Collective Syntheses of 2-(3-Methylbenzofuran-2-yl)phenol-Derived

Sep 25, 2017 - A cascade [3,3]-sigmatropic rearrangement/aromatization strategy to the synthesis of 2-(3-methylbenzofuran-2-yl)phenol derivatives was ...
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Article Cite This: J. Org. Chem. 2017, 82, 11102-11109

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Collective Syntheses of 2‑(3-Methylbenzofuran-2-yl)phenol-Derived Natural Products by a Cascade [3,3]-Sigmatropic Rearrangement/ Aromatization Strategy Yingzhan Tang,†,‡ Chongguo Jiang,†,‡ Xinhang Zhang,†,‡,§ Chengjun Liu,†,‡,§ Jingsheng Lin,†,‡,§ Yanshi Wang,†,‡ Chuan Du,†,‡ Xiaoshi Peng,†,‡ Wei Li,∥ Yongxiang Liu,*,†,‡,§ and Maosheng Cheng*,†,‡ †

Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, Shenyang 110016, P. R. China ‡ Institute of Drug Research in Medicine Capital of China, Benxi 117000, P. R. China § Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, P. R. China ∥ Faculty of Pharmaceutical Sciences, Toho University, Miyama 2-2-1, Funabashi, Chiba 274-8510, Japan S Supporting Information *

ABSTRACT: A cascade [3,3]-sigmatropic rearrangement/ aromatization strategy to the synthesis of 2-(3-methylbenzofuran-2-yl)phenol derivatives was developed and applied to the collective syntheses of seven 2-arylbenzofuran-containing natural products, namely glycybenzofuran, glycyuralin E, lespedezol A1, puerariafuran, 7,2′,4′-trihydroxy-3-benzofurancarboxylic acid, coumestrol, and 4′-O-methylcoumestrol. Among them, the total syntheses of glycybenzofuran, glycyuralin E, puerariafuran, 7,2′,4′-trihydroxy-3-benzofurancarboxylic acid, and 4′O-methylcoumestrol were reported for the first time. The practicality of this novel strategy in preparation of the key intermediates was demonstrated by performing the reaction on gram scale and by synthesizing a series of natural products with 2(3-methylbenzofuran-2-yl)phenol scaffolds in a common strategy.

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INTRODUCTION 2-Arylbenzofuran-containing natural products, isolated from botanical families1 such as the moraceae,1a,b asteraceae,1c and leguminosae1d attracting considerable attention for their extensive biological activities,2 including antitumor, antimicrobial, analgesic, anti-inflammatory, and antiviral, contain a common scaffold 2-(3-methylbenzofuran-2-yl)phenol. Many synthetic strategies to natural products like lespedezol A13c and coumestrol3f (Scheme 1a), with methyl group oxidation state modification in the 3-position of the arylbenzofuran moiety in this scaffold, have been developed,4 including construction of furan rings4c,d,f and directed arylation by carbon−carbon bond formation.4a,b,e,g,i In this study, an unprecedented collective syntheses strategy, outlined in Scheme 1, was reported including the syntheses of glycybenzofuran (3-methyl),3e 7,2′,4′-trihydroxy-3-benzofurancarboxylic acid (3-carboxy),3a coumestrol,3f 4′-O-methylcoumestrol (3-phenoxo),3b lespedezol A1 (3-phenoxymethyl),3c glycyuralin E (3-hydroxymethyl),3g and puerariafuran (3-formyl),3d which circumvented previous cumbersome and respective strategies.

zofuran-2-yl)phenol framework, which would afford the general structural motifs for the collective syntheses of a number of 2arylbenzofuran type natural products via the SeO2-mediated oxidation of the methyl groups5 and some manipulations of functional groups (Scheme 1b). Strategically, the γ,δ-unsaturated ketone intermediate A, prone to isomerizing to the 2-(3methylbenzofuran-2-yl)phenol driven by aromatization once upon formation, could be generated from the 3(phenoxymethyl)benzofuran substrate B via a [3,3]-sigmatropic rearrangement.6 The precursor B can be facilely prepared from an etherification of benzofuran-3-ylmethanol C and phenol D by a Mitsunobu reaction.7 To test the feasibility of this [3,3]-sigmatropic rearrangement/aromatization reaction, an ether precursor 1 was used, synthesized by Mitsunobu reaction from two readily available fragments (see the Supporting Information for the detailed synthetic route).8 The synthesized substrate 1 was heated to 180 °C under the neat conditions for 8 h, and as expected, the desired product 2 was engendered with an isolated yield of 56% (Table 1, entry 1), while a lower yield (32%) was obtained by using the same temperature and mesitylene as solvent (Table 1, entry 2). To our delight, when the substrate was dispersed in a quantitative amount of silica gel, the temperature could be

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RESULTS AND DISCUSSION Inspired by the similarities in structures of these natural products, we proposed a highly atom-economical transformation involving a cascade [3,3]-sigmatropic rearrangement/aromatization synthetic strategy to the 2-(3-methylben© 2017 American Chemical Society

Received: August 15, 2017 Published: September 25, 2017 11102

DOI: 10.1021/acs.joc.7b02066 J. Org. Chem. 2017, 82, 11102−11109

Article

The Journal of Organic Chemistry

With the optimal conditions in hand (Table 1, entry 3), the [3,3]-sigmatropic rearrangement/aromatization strategy was assessed with the synthesis of glycybenzofuran. These metalfree conditions allowed us to prepare the 2-(3-methylbenzofuran-2-yl)phenol 2 on a gram scale, which assured the synthesis of the target natural product on a large scale. After several functional group manipulations including O-methylation, deprotection of benzyl groups, and MOM protection of hydroxyl groups, the intermediate 5 was obtained in a moderate yield. Bromination on the electron-rich phenyl ring of 5 afforded the precursor 6 in 35% yield,10 which could be purified by the column chromatography to eliminate another major bromo-regioisomer byproduct. After conducting a palladiumcatalyzed Suzuki coupling10 between the bromide precursor 6 and prenyl boronic ester11 and a CSA-promoted deprotection of MOM group, the total synthesis of glycybenzofuran 8 has been accomplished for the first time via a six-step sequence starting from the key intermediate 2-(3-methylbenzofuran-2yl)phenol 2 (Scheme 2). With the collective synthesis concept based on the methyl oxidation state modification of 2-(3-methylbenzofuran-2-yl)phenol derivatives in mind, we intended to convert the key intermediate 7 in the synthesis of glycybenzofuran to glycyuralin E 12 by a ring closure etherification and oxidation of the methyl group as shown in Scheme 2. An acid-catalyzed deprotection of MOM and sequential cyclization of the intermediate 7 provided the chroman derivative 9 followed by a benzyl protection of phenol moiety to form the intermediate 10. On treatment with SeO2, intermediate 10 underwent a benzylic oxidation to deliver the aldehyde 11, which was then exposed to a hydrogen atmosphere under the catalysis of Pd/C to reduce the aldehyde into alcohol and remove the benzyl groups simultaneously, allowing for the first access to glycyuralin E 12 with an acceptable yield in eight steps from 2-(3-methylbenzofuran-2-yl)phenol 2. In the synthetic route to coumestrol 17 (Scheme 3), benzofuran-3-ylmethanol moiety 1a was coupled with phenol 13 to afford the precursor 14 through Mitsunobu reaction, followed by a transformation into 2-(3-methylbenzofuran-2yl)phenol 15 under the standard conditions. It is worth mentioning that the lactonization was realized by a domino SeO2-mediated benzylic oxidation/hemiacetal formation and oxidation one-pot sequence in a good yield. Full deprotection of methyl and benzyl ethers provided access to coumestrol 17 in two steps based on the key intermediate 15. A subsequent hydrolysis of the lactone in coumestrol 17 under the basic conditions led to 7,2′,4′-trihydroxy-3-benzofurancarboxylic acid 18 in 75% yield in three steps based on the same intermediate 15 for the first time. Next, the synthetic strategy was further demonstrated by the syntheses of 4′-O-methylcoumestrol and lespedezol A1. A selective deprotection of the benzyl group in the intermediate 16 by BBr3 was followed by a SeO2-mediated oxidization/ esterification protocol from intermediate 15 as shown in Scheme 3; thus, the 4′-O-methylcoumestrol 19 was synthesized in a yield of 80%. TBS protection of 4′-O-methylcoumestrol 19 provided the corresponding silyl ether 20 in 95% yield, which was converted into lespedezol A1 21 after the reduction of lactone to ether. The total syntheses of four natural products were achieved by a single intermediate 15 via several functional group transformations. Finally, the total synthesis of puerariafuran was conducted by a Mitsunobu reaction using benzofuran-3-ylmethanol 1a and 3-

