4. METODOLOGÍA
4.5. DESCRIPCIÓN Y APLICACIÓN DE LOS INSTRUMENTOS DE
4.5.1. Modelo de Calidad Total para Gobiernos Municipales
1,3-dimethoxy-5-methylbenzene (3.16). A solution of orcinol (1.00 g, 8.12 mmol) in acetone (20 mL) was added to a round bottom flask. Then potassium carbonate (4.3 eq., 4.86 g, 35.24 mmol) was added to the flask. After that methyl iodide (4.3 eq., 2.20 mL, 35.24 mmol) was added to the flask, and the reaction mixture was stirred and refluxed. The reaction was monitored by TLC and GC-MS, and was continued until the starting material was consumed. The reaction mixture was concentrated in vacuo and the residue was suspended in water and acidified by 1 M HCl, followed by extraction with EtOAc three times. The combined organic layer was washed with deionised water and dried over Na2SO4 and concentrated
in vacuo. The residue was subjected to flash column chromatography on silica using 25% EtOAc in petroleum ether as eluent to return the title compound as a viscous yellow oil (95%, 1.17 g, 7.70 mmol).241H NMR (400 MHz, CDCl3): δ 2.32 (3H, s, 5-Me), 3.78 (6H, s,
1,3-OMe), 6.30 (1H, brs, 2-H), 6.35 (2H, brs, 4,6-H). 13C NMR (100 MHz, CDCl3): δ 21.9 (5-
Me), 55.3 (1,3-OMe), 97.6 (2-C), 107.2 (4,6-C), 140.3 (5-C), 160.8 (1, 3-C). EIMS: m/z 152 [M]·+ (100), 123 (33).
2-bromo-1,5-dimethoxy-3-methylbenzene (3.17). A solution of compound 3.16 (1.07 g, 7.03 mmol) in dichloromethane (15 mL) was added to a round bottom flask. Then N-Bromosuccinimide (NBS) (1.4 eq., 1.75 g, 9.83 mmol) was added to the flask, and the reaction mixture was stirred and refluxed for 4 h. Then the reaction mixture was filtered, the filtrate was concentrated in vacuo and the residue was subjected to flash column chromatography on silica using 5% EtOAc in petroleum ether as eluent to return the title compound as a low-melting solid (51%, 0.83 g, 3.58 mmol).241H NMR (400 MHz, CDCl3): δ 2.39 (3H, s, 3-
Me), 3.78 (3H, s, 5-OMe), 3.86 (3H, s, 1-OMe), 6.34 (1H, brs, 6-H), 6.43 (1H, brs, 4-H). 13C
NMR (100 MHz, CDCl3): δ 23.7 (3-Me), 55.6 (5-OMe), 56.4 (1-OMe), 97.3 (6-C), 105.2 (2- 1 3 5 OMe OMe 5 1 3 OMe OMe Br
C), 107.3 (4-C), 139.9 (3-C), 156.7 (5-C), 159.4 (1-C). EIMS: m/z 232 [M+2]·+ (97), 230 [M]·+
(100), 189 (19), 187 (23), 149 (41).
(3’-methylbut-2’-en-1’-yl)benzene (3.19). A solution of phenylboronic acid (100 mg, 0.57 mmol) in anhydrous toluene (5 mL) was added to a oven-dried 2-neck round bottom flask. Then prenyl bromide (1.0 eq., 66 μl, 0.57 mmol) and potassium carbonate (1.0 eq., 79 mg, 0.57 mmol) were added to the flask, and the reaction mixture was stirred and refluxed for 6 h under an argon atmosphere. The reaction mixture was diluted with diethyl ether (5 mL) and washed with deionised water twice. The organic layer was dried over Na2SO4 and
concentrated in vacuo and the residue was subjected to flash column chromatography on silica using 10% EtOAc in petroleum ether as eluent to return the title compound as a colourless oil (6%, 5 mg, 0.03 mmol).271H NMR (400 MHz, CDCl3): δ 1.73 (3H, s, 4’ or
5’-H), 1.75 (3H, s, 4’ or 5’-H), 3.35 (2H, d, J= 6.9 Hz, 1’-H), 5.34 (1H, t, J= 6.9 Hz, 2’-H), 7.17-7.45 (5H, m, 1, 3,4,5,6-H). EIMS: m/z 146 [M]·+ (17), 131 (100), 115 (16), 91 (83).
