| 86% |
In diphenylether at 175℃; for 0.5h; Inert atmosphere; |
3.1.4. 2-(2,2-Diphenylbenzo[d][1,3]dioxol-5-yl)-3,5,7-trihydroxy-4H-chromen-4-one (9)
To a stirring mixture of quercetin (1) (302 mg, 1 mmol) in diphenyl ether (20 ml) was added dichlorodiphenylmethane (0.30 ml, 1.5 mmol, 1.5 equiv.), and the reaction mixture was heated at 175 °C for 30 min. The mixture was cooled to room temperature and the solid compound was obtained as the petroleum ether (50 ml) was added, then the solid was filtered, purified by column chromatography (25% ethyl acetate in petroleum ether) to yield 9 (400 mg, 86%) as a yellow solid [16]. Mp 218-219 °C (lit. [16] 222-224 °C). 1H NMR (DMSO-d6, 300 MHz) δ: 6.20 (d, J = 2.0 Hz, 1H, 6-H), 6.47 (d, J = 2.0 Hz, 1H, 8-H), 7.22 (d, J = 8.8 Hz, 1H, 5'-H), 7.46 (m, 6H, aromatic H), 7.58 (m, 4H, aromatic H), 7.79 (dd, J = 1.8, 8.8 Hz, 1H, 6'-H), 7.82 (d, J = 1.8 Hz, 1H, 2'-H), 9.61 (s, 1H, 3-OH), 10.81 (s, 1H, 7-OH), 12.37 (s, 1H, 5-OH). ESI-MS m/z: 467 [M + H]+, 489 [M + Na]+. |
| 86% |
In diphenylether at 175℃; |
|
| 86% |
In diphenylether at 180℃; for 0.5h; |
|
| 86% |
In diphenylether at 175℃; for 0.5h; |
2 Compound 5:
Quercetin 1 (302 mg, 1.00 mmol) was dissolved in 20 mL of diphenyl ether,L, 1.50 mmol). The reaction was stirred at 175°C for 0.5 h.The TLC test material disappeared. After the reaction solution was cooled to room temperature, a dark red solid precipitated out after adding 50 mL of petroleum ether. The crude product was filtered and the crude product was subjected to column chromatography (PE:EtOAc=4:1) to give Compound 5 in a yield of 86% |
| 86% |
In diphenylether at 170 - 180℃; for 0.5h; |
1 Preparation of compound A-1:
Diphenyl ether 30 mL (Tokyo Chemical Industry Co., Ltd.)In the quercetin 1.0 g (3.48 mmol, Sigma Aldrich Co., Ltd.) dissolved,Dichlorodiphenylmethane 1.38 mL (6.96 mmol, Alpha Eisa)After adding, acetalize quercetin by reacting for 30 minutes at a temperature of 170-180 °C while stirring,It was cooled to room temperature. Then, 200 ml of petroleum ether was added to precipitate a solid and the solvent was removed.The solid was purified by column chromatography (a mixed solution of n-hexane and ethyl acetate (4:1 by volume) was used) to obtain compound A-1 (Yield: 86%). |
| 78% |
In Diphenylmethane at 180℃; for 1h; |
General method for Synthesis of 2-(2,2-diphenylbenzo[1,3]dioxol-5-yl)-3,5,7-trihydroxy-4H -chromen-4-one (Qr-1)
Quercetin (1.66 mmol) and 1,1-dichlorodiphenylmethane (2.50 mmol) were dissolved in diphenyl ether (20 mL). The mixture was warmed at 180 °C with stirring to react for 1 h. After the reaction, the mixture was cooled to room temperature, petroleum ether (50 mL) was added, and the yellow crude product was obtained by filtration. Ethyl acetate/petroleum ether (v:v, 1:5) was selected as the eluent, and a yellow solid QR-1 was obtained by pressure column chromatography; yield 78.0%; m.p. 221.3-222.2 °C (lit.22 230-232 °C). |
| 71% |
In diphenylether at 180℃; for 3h; |
3′,4′-O-Diphenylmethane quercetin:
This synthesis followed the procedure of Li et al. (40). 6.15 g (18.2 mmol) of quercetin hydrate was dried at 110° C. under high vacuum for 1 hour. 250 mL of diphenyl ether was then added, along with 5.4 mL (27.3 mmol) of Ph2CCl2. The mixture was heated to 180° C. and stirred for 3 hours. The material was precipitated by adding 800 mL of pet ether, then filtered and purified by silica gel chromatography with 5% EtOAc/toluene. The material was further purified by recrystallization in chloroform. 6.02 g (12.91 mmol) of 3′,4′-O-diphenylmethane quercetin was isolated as a yellow powder (71% yield). 1H NMR (300 MHz, CDCl3; δ 12.10 (s, 1H), 9.70 (br, 1H), 8.22 (br, 1H), 7.34 (m, 12H), 6.96 (d, J=6.9 Hz, 1H), 6.33 (d, J=1.8 Hz, 1H), 6.26 (d, J=1.7 Hz, 1H); 13C NMR (150 MHz, acetone-d6) δ 176.6, 165.0, 162.3, 157.7, 149.3, 148.2, 145.9, 140.8, 137.1, 130.2, 129.3, 126.9, 126.2, 123.9, 118.4, 109.5, 108.7, 104.1, 99.1, 94.5; ESI-MS: m/z: 467 [M+H]+ |
| 68% |
In diphenylether at 180℃; for 0.5h; |
|
| 68% |
In diphenylether at 175℃; for 24h; |
2-(20,20-Diphenylbenzo[d][10,30]dioxol-5-yl)-3,5,7-trihydroxy-4H-chromen-4-one (2):
To a stirredsolution of quercetin 1 (3.0 g, 9.93 mmol) in diphenylether (60 mL) at 60 C was addeddichlorodiphenylmethane (2.85 mL, 14.89 mmol). The reaction mixture was then stirredat 175 C for 24 h. The mixture was cooled to r.t. and petroleum ether (50 mL) wasadded to precipitate the crude product. The precipitate was filtered and further washedwith petroleum ether (60 mL). The crude solid was dissolved in EtOAc and the solventremoved in vacuo. The resulting crude product was purified by flash chromatography (4:1Petroleum ether:EtOAc) to give the title compound 2 (3.13 g, 68%) as a yellow solid. Rf: 0.30(4:1 Petroleum ether:EtOAc). M.P.: 240-242 C (literature 218-219 C) [17]. H (400 MHz;d6-DMSO): 6.20 (1H, d, J = 2.0 Hz, 6-H), 6.47 (1H, d, J = 2.0 Hz, 8-H), 7.22 (1H, d, J = 8.3 Hz,70-H), 7.43-7.49 (6H, m, Ar-H), 7.55-7.58 (4H, m, Ar-H), 7.80-7.83 (2H, m, 40-H and 60-H),9.63 (1H, s, 3-OH), 10.82 (1H, s, 7-OH), 12.38 (1H, s, 5-OH). C (100 MHz; d6-DMSO): 93.6(C-8), 98.3 (C-6), 103.1 (C-4a), 107.8 (C-40), 108.8 (C-70), 117.0 (C-20), 123.0 (C-60), 125.2 (C-50),125.8 (C-200), 128.6, 129.5 (C-300 and C-400), 136.4 (C-3), 139.4 (C-100), 145.6 (C-2), 146.7 (C-30a),147.6 (C-70a), 156.2 (C-8a), 160.7 (C-5), 164.1 (C-7), 176.0 (C-4). IR: max/cm1; 696, 730,747, 757, 775, 817, 827, 850, 871, 906, 951, 987, 1003, 1019, 1044, 1093, 1122, 1155, 1190, 1209,1237, 1256, 1316, 1347, 1389, 1439, 1487, 1522, 1566, 1596, 1614, 1631, 1653, 2586, 3064, 3334.HRMS (ESI+): Found (MNa+) 489.0929, C28H18NaO7 requires 489.0945. The 1H NMR values are in agreement with literature [17]. |
| 66% |
In diphenylether at 175℃; for 0.5h; |
3',4'-O-Diphenylmethane Quercetin (2)