Scheme 1. 2-(3-Methylbenzofuran-2-yl)phenol-Derived Natural Products and Our Proposed Common Synthetic Strategy

Table 1. Screening of [3,3]-Sigmatropic Rearrangement/ Aromatization Conditions of Substrate 1

entry 1 2 3 4 5 6 7 8 9 10

solvent mesitylene

toluene toluene toluene toluene toluene

T (°C) 180 180 140 120 100 140 140 140 20 20

additive

time (h)

yielda (%)

silica gel silica gel silica gel InF3 ZnCl2 SnCl2 TiCl4 BF3·Et2O

8 8 4 4 4 4 4 4 4 4

56 32 75b 38b 0b 0c 38c 35c 40c 41c

a c

Isolated yields. b1.0 g of silica gel was used for 1.0 mmol of substrate. The reaction was run in the presence of 10 mol % catalysts.

decreased to 140 °C and the reaction time shortened to 4 h without compromising the yield (75%) (Table 1, entry 3). Further attempts to lower the reaction temperature with the use of silica gel proved unsuccessful (Table 1, entries 4 and 5). In the examination of a catalytic amount of Lewis acids such as InF3, ZnCl2, and SnCl2, relatively lower yields and unidentified byproducts were met (Table 1, entries 6−8). A catalytic amount of TiCl4 and BF3·Et2O could prompt the [3,3]sigmatropic rearrangement/aromatization to occur at room temperature; however, relatively lower yields prevented the further applications of these catalysts (Table 1, entries 9 and 10). A similar result was reported by Kim et al. as a side reaction in the synthesis of pterocarpenes and coumestans.9 Finally, the optimal conditions were determined as follows: heat the mixture of the substrate (1.0 mmol) and silica gel (1.0 g) at 140 °C under neat conditions for 4 h (Table 1, entry 3). 11103

DOI: 10.1021/acs.joc.7b02066 J. Org. Chem. 2017, 82, 11102−11109

Article

The Journal of Organic Chemistry Scheme 2. Total Synthesis of Glycybenzofuran and Glycyuralin E

Scheme 3. Total Synthesis of Coumestrol, 7,2′,4′-Trihydroxy-3-benzofurancarboxylic Acid, 4′-O-Methylcoumestrol, and Lespedezol A1

(benzyloxy)phenol 22 as the starting materials. The resulted ether 23 was subjected to Claisen rearrangement/aromatization reaction conditions to generate the phenol 24. Protection of the phenol 24 with methyl iodide followed by a SeO2-mediated benzylic oxidation gave the aldehyde 26, which was treated with BBr3 to deprotect the benzyl group leading to the first total synthesis of puerariafuran 27 in three steps from the key intermediate 2-(3-methylbenzofuran-2-yl)phenol 24 (Scheme 4).

Scheme 4. Total Synthesis of Puerariafuran

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CONCLUSION In summary, a metal-free thermally promoted [3,3]-sigmatropic rearrangement/aromatization strategy to the synthesis of 2-(3methylbenzofuran-2-yl)phenol derivatives based on the simple ether substrates has been developed for the first time. The manipulation of the methyl group led to the collective syntheses of a series of natural products derived from 2-(3-

methylbenzofuran-2-yl)phenol. This unprecedented strategy represents a highly atom-economical process allowing facile preparation of seven 2-arylbenzofuran type natural products, in 11104

DOI: 10.1021/acs.joc.7b02066 J. Org. Chem. 2017, 82, 11102−11109

Article

The Journal of Organic Chemistry

2H), 5.01 (s, 4H); 13C NMR (150 MHz, CDCl3) δ 160.8, 160.6, 157.6, 156.6, 142.5, 137.0, 136.9, 128.8, 128.7, 128.6, 128.2, 128.1, 127.7, 127.6, 127.4, 120.5, 120.3, 116.7, 112.9, 97.6, 95.2, 95.0, 70.7, 70.3, 61.5; IR (thin film, cm−1) 3430, 3031, 2873, 1624, 1599, 1454, 1378, 1164, 1134, 1058; HRMS (ESI) m/z [M + H]+ calcd for C36H31O5 543.2166, found 543.2174. 3,5-Bis(benzyloxy)-2-(6-(benzyloxy)-3-methylbenzofuran-2-yl)phenol (2). To a solution of 6-(benzyloxy)-3-((3,5-bis(benzyloxy)phenoxy)methyl)benzofuran 1 (1.0 g, 1.8 mmol) in DCM (10 mL) was added silica gel (2.0 g), and the DCM was removed in vacuo. The mixture was heated at 140 °C for 4 h. The crude mixture was purified by a flash column chromatography on silica gel (ethyl acetate/ petroleum ether = 1:10, Rf = 0.2) to afford the product 2 (713 mg) as a yellow oil with a yield of 73%: 1H NMR (600 MHz, CDCl3) δ 7.47 (dd, J = 7.9, 0.9 Hz, 2H), 7.44−7.42 (m, 2H), 7.41−7.38 (m, 5H), 7.36−7.32 (m, 2H), 7.29−7.27 (m, 3H), 7.26−7.23 (m, 2H), 7.09 (d, J = 2.1 Hz, 1H), 6.98 (dd, J = 8.5, 2.2 Hz, 1H), 6.32 (d, J = 2.3 Hz, 1H), 6.29 (d, J = 2.3 Hz, 1H), 5.95 (s, 1H), 5.13 (s, 2H), 5.05 (s, 2H), 5.03 (s, 2H), 2.10 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 161.7, 158.6, 157.3, 156.7, 155.6, 143.9, 137.1, 136.8, 136.7, 128.8, 128.7, 128.6, 128.3, 128.1, 127.8, 127.7, 127.6, 127.1, 124.1, 119.7, 115.8, 112.2, 100.4, 97.3, 94.7, 94.2, 70.8, 70.6, 70.3, 9.3; IR (thin film, cm−1) 3433, 3032, 2921, 2854, 1629, 1452, 1384, 1151; HRMS (ESI) m/z [M + H]+ calcd for C36H31O5 543.2166, found 543.2173. 6-(Benzyloxy)-2-(2,4-bis(benzyloxy)-6-methoxyphenyl)-3-methylbenzofuran (3). To a suspension of NaH (60% dispersion in paraffin oil) (40 mg, 1.0 mmol) in THF (4 mL) was added a solution of 3,5bis(benzyloxy)-2-(6-(benzyloxy)-3-methylbenzofuran-2-yl)phenol 2 (488 mg, 0.9 mmol) in dry THF (1 mL) at 0 °C with stirring under a nitrogen atmosphere. The mixture was then stirred for 1 h at room temperature, and iodomethane (255 mg, 1.8 mmol) was added dropwise over 10 min. The reaction was stirred at room temperature overnight; the reaction mixture was quenched by the addition of a saturated aqueous solution of ammonium chloride (20 mL) and extracted with ethyl acetate (20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, evaporated to dryness, and purified by a flash column chromatography on silica gel (ethyl acetate/petroleum ether = 1:20, Rf = 0.3) to give the product 3 (473 mg) as a yellow oil with a yield of 85%: 1H NMR (600 MHz, CDCl3) δ 7.49−7.29 (m, 11H), 7.25−7.18 (m, 5H), 7.09 (d, J = 2.2 Hz, 1H), 6.94 (dd, J = 8.5, 2.2 Hz, 1H), 6.30 (dd, J = 12.4, 2.2 Hz, 2H), 5.12 (s, 2H), 5.06 (s, 2H), 5.02 (s, 2H), 3.75 (s, 3H), 2.07 (s, 3H); 13C NMR (150 MHz, DMSO-d6) δ 161.6, 160.4, 159.4, 156.7, 155.6, 145.2, 137.4, 137.1, 136.7, 128.8, 128.7, 128.5, 128.0, 127.8, 127.7, 127.6, 126.9, 124.4, 119.3, 114.4, 111.4, 102.7, 97.4, 93.6, 92.4, 70.8, 70.7, 70.4, 56.1, 9.0; IR (thin film, cm−1) 3428, 2923, 2855, 1630, 1384, 1101; HRMS (ESI) m/z [M + H]+ calcd for C37H33O5 557.2323, found 557.2332. 4-(6-Hydroxy-3-methylbenzofuran-2-yl)-5-methoxybenzene-1,3diol (4). To a solution of 6-(benzyloxy)- 2-(2,4-bis(benzyloxy)-6methoxyphenyl)-3-methylbenzofuran 3 (390 mg, 0.7 mmol) in methanol (10 mL) was added 10% Pd/C (40 mg). The reaction vessel was then evacuated and the atmosphere replaced with hydrogen. After vigorous stirring for 8 h, the reaction mixture was filtered through silica gel, and the filtrate was evaporated to dryness and purified by a flash column chromatography on silica gel (ethyl acetate/ petroleum ether = 1:2, Rf = 0.1) to give the product 4 (170 mg) as a colorless oil with a yield of 85%: 1H NMR (600 MHz, CD3OD) δ 7.25 (d, J = 8.3 Hz, 1H), 6.80 (d, J = 2.1 Hz, 1H), 6.70 (dd, J = 8.3, 2.1 Hz, 1H), 6.04 (dd, J = 6.7, 2.1 Hz, 2H), 3.68 (s, 3H), 2.00 (s, 3H); 13C NMR (150 MHz, DMSO-d6) δ 160.5, 159.9, 157.8, 155.6, 154.5, 145.1, 123.2, 118.4, 113.4, 110.3, 98.9, 97.0, 95.0, 90.7, 54.6, 7.4; IR (thin film, cm−1) 3450, 2967, 2788, 1695, 1314; HRMS (ESI) m/z [M + H]+ calcd for C16H16O5 287.0914, found 287.0910. 2-(2-Methoxy-4,6-bis(methoxymethoxy)phenyl)-6-(methoxymethoxy)-3-methylbenzofuran (5). To a suspension of NaH (60% dispersion in paraffin oil) (40 mg, 1.0 mmol) in dry dimethylformamide (5 mL) was added a solution of 4-(6-hydroxy-3-methylbenzo furan-2-yl)-5-methoxybenzene-1,3-diol 4 (286 mg, 1.0 mmol) in dry dimethylformamide (2 mL) at 0 °C with stirring under a nitrogen