1’-(2,4-dimethoxy-6-methylphenyl)-3’-methylbut-2’-en-1’-one
(3.21). A solution of 3-methylcrotonic acid (1.00 g, 10.00 mmol) in anhydrous DCM (50 mL) was added to a oven-dried 2-neck round bottom flask. Then trifluoroacetic anhydride (TFAA) (2.0 eq., 2.80 mL, 20.00 mmol) was added dropwise to the flask at 0 °C, and the reaction mixture was stirred at room temperature under an argon atmosphere. The reaction was monitored by GC-MS, and was continued until the starting material was consumed. The reaction mixture was concentrated in vacuo without further purification to return an anhydride 3.20 as a yellow oil (68%, 615 mg, 3.38 mmol). This product was used immediately for the next reaction. A solution of anhydride 3.20 (610 mg, 3.35 mmol) in anhydrous toluene (5 mL) was added to a oven-dried 2-neck round bottom flask. Then compound 3.16 (0.2 eq., 125 mg, 0.82 mmol) and anhydrous p-toluenesulfonic acid were added to the flask, and the reaction mixture was stirred at room temperature under an argon atmosphere. The reaction was monitored by TLC and GC-MS, and was continued until compound 3.16 was consumed. The reaction mixture was washed with potassium carbonate aqueous solution, the organic layer was dried over Na2SO4 and concentrated
in vacuo. The residue was subjected to flash column chromatography on silica using 10% EtOAc in petroleum ether as eluent to return the title compound as a viscous yellow oil
1 3 5 1' 3' 5' 5 3 1 OMe OMe 1' 3' 5' O
(50%, 95 mg, 0.41 mmol). 1H NMR (400 MHz, CDCl3): δ 1.91 (3H, s, 4’-H), 2.14 (3H, s, 5’-
H), 2.22 (3H, s, 6-Me), 3.76 (3H, s, 2-OMe), 3.80 (3H, s, 4-OMe), 6.26 (1H, s, 2’-H), 6.31 (2H, brs, 3,5-H). 13C NMR (100 MHz, CDCl3): δ 19.8 (6-Me), 20.8 (5’-C), 28.1 (4’-C), 55.5
(2-OMe), 55.9 (4-OMe), 96.3 (3-C), 107.1 (5-C), 125.7 (1-C), 127.1 (2’-C), 137.6 (6-C), 154.4 (3’-C), 157.9 (2-C), 160.9 (4-C), 196.4 (1’-C). EIMS: m/z 234 [M]·+ (36), 219 (100),
203 (24), 191 (26), 179 (47), 83 (19). HREIMS: m/z 234.1257 (calculated for C14H18O3
234.1256).
1’-(2,6-dimethoxy-4-methylphenyl)-3’-methylbut-2’-en-1’-one
(3.22). This compound was isolated from the same reaction mixture generating 3.21 as a viscous yellow oil (16%, 31 mg, 0.13 mmol). 1H
NMR (400 MHz, CDCl3): δ 1.90 (3H, s, 4’-H), 2.17 (3H, s, 5’-H), 2.34
(3H, s, 4-Me), 3.76 (6H, s, 2,6-OMe), 6.24 (1H, s, 2’-H), 6.36 (2H, s, 3,5-H). 13C NMR (100
MHz, CDCl3): δ 20.9 (5’-C), 22.4 (4-Me), 28.0 (4’-C), 56.0 (2,6-OMe), 105.1 (3,5-C), 119.3
(1-C), 126.9 (2’-C), 140.9 (4-C), 154.6 (3’-C), 157.1 (2,6-C), 194.0 (1’-C). EIMS: m/z 234 [M]·+ (40), 219 (23), 203 (100), 179 (70), 83 (34). HREIMS: m/z 234.1256 (calculated for
C14H18O3 234.1256).
