An Efficient One-Pot Synthesis of 4'- Substituted Flavones

Supporting Information

An efficient one-pot synthesis of 4'-substituted flavones

Xuejun Wang ,Jianli Liu ,Yilin Zhang, Xuhua Liang

Experimental Procedures

General

All melting points were taken on a XT5A melting point instrument. NMR spectra were obtained using a VARIAN INOVA (400 MHz) spectrometers with TMS as the internal standard. All chemical shifts are reported in ppm. Analytical thin-layer chromatography (TLC) was carried out on Merck precoated aluminum silica gel sheets (Kieselgel 60 F-254). Column chromatography was carried out with silica gel 60 (230-400 mesh) from Merck. All target compounds were characterized by 1HNMR and MS analyses.

General procedure for preparation of flavones 16a-16e,19a-19e,22a-22e,25a-25d

To a solution of acetophenone (1 mmol) in wet acetone (containing 1% w/w water) (20 mL/mmol) was added potassium carbonate (8 eq) and then pyridine (4 eq). The solution was stirred at 60 ℃ for 15 min and aroyl chloride (2 eq) was slowly added. The reaction mixture was stirred at reflux for 24-48 h. After cooling to room temperature, the acetone was evaporated and was added 10% acetic acid (50 mL/mmol), the solution was stirred fully until it stop to bubbled, and then filtered, washed with water (2×50 ml) to neutral. the residue was vacuum-dried and then crystallized from acetone (20 mL) to obtain pure flavones 16a-16e, 19a-19e, 22a-22e, 25a-25d (70%-83%).

2-phenyl-4H-chromen-4-one(16a)

Yield: 83%; Mp:96～99 ℃ (Chee et al. 2011); 1H NMR (400 MHz, CDCl3): δ 8.25 (d, J=8.0 Hz, 1H, 5-H), 8.02–7.89 (m, 2H, 2′,6′-H), 7.73 (t, J =7.7 Hz, 1H, 7-H), 7.65–7.49 (m,4H, 3′,4′,5′, 8-H), 7.45 (t, J=7.5 Hz, 1H, 6-H), 6.90 (s, 1H, 3-H); ESI-MS [M+Na]+ for C15H10O2: calcd, 245.24; obsd. 245.08.

4′-fluoroflavone(16b)

Yield: 80%; Mp: 133～135 ℃ (Franco et al. 2010)；1H NMR(400 MHz, CDCl3): δ 8.24 (d, J=7.8 Hz, 1H, 5-H), 8.03–7.89 (m, 2H, 2′,6′-H), 7.73 (t, J=7.7 Hz, 1H, 7-H), 7.62–7.52 (m, 1H, 8-H), 7.45 (t, J=7.5 Hz, 1H, 6-H), 7.23 (d, J=8.3 Hz, 2H, 3′,4′-H), 6.83 (s, 1H, 3-H); ESI-MS [M+H]+ for C15H9O2F:calcd. 241.18, obsd. 241.00.

4′-chloroflavone(16c)

Yield: 78%; Mp:186～187 ℃ (Jae et al. 2005)；1H NMR (400 MHz, CDCl3) δ 8.24 (d, J=7.9 Hz, 1H, 5-H), 7.89 (d, J=8.5 Hz, 2H, 2′,6′-H), 7.73 (t, J=7.8 Hz, 1H, 7-H), 7.58 (d, J=8.4 Hz, 1H, 8-H), 7.52 ( d, J=8.5 Hz, 2H, 3′,4′-H), 7.45 ( t, J=7.5 Hz, 1H, 6-H), 6.83 (s, 1H, 3-H); ESI-MS [M+H]+ for C15H9O2Cl: calcd. 257.70, obsd. 257.50.

4′-methylflavone(16d)

Yield: 70%; Mp: 227～229 ℃ (Franco et al. 2010); 1H NMR (400 MHz, CDCl3): δ 8.24 (d, J=7.9 Hz, 1H, 5-H), 7.85 (d, J=8.0 Hz, 2H, 2′,6′-H), 7.72 (t, J=7.7 Hz, 1H, 7-H), 7.59 (d, J=8.4 Hz, 1H, 8-H), 7.44 (t, J=7.5 Hz, 1H, 6-H), 7.34 (d, J=8.0 Hz, 2H, 3′,4′-H), 6.87 (s, 1H, 3-H), 2.45 (s, 3H, CH3); ESI-MS [M+H]+ for C16H12O2: calcd. 237.22, obsd. 237.0.

