English

• 1.   Introduction

  Coumarins play a key role in the medicinal area because of their structural diversity and pharmaceutical properties. Various synthetic coumarin derivatives constitute one of the most widely used groups of anti-human immunodeficiency virus, ^[1] anti-inflam-matory, ^{[2, 3]} antioxidant^[4] and anticancer agents.^[5~7] Further, 2-aminothiazoles have been employed in the preparation of different important drugs required for the treatment of allergies, hypertension, inflammation, bacterial, and human immunodeficiency virus (HIV) infections.^[8~11] Therefore, it is very meaningful to synthesize 2-amino-4-thiazolyl coumarin derivatives in medicinal chemistry area.

  Numerous methods were reported for the preparation of 2-amino-4-thiazolyl coumarin derivatives. In general, Hantzsch thiazole synthesis, involving the reaction of 3-(2-bromoacetyl) coumarin and various thioureas, is the most widely used methods.^[12~21] In recent years, much attention has been paid to one-pot synthesis, ^[22~26] which is a strategy to improve the efficiency of a chemical reaction because of avoiding a separation process and purification of the intermediates. The use of molecular iodine in organic synthesis has been known for a long time.^[27~29] Recently, Zhu and co-workers^[30] developed a I₂/CuO-catalyzed tandem cyclization strategy involving the direct use of aromatic methyl ketones and thiourea for one-pot synthesis of substituted 2-aminothiozole. Although 3-acetylcoumarins also belong to methyl ketone, to the best of our knowledge, the direct use of 3-acetylcoumarin and thiourea for one-pot synthesis of 2-amino-4-thiazolyl coumarin has not been reported. Herein, we reported a facile, efficient method for synthesis of 3-(2-amino-4-thiazolyl) coumarins from 3-acetylcoumarins and thioureas.

  2.   Results and discussion

  To explore optimized reaction condition, 3-acetylcoumarin (1a) was first used as the model substrate to react with thiourea in different solvents for the synthesis of desired product 3-(2-aminothiazol-4-yl)coumarin (3a). As shown in Eq. 1 and Table 1, the product 3a was successful obtained in 72%~5% yields using ethanol, methanol, propanol and butanol as solvents under the media of I₂/CuO (Table 1, Entries 1~4). However, 3a was not obtained when tertbutanol (t-BuOH), acetonitrile (MeCN), tetrahydrofuran (THF), toluene or dimethylformamide (DMF) was used as solvent (Entries 5~9). It was obvious that EtOH was the optimal solvent in the reaction. Furtherly, the molar ratio of substrate, I₂ and CuO was also optimized. When the molar ratio of n(1a)/n(2a)/ n(CuO)/n(I₂) was varied from 1.0:1.0:1.0:1.0 to 1.0:1.1:1.1:1.1 (Entries 10~12), the product 3a was afforded in 86%~88% yields in ethanol at reflux. Therefore, n(1a):n(2a):n(I₂):n(CuO)＝1.0:1.0:1.1:1.1 is the optimal condition. Finally, the effect of reaction temperature on the yield of the product 3a was also examined (Entry 13). The experiment result indicates that 78 ℃ is the optimal temperature.

  Table 1

  

  Table 1.  Effect of solvent, temperature and molar ratio of n(1a)/n(2a)/n(CuO)/n(I₂) on the yield of 3a

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  Entry	Solvent	t/℃	n(1a):n(2a):n(CuO):n(I2)	Yielda/%
  1	EtOH	78	1.0:1.0:1.0:1.0	85
  2	MeOH	65	1.0:1.0:1.0:1.0	82
  3	PrOH	97	1.0:1.0:1.0:1.0	78
  4	BuOH	118	1.0:1.0:1.0:1.0	72
  5	t-BuOH	83	1.0:1.0:1.0:1.0	0b
  6	MeCN	82	1.0:1.0:1.0:1.0	0b
  7	THF	66	1.0:1.0:1.0:1.0	0b
  8	Toluene	111	1.0:1.0:1.0:1.0	0b
  9	DMF	90	1.0:1.0:1.0:1.0	0b
  10	EtOH	78	1.0:1.0:1.1:1.1	88
  11	EtOH	78	1.0:1.0:1.5:1.5	86
  12	EtOH	78	1.0:1.1:1.1:1.1	87
  13	EtOH	65	1.0:1.0:1.1:1.1	75
  a Isolated yield. b No reaction.

