HETEROCYCLES

Note | Special issue | Vol. 77, No. 1, 2009, pp. 603-610
Received, 20th June, 2008, Accepted, 15th August, 2008, Published online, 18th August, 2008.
DOI: 10.3987/COM-08-S(F)29

■ Dihydroxylation of Functionalized Coumarin Derivatives

Keiko Fusegi, Takuya Kumamoto,* Waka Nakanishi, and Tsutomu Ishikawa*

Graduate School of Pharmaceutical Science, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan

Abstract

7-Acetoxy- and 7-tosyloxycoumarins were successfully dihydroxylated in RuCl₃/NaIO₄/CeCl₃ system to give the corresponding glycol derivatives in excellent yields. Tricyclic coumarin with tetrasubstituted olefin function also gave the desired diol in good yield. Introduction of electron-deficient protecting group to coumarin skeleton is critical for the successful dihydroxylation.

Coumarins are one of the most popular constituents in medicinal plants and also have been used as substrates for the synthesis of natural products.1 In our synthetic approaches2 towards phytoestrogenic miroestrol (1)3,4 and the deoxy isomer deoxymiroestrol (2),5 we planned the dihydroxylation of 7-hydroxy-4-substituted coumarin derivatives 3 to the corresponding diols 4 (Scheme 1a).

A number of examples of dihydroxylation of simple olefins have been investigated;6 however, the successful results for the olefin units in coumarin skeletons are so limited. Plietker et al.7 reported that the addition of cerium chloride (CeCl3) was effective for dihydroxylation of electron-deficient olefins including coumarin itself (5) in RuCl3/ NaIO4 system, in which oxidative cleavage of carbon-carbon double bond was avoided (Scheme 1b). We applied this reaction condition to the dihydroxylation of functionalized coumarins.
7-Hydroxycoumarin with isopropyl group at position 4 was synthesized by conventional Pechman condensation8 of resorcinol (7) and β-ketoester 8 in the presence of concentrated sulfuric acid in 76% yield. The corresponding acetate 9b and tosylate 9c were prepared from 9a (Scheme 2).
Trial for the dihydroxylation of the non-protected hydroxycoumarin 9a in the presence of 10 mol% of Ru species gave no desired product 10a, instead iodocoumarins 11 and 12 in low yields (run 1, Table 1). Electron-rich coumarin 139 gave the corresponding 8-iodo derivative 14 under the same reaction

conditions (run 2).10,11 It was supposed that molecular iodine (I2) generated by the reduction of periodinate12 by low-valent Ru species would react with electron-rich coumarins such as 9a and 13. Thus, electron-deficient group-substituted hydroxycoumarins were targeted. Dihydroxylation of acetate 9b proceeded smoothly to give the corresponding 1,2-diol 10b in 88% yield (run 3). The reduced amount of RuCl3 did not affected to the yield (run 4). Tosylate 9c also afforded the corresponding diol 10c in excellent yield (run 5).
Application to tricyclic coumarin with tetrasubstituted olefin function was examined (Scheme 3). Tricyclic coumarin 16c, prepared by Pechman condensation of 7 and β-ketoester 15 followed by tosylation, was dihydroxylated in the same manner as those for 9c to give the corresponding diol 17 in 76% yield (Scheme 3).

In conclusion, dihydroxylation of functionalized coumarins was succeeded with RuCl3/NaIO4/CeCl3 system. Introduction of electron-deficient protecting group on 7-hydroxy group is important for this reaction. Tricyclic coumarin derivative with tetrasubstituted olefin function was also subjected to the dihydroxylation conditions to give the corresponding diol in good yield. Further trials for the synthetic studies towards miroestrols are now under investigation.

EXPERIMENTAL
General: All melting points were measured on Yanagimoto MPSI melting point apparatus and are uncorrected. IR spectra were recorded with Attenuated Total Reflectance (ATR) system on a JASCO FT / IR-300E spectrophotometer. 1H- (400 MHz) and 13C-NMR (100 MHz) spectra were recorded on a JEOL JNM-GSX-400α or JEOL JNM-ECP-400. MS spectra were measured on JEOL JNM MS-GCMATE for EIMS, and JEOL JMS-HX110 or JEOL JMS-AX505 for FABMS. For column chromatography was used Kanto Chemical silica gel 60 spherical. For TLC were used Merck Art 5715 DC-Fertigplatten Kieselgel 60 F254.

