INTRODUCTION

O-Desmethylangolensin (O-DMA) is created in the ring cleavage of dihydrodiadzein, an intestinal bacteria metabolite of the diadzein that is found mainly in soybean (Scheme 1).1 Approximately 80−90% of people produces O-DMA after consumption of diadzein, which is detected in human urine, plasma, serum, and breast milk.2 The analysis of O-DMA has been performed with various instruments3 including GC-MS/SPE-HPLC, and the (R)-enantiomer was identified as the main metabolite by circular dichroism.4 O-DMA has attracted much attention for various biological activities that include estrogenic activity,5 diminution of plasma lipids concentration,6 radical scavenging effect,7 and antimicrobial susceptibility.8 Recently we reported that O-DMA inhibited cell proliferation of human breast cancer MCF-cells by inducing apoptosis.9

Scheme 1.Chemical structures of diadzein, dihydrodiadzein, and O-DMA.

O-DMA analogues have generally been synthesized by Friedel-Crafts acylation of substituted phenols and 2-phenylpropionic acids using BF3·Et2O at 120 ℃, but yields were low to moderate.7 A similar condensation of 1,3- dimethoxybenzene and 2-(4-methoxyphenyl)propionic acid in polyphosphoric acid at 75 ℃ afforded trimethoxy-α-methyldesoxybenzoin, which was demethylated with 4 equiv of boron tribromide to give O-DMA.10 However, 2-phenylpropionic acids are typically synthesized from 1-phenylethanol11 or phenylacetic acids12 in three steps. The condensation of resorcinol and 4-hydroxyphenylacetic acid13 or 4-benzyloxybenzyl cyanide14 using BF3·Et2O and zinc chloride, respectively, afforded the corresponding deoxybenzoin, which was C-methylated with methyl iodide to give O-DMA.15 Another condensation of resorcinol and 2-(4-hydroxyphenyl)propionic acid using bis[(trifluoromethyl) sulfanyl]amine under microwave irradiation also afforded O-DMA.16

The reaction of 2'-hydroxypropiophenones and o-nitrofluorobenzenes using potassium carbonate in DMSO afforded the corresponding diaryl ethers, which were rearranged to form O-DMA derivatives.17 However, this method was only effective for fluorobenzenes with an electronwithdrawing substituent such as a nitro group. The reduction of hydroxy and/or methoxy-substituted isoflavones with an excess of lithium aluminum hydride afforded O-DMA analogues, but yields were low to moderate.18 The reduction of methoxy-substituted isoflavones with lithium tri(t-butoxy)aluminum hydride improved the yields of O-DMA derivatives, but the corresponding propenals were also obtained as minor products.19

Although several methods for the synthesis of O-DMA analogues have been reported, the scope of these procedures has not been fully investigated. Furthermore, the synthesis by Friedel-Crafts acylation was effective for symmetrical phenols as starting materials and some methods suffered from the harsh reaction conditions and low yields. In this paper we describe a versatile synthesis of O-DMA analogues from commercially inexpensive methoxysubstituted benzoic acids under mild conditions.

EXPERIMENTAL

4'-Methoxypropiophenone (2b)

To a solution of 4-methoxybenzoic acid (1b, 1.22 g, 8.0 mmol) in THF (16 mL) was added ethyllithium (0.5 M, 32.0 mL, 16.0 mmol) at 0 ℃, and the solution was stirred for 0.5 h. The mixture was quenched with 1 N HCl solution (5 mL) and THF was evaporated in vacuo. The mixture was poured into 0.5 N HCl solution (40 mL) and was extracted with methylene chloride (3×25 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography using 20% EtOAc/ n-hexane as eluant to afford 2b (1.26 g, 96%). 1H NMR (300 MHz, CDCl3) δ 7.95 (d, J = 8.9 Hz, 2H), 6.93 (d, J = 8.9 Hz, 2H), 3.86 (s, 3H), 2.95 (q, J = 7.3 Hz, 2H), 1.21 (t, J = 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 193.3, 163.3, 130.2 (overlapped), 113.7, 55.4, 31.4, 8.4; FT-IR (film) 1675 (C=O) cm−1; Ms m/z (%) 164 (M+, 56), 135 (100), 107 (36), 92 (40), 77 (55).