  (1)

  After the optimization of reaction conditions, the reactions of different acetylcoumarins (1) with thiourea and N-substituted thioureas (Eq. 2) were examined to establish the generality of the present transformation. The results are listed in Table 2. The condensation of different 3-acetylcoumarins including electron-donating groups (such as Me, NEt₂) or electron-withdrawing groups (such as OMe, Cl, Br and NO₂) on their phenyl ring with thiourea gave the expected products 3-(2-amino-4-thiazolyl) coumarins 3b~3h in good to excellent yields (80%~89%). Furthermore, it was found that the reaction of N-substituted thioureas (such as N-methylthiourea and N-phenylthiourea) and acetylcoumarins could afford the 2-aminothiazole derivatives 3i~3x in 58%~85% yields. The treatment of 1a with thiourea, N-methylthiourea and N-phenylthiourea gave the desired products 3a, 3i and 3q in 88%, 84% and 66% yields, respectively. The slightly lower yields might be attributed to the steric hindrance of N-methylthiourea and N-phenylthiourea.

  Table 2

  

  Table 2.  Synthesis of 3 from 3-acetylcoumarins and thiourea

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  Compd.	R1	R2	R3	R4	R5	Yielda/%
  3a	H	H	H	H	H	88
  3b	H	Me	H	H	H	82
  3c	H	H	H	OMe	H	89
  3d	H	Cl	H	H	H	85
  3e	H	Br	H	H	H	83
  3f	H	NO2	H	H	H	81
  3g	H	H	NEt2	H	H	80
  3h	Benzo		H	H	H	82
  3i	H	H	H	H	Me	84
  3g	H	Me	H	H	Me	76
  3k	H	H	H	OMe	Me	85
  3l	H	Cl	H	H	Me	82
  3m	H	Br	H	H	Me	79
  3n	H	NO2	H	H	Me	74
  3o	H	H	NEt2	H	Me	75
  3p	Benzo		H	H	Me	77
  3q	H	H	H	H	Ph	66
  3r	H	Me	H	H	Ph	63
  3s	H	H	H	OMe	Ph	68
  3t	H	Cl	H	H	Ph	65
  3u	H	Br	H	H	Ph	62
  3v	H	NO2	H	H	Ph	58
  3w	H	H	NEt2	H	Ph	60
  3x	Benzo		H	H	Ph	63
  a Isolated yield.

  (2)

  Based on previous report, ^[30] a proposed mechanism for this reaction is given in Scheme 1. Initially, 3-acetyl-coumarins (1) undergoes the formation of intermediate 3-(2-iodoacetyl)coumarin in the media of I₂ and CuO, then, 3-(2-iodoacetyl)coumarins reacted with thiourea giving the corresponding 3-(2-amino-4-thiazolyl) coumarins.

  Scheme 1

  

  Scheme 1.  Proposed mechanism for the synthesis of 2-aminothiazolyl coumarins (3)

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  3.   Conclusions

  A facile, efficient one-pot synthesis of 3-(2-amino-4-thiazolyl) coumarins from 3-acetylcoumarins and thiourea under the media of I₂/CuO in refluxing ethanol was developed. Further application of this methodology for the synthesis of various coumarin-based heterocyclic compounds is under way in our laboratory.

  4.   Experimental section

  4.1   Instruments and reagents

  NMR spectra were measured on a VXR 300 instrument. Chemical shifts are reported relative to the internal standard of tetramethylsilane (TMS). IR spectra were obtained as KBr pellet samples on a Nicolet 5700 FTIR spectrometer. Mass spectra were measured on an LCQ Advantage MAX (ESI). The elemental analyses were measured on a Vario EL-III instrument CHNSO elemental analyzer. 3-Acetylcoumarins (1) were synthesized according to literature method.^[31] Other reagents were obtained from commercial suppliers and used without further purification.

  4.2   General procedure for the synthesis of 3-(2-amino-4-thiazolyl) coumarin derivatives 3a~3x

  A mixture of 3-acetylcoumarin (1) (1.0 mmol), iodine (279.2 mg, 1.1 mmol), and CuO (88 mg, 1.1 mmol) in anhydrous ethanol (30 mL) was heated at reflux. After the reaction (1~5 h, monitored by TLC), thiourea (2) (1.0 mmol) was added and the mixture was refluxed for 1 h. After that, the solvent was removed under reduce pressure, and 50 mL of water was added to the residue. The mixture was extracted with EtOAc three times (50 mL×3). The extract was washed with 10% Na₂S₂O₃ and then a small amount of 5% NaOH solution, dried over anhydrous Na₂SO₄ and concentrated in vacuo. The residue was purified by column chromatography on silica gel using petroleum ether/EtOAc as the eluent to afford the corresponding purified products 3.