which five of them were synthesized for the first time. The collective syntheses of these natural products lay a solid foundation for the further bioactive evaluation of 2arylbenzofuran-containing natural products and their derivatives.

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EXPERIMENTAL SECTION

General Experimental Methods. Unless otherwise noted, reagents were obtained commercially and used without further purification. Tetrahydrofuran (THF) was distilled from sodium under a nitrogen atmosphere. Dichloromethane (DCM) was distilled from calcium hydride under a nitrogen atmosphere. Toluene was distilled from sodium under a nitrogen atmosphere. TLC analysis of reaction mixtures was performed on Dynamicadsorbents silica gel F254 TLC plates. Flash chromatography was carried out on Zeoprep 60 (200−300 mesh) silica gel. 1H and 13C NMR spectra were recorded with Bruker Avance-III 600 spectrometers and referenced to CDCl3, DMSO-d6, and CD3OD. HR-ESIMS was recorded on a Bruker microTOFQ-Q instrument. IR spectra were recorded on a Bruker IFS 55 spectrometer. Melting points (mp) were tested on a Thomas-Hoover capillary melting point apparatus. Experimental Procedures and Spectroscopic Data of the Synthesized Compounds. (6-(Benzyloxy)benzofuran-3-yl)methanol (1a). To a vigorously stirred solution of potassium carbonate (50 g, 0.36 mol) in water (400 mL) was added 2-(2acetyl-5-(benzyloxy)phenoxy)acetic acid ethyl ester a5 (100 g, 0.3 mol), and the mixture was gently refluxed for 3 h. The solution was cooled to 5 °C and acidified carefully with a solution of concentrated HCl. The deposited precipitate was filtered off and washed with cold water. The resulting crude product and anhydrous sodium acetate (96 g, 1.2 mol) were dissolved in acetic anhydride (390 g, 2.8 mol), and the mixture was heated at 160 °C for 3 h. After cooling, the mixture was poured into water (900 mL) and then extracted with diethyl ether. The combined organic layers were washed with a saturated aqueous solution of Na2CO3 and brine, dried over anhydrous Na2SO4, and then evaporated to dryness. The mixture of the dry crude product and selenium dioxide (33 g, 0.3 mol) in dry 1,4-dioxane (200 mL) was refluxed for 48 h. The resulting black precipitate was filtered off, and the crude product was evaporated to dryness. To a stirred solution of the crude mixture in methanol (100 mL) was added NaBH4 in small portions at room temperature until the entire amount of the aldehyde was transformed. Then the reaction mixture was treated with 5 M HCl (10 mL). The crude product was treated with a mixture of ethyl acetate and water (1:1, v/v). The organic layers were separated, washed with water and brine, and then dried over anhydrous Na2SO4, evaporated to dryness, and purified by a flash column chromatography on silica gel (ethyl acetate/petroleum ether = 1:5, Rf = 0.1) to give the product 1a (48.0 g) as a yellow powder with a yield of 63%: mp 126.6−127.1 °C; 1H NMR (600 MHz, CDCl3) δ 7.55−7.51 (m, 2H), 7.46 (d, J = 7.4 Hz, 2H), 7.40 (t, J = 7.6 Hz, 2H), 7.34 (d, J = 7.4 Hz, 1H), 7.09 (d, J = 2.2 Hz, 1H), 6.99 (dd, J = 8.5, 2.2 Hz, 1H), 5.11 (s, 2H), 4.80 (s, 2H); 13C NMR (150 MHz, CDCl3) δ 157.5, 156.7, 141.6, 137.0, 128.8, 128.2, 127.6, 120.5, 120.4, 120.2, 112.7, 97.6, 70.7, 56.2; IR (thin film, cm−1) 3402, 3052, 2928, 2843, 1597, 1483, 1120; HRMS (ESI) m/z [M + H]+ calcd for C16H15O3 255.1021, found 255.1016. 6-(Benzyloxy)-3-((3,5-bis(benzyloxy)phenoxy)methyl)benzofuran (1). To a solution of (6-(benzyloxy)benzofuran- 3-yl)methanol 1a (2.0 g, 8 mmol), 3,5-dibenzyloxy phenol a3 (2.9 g, 9.6 mmol), and triphenylphosphine (3.2 g, 12 mmol) in dry THF was added diisopropyl azodiformate (2.4 g, 12 mmol) dropwise at 0 °C for 15 min under a nitrogen atmosphere. The reaction was stirred at room temperature for 4 h. The crude mixture was evaporated to dryness and purified by a flash column chromatography on silica gel (ethyl acetate/ petroleum ether = 1:50, Rf = 0.3) to afford the product 1 (1.9 g) as a yellow oil with a yield of 45%: 1H NMR (600 MHz, CDCl3) δ 7.57 (s, 1H), 7.50 (d, J = 8.5 Hz, 1H), 7.46 (d, J = 7.4 Hz, 2H), 7.37−7.43 (m, 4H), 7.39 (t, J = 7.5 Hz, 6H), 7.32−7.35 (m, 3H), 7.09 (d, J = 2.2 Hz, 1H), 6.99 (dd, J = 8.5, 2.2 Hz, 1H), 6.29 (s, 3H), 5.12 (s, 2H), 5.10 (s, 11105