Ethyl 2-(4-methoxyphenyl)propionate (3b)

To a solution of 2b (1.15 g, 7.0 mmol) in triethyl orthoformate (35 mL) was added perchloric acid (70%, 1.2 mL, 14.0 mmol) and then lead(IV) acetate (3.10 g, 7.0 mmol) at room temperature. After stirring for 2 h, the excess triethyl orthoformate was evaporated in vacuo. The mixture was redissolved in methylene chloride (40 mL) and the resulting precipitate was removed by filtration. The organic phase was washed with saturated NaHCO3 solution (40 mL), dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by vacuum distillation using a Kugelrohr apparatus to give 3b (1.21 g, 83%). 1H NMR (300 MHz, CDCl3) δ 7.23 (d, J = 8.7 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 4.11 (q, J = 7.2 Hz, 2H), 3.78 (s, 3H), 3.65 (q, J = 7.2 Hz, 1H), 1.47 (d, J = 7.2 Hz, 3H), 1.20 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 174.8, 158.6, 132.8, 128.5, 113.9, 60.7, 55.2, 44.7, 18.7, 14.1; FT-IR (film) 1726 (C=O) cm−1. Ms m/z (%) 208 (M+, 93), 135 (100), 105 (72), 91 (63).

2-(4-Methoxyphenyl)propionic acid (4b)

To a solution of 3b (1.04 g, 5.0 mmol) in H2O (8 mL) was added 0.5 N KOH (0.5 N in CH3OH, 12.0 mL, 6.0 mmol) at room temperature. After stirring overnight, CH3OH was evaporated in vacuo. The mixture was acidified with 1 N HCl solution (6 mL) and extracted with methylene chloride (3×20 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography using 50% EtOAc/n-hexane as eluant to give 4b (838 mg, 93%). 1H NMR (300 MHz, CDCl3) δ 10.10 (br s, 1H), 7.24 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 3.79 (s, 3H), 3.68 (q, J = 7.2 Hz, 1H), 1.48 (d, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 181.2, 158.9, 131.8, 128.6, 114.1, 55.3, 44.5, 18.2; FT-IR (film) 3430 (broad, COOH), 1706 (C=O) cm-1; Ms m/z (%) 180 (M+, 49), 135 (100), 105 (19), 91 (15).

2-Pyridyl 2-(4-methoxyphenyl)propionate (5b)

To a solution of 4b (721 mg, 4.0 mmol) in methylene chloride (20 mL) were added di-2-pyridyl carbonate (865 mg, 4.0 mmol) and 4-(dimethylamino)pyridine (49 mg, 0.4 mmol) at room temperature, and the solution was stirred for 2 h. The mixture was poured into saturated NaHCO3 solution (30 mL) and was extracted with methylene chloride (3×20 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by short pathway Davisil® (pH=7) column chromatography using 50% EtOAc/n-hexane as eluant to give 5b (834 mg, 81%). 1H NMR (300 MHz, CDCl3) δ 8.38 (d, J = 5.6 Hz, 1H), 7.69−7.75 (m, 1H), 7.34 (d, J = 8.4 Hz, 2H), 7.15−7.20 (m, 1H), 6.92−6.96 (m, 1H), 6.92 (d, J = 8.4 Hz, 2H), 3.96 (q, J = 7.2 Hz, 1H), 3.79 (s, 3H), 1.61 (d, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 172.9, 158.9, 158.0, 148.5, 139.4, 131.8, 128.7, 122.0, 116.3, 114.2, 55.3, 44.8, 18.5; FT-IR (film) 1758 (C=O) cm−1; Ms m/z (%) 180 (98), 135 (100), 105 (71), 91 (55).

1-(2,4-Dimethoxyphenyl)-2-(4-methoxyphenyl)propan-1-one (7bf)

