3.1.2. Two-Step Reaction: Friedel–Crafts Acylation and Direct C-Alkylation (3d, 4a–g)
Friedel–Crafts acylation: Small amounts of phloroglucinol (0.05 mol) and anhydrous aluminum chloride (0.1 mol) were first dissolved in dichloromethane (50 mL) and kept heated for 1 h at 40 °C. Acyl chloride (0.05 mole) was added dropwise into the reaction mixture, refluxed for 8 h, and quenched with 0.05 mole of HCl upon completion of the reaction. After the reaction was completed, the reaction mixture was extracted with ethyl acetate and concentrated under reduced pressure. The residues were subjected to column chromatography using silica gel eluted with hexane/ethyl acetate (10:1) [
25]. Direct
C-alkylation: A well-mixed mixture of acylphloroglucinol (1 mmol), geranyl bromide or prenyl bromide (1 mmol), and anhydrous potassium carbonate (0.5 mmol) in dry methanol (3 mL) was refluxed for 8 h. After completion of the reaction, excess methanol was removed through high vacuum and the residues were extracted with ethyl acetate. The organic layers were combined, dried, and concentrated. Column chromatography over silica gel eluted with petroleum ether/ethyl acetate (10:1) gave geranylated/prenylated compounds [
11].
(E)-1-(3-(3,7-dimethylocta-2,6-dienyl)-2,4,6-trihydroxyphenyl)butan-1-one (3d). Light yellow solid (9.7%), m.p. 116–118 °C. 1H-NMR (500 MHz, Methanol-d4) d 5.89 (1H, s, H-4), 5.17 (1H, t, J = 6.5 Hz, H-2″), 5.05 (1H, t, J = 6.6 Hz, H-7″), 3.18 (2H, d, J = 7.0 Hz, H-1″), 3.01 (2H, t, J = 7.2 Hz, H-2′), 2.04 (2H, q, J = 7.4 Hz, H-6″), 1.93 (2H, t, J = 7.4 Hz, H-5″), 1.73 (3H, s, H-4″), 1.66–1.70 (2H, m, H-3′), 1.60 (3H, s, H-10″), 1.55 (3H, s, H-9″), 0.97 (3H, t, J = 7.4 Hz, H-4′). 13C-NMR (126 MHz, methanol-d4) 205.96 (C-1′), 163.55 (C-3) 162.14 (C-1), 160.01 (C-5), 133.27 (C-3″), 130.54 (C-8″), 124.09 (C-7″), 123.22 (C-2″), 106.63 (C-2), 103.85 (C-6), 93.43 (C-4), 45.46 (C-2′), 39.49 (C-5″), 26.30 (C-6″), 24.41 (C-10″), 20.65 (C-1″), 18.25 (C-9″), 16.27 (C-3′), 14.77 (C-4″), 13.0 (C-4′). DIP: m/z 332.15.
1-(2,4,6-trihydroxy-3-(3-methylbut-2-enyl)phenyl)ethanone (4a). Light yellow solid (12.5%), m.p. 164–166 °C. 1H-NMR (500 MHz, methanol-d4) d 5.89 (1H, s, H-4), 5.16 (1H, t, J = 7.1 Hz, H-2″), 3.16 (2H, d, J = 7.1 Hz, H-1″), 2.59 (3H, s, H-2′), 1.73 (3H, s, H-5″), 1.63 (3H, s, H-4″). 13C-NMR (126 MHz, Methanol-d4) d 203.14 (C-1′), 163.36 (C-3), 162.47 (C-1), 160.36 (C-5), 129.63 (C-3″), 123.09 (C-2″), 106.47 (C-2), 104.07 (C-6), 93.32 (C-4), 31.39 (C-2′), 24.51 (C-4″), 20.68 (C-1″), 16.40 (C-5″). DIP: m/z 236.10.
2-methyl-1-(2,4,6-trihydroxy-3-(3-methylbut-2 enyl)phenyl)propan-1-one (4b). Yellow solid (10.8%), m.p. 142–144 °C. 1H-NMR (500 MHz, methanol-d4) d 5.88 (1H, s, H-4), 5.16 (1H, t, J = 6.5 Hz, H-2″), 3.95–4.03 (1H, m, H-2′), 3.17 (2H, d, J = 7.1 Hz, H-1″), 1.73 (3H, s, H-4″), 1.63 (3H, s, H-5″), 1.12 (6H, d, J = 6.9 Hz, H-3′, 4′). 13C-NMR (126 MHz, Methanol-d4) 210.30 (C-1′), 163.85 (C-3), 161.98 (C-5), 159.58 (C-1), 129.60 (C-3″), 123.16 (C-2″), 106.71 (C-6), 103.07 (C-2), 93.53 (C-4), 38.48 (C-2′), 24.52 (C-5″), 20.78 (C-1″), 18.36 (C-3′, 4′), 16.41 (C-4″). DIP: m/z 264.10.