  3-(2-Aminothiazol-4-yl)-2H-chromen-2-one (3a): Yellow solid; m.p. 224~225 ℃ (lit.^[12] 225~227 ℃); ¹H NMR (300 MHz, DMSO-d₆) δ: 8.51 (s, 1H), 7.83 (d, J＝7.4 Hz, 1H), 7.61 (t, J＝7.4 Hz, 1H), 7.51 (s, 1H), 7.45~7.35 (m, 2H), 7.15 (br, 2H); ¹³C NMR (75 MHz, DMSO-d₆), δ:167.4, 158.8, 152.2, 143.3, 138.0, 131.4, 128.8, 124.5, 120.5, 119.3, 115.7, 108.6; IR (KBr) ν_max: 3388, 1691, 1639, 1531, 1442, 1374, 1091, 751 cm^－1; ESI-MS m/z: 244.89 [M+H]⁺.

  3-(2-Aminothiazol-4-yl)-6-methyl-2H-chromen-2-one (3b): Yellow solid, m.p. 235~237 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 8.39 (s, 1H), 7.70 (s, 1H), 7.18~7.23 (m, 3H), 4.97 (s, 2H, NH₂), 2.34 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ: 166.2, 151.0, 143.9, 138.8, 134.2, 132.4, 127.9, 120.7, 119.3, 116.5, 116.0, 111.0, 20.8; IR (KBr) ν_max: 3395, 1630, 1535, 1378, 1262, 1091, 1024, 805 cm^－1; ESIMS m/z: 259.05 [M+H]⁺. Anal. calcd for C₁₃H₁₀N₂O₂S: C 60.45, H 3.90, N 10.85; found C 60.32, H 3.79, N 10.71.

  3-(2-Aminothiazol-4-yl)-8-methoxy-2H-chromen-2-one (3c): Yellow solid, m.p. 256~258 ℃ (lit.^[18] 256~258 ℃); ¹H NMR (300 MHz, CDCl₃) δ: 8.47 (s, 1H), 7.37~7.51 (m, 1H), 7.30~7.36 (m, 1H), 7.29~7.30 (m, 2H), 7.18 (s, 2H), 3.93 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ: 167.4, 158.5, 146.2, 143.2, 138.3, 133.7, 131.6, 124.6, 120.6, 119.9, 113.7, 108.8, 56.0; IR (KBr) ν_max: 3452, 2962, 1631, 1391, 1262, 1094, 1026, 804 cm^－1; ESI-MS m/z: 274.89 [M+H]⁺.

  3-(2-Aminothiazol-4-yl)-6-chloro-2H-chromen-2-one (3d): Yellow solid, m.p. 204~205 ℃ (lit.^[18] 206~208 ℃); ¹H NMR (300 MHz, DMSO-d₆) δ: 8.45 (s, 1H), 7.98 (d, J＝2.4 Hz, 1H), 7.45~7.64 (m, 3H), 7.18 (s, 2H, NH₂); ¹³C NMR (75 MHz, DMSO-d₆) δ: 167.9, 158.8, 151.2, 143.5, 137.1, 131.3, 128.9, 128.0, 121.8, 121.2, 118.2, 110.0; IR (KBr) ν_max: 3444, 1639, 1372, 1086, 708 cm^－1; ESI-MS m/z: 278.84 [M+H]⁺.

  3-(2-Aminothiazol-4-yl)-6-bromo-2H-chromen-2-one (3e): Yellow solid, m.p. 208~209 ℃ (lit.^[18] 210~212 ℃); ¹H NMR (300 MHz, CDCl₃) δ: 8.40 (s, 1H), 7.77~7.79 (s, 1H), 7.67~7.70 (m, 1H), 7.71~7.74 (m, 1H), 7.56~7.59 (m, 1H), 5.08 (s, 2H, NH₂); ¹³C NMR (75 MHz, CDCl₃) δ: 166.4, 159.0, 154.1, 151.6, 145.9, 137.1, 133.8, 132.2, 130.3, 118.0, 117.1, 112.0; IR (KBr) ν_max: 3422, 1721, 1625, 1541, 1363, 1196, 1094, 823 cm^－1; ESI-MS m/z: 323.05 [M+H]⁺.

