Solution-phase Synthesis of a Combinatorial Library of 3-[4-(Coumarin-3-yl)-1,3-thiazol-2-ylcarbamoyl]propanoic acid Amides
National Pharmaceutical University, Kharkiv, Ukraine
*
Author to whom correspondence should be addressed.
Molecules 2005, 10(2), 444-456; https://doi.org/10.3390/10020444
Submission received: 27 August 2004
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Revised: 23 December 2004
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Accepted: 24 December 2004
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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.
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.
The synthesis of 3-[4-(R1-coumarin-3-yl)-1,3-thiazol-2-ylcarbamoyl]- propanoic acids 6{1-5}.
Scheme 1.
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 |
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) | ||||||
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
Scheme 2.
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.
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.
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
| 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} |  | C23H25N3O4S | 262-63 | 77 | 9.56 | 3320 | 1696 | 1642 |
| 439.54 | 9.60 | 1604 | ||||||
| 1538 | ||||||||
| 9{2} |  | C23H23N3O4S | 278-80 | 85 | 9.88 | 3316 | 1696 | 1644 |
| 425.51 | 9.85 | 3292 | 1604 | |||||
| 1537 | ||||||||
| 9{3} |  | C23H18ClN3O4S | 244-46 | 65 | 8.98 | 3317 | 1696 | 1643 |
| 467.93 | 9.01 | 3292 | 1604 | |||||
| 1538 | ||||||||
| 9{4} |  | C26H25N3O6S | 507.57 | 73 | 8.28 | 3344 | 1719 | 1641 |
| 507.57 | 8.30 | 1686 | 1605 | |||||
| 1547 | ||||||||
| 9{5} |  | C20H19N3O5S | 273-75 | 60 | 10.16 | 3176 | 1719 | 1627 |
| 413.46 | 10.15 | 1648 | ||||||
| 1527 | ||||||||
| 9{6} |  | C25H21N3O4S | 259-61 | 78 | 9.14 | 3423 | 1711 | 1616 |
| 459.53 | 9.15 | 3256 | 1546 | |||||
| 9{7} |  | C28H28N4O4S | 243-45 | 92 | 11.15 | 3407 | 1695 | 1641 |
| 516.62 | 11.14 | 3314 | 1544 | |||||
| 3295 | ||||||||
| 9{8} |  | C23H26N4O5S | 239-41 | 90 | 11.91 | 3407 | 1699 | 1656 |
| 470.55 | 11.88 | 3340 | 1553 | |||||
| 3244 | ||||||||
| 9{9} |  | C26H32N4O5S | 182-84 | 65 | 10.93 | 3254 | 1728 | 1640 |
| 512.63 | 10.94 | 1605 | ||||||
| 1549 | ||||||||
| 9{10} |  | C25H21N3O7S | 253-55 | 73 | 8.28 | 3255 | 1720 | 1647 |
| 507.53 | 8.31 | 1604 | ||||||
| 1577 | ||||||||
| 9{11} |  | C23H25N3O4S | 252-53 | 89 | 7.82 | 3344 | 1710 | 1634 |
| 439.54 | 7.82 | 1688 | 1607 | |||||
| 1577 | ||||||||
| 9{12} |  | C21H21N3O6S | 272-73 | 63 | 9.48 | 3245 | 1710 | 1628 |
| 443.48 | 9.50 | 1691 | 1573 | |||||
| 9{13} |  | C26H25N3O5S | 252-54 | 76 | 8.55 | 3408 | 1700 | 1642 |
| 491.57 | 8.54 | 3294 | 1545 | |||||
| 9{14} |  | C25H22ClN3O5S | 275-77 | 72 | 8.21 | 3292 | 1700 | 1647 |
| 511.99 | 8.23 | 1572 | ||||||
| 1548 | ||||||||
| 9{15} |  | C24H27N3O5S | 257-59 | 58 | 8.95 | 3430 | 1688 | 1637 |
| 469.56 | 8.97 | 3301 | 1545 | |||||
| 9{16} |  | C23H24N4O6S | 306-08 | 47 | 11.24 | 3448 | 1726 | 1656 |
| 484.53 | 11.27 | 3252 | 1694 | 1624 | ||||
| 3223 | 1550 | |||||||
| 9{17} |  | C22H19N3O6S | 281-82 | 63 | 9.27 | 3355 | 1719 | 1650 |
| 453.48 | 8.28 | 3236 | 1686 | 1571 | ||||
| 1547 | ||||||||
| 9{18} |  | C24H20ClN3O5S | 282-83 | 68 | 8.44 | 3426 | 1700 | 1639 |
| 497.96 | 8.43 | 3293 | 1575 | |||||
| 1545 | ||||||||
| 9{19} |  | C26H23N3O5S | 259-60 | 73 | 8.58 | 3408 | 1721 | 1627 |