To a solution of 5b (772 mg, 3.0 mmol) in THF (9 mL) was added 2,4-dimethoxyphenylmagnesium bromide (6f, 0.5 M in THF, 6.0 mL, 3.0 mmol) at 0 ℃. After stirring for 0.5 h, the mixture was quenched with saturated NH4Cl solution (5 mL) and THF was evaporated in vacuo. The mixture was poured into saturated NH4Cl solution (30 mL) and was extracted with methylene chloride (3×20 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography using 30% EtOAc/ n-hexane as eluant to give 7bf (802 mg, 89%). 1H NMR (300 MHz, CDCl3) δ 7.64 (d, J = 8.7 Hz, 1H), 7.14 (d, J = 8.7 Hz, 2H), 6.78 (d, J = 8.7 Hz, 2H), 6.44 (dd, J1 = 8.7 Hz, J2 = 2.4 Hz, 1H), 6.36 (d, J = 2.4 Hz, 1H), 4.72 (q, J = 6.9 Hz, 1H), 3.82 (s, 3H), 3.80 (s, 3H), 3.73 (s, 3H), 1.45 (d, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 201.9, 164.0, 159.9, 158.1, 134.2, 133.0, 129.1, 121.4, 113.8, 105.0, 98.3, 55.4, 55.3, 55.2, 50.3, 19.3; FT-IR (film) 1666 (C=O) cm−1; Ms m/z (%) 300 (M+, 81), 165 (100), 135 (94), 107 (40), 77 (43).

1-(2,4-Dihydroxyphenyl)-2-(4-hydroxyphenyl)propan-1-one (12)

To a solution of 7bf (751 mg, 2.5 mmol) in methylene chloride (12 mL) was slowly added boron tribromide (1 M in CH2Cl2, 10.0 mL, 10.0 mmol) at 0 ℃. Stirring was continued for 24 h at room temperature, and then the reaction was quenched by the slow addition of H2O. After evaporation of CH2Cl2, the mixture was poured into 5% NaHCO3 solution (30 mL) and was extracted with ethyl acetate (3×20 mL). The combined organic phases were dried over MgSO4, filtered, and concentrated in vacuo. The residue was recrystallized twice from 20% EtOAc/n-hexane to give 12 (581 mg, 90%) as a pale yellow solid. mp 102−103 ℃ (lit.10 103 ℃); 1H NMR (300 MHz, DMSO-d6) δ 12.77 (s, 1H), 10.64 (s, 1H), 9.33 (s, 1H), 7.88 (d, J = 9.0 Hz, 1H), 7.13 (d, J = 8.7 Hz, 2H), 6.69 (d, J = 8.7 Hz, 2H), 6.31 (dd, J1 = 9.0 Hz, J2 = 2.4 Hz, 1H), 6.22 (d, J = 2.4 Hz, 1H), 4.77 (q, J = 6.6 Hz, 1H), 1.34 (d, J = 6.6 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ 204.9, 165.0, 164.7, 156.1, 133.3, 131.9, 128.4, 115.5, 111.4, 108.1, 102.5, 44.4, 18.9; FT-IR (KBr) 3399 (OH), 1629 (C=O) cm−1; Ms m/z (%) 258 (M+, 65), 137 (100), 121 (89), 91 (21), 77 (31).

1-(2-Hydroxy-4-methoxyphenyl)-2-(3-methoxyphenyl) propan-1-one (8): mp 70−71 ℃; 1H NMR (300 MHz, CDCl3) δ 12.90 (s, 1H), 7.69 (d, J = 9.0 Hz, 1H), 7.22 (t, J = 7.9 Hz, 1H), 6.88 (d, J = 7.7 Hz, 1H), 6.82−6.84 (m, 1H), 6.73−6.77 (m, 1H), 6.39 (d, J = 2.5 Hz, 1H), 6.34 (dd, J1 = 8.9 Hz, J2 = 2.5 Hz, 1H), 4.60 (q, J = 6.9 Hz, 1H), 3.78 (s, 3H), 3.77 (s, 3H), 1.52 (d, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 204.4, 166.1, 165.9, 160.1, 143.1, 131.9, 129.9, 120.0, 113.5, 112.9, 112.2, 107.5, 101.2, 55.4, 55.2, 47.0, 19.0; FT-IR (KBr) 3646 (OH), 1626 (C=O) cm−1; Ms m/z (%) 286 (M+, 59), 151 (100), 135 (12), 108 (27), 95 (26).

1-(2,4-Dihydroxyphenyl)-2-(3-hydroxyphenyl)propan-1-one (9): viscous liquid; 1H NMR (300 MHz, DMSO-d6) δ 12.72 (s, 1H), 10.67 (s, 1H), 9.37 (s, 1H), 7.86 (d, J = 9.0 Hz, 1H), 7.10 (t, J = 7.8 Hz, 1H), 6.77 (d, J = 7.7 Hz, 1H), 6.69−6.73 (m, 1H), 6.60 (dd, J1 = 8.0 Hz, J2 = 1.6 Hz, 1H), 6.32 (dd, J1 = 8.9 Hz, J2 = 2.3 Hz, 1H), 6.24 (d, J = 2.3 Hz, 1H), 4.79 (q, J = 6.8 Hz, 1H), 1.36 (d, J = 6.8 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ 205.0, 165.5, 165.3, 158.0, 143.7, 133.7, 130.2, 118.7, 114.6, 114.3, 112.2, 108.6, 103.0, 45.9, 19.3; FT-IR (film) 3436 (OH), 1626 (C=O) cm−1; Ms m/z (%) 258 (M+, 39), 137 (100), 81 (34), 77 (18).