  3-(2-Aminothiazol-4-yl)-6-nitro-2H-chromen-2-one (3f): Yellow solid, m.p. 181~182 ℃; ¹H NMR (300 MHz, DMSO-d₆) δ: 8.52 (d, J＝2.7 Hz, 1H), 8.18~8.22 (m, 3H), 7.48 (s, 2H), 7.34 (d, J＝9.0 Hz, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ: 169.7, 157.5, 156.8, 148.3, 143.7, 142.6, 126.9, 124.7, 123.5, 118.9, 117.8, 114.5; IR (KBr) ν_max: 3426, 1737, 1616, 1526, 1344, 1093, 841 cm^－1; ESI-MS m/z: 289.14 [M]⁺. Anal. calcd for C₁₂H₇N₃O₄S: C 49.83, H 2.44, N 14.53; found C 49.76, H 2.37, N 14.47.

  3-(2-Aminothiazol-4-yl)-7-(diethylamino)-2H-chromen-2-one (3g): Yellow solid, m.p. 198~199 ℃ (lit.^[32] 199~201 ℃); ¹H NMR (300 MHz, CDCl₃) δ: 8.37 (s, 1H), 7.59 (s, 1H), 7.27~7.35 (m, 1H), 6.35 (d, J＝8.9 Hz, 1H), 6.51 (s, 1H), 5.03 (s, 2H, NH₂), 3.42 (q, J＝7.2 Hz, 4H, CH₂), 1.22 (q, J＝7.2 Hz, 6H, CH₃); ¹³C NMR (75 MHz, CDCl₃) δ: 166.1, 160.7, 155.7, 150.6, 144.9, 139.6, 129.3, 114.5, 109.2, 109.0, 107.9, 97.1, 44.8, 12.5; IR (KBr) ν_max: 3438, 2972, 1704, 1623, 1526, 1410, 1238, 1125, 770 cm^－1; ESI-MS m/z: 316.15 [M+H]⁺.

  2-(2-Aminothiazol-4-yl)-3H-benzo[f]chromen-3-one (3h): Yellow solid, m.p. 286~287 ℃ (lit.^[18] 287~289 ℃); ¹H NMR (300 MHz, CDCl₃) δ: 9.33 (s, 1H), 8.44~8.47 (m, 1H), 7.90~7.98 (m, 2H), 7.84 (s, 1H), 7.68~7.73 (m, 1H), 7.47~7.60 (m, 2H), 5.06 (s, 2H); ¹³C NMR (75 MHz, CDCl₃) δ: 162.3, 159.8, 156.2, 153.2, 143.5, 134.7, 132.5, 130.4, 129.5, 128.9, 128.1, 126.0, 122.1, 119.9, 116.6, 111.1; IR (KBr) ν_max: 3442, 2972, 1694, 1638, 1526, 1373, 1238, 1086, 786 cm^－1; ESI-MS m/z: 259.05 [M+H]⁺.

  3-(2-(Methylamino)thiazol-4-yl)-2H-chromen-2-one (3i): Yellow solid, m.p. 170~171 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 8.54 (s, 1H), 7.78 (s, 1H), 7.51~7.60 (m, 2H), 7.29~7.36 (m, 2H), 5.24 (s, 1H), 3.05 (d, J＝4.8 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ: 169.4, 159.7, 152.8, 144.2, 138.5, 131.1, 128.1, 124.5, 121.1, 119.7, 116.3, 109.4, 32.2; IR (KBr) ν_max: 3443, 2127, 1638, 1378, 1084, 471 cm^－1; ESI-MS m/z: 259.01 [M+H]⁺. Anal. calcd for C₁₃H₁₀N₂O₂S: C 60.45, H 3.90, N 10.85; found C 60.23, H 3.78, N 10.67.

  6-Methyl-3-(2-(methylamino)thiazol-4-yl)-2H-chromen-2-one (3j): Yellow solid, m.p. 129~130 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 8.49 (s, 1H), 7.76 (s, 1H), 7.30~7.37 (m, 3H), 5.33 (s, 1H), 3.06 (d, J＝4.5 Hz, 3H), 2.42 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ: 169.5, 159.9, 151.0, 143.8, 138.7, 134.1, 132.3, 128.0, 120.6, 119.4, 116.0, 109.0, 32.3, 20.8; IR (KBr) ν_max: 3444, 1638, 1086, 476 cm^－1; ESI-MS m/z: 273.01 [M+H]⁺. Anal. calcd for C₁₄H₁₂N₂O₂S: C 61.75, H 4.44, N 10.29; found C 61.87, H 4.24, N 10.01.