DOI: 10.1021/acs.joc.7b02066 J. Org. Chem. 2017, 82, 11102−11109

Article

The Journal of Organic Chemistry atmosphere. The mixture was stirred at room temperature for 1 h, and chloromethyl methyl ether (161 mg, 2.0 mmol) was added dropwise at 0 °C over 30 min. The reaction was stirred at room temperature for 6 h, quenched by the addition of a saturated aqueous solution of NH4Cl (20 mL), and extracted with ethyl acetate (20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and evaporated to dryness. The crude material was purified by a flash column chromatography on silica gel (ethyl acetate/petroleum ether = 1:10, Rf = 0.1) to give the product 5 (347 mg) as a colorless oil with a yield of 83%: 1H NMR (600 MHz, DMSO-d6) δ 7.44 (d, J = 8.5 Hz, 1H), 7.17 (d, J = 2.1 Hz, 1H), 6.95 (dd, J = 8.5, 2.1 Hz, 1H), 6.52 (d, J = 2.1 Hz, 1H), 6.47 (d, J = 2.1 Hz, 1H), 5.26 (s, 2H), 5.22 (s, 2H), 5.11 (s, 2H), 3.70 (s, 3H), 3.43 (s, 3H), 3.40 (s, 3H), 3.25 (s, 3H), 1.98 (s, 3H); 13C NMR (150 MHz, DMSO-d6) δ 159.8, 159.7, 157.3, 154.5, 154.4, 145.2, 124.4, 119.2, 113.4, 112.3, 102.4, 98.9, 95.6, 94.5, 94.2, 94.0, 93.8, 55.9, 55.8, 55.6, 55.5, 8.4; IR (thin film, cm−1) 3422, 2922, 2853, 1804, 1697, 1492, 1454, 1153, 1025; HRMS (ESI) [M + H]+ m/z calcd for C22H27O8 419.1700, found 419.1709. 2-(3-Bromo-2-methoxy-4,6-bis(methoxymethoxy)phenyl)-6-(methoxymethoxy)-3-methylbenzofuran (6). To a solution of 2-(2methoxy-4,6-bis(methoxymethoxy)phenyl)-6-(methoxymethoxy)-3methylbenzofuran 5 (418 mg, 1.0 mmol) in DCM (10 mL) was added a solution of N-bromosuccinimide (178 mg, 1.0 mmol) in DCM (5 mL) dropwise with stirring under a nitrogen atmosphere at 0 °C. The mixture was stirred at room temperature for 1 h. The reaction mixture was evaporated to dryness. The crude material was purified by a flash column chromatography on silica gel (ethyl acetate/petroleum ether = 1:10, Rf = 0.1) to give the product 6 (174 g) as a colorless oil with a yield of 35%: 1H NMR (600 MHz, CDCl3) δ 7.42 (d, J = 8.4 Hz, 1H), 7.20 (d, J = 2.1 Hz, 1H), 7.00 (dd, J = 8.4, 2.1 Hz, 1H), 6.90 (s, 1H), 5.30 (s, 2H), 5.22 (s, 2H), 5.09 (s, 2H), 3.58 (s, 3H), 3.56 (s, 3H), 3.52 (s, 3H), 3.38 (s, 3H), 2.12 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 158.2, 156.9, 156.3, 155.4, 155.3, 144.5, 124.9, 119.5, 115.0, 112.6, 110.2, 101.1, 99.6, 99.5, 95.3, 95.2, 61.5, 56.8, 56.4, 56.1, 8.8; IR (thin film, cm−1) 3422, 2922, 2253, 2126, 1652, 1384, 1051, 1026, 1005; HRMS (ESI) m/z [M + H]+ calcd for C22H26O8Br 497.0811, found 497.0815. 2-(2-Methoxy-4,6-bis(methoxymethoxy)-3-(3-methylbut-2-en-1yl)phenyl)-6-(methoxymethoxy)-3-methylbenzofuran (7). To a solution of 2-(3-bromo-2-methoxy-4,6-bis(methoxymethoxy)phenyl)6-(methoxymethoxy)-3-methylbenzofuran 6 (99 mg, 0.2 mmol) in dry dimethylformamide (5 mL) were added cesium carbonate (130 mg, 0.4 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (7 mg, 0.01 mmol), and 4,4,5,5-tetramethyl-2-(3-methylbut-2-en1-yl)-1,3,2-dioxaborolane (59 mg, 0.3 mmol) under a nitrogen atmosphere. The mixture was stirred at 90 °C for 9 h. The reaction was monitored by TLC until the complete consumption of the starting material. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with water (15 mL). The organic layers were washed with brine, dried over anhydrous Na2SO4, and evaporated to dryness. The crude material was purified by a flash column chromatography on silica gel (ethyl acetate/petroleum ether = 1:10, Rf = 0.1) to afford the product 7 (76 mg) as a colorless oil with a yield of 78%: 1H NMR (600 MHz, CDCl3) δ 7.39 (d, J = 8.4 Hz, 1H), 7.21 (d, J = 2.0 Hz, 1H), 6.97 (dd, J = 8.4, 2.1 Hz, 1H), 6.61 (s, 1H), 5.25 (s, 2H), 5.24− 5.22 (m, 1H), 5.21 (s, 2H), 4.64 (s, 2H), 3.75 (s, 3H), 3.51 (s, 6H), 3.40 (d, J = 6.7 Hz, 2H), 3.16 (s, 3H), 2.09 (s, 3H), 1.78 (s, 3H), 1.68 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 158.1, 157.9, 156.3, 155.4, 155.1, 146.1, 131.1, 125.2, 123.6, 119.3, 117.0, 114.5, 112.4, 107.3, 99.8, 99.7, 95.4, 94.8, 94.5, 57.3, 56.21, 56.17, 56.1, 25.9, 23.3, 18.0, 8.8; IR (thin film, cm−1) 3425, 2921, 2827, 1589, 1469, 1381, 1152, 1105; HRMS (ESI) [M + H]+ m/z calcd for C27H35O8 487.2326, found 487.2335. Glycybenzofuran (8). To a solution of 2-(2-methoxy-4,6-bis(methoxymethoxy)-3-(3-methylbut-2-en-1-yl)phenyl)-6-(methoxymethoxy)-3-methylbenzofuran 7 (29 mg, 0.06 mmol) in methanol (5 mL) was added CSA (3 mg, 0.012 mmol), and the resulting mixture was stirred at room temperature for 72 h. The reaction was monitored by TLC until the complete consumption of the starting material. The reaction mixture was quenched by the addition of a saturated aqueous

solution of Na2CO3 (10 mL) and was extracted with ethyl acetate (10 mL). The organic layers were washed with brine, dried over anhydrous Na2SO4, and evaporated to dryness. The crude material was purified by a flash column chromatography on silica gel (ethyl acetate/ petroleum ether = 1:2, Rf = 0.2) to afford the product 8 (16 mg) as a colorless oil with a yield of 75%: 1H NMR (600 MHz, CD3OD) δ 7.30 (d, J = 8.4 Hz, 1H), 6.85 (d, J = 2.0 Hz, 1H), 6.73 (dd, J = 8.3, 2.1 Hz, 1H), 6.24 (s, 1H), 5.24−5.19 (m, 1H), 3.36 (s, 3H), 3.26 (d, J = 6.9 Hz, 2H), 2.06 (s, 3H), 1.75 (s, 3H), 1.67 (d, J = 0.9 Hz, 3H); 13C NMR (150 MHz, CD3OD) δ 160.4, 159.0, 157.0, 156.6, 156.1, 146.7, 130.9, 125.4, 124.4, 120.0, 114.9, 114.5, 112.0, 104.5, 99.4, 98.5, 61.3, 26.0, 23.5, 17.9, 8.8; IR (thin film, cm−1) 3423, 2922, 2854, 1703, 1608, 1443, 1347, 1122; HRMS (ESI) [M + H]+ m/z calcd for C21H23O5 355.1540, found 355.1542. 7-(Benzyloxy)-6-(6-(benzyloxy)-3-methylbenzofuran-2-yl)-5-methoxy-2,2-dimethylchromane (10). To a solution of 2-(2-methoxy4,6-bis(methoxymethoxy)-3-(3-methylbut-2-en-1-yl)phenyl)-6-(methoxymethoxy)-3-methylbenzofuran 8 (71 mg, 0.2 mmol) in methanol (5 mL) was added CSA (23 mg, 0.1 mmol), and the resulting mixture was stirred at 50 °C for 12 h. The reaction was monitored by TLC until the complete consumption of the starting material. The reaction mixture was quenched by the addition of a saturated aqueous solution of Na2CO3 (10 mL) and extracted with ethyl acetate (10 mL). The organic layers were washed with brine, dried over anhydrous Na2SO4, and evaporated to dryness to give the crude compound 9. The crude compound 9 was dissolved in dry dimethylformamide (2 mL) and added to a suspension of NaH (60% dispersion in paraffin oil) (20 mg, 0.5 mmol) in dry dimethylformamide (5 mL) at 0 °C with stirring under a nitrogen atmosphere. The mixture was stirred at room temperature for 30 min, and benzyl bromide (86 mg, 0.5 mmol) was added dropwise at 0 °C over 10 min. The reaction was stirred at room temperature for 3 h. The reaction mixture was quenched by the addition of a saturated aqueous solution of NH4Cl (5 mL) and extracted with ethyl acetate (10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and evaporated to dryness. The crude material was purified by a flash column chromatography on silica gel (ethyl acetate/petroleum ether = 1:10, Rf = 0.2) to afford the product 10 (81 mg) as a colorless oil with a yield of 76%: 1H NMR (600 MHz, CDCl3) δ 7.48 (d, J = 7.4 Hz, 2H), 7.40 (t, J = 8.4 Hz, 3H), 7.34 (t, J = 7.4 Hz, 1H), 7.22−7.26 (m, 5H), 7.12 (d, J = 2.1 Hz, 1H), 6.96 (dd, J = 8.5, 2.1 Hz, 1H), 6.30 (s, 1H), 5.13 (s, 2H), 5.00 (s, 2H), 3.48 (s, 3H), 2.72 (t, J = 6.7 Hz, 2H), 2.11 (s, 3H), 1.80 (t, J = 6.7 Hz, 2H), 1.36 (s, 6H); 13C NMR (150 MHz, CDCl3) δ 159.0, 157.3, 156.8, 156.5, 155.5, 145.6, 137.3, 137.2, 128.7, 128.4, 128.1, 127.7, 127.6, 126.9, 124.4, 119.3, 114.3, 111.4, 107.5, 105.3, 97.7, 97.3, 74.9, 70.7, 70.4, 60.5, 32.5, 17.2, 9.1; IR (thin film, cm−1) 3422, 2972, 2922, 2853, 1753, 1601, 1453, 1384, 1118; HRMS (ESI) m/z [M + H]+ calcd for C35H35O5535.2479, found 535.2476. Glycyuralin E (12). The mixture of 7-(benzyloxy)-6-(6-(benzyloxy)3-methylbenzofuran-2-yl)-5-methoxy-2,2-dimethylchromane 10 (53 mg, 0.1 mmol) and selenium dioxide (11 mg, 0.1 mmol) in dry 1,4dioxane (3 mL) was refluxed for 48 h. The resulting black precipitate was filtered off, and the crude product was evaporated to dryness. To the solution of the crude material in methanol (3 mL) was added 20% Pd/C (10 mg). The reaction vessel was then evacuated and the atmosphere replaced with hydrogen. After vigorous stirring for 8 h, the reaction mixture was filtered through silica gel and the filtrate was evaporated to dryness. The crude product was purified by flash column chromatography on silica gel (ethyl acetate/petroleum ether = 1:2, Rf = 0.1) to afford the product 12 (20 mg) as a colorless oil with a yield of 54%: 1H NMR (600 MHz, DMSO-d6) δ 9.43 (s, 1H), 9.37 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 6.83 (d, J = 2.1 Hz, 1H), 6.71 (dd, J = 8.4, 2.1 Hz, 1H), 6.10 (s, 1H), 4.75 (t, J = 5.4 Hz, 1H), 4.39 (d, J = 5.4 Hz, 2H), 3.41 (s, 3H), 2.58 (t, J = 6.7 Hz, 2H), 1.73 (t, J = 6.7 Hz, 2H), 1.28 (s, 6H); 13C NMR (150 MHz, DMSO-d6) δ 158.4, 155.9, 155.7, 155.2, 154.9, 144.9, 121.0, 120.5, 118.0, 111.1, 105.3, 103.1, 99.0, 97.2, 74.3, 60.0, 54.8, 31.8, 26.5, 18.6, 16.6; IR (thin film, cm−1) 3423, 2922, 2852, 1630, 1458, 1384, 1269, 1110; HRMS (ESI) m/z [M + H]+ calcd for C21H23O6 371.1489, found 371.1490. 11106