1-(2,5-Dihydroxyphenyl)-2-(3-hydroxyphenyl)propan-1-one (10): viscous liquid; 1H NMR (300 MHz, DMSOd6) δ 11.39 (s, 1H), 9.41 (s, 1H), 9.17 (s, 1H), 7.20 (d, J = 2.9 Hz, 1H), 7.11 (t, J = 7.8 Hz, 1H), 6.94 (dd, J1 = 8.9 Hz, J2 = 2.9 Hz, 1H), 6.78 (d, J = 8.9 Hz, 1H), 6.72 (d, J = 7.7 Hz, 1H), 6.59−6.66 (m, 2H), 4.80 (q, J = 6.7 Hz, 1H), 1.36 (d, J = 6.7 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ 206.3, 158.1, 154.6, 149.7, 143.3, 130.3, 124.7, 120.0, 118.9, 118.7, 115.7, 114.7, 114.4, 47.3, 19.4; FT-IR (film) 3441 (OH), 1666 (C=O) cm−1; Ms m/z (%) 258 (M+, 98), 137 (100), 109 (31), 81 (33).

1-(2-Hydroxy-4-methoxyphenyl)-2-(4-methoxyphenyl) propan-1-one (11): viscous liquid; 1H NMR (300 MHz, CDCl3) δ 12.92 (s, 1H), 7.69 (d, J = 8.9 Hz, 1H), 7.21 (d, J = 8.7 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H), 6.39 (d, J = 2.1 Hz, 1H), 6.35 (dd, J1 = 8.9 Hz, J2 = 2.5 Hz, 1H), 4.59 (q, J = 6.8 Hz, 1H), 3.79 (s, 3H), 3.76 (s, 3H), 1.50 (d, J = 6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 204.9, 166.2, 165.9, 158.7, 133.7, 131.9, 128.5, 114.5, 112.9, 107.4, 101.2, 55.4, 55.2, 46.0, 19.1; FT-IR (film) 3436 (OH), 1628 (C=O) cm−1; Ms m/z (%) 286 (M+, 79), 151 (100), 135 (95), 108 (21), 91 (25).

1-(2-Hydroxyphenyl)-2-(3,4-dihydroxyphenyl)propan-1-one (13): viscous liquid; 1H NMR (300 MHz, DMSOd6) δ 12.06 (s, 1H), 8.88 (s, 1H), 8.82 (s, 1H), 7.92 (dd, J1 = 8.0 Hz, J2 = 1.3 Hz, 1H), 7.43−7.48 (m, 1H), 6.84−6.94 (m, 2H), 6.67 (d, J = 2.1 Hz, 1H), 6.65 (d, J = 8.7 Hz, 1H), 6.59 (dd, J1 = 8.1 Hz, J2 = 2.0 Hz, 1H), 4.83 (q, J = 6.7 Hz, 1H), 1.35 (d, J = 6.7 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ 207.3, 161.7, 145.9, 144.8, 136.3, 132.6, 131.5, 120.0, 119.4, 119.0, 118.2, 116.4, 115.2, 46.4, 19.3; FT-IR (film) 3437 (OH), 1666 (C=O) cm−1; Ms m/z (%) 258 (M+, 79), 241 (46), 137 (100), 121 (98), 91 (35).

1-(2-Hydroxyphenyl)-2-(3,5-dihydroxyphenyl)propan-1-one (14): viscous liquid; 1H NMR (300 MHz, DMSOd6) δ 12.02 (s, 1H), 9.22 (s, 2H), 7.90 (dd, J1 = 8.0 Hz, J2 = 1.3 Hz, 1H), 7.44−7.50 (m, 1H), 6.93 (d, J = 8.3 Hz, 1H), 6.85−6.91 (m, 1H), 6.16 (d, J = 2.0 Hz, 2H), 6.05 (t, J = 2.1 Hz, 1H), 4.80 (q, J = 6.7 Hz, 1H), 1.35 (d, J = 6.7 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ 206.9, 161.7, 159.1, 143.8, 136.4, 131.4, 120.1, 119.5, 118.2, 106.1, 101.7, 47.1, 19.1; FT-IR (film) 3437 (OH), 1667 (C=O) cm−1; Ms m/z (%) 258 (M+, 97), 137 (17), 121 (100), 93 (45), 65 (53).