1’,1’’-(4,6-dimethoxy-2-methyl-1,3-phenylene)bis(3’- methylbut-2’-en-1’-one) (3.23). This compound was isolated from the same reaction mixture generating 3.21 as a viscous yellow oil (39%, 101 mg, 0.32 mmol). 1H NMR (400 MHz, CDCl3):
δ 1.90 (6H, s, 4’,4’’-H), 2.05 (3H, s, 2-Me), 2.14 (6H, s, 5’,5’’-H), 3.79 (6H, s, 4,6-OMe), 6.20 (2H, s, 2’,2’’-H), 6.31 (1H, s, 5-H). 13C NMR (100 MHz, CDCl3): δ 16.1 (2-Me), 20.9 (5’,5’’-C), 28.0 (4’,4’’-C), 55.9 (4,6-OMe), 93.1 (5-C), 126.1 (1,3-C), 126.8 (2’,2’’-C), 133.6 (2-C), 155.4 (3’,3’’-C), 157.5 (4,6-C), 196.2 (1’,1’’-C). EIMS: m/z 316 [M]·+ (36), 301 (100), 273 (23), 261 (33), 245 (63), 219 (20), 83 (48). HREIMS: m/z 316.1678 (calculated for C19H24O4 316.1675). 1’-(2,4-dimethoxy-6-methylphenyl)-3’-methylbutan-1’-one
(3.24). A solution of compound 3.21 (131 mg, 0.56 mmol) in anhydrous ethanol (8 mL) was added to a oven-dried 2-neck round bottom flask. Then triethylsilane (2.0 eq., 182 μl, 1.12 mmol) and palladium (II) chloride (14%, 14 mg, 0.08 mmol) were added to the flask, and the reaction mixture was stirred overnight under an argon atmosphere. The reaction
3 1 5 OMe OMe 1' 3' 5' O 1 5 3 OMe OMe 1' 3' 5' O 1'' 3'' 5'' O 5 3 1 OMe OMe 1' 3' 5' O
was quenched by adding water, the reaction mixture was extracted with DCM twice. The combined organic layer was dried over Na2SO4 and concentrated in vacuo. The
residue was subjected to flash column chromatography on silica using 30% EtOAc in petroleum ether as eluent to return the title compound as a colourless oil (45%, 59 mg, 0.25 mmol). 1H NMR (400 MHz, CDCl3): δ 0.95 (3H, s, 4’ or 5’-H), 0.96 (3H, s, 4’ or 5’-H), 2.19-2.29 (1H, m, 3’-H), 2.23 (3H, s, 6-Me), 2.65 (2H, d, J= 6.8 Hz, 2’-H), 3.78 (3H, s, 2- OMe), 3.80 (3H, s, 4-OMe), 6.30 (1H, d, J= 2.2 Hz, 3-H), 6.31 (1H, d, J= 2.2 Hz, 5-H). 13C NMR (100 MHz, CDCl3): δ 19.9 (6-Me), 22.9 (4’,5’-C), 24.7 (3’-C), 54.0 (2’-C), 55.5 (4-OMe), 55.6 (2-OMe), 96.2 (3-C), 107.3 (5-C), 124.7 (1-C), 137.7 (6-C), 158.3 (2-C), 161.1 (4-C), 207.2 (1’-C). EIMS: m/z 236 [M]·+ (11), 221 (4), 193 (14), 179 (100), 136 (7). HREIMS: m/z 236.1411 (calculated for C14H20O3 236.1412). 2-isopentyl-1,5-dimethoxy-3-methylbenzene (3.25). This compound was isolated from the same reaction mixture generating 3.24 as a viscous yellow oil (46%, 57 mg, 0.25 mmol).
1H NMR (400 MHz, CDCl3): δ 0.94 (3H, s, 4’ or 5’-H), 0.96 (3H, s, 4’ or 5’-H), 1.23-1.27 (2H,
m, 2’-H), 1.57-1.65 (1H, m, 3’-H), 2.28 (3H, s, 3-Me), 2.52-2.56 (2H, m, 1’-H), 3.78 (6H, s, 1,5-OMe), 6.32 (2H, brs, 4,6-H). 13C NMR (100 MHz, CDCl3): δ 19.9 (3-Me), 22.7 (4’,5’-C),
23.8 (1’-C), 28.7 (3’-C), 38.9 (2’-C), 55.4 (1 or 5-OMe), 55.6 (1 or 5-OMe), 96.2 (6-C), 106.5 (4-C), 122.7 (2-C), 137.7 (3-C), 158.1 (1 or 5-C), 158.5 (1 or 5-C). EIMS: m/z222 [M]·+ (34),
199 (9), 179 (8), 165 (100), 149 (26), 135 (30). HREIMS: m/z 222.1620 (calculated for C14H22O2 222.1620).
