4.2. General Procedure for Preparation of 2-Hydroxyacetophenone Derivatives (I)
The synthesis of
5–
9 was conducted according to literature [
9]. Thus, phenol derivatives (
1–
4) (13.2 mmol) dissolved in acetic anhydride (Ac
2O) (3 mL, 30 mmol) were added in ethyl acetate (AcOEt) (5 mL). Then, boron trifluoride-diethyl ether (BF
3-Et
2O, 800 µL, 6.4 mmol) was slowly added to the reaction mixtures, a reflux setup allowed the mixtures to be heated in a controlled manner at 50 °C for 12 h without the loss of solvent. The work-up process was performed using 100 mL of water, neutralization with NaHCO
3, and extraction with CH
2Cl
2 (3 × 100 mL). The organic phase was brought to dryness and the resulting solid was eluted on a silica gel 60 columns using hexane:ethyl acetate (Hex:AcOEt) (2:1) (
v:v). The synthesis of
5–
9 was achieved in an overall yield of 16.5–56%.
4.2.1. Compound (5)
1-(2,4-Dihydroxyphenyl)ethan-1-one (5). Yield 30.4%, yellow solid, m.p.: 144–145 °C. 1H NMR (300 MHz, CDCl3) δ 7.56 (d, J = 8.8 Hz, 1H), 6.35 (dd, J = 8.8, 2.4 Hz, 1H), 6.29 (d, J = 2.3 Hz, 1H), 2.50 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 202.71, 164.72, 164.64, 133.03, 113.38, 108.34, 102.91, 26.10. HRMS (ESI) m/z, calculated for C8H9O3 [M+H]+ 153.0546; found 153.0547.
4.2.2. Compound (6)
1-(2,5-Dihydroxyphenyl)ethan-1-one (6). Yield 26.3%, yellow solid, m.p.: 200–204 °C. 1H NMR (300 MHz, CDCl3) δ 7.13 (d, J = 2.9 Hz, 1H), 7.00 (dd, J = 8.9, 2.9 Hz, 1H), 6.78 (d, J = 8.9 Hz, 1H), 2.54 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 204.48, 155.41, 148.76, 125.04, 119.35, 118.76, 115.34, 26.67. HRMS (ESI) m/z, calculated for C8H9O3 [M+H]+ 153.0546; found 153.0546.
4.2.3. Compound (7)
1-(2,6-Dihydroxyphenyl)ethan-1-one (7). Yield 49.1%, yellow solid, m.p.: 160–162 °C. 1H NMR (300 MHz, CDCl3) δ 7.20 (t, J = 8.2 Hz, 1H), 6.40 (d, J = 8.2 Hz, 2H), 2.74 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 205.83, 161.97, 136.30, 110.47, 108.04, 33.64. HRMS (ESI) m/z, calculated for C8H9O3 [M+H]+ 153.0546; found 153.0546.
4.2.4. Compound (8)
1-(2,3,4-Trihydroxyphenyl)ethan-1-one (8). Yield 56.0%, yellow solid, m.p.: 170–172 °C. 1H NMR (300 MHz, CDCl3) δ 7.14 (d, J = 8.9 Hz, 1H), 6.36 (d, J = 8.9 Hz, 1H), 2.46 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 203.50, 151.85, 151.43, 131.83, 123.10, 113.62, 107.47, 26.07. HRMS (ESI) m/z, calculated for C8H9O4 [M+H]+ 169.0495; found 169.0494.
4.2.5. Compound (9)
1-(2,4,6-Trihydroxyphenyl)ethan-1-one (9). Yield 16.5%, yellow solid, m.p.: 137–138 °C. 1H NMR (300 MHz, Acetone) δ 5.92 ppm (s, 2H), 2.60 (s, 3H). 13C NMR (75 MHz, Acetone) δ 203.10, 164.91, 164.90, 104.79, 95.07, 32.17. HRMS (ESI) m/z, calculated for C8H9O4 [M+H]+ 169.0495 found 169.0400.
4.3. General Procedure for Prenylation of 2-Hydroxyacetophenone Derivatives (III)
Into round-bottom flasks (10 mL) the 2-Hydroxyacetophenone derivatives
5–
9 (4 mmol) were dissolved individually in 3-Methyl-2-buten-1-ol (2 mL, 20 mmol). The resulting mixtures were stirred at 50 °C for 15 min to obtain a full homogenization. Then, the reaction mixtures were poured into ice-water, and BF
3-Et
2O (150 µL, 1.20 mmol) was added dropwise [
10]. After the addition of BF
3.Et
2O, the mixtures were then stirred at room temperature for 24 h. The work-up process consisted of an addition of 50 mL water, and successive extractions with dichloromethane. The organic layer was dried over sodium sulfate and concentrated to dryness. The compounds
14–
18 were purified using column chromatography with silica gel 60, eluting with Hex:AcOEt (2:1) (
v/
v). The synthesis of
14–
18 has been achieved in an overall yield of 5.1–12.3%.