4′-methoxylflavone(16e)

Yield: 70%; Mp: 158～160 ℃(Jae et al. 2005); 1H NMR (400 MHz, CDCl3): δ 8.24 (dd, J=7.9, 1.5 Hz, 1H, 5-H), 7.98–7.86 (m, 2H, 2′,6′-H), 7.70 (ddd, J=8.6, 7.2, 1.7 Hz, 1H, 7-H), 7.57 (d, J=8.3 Hz, 1H, 8-H), 7.43 (dd, J=11.1, 4.0 Hz, 1H, 6-H), 7.04 (d, J=8.9 Hz, 2H, 3′,4′-H), 6.79 (s, 1H, 3-H), 3.90 (s, 3H, OCH3); ESI-MS [M+H]+ for C16H12O3: calcd. 253.28, obsd. 253.08.

7-hydroxyflavone(19a)

Yield: 80%; Mp: 241～242 ℃ (Chee et al. 2011)；1H NMR (400 MHz, CD3OD): δ 8.08–8.00 (m, 3H, 2′,6′,5-H), 7.64–7.54 (m, 3H, 3′,4′,5′-H), 7.03 (d, J=2.2 Hz, 1H, 8-H), 6.98 (dd, J=8.8, 2.2 Hz, 1H, 6-H), 6.84 (s, 1H, 3-H); ESI-MS [M+Na]+ for C15H10O3: calcd. 261.23, obsd. 261.00.

7-hydroxy-4′-fluoroflavone(19b)

Yield: 77%; Mp: 246～248 ℃ (Jiraporn et al. 2011); 1H NMR (400MHz, (CD3)2CO): δ 9.74 (s, 1H, -OH), 8.29–8.12 (m, 2H, 2′,6′-H), 8.03 (d, J=8.7 Hz, 1H, 5-H), 7.42 (t, J=8.8 Hz, 2H, 3′,4′-H), 7.12 (d, J=2.2Hz, 1H, 8-H), 7.05 (dd, J=8.7, 2.3 Hz, 1H, 6-H), 6.79 (s, 1H, 3-H); ESI-MS [M+Na]+ for C15H9O3F: calcd. 257.24, obsd. 257.00.

7-hydroxy-4′-chloroflavone(19c)

Yield: 75%; Mp: 280～282 ℃ (Chee et al. 2011)；1H NMR (400 MHz, CD3OD): δ 9.80 (s, 1H, -OH), 8.14 (d, J=8.7 Hz, 2H, 2′,6′-H), 8.03 (d, J=8.7 Hz, 1H, 5-H), 7.68 (d, J=8.6 Hz, 2H, 3′,4′-H), 7.12 (d, J=2.2 Hz, 1H, 8-H), 7.05 (dd, J=8.7, 2.2 Hz, 1H, 6-H), 6.83 (s, 1H, 3-H); ESI-MS [M+Na]+ for C15H9O3Cl: calcd. 295.67, obsd. 295.23.

7-hydroxy-4′-methylflavone(19d)

Yield: 71%; Mp: 278～280 ℃ (Wang and Liu 2014); 1H NMR (400 MHz, CD3OD): δ 9.67 (s, 1H-OH), 8.01 (dd, J=9.9, 8.6 Hz, 3H, 2′,6′,5-H), 7.45 (d, J=8.1 Hz, 2H, 3′,4′-H), 7.11 (d, J=2.2 Hz, 1H, 8-H), 7.04 (dd, J=8.7, 2.3Hz, 1H, 6-H), 6.76 (s, 1H, 3-H), 2.48 (s, 3H, -CH3). ESI-MS [M+Na]+ for C16H12O3: calcd. 275.26, obsd. 275.00.

7-hydroxy-4′-methoxylflavone(19e)

Yield: 70%; Mp: 263～265 ℃ (Chee et al. 2011); 1H NMR (400 MHz, CD3OD): δ 8.07–8.03 (m, 2H, 2′,6′-H), 8.00 (d, J=8.7 Hz, 1H, 5-H), 7.18–7.12 (m, 2H, 3′,4′-H), 7.08 (d, J=2.2 Hz, 1H, 8-H), 7.01 (dd, J=8.7, 2.3 Hz, 1H, 6-H), 6.69 (s, 1H, 3-H), 3.94 (s, 3H, -OCH3); ESI-MS [M+Na]+ for C16H12O4:calcd. 291.26, obsd. 291.00.

6-hydroxyflavone(22a)

Yield: 79%; Mp: 232～235 ℃(Chee et al. 2011); 1H NMR (400 MHz, CD3OD): δ 8.12–7.99 (m, 2H, 2′,6′-H), 7.63 (m, 4H, 3′,4′,5′,7-H), 7.47 (d, J=2.9 Hz, 1H, 8-H), 7.33 (dd, J=9.0, 2.9 Hz, 1H, 6-H), 6.90 (s, 1H, 3-H), ESI-MS [M+Na]+ for C15H10O3:calcd. 261.23, obsd.261.00.