DOI: 10.1021/acs.joc.7b02066 J. Org. Chem. 2017, 82, 11102−11109

Article

The Journal of Organic Chemistry 6-(Benzyloxy)-3-((3-methoxyphenoxy)methyl)benzofuran (14). To a solution of (6-(benzyloxy)benzofuran-3-yl) methanol 1a (2.0 g, 8 mmol), 3-methoxyphenol 13 (1.2 g, 9.6 mmol), and triphenylphosphine (3.2 g, 12 mmol) in dry THF was added diisopropyl azodiformate (2.4 g, 12 mmol) dropwise at 0 °C under a nitrogen atmosphere over 15 min. The reaction was stirred at room temperature for 4 h. The crude mixture was evaporated to dryness and purified by a flash column chromatography on silica gel (ethyl acetate/petroleum ether = 1:20, Rf = 0.4) to afford the product 14 (1.5 g) as a yellow oil with a yield of 54%: 1H NMR (600 MHz, CDCl3) δ 7.61 (s, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.47 (d, J = 7.4 Hz, 2H), 7.41 (t, J = 7.4 Hz, 2H), 7.35 (d, J = 7.4 Hz, 1H), 7.22 (t, J = 8.2 Hz, 1H), 7.11 (d, J = 2.2 Hz, 1H), 7.00 (dd, J = 8.0, 2.2 Hz, 1H), 6.63 (dd, J = 8.0, 2.1 Hz, 1H), 6.58 (t, J = 2.1 Hz, 1H), 6.56 (dd, J = 8.2, 2.2 Hz, 1H), 5.15 (d, J = 0.6 Hz, 2H), 5.12 (s, 2H), 3.80 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 161.0, 160.0, 157.5, 156.6, 142.4, 136.9, 130.1, 128.8, 128.2, 127.6, 120.5, 120.4, 116.8, 112.8, 106.9, 106.8, 101.5, 97.5, 70.7, 61.4, 55.4; IR (thin film, cm−1) 3501, 2923, 1626, 1592, 1491, 1266, 1154, 1039; HRMS (ESI) m/z [M + H]+ calcd for C23H21O4 361.1434, found 361.1439. 2-(6-(Benzyloxy)-3-methylbenzofuran-2-yl)-5-methoxyphenol (15). To a solution of 6-(benzyloxy)-3-((3,5-bis(benzyloxy)phenoxy)methyl)benzofuran 14 (1.0 g, 2.8 mmol) in DCM (10 mL) was added silica gel (2.0 g), and the DCM was removed in vacuo. The mixture was heated at 140 °C for 4 h. The crude mixture was purified by a flash column chromatography on silica gel (ethyl acetate/petroleum ether = 1:10, Rf = 0.2) to afford the product 15 (655 mg) as a yellow oil with a yield of 65%: 1H NMR (600 MHz, CDCl3) δ 7.47 (d, J = 7.4 Hz, 2H), 7.41 (dd, J = 7.9, 5.5 Hz, 3H), 7.35 (dd, J = 7.8, 4.8 Hz, 2H), 7.09 (d, J = 2.0 Hz, 1H), 7.01 (dd, J = 8.5, 2.1 Hz, 1H), 6.94 (s, 1H), 6.61 (d, J = 2.4 Hz, 1H), 6.59 (dd, J = 8.5, 2.4 Hz, 1H), 5.13 (s, 2H), 3.84 (s, 3H), 2.33 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 161.5, 157.3, 155.5, 154.3, 148.3, 137.0, 129.9, 128.8, 128.2, 127.6, 124.2, 119.6, 112.6, 111.9, 109.7, 107.3, 102.0, 97.2, 70.8, 55.5, 9.3; IR (thin film, cm−1) 3486, 2923, 2865, 1626, 1593, 1491, 1336, 1254, 1155; HRMS (ESI) m/z [M + H]+ calcd for C23H21O4 361.1434, found 361.1432. 9-(Benzyloxy)-3-methoxy-6H-benzofuro[3,2-c]chromen-6-one (16). The mixture of 2-(6-(benzyloxy)-3-methylbenzofuran-2-yl)-5methoxyphenol 15 (505 mg, 1.4 mmol) and selenium dioxide (155 mg, 1.4 mmol) in dry 1,4-dioxane (5 mL) was refluxed for 48 h. The resulting black precipitate was filtered off, and the crude product was evaporated to dryness. The crude mixture was purified by a flash column chromatography on silica gel (ethyl acetate/petroleum ether = 1:5, Rf = 0.3) to afford the product 16 (375 mg) as a white solid with a yield of 72%: mp 222.4−223.2 °C; 1H NMR (600 MHz, CDCl3) δ 7.95 (d, J = 8.5 Hz, 1H), 7.86 (d, J = 8.2 Hz, 1H), 7.48 (d, J = 7.6 Hz, 2H), 7.42 (t, J = 7.6 Hz, 2H), 7.36 (t, J = 7.6 Hz, 1H), 7.22 (d, J = 2.2 Hz, 1H), 7.12 (dd, J = 8.5, 2.2 Hz, 1H), 6.96−6.98 (m, 2H), 5.16 (s, 2H), 3.90 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 162.7, 160.3, 158.6, 158.4, 156.5, 155.3, 136.6, 128.8, 128.3, 127.7, 122.6, 121.8, 117.0, 114.1, 113.2, 106.2, 103.6, 101.5, 98.1, 70.8, 56.0; IR (thin film, cm−1) 3426, 2921, 2851, 1737, 1625, 1494, 1273, 1257, 1078; HRMS (ESI) m/z [M + H]+ calcd for C23H17O5 373.1071, found 373.1070. Coumestrol (17). To a solution of 9-(benzyloxy)-3-methoxy-6Hbenzofuro[3,2-c]chromen-6-one 16 (101 mg, 0.27 mmol) in dry DCM (5 mL) was added tribromoborane (150 mg, 0.6 mmol) dropwise at −78 °C over 10 min under a nitrogen atmosphere. The reaction was stirred at room temperature for 12 h and quenched with methanol at −78 °C. The crude mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous Na2SO4, and evaporated to dryness. The crude material was purified by a flash column chromatography on silica gel (methanol/DCM = 1:20, Rf = 0.2) to afford the product 17 (58 mg) as a white solid with a yield of 80%: mp 386.0−387.5 °C; 1H NMR (600 MHz, DMSO-d6) δ 10.72 (s, 1H), 10.05 (s, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.17 (d, J = 1.9 Hz, 1H), 6.95 (dd, J = 8.5, 1.9 Hz, 1H), 6.93 (dd, J = 8.5, 2.1 Hz, 1H), 6.91 (d, J = 2.1 Hz, 1H); 13C NMR (150 MHz, DMSOd6) δ 161.7, 160.0, 158.1, 157.5, 156.4, 155.1, 123.2, 121.1, 115.1, 114.5, 114.2, 104.7, 103.5, 102.5, 99.2; IR (thin film, cm−1) 3420,