| 489.55 | 8.58 | 3236 | 1688 | 1544 | ||||
| 9{20} |  | C28H27ClN4O4S | 274-75 | 83 | 8.90 | 3407 | 1704 | 1649 |
| 491.92 | 8.94 | 3334 | 1547 | |||||
| 3244 | ||||||||
| 9{21} |  | C28H27N4O4S | 259-60 | 87 | 10.17 | 3448 | 1736 | 1666 |
| 551.07 | 10.18 | 3255 | 1556 | |||||
| 9{22} |  | C24H19Cl2N3O4S | 246-47 | 76 | 8.14 | 3360 | 1726 | 1657 |
| 516.41 | 8.15 | 1640 | ||||||
| 1557 | ||||||||
| 1534 | ||||||||
| 9{23} |  | C23H24ClN3O4S | 255-56 | 69 | 8.87 | 3252 | 1734 | 1657 |
| 473.98 | 8.91 | 1632 | ||||||
| 1556 | ||||||||
| 1547 | ||||||||
| 9{24} |  | C23H25ClN4O4S | 229-30 | 56 | 11.46 | 3366 | 1704 | 1659 |
| 489.00 | 11.45 | 3348 | 1552 | |||||
| 3238 | ||||||||
| 9{25} |  | C26H24ClN3O6S | 243-45 | 74 | 7.75 | 3360 | 1729 | 1547 |
| 542.01 | 7.74 | 3179 | 1655 | |||||
| 9{26} |  | C23H25N3O5S | 270-72 | 66 | 9.22 | 3292 | 1708 | 1644 |
| 455.54 | 9.22 | 3228 | 1684 | 1612 | ||||
| 1564 | ||||||||
| 1540 | ||||||||
| 9{27} |  | C25H22ClN3O5S | 249-50 | 72 | 8.21 | 3324 | 1716 | 1664 |
| 511.99 | 8.25 | 3288 | 1648 | |||||
| 3256 | 1552 | |||||||
| 9{28} |  | C25H30N4O5S | 196-98 | 56 | 11.24 | 3360 | 1716 | 1648 |
| 498.61 | 11.21 | 3248 | 1688 | 1620 | ||||
| 1560 | ||||||||
| 9{29} |  | C22H19N3O6S | 307-08 | 63 | 9.27 | 3360 | 1716 | 1648 |
| 453.48 | 9.31 | 3232 | 1688 | 1616 | ||||
| 1548 | ||||||||
| 1540 | ||||||||
| 9{30} |  | C23H21N3O6S | 277-79 | 82 | 8.99 | 3364 | 1724 | 1648 |
| 467.50 | 8.98 | 3236 | 1712 | 1616 | ||||
| 1688 | 1548 | |||||||
| 9{31} |  | C22H31N3O5S | 267-68 | 66 | 9.52 | 3228 | 1708 | 1648 |
| 441.51 | 9.50 | 1696 | 1620 | |||||
| 1684 | 1540 | |||||||
| 9{32} |  | C28H27N3O5S | 301-02 | 79 | 8.12 | 3308 | 1720 | 1616 |
| 517.61 | 8.16 | 1696 | 1604 | |||||
| 1540 | ||||||||
| 9{33} |  | C22H23N3O5S | 210-12 | 71 | 10.64 | 3208 | 1708 | 1616 |
| 526.66 | 10.65 | 1684 | 1604 | |||||
| 1544 | ||||||||
| 9{34} |  | C25H30N4O5S | 208-10 | 53 | 11.24 | 3332 | 1708 | 1648 |
| 498.61 | 11.28 | 3280 | 1684 | 1616 | ||||
| 1604 | ||||||||
| 1572 | ||||||||
| 1544 | ||||||||
| 9{35} |  | C29H32N4O5S | 230-32 | 87 | 10.21 | 3356 | 1720 | 1644 |
| 548.67 | 10.23 | 1688 | 1604 | |||||
| 1552 | ||||||||
| 9{36} |  | C26H32N4O5S | 213-15 | 62 | 10.93 | 3304 | 1720 | 1652 |
| 512.63 | 10.95 | 1700 | 1604 | |||||
| 1572 | ||||||||
| 9{37} |  | C23H26N4O5S | 259-61 | 56 | 11.91 | 3439 | 1717 | 1624 |
| 470.55 | 11.96 | 3258 | 1695 | 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. 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.
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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Zhuravel, I.; Kovalenko, S.; Vlasov, S.; Chernykh, V. Solution-phase Synthesis of a Combinatorial Library of 3-[4-(Coumarin-3-yl)-1,3-thiazol-2-ylcarbamoyl]propanoic acid Amides. Molecules 2005, 10, 444-456. https://doi.org/10.3390/10020444
AMA Style
Zhuravel I, Kovalenko S, Vlasov S, Chernykh V. Solution-phase Synthesis of a Combinatorial Library of 3-[4-(Coumarin-3-yl)-1,3-thiazol-2-ylcarbamoyl]propanoic acid Amides. Molecules. 2005; 10(2):444-456. https://doi.org/10.3390/10020444
Chicago/Turabian StyleZhuravel, I., S. Kovalenko, S. Vlasov, and V. Chernykh. 2005. "Solution-phase Synthesis of a Combinatorial Library of 3-[4-(Coumarin-3-yl)-1,3-thiazol-2-ylcarbamoyl]propanoic acid Amides" Molecules 10, no. 2: 444-456. https://doi.org/10.3390/10020444