  8-Methoxy-3-(2-(methylamino)thiazol-4-yl)-2H-chromen-2-one (3k): Yellow solid, m.p. 178~179 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 8.50 (s, 1H), 7.77 (s, 1H), 7.14~7.23 (m, 2H), 7.05 (d, J＝7.4 Hz, 1H), 5.32 (s, 1H), 3.40 (s, 3H), 3.04 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ: 169.5, 159.1, 146.8, 144.2, 142.4, 138.6, 124.2, 121.3, 120.3, 119.7, 113.0, 109.5, 56.2, 32.2; IR (KBr) ν_max: 3443, 1721, 1639, 1469, 1269, 1094, 713 cm^－1; ESI-MS m/z: 289.09 [M+H]⁺. Anal. calcd for C₁₄H₁₂N₂O₃S: C 58.32, H 4.20, N 9.72; found C 58.20, H 4.07, N 9.59.

  6-Chloro-3-(2-(methylamino)thiazol-4-yl)-2H-chromen-2-one (3l): Yellow solid, m.p. 172~173 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 8.45 (s, 1H), 7.78 (s, 1H), 7.55~7.56 (m, 1H), 7.45~7.46 (m, 1H), 7.30~7.43 (m, 1H), 5.19 (s, 1H), 3.06 (d, J＝5.0 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ: 169.4, 159.1, 151.1, 143.8, 137.1, 134.3, 130.9, 127.2, 122.0, 120.8, 117.7, 110.2, 32.2; IR (KBr) ν_max: 3440, 1732, 1689, 1557, 1470, 1364, 1081, 773 cm^－1; ESI-MS m/z: 292.87 [M+H]⁺. Anal. calcd for C₁₃H₉Cl-N₂O₂S: C 53.34, H 3.10, N 9.57; found C 53.18, H 3.01, N 9.36.

  6-Bromo-3-(2-(methylamino)thiazol-4-yl)-2H-chromen-2-one (3m): Yellow solid, m.p. 185~186 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 8.40~8.45 (d, J＝12.8 Hz, 1H), 7.70~7.79 (m, 3H), 7.56~7.59 (m, 1H), 5.15 (s, 1H), 3.06 (d, J＝5.0 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ: 169.4, 154.1, 151.6, 145.9, 137.0, 132.2, 130.2, 125.4, 121.4, 118.4, 118.0, 110.3, 32.1; IR (KBr) ν_max: 3440, 1722, 1669, 1551, 1476, 1402, 1356, 1201, 1081, 822, 774 cm^－1; ESI-MS m/z: 336.99 [M+H]⁺. Anal. calcd for C₁₃H₉BrN₂O₂S: C 46.31, H 2.69, N 8.31; found C 46.24, H 2.58, N 8.16.

  3-(2-(Methylamino)thiazol-4-yl)-6-nitro-2H-chromen-2-one (3n): Yellow solid, m.p. 146~147 ℃; ¹H NMR (300 MHz, DMSO-d₆) δ: 8.50~8.59 (m, 2H), 8.33~8.37 (m, 1H), 7.79 (s, 1H), 7.44~7.47 (m, 1H), 5.15 (s, 1H), 3.07 (d, J＝5.0 Hz, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ: 169.4, 158.1, 156.0, 144.2, 143.3, 136.6, 125.5, 123.7, 122.9, 119.9, 117.3, 111.1, 32.1; IR (KBr) ν_max: 3408, 1742, 1720, 1620, 1583, 1476, 1342, 1213, 1092, 839, 746 cm^－1; ESI-MS m/z: 303.00 [M]⁺. Anal. calcd for C₁₃H₉-N₃O₄S: C 51.48, H 2.99, N 13.85; found C 51.40, H 2.89, N 13.76.

