HETEROCYCLES

Note | Special issue | Vol. 77, No. 2, 2009, pp. 1409-1416
Received, 17th September, 2008, Accepted, 10th October, 2008, Published online, 14th October, 2008.
DOI: 10.3987/COM-08-S(F)117

■ Preparation of 5H,7H-Dibenz[c,e]oxepin-5-one Derivative through Reconstruction of the Lactone Ring

Hitoshi Abe,* Masatsugu Arai, Yasuo Takeuchi, and Takashi Harayama*

Faculty of Engineering, Toyama University, Gofuku 3190, Toyama 930-8555, Japan

Abstract

The systematic investigation of the efficient transformation of 6H-dibenzo[b,d]pyran-6-one into 5H,7H-dibenz[c,e]oxepin-5-one is described.

The 5H,7H-dibenz[c,e]oxepin-5-one skeleton is a structurally rare ring system among natural products.1 However, recent research has shown that the naturally occurring compounds containing this ring system exhibit quite interesting biological activities, such as anti-tumor1d and tyrosine kinase inhibiting properties.1b,1c
Based on such informaion, we have demonstrated the short-step syntheses of the compounds, graphislactone D2 and ulocladol,3 using a palladium-mediated biaryl coupling reaction.4 In our synthetic route for these compounds, a lactone reconstruction process was the key step for the formation of the 5H,7H-dibenz[c,e]oxepin-5-one skeleton (Scheme 1).5 Although this useful transformation is thought to be applicable for other synthetic uses, there has been no systematic investigation of this type of transformation. In this report, we describe the scope and limitations of the ring transformation of the 6H-dibenzo[b,d]pyran-6-one into 5H,7H-dibenz[c,e]oxepin-5-one.

We initially examined the reaction of the six-membered ring lactone 16 as a substrate using various alcohols (Table 1). Under elevated temperature conditions, 1 was transformed into a seven-membered ring lactone 2 accompanied by the ring opened products 3 and 4 when normal-alkyl alcohols were used (Runs 1-3). On the other hand, when the branched alcohols were employed, the lactone-opened biphenyls 3 and 4 were mainly generated (Run 4). Especially, when secondary alcohol was employed, the acetoxy compound 4 was exclusively formed (Runs 5 and 6).

These results suggest that the reactivity of this transformation is related to the size of the alkyl moiety of the alcohol. The acetoxy group can be easily removed by methanol or ethanol, followed by the lactone formation to afford the seven-membered ring (Runs 1 and 2). However, it seems different from the previously reported ones, namely, as illustrated in Scheme 2, similar transformations successfully produced the corresponding seven-membered ring lactone compounds in high yields without generating the biphenyls.2,3

Based on the difference in the above reactivity, the presence of a substituent on the 10-position might be crucial for this conversion. In order to clarify the importance of the 10-position, we examined the same reaction using the 10-demethoxy compound 5, which was prepared by the simple esterification between carboxylic acid 67 and phenol 78 followed by the intramolecular coupling reaction (Scheme 3). During the reaction of 5 with the methanol and potassium carbonate system, the expected transformation into the seven-membered ring lactone 8 took place without the generation of the corresponding biphenyl (Scheme 4).

In summary, we investigated the facile ring transformation of 6H-dibenzo[b,d]pyran-6-one into 5H,7H-dibenz[c,e]oxepin-5-one in the presence of an alcohol under basic conditions. In this reaction, the absence of the substituent at the 10-position of the 6H-dibenzo[b,d]pyran-6-one system was essential for the formation of the desired seven-membered ring lactone.

