INTRODUCTION
The hydroxylated flavones (2-phenyl-4H-1-benzopyran-4-ones) are found naturally in plant tissues of berries, apple skins, celery, and red pepper and also widely consumed in dietary supplements by humans.1 The ring-A hydroxylated flavones have attracted special attention due to biological activities such as antioxidative effect, potent inhibitor of cell proliferation, and chemotherapy of a retrovirusassociated human disease.2 Currently some methods available for the synthesis of ring-A hydroxylated flavones have been developed.3 The reaction of resacetophenone with benzoic anhydrides in the presence of potassium carbonate at reflux, followed by hydrolysis to afford hydroxyflavones, but the desired products are obtained in low to moderate yields with the corresponding coumarins as side products.4 Although the direct synthesis of 5,7-dihydroxyflavones is accomplished by the microwaveassisted cyclocondensation of phloroglucinol with an excess of ethyl benzoylacetates at 240 ℃, this method is limited to the symmetric phenol such as phloroglucinol.5 The condensation of polylithiated enolates, generated from hydroxylated acetophenones and an excess of lithium diisopropylamide, with benzoyl chlorides or methyl benzoates gives the 1,3-diketone intermediates, which are cyclodehydrated with sulfuric acid in HOAc to afford hydroxyflavones.6 1,3-Diketones are also prepared by the reaction of 2'-hydroxyacetophenones and benzoyl chlorides with potassium carbonate using phase transfer catalyst7 or the rearrangement of 2-acetylphenyl benzoates with bases such as KOH in pyridine8 and K2CO3 in acetone,9 but the former requires an excess of benzoyl chlorides and the latter proceeds in moderate yields or requires prolonged reaction time. The oxidative cyclization of 2'-hydroxychalcones, derived from the condensation of 2'-hydroxyacetophenones with benzaldehydes or the acylation of methoxy substituted phenols with cinnamoyl chloride, with PhI(OAc)2/KOH in CH3OH,10 I2-triethylene glycol,11 and DDQ in toluene/dioxane12 affords hydroxyflavones at high temperature. An alternative method includes the Wittig olefination, in which phosphoranes, derived from o-hydroxyphenacyl chloride or o-benzoyloxyphenacyl bromide and triphenylphosphine, are condensed with benzoyl chlorides to afford hydroxyflavones after saponification in multiple steps from 2'-hydroxyacetophenones.13 As part of our continuing studies of flavonoids,14 we report an efficient synthesis of ring-A hydroxylated flavones by the concomitant cyclodehydration/hydrolysis of 1-(2-hydroxyphenyl)-3-phenyl-1,3-propanediones, derived from 2'-aroyloxyacetophenones and lithium diisopropylamide under mild conditions, with aq HBr in overall high yields.
EXPERIMENTAL
Preparation of 2',4'-di(benzoyloxy)acetophenone 3a
Preparation of 1-(2-hydroxy-4-benzoyloxy)-3-phenyl-1,3-propanedione 4a
Preparation of 7-hydroxyflavone 5a
7-Hydroxy-4'-methoxyflavone (5b): mp 261-263 ℃ (lit.7 264 ℃); 1H NMR (300 MHz, DMSO-d6) δ 10.81 (s, 1H), 8.02 (d, J = 8.9 Hz, 2H), 7.87 (d, J = 8.7 Hz, 1H), 7.11 (d, J = 8.9 Hz, 2H), 6.99 (d, J = 2.1 Hz, 1H), 6.91 (dd, J1 = 8.7 Hz, J2 = 2.2 Hz, 1H), 6.80 (s, 1H), 3.85 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 176.7, 163.0, 162.4, 162.3, 157.7, 128.3, 126.8, 123.8, 116.4, 115.2, 114.9, 105.5, 102.9, 55.8; FT-IR (KBr) 3107, 2969, 1622 (C=O), 1593, 1454, 1386, 1313, 1175, 1095, 815 cm-1; MS m/z (%) 268 (M+, 100), 267 (34), 240 (18), 225 (19), 132 (43).
7-Hydroxy-3',4',5'-trimethoxyflavone (5c): mp 280-281 ℃ (lit.6a279-280 ℃); 1H NMR (300 MHz, DMSO-d6) δ 10.50 (s, 1H), 7.87 (d, J = 8.7 Hz, 1H), 7.33 (s, 2H), 7.04 (d, J = 2.1 Hz, 1H), 6.99 (s, 1H), 6.92 (dd, J1 = 8.7 Hz, J2 = 2.2 Hz, 1H), 3.91 (s, 6H), 3.74 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 176.8, 163.2, 162.1, 157.8, 153.6, 140.7, 127.0, 126.8, 116.4, 115.4, 106.9, 104.2, 103.1, 60.5, 56.6; FT-IR (KBr) 3054, 2997, 1629 (C=O), 1584, 1501, 1450, 1387, 1243, 1120, 1095, 826 cm-1; MS m/z (%) 328 (M+, 100), 313 (40), 257 (10), 137 (10).