4.3.1. Compound (14)
1-(2,4-Dihydroxy-5-(3-methylbut-2-en-1-yl)phenyl)ethan-1-one (14). Yield 7.6%, white solid. m.p.: 137 °C. 1H NMR (300 MHz, Acetone) δ 12.63 (s, 1H), 9.52 (s, 1H), 7.60 (s, 1H), 6.36 (s, 1H), 5.41–5.26 (m, 1H), 3.26 (d, J = 7.2 Hz, 2H), 2.53 (s, 3H), 1.72 (s, 6H). 13C NMR (75 MHz, Acetone) δ 202.67, 163.46, 162.49, 132.20, 131.90, 122.57, 120.29, 113.12, 102.24, 27.53, 25.35, 25.00, 16.96. HRMS (ESI) m/z, calculated for C13H17O3 [M+H]+ 221.1172 found 221.1173.
4.3.2. Compound (15)
1-(2,4-Dihydroxy-3-(3-methylbut-2-en-1-yl)phenyl)ethan-1-one (15). Yield 6.3%, white solid. m.p.: 148 °C. 1H NMR (300 MHz, Acetone) δ 13.11 (s, 1H), 9.35 (s, 1H), 7.63 (d, J = 8.7 Hz, 2H), 6.50 (d, J = 8.7 Hz, 2H), 5.33–5.16 (m, 2H), 3.35 (d, J = 7.2 Hz, 2H), 1.77 (s, 3H), 1.64 (s, 3H), 1.29 (s, 3H). 13C NMR (75 MHz, Acetone) δ 203.02, 162.78, 161.79, 130.64, 130.38, 122.32, 114.97, 113.24, 107.12, 25.36, 25.01, 21.29, 17.03. HRMS (ESI) m/z, calculated for C13H17O3 [M+H]+ 221.1172 found 221.1177.
4.3.3. Compound (16)
1-(2,6-Dihydroxy-3-(3-methylbut-2-en-1-yl)phenyl)ethan-1-one (16). Yield 9.1%, white solid. m.p.: 75–76 °C. 1H NMR (300 MHz, CDCl3) δ 10.75 (s, 1H), 9.25 (s, 1H), 7.12 (d, J = 8.3 Hz, 1H), 6.33 (d, J = 8.3 Hz, 1H), 5.34–5.19 (m, 1H), 3.27 (d, J = 7.2 Hz, 2H), 2.74 (s, 3H), 1.76 (s, 3H), 1.74 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 206.01, 160.21, 159.17, 136.46, 134.73, 121.82, 119.72, 110.29, 107.12, 33.68, 28.50, 25.93, 17.94. HRMS (ESI) m/z, calculated for C13H17O3 [M+H]+ 221.1172, found 221.1170.
4.3.4. Compound (17)
1-(2,4,6-Trihydroxy-3-(3-methylbut-2-en-1-yl)phenyl)ethan-1-one (17). Yield 10.1%. white solid. m.p.: 174 °C. 1H NMR (300 MHz, CDCl3) δ 5.84 (s, 1H), 5.21 (t, J = 6.9 Hz, 1H), 3.26 (d, J = 6.9 Hz, 2H), 2.64 (s, 3H), 1.77 (s, 3H), 1.68 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 203.93, 164.31, 162.13, 160.53, 132.45, 122.66, 106.58, 104.81, 94.89, 32.59, 25.70, 21.27, 17.70. HRMS (ESI) m/z, calculated for C13H17O4 [M+H]+ 237.1121, found 237.1122.
4.3.5. Compound (18)
1-(2,3,4-Trihydroxy-5-(3-methylbut-2-en-1-yl)phenyl)ethan-1-one (18). Yield 12.3%, white solid. m.p.: 110–115 °C. 1H NMR (300 MHz, CDCl3) δ 7.01 (s, 1H), 5.24 (t, J = 7.8 Hz, 1H), 3.22 (d, J = 7.1 Hz, 2H), 2.48 (s, 3H), 1.70 (s, 3H), 1.67 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 203.64, 149.74, 149.62, 133.14, 131.12, 122.37, 121.93, 120.01, 112.99, 27.76, 26.11, 25.72, 17.74. HRMS (ESI) m/z, calculated for C13H17O4 [M+H]+ 237.1121 found 237.1122.
