 1H), 1.30 – 1.65 (m, 12Н), 3.68 (s, 1Н)
7.63 (t, 1Н, Н-7), 7.83 (d, 1H, Н-5) 2.65 (t, 2Н), 12.30 (s, 1H)
9{2} 7.38 (t, 1Н, Н-6), 7.44 (d, 1Н, Н-8), 8.52 7.96 2.38 (t, 2Н), 7.73 (br.d, 1H), 1.10 (m, 5Н), 1.60 (m, 5Н), 3.48 (s, 1Н)
7.63 (t, 1Н, Н-7), 7.83 (d, 1H, Н-5) 2.65 (t, 2Н) 12.41 (s, 1H)
9{3} 7.35 (t, 1Н, Н-6), 7.43 (d, 1Н, Н-8), 8.56 7.77 2.38 (t, 2Н), 8.44 (br.d, 1H), 4.32 (d, 2Н, CH2), 7.30 (m, 4Н, Ar)
7.63 (t, 1Н, Н-7), 7.83 (d, 1H, Н-5) 2.65 (t, 2Н) 12.18 (s, 1H)
9{4} 7.35 (t, 1Н, Н-6), 7.46 (d, 1Н, Н-8), 8.51 7.99 2.52 (t, 2Н), 7.99 (br.d, 1H), 2.60 (t, 2Н, CH2CH2), 3.20 (q, 2Н, CH2CH2),
7.62 (t, 1Н, Н-7), 7.82 (d, 1H, Н-5) 2.78 (t, 2Н) 12.30 (s, 1H) 3.70 (s, 6Н, 2OCH3), 6.40 (d, 1Н), 6.65 (d, 2Н)
9{5} 7.36 (t, 1Н, Н-6), 7.42 (d, 1Н, Н-8), 8.55 7.95 2.65 (t, 4Н) 12.1 (s, 1H), 3.47 (br.d, 8Н, 4CH2)
7.60 (t, 1Н, Н-7), 7.79 (d, 1H, Н-5) 12.18 (s, 1H)
9{6} 7.39 (t, 1Н, Н-6), 7.46 (d, 1Н, Н-8), 8.58 7.98 2.72 (m, 4Н) 12.18 (s, 1H) 2.89 (d, 2H, CH2), 3.69 (d, 2H, CH2),
7.64 (t, 1Н, Н-7), 7.83 (d, 1H, Н-5) 4.62 (d, 2H, CH2),7.18 (m, 4H, Ar)
9{7} 7.37 (t, 1Н, Н-6), 7.44 (d, 1Н, Н-8), 8.62 7.96 2.40 (t, 2Н), 7.25 (m, 1Н), 1.33 (t, 2H, CH2), 1.62 (d, 2H, CH2),
7.63 (t, 1Н, Н-7), 7.82 (d, 1H, Н-5) 2.65 (m, 2Н) 12.23 (s, 1H) 1.95 (t, 2H, CH2), 2.65 (m, 2H, CH2),
3.37 (s, 2H, CH2Ar), 3.50 (m, 1Н, СH),
7.25 (m, 5Н Ar)
9{8} 7.37 (t, 1Н, Н-6), 7.43 (d, 1Н, Н-8), 8.54 7.94 2.43 (t, 2Н), 7.69 (m, 1Н), 1.53 (m, 2H, CH2), 2.26 (m, 6H, 3CH2),
7.63 (t, 1Н, Н-7), 7.79 (d, 1H, Н-5) 2.68 (t, 2Н) 12.12 (s, 1H) 3.07 (q, 2H, CH2), 3.55 (m, 4H, 2CH2)
9{9} 3.80 (s, 3Н, OCH3), 7.65 (m, 3H) 8.55 7.99 2.38 (t, 2Н), 7.87 (t, 1Н), 0.60 (t, 3H, CH3), 1.07 (dt, 2H, CH2),
2.65 (t, 2Н) 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} 3.85 (s, 3Н, OCH3), 7.32 (m, 3H) 8.52 7.99 2.40 (t, 2Н), 8.35 (t, 1Н), 4.15 (d, 2Н, CH2), 5.95 (s, 1Н, OCH2O),
2.60 (t, 2Н) 12.32 (s, 1H) 6.37 (d, 1Н), 6.51 (d, 2Н)