6-Hydroxy-4'-chloroflavone (5d): mp 275-276 ℃; 1H NMR (300 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.11 (d, J = 8.7 Hz, 2H), 7.65 (d, J = 8.9 Hz, 1H), 7.64 (d, J = 8.7 Hz, 2H), 7.32 (d, J = 2.9 Hz, 1H), 7.27 (dd, J1 = 8.9 Hz, J2 = 3.0 Hz, 1H), 7.00 (s, 1H); 13C NMR (75 MHz, DMSO-d6) δ 177.4, 161.4, 155.4, 149.6, 136.8, 130.6, 129.5, 128.4, 124.5, 123.6, 120.2, 107.8, 106.5; FT-IR (KBr) 3050, 1641 (C=O), 1595, 1474, 1359, 1228, 1094, 912, 827 cm-1; MS m/z (%) 274 (M++2, 30), 272 (M+, 87), 244 (5), 136 (100), 108 (14).
6-Hydroxy-4'-methoxyflavone (5e): mp 249-250 ℃ (lit.13a 250 ℃); 1H NMR (300 MHz, DMSO-d6) δ 10.01 (s, 1H), 8.04 (d, J = 9.0 Hz, 2H), 7.64 (d, J = 9.0 Hz, 1H), 7.32 (d, J = 3.0 Hz, 1H), 7.25 (dd, J1 = 9.0 Hz, J2 = 3.0 Hz, 1H), 7.12 (d, J = 9.0 Hz, 2H), 6.87 (s, 1H), 3.86 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 177.2, 162.6, 162.3, 155.1, 149.6, 128.4, 124.5, 123.8, 123.2, 120.1, 114.9, 107.9, 104.9, 55.9; FT-IR (KBr) 3047, 2942, 1638 (C=O), 1599, 1472, 1359, 1265, 1183, 1019, 821 cm-1; MS m/z (%) 268 (M+, 100), 267 (21), 237 (5), 136 (44), 132 (36).
5-Hydroxyflavone (5f): mp 159-160 ℃ (lit.7 159 ℃); 1H NMR (300 MHz, CDCl3) δ 12.58 (s, 1H), 7.89-7.95 (m, 2H), 7.50-7.58 (m, 4H), 7.01 (dd, J1 = 8.4 Hz, J2 = 0.8 Hz, 1H), 6.82 (dd, J1 = 8.3 Hz, J2 = 0.6 Hz, 1H), 6.75 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 183.6, 164.6, 160.8, 156.5, 135.4, 132.1, 131.2, 129.1, 126.4, 111.5, 110.9, 107.1, 106.1; FT-IR (KBr) 3059, 1654 (C=O), 1613, 1450, 1225, 1078, 843, 752, 675 cm-1; MS m/z (%) 238 (M+, 100), 210 (17), 136 (34), 108 (28).
5-Hydroxy-4'-chloroflavone (5g): mp 188-189 ℃; 1H NMR (300 MHz, CDCl3) δ 12.50 (s, 1H), 7.86 (d, J = 8.7 Hz, 2H), 7.56 (dd, J1 = 8.4 Hz, J2 = 8.3 Hz, 1H), 7.52 (d, J = 8.7 Hz, 2H), 7.00 (d, J = 8.4 Hz, 1H), 6.83 (d, J = 8.3 Hz, 1H), 6.71 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 183.9, 163.8, 161.2, 156.7, 138.8, 136.0, 130.0, 129.9, 128.1, 112.1, 111.2, 107.4, 106.6; FT-IR (KBr) 3074, 1658 (C=O), 1619, 1475, 1265, 1094, 830, 746 cm-1; MS m/z (%) 274 (M++2, 46), 272 (M+, 100), 244 (9), 136 (36), 108 (26).
5,7-Dihydroxyflavone (5h): mp 275-277 ℃ (lit.7 273-274 ℃); 1H NMR (300 MHz, DMSO-d6) δ 12.85 (s, 1H), 10.94 (s, 1H), 8.03-8.10 (m, 2H), 7.53-7.66 (m, 3H), 6.98 (s, 1H), 6.53 (d, J = 2.0 Hz, 1H), 6.24 (d, J = 2.0 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) δ 187.5, 170.0, 168.7, 167.0, 163.0, 137.6, 136.3, 134.7, 132.0, 110.7, 109.6, 104.6, 99.7; FT-IR (KBr) 3018, 1653 (C=O), 1612, 1577, 1498, 1358, 1168, 1032, 840, 781, 691 cm-1; MS m/z (%) 254 (M+, 100), 226 (21), 152 (16), 124 (14).