2921, 2852, 1629, 1454, 1384, 1261, 1108; HRMS (ESI) m/z [M + H]+ calcd for C15H9O5 269.0444, found 269.0446. 7,2′,4′-Trihydroxy-3-benzofurancarboxylic Acid (18). Coumestrol 17 (48 mg, 0.18 mmol) was added to an aqueous solution of 5% NaOH (5 mL), and the reaction was refluxed for 3 h. After cooling, cation-exchange resin (001 × 7) was added to the solution with stirring at room temperature until the pH of the solution was below 4. The solution was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, evaporated to dryness, and purified by a flash column chromatography on silica gel (methanol/DCM = 1:2, Rf = 0.1) to afford the product 18 (39 mg) as a white solid with a yield of 75%: mp 218.1−219.6 °C; 1H NMR (600 MHz, DMSO-d6) δ 9.48 (s, 1H), 9.44 (s, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 8.5 Hz, 1H), 6.81 (d, J = 2.0 Hz, 1H), 6.70 (dd, J = 8.5, 2.0 Hz, 1H), 6.32 (dd, J = 8.5, 2.4 Hz, 1H), 6.22 (d, J = 2.4 Hz, 1H); 13C NMR (150 MHz, DMSO-d6) δ 170.4, 159.8, 159.7, 154.9, 154.1, 153.2, 131.2, 123.0, 121.6, 114.6, 112.6, 111.7, 106.7, 106.0, 96.6; IR (thin film, cm−1) 3423, 2924, 2853, 1761, 1600, 1464, 1384, 1258, 1211; HRMS (ESI) m/z [M − H]− calcd for C15H9O6 285.0405, found 285.0401. 4′-O-Methylcoumestrol (19). To a solution of 9-(benzyloxy)-3methoxy-6H-benzofuro[3,2-c]chromen-6-one 16 (197 mg, 0.53 mmol) in dry DCM (5 mL) was added tribromoborane (150 mg, 0.6 mmol) dropwise at −78 °C over 10 min under a nitrogen atmosphere. The reaction was stirred for 3 h and quenched with methanol at −78 °C. The crude mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous Na2SO4, and evaporated to dryness. The crude material was purified by flash column chromatography on silica gel (methanol/DCM = 1:20, Rf = 0.2) to afford the product 19 (120 mg) as a white solid with a yield of 80%: mp 276.7−278.2 °C; 1H NMR (600 MHz, DMSO-d6) δ 10.08 (s, 1H), 7.94 (d, J = 8.7 Hz, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.20 (d, J = 2.4 Hz, 1H), 7.19 (d, J = 2.1 Hz, 1H), 7.09 (dd, J = 8.7, 2.4 Hz, 1H), 6.96 (dd, J = 8.4, 2.1 Hz, 1H), 3.90 (s, 3H); 13C NMR (150 MHz, DMSO-d6) δ 162.3, 159.1, 157.5, 157.2, 156.1, 154.6, 122.5, 120.8, 114.5, 114.2, 113.1, 105.4, 102.8, 101.6, 98.7, 56.1; IR (thin film, cm−1) 3426, 2921, 2851, 1737, 1625, 1494, 1273, 1257; HRMS (ESI) m/z [M + H]+ calcd for C16H11O5 283.0601, found 283.0603. 9-((tert-Butyldimethylsilyl)oxy)-3-methoxy-6H-benzofuro[3,2-c]chromen-6-one (20). To a solution of 4′-O-methylcoumestrol 19 (100 mg, 0.35 mmol) in anhydrous dimethylformamide (5 mL) were added tert-butyldimethylsilyl chloride (60 mg, 0.4 mmol) and imidazole (27 mg, 0.4 mmol) at 0 °C under a nitrogen atmosphere. The reaction was stirred at room temperature for 1 h. The crude mixture was diluted with water and extracted with diethyl ether, and the combined organic layers were washed with water and brine, dried over anhydrous Na2SO4, evaporated to dryness, and purified by a flash column chromatography on silica gel (ethyl acetate/petroleum ether = 1:20, Rf = 0.3) to afford the product 20 (133 mg) as a pale solid with a yield of 95%: mp 198.0−199.0 °C; 1H NMR (600 MHz, CDCl3) δ 7.90 (d, J = 8.4 Hz, 1H), 7.84−7.85 (m, 1H), 7.10 (d, J = 2.0 Hz, 1H), 6.94−6.97 (m, 3H), 3.90 (s, 3H), 1.02 (s, 9H), 0.25 (s, 6H); 13C NMR (150 MHz, CDCl3) δ 162.6, 160.2, 158.5, 156.2, 155.2, 155.0, 122.5, 121.4, 118.4, 117.3, 113.0, 106.1, 103.50, 103.48, 101.4, 55.8, 25.7, 18.3, 4.4; IR (thin film, cm−1) 3455, 2923, 2862, 1751, 1732, 1344, 923, 885; HRMS (ESI) m/z [M + H]+ calcd for C22H25O5Si 397.1393, found 397.1388. Lespedezol A1 (21). To a solution of 9-((tert-butyldimethylsilyl)oxy)-3-methoxy-6H-benzofuro[3,2-c]chromen-6-one 20 (95 mg, 0.24 mmol) in dry THF (2 mL) was added borane−methyl sulfide complex (2 mol/L solution in THF, 1.8 mL, 3.5 mmol) dropwise at 0 °C under a nitrogen atmosphere over 10 min. The reaction was stirred at room temperature for 16 h, quenched with methanol, extracted with ethyl acetate, washed with water and brine, dried over anhydrous Na2SO4, and evaporated to dryness. The crude mixture was dissolved in THF (5 mL), and tetrabutylammonium fluoride (105 mg, 0.4 mmol) was added at 0 °C under a nitrogen atmosphere over 10 min. The reaction was stirred at room temperature for 1 h, quenched with water, extracted with ethyl acetate, washed with brine, dried over anhydrous Na2SO4, evaporated to dryness, and purified by a flash column 11107