  7-Diethylamino-3-(2-(methylamino)thiazol-4-yl)-2H-chromen-2-one (3o): Yellow solid, m.p. 123~124 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 8.41 (s, 1H), 7.58 (s, 1H), 7.36 (d, 1H), 6.61~6.62 (m, 1H), 6.52~6.59 (m, 1H), 5.21 (s, 1H), 3.42 (q, J＝7.1 Hz, 4H), 3.03 (d, J＝4.7 Hz, 3H), 1.22 (t, J＝7.0 Hz, 6H); ¹³C NMR (75 MHz, CDCl₃) δ: 169.4, 160.8, 155.6, 150.5, 145.1, 139.5, 129.3, 114.6, 109.1, 109.0, 106.1, 97.0, 44.8, 32.2, 12.5; IR (KBr) ν_max: 3442, 1712, 1623, 1403, 1235, 1125, 771 cm^－1; ESI-MS m/z: 330.13 [M+H]⁺. Anal. calcd for C₁₇H₁₉N₃O₂S: C 61.98, H 5.81, N 12.76; found C 61.81, H 5.69, N 12.64.

  2-(2-(Methylamino)thiazol-4-yl)-3H-benzo[f]chromen-3-one (3p): Yellow solid, m.p. 200~201 ℃; ¹H NMR (300 MHz, CDCl₃) δ: 9.35 (s, 1H), 8.43 (d, J＝8.4 Hz, 1H), 7.89~7.91 (m, 2H), 7.83 (s, 1H), 7.67~7.72 (m, 1H), 7.47~7.57 (m, 2H), 5.28 (s, 1H), 3.09 (d, 3H, J＝4.8 Hz); ¹³C NMR (75 MHz, CDCl₃) δ: 169.6, 159.8, 152.3, 144.8, 134.5, 132.4, 130.4, 129.4, 128.9, 128.0, 126.0, 122.1, 120.2, 116.6, 114.0, 109.3, 32.3; IR (KBr) ν_max: 3441, 1632, 1554, 1378, 1086, 810 cm^－1; ESI-MS m/z: 309.14 [M+H]⁺. Anal. calcd for C₁₇H₁₂N₂O₂S: C 66.22, H 3.92, N 9.08; found C 66.11, H 3.76, N 9.01.

  3-(2-(Phenylamino)thiazol-4-yl)-2H-chromen-2-one (3q): Yellow solid, m.p. 187~189 ℃ (lit.^[18] 188~190 ℃); ¹H NMR (300 MHz, DMSO-d₆) δ: 10.36 (s, 1H), 8.70 (s, 1H), 7.97 (d, J＝6.9 Hz, 1H), 7.75~7.79 (m, 2H), 7.62~7.67 (m, 1H), 7.36~7.48 (m, 5H), 7.01 (t, J＝7.3 Hz, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ: 162.5, 158.8, 152.3, 143.6, 141.0, 138.6, 131.7, 129.1, 129.0, 124.7, 121.5, 120.3, 119.3, 117.1, 115.9, 109.9; IR (KBr) ν_max: 3442, 2921, 1606, 1543, 1087, 740 cm^－1; ESI-MS m/z: 321.17 [M+H]⁺.

  6-Methyl-3-(2-(phenylamino)thiazol-4-yl)-2H-chromen-2-one (3r): Yellow solid, m.p. 123~124 ℃; ¹H NMR (300 MHz, DMSO-d₆) δ: 10.36 (s, 1H), 8.64 (s, 1H), 7.75~7.78 (m, 4H), 7.34~7.44 (m, 4H), 7.01 (t, J＝7.32 Hz, 1H), 2.41 (s, 3H, CH₃); ¹³C NMR (75 MHz, DMSO-d₆) δ: 162.5, 160.0, 150.5, 143.7, 141.0, 138.6, 134.0, 132.6, 129.1, 128.6, 121.4, 120.2, 119.0, 117.1, 115.6, 109.8, 20.3; IR (KBr) ν_max: 3436, 1704, 1604, 1543, 1497, 1440, 1313, 1094, 744 cm^－1; ESI-MS m/z: 335.08 [M+ H]⁺. Anal. calcd for C₁₉H₁₄N₂O₂S: C 68.24, H 4.22, N 8.38; found C 68.12, H 4.13, N 8.26.