EXPERIMENTAL
General: Melting points were measured using a Yanagimoto micro melting point hot-plate apparatus and are uncorrected. The IR spectra were recorded using a JASCO FTIR-350 spectrophotometer. The NMR spectra were obtained using a Varian MERCURY-300 or VXR-500 instrument with the chemical shifts being reported in δ ppm. The FAB-MS was obtained using a VG-Autospec instrument with m-nitrobenzyl alcohol as the matrix. Silica-gel column chromatography was carried out using Merck 9385 Kieselgel 60.
General procedure for the ring transformation (Table 1)
A mixture of 1 (280 mg, 0.674 mmol), potassium carbonate (187 mg, 1.35 mmol), and an alcohol (15 mL) was heated at 90 °C with stirring for 2 h. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over magnesium sulfate, and evaporated to give a residue, which was purified by silica-gel column chromatography using hexane-EtOAc as the eluent.
11-Hydroxy-1,2,3,9,10-pentamethoxy-5H,7H-dibenz[c,e]oxepin-5-one (2)
Colorless needles, mp 205 °C (CH2Cl2-hexane). 1H-NMR (300 MHz, CDCl3) δ: 3.77 (3H, s, OCH3), 3.928 (3H, s, OCH3), 3.930 (3H, s, OCH3), 3.95 (3H, s, OCH3), 3.98 (3H, s, OCH3), 4.81 (1H, d, A of AB, J = 11.7 Hz, ArCHAHBO), 4.97 (1H, d, B of AB, J = 11.7 Hz, ArCHAHBO), 6.64 (1H, s, 8-H), 6.70 (1H, s, OH, exchangeable with D2O), 7.22 (1H, s, 4-H). 13C-NMR (75 MHz, CDCl3) δ: 56.1, 56.3, 61.1, 61.2, 61.9, 69.9, 104.7, 109.9, 115.8, 120.9, 127.1, 131.2, 138.0, 145.1, 148.3, 149.9, 152.4, 153.0, 169.6.
IR (KBr) cm-1: 3400 (OH), 1720 (C=O), 1460, 1400, 1350, 1330, 1150, 1110 (O-C=O), 1000. FAB-Mass (positive ion mode) m/z: 376 [M]+, 377 [M+1]+. HRMS (FAB) calcd for C19H20O8 [M]+: 376.1158. Found: 376.1131. Anal. Calcd for C19H20O8: C, 60.63; H, 5.36. Found: C, 60.35; H, 5.32.
2-Hydroxy-6-hydroxymethyl-2’,3,3’,4,4’-pentamethoxy-6’-methoxycarbonyl-1,1’-biphenyl (3a)
Colorless needles, mp 143-144 °C (CH2Cl2-hexane). 1H-NMR (300 MHz, CDCl3) δ: 3.57 (3H, s, COOCH3), 3.66 (3H, s, OCH3), 3.91 (3H, s, OCH3), 3.94 (3H, s, OCH3), 3.95 (3H, s, OCH3), 3.96 (3H, s, OCH3), 4.22 (1H, d, A of AB, J = 11.6 Hz, ArCHAHBOH), 4.27 (1H, d, B of AB, J = 11.6 Hz, ArCHAHBOH), 5.72 (1H, bs, Ar-OH, exchangeable with D2O), 6.71 (1H, s, 5-H), 7.34 (1H, s, 5’-H). 13C-NMR (75 MHz, CDCl3) δ: 52.3, 55.7, 56.1, 61.05, 61.08, 61.13, 64.2, 104.6, 109.6, 115.2, 124.1, 126.5, 134.5, 135.1, 145.7, 146.3, 151.4, 151.5, 152.4, 167.3. IR (KBr) cm-1: 3500 (OH), 3340 (OH), 1720 (C=O), 1100 (O-C=O). FAB-Mass (positive ion mode) m/z: 408 [M]+. Anal. Calcd for C20H24O9: C, 58.82; H, 5.92. Found: C, 58.64; H, 5.92.
6-Ethoxycarbonyl-2’-hydroxy-6’-hydroxyethyl-2,3,3’,4,4’-pentamethoxy-1,1’-biphenyl (3b)