4.5. General Procedure for Preparation of Prenylated Chalcones (VI)
The synthesis of chalcones was achieved according to the previously reported procedures for the Claisen−Schmidt reaction (
4) [
12,
13]. Briefly, methoxy-methylated acetophenone (
19) (1 mmol) and benzaldehyde derivatives (1.05 mmol) were dissolved in ethanol (10 mL), the resulting reaction mixtures were kept at room temperature and magnetic stirring for 5 min. Then, a KOH/EtOH solution (1.1 mmol on 10 mL) was added dropwise and stirring was continued at 40 °C for 12 h. The compounds
27–
28 were purified using column chromatography with silica gel 60, eluting with Hex: AcOEt (2:1) (
v/
v). The synthesis of prenylated chalcones has been achieved in an overall yield of 46.3–77.5%.
4.5.1. Compound (27)
1-(2-Hydroxy-4-(methoxymethoxy)-5-(3-methylbut-2-en-1-yl)phenyl)-3-(4-methoxyphenyl)prop-2-en-1-one (27). Yield 56.3%, white solid. m.p.: 108–109 °C. 1H NMR (300 MHz, CDCl3) δ 13.38 (s, 1H), 7.91 (d, J = 15.4 Hz, 1H), 7.67 (d, J = 6.8 Hz, 3H), 7.50 (d, J = 15.3 Hz, 1H), 7.01 (d, J = 8.3 Hz, 2H), 6.70 (s, 1H), 5.35–5.30 (m, 3H), 3.92 (s, 3H), 3.53 (s, 3H), 3.34 (d, J = 7.3 Hz, 2H), 1.80 (s, 6H). 13C NMR (75 MHz, CDCl3) δ 192.01, 164.81, 161.79, 161.35, 144.15, 132.84, 130.38, 130.07, 126.10, 122.45, 121.92, 118.00, 114.50, 114.29, 102.18, 93.98, 56.39, 55.49, 28.44, 25.84, 17.90. HRMS (ESI) m/z, calculated for C23H26O5Na [M+Na]+ 405.1672, found 405.1673.
4.5.2. Compound (28)
3-(4-Chlorophenyl)-1-(2-hydroxy-4-(methoxymethoxy)-5-(3-methylbut-2-en-1-yl)phenyl)prop-2-en-1-one (28). Yield 77.5%, white solid. m.p.: 103–105 °C. 1H NMR (300 MHz, CDCl3) 13.18 (s, OH), 7.80 (d, J = 15.5 Hz, 1H), 7.59 (d, J = 5.9 Hz, 2H), 7.53 (d, J = 16.8 Hz, 2H), 7.40 (d, J = 8.5 Hz, 2H), 6.65 (s, 1H), 5.37–5.19 (m, 3H), 3.48 (s, 3H), 3.29 (d, J = 7.1 Hz, 2H), 1.75 (s, 6H). 13C NMR (75 MHz, CDCl3) δ 191.62, 165.00, 161.69, 142.73, 136.52, 133.38, 132.90, 130.09, 129.68, 129.31, 122.37, 122.18, 120.95, 114.15, 102.20, 93.98, 56.41, 28.46, 25.84, 17.94. HRMS (ESI) m/z, calculated for C22H23ClO4Na [M+Na]+ 409.1177, found 409.1135.
4.6. General Procedure for Preparation of Prenylated Flavones (VII)
The hydroxychalcones (
27–
28) (0.5 mmol) were dissolved in DMSO (5 mL) and these solutions were treated with a catalytic amount of iodine [
14]. The resulting mixtures were charged in 10 mL glass tubes containing a magnetic stirring bar and a rubber cap. The tubes were subjected to MW at 120 °C for 5 min. After completion of the reaction, the tubes were removed, cooled to room temperature, and the mixture was purified by column chromatography with silica gel 60, eluting Hex:AcOEt (2:1) (
v/v). The synthesis of prenylated flavones (
29–
30) has been achieved in an overall yield of 7.5–41.3%.