compound 1(302 mg, 1 mmol, 1 equiv) and dichlorodiphenylmethane(0.3 mL, 1.5 mmol, 1.5 equiv) in diphenyl ether (15 mL)were mixed and heated at 175 °C for 30 min. The residuewas cooled to room temperature and petroleum ether (30mL) was added to give a solid compound. Then solid wascollected by filteration and purified by a silica gel columnchromatography using petroleum ether/ethyl acetate (4:1) aseluent to afford a yellow solid 2. Yield = 66% (306 mg). Rf (petroleum ether/ethyl acetate 4:1) 0.50. mp 219-220 °C(lit.21 222-224 °C). 1H NMR (400 MHz, DMSO-d6) 12.35(s, 1H), 10.79 (s, 1H), 9.60 (s, 1H), 7.81 (d, J = 1.8 Hz, 1H),7.77 (dd, J = 8.8, 1.8 Hz, 1H), 7.58 (m, 4H), 7.46 (m, 6H),7.23 (d, J = 8.8 Hz, 1H), 6.47 (d, J = 2.0 Hz, 1H), 6.21 (d, J= 2.0 Hz, 1H). 13C NMR (100 MHz, DMSO-d6) 178.2,164.5, 161.4, 156.6, 155.4, 148.7, 146.8, 139.4, 137.4,129.8, 128.8, 126.0, 124.3, 124.2, 117.5, 109.1, 108.8,104.5, 98.9, 94.1. Anal. calcd. for C28H18O7: C, 72.10; H,3.89; O, 24.01; Found: C, 72.12; H, 3.88; O, 24.00. |
| 62% |
In diethyl ether at 175℃; for 6h; |
|
| 56% |
In diethylene glycol dimethyl ether for 2h; Reflux; Inert atmosphere; |
Synthesis of 2-(2,2-diphenylbenzo[1,3]dioxol-5-yl)-3,5,7-trihydroxy-4H-chromen-4-one (7)
Quercetin (2.0 g, 6.6 mmol) and 1,1-dichlorodiphenylmethane (2.0 mL,10.4 mmol) were dissolved in bis(2-methoxyethyl) ether (20 mL). Themixture was warmed to reflux under an atmosphere of nitrogen for2 h. The reaction solution was concentrated in vacuo to give a yellowsolid which was purified on silica gel eluting with hexane/EtOAc toafford 7 as a yellow solid; yield 1.73 g (56%); m.p. 230-232 °C (lit.17222-224 °C); 1H NMR (300 MHz, CDCl3): δ 11.77 (s, 1H, 5OH),7.83-7.75 (m, 2H, H6′, H2′), 7.66-7.52 (m, 4H, Ph), 7.47-7.32 (m, 6H,Ph), 7.02 (d, J = 8.2 Hz, 1H, H5′), 6.43 (d, J = 2.1 Hz, 1H, H8), 6.29 (d,J = 2.1 Hz, 1H, H6). |
| 40% |
at 170℃; |
1.1
(Example 1-1) Synthesis of intermediate 2 for glucose derivative () 2-(2,2-Diphenylbenzo[d][1,3]dioxol-5-yl)-3,5,7-trihydroxy-4H-c hromen-4-one (2) A mixture of a compound 1 (quercetin, 1 g, 3 mmol) and Ph2CCl2 (1.7 mL, 8.9 mmol) was stirred at 170°C for 7 to 8 minutes, and an oily composition was dissolved in AcOEt (3 ml) in as small an amount as possible. Further, the solution was added to n-hexane (20 mL), and a gray solid precipitated was separated by filtration. The resultant gray solid was subjected to silica gel flash column chromatography, and a yellow solid 2 (0.62 g, 40%) was obtained from a fraction eluted with AcOEt:n-hexane (1:4, v/v). Melting point (m.p.) 238-239°C (lit. 239-240°C). Rf=0.15 (AcOEt:n-hexane (1:4, v/v)). IR (KBr) cm-1; 1600 (C=C), 1638 (C=O). 1HNMR (DMSO-d6, 300 MHz) δ 6.20 (d, 4J=1.8 Hz, 1H, 8-H), 6.46 (d, 4J=1.8 Hz, 1H, 6-H), 7.21 (d, J=8.1 Hz, 1H, 3'-H), 7.44-7.50 (m, 6H, Ar-H), 7.54-7.59 (m, 4H, Ar-H), 7.59-7.82 (m, 2H, 7.79-7.82 (m, 2H, 2'-H, 6'-H), 9.63 [s, 1H, 3-OH (exchangeable with D2O)], 10.81 [s, 1H, 7-OH (exchangeable with D2O)], 12.37 [s, 1H, 5-OH (exchangeable with D2O)]. |
| 39% |
at 180℃; for 0.166667h; |
4.2.1. 2-(2,2-Diphenylbenzo[1,3]dioxol-5-yl)-3,5,7-trihydroxy-4H-chromen-4-one 2