Colorless needles, mp 146-147 °C (CH2Cl2-hexane). 1H-NMR (300 MHz, CDCl3) δ: 1.05 (3H, t, J = 7.2 Hz, COOCH2CH3), 3.57 (3H, s, OCH3), 3.91 (3H, s, OCH3), 3.93 (3H, s, OCH3), 3.95 (3H, s, OCH3), 3.96 (3H, s, OCH3), 4.08 (2H, q, J = 7.2 Hz, COOCH2CH3), 4.24 (1H, d, A of AB, J = 11.4 Hz, ArCHAHBOH), 4.25 (1H, d, B of AB, J = 11.4 Hz, ArCHAHBOH), 5.75 (1H, bs, Ar-OH, exchangeable with D2O), 6.70 (1H, s, 5’-H), 7.33 (1H, s, 5-H). 13C-NMR (75 MHz, CDCl3) δ: 13.9, 55.7, 56.1, 61.0, 61.1, 61.1, 64.1, 104.5, 109.5, 115.4, 123.6, 127.2, 134.5, 135.1, 145.5, 146.4, 151.3, 151.4, 152.5, 167.1. IR (KBr) cm-1: 3360 (OH), 3200 (OH), 1690 (C=O), 1110 (O-C=O). Anal. Calcd for C21H26O9: C, 59.71; H, 6.20. Found: C, 59.63; H, 6.02.
6-Butoxycarbonyl-2’-hydroxy-6’-hydroxymethyl-2,3,3’,4,4’-pentamethoxy-1,1’-biphenyl (3c)
Colorless needles, mp 126-127 °C (CH2Cl2-hexane). 1H-NMR (300 MHz, CDCl3) δ: 0.85 (3H, t, J = 7.2 Hz, CH2CH3), 1.20 (2H, sxt, J = 7.5 Hz, CH2CH2CH3), 1.33-1.45 (2H, m, CH2CH2CH2), 2.81 (1H, bs, CH2OH), 3.56 (3H, s, 2-OCH3), 3.91 (3H, s, OCH3), 3.93 (3H, s, OCH3), 3.95 (3H, s, OCH3), 3.96 (6H, s, 2×OCH3), 4.03 (2H, td, J = 3.0, 6.6 Hz, COOCH2), 4.24 (2H, s, CH2OH), 5.73 (1H, s, Ar-OH), 6.70 (1H, s, 5’-H), 7.34 (1H, s, 5-H). 13C-NMR (75 MHz, CDCl3) δ: 13.8, 19.1, 30.5, 55.7, 56.1, 61.0, 61.09, 61.14, 64.2, 65.1, 104.6, 109.6, 115.4, 123.6, 127.2, 134.5, 135.2, 145.5, 146.4, 151.3, 151.4, 152.5, 167.3. IR (KBr) cm-1: 3400 (OH), 3300 (OH), 1700 (C=O), 1460, 1340, 1230, 1125, 1110, 1000. Anal. Calcd for C23H30O9: C, 61.32; H, 6.71. Found: C, 61.26; H, 6.57.
6-Acetoxymethyl-6’-butoxycabonyl-2-hydroxy-2’,3,3’,4,4’-pentamethoxy-1,1’-biphenyl (4c)
Pale yellow oil. 1H-NMR (500 MHz, CDCl3) δ: 0.82 (3H, t, J­ = 7.3 Hz, CH2CH3), 1.13 (2H, sxt, J = 7.5 Hz, CH2CH2CH3), 1.32 (2H, quint, J = 7.0 Hz, CH2CH2CH2), 1.97 (3H, s, OCOCH3), 3.62 (3H, s, 2’-OCH3), 3.92 (3H, s, OCH3), 3.93 (3H, s, OCH3), 3.94 (6H, s, 2×OCH3), 3.99 (2H, td, J = 2.7, 5.4 Hz, COOCH2), 4.65 (1H, d, A of AB, J = 12.5 Hz, CHAHBOAc), 4.78 (1H, d, B of AB, J = 12.5 Hz, CHAHBOAc), 5.77 (1H, s, Ar-OH), 6.60 (1H, s, 5-H), 7.39 (1H, s, 5’-H). 13C-NMR (75 MHz, CDCl3) δ: 13.8, 19.1, 21.0, 30.5, 55.8, 56.1, 60.87, 60.91, 61.0, 64.79, 64.84, 104.5, 109.7, 117.3, 123.1, 126.7, 129.7, 134.9, 145.5, 146.7, 151.1, 151.7, 152.6, 166.7, 170.5. IR (neat) cm-1: 3420 (OH), 1740 (C=O), 1700 (C=O), 1590, 1490, 1460, 1330, 1230, 1100, 1000. FAB-Mass (positive ion mode) m/z: 492 [M]+.
6-(2-Methylpropoxy)carbonyl-2’-hydroxy-6’-hydroxymethyl-2,3,3’,4,4’-pentamethoxy-1,1’-biphenyl (3d)