9{11} 3.91 (s, 3Н, OCH3), 7.32 (m, 3H) 8.52 7.95 2.40 (t, 2Н), 7.90 (br.t, 1H), 2.65 (t, 2Н, CH2), 3.15 (q, 2Н, CH2),
2.63 (t, 2Н) 12.24 (s, 1H) 3.66 (s, 3H, OCH3), 3.71 (s, 3Н, OCH3),
6.20 (d, 1Н), 6.78 (d, 2Н)
9{12} 3.89 (s, 3Н, OCH3), 7.28 (m, 3H) 8.49 7.92 2.65 (s, 4Н), 12.20 (s, 1H) 3.45 (br.d, 8Н, 4CH2)
9{13} 3.94 (s, 3Н, OCH3), 7.31 (m, 3H) 8.54 7.96 2.39 (t, 2Н), 7.89 (m, 1H), 2.65 (m, 2H, СН2), 3.15 (s, 2H, CH2),
2.65 (t, 2Н) 12.22 (s, 1H) 7.06 (s, 4H)
9{14} 3.92 (s, 3Н, OCH3), 7.27 (m, 3H) 8.52 7.94 2.35 (t, 2Н), 7.97 (br.t, 1H), 2.78 (t, 2Н, CH2), 3.20 (s, 2H, CH2),
2.62 (t, 2Н) 12.19 (s, 1H) 7.27 (m, 4Н)
9{15} 3.94 (s, 3Н, OCH3), 7.30 (m, 3H) 8.53 7.96 2.39 (t, 2Н), 7.53 (br.d, 1H), 0.80 (d, 3Н, СН3), 1.40 (m, 8H, 4СН2),
2.65 (m, 2Н) 12.25 (s, 1H) 1.73 (m, 2Н, 2СН)
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)
9{17} 3.87 (s, 3Н, OCH3), 7.27 (m, 3H) 8.49 7.93 2.46 (t, 2Н), 8.34 (br.t, 1H), 4.23 (d, 2H, CH2), 6.22 (d, 1H), 6.39 (t, 1H),
2.67 (t, 2Н) 12.18 (s, 1H) 7.52 (d, 1Н)
9{18} 3.88 (s, 3Н, OCH3), 7.30 (m, 3H) 8.49 7.97 2.55 (t, 2Н), 8.47 (br.t, 1H), 4.29 (d, 2H, СН2), 7.30 (m, 4H)
2.73 (t, 2Н) 12.42 (s, 1H)
9{19} 3.92 (s, 3Н, OCH3), 7.23 (m, 3H) 8.53 7.94 2.63 (m, 4Н) 12.18 (s, 1H) 2.87 (d, 2H, CH2), 3.68 (d, 2H, CH2),
4.62 (d, 2H, CH2), 7.12 (m, 4H)
9{20} 7.44 (d, 1Н, H-8), 7.71 (dd, 1Н, H-7), 8.49 7.99 2.42 (t, 2Н), 8.24 (br.t, 1H), 2.12 (s, 3H, CH3), 4.15 (d, 2H, CH2),
7.94 (d, 1H, H-5) 2.65 (t, 2Н) 12.21 (s, 1H) 5.93 (d, 1H), 6.07 (d, 1H)
9{21} 7.39 (d, 1Н, H-8), 7.53 (dd, 1Н, H-7), 8.52 7.99 2.45 (t, 2Н), 7.62 (br.d, 1H), 1.44 (m, 2H, CH2), 1.72 (m, 2H, CH2),
7.89 (d, 1H, H-5) 2.67 (t, 2Н) 12.18 (s, 1H) 2.04 (m, 2H, CH2), 2.75 (m, 2H, CH2),
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), 8.47 7.98 2.35 (t, 2Н), 7.97 (m, 1H), 2.79 (t, 2Н, CH2), 3.20 (s, 2H CH2),
7.94 (d, 1H, H-5) 2.63 (t, 2Н) 12.22 (s, 1H) 7.28 (m, 4Н)