4.6.1. Compound (29)
7-(Methoxymethoxy)-2-(4-methoxyphenyl)-6-(3-methylbut-2-en-1-yl)-4H-chromen-4-one (29). Yield 41.3%, white solid. m.p.: 70.5 °C. 1H NMR (300 MHz, CDCl3) δ 7.98 (s, 1H), 7.88 (d, J = 8.9 Hz, 2H), 7.20 (s, 1H), 7.02 (d, J = 11.8 Hz, 2H), 6.77 (s, 1H), 5.39–5.26 (m, 3H), 3.89 (s, 3H), 3.52 (s, 3H), 3.40 (d, J = 7.4 Hz, 2H), 1.74 (m, 6H). 13C NMR (75 MHz, CDCl3) δ 178.02, 163.4, 162.37, 159.52, 156.33, 133.44, 129.70, 128.01, 125.59, 124.10, 121.44, 117.7, 114.46, 105.77, 101.51, 94.29, 56.40, 55.56, 28.62, 25.92, 17.88. HRMS (ESI) m/z, calculated for C23H25O5 [M+H]+ 381.1696, found 381.1704.
4.6.2. Compound (30)
2-(4-Chlorophenyl)-7-(methoxymethoxy)-6-(3-methylbut-2-en-1-yl)-4H-chromen-4-one (30). Yield 30.1%, white solid. m.p.: 108–109 °C. 1H NMR (300 MHz, Acetone) δ 8.10 (d, J = 8.7 Hz, 2H), 7.86 (s, 1H), 7.62 (d, J = 8.7 Hz, 2H), 7.34 (s, 1H), 6.81 (s, 1H), 5.45 (s, 2H), 5.35 (t, J = 7.9 Hz, 1H), 3.51 (s, 3H), 3.41 (d, J = 7.4 Hz, 2H), 1.75 (s, 6H). 13C NMR (75 MHz, Acetone) δ 177.13, 162.07, 160.17, 156.85, 137.58, 133.58, 131.48, 130.15, 129.92, 128.58, 125.66, 122.43, 118.53, 107.90, 102.45, 95.01, 56.43, 28.1, 25.77, 17.71. HRMS (ESI) m/z, calculated for C22H22ClO4 [M+H]+ 385.1201, found 385.1203.
4.7. General Procedure for Preparation of Chromones (II and V)
The series of compounds
5–
9 and
19–
22 (1 mmol) were suspended in triethyl orthoformate (TEOF) (0.5 mL), the resulting solutions were treated with 70% HClO
4 (0.01 mL, 0.17 mmol) slowly [
15]. The mixtures were then stirred at room temperature for 2 h, and ether (200 mL) was added, subsequently, the solution was filtered and the solid was purified by column chromatography with silica gel 60, eluting Hex:AcOEt (2:1) (
v/v). The synthesis of chromones (
10–
13) and prenylated chromones (
23–
26) was achieved in an overall yield of 30.4–70.2% and 8.21–40.1% respectively.
4.7.1. Compound (10)
7-Hydroxy-4H-chromen-4-one (10). Yield 56.9%, white solid, m.p.: 215 °C. 1H NMR (300 MHz, Acetone) δ 8.03 (d, J = 6.0 Hz, 1H), 7.97 (d, J = 8.7 Hz, 1H), 6.98 (d, J = 9.8 Hz, 1H), 6.89 (s, 1H), 6.19 (d, J = 6.0 Hz, 1H). 13C NMR (75 MHz, Acetone) δ 175.81, 162.51, 158.25, 155.53, 127.00, 117.95, 114.75, 112.21, 102.48. HRMS (ESI) m/z, calculated for C9H7O3 [M+H]+ 163.0389, found 163.0388.
4.7.2. Compound (11)
6-Hydroxy-4H-chromen-4-one (11). Yield 30.55%, white solid, m.p.: 242–243 °C. 1H NMR (300 MHz, DMSO) δ 10.07 (s, OH), 8.2 (d, J = 6.0 Hz, 1H), 7.50 (d, J = 9.0 Hz, 1H), 7.29 (d, J = 3.0 Hz, 1H), 7.22 (dd, J = 9.0, 3.0 Hz, 1H), 6.25 (d, J = 6.0 Hz, 1H). 13C NMR (75 MHz, DMSO) δ 176.47, 156.68, 154.89, 149.84, 125.23, 123.25, 119.97, 111.21, 107.58. HRMS (ESI) m/z, calculated for C9H7O3 [M+H]+ 163.0389, found 163.0399.
4.7.3. Compound (12)
5-Hydroxy-4H-chromen-4-one (12). Yield 40.1%, white solid, m.p.: 125–126 °C. 1H NMR (300 MHz, Acetone) δ 12.57 (s, 1H), 8.21 (d, J = 5.9 Hz, 1H), 7.64 (t, J = 8.4 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.78 (d, J = 8.2 Hz, 1H), 6.35 (d, J = 5.9 Hz, 1H). 13C NMR (75 MHz, Acetone) δ 183.03, 160.90, 157.80, 156.81, 135.72, 111.51, 111.14, 110.98, 107.16. HRMS (ESI) m/z, calculated for C9H7O3 [M+H]+ 163.0389, found 163.0389.