1-(2,4,6-trihydroxy-3-(3-methylbut-2-enyl)phenyl)propan-1-one (4c). Light brown solid (8.0%), m.p. 138–140 °C. 1H-NMR (500 MHz, methanol-d4) d 5.88 (1H, s, H-4), 5.16 (1H, t, J = 7.5 Hz, H-2″), 3.17 (2H, d, J = 7.1 Hz, H-1″), 3.05 (1H, q, J = 7.3 Hz, H-2′), 1.73 (3H, s, H-4″), 1.63 (3H, s, H-5″), 1.12 (3H, t, J = 7.3 Hz, H-3′). 13C-NMR (126 MHz, methanol-d4) 206.52 (C-1′), 163.40 (C-3), 162.04 (C-5), 160.03 (C-1), 129.61 (C-3″), 123.15 (C-2″), 106.55 (C-6), 103.66 (C-2), 93.38 (C-4), 36.58 (C-2′), 24.52 (C-5″), 20.73 (C-1″), 16.41 (C-4″), 7.94 (C-3′). DIP: m/z 250.10.
1-(2,4,6-trihydroxy-3-(3-methylbut-2-enyl)phenyl)butan-1-one (4d). Light yellow solid (9.1%), m.p. 138–140 °C. 1H-NMR (500 MHz, methanol-d4) d 5.88 (1H, s, H-4), 5.16 (1H, t, J = 7.1 Hz, H-2″), 3.16 (2H, d, J = 7.1 Hz, H-1″), 2.99–3.02 (2H, m, H-2′), 1.73 (3H, s, H-4″), 1.68 (2H, dd, J = 7.4, 14.8 Hz, H-3′), 1.63 (3H, s, H-5″), 0.97 (3H, t, J = 7.4 Hz, H-4′). 13C-NMR (126 MHz, methanol-d4) 205.92 (C-1′), 163.53 (C-3), 162.11 (C-1), 160.00 (C-5), 129.60 (C-3″), 123.15 (C-2″), 106.57 (C-2), 103.82 (C-6), 93.40 (C-4), 45.45 (C-2′), 24.51 (C-5″), 20.72 (C-1″), 18.21 (C-4″), 16.40 (C-3′), 12.98 (C-4′). DIP: m/z 264.10.
1-(2,4,6-trihydroxy-3-(3-methylbut-2-enyl)phenyl)pentan-1-one (4e). Light yellow solid (5.5%), m.p. 133–135 °C. 1H-NMR (500 MHz, methanol-d4) d 5.88 (1H, s, H-4), 5.16 (1H, t, J = 6.5 Hz, H-2″), 3.16 (2H, d, J = 7.1 Hz, H-1″), 3.01–3.04 (2H, m, H-2′), 1.73 (3H, s, H-5″), 1.60–1.63 (5H, m, H-3′, 4″), 1.35–1.41 (2H, m, H-4′), 0.94 (3H, t, J = 7.4 Hz, H-5′). 13C-NMR (126 MHz, methanol-d4) 206.14 (C-1′), 163.54 (C-3), 162.13 (C-1), 159.98 (C-5), 129.61 (C-3″), 123.14 (C-2″), 106.57 (C-2), 103.79 (C-6), 93.40 (C-4), 43.21 (C-2′), 27.16 (C-3′), 24.51 (C-5″), 22.31 (C-4′), 20.73 (C-1″), 16.41 (C-4″), 12.88 (C-5′). DIP: m/z 278.10.