DOI: 10.1021/acs.joc.7b02066 J. Org. Chem. 2017, 82, 11102−11109

Article

The Journal of Organic Chemistry

6-(Benzyloxy)-2-(4-(benzyloxy)-2-methoxyphenyl)benzofuran-3carbaldehyde (26). A mixture of 6-(benzyloxy)- 2-(4-(benzyloxy)-2methoxyphenyl)-3-methylbenzofuran 25 (302 mg, 0.67 mmol) and selenium dioxide (74 mg, 0.67 mmol) in dry 1,4-dioxane (5 mL) was refluxed for 48 h. The resulting black precipitate was filtered off, and the crude material was evaporated to dryness and purified by a flash column chromatography on silica gel (ethyl acetate/petroleum ether = 1:5, Rf = 0.4) to afford the product 26 (212 mg) as a colorless oil with a yield of 68%: 1H NMR (600 MHz, CDCl3) δ 10.06 (s, 1H), 8.12 (d, J = 8.5 Hz, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7.41 (m, 10H), 7.12 (s, 1H), 7.07 (d, J = 8.6 Hz, 1H), 6.72 (d, J = 8.6 Hz, 1H), 6.69 (s, 1H), 5.15 (s, 2H), 5.13 (s, 2H), 3.83 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 187.9, 162.5, 162.4, 158.7, 157.7, 155.4, 136.8, 136.3, 132.9, 128.9, 128.7, 128.4, 128.2, 127.7, 127.6, 122.7, 118.9, 117.8, 113.8, 111.0, 106.2, 100.0, 97.1, 70.6, 70.5, 55.8; IR (thin film, cm−1) 3032, 2925, 2854, 1734, 1664, 1611, 1583, 1494, 1380, 1260, 1141, 1064; HRMS (ESI) m/z [M + H]+ calcd for C30H25O5 465.1697, found 465.1702. Puerariafuran (27). To a solution of 6-(benzyloxy)-2-(4-(benzyloxy)-2-methoxyphenyl)benzofuran-3-carbaldehyde 26 (186 mg, 0.4 mmol) in dry DCM (5 mL) was added tribromoborane (200 mg, 0.8 mmol) dropwise at −78 °C under a nitrogen atmosphere over 10 min. The reaction was stirred for 3 h and quenched with methanol at −78 °C. The crude mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous Na2SO4, and evaporated to dryness. The crude material was purified by a flash column chromatography on silica gel (ethyl acetate/petroleum ether = 1:2, Rf = 0.1) to afford the product 27 (96 mg) as a yellow solid with a yield of 85%: mp 293.6−295.1 °C; 1H NMR (600 MHz, DMSO-d6) δ 9.89 (s, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.00 (d, J = 1.7 Hz, 1H), 6.85 (dd, J = 8.4, 1.7 Hz, 1H), 6.61 (d, J = 1.6 Hz, 1H), 6.56 (dd, J = 8.4, 1.6 Hz, 1H), 3.77 (s, 3H); 13C NMR (150 MHz, DMSO-d6) δ 187.2, 162.3, 161.7, 158.6, 156.3, 154.9, 132.7, 121.6, 116.6, 113.6, 108.0, 107.8, 99.7, 97.7, 55.6; IR (thin film, cm−1) 3405, 2924, 2852, 1621, 1443, 1383, 1132; HRMS (ESI) m/z [M + H]+ calcd for C16H13O5 285.0757, found 285.0761.

chromatography on silica gel (ethyl acetate/petroleum ether = 1:2, Rf = 0.2) to afford the product 21 (46 mg) as a pale solid with a yield of 49%: mp 136.2−138.0 °C; 1H NMR (600 MHz, CDCl3) δ 7.39 (d, J = 7.9 Hz, 1H), 7.18 (d, J = 8.3 Hz, 1H), 7.02 (d, J = 8.8 Hz, 1H), 6.78 (d, J = 6.7 Hz, 1H), 6.54 (dd, J = 8.4, 2.4 Hz, 1H), 6.51 (s, 1H), 5.56 (s, 2H), 5.00 (s, 1H), 3.81 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 161.0, 156.3, 155.2, 153.4, 147.5, 121.2, 119.8, 118.7, 112.1, 109.9, 107.3, 105.8, 102.6, 99.1, 65.7, 55.6; IR (thin film, cm−1) 3375, 2922, 2851, 1704, 1632, 1382, 1261, 1093; HRMS (ESI) m/z [M + H]+ calcd for C16H13O4 269.0808, found 269.0810. 6-(Benzyloxy)-3-((3-(benzyloxy)phenoxy)methyl)benzofuran (23). To a solution of (6-(benzyloxy)benzofuran-3-yl)methanol 1a (2.0 g, 8 mmol), 3-(benzyloxy)phenol 22 (1.9 g, 9.6 mmol), and triphenylphosphine (3.1 g, 12 mmol) in dry THF was added diisopropyl azodiformate (2.4 g, 12 mmol) dropwise at 0 °C under a nitrogen atmosphere over 15 min. The reaction was stirred at room temperature for 4 h. The crude mixture was evaporated to dryness and purified by a flash column chromatography on silica gel (ethyl acetate/petroleum ether = 1:50, Rf = 0.2) to afford the product 23 (2.1 g) as a colorless oil with a yield of 61%: 1H NMR (600 MHz, CDCl3) δ 7.59 (s, 1H), 7.51 (d, J = 8.5 Hz, 1H), 7.46 (d, J = 7.6 Hz, 2H), 7.43 (d, J = 7.5 Hz, 2H), 7.39 (q, J = 6.9 Hz, 4H), 7.34 (dd, J = 6.5, 2.9 Hz, 2H), 7.21 (t, J = 8.2 Hz, 1H), 7.09 (s, 1H), 6.99 (d, J = 8.5 Hz, 1H), 6.63 (dd, J = 15.6, 7.8 Hz, 3H), 5.14 (s, 2H), 5.12 (s, 2H), 5.04 (s, 2H); 13C NMR (150 MHz, CDCl3) δ 160.0, 159.8, 157.4, 156.5, 142.3, 136.9, 136.8, 130.0, 128.6, 128.6, 128.0,128.0, 127.5, 127.5, 120.4, 120.2, 116.6, 112.7, 107.6, 107.3, 102.2, 97.4, 70.6, 70.0, 61.3; IR (thin film, cm−1) 3423, 2922, 2851, 1726, 1601, 1588, 1491, 1454, 1386, 1146; HRMS (ESI) m/z [M + H]+ calcd for C29H25O4 437.1747, found 437.1746. 5-(Benzyloxy)-2-(6-(benzyloxy)-3-methylbenzofuran-2-yl)phenol (24). To a solution of 6-(benzyloxy)-3-((3-(benzyloxy)phenoxy)methyl)benzofuran 23 (960 mg, 2.2 mmol) in DCM (10 mL) was added silica gel (2.0 g). The DCM was removed in vacuo. The mixture was heated at 140 °C for 4 h. The crude mixture was purified by a flash column chromatography on silica gel (ethyl acetate/petroleum ether = 1:10, Rf = 0.2) to afford the product 24 (509 mg) as a colorless oil with a yield of 53%: 1H NMR (600 MHz, CDCl3) δ 7.47 (t, J = 8.3 Hz, 4H), 7.40−7.43 (m, 5H), 7.34−7.37 (m, 3H), 7.09 (d, J = 2.1 Hz, 1H), 7.01 (dd, J = 8.5, 2.1 Hz, 1H), 6.96 (s, 1H), 6.69 (d, J = 2.5 Hz, 1H), 6.66 (dd, J = 8.5, 2.5 Hz, 1H), 5.14 (s, 2H), 5.10 (s, 2H), 2.34 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 160.6, 157.3, 155.5, 154.3, 148.3, 136.9, 136.8, 129.9, 128.8, 128.22, 128.18, 127.7, 126.6, 119.6, 112.6, 112.0, 110.0, 108.0, 103.0, 97.2, 70.8, 70.2, 9.3; IR (thin film, cm−1) 3488, 2921, 2863, 1623, 1489, 1249, 1155; HRMS (ESI) m/z [M + H]+ calcd for C29H25O4 437.1747, found 437.1750. 6-(Benzyloxy)-2-(4-(benzyloxy)-2-methoxyphenyl)-3-methylbenzofuran (25). To a suspension of NaH (60% dispersion in paraffin oil) (48 mg, 1.2 mmol) in THF (4 mL) was added solution of 5(benzyloxy)-2-(6-(benzyloxy)-3-methylbenzofuran-2-yl)phenol 24 (480 mg, 1.1 mmol) in dry THF (1 mL) at 0 °C with stirring under a nitrogen atmosphere. The mixture was stirred at room temperature for 1 h, and iodomethane (312 mg, 2.2 mmol) was added dropwise over 10 min. The reaction was stirred at room temperature overnight. The reaction mixture was quenched by the addition of a saturated aqueous solution of NH4Cl (20 mL) and extracted with ethyl acetate (20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO,4 and evaporated to dryness. The crude material was purified by a flash column chromatography on silica gel (ethyl acetate/petroleum ether = 1:20, Rf = 0.2) to give the product 25 (372 mg) as a colorless oil with a yield of 75%: 1H NMR (600 MHz, CDCl3) δ 7.47−7.27 (m, 12H), 7.07 (d, J = 2.0 Hz, 1H), 6.94 (dd, J = 8.5, 2.1 Hz, 1H), 6.67−6.61 (m, 2H), 5.09 (s, 4H), 3.79 (s, 3H), 2.17 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 160.7, 158.5, 156.8, 155.2, 148.5, 137.2, 136.8, 132.0, 128.8, 128.7, 128.2, 128.0, 127.7, 127.6, 124.7, 119.4, 113.4, 112.5, 111.8, 105.6, 99.9, 97.2, 70.7, 70.3, 55.8, 9.3; IR (thin film, cm−1) 3524, 2923, 2853, 1627, 1384, 1111; HRMS (ESI) m/z [M − H]− calcd for C30H25O4 449.1759, found 449.1751.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02066. 1 H and 13C NMR spectra for all compounds (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Wei Li: 0000-0003-4143-8597 Yongxiang Liu: 0000-0003-0364-0137 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We were grateful to the Natural Science Foundation of Liaoning Province of China for financial support (Grant No. 20170540855). We acknowledge the program for innovative research team of the Ministry of Education and the program for Liaoning innovative research team in university.