7-Hydroxy-4-isopropylcoumarin (9a)
To a mixture of resorcinol (7, 1.08 g, 9.84 mmol) and β-ketoester 8 (1.84 g, 12.4 mmol), conc. H2SO4 (2.0 mL) was added under ice cooling and the whole was stirred at rt for 1 h. Ice (ca. 40 mL) was added and the whole was stirred at rt for 6 h. The precipitate was filtered off, washed with cold H2O, and dried to give pale brown solids, which was recrystallized from CHCl3 to give 9a (1.46 g, 73%).
Colorless plates. mp 133.5-136 °C (lit.,13 129.4-130.8 °C). IR (cm-1): 3145 (OH), 1675 (C=O). 1H-NMR (DMSO-d6) δ (ppm): 1.21 (6H, d, J = 6.8 Hz, 2 x Me), 3.29 (1H, sep, J = 6.8 Hz, CH), 6.06 (1H, s, 3-H), 6.70 (1H, d, J = 2.4 Hz, 8-H), 6.80 (1H, dd, J = 8.8, 2.4 Hz, 6-H), 7.68 (1H, d, J = 8.8 Hz, 5-H), 10.52 (1H, s, OH, D2O exchangeable). 13C-NMR (DMSO-d6) δ (ppm): 21.56, 27.90, 102.51, 106.45, 110.59, 112.94, 125.98, 155.13, 160.77, 160.89, 162.60.

7-Acetoxy-4-isopropylcoumarin (9b)
A mixture of 9a (5.00 g, 24.5 mmol), pyridine (4.0 mL, 49.0 mmol), and acetic anhydride (2.5 mL, 26.9 mmol) was stirred at rt for 2 h. Ice (ca. 5 mL) was added and the whole was stirred at rt for 3 h and then filtered. The precipitate was washed with cold H2O, dried and recrystallized from hexane - AcOEt (10 : 1) to give 9b (4.84 g, 80%).
Colorless pillars. mp 88-89 °C. Anal. Calcd for C14H14O4: C: 68.28, H: 5.73. Found: C: 67.98, H: 5.67. IR (cm-1): 1733 (C=O). 1H-NMR (CDCl3) δ (ppm): 1.33 (6H, d, J = 6.8 Hz, 2 x Me), 2.35 (3H, s, Ac), 3.27 (1H, sep, J = 6.8 Hz, CH), 6.30 (1H, s, 3-H), 7.08 (1H, dd, J = 8.6, 2.2 Hz, 6-H), 7.13 (1H, d, J = 2.2 Hz, 8-H), 7.69 (1H, d, J = 8.6 Hz, 5-H). 13C-NMR (CDCl3) δ (ppm): 21.06, 21.67, 28.69, 110.67, 110.74, 116.64, 117.95, 124.88, 152.72, 154.45, 161.11, 161.40, 168.69. EIMS m/z 246 (M+, 12.5), 204 (100), 161 (65.9).

4-Isopropyl-2-oxo-2H-chromen-7-yl p-toluenesulfonate (9c)
A mixture of 9a (3.00 g, 14.7 mmol), K2CO3 (5.08 g, 36.7 mmol), and TsCl (3.17 g, 16.3 mmol) in acetone (25 mL) was refluxed for 2 h. After cooling, the solvent was evaporated. H2O (70 mL) was added to the residue and the whole was extracted with AcOEt (3 x 100 mL). The combined organic layer was washed with H2O (3 x 80 mL) and brine (1 x 100 mL) and was dried over MgSO4. The solvent was evaporated in vacuo and the residue was recrystallized from hexane - AcOEt (7 : 1) to give 9c (4.83 g, 92%).
Colorless pillars. mp 117.5-119 °C. Anal. Calcd for C19H18O5S: C: 63.67, H: 5.06. Found: C: 63.76, H: 5.06. IR (cm-1): 1730 (C=O). 1H-NMR (CDCl3) δ (ppm): 1.32 (6H, d, J = 6.8 Hz, 2 x Me), 2.48 (3H, s, Me), 3.23 (1H, sep, J = 6.8 Hz, CH), 6.30 (1H, s, 3-H), 6.84 (1H, d, J = 2.4 Hz, 8-H), 7.12 (1H, dd, J = 8.8, 2.4 Hz, 6-H), 7.35 (2H, d, J = 8.4 Hz, Ts-meta), 7.65 (1H, d, J = 8.8 Hz, 5-H), 7.75 (2H, d, J = 8.4 Hz, Ts-ortho). 13C-NMR (CDCl3) δ (ppm): 21.40, 21.49, 28.47, 110.90, 110.99, 117.46, 118.35, 125.19, 128.15, 129.83, 131.66, 145.83, 150.99, 153.92, 160.41, 161.04. EIMS m/z 358 (M+, 23.5), 207 (73.7), 155 (72.2), 91 (100).