9{23} 7.44 (d, 1Н, H-8), 7.62 (dd, 1Н, H-7), 8.49 7.93 2.39 (t, 2Н), 7.62 (d, 1Н), 1.39 (m, 10Н, 5СН2), 1.72 (m, 2Н, СН2),
7.93 (d, 1H, H-5) 2.65 (t, 2Н) 12.05 (s, 1H) 3.68 (m, 1Н, СH)
9{24} 7.45 (d, 1Н, H-8), 7.62 (dd, 1Н, H-7), 8.48 7.98 2.33 (m, 2Н), 7.30 (br.t, 1H), 1.25 (m, 2H, CH2), 1.49 (m, 2Н, CH2),
7.93 (d, 1H, H-5) 2.67 (t, 2Н) 1.63 (m, 4Н, 2СН2), 2.32 (m, 6Н, 3CH2),
3.05 (q, 2Н, СH2)
9{25} 7.46 (d, 1Н, H-8), 7.65 (dd, 1Н, H-7), 8.50 7.99 2.43 (m, 2Н), 7.84 (br.t, 1H), 2.65 (m, 2Н, СН2), 3.22 (m, 2H, CH2),
7.94 (d, 1H, H-5) 2.63 (m, 2Н) 12.12 (s, 1H) 3.71 (s, 6Н, 2OCH3), 6.70 (m, 3Н)
9{26} 3.92 (s, 3Н, OCH3), 6.97 (dd, 1Н, H-6), 8.51 7.84 2.38 (m, 2Н), 7.62 (br.d, 1H), 1.10 (m, 5Н), 3.48 (s, 1Н), 1.60 (m, 5Н)
7.03 (s, 1Н, H-8), 7.72 (d, 1H, H-5) 2.65 (t, 2Н) 12.01 (s, 1H)
9{27} 3.89 (s, 3Н, OCH3), 6.97 (dd, 1Н, H-6), 8.51 7.84 2.38 (m, 2Н), 7.87 (br.t, 1H), 2.83 (t, 2Н, CH2), 3.28 (q, 2H, CH2),
7.03 (s, 1Н, H-8), 7.72 (d, 1H, H-5) 2.65 (t, 2Н) 12.09 (s, 1H) 7.28 (m, 4Н)
9{28} 3.87 (s, 3Н, OCH3), 6.97 (dd, 1Н, H-6), 8.51 7.84 2.38 (m, 2Н), 7.60 (br.t, 1H), 0.96 (d, 3Н, СН3), 1.15 - 3.05 (m, 13Н)
7.03 (s, 1Н, H-8), 7.72 (d, 1H, H-5) 2.65 (m, 2Н) 12.05 (s, 1H)
9{29} 3.87 (s, 3Н, OCH3), 6.97 (dd, 1Н, H-6), 8.49 7.84 2.38 (m, 2Н), 8.23 (br.t, 1H), 4.24 (d, 2H, CH2), 6.21 (d, 1H), 6.39 (t, 1H),
7.03 (s, 1Н, H-8), 7.72 (d, 1H, H-5) 2.65 (m, 2Н) 11.99 (s, 1H) 7.49 (d, 1Н)
9{30} 3.85 (s, 3Н, OCH3), 6.97 (dd, 1Н, H-6), 8.49 7.84 2.38 (m, 2Н), 8.16 (br.t, 1H), 2.09 (s, 3H, CH3), 4.15 (d, 2H, CH2),
7.03 (s, 1Н, H-8), 7.72 (d, 1H, H-5) 2.65 (m, 2Н) 12.09 (s, 1H) 5.93 (d, 1H), 6.07 (d, 1H)
9{31} 3.87 (s, 3Н, OCH3), 6.97 (dd, 1Н, H-6), 8.52 7.85 2.38 (t, 2Н), 7.64 (br.t, 1H), 1.50 (m, 8Н, 4СН2), 3.97 (m, 1Н, СН)
7.03 (s, 1Н, H-8), 7.72 (d, 1H, H-5) 2.65 (t, 2Н) 12.05 (s, 1H)
9{32} 1.35 (t, 3H, OСН2СН3), 8.53 7.92 2.48 (m, 2Н), 8.11 (br.d, 1H), 1.70 (m, 4H, 2СН2), 2.60 (m, 2Н, СН2),