3-methoxy-5-methylphenol (3.26). A solution of orcinol (5.00 g, 40.30 mmol) in acetone (150 mL) was added to a round bottom flask. Then potassium carbonate (1.1 eq., 6.11 g, 44.30 mmol) was added to the flask. After that methyl iodide (1.1 eq., 2.80 mL, 44.30 mmol) was added to the flask, and the reaction mixture was stirred and refluxed for 2 h. The reaction mixture was concentrated in vacuo and the residue was suspended in water and acidified by 1 M HCl, then extracted with EtOAc three times. The combined organic layer was washed with deionised water and dried over Na2SO4 and concentrated in vacuo. The residue was
subjected to flash column chromatography on silica using 30% EtOAc in petroleum ether as eluent to return the title compound as a viscous yellow oil (31%, 1.73 g, 12.58 mmol).421H NMR (400 MHz, CDCl3): δ 2.27 (3H, s, 5-Me), 3.76 (3H, s, 3-OMe), 5.12 (1H,
5 1 3 OMe OMe 1' 3' 5' 1 3 5 OH OMe
brs, 1-OH), 6.24 (1H, dd, J= 2.3, 1.8 Hz, 2-H), 6.27 (1H, brs, 6-H), 6.33 (1H, brs, 4-H). 13C
NMR (100 MHz, CDCl3): δ 21.7 (5-Me), 55.4 (3-OMe), 98.8 (2-C), 107.5 (4-C), 108.8 (6-C),
140.8 (5-C), 156.6 (1-C), 160.9 (3-C). EIMS: m/z 138 [M]·+ (100), 121 (8), 109 (33).
1-(allyloxy)-3-methoxy-5-methylbenzene (3.27). A solution of compound 3.26 (1.73 g, 12.58 mmol) in acetone (50 mL) was added to a round bottom flask. Then potassium carbonate (1.5 eq., 2.60 g, 18.87 mmol) and that allyl bromide (1.5 eq., 1.60 mL, 18.87 mmol) were added to the flask, and the reaction mixture was stirred and refluxed for 6 h. The reaction mixture was concentrated in vacuo, the residue was suspended in water and extracted with EtOAc three times. The combined organic layer was washed with deionised water and dried over Na2SO4 and concentrated in vacuo. The residue was
subjected to flash column chromatography on silica using 30% EtOAc in petroleum ether as eluent to return the title compound as a viscous yellow oil (92%, 2.06 g, 11.59 mmol).311H NMR (400 MHz, CDCl3): δ 2.30 (3H, s, 5-Me), 3.77 (3H, s, 3-OMe), 4.50 (2H,
d, J= 5.6 Hz, 1’-H), 5.28 (1H, d, J= 10.5 Hz, 3’-Ha), 5.40 (1H, d, J= 17.3 Hz, 3’-Hb), 6.00- 6.10 (1H, m, 2’-H), 6.31 (1H, dd, J= 2.3, 2.1 Hz, 2-H), 6.35 (2H, brs, 4,6-H). 13C NMR (100
MHz, CDCl3): δ 22.0 (5-Me), 55.4 (3-OMe), 68.9 (1’-C), 98.4 (2-C), 107.5 (4 or 6-C), 108.0
(4 or 6-C), 117.7 (3’-C), 133.5 (2’-C), 140.3 (5-C), 159.8 (1-C), 160.8 (3-C). EIMS: m/z 178 [M]·+ (100), 163 (36), 135 (25), 123 (11), 109 (36).
2-allyl-5-methoxy-3-methylphenol (3.28). The neat compound
3.27 (2.06 g, 11.59 mmol) was rapidly heated up to 220 °C in a round bottom flask under an argon atmosphere. The reaction was monitored by TLC, and was continued until the starting material was consumed. The reaction mixture was recovered after it cooled down to room temperature, then was subjected to flash column chromatography on silica using 10% EtOAc in petroleum ether as eluent to return the title compound as a viscous yellow oil (19%, 401 mg, 2.25 mmol).311H NMR (400 MHz, CDCl3): δ 2.26 (3H, s, 3-Me), 3.36 (2H, dt, J= 5.8, 1.8 Hz, 1’- H), 3.75 (3H, s, 5-OMe), 4.93 (1H, brs, 1-OH), 5.00-5.09 (2H, m, 3’-H), 5.90-6.00 (1H, m, 2’-H), 6.28 (1H, d, J= 2.5 Hz, 4 or 6-H), 6.37 (1H, d, J= 2.5 Hz, 4 or 6-H). 13C NMR (100 MHz, CDCl3): δ 20.1 (3-Me), 30.2 (1’-C), 55.5 (5-OMe), 99.6 (6-C), 108.7 (4-C), 115.4 (3’-C), 116.1 (2-C), 136.1 (2’-C), 139.0 (3-C), 155.1 (1-C), 158.7 (5-C). EIMS: m/z178 [M]·+ (100), 163 (56), 151 (58), 135 (28), 117 (13), 91 (28). 1 3 5 O OMe 1' 3' 5 1 3 OMe OH 1' 3'
6-methoxy-2,4-dimethyl-2,3-dihydrobenzofuran (3.29). This compound was isolated from the same reaction mixture generating
3.28 as a viscous yellow oil (16%, 325 mg, 1.82 mmol). 1H NMR (400
MHz, CDCl3): δ 1.46 (3H, d, J= 6.2 Hz, 2-Me), 2.19 (3H, s, 4-Me), 2.63-
2.68 (1H, m, 3-Ha), 3.15-3.21 (1H, m, 3-Hb), 3.75 (3H, s, 6-OMe), 4.90-4.98 (1H, m, 2-H), 6.22 (1H, d, J= 2.3 Hz, 5 or 7-H), 6.23 (1H, d, J= 2.3 Hz, 5 or 7-H). 13C NMR (100 MHz,
CDCl3): δ 19.4 (4-Me), 22.1 (2-Me), 35.6 (3-C), 55.6 (6-OMe), 80.3 (2-C), 93.6 (7-C), 106.8
(5-C), 118.1 (4a-C), 135.1 (4-C), 160.4 (6,7a-C). EIMS: m/z 178 [M]·+ (100), 163 (45), 151
(16), 135 (19), 119 (7), 91 (19). HREIMS: m/z 178.0994 (calculated for C11H14O2 178.0994).