Trials for dihydroxylation of hydroxycoumarin 9a. Generation of 8-iodo- (11) and 6,8-diiodo- (12) coumarins (run 1 in Table 1)
A mixture of CeCl3·7H2O (13.1 mg, 35 µM) and NaIO4 (81 mg, 0.38 mmol) in distilled H2O (0.1 mL) was stirred for ca. 10 min until the color of the suspension turned to yellow. Under ice-cooling, AcOEt (0.1 mL) and MeCN (0.3 mL) was added and the whole was stirred at rt for 2 min. 0.1 M aq. RuCl3 (0.25 mL, 0.025 mmol, 10 mol%) was added and the whole was stirred at rt for 2 min. A solution of 9a (50 mg, 0.24 mmol) in AcOEt (0.2 mL) was added and the whole was stirred at 0 °C for 3 h and at rt for 7 h. AcOEt (3 mL) and Na2SO4 (ca. 200 mg) were added and the whole was filtered off. The precipitate was washed with AcOEt. The filtrate and the washing were combined and the whole was washed with sat. aq. Na2SO3 (1 x 10 mL) and was dried over Na2SO4. The solvent was evaporated in vacuo and the residue was purified by silica gel column chromatography (CC, hexane - AcOEt = 5 : 1) to give less polar 12 (15 mg, 14%) and more polar 11 (8 mg, 10%).
7-Hydroxy-6,8-diiodo-4-isopropylcoumarin (12)
Yellow solids. mp 137-146 °C. IR (cm-1): 3259 (OH), 1695 (C=O). 1H-NMR (CDCl3) δ (ppm): 1.32 (6H, d, J = 6.7 Hz, 2 x Me), 3.21 (1H, sep, J = 6.7 Hz, CH), 6.19 (1H, s, 3-H), 8.01 (1H, s, 5-H). 13C-NMR (CDCl3) δ (ppm): 21.84, 28.67, 74.38, 77.20, 109.36, 115.09, 134.16, 154.51, 156.52, 160.47, 160.74. HREIMS m/z 455.8734 (Calcd for C12H10I2O3: 455.8720).
7-Hydroxy-8-iodo-4-isopropylcoumarin (11)
Colorless solids. mp 133-140 °C. IR (cm-1): 3282 (OH), 1691 (C=O). 1H-NMR (CDCl3) δ (ppm): 1.32 (6H, d, J = 6.8 Hz, 2 x Me), 3.26 (1H, sep, J = 6.8 Hz, CH), 6.20 (1H, s, 3-H), 7.00 (1H, d, J = 8.8 Hz, 5-H), 7.58 (1H, d, J = 8.6 Hz, 6-H). 13C-NMR (CDCl3) δ (ppm): 21.86, 28.75, 77.20, 104.48, 113.12, 125.52, 154.17, 158.42, 161.20, 162.03 (one carbon lacked, provably because of overlap with the peak of CDCl3). HREIMS m/z 329.9753 (Calcd for C12H11IO3: 329.9753).

8-Iodo-5,7-dimethoxy-4-propylcoumarin (14) (run 2 in Table 1)
Identical procedure for the synthesis of 11 and 12 was applied with 139 (50 mg, 0.20 mmol), CeCl3·7H2O (8.1 mg, 22 µmol), NaIO4 (65 mg, 0.31 mmol), and 0.1 M aq. RuCl3 (0.15 mL, 15 µM) in AcOEt - MeCN - H2O (3 : 3 : 1, 0.7 mL) to give 14 (11 mg, 15%) with recovery of 13 (20 mg, 41%) after the purification by CC (hexane - AcOEt = 4 : 1 to 2 : 1).
Colorless solids. mp 111-116 °C. IR (cm-1): 1711 (C=O). 1H-NMR (CDCl3) δ (ppm): 1.01 (3H, t, J = 7.5 Hz, Me), 1.61 (2H, diffused sep, J = 7.5 Hz, MeCH2), 2.87 (2H, t, J = 7.5 Hz, CH2Ar), 3.96, 3.99 (each 3H, s, 2 x OMe), 6.00 (1H, s, 3-H), 6.36 (1H, s, 6-H). 13C-NMR (CDCl3) δ (ppm): 14.00, 22.76, 38.41, 56.00, 56.66, 66.38, 91.22, 105.11, 111.45, 155.51, 157.69, 159.45, 160.35, 161.25. HREIMS m/z 374.0013 (Calcd for C14H15IO4: 374.0015).