  8-Methoxy-3-(2-(phenylamino)thiazol-4-yl)-2H-chromen-2-one (3s): Yellow solid, m.p. 169~170 ℃; ¹H NMR (300 MHz, DMSO-d₆) δ: 10.36 (s, 1H), 8.66 (s, 1H), 7.74~7.80 (m, 3H), 7.49~7.51 (m, 1H), 7.32~7.41 (m, 4H), 7.00 (t, J＝7.3 Hz, 1H), 3.94 (s, 3H, OCH₃-H); ¹³C NMR (75 MHz, DMSO-d₆) δ: 162.5, 158.5, 147.3, 146.2, 143.5, 141.6, 140.9, 138.8, 129.1, 124.6, 121.4, 120.4, 119.8, 117.1, 113.8, 110.0, 56.1; IR (KBr) ν_max: 3436, 1639, 1266, 1097, 804 cm^－1; ESI-MS m/z: 350.99 [M+ H]⁺. Anal. calcd for C₁₉H₁₄N₂O₃S: C 65.13, H 4.03, N 7.99; found C 65.01, H 3.97, N 7.81.

  6-Chloro-3-(2-(phenylamino)thiazol-4-yl)-2H-chromen-2-one (3t): Yellow solid, m.p. 215~216 ℃ (lit.^[18] 215~217 ℃); ¹H NMR (300 MHz, DMSO-d₆) δ: 10.36 (s, 1H), 8.60 (s, 1H), 8.07~8.15 (m, 2H), 7.67~7.81 (m, 3H), 7.63~7.67 (m, 1H), 7.47~7.51 (m, 1H), 7.39 (d, J＝7.8 Hz, 1H), 7.02 (t, J＝7.2 Hz, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ: 162.5, 158.4, 150.9, 143.4, 140.9, 137.3, 133.8, 131.0, 129.1, 128.4, 121.4, 120.8, 119.5, 117.8, 117.1, 110.7; IR (KBr) ν_max: 3441, 1721, 1612, 1548, 1076, 745 cm^－1; ESI-MS m/z: 354.92 [M+H]⁺.

  6-Bromo-3-(2-(phenylamino)thiazol-4-yl)-2H-chromen-2-one (3u): Yellow solid, m.p. 229~231 ℃ (lit.^[18] 229~231 ℃); ¹H NMR (300 MHz, DMSO-d₆) δ: 10.36 (s, 1H), 8.60 (s, 1H), 8.30 (s, 1H), 7.75~7.81 (m, 3H), 7.36~7.44 (m, 3H), 7.18 (s, 1H), 7.00~7.02 (m, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ: 162.5, 158.0, 153.6, 145.6, 143.4, 140.9, 137.2, 136.6, 132.5, 129.1, 125.4, 121.4, 120.0, 118.4, 117.1, 116.3; IR (KBr) ν_max: 3443, 1717, 1605, 1545, 1094, 741 cm^－1; ESI-MS m/z: 398.96 [M+H]⁺.

  6-Nitro-3-(2-(phenylamino)thiazol-4-yl)-2H-chromen-2-one (3v): Yellow solid; m.p. 190~191 ℃; ¹H NMR (300 MHz, DMSO-d₆) δ: 10.13 (s, 1H), 8.34 (br, 1H), 7.85 (br, 1H), 7.69~7.70 (m, 1H), 7.39~7.44 (m, 3H), 7.26~67.28 (m, 4H); ¹³C NMR (75 MHz, DMSO-d₆) δ: 176.6, 166.9, 138.5, 137.0, 131.6, 131.5, 130.1, 129.7, 129.6, 129.3, 128.6, 126.2, 124.3, 122.4, 114.8, 103.8; IR (KBr) ν_max: 3425, 1613, 1526, 1384, 1263, 599 cm^－1; ESI-MS m/z: 365.99 [M+H]⁺. Anal. calcd for C₁₈H₁₁N₃O₄S: C 59.17, H 3.03, N 11.50; found C 59.10, H 2.96, N 11.42.

  7-(Diethylamino)-3-(2-(phenylamino)thiazol-4-yl)-2H-chromen-2-one (3w): Yellow solid, m.p. 198~199 ℃; ¹H NMR (300 MHz, DMSO-d₆) δ: 10.27 (s, 1H), 8.52 (s, 1H), 7.74 (d, J＝10.8 Hz, 2H), 7.66 (d, J＝8.8 Hz, 1H), 7.55 (s, 1H), 7.35~7.40 (m, 2H), 6.96~7.01 (m, 1H), 6.75~6.78 (m, 1H), 6.60 (s, 1H), 3.46 (q, J＝7.2 Hz, 4H, CH₂), 1.45 (t, J＝7.2 Hz, 6H, CH₃); ¹³C NMR (75 MHz, DMSO-d₆) δ: 162.2, 159.9, 158.3, 155.3, 152.9, 147.6, 144.6, 139.6, 132.4, 129.8, 122.5, 121.2, 116.9, 114.9, 110.1, 107.5, 44.4, 12.3; IR (KBr) ν_max: 3438, 1694, 1616, 1508, 1124, 1079, 744 cm^－1; ESI-MS m/z: 392.01 [M+H]⁺. Anal. calcd for C₂₂H₂₁N₃O₂S: C 67.50, H 5.41, N 10.73; found C 67.43, H 5.28, N 10.61.