Colorless oil. 1H-NMR (300 MHz, CDCl3) δ: 0.79 (3H, d, J = 4.8 Hz, -CH3), 0.81 (3H, d, J = 4.5 Hz, -CH3), 1.73 (2H, sep, J = 6.6 Hz, CH2CH(CH3)2), 3.56 (3H, s, OCH3), 3.77 - 3.91 (2H, m, J = 6.6 Hz, COOCH2CH), 3.90 (3H, s, OCH3), 3.93 (3H, s, OCH3), 3.95 (6H, s, OCH3), 3.96 (6H, s, OCH3), 4.23 (1H, d, A of AB, J = 11.7 Hz, ArCHAHBOH), 4.27 (1H, d, B of AB, J = 11.7 Hz, ArCHAHBOH), 5.71 (1H, s, Ar-OH), 6.70 (1H, s, 5’-H), 7.36 (1H, s, 5-H). 13C-NMR (75 MHz, CDCl3) δ: 18.9, 19.0, 55.7, 56.0, 60.9, 61.0, 61.1, 64.1, 71.3, 104.7, 109.7, 115.4, 123.8, 127.2, 134.6, 135.3, 145.6, 146.5, 151.48, 151.54, 152.6, 167.4. IR (CHCl3) cm-1: 3520 (OH), 1700 (C=O), 1460, 1340, 1220, 1100. FAB-Mass (positive ion mode) m/z: 492 [M]+.
6-Acetoxymethyl-6’-(2-methylpropoxy)carbonyl-2-hydroxy-2’,3,3’,4,4’-pentamethoxy-1,1’-biphenyl (4d)
Colorless oil. 1H-NMR (500 MHz, CDCl3) δ: 0.75 (3H, s, -CH3), 0.77 (3H, s, -CH3), 1.65 (1H, sep, J = 6.6 Hz, CH2CH(CH3)2), 1.96 (3H, s, OCOCH3), 3.62 (3H, s, OCH3), 3.79 (2H, d, J = 6.6 Hz, COOCH2CH), 3.92 (3H, s, OCH3), 3.93 (3H, s, OCH3), 3.95 (6H, s, ArOCH3), 4.66 (1H, d, A of AB, J = 12.0 Hz, ArCHAHBOAc), 4.79 (1H, d, B of AB, J = 12.0 Hz, ArCHAHBOAc), 5.77 (1H, s, Ar-OH), 6.61 (1H, s, 5-H), 7.41 (1H, s, 5’-H). 13C-NMR (75 MHz, CDCl3) δ: 18.99, 19.04, 20.9, 27.5, 55.8, 56.0, 60.8, 60.85, 60.91, 64.8, 71.3, 104.7, 109.8, 117.3, 123.3, 126.7, 129.7, 135.1, 145.6, 146.8, 151.2, 151.9, 152.7, 166.8, 170.7. IR (CHCl3) cm-1: 3520 (OH), 1730 (C=O), 1700 (C=O), 1460, 1330, 1240, 1110. FAB-Mass (positive ion mode) m/z: 450 [M]+.
6-Acetoxymethyl-2-hydroxy-6’-isopropoxycarbonyl-2’,3,3’,4,4’-pentamethoxy-1,1’-biphenyl (4e)
Colorless needles, mp 123-124 °C (CH2Cl2-hexane). 1H-NMR (300 MHz, CDCl3) δ: 0.92 (3H, d, J = 6.0 Hz, CH(CH3)2), 1.01 (3H, d, J = 6.0 Hz, CH(CH3)2), 1.98 (3H, s, OCOCH3), 3.65 (3H, s, OCH3), 3.92 (3H, s, OCH3), 3.94 (3H, s, OCH3), 3.94 (6H, s, 2×OCH3), 4.66 (1H, d, A of AB, J = 12.3 Hz, ArCHAHBOAc), 4.76 (1H, d, B of AB, J = 12.3 Hz, ArCHAHBOAc), 4.92 (1H, sep, J = 6.3 Hz, CH(CH3)2), 5.75 (1H, s, Ar-OH), 6.60 (1H, s, 5-H), 7.36 (1H, s, 5’-H). 13C-NMR (75 MHz, CDCl3) δ: 21.0, 21.4, 21.5, 55.9, 56.1, 60.9, 61.0, 64.8, 67.9, 104.4, 109.5, 117.5, 122.7, 127.4, 129.8, 134.9, 145.3, 146.8, 151.1, 151.7, 152.7, 166.3, 170.6. IR (KBr) cm-1: 3520 (OH), 1730 (C=O), 1695 (C=O), 1360, 1250, 1105. Anal. Calcd for C24H30O10: C, 60.24; H, 6.32. Found: C, 60.25; H, 6.25.
6-Acetoxymethyl-6’-sec-butoxycarbonyl-2-hydroxy-2’,3,3’,4,4’-pentamethoxy-1,1’-biphenyl (4f)
1:1 Mixture of diastereomers. Colorless needles, mp 91-94 °C (CH­2Cl2-hexane). 1H-NMR (300 MHz, CDCl3) δ: 0.72 (1.5H, t, J = 7.5 Hz, COOCH(CH3)CH2CH3), 0.77 (1.5H, t, J = 7.5 Hz, COOCH(CH3)CH2CH3), 0.90 (1.5H, d, J = 6.3 Hz, COOCH(CH3)CH2CH3), 0.99 (1.5H, d, J = 6.3 Hz, COOCH(CH3)CH2CH3), 1.19-1.37 (2H, m, COOCH(CH3)CH2CH3), 1.98 (1.5H, s, OCOCH3), 1.98 (1.5H, s, OCOCH3), 3.63 (1.5H, s, OCH3), 3.66 (1.5H, s, OCH3), 3.92-3.95 (12H, s, 4×OCH3), 4.63-4.82 (3H, m, ArCH2OAc and COOCH(CH3)CH2CH3), 5.74 (0.5H, s, OH), 5.75 (0.5H, s, OH), 6.59 (0.5H, s, 5-H), 6.61 (0.5H, s, 5-H), 7.37 (0.5H, s, 5’-H), 7.39 (0.5H, s, 5’-H). IR (KBr) cm-1: 3440 (OH), 1730 (C=O), 1695 (C=O), 1490, 1460, 1400, 1360, 1325, 1270, 1230, 1110, 1100, 1020, 1010. Anal. Calcd for C25H32O10: C, 60.97; H, 6.55. Found: C, 61.07; H, 6.34.