5,7-Dihydroxy-4'-methoxyflavone (5i): mp 263-265 ℃ (lit.6a260-261 ℃); 1H NMR (300 MHz, DMSO-d6) δ 12.94 (s, 1H), 10.89 (s, 1H), 8.02 (d, J = 9.0 Hz, 2H), 7.10 (d, J = 9.0 Hz, 2H), 6.86 (s, 1H), 6.50 (d, J = 2.1 Hz, 1H), 6.21 (d, J = 2.1 Hz, 1H), 3.86 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 182.1, 164.5, 163.6, 162.6, 161.8, 157.7, 128.6, 123.1, 114.9, 104.1, 103.8, 99.2, 94.4, 55.9; FT-IR (KBr) 3020, 1650 (C=O), 1608, 1510, 1430, 1369, 1165, 1033, 824, 759 cm-1; MS m/z (%) 284 (M+, 100), 283 (14), 256 (5), 241 (14), 132 (19).
RESULTS AND DISCUSSION
The O-aroylation of hydroxylated acetophenones 1a-d with 2 or 3 equiv of aroyl chlorides 2a-d in the presence of triethylamine proceeded readily in methylene chloride for 0.5-1 h between 0 ℃ and room temperature. After usual workup, the residue was subjected to silica gel chromatography to give 2'-aroyloxyacetophenones 3a-i as colorless solids in 92-98% yields (Scheme 1).
The key step in ring-A hydroxylated flavone syntheses involves the intramolecular rearrangement of 3 to 1-(2-hydroxyphenyl)-3-phenyl-1,3-propanediones 4. The rearrangement of 2',4'-di(benzoyloxy)acetophenone 3a to 1-(2-hydroxyphenyl)-3-phenyl-1,3-propanedione 4a was attempted by the treatment of 3a with 2 equiv of lithium diisopropylamide in THF. The reaction proceeded rapidly between -15 ℃ and 0 ℃ and 4a was obtained in 85% yield after 0.5 h. However, the reaction using 1 equiv of lithium diisopropylamide was not completed even after 24 h at room temperature. It seems that additive equimolar amount of lithium diisopropylamide abstracts the C2 methylene proton of 1,3-dicarbonyl group in 1-(2-lithiumoxyphenyl)-3-phenyl-1,3-propanedione, produced by the intramolecular rearrangement of lithium enolate of 3a, to shift equilibrium to more conjugated lithium dialkoxide intermediate. After acidic workup, the residue was recrystallized twice in 20% EtOAc/n-hexane to give 4 as yellow solids in 83-95% yields. All of 4 existed as enolic forms mostly by 1H NMR analysis, which showed enolic OH signals of enol forms at the 15.31-15.90 ppm and C2 proton signals of keto forms at the 4.50-4.64 ppm.
Scheme 1
The conversion of 4 to ring-A hydroxylated flavones 5 was initially attempted using sulfuric acid according to our previous procedure.14a The treatment of 2-hydroxy-6-benzoyloxy-3-phenyl-1,3-propanedione 4f as a model substrate with 1 equiv of sulfuric acid in acetonitrile for 2.5 h at room temperature afforded 5-benzoyloxyflavone in 96% yield, and thus the hydrolysis of 6-benzoyl group in 4f didn't occur. However, the reaction of 4f with 1 equiv of 48% HBr in glacial acetic acid for 2.5 h at 80 ℃ afforded 5-hydroxyflavone 5f in 91% yield. Under these conditions the cyclodehydration of 4f proceeded at first and then followed by the hydrolysis of 5-benzoyl group to give 5f. After evaporation of acetic acid, the mixture was washed with sat. NaHCO3 solution and the residue was recrystallized twice from 10% EtOAc/n-hexane to give 5a-i as pale yellow solids in high yields (80-97%).
Table 1aThe numbers in parentheses indicate the overall yields of three steps from the starting 2'-hydroxyacetophenones 1a-d.
As shown in Table 1, various ring-A hydroxylated flavones were synthesized in overall high yields (62-78%) from the starting 1. The reaction worked well regardless of the kind and the position of aroyl group in A-ring of 4 under the present reaction conditions. The reaction also worked well both for the methoxy (5b, 5c, 5e, 5i) and the chloro (5d, 5g) substituent on the B-ring of 4.
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