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REFERENCES

(1) (a) Chang, H. M.; Cheng, K. P.; Tai, F. C.; Chow, H. F.; Chui, K. Y. J. Org. Chem. 1990, 55, 3537−3543. (b) Wine-Show, S.; Ian-Lih, T.; Teng, C. M.; Chen, I. S. Phytochemistry 1994, 36, 213−215. (c) Melo, P. A.; Nascimento, M. C. D.; Mors, W. B.; Suarez-Kurtz, G. Toxicon 1994, 32, 595−603. (d) Chen, Y.; Wei, X. Y.; Xie, H. H.; Deng, H. Z. J.

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Article

The Journal of Organic Chemistry Nat. Prod. 2008, 71, 929−932. (e) Mori-Hongo, M.; Takimoto, H.; Katagiri, T.; Kimura, M.; Ikeda, Y.; Miyase, T. J. Nat. Prod. 2009, 72, 194−203. (2) (a) Khanam, H.; Shamsuzzaman. Eur. J. Med. Chem. 2015, 97, 483−504. (b) Naik, R.; Harmalkar, D. S.; Xu, X.; Jang, K.; Lee, K. Eur. J. Med. Chem. 2015, 90, 379−393. (3) (a) Bickoff, E. M.; Booth, A. N.; Lyman, R. L.; Livingston, A. L.; Thompson, C. R.; Kohler, G. O. J. Agric. Food Chem. 1958, 6, 536− 539. (b) Bickoff, E. M.; Livingston, A. L.; Witt, S. C.; Lundin, R. E.; Spencer, R. R. J. Agric. Food Chem. 1965, 13, 597−599. (c) Miyase, T.; Sano, M.; Nakai, H.; Muraoka, M.; Nakazawa, M.; Suzuki, M.; Yoshino, K.; Nishihara, Y.; Tanai, J. Phytochemistry 1999, 52, 303−310. (d) Kim, N. H.; Kim, Y. S.; Lee, Y. M.; Jang, D. S.; Kim, J. S. Biol. Pharm. Bull. 2010, 33, 1605−1609. (e) Li, S. P.; Li, W.; Wang, Y. H.; Asada, Y.; Koike, K. Bioorg. Med. Chem. Lett. 2010, 20, 5398−5401. (f) Yuk, H. J.; Lee, J. H.; Curtis-Long, M. J.; Lee, J. W.; Kim, Y. S.; Ryu, H. W.; Park, C. G.; Jeong, T. S.; Park, K. H. Food Chem. 2011, 126, 1057−1063. (g) Ji, S.; Li, Z.; Song, W.; Wang, Y.; Liang, W.; Li, K.; Tang, S.; Wang, Q.; Qiao, X.; Zhou, D.; Yu, S.; Ye, M. J. Nat. Prod. 2016, 79, 281−292. (4) (a) Mann, I.; Widdowson, D.; Clough, J. Tetrahedron 1991, 47, 7991−8000. (b) Yao, T.; Yue, D.; Larock, R. J. Org. Chem. 2005, 70, 9985−9989. (c) Furstner, A.; Heilmann, E. K.; Davies, P. W. Angew. Chem., Int. Ed. 2007, 46, 4760−4763. (d) Kaur, N.; Xia, Y.; Jin, Y.; Dat, N. T.; Gajulapati, K.; Choi, Y.; Hong, Y.; Lee, J. J.; Lee, K. Chem. Commun. 2009, 40, 1879−1881. (e) Pahari, P.; Rohr, J. J. Org. Chem. 2009, 74, 2750−2754. (f) Tricotet, T.; Fleming, P.; Cotter, J.; Hogan, A. M.; Strohmann, C.; Gessner, V.; O’Shea, D. J. Am. Chem. Soc. 2009, 131, 3142−3143. (g) Tang, L.; Pang, Y.; Yan, Q.; Shi, L.; Huang, J.; Du, Y.; Zhao, K. J. Org. Chem. 2011, 76, 2744−2752. (h) Kapdi, A. R.; Karbelkar, A.; Naik, M.; Pednekar, S.; Fischer, C.; Schulzke, C.; Tromp, M. RSC Adv. 2013, 3, 20905−20912. (i) Kshirsagar, U. A.; Parnes, R.; Goldshtein, H.; Ofir, R.; Zarivach, R.; Pappo, D. Chem. Eur. J. 2013, 19, 13575−13583. (5) (a) Wang, E. C.; Wein, Y. S.; Kuo, Y. H. Tetrahedron Lett. 2006, 47, 9195−9197. (b) Zhang, J.; Qiu, J.; Xiao, C.; Yu, L.; Yang, F.; Tang, J. Eur. J. Org. Chem. 2016, 2016, 3380−3385. (6) (a) Verma, P.; Singh, S. Synthesis 1988, 1988, 68−70. (b) Pearson, J.; Porter, Q. Aust. J. Chem. 1991, 44, 907−917. (c) Zhu, J. B.; Wang, P.; Liao, S.; Tang, Y. Org. Lett. 2013, 15, 3054−3057. (d) Ghosh, R.; Stridfeldt, E.; Olofsson, B. Chem. - Eur. J. 2014, 20, 8888−8892. (e) Iwabuchi, Y.; Shibuta, T.; Sato, S.; Shibuya, M.; Kanoh, N.; Taniguchi, T.; Monde, K. Heterocycles 2014, 89, 631−639. (f) Zhou, Z.; Liu, G.; Chen, Y.; Lu, X. Org. Lett. 2015, 17, 5874−5877. (7) (a) Mitsunobu, O. Synthesis 1981, 1981, 1−28. (b) Zürcher, M.; Hof, F.; Barandun, L.; Schütz, A.; Schweizer, W. B.; Meyer, S.; Bur, D.; Diederich, F. Eur. J. Org. Chem. 2009, 2009, 1707−1719. (c) Yin, B.; Cai, C.; Zeng, G.; Zhang, R.; Li, X.; Jiang, H. Org. Lett. 2012, 14, 1098−1101. (d) Fowler, K.; Ellis, J.; Morrow, G. Synth. Commun. 2013, 43, 1676−1682. (8) (a) Hatayama, K.; Yokomori, S.; Kawashima, Y.; Saziki, R.; Kyogoku, K. Chem. Pharm. Bull. 1985, 33, 1327−1333. (b) Hughes, D. L. Org. Prep. Proced. Int. 1996, 28, 127−164. (c) Dodge, J.; Jones, S. Rec. Res. Dev. Org. Chem. 1997, 1, 273−283. (d) Viton, F.; Landreau, C. Eur. J. Org. Chem. 2008, 2008, 6069−6078. (e) Kishali, N.; Polat, M.; Altundas, R.; Kara, Y. Helv. Chim. Acta 2008, 91, 67−72. (f) Yuan, H.; Bi, K. J.; Li, B.; Yue, R. C.; Ye, J. Org. Lett. 2013, 15, 4742−4745. (9) Nayak, M.; Jung, Y.; Kim, I. Org. Biomol. Chem. 2016, 14, 8074− 8087. (10) Sun, H.; Li, Y.; Zhang, X.; Lei, Y.; Ding, W.; Zhao, X.; Wang, H.; Song, X.; Yao, Q. W.; Zhang, Y.; Ma, Y. Bioorg. Med. Chem. Lett. 2015, 25, 4567−4571. (11) Miralles, N.; Alam, R.; Szabó, K.; Fernández, E. Angew. Chem., Int. Ed. 2016, 55, 4303−4307.

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DOI: 10.1021/acs.joc.7b02066 J. Org. Chem. 2017, 82, 11102−11109