(3R*,4R*)-7-Acetoxy-3,4-dihydroxy-4-isopropylchroman-2-one (10b) (Run 4 in Table 1)
Identical procedure for the synthesis of 11 and 12 was applied with 9b (901 mg, 3.66 mmol), CeCl3·7H2O (139 mg, 0.37 mmol), NaIO4 (1.17 g, 5.48 mmol), and 0.1 M aq. RuCl3 (0.10 mL, 10 µM) in AcOEt - MeCN - H2O (3 : 3 : 1, 12.6 mL) to give 10b (906 mg, 88%) after the purification by CC (hexane - AcOEt = 3 : 1 to 1 : 1). An aliquot was recrystallized from hexane - acetone (15 : 1) to give an authentic sample.
Colorless prisms. mp 132.5-134 °C. Anal. Calcd for C14H16O6: C: 59.99, H: 5.75. Found: C: 59.61, H: 5.73. IR (cm-1): 3464 (OH), 1759 (C=O). 1H-NMR (CDCl3) δ (ppm): 1.07, 1.11 (each 3H, d, J = 7.1 Hz, 2 x Me), 2.31 (3H, s, Ac), 2.33 (1H, sep, J = 7.1 Hz, CH), 2.78, 3.26 (each 1H, s, 2 x OH, exchangeable with D2O), 4.53 (1H, s, 3-H), 6.89 (1H, d, J = 2.4 Hz, 8-H), 6.98 (1H, dd, J = 8.6, 2.4 Hz, 6-H), 7.56 (1H, d, J = 8.6 Hz, 5-H). 13C-NMR (100 MHz) δ (ppm): 16.72, 16.91, 21.00, 34.02, 71.06, 75.42, 110.44, 117.92, 123.35, 128.17, 149.78, 141.12, 168.53, 169.35. EIMS m/z 281 [(M+1)+, 13%], 262 (11%), 207 (100%).

(3R*,4R*)-3,4-Dihydroxy-4-propyl-2-oxo-2H-chromen-7-yl p-toluenesulfonate (10c) (Run 5 in Table 1)
Identical procedure for the synthesis of 11 and 12 was applied with 9c (1.00 g, 2.80 mmol), CeCl3·7H2O (108 mg, 0.29 mmol), NaIO4 (896 mg, 4.19 mmol), and 0.1 M aq. RuCl3 (70 µL, 7.0 µM) in AcOEt - MeCN - H2O (3 : 3 : 1, 14 mL) to give 10c (1.04 g, 95%) after the purification by CC (hexane - AcOEt 3 : 1 to 1 : 1). An aliquot was recrystallized from benzene to give an authentic sample.
Colorless prisms. mp 145-146.5 °C. Anal. Calcd for C19H20O7S: C: 58.15, H: 5.14. Found: C: 58.19, H: 5.20. IR (cm-1) 3543, 3469 (OH), 1745 (C=O). 1H-NMR (CDCl3) δ (ppm): 1.03, 1.06 (each 3H, d, J = 7.0 Hz, 2 x Me), 2.25 (1H, sep, J = 7.0 Hz, CH), 2.47 (3H, s, Me), 2.79 (1H, s, OH, exchangeable with D2O), 3.24 (1H, d, J = 3.3 Hz, OH, exchangeable with D2O), 4.50 [1H, d (s with D2O), J = 3.3 Hz, 3-H], 6.72 (1H, d, J = 2.4 Hz, 8-H), 6.94 (1H, dd, J = 8.6, 2.4 Hz, 6-H), 7.34 (2H, d, J = 8.1 Hz, Ts-meta), 7.50 (1H, d, J = 8.6 Hz, 5-H), 7.75 (2H, d, J = 8.1 Hz, Ts-ortho). 13C-NMR (100 MHz) δ (ppm): 16.70, 17.06, 21.72, 33.95, 70.93, 75.31, 111.17, 118.74, 124.43, 128.36, 128.40, 129.94, 132.05, 145.85, 149.87, 150.00, 168.26. EIMS m/z 392 (M+, 20%), 374 (12%), 349 (25%), 219 (32%), 155 (89%), 91 (100%).