A mixture of quercetin 1 (3.00 g, 8.87 mmol) and dichlorodiphenylmethane (4.3 ml, 22.5 mmol) was intimately mixed, and then heated at 180 °C for 10 min. The crude reaction mixture was then purified by flash column chromatography using CH2Cl2/EtOAc (85:15) as eluent and was recrystallized from CHCl3 to afford 2 (1.62 g, 39% yield). Mp 222-224 °C (lit.21 218-219 °C; lit.18 222-224 °C). 1H NMR (DMSO-d6): 6.20 (d, J=1.9 Hz, 1H), 6.47 (d, J=1.9 Hz, 1H), 7.17 (d, J=8.3 Hz, 1H), 7.44-7.58 (m, 10H), 7.79 (dd, J=8.3, 1.6 Hz, 1H), 7.81 (d, J=1.6 Hz, 1H). 13C NMR (DMSO-d6): 93.6, 98.3, 103.1, 107.8, 108.8, 117.0, 123.0, 125.2, 125.7, 128.6, 129.5, 136.4, 139.4, 145.5, 146.7, 147.6, 156.2, 160.7, 164.2, 177.8. Elemental analysis: calculated for C28H18O7 C, 72.10; H, 3.89; O, 24.09. Observed C, 71.83; H, 3.74; O, 23.89. |
| 38% |
In diphenylether at 180℃; for 0.333333h; |
5.1.62 2-(2,2-Diphenylbenzo[d][1,3]dioxol-5-yl)-3,5,7-trihydroxy-4H-chromen-4-one (30)
A mixture of 1 (2g, 6.57mmol) and dichlorodiphenylmethane (2mL, 10.42mmol) in 5mL diphenyl ether was heated at 180°C for 20min. The reaction mixture was washed by ether and diluted with hot acetone. Then, the filtrate was purified by flash column chromatography using petroleum ether/ EtOAc (6:1 to 1:1) as eluent to give 30 (1.25g, 38% yield) as a yellow solid. 1H NMR (300MHz, d6-DMSO): δ 7.86-7.79 (m, 2H), 7.67-7.53 (m, 4H), 7.53-7.42 (m, 6H), 7.24 (d, J=8.7Hz, 1H), 6.59 (d, J=2.1Hz, 1H), 6.21 (s, 1H). |
| 37% |
at 180℃; for 0.166667h; |
|
| 37% |
at 180℃; for 0.166667h; |
1.1
A mixture of quercetin IXa (5 g, 15 mraol) and PI12CCI2 (8.5 mL, 45 mmol) in a 50 mL round bottom flask was stirred at 180 0C for 10 min. The reaction mixture was purified by flash chromatography on silica gel and eluted with a mixture of EtOAc/petroleum ether (1:4, v/v) to afford IXb (2.5 g, 37 %) as a yellow solid: Mp 239-240 0C, 1H-NMR (DMSO-d6) δ: 6.22 (IH, d) , 6.50 (IH, d) , 7.26 (IH, d) , 7.44-7.60 (1OH, m) , 7.80-7.83 (2H, m) . |
| 35% |
at 180℃; for 0.5h; |
|
| 35% |
at 180℃; for 0.5h; |
|
| 35% |
at 180℃; for 0.5h; |
4.2.4 2-(2,2-Diphenyl-benzo[1,3]dioxol-5-yl)-3,5,7-trihydroxy-chromen-4-one (10)
A mixture of quercetin (1) (5 g, 14.8 mmol) and dichlorodiphenylmethane (8.5 mL, 44.3 mmol) was stirred for 30 min at 180 °C. The reaction mixture was taken with CHCl3 and concentrated under reduced pressure. The residue was purified by column chromatography (hexane/EtOAc = 4:1) on silica gel as eluent and was recrystallized from CHCl3 to afford 10 (2.4 g, 5.2 mmol, 35% yield) as yellow powder; mp 222-224 °C (rec. CHCl3) (lit.14 mp 222-224 °C); 1H NMR (400 MHz, acetone-d6) δ (ppm) 12.18 (s, 1H), 7.89-7.92 (m, 2H), 7.63-7.69 (m, 5H), 7.45-7.49 (m, 5H), 7.19 (d, J = 10.5 Hz, 1H), 6.58 (s, 1H), 6.28 (s,1H); 13C NMR (100 MHz, DMSO-d6) δ (ppm) 176.1, 164.2, 160.8, 156.3, 147.7, 146.8, 145.6, 139.5, 136.5, 129.5, 128.7, 125.8, 125.3, 123.1, 117.1, 108.9, 107.9, 101.1, 98.4, 93.7; HR-FABMS (m/z): Found: 467.1135 [M+H]+; Calcd for C28H18O7: 466.1056. |
| 33% |
With pyridine at 170℃; for 0.25h; |
|
| 7% |
In diphenylether at 175℃; for 5h; |
|
|
at 180℃; for 0.0833333h; |
|
|
|
1; 2; 3; 4; 5; 6
EXAMPLE 1; Synthesis Of Quercetin-3-Curcumin (Compound 8)Preparation of diphenyl ketal aminoαuercetin (compound 3)[0073] Quercetin (compound 1 ) was reacted with Ph2CCI2 to form diphenylketalquercetin (compound 2). |
|
at 190℃; for 0.25h; |
|
|
at 170℃; |
|
|
at 170 - 180℃; for 0.166667h; |
|
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