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

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.

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}.

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

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}		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

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)

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- D 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-(R (7{1-4}) were prepared according to the reported method [26].

Synthesis of 3-[4-(R 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-(R 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.