5-Acetoxymethyl-2,3-dimethoxyphenyl 2-iodo-4,5-dimethoxybenzoate
A solution of 67 (2.47 g, 8.02 mmol), 78 (1.65 g, 7.29 mmol), EDC (1.40 g, 7.29 mmol), and DMAP (178 mg, 1.46 mmol) in CH2Cl2 (70 mL) was stirred for 1 h at rt, and then the mixture was poured into water and extracted with CH2Cl2. The organic layer was washed with brine and dried over magnesium sulfate. After evaporation, the resulting residue was purified by silica-gel column chromatography using hexane- EtOAc to give colorless needles (3.37 g, 90%), mp 100-102 oC (Et2O). 1H-NMR (300 MHz, CDCl3) δ: 2.12 (3H, s, OCOCH3), 3.87 (3H, s, OCH3), 3.94 (3H, s, OCH3), 3.96 (3H, s, OCH3), 3.96 (3H, s, OCH3), 5.06 (2H, s, OCH2Ar), 6.85 (2H, s, phenoxy-4,6-H), 7.46 (1H, s, benzoate-3-H), 7.70 (1H, s, benzoate-6-H). 13C-NMR (75 MHz, CDCl3) δ: 21.1, 56.1, 56.2, 56.4, 60.9, 65.8, 85.8, 110.4, 114.3, 115.2, 123.9, 124.5, 131.3, 140.9, 143.8, 148.6, 152.3, 153.5, 153.5, 163.3. IR (KBr) cm-1: 1750 (C=O), 1730 (C=O), 1510, 1270, 1250, 1210, 1175, 1095. Anal. Calcd for C20H21IO8: C, 46.53; H, 4.10. Found: C, 46.47; H, 3.98.
1-Acetoxymethyl-3,4,8,9-tetramethoxy-6H-dibenzo[b,d]pyran-6-one (5)
A mixture of the ester (500 mg, 0.968 mmol), PdCl2(Ph3P)2 (169 mg, 0.242 mmol), and sodium acetate (158 mg, 1.94 mmol) was dried under reduced pressure for 3 h. This was dissolved in DMA (15 mL), and the mixture was stirred for 5 h at 120oC. After filtration, the mixture was extracted with ethyl acetate, and then the organic layer was washed with brine, dried over magnesium sulfate, and evaporated. The resulting residue was purified by silica-gel column chromatography using chloroform to give colorless needles (5, 244 mg, 65%), mp 191-193 oC (CH2Cl2-hexane). 1H-NMR (300 MHz, CDCl3) δ: 2.17 (3H, s, OCOCH3), 3.98 (3H, s, OCH3), 4.02 (3H, s, OCH3), 4.028 (3H, s, OCH3), 4.031 (3H, s, OCH3), 5.49 (2H, s, OCH2Ar), 7.06 (1H, s, 2-H), 7.63 (1H, s, 10-H), 7.84 (1H, s, 7-H). 13C-NMR (75 MHz, CDCl3) δ: 21.2, 56.1, 56.22, 56.25, 61.5, 66.3, 107.0, 110.9, 112.9, 113.5, 114.2, 125.9, 129.7, 137.1, 145.9, 148.9, 151.9, 154.3, 160.2, 170.3. IR (KBr) cm-1: 1740 (C=O), 1720 (C=O), 1610, 1500, 1320, 1250, 1230, 1150, 1100, 1030. Anal. Calcd for C20H20O8: C, 61.85; H, 5.19. Found: C, 61.64; H, 5.12.

ACKNOWLEDGEMENTS
We thank the SC-NMR Laboratory of Okayama University for performing the NMR experiments.


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

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