2-allyl-3-methoxy-5-methylphenol (3.30). This compound was isolated from the same reaction mixture generating 3.28 as a viscous yellow oil (34%, 701 mg, 3.94 mmol).311H NMR (400 MHz, CDCl3): δ
2.29 (3H, s, 5-Me), 3.43 (2H, d, J= 6.1 Hz, 1’-H), 3.80 (3H, s, 3-OMe), 4.97 (1H, brs, 1-OH), 5.05-5.13 (2H, m, 3’-H), 5.92-6.02 (1H, m, 2’-H), 6.33 (2H, brs, 4,6-H). 13C NMR (100 MHz, CDCl3): δ 21.7 (5-Me), 27.3 (1’-C), 55.9 (3-OMe), 104.5 (4 or 6-C), 109.6 (4 or 6-C), 110.6 (2-C), 115.4 (3’-C), 136.7 (2’-C), 137.9 (5-C), 155.1 (1-C), 158.1 (3-C). EIMS: m/z 178 [M]·+ (100), 149 (42), 135 (36), 121 (44), 91 (33). 2’-(2-hydroxy-4-methoxy-6- methylphenyl)acetaldehyde (3.31). A solution of compound 3.28 (82 mg, 0.46 mmol) in DCM/MeOH (1:1) (15 mL) was added to a round bottom flask. Then O2/O3 (30:70) stream was bubbled into the solution for 10
min with the flow rate 1 L/min at -78 °C, then N2 stream was bubbled for 10 min to
remove O3 residue. After that, dimethyl sulfide (1.3 eq., 46 μl, 0.59 mmol) was added
dropwise into the solution and the reaction mixture was stirred for 0.5 h at room temperature. The reaction mixture was concentrated in vacuo and the residue was subjected to flash column chromatography on silica using 30% EtOAc in petroleum ether as eluent to return the title compound as a viscous yellow oil (21%, 17.2 mg, 0.10 mmol). This compound is represented as a mixture of aldehyde and semi-acetal. 1H NMR (400
MHz, CDCl3): δ 2.21 (3H, s, 6-Me), 2.89 (1H, dd, J= 16.2, 2.0 Hz, 2’’-Ha), 3.10 (2H, d, J= 7.0 Hz, 2’-H), 3.23 (1H, dd, J= 16.2, 6.5 Hz, 2’’-Hb), 3.36 (1H, d, J= 5.4 Hz, 1’’-OH), 3.75 (3H, s, 4-OMe), 6.07 (1H, m, 1’’-H), 6.29 (2H, brs, 3,5-H), 9.77 (1H, s, 1’-H). 13C NMR (100 4a 7a 7 6 5 4 OMe 3 2 O 6 1 2 3 4 5 OH OMe 1' 2' 3' 5 4 3 2 1 6 OMe OH 2' 1' O OMe 2'' 1'' O HO
MHz, CDCl3): δ 19.3 (6-Me), 36.4 (2’ and 2’’-C), 55.6 (4-OMe), 94.1 (1’’-C), 101.6 (3 or 5-
C), 107.9 (3 or 5-C), 115.8 (1-C), 135.3 (6-C), 158.5 (4-C), 160.5 (2-C), 198.2 (1’-C). EIMS:
m/z 180 [M]·+ (30), 151 (100), 137 (3), 123 (6), 91 (11).