3-Hydroxy-7,8,9,10-tetrahydrobenzo[c]chromen-6-one (16a)
Identical procedure for the synthesis of 9a was applied with 7 (1.00 g, 9.12 mmol), 15 (2.01 g, 10.3 mmol) and conc. H2SO4 (2.0 mL) to give 16a (2.02 g, quant).
Pale pink solid. mp 205-208 °C (lit.,14 203-204°C). IR (cm-1) 3452 (OH), 1738 (C=O). 1H-NMR (DMSO-d6) δ (ppm): 1.73-1.79 (4H, m, 8,9-H2), 2.41 (2H, t, J = 6.0 Hz, 10-H2), 2.76 (2H, t, J = 6.0 Hz, 7-H2), 6.71 (1H, d, J = 2.4 Hz, 4-H), 6.81 (1H, dd, J = 8.6, 2.4 Hz, 2-H), 7.56 (1H, d, J = 8.6 Hz, 1-H), 10.38 (1H, s, OH, D2O exchangeable). FABMS m/z 217 (MH+).

6-Oxo-7,8,9,10-tetrahydrobenzo[c]chromen-3-yl p-toluenesulfonate (16c)
Identical procedure for the synthesis of 9c was applied with 16a (200 mg, 0.93 mmol), TsCl (207 mg, 1.06 mmol), K2CO3 (325 mg, 2.35 mmol) and acetone (2.0 mL) to give 16c (244 mg, 71%, after recrystallization from hexane - CHCl3 = 3 : 2).
Colorless prisms. mp 183.5-184.5 °C. Anal. Calcd for C20H18O5S: C: 64.85, H: 4.90. Found: C: 64.72, H: 4.76. IR (cm-1): 1718 (C=O). 1H-NMR (CDCl3) δ (ppm): 1.77-1.89 (4H, m, 8,9-H2), 2.47 (3H, s, Me), 2.57 (2H, t, J = 5.9 Hz, 7- or 10-H2), 2.75 (2H, t, J = 6.0 Hz, 10- or 7-H2), 6.78 (1H, d, J = 2.4 Hz, 4-H), 7.09 (1H, dd, J = 8.8, 2.4 Hz, 2-H), 7.33 (2H, d, J = 8.1 Hz, Ts-meta), 7.53 (1H, d, J = 8.8 Hz, 1-H), 7.72 (2H, d, J = 8.1 Hz, Ts-ortho). 13C-NMR (CDCl3) δ (ppm): 21.14, 21.35, 21.73, 23.96, 25.19, 110.45, 118.60, 119.08, 124.00, 124.26, 128.41, 129.95, 131.83, 145.89, 146.39, 150.30, 152.07, 161.09. EIMS m/z 370 (M+, 100), 215 (74.7), 155 (93.4).

(6aR*,10aR*)-6a,10a-Dihydroxy-6-Oxo-7,8,9,10-tetrahydrobenzo[c]chromen-3-yl p-toluenesulfonate (17)
Identical procedure for the synthesis of 11 and 12 was applied with 16c (51 mg, 0.14 mmol), CeCl3·7H2O (7 mg, 19 µmol), NaIO4 (49 mg, 0.23 mmol), and 0.1 M aq. RuCl3 (3.5 µL, 0.35 µM) in AcOEt - MeCN - H2O (3 : 3 : 1, 0.7 mL) to give 17 (46 mg, 83%) after the purification by CC (hexane - AcOEt = 3 : 1 to 1 : 1).
A colorless oil. IR (cm-1) 3464 (OH), 1768 (C=O). 1H-NMR (CDCl3) δ (ppm): 1.27 (1H, diffused t, J = 12.4 Hz, one of CH2), 1.50 (1H, m, one of CH2), 1.58-1.78 (4H, m, CH2), 1.93 (1H, td, J = 13.3, 3.8 Hz, 10-H), 2.30 (1H, br d, J = 13.3 Hz, 10-H), 2.47 (3H, s, Me), 2.89, 3.42 (each 1H, s, 2 x OH, exchangeable with D2O), 6.73 (1H, d, J = 2.4 Hz, 4-H), 6.97 (1H, dd, J = 8.6, 2.4 Hz, 2-H), 7.35 (2H, d, J = 8.2 Hz, Ts-meta), 7.48 (1H, d, J = 8.6 Hz, 1-H), 7.75 (2H, d, J = 8.2 Hz, Ts-ortho). 13C-NMR (CDCl3) δ (ppm): 19.34, 21.70, 22.17, 31.28, 32.38, 71.86, 74.71, 111.51, 119.01, 123.08, 127.71, 128.39, 129.95, 132.03, 145.86, 150.38, 150.67, 171.78. HREIMS m/z 404.0906 (Calcd for C20H18O7S: 404.0930).

†This article is dedicated to Professor Emeritus Keiichiro Fukumoto on the occasion of his 75th birthday.

References

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