4.7.4. Compound (13)
7,8-Dihydroxy-4H-chromen-4-one (13). Yield 34.1%, white solid, m.p.: 265 °C. 1H NMR (300 MHz, MeOD) δ 8.11 (d, J = 5.9 Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 6.26 (d, J = 5.9 Hz, 1H). 13C NMR (75 MHz, MeOD) δ 178.61, 156.12, 150.59, 147.22, 132.94, 117.50, 115.44, 113.98, 110.88. HRMS (ESI) m/z, calculated for C9H7O4 [M+H]+ 179.0338 found 179.0338.
4.7.5. Compound (23)
7-Hydroxy-6-(3-methylbut-2-en-1-yl)-4H-chromen-4-one (23). Yield 17.32%, white solid. m.p.: 120–125 °C. 1H NMR (300 MHz, CDCl3) δ 8.73 (s, 1H), 7.96 (s, 1H), 7.79 (d, J = 6.0 Hz, 1H), 6.97 (s, 1H), 6.32 (d, J = 6.0 Hz, 1H), 5.35 (t, J = 7.3 Hz, 1H), 3.43 (d, J = 7.2 Hz, 2H), 1.74 (s, 6H). 13C NMR (75 MHz, CDCl3) δ 178.22, 160.98, 157.13, 155.31, 134.90, 128.19, 126.08, 120.98, 117.66, 112.18, 102.82, 28.85, 25.86, 17.91. HRMS (ESI) m/z, calculated for C14H15O3 [M+H]+ 231.1015, found 231.1023.
4.7.6. Compound (24)
7-Hydroxy-8-(3-methylbut-2-en-1-yl)-4H-chromen-4-one (24). Yield 21.14%, white solid. m.p.: 172–173 °C. 1H NMR (300 MHz, CDCl3) δ 8.44 (s, 1H), 7.96 (d, J = 8.8 Hz, 1H), 7.88 (d, J = 5.9 Hz, 1H), 7.04 (d, J = 8.8 Hz, 1H), 6.32 (d, J = 5.9 Hz, 1H), 5.26 (t, J = 7.2 Hz, 1H), 3.58 (d, J = 7.1 Hz, 2H), 1.83 (s, 3H), 1.71 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 178.51, 160.14, 156.21, 155.43, 134.13, 124.55, 120.92, 118.10, 115.37, 115.14, 112.02, 25.82, 22.28, 17.98. HRMS (ESI) m/z, calculated for C14H15O3 [M+H]+ 231.1015, found 231.1012.
4.7.7. Compound (25)
5-Hydroxy-6-(3-methylbut-2-en-1-yl)-4H-chromen-4-one (25). Yield 5.21%, white solid. m.p.: 235–236 °C. 1H NMR (300 MHz, CDCl3) δ 12.67 (s, 1H), 7.81 (d, J = 5.9 Hz, 1H), 7.42 (d, J = 8.7 Hz, 1H), 6.85 (d, J = 8.6 Hz, 1H), 6.26 (d, J = 5.9 Hz, 2H), 5.30 (dd, J = 14.6, 7.1 Hz, 1H), 3.36 (d, J = 7.2 Hz, 2H), 1.74 (d, J = 7.5 Hz, 6H). 13C RMN (75 MHz, CDCl3) δ 183.35, 158.90, 157.89, 156.22, 135.55, 133.55, 124.20, 121.56, 111.35, 111.10, 106.48, 27.06, 25.83, 17.85. HRMS (ESI) m/z, calculated for C14H15O3 [M+H]+ 231.1015, found 231.1001.
4.7.8. Compound (26)
7,8-Dihydroxy-6-(3-methylbut-2-en-1-yl)-4H-chromen-4-one (26). Yield 8.21%, white solid. m.p.: 255–258 °C. 1H NMR (300 MHz, Acetone) δ 7.86 (d, J = 6.0 Hz, 1H), 7,27 (s, 1H), 5.98 (d, J = 6.0 Hz, 1H), 5.26 (t, J = 7.4 Hz, 1H), 3.29 (d, J = 7.7 Hz, 2H), 1.60 (s, 6H). 13C NMR (75 MHz, Acetone) δ 175.96, 154.60, 148.54, 141.61, 132.59, 132.39, 126.80, 122.07, 117.58, 114.64, 111.78, 26.72, 25.04, 16.94. HRMS (ESI) m/z, calculated for C14H15O4 [M+H]+ 247.0964, found 247.0921.