1-(2-Hydroxy-5-methoxyphenyl)-2-(3,5-dimethoxyphenyl) propan-1-one (15): viscous liquid; 1H NMR (300 MHz, CDCl3) δ 11.97 (s, 1H), 7.25 (d, J = 3.0 Hz, 1H), 7.03 (dd, J1 = 9.1 Hz, J2 = 3.0 Hz, 1H), 6.88 (d, J = 9.1 Hz, 1H), 6.43 (d, J = 2.2 Hz, 1H), 6.32 (t, J = 2.2 Hz, 1H), 4.57 (q, J = 6.8 Hz, 1H), 3.75 (s, 6H), 3.69 (s, 3H), 1.52 (d, J = 6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 205.5, 161.4, 157.6, 151.6, 143.6, 124.3, 119.4, 118.3, 113.1, 105.9, 98.9, 55.8, 55.3, 48.0, 18.9; FT-IR (film) 3646 (OH), 1643 (C=O) cm−1; Ms m/z (%) 316 (M+, 94), 165 (23), 151 (100), 123 (24), 108 (20).

1-(2,5-Dihydroxyphenyl)-2-(3,5-dihydroxyphenyl)propan-1-one (16): viscous liquid; 1H NMR (300 MHz, DMSOd6) δ 11.44 (s, 1H), 9.23 (s, 2H), 9.18 (s, 1H), 7.19 (d, J = 2.9 Hz, 1H), 6.95 (dd, J1 = 8.9 Hz, J2 = 2.9 Hz, 1H), 6.78 (d, J = 8.9 Hz, 1H), 6.12 (d, J = 2.1 Hz, 2H), 6.06 (t, J = 2.1 Hz, 1H), 4.66 (q, J = 6.7 Hz, 1H), 1.32 (d, J = 6.7 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ 206.4, 159.1, 154.7, 149.6, 143.8, 124.8, 120.0, 118.8, 115.8, 106.1, 101.7, 47.3, 19.2; FT-IR (film) 3442 (OH), 1666 (C=O) cm−1; Ms m/z (%) 274 (M+, 98), 137 (100), 109 (28), 81 (28).

RESULTS AND DISCUSSION

Methoxypropiophenones (2) were efficiently prepared by treatment of methoxybenzoic acids (1) with 2 equiv of ethyllithium in THF for 0.5 h at 0 ℃. After an acidic workup, the residue was purified by silica gel column chromatography to give 2 (2a: 91%, 2b: 96%, 2c: 92%, 2d: 88%) (Scheme 2). The conversion of 2 to ethyl 2-(methoxyphenyl) propionates (3) was carried out using 70% perchloric acid and lead (IV) acetate in triethyl orthoformate for 2−4 h at room temperature in a similar method of the previous report.10,20 It appears that the enolized methoxypropiophenone by perchloric acid substitute an acetate group of lead (IV) acetate accompanying ketalization to form the corresponding hemiketal lead intermediate. This intermediate underwent 1,2-rearrangement of the methoxyphenyl group by electron participation of the hydroxy group, followed by elimination of lead (II) acetate, to form 3. After evaporation of triethyl orthoformate and filtration of the precipitate, the extracted residue was purified by vacuum distillation using a Kugelrohr apparatus to give 3 (3a: 80%, 3b: 83%, 3c: 86%, 3d: 78%). The products 3 were further hydrolyzed by treatment with 0.5 N KOH in aq CH3OH overnight. The mixture was acidified with 1 N HCl solution and was separated by the usual workup after evaporation of CH3OH. The condensed residue was purified by silica gel column chromatography to give 4 (4a: 91%, 4b: 93%, 4c: 92%, 4d: 92%).

Scheme 2.Synthesis of O-DMA analogues from methoxy-substituted benzoic acids.