2-allyl-1,5-dimethoxy-3-methylbenzene (3.32). A solution of compound 3.28 (500 mg, 2.81 mmol) in acetone (15 mL) was added to a round bottom flask. Then potassium carbonate (1.5 eq., 582 mg, 4.22 mmol) and methyl iodide (3.0 eq., 525 μl, 8.43 mmol) were added to the flask, and the reaction mixture was stirred and refluxed overnight. The reaction mixture was concentrated in vacuo, then the residue was suspended in water and extracted with EtOAc three times. The combined organic layer was dried over Na2SO4
and concentrated in vacuo, and the residue was subjected to flash column chromatography on silica using 15% EtOAc in petroleum ether as eluent to return the title compound as a viscous yellow oil (95%, 513 mg, 2.67 mmol).311H NMR (400 MHz,
CDCl3): δ 2.28 (3H, s, 3-Me), 3.35 (2H, m, 1’-H), 3.80 (6H, s, 1,5-OMe), 4.88-4.96 (2H, m,
3’-H), 5.84-5.95 (1H, m, 2’-H), 6.35 (2H, brs, 4,6-H). 13C NMR (100 MHz, CDCl3): δ 19.9 (3-
Me), 30.0 (1’-C), 55.4 (1 or 5-OMe), 55.8 (1 or 5-OMe), 96.3 (6-C), 106.7 (4-C), 114.1 (3’- C), 119.0 (2-C), 136.8 (2’-C), 138.6 (3-C), 158.5 (1 or 5-C), 158.7 (1 or 5-C). EIMS: m/z 192 [M]·+ (100), 177 (65), 165 (47), 135 (41), 115 (13), 91 (28).
2’-(2,4-dimethoxy-6-methylphenyl)-1’-methoxyethan-1’-ol
(3.33). A solution of compound 3.32 (135 mg, 0.70 mmol) in DCM/MeOH (1:1) (15 mL) was added to a round bottom flask. Then O2/O3 (30:70) stream was bubbled into the solution for 10 min with the flow rate
1 L/min at -78 °C, then N2 stream was bubbled for 10 min to remove O3 residue. After
that, dimethyl sulfide (1.3 eq., 72 μl, 0.91 mmol) was added dropwise into the solution and the reaction mixture was stirred for 0.5 h at room temperature. The reaction mixture was concentrated in vacuo, and the residue was subjected to flash column chromatography on silica using 30% EtOAc in petroleum ether as eluent to return the title compound as a viscous yellow oil (28%, 45 mg, 0.20 mmol). 1H NMR (400 MHz,
CDCl3): δ 2.31 (3H, s, 6-Me), 2.86 (1H, dd, J= 14.5, 4.0 Hz, 2’-Ha), 3.18 (1H, dd, J= 14.5,
7.8 Hz, 2’-Hb), 3.49 (3H, s, 1’-OMe), 3.79 (3H, s, 4-OMe), 3.85 (3H, s, 2-OMe), 4.75-4.79 (1H, m, 1’-H), 6.37 (1H, d, J= 2.6 Hz, 3 or 5-H), 6.38 (1H, d, J= 2.6 Hz, 3 or 5-H), 8.90 (1H, s, 1’-OH). 13C NMR (100 MHz, CDCl3): δ 20.4 (6-Me), 28.5 (2’-C), 55.4 (4-OMe), 56.0 (1’-
5 1 3 OMe OMe 1' 3' 5 3 1 OMe OMe 1' HO MeO
OMe), 56.1 (2-OMe), 96.6 (3-C), 107.5 (5-C), 107.7 (1’-C), 115.5 (1-C), 139.5 (6-C), 158.7 (4-C), 159.2 (2-C). ESIMS: m/z 265 [M+K]+ (19), 247 (19), 233 (22), 209 (14), 193 (21), 165
(100).