  2-(2-(Phenylamino)thiazol-4-yl)-3H-benzo[f]chromen-3-one (3x): Yellow solid, m.p. 201~202 ℃; ¹H NMR (300 MHz, DMSO-d₆) δ: 10.43 (s, 1H), 9.37 (s, 1H), 8.44 (d, J＝8.4 Hz, 1H), 8.22 (d, J＝9.0 Hz, 1H), 8.11 (d, J＝8.1 Hz, 1H), 7.78~7.90 (m, 4H), 7.64~7.71 (m, 2H), 7.45 (t, J＝7.8 Hz, 2H), 7.05 (t, J＝7.2 Hz, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ: 162.8, 158.8, 151.9, 143.8, 141.0, 133.9, 133.0, 130.1, 129.2, 129.1, 128.7, 128.6, 126.2, 121.6, 121.5, 119.5, 117.2, 116.5, 113.2, 109.9; IR (KBr) ν_max: 3441, 1632, 1554, 1378, 1086, 810, 778 cm^－1; ESI-MS m/z: 371.09 [M+H]⁺.

  
  
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• 

  Scheme 1  Proposed mechanism for the synthesis of 2-aminothiazolyl coumarins (3)

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  Table 1.  Effect of solvent, temperature and molar ratio of n(1a)/n(2a)/n(CuO)/n(I₂) on the yield of 3a

  Entry	Solvent	t/℃	n(1a):n(2a):n(CuO):n(I2)	Yielda/%
  1	EtOH	78	1.0:1.0:1.0:1.0	85
  2	MeOH	65	1.0:1.0:1.0:1.0	82
  3	PrOH	97	1.0:1.0:1.0:1.0	78
  4	BuOH	118	1.0:1.0:1.0:1.0	72
  5	t-BuOH	83	1.0:1.0:1.0:1.0	0b
  6	MeCN	82	1.0:1.0:1.0:1.0	0b
  7	THF	66	1.0:1.0:1.0:1.0	0b
  8	Toluene	111	1.0:1.0:1.0:1.0	0b
  9	DMF	90	1.0:1.0:1.0:1.0	0b
  10	EtOH	78	1.0:1.0:1.1:1.1	88
  11	EtOH	78	1.0:1.0:1.5:1.5	86
  12	EtOH	78	1.0:1.1:1.1:1.1	87
  13	EtOH	65	1.0:1.0:1.1:1.1	75
  a Isolated yield. b No reaction.

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  Table 2.  Synthesis of 3 from 3-acetylcoumarins and thiourea

  Compd.	R1	R2	R3	R4	R5	Yielda/%
  3a	H	H	H	H	H	88
  3b	H	Me	H	H	H	82
  3c	H	H	H	OMe	H	89
  3d	H	Cl	H	H	H	85
  3e	H	Br	H	H	H	83
  3f	H	NO2	H	H	H	81
  3g	H	H	NEt2	H	H	80
  3h	Benzo		H	H	H	82
  3i	H	H	H	H	Me	84
  3g	H	Me	H	H	Me	76
  3k	H	H	H	OMe	Me	85
  3l	H	Cl	H	H	Me	82
  3m	H	Br	H	H	Me	79
  3n	H	NO2	H	H	Me	74
  3o	H	H	NEt2	H	Me	75
  3p	Benzo		H	H	Me	77
  3q	H	H	H	H	Ph	66
  3r	H	Me	H	H	Ph	63
  3s	H	H	H	OMe	Ph	68
  3t	H	Cl	H	H	Ph	65
  3u	H	Br	H	H	Ph	62
  3v	H	NO2	H	H	Ph	58
  3w	H	H	NEt2	H	Ph	60
  3x	Benzo		H	H	Ph	63
  a Isolated yield.

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•