2-Pyridyl 2-(methoxyphenyl)propionates (5) were prepared by the addition of di-2-pyridyl carbonate (2-DPC)21 to a solution of 4 in methylene chloride in the presence of 0.1 equiv of 4-(dimethylamino)pyridine (4-DMAP) for 2 h at room temperature. The reaction proceeded via N-acylpyridinium salts, with the evolution of carbon dioxide, which were then converted to the corresponding 5 by nucleophilic acyl substitution of 2-pyridyl oxide. After a typical basic workup, the residue was purified by short pathway Davisil® column chromatography to give 5 (5a: 82%, 5b: 81%, 5c: 84%, 5d: 78%). The synthesis of methoxy-α- methyldesoxybenzoins (7) was successfully accomplished by acylation of 5 with methoxy-substituted phenylmagnesium bromides (6) in THF for 0.5 h at 0 ℃. The addition of 6 to a solution of 5 in THF led to a precipitate, which was hydrolyzed with saturated NH4Cl solution. The mixture was subjected to an acidic workup and the residue was purified by silica gel column chromatography to give 7 in 78−94% yields (Table 1).

Table 1.Preparation of methoxy-α-methyldesoxybenzoins 7 from 2-pyridyl 2-(methoxyphenyl)propionates 5 and Grignard reagents 6

Selective demethylation of the ortho-methoxy group in 7 was successfully accomplished using 1 equiv of boron tribromide. Mechanistically, treatment of 1-(2,4-dimedimethoxyphenyl)-2-(4-methoxyphenyl)propan-1-one (7bf) with 1 equiv of boron tribromide for 1 h at 0 ℃ afforded a sixmembered chelate between the 2-methoxy/carbonyl oxygen and boron atoms. Subsequent substitution of the methyl group by bromide anion afforded the corresponding borate intermediate, which was hydrolyzed with H2O to give 1-(2-hydroxy-4-methoxyphenyl)-2-(4-methoxyphenyl)propan-1-one (11) in 75% yield (Scheme 3). This method has an advantage over the previous method,22 where 11 was prepared by substitution of the dianion of O-desmethylangolensin using 2.6 equiv of methyl iodide for 48 h at 40 ℃ in 70% yield. Similarly, ortho-methoxy groups in 7af and 7dg were selectively demethylated with 1 equiv of boron tribromide to afford 8 and 15 in 83% and 89% yield, respectively. The characteristic 1H NMR signal of the hydroxyl proton in 11 was appeared at δ 12.92 ppm, which is indicative of an intramolecular hydrogen bond between the 2-hydroxyl proton and carbonyl oxygen atom.

Scheme 3.Demethylation of 7bf using boron tribromide.

Treatment of 7 with 4−5 equiv of boron tribromide afforded the corresponding alkoxyborate intermediates, with the evolution of methyl bromide, which were hydrolyzed with H2O to give the O-desmethylangolensin analogues. For example, the treatment of 7bf with 4 equiv of boron tribromide for 24 h between 0 ℃ and room temperature afforded the borate complex. This intermediate was quenched by the slow addition of H2O, extracted with ethyl acetate, and washed with 5% NaHCO3 solution. The condensed residue was recrystallized twice from 20% EtOAc/n-hexane to give 1-(2,4-dihydroxyphenyl)-2-(4-hydroxyphenyl) propan-1-one (12) in 90% yield (Scheme 3). Characteristic 1H NMR signals of the 2-hydroxyl protons in 9, 10, 12−14, and 16 were appeared at δ 11.39−12.77 ppm due to intramolecular hydrogen bonding, while other hydroxyl protons appeared at δ 8.82−10.67 ppm.

As shown in Tables 1 and 2, various methoxy-α-methyldesoxybenzoins 7 and O-DMA analogues 8−16 were synthesized in 78−94% and 75−92% yields, respectively. The nucleophilic acyl substitution of 5 with 6 proceeded regardless of 3, 4, or 5-methoxy group substitution of 5 and 2, 4, or 5-methoxy substitution of 6. Selective demethylation of the ortho-methoxy group of 7af, 7bf, 7dg was accomplished with 1 equiv of boron tribromide to give the corrresponding 8, 11, 15 in 83%, 75%, 89% yields, respectively. In addition, all of the methoxy groups of 7 could be fully demethylated with a slight excess of boron tribromide to give the corresponding 9, 10, 12−14, and 16 in 85−92% yields.

Table 2.aThe numbers in parentheses indicate the overall yields from methoxybenzoic acids 1.