3-(allyloxy)-5-methylphenol (3.34). A solution of orcinol (1.00 g, 8.06 mmol) in acetone (30 mL) was added to a round bottom flask. Then potassium carbonate (1.3 eq., 1.45 g, 10.48 mmol) was added to the solution. After that allyl bromide (1.3 eq., 888 μl, 10.48 mmol) was added to a dropping funnel contaning 10 mL acetone, and added dropwise to the flask, and the reaction mixture was stirred and refluxed under an argon atmosphere. The reaction was monitored by TLC and GC-MS and was continued until the starting material was consumed. The reaction mixture was concentrated in vacuo, then the residue was suspended in water and acidified by 0.1 M HCl, then extracted with EtOAc three times. The combined organic layer was washed with deionised water and dried over Na2SO4
and concentrated in vacuo, the residue was subjected to flash column chromatography on silica using 25% EtOAc in petroleum ether as eluent to return the title compound as a sticky yellow oil (67%, 595 mg, 3.62 mmol). 1H NMR (400 MHz, CDCl3): δ 2.26 (3H, s, 5-
Me), 4.48 (2H, dt, J= 5.3, 1.5 Hz, 1’-H), 5.29 (1H, dt, J= 10.5, 1.5 Hz, 3’-Ha), 5.41 (1H, dt, J= 17.3, 1.5 Hz, 3’-Hb), 5.99-6.09 (1H, m, 2’-H), 6.30 (2H, m, 2, 6-H), 6.37 (1H, brs, 4-H). 13C NMR (100 MHz, CDCl3): δ 21.6 (5-Me), 69.0 (1’-C), 99.6 (2-C), 108.4 (4-C), 109.2 (6- C), 117.9 (3’-C), 133.2 (2’-C), 140.7 (5-C), 156.4 (1-C), 159.7 (3-C). EIMS: m/z 164 [M]·+ (100), 149 (47), 121 (39), 109 (29), 95 (31), 77 (24). HREIMS: m/z 164.0837 (calculated for C10H12O2 164.0837).
4-allyl-5-methylbenzene-1,3-diol (3.35). A solution of compound
3.34 (595 mg, 3.62 mmol) in N,N-diethylaniline (1 mL) was added to a reaction vessel. Then the solution was heated up to 250 °C by microwave followed by the procedure (250 W, ramp 5 min) and kept 250 °C for 20 min. The reaction mixture was diluted by EtOAc (50 mL) after cooling down to the room temperature, then washed with 1 M HCl twice. The organic layer was washed with brine and dried over Na2SO4 before concentration in vacuo, the residue was subjected to flash
column chromatography on silica using 30% EtOAc in petroleum ether as eluent to return the title compound as a viscous colourless oil (53%, 316 mg, 1.93 mmol). 1H NMR
(400 MHz, CDCl3): δ 2.21 (3H, s, 5-Me), 3.33 (2H, d, J= 5.8 Hz, 1’-H), 4.98-5.06 (2H, m, 3’- 1 3 5 OH O 1' 3' 1 3 5 OH OH 1' 3'
H), 5.88-5.98 (1H, m, 2’-H), 6.22 (1H, d, J= 2.3 Hz, 2-H), 6.28 (1H, d, J= 2.3 Hz, 6-H). 13C
NMR (100 MHz, CDCl3): δ 19.8 (5-Me), 30.1 (1’-C), 101.1 (2-C), 110.0 (6-C), 115.3 (3’-C),
116.4 (4-C), 136.1 (2’-C), 139.3 (5-C), 154.4 (1-C), 155.0 (3-C). EIMS: m/z164 [M]·+ (100),
153 (19), 149 (49), 137 (50), 123 (34), 91 (13), 77 (16). HREIMS: m/z 164.0837 (calculated for C10H12O2 164.0837).
2,4-dimethyl-2,3-dihydrobenzofuran-6-ol (3.36). This compound was isolated from the same reaction mixture generating 3.35 as a pale yellow solid (5%, 30 mg, 0.18 mmol). 1H NMR (400 MHz, CDCl3): δ 1.45
(3H, d, J= 6.3 Hz, 2-Me), 2.16 (3H, s, 4-Me), 2.61-2.64 (1H, m, 3-Ha), 3.12-3.18 (1H, m, 3-Hb), 4.89-4.97 (1H, m, 2-H), 6.13 (1H, d, J= 1.9 Hz, 7-H), 6.14 (1H, d,
J= 1.9 Hz, 5-H). 13C NMR (100 MHz, CDCl3): δ 19.2 (4-Me), 22.1 (2-Me), 35.6 (3-C), 80.4
(2-C), 95.0 (7-C), 108.0 (5-C), 118.3 (4a-C), 135.4 (4-C), 156.0 (6-C), 160.5 (7a-C). EIMS:
m/z 164 [M]·+ (100), 149 (56), 137 (19), 121 (28), 91 (19). HREIMS: m/z 164.0836
(calculated for C10H12O2 164.0837).