4.18 (q, 2H, OСН2СН3), 2.72 (m, 2Н) 12.12 (s, 1H) 4.95 (s, 1Н, СН), 7.08 (m, 4Н)
7.28 (m, 3H, Ar)
9{33} 1.35 (t, 3H, OCH2CH3), 8.52 7.96 2.38 (t, 2Н), 7.72 (br.t, 1H), 0.64 (t, 3H, CH3), 1.07 (dt, 2H, CH2),
4.19 (q, 2H, OCH2CH3), 2.65 (t, 2Н) 12.04 (s, 1H), 1.40 (m, 1Н, CH), 1.45 (m, 4H, 2CH2),
7.28 (m, 3H, Ar), 1.75 (t, 2H, CH2), 2.70 (m, 4H 2CH2),
3.05 (q, 2H, CH2)
9{34} 1.40 (t, 3H, OCH2CH3), 8.52 7.94 2.33 (m, 2Н), 7.69 (br.t, 1H), 1.63 (m, 8Н, 4CH2), 2.32 (m, 4Н, 2CH2),
4.19 (q, 2H, OCH2CH3), 2.65 (t, 2Н) 12.05 (s, 1H) 3.05 (q, 2Н, СH2)
7.28 (m, 3H, Ar)
9{35} 1.35 (t, 3H, OCH2CH3), 7.96 2.39 (m, 2Н), 7.64 (br.t, 1H), 1.02 (t, 3Н, CH3), 1.63 (m, 2H, CH2),
4.19 (q, 2H, OCH2CH3), 2.65 (t, 2Н) 12.11 (s, 1H), 3.05 (d, 2Н, CH2), 3.20 (d, 2Н, CH2),
7.31 (m, 3H, Ar), 8.52 (s, 1H, H-4) 3.25 (q, 2Н, CH2), 6.53 (t, 2Н), 6.63 (d, 2Н),
7.11 (t, 2Н)
9{36} 1.35 (t, 3H, OCH2CH3), 7.96 2.39 (m, 2Н), 7.62 (br.t, 1H), 0.96 (d, 3Н, CH3), 1.15 (m, 2H, CH2),
4.19 (q, 2H, OCH2CH3), 2.65 (t, 2Н) 12.09 (s, 1H) 1.50 (m, 4H, 2CH2), 2.22 (m, 2H, CH2),
7.34 (m, 3H, Ar), 8.52 (s, 1H, H-4) 2.68 (m, 2H, CH2), 3.05 (m, 3Н, CH2 + CH)
9{37} 1.39 (t, 3H, OCH2CH3), 7.92 2.65 (s, 4Н) 11.95 (s, 1H), 2.09 (s, 4Н, CH2), 2.25 (s, 4Н, 2CH2),
4.19 (q, 2H, OCH2CH3), 3.39 (s, 4Н, CH2)
7.34 (m, 3H, Ar), 8.51 (s, 1H, H-4)
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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.

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. 1H-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 the resulting product was crystallized from 10 % acetic acid to form yellow crystals of the title compound. Yield 80%, m.p.210-211°C [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°C.

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°C.

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.

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