Cyclohexyl(2,4,6-trihydroxy-3-(3-methylbut-2-enyl)phenyl)methanone (4f). Dark brown oil (6.5%). 1H-NMR (500 MHz, methanol-d4) d 5.87 (1H, s, H-4), 5.16 (1H, t, J = 7.2 Hz, H-2″), 3.70–3.74 (1H, m, H-2′), 3.16 (2H, d, J = 7.1 Hz, H-1″), 1.73–1.90 (4H, m, H-3′, 7′), 1.73 (3H, s, H-5″), 1.65 (3H, s, H-4″), 1.25–1.40 (6H, m, H-4′, 5′, 6′). 13C-NMR (126 MHz, methanol-d4) 209.39 (C-1′), 167.98 (C-3), 161.90 (C-5), 159.62 (C-1), 129.61 (C-3″), 123.16 (C-2″), 106.71 (C-2), 103.23 (C-6), 93.56 (C-4), 49.19 (C-2′), 29.39 (C-3′, 7′), 25.93 (C-4′, 5′, 6′), 24.51 (C-4″), 20.77 (C-1″), 16.41 (C-5″). DIP: m/z 304.10.
(E)-3-phenyl-1-(2,4,6-trihydroxy-3-(3-methylbut-2-enyl)phenyl)prop-2-en-1-one (4g). Yellow solid (13.9%), m.p. 203–205 °C. 1H-NMR (500 MHz, methanol-d4) d 7.49 (2H, d, J = 7.5 Hz, H-5′, 9′), 7.41 (2H, t, J = 7.5 Hz, H-6′, 8′), 7.36 (1H, d, J = 7.4 Hz, H-7′), 5.97 (1H, s, H-4), 5.43 (1H, d, J = 17.5 Hz, H-2′), 5.19 (1H, t, J = 7.1 Hz, H-2″), 3.20 (2H, d, J = 7.1 Hz, H-1″), 2.76 (1H, d, J = 17.5 Hz, H-3′), 1.75 (3H, s, H-5″), 1.65 (3H, s, H-4″). 13C-NMR (126 MHz, methanol-d4) 197.43 (C-1′), 166.02 (C-3), 162.50 (C-1), 162.38 (C-5), 140.63 (C-4′), 131.66 (C-3″), 129.72 (C-6′, 8′), 129.61 (C-7′), 127.36 (C-5′, 9′), 123.88 (C-2″), 109.83 (C-2), 103.25 (C-6), 95.48 (C-4), 80.46 (C-2′), 44.39 (C-3′), 25.99 (C-5″), 21.91 (C-1″), 17.88 (C-5″). DIP: m/z 323.95.
3.1.3. Three-Step Reaction: Friedel–Crafts Acylation, Direct C-Alkylation, and Methylation (5a, 5e, 6a, and 6e)
Methylation: A well-mixed mixture of geranylated/prenylated acylphloroglucinols (0.5 mmol) and K
2CO
3 (3 mmol), and 20 mL of dimethylformamide (DMF) were allowed to react, with constant stirring, for 20 min. Methyl iodide (2.3 mmol) was added dropwise into the reaction mixture and the mixture was heated for 9 h at 80 °C. Concentrated HCl (15 mL, 1 M) was added to quench the reaction, and it was stirred for another 10 min. The resultant products were extracted with dichloromethane (DCM) followed by cold water 3 times. The residue was purified using silica gel column chromatography (hexane:ethyl acetate = 10:1) [
26].
(E)-1-(3-(3,7-dimethylocta-2,6-dienyl)-2-hydroxy-4,6-dimethoxyphenyl)ethanone (5a). Light yellow solid (35.0%), m.p. 72–74 °C. 1H-NMR (500 MHz, methanol-d4) d 6.16 (1H, s, H-4), 5.11 (1H, t, J = 7.7 Hz, H-2″), 5.03 (1H, t, J = 7.9 Hz, H-7″), 3.93 (3H, s, 2′′′), 3.90 (3H, s, H-1′′′), 3.21 (2H, d, J = 7.1 Hz, H-1″), 2.58 (3H, s, H-2′), 2.02 (2H, q, J = 7.9 Hz, H-6″), 1.92 (2H, t, J = 7.9 Hz, H-5″), 1.73 (3H, s, H-4″), 1.59 (3H, s, H-10″), 1.54 (3H, s, H-9″). 13C-NMR (126 MHz, methanol-d4) 203.39 (C-1′), 163.67 (C-3), 162.82 (C-1), 162.11 (C-5), 133.67 (C-3″), 130.52 (C-8″), 124.01 (C-7″), 122.69 (C-2″), 108.98 (C-2), 105.31 (C-6), 86.08 (C-4), 54.71 (C-1′′′), 54.66 (C-2′′′), 39.43 (C-5″), 31.86 (C-2′), 26.27 (C-6″), 24.39 (C-10″), 20.57 (C-1″), 16.25 (C-9″), 14.71 (C-4″). DIP: m/z 332.20.