6-hydroxy-4′-fluoroflavone(22b)

Yield: 75%; Mp: 261～263 ℃ (Jiraporn et al. 2011); 1H NMR (400 MHz, CD3OD): δ 8.03 (dd, J=9.1, 5.2 Hz, 2H, 2′,6′-H), 7.54 (d, J=9.0 Hz, 1H, 5-H), 7.35 ( d, J=3.0 Hz, 1H, 7-H), 7.29–7.18 (m, 3H, 3′,4′,8-H), 6.77 (s, 1H, 3-H); ESI-MS [M+Na]+ for C15H9O3F: calcd. 279.22, obsd. 279.00.

6-hydroxy-4′-chloroflavone(22c)

Yield: 78%; Mp: 283～286 ℃ (Wang and Liu 2014); 1H NMR (400 MHz, CD3OD): δ 8.09 (d, J=8.0 Hz, 2H, 2′,6′-H), 7.65 (dd, J=15.3, 8.5 Hz, 3H, 3′,4′,5′-H), 7.48 (d, J =3.0 Hz, 1H, 7-H), 7.39–7.29 (m, 1H, 8-H), 6.92 (d, J=1.0 Hz, 1H, 3-H); ESI-MS [M+Na]+ for C15H9O3Cl: calcd. .295.67, obsd. 295.00.

6-hydroxy-4′-methylflavone(22d)

Yield: 72%; Mp: 282～285 ℃ (Wang and Liu 2014); 1H NMR (400 MHz, CD3OD): δ 7.97 (d, J=8.2 Hz, 2H, 2′,6′-H), 7.65 (d, J=9.0 Hz, 1H, 7-H), 7.44 (dd, J=16.5, 5.5 Hz, 3H, 3′,4′,5′-H), 7.32 (dd, J=9.0, 3.0 Hz, 1H, 8-H), 6.87 (s, 1H, 3-H), 2.47 (s, 3H, -CH3); ESI-MS [M+Na]+ for C16H12O3: calcd. 275.26, obsd. 275.00.

6-hydroxy-4′-methoxylflavone(22e)

Yield: 70%; Mp: 254～257 ℃ (Wang and Liu 2014); 1H NMR (400 MHz, (CD3)2CO): δ 8.00 (d, J=8.9 Hz, 2H, 2′,6′-H), 7.60 (d, J=9 Hz, 1H, 7-H), 7.42(d, J=3.0 Hz, 1H, 8-H), 7.27 (dd, J=9.0, 3.0 Hz, 1H, 5′-H), 7.10(d, J=9.0Hz, 2H, 3′,4′-H), 6.78 (s, 1H, 3-H), 3.89 (s, 3H, -OCH3); ESI-MS [M+Na]+ for C16H12O4:calcd. 291.26, obsd. 291.00.

5-hydroxyflavone(25a)

Yield: 75%; Mp: 160～162 ℃ (Chee et al. 2011); 1H NMR (400 MHz, CDCl3): δ 7.93 (dd, J=8.0, 1.6 Hz, 2H, 2′,6′-H), 7.6–7.47 (m, 4H, 3′,4′,5′,7-H), 7.02 (d, J=8.4 Hz, 1H, 8-H), 6.83 (d, J=8.2 Hz, 1H, 6-H), 6.75 (s, 1H, 3-H); ESI-MS [M+H]+ for C15H10O3: calcd. 239.25, obsd. 239.08.

5-hydroxy-4′-fluoroflavone(25b)

Yield: 73%; Mp: 158～160 ℃ (Masato et al. 2010); 1H NMR (400 MHz, CDCl3): δ 12.54 (s, 1H, OH), 7.93 (dd, J=8.0, 5.4 Hz, 2H, 2′,6′-H), 7.55 (q, J=8.5 Hz, 1H, 7-H), 7.23 (d, J=8.3 Hz, 2H, 3′,4′-H), 7.00 (d, J=8.4 Hz, 1H, 8-H), 6.83 (d, J=8.2 Hz, 1H, 6-H), 6.69 (s, 1H, 3-H); ESI-MS [M+H]+ for C15H9O3F: calcd. 257.24, obsd. 257.10.

5-hydroxy-4′-chloroflavone(25c)

Yield: 72%; Mp: 192～194 ℃ (Jae et al. 2005); 1H NMR (400 MHz, CDCl3): δ 12.51 (s, 1H), 7.87 (d, J=8.6 Hz, 2H, 2′,6′-H), 7.62–7.47 (m, 3H, 3′,5′,7-H), 7.01 (d, J=8.4 Hz, 1H, 8-H), 6.84 (d, J=8.3 Hz, 1H, 6-H), 6.72 (s, 1H, 3-H); ESI-MS [M+H]+ for C15H9O3Cl: calcd. 273.70, obsd. 273.57.