(E)-1-(3-(3,7-dimethylocta-2,6-dienyl)-2-hydroxy-4,6-dimethoxyphenyl)pentan-1-one (5e). Brown oil (46.6%). 1H-NMR (500 MHz, methanol-d4) d 6.16 (1H, s, H-4), 5.10–5.13 (1H, m, H-2″), 5.01–5.04 (1H, m, H-7″), 3.93 (3H, s, 2′′′), 3.90 (3H, s, H-1′′′), 3.21 (2H, d, J = 7.0 Hz, H-1″), 2.97–3.00 (2H, m, H-2′), 2.03 (2H, dd, J = 6.6, 14.0 Hz, H-6″), 1.92 (2H, t, J = 7.5 Hz, H-5″), 1.73 (3H, s, H-4″), 1.63 (2H, dd, J = 7.5, 14.9 Hz, H-3′), 1.59 (3H, s, H-10″), 1.54 (3H, s, H-9″), 1.39 (2H, td, J = 7.2, 14.6 Hz, H-3′), 0.95 (3H, t, J = 7.4 Hz, H-5′). 13C-NMR (126 MHz, methanol-d4) 207.68 (C-1′), 164.77 (C-3), 164.37 (C-1), 163.18 (C-5), 135.05 (C-3″), 131.96 (C-8″), 125.45 (C-7″), 124.17 (C-2″), 110.48 (C-2), 106.48 (C-6), 87.49 (C-4), 56.13 (C-1′′′), 56.09 (C-2′′′), 45.23 (C-2′), 40.89 (C-5″), 28.40 (C-3′), 27.70 (C-6″), 25.88 (C-10″), 23.73 (C-4′), 22.08 (C-1″), 17.73 (C-9″), 16.19 (C-4″), 14.41 (C-5′). DIP: m/z 374.10.
1-(2-hydroxy-4,6-dimethoxy-3-(3-methylbut-2-enyl)phenyl)ethanone (6a). Light yellow solid (9.1%), m.p. 97–99 °C. 1H-NMR (500 MHz, methanol-d4) d 5.95 (1H, s, H-4), 5.17 (1H, t, J = 6.3 Hz, H-2″), 3.88 (3H, s, 2′′′), 3.88 (3H, s, H-1′′′), 3.26 (2H, d, J = 6.8 Hz, H-1″), 2.60 (3H, s, H-2′), 1.76 (3H, s, H-5″), 1.66 (3H, s, H-4″). 13C-NMR (126 MHz, methanol-d4) 203.26 (C-1′), 163.52 (C-3), 163.20 (C-1), 161.68 (C-5), 131.31 (C-3″), 122.66 (C-2″), 109.76 (C-2), 105.99 (C-6), 85.84 (C-4), 55.45 (C-1′′′), 55.33 (C-2′′′), 33.08 (C-2′), 25.76 (C-4″), 21.27 (C-1″), 17.71 (C-5″). DIP: m/z 264.10.
1-(2-hydroxy-4,6-dimethoxy-3-(3-methylbut-2-enyl)phenyl)pentan-1-one (6e). Light yellow solid (38.0%), m.p. 84–86 °C. 1H-NMR (500 MHz, methanol-d4) d 5.95 (1H, s, H-4), 5.18 (1H, t, J = 7.0 Hz, H-2″), 3.89 (3H, s, 2′′′), 3.88 (3H, s, H-1′′′), 3.26 (2H, d, J = 7.0 Hz, H-1″), 2.96–2.99 (2H, m, H-2′), 1.76 (3H, s, H-5″), 1.60–1.66 (5H, m, H-3′, 4″), 1.35–1.42 (2H, m, H-4′), 0.94 (3H, t, J = 7.3 Hz, H-5′). 13C-NMR (126 MHz, methanol-d4) 206.31 (C-1′), 163.62 (C-3), 162.88 (C-1), 161.42 (C-5), 131.39 (C-3″), 122.69 (C-2″), 109.96 (C-2), 106.09 (C-6), 85.82 (C-4), 55.45 (C-1′′′), 55.34 (C-2′′′), 44.20 (C-2′), 29.70 (C-3′), 27.07 (C-5″), 25.83 (C-4′), 22.66 (C-1″), 21.32 (C-4″), 14.04 (C-5′). DIP: m/z 306.05.