5-hydroxy-4′-methylflavone(25d)

Yield: 17.2%; Mp: 184～186 ℃ (Pinto et al. 2002); 1H NMR (400 MHz, CDCl3): δ 12.51 (s, 1H), 7.94 (dd, J=8.0, 1.6 Hz, 2H, 2′,6′-H), 7.5–7.42 (m, 3H, 3′,5′,7-H), 7.03 (d, J=8.4 Hz, 1H, 8-H), 6.82 (d, J=8.2 Hz, 1H, 6-H), 6.74 (s, 1H, 3-H), 2.44 (s, 3H, -CH3); ESI-MS [M+H]+ for C16H12O3: calcd. 253.27, obsd. 253.17.

General procedure for synthesis of 3-aroylflavones 26a-26d

To a solution of acetophenone (1 mmol) in wet acetone (containing 1% w/w water) (20 mL/mmol) was added potassium carbonate (8 eq). The solution wasstirred at 60 ℃ for 15 min and aroyl chloride (3 eq) was slowly added. The mixture was stirred at reflux for 24-48 h. After cooling to room temperature, the acetone was evaporated and was added 10% acetic acid (50 mL/mmol), the solution was stirred fully until it stop to bubbled, and then filtered, washed with water (2×50 ml) to neutral and dried in vacuum. 3-Aroylflavones 26a-26d were afforded after the precipitate was purified by column chromatography using petroleumether:ethyl acetate (10:1) as eluent.

3-benzoyl-5-hydroxyflavone(26a)

Yield: 15%; Mp: 164～166 ℃ (Chee et al. 2011); 1H NMR (400 MHz, CDCl3): δ 12.17 (s, 1H, OH), 7.93 (d, J=7.9 Hz, 2H, 2H, 2′,6′-H), 7.59 (m, 4H), 7.48–7.32 (m, 5H), 7.02 (t, J=10.6 Hz, 1H, 8-H), 6.86 (t, J=8.2 Hz, 1H, 6-H); ESI-MS [M+H]+ for C22H14O4 : calcd. 343.09, obsd. 343.29.

3-(4-fluorobenzoyl)-5-hydroxy-4′-fluoroflavone(26b)

Yield: 12%; Mp: 133～136℃; 1H NMR (400 MHz, CDCl3): δ 12.09 (s, 1H, OH), 8.00–7.90 (m, 2H, 2′,6′-H), 7.64 (m, 3H, Ar-H), 7.13–7.01 (m, 5H, Ar-H), 6.88 (d, J=8.3 Hz, 1H, 6-H); 13C NMR (67.9 MHz, CDCl3): δ 192.73, 174.86, 163.57, 160.60, 157.72, 135.66, 132.20, 132.02, 131.18, 130.73, 130.31, 128.52, 126.89, 125.27, 121.58, 115.81, 115.32, 102.69; HRMS [M+H]+ for C22H12O4F2 :calcd. 379.0776, obsd. 379.0768.

3-(4-chlorobenzoyl)-5-hydroxy-4′-chloroflavone(26c)

Yield: 12%; Mp: 164-166 ℃ (Pinto et al. 1997);1H NMR (400 MHz, CDCl3) δ12.05 (s,1H), 7.86 (d, J=8.2 Hz, 2H, 2′,6′-H), 7.64 (t, J=8.4 Hz, 1H, 7-H), 7.57(d, J=8.2 Hz, 2H), 7.43 (d, J=8.3 Hz, 2H), 7.37 (d, J=8.3 Hz, 2H), 7.03 (d, J=8.4 Hz, 1H, 8-H), 6.89 (d, J=8.4 Hz, 1H, 6-H); ESI-MS [M+H]+ for C22H12O4Cl2:calcd. 412.24, obsd. 412.01.

3-(4-methylbenzoyl)-5-hydroxy-4′-methylflavone(26d)

Yield: 15%; Mp: 223～225 ℃ (Pinto et al. 2002); 1H NMR (400 MHz, CDCl3): δ 12.23(s, 1H), 7.84 (d, J =8.1 Hz, 2H, 2′,6′-H), 7.65–7.52 (m, 3H, Ar-H), 7.24 (d, J=8.0 Hz, 2H, Ar-H), 7.17 (d, J=8.1Hz, 2H, Ar-H), 7.02 (d, J=8.4 Hz, 1H, 8-H), 6.85 (d, J=8.3 Hz, 1H, 6-H), 2.39 (s, 3H, -CH3), 2.34 (s, 3H, -CH3); ESI-MS [M+H]+ for C24H18O4: calcd. 371.41, obsd. 371.21.

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