2-allyl-5-methylbenzene-1,3-diol (3.37). This compound was isolated from the same reaction mixture generating 3.33 as a viscous yellow oil (31%, 185 mg, 1.13 mmol).43 1H NMR (400 MHz, CDCl3): δ 2.22 (3H, s, 5-Me), 3.44 (2H, dt, J= 6.0, 1.8 Hz, 1’-H), 5.11-5.19 (2H, m, 3’-H), 5.95-5.05 (1H, m, 2’-H), 6.26 (2H, s, 4,6-H). 13C NMR (100 MHz, CDCl3): δ 21.3 (5-Me), 27.5 (1’-C), 108.9 (2-C), 109.3 (4,6-C), 116.1 (3’-C), 116.4 (6-C), 136.3 (2’-C), 138.2 (5-C), 154.9 (1,3-C). EIMS: m/z 164 [M]·+ (100), 149 (39), 137 (36), 121 (30), 91 (20). HREIMS: m/z 164.0836 (calculated for C10H12O2 164.0837). 5-methyl-2-(3’-methylbut-2’-en-1’-yl)benzene-1,3-diol (3.1). A solution of compound 3.37 (51 mg, 0.31 mmol) in anhydrous trimethylethylene solution (2M in THF, 100 eq., 15.5 mL, 31 mmol) was added to a oven-dried and air-free 2-neck round bottom flask, the solution at 0 °C was then exposed to a stream of argon. After that, Grubb’s 2nd generation catalyst (5%,
13 mg, 0.02 mmol) was added, and the reaction mixture was stirred at room temperature under an argon atmosphere. The reaction was monitored by TLC and GC- MS, and was continued until the starting material was consumed. The reaction mixture was concentrated in vacuo and the residue was subjected to flash column chromatography on silica using 50% EtOAc in petroleum ether as eluent to return the
1 3 5 OH OH 1' 3' 5' 4a 7a 7 6 5 4 OH 3 2 O 1 3 5 OH OH 1' 3'
title compound as a viscous green oil (99%, 60 mg, 0.31 mmol).44 1H NMR (400 MHz, CD3OD): δ 1.64 (3H, s, 4’-H), 1.74 (3H, s, 5’-H), 2.13 (3H, s, 5-Me), 3.23 (2H, d, J= 7.1 Hz, 1’-H), 5.21 (1H, t, J= 7.1 Hz, 2’-H), 6.12 (2H, s, 4,6-H). 13C NMR (100 MHz, CD3OD): δ 17.9 (5’-C), 21.3 (5-Me), 23.0 (1’-C), 26.0 (4’-C), 108.5 (4,6-C), 113.3 (2-C), 125.0 (2’-C), 130.8 (3’-C), 137.1 (5-C), 156.9 (1,3-C). EIMS: m/z 192 [M]·+ (61), 177 (31), 137 (100), 136 (31), 121 (16), 108 (18). 3-methoxy-5-methyl-2-(3’-methylbut-2’-en-1’-yl)phenol (3.2). A solution of compound 3.1 (54 mg, 0.28 mmol) in anhydrous acetone (8 mL) was added to a oven-dried 2-neck round bottom flask. Then potassium carbonate (1.3 eq., 52 mg, 0.37 mmol) was added to the flask. After that dimethylsulfate (1.3 eq., 35 μl, 0.37 mmol) was added to a dropping funnel contaning 5 mL anhydrous acetone, and added dropwise to the flask, and the reaction mixture was stirred and refluxed under an argon atmosphere. The reaction was monitored by TLC and GC-MS, and was continued until the starting material was consumed. The reaction mixture was concentrated in vacuo, the residue was suspended in water and acidified by 0.1 M HCl, then extracted with EtOAc three times. The combined organic layer was washed with deionised water, dried over Na2SO4 and
concentrated in vacuo, the residue was subjected to flash column chromatography on silica using 20% EtOAc in petroleum ether as eluent to return the title compound as a viscous yellow oil (26%, 12 mg, 0.06 mmol). 1H NMR (400 MHz, CD3OD): δ 1.63 (3H, s, 4’-
H), 1.73 (3H, s, 5’-H), 2.21 (3H, s, 5-Me), 3.23 (2H, d, J= 7.1 Hz, 1’-H), 3.74 (3H, s, 3-OMe), 5.16 (1H, t, J= 7.1 Hz, 2’-H), 6.24 (2H, brs, 4,6-H). 13C NMR (100 MHz, CD3OD): δ 17.8 (5’- C), 21.7 (5-Me), 22.9 (1’-C), 26.0 (4’-C), 56.0 (3-OMe), 104.3 (4-C), 109.8 (6-C), 114.7 (2- C), 124.9 (2’-C), 130.8 (3’-C), 137.4 (5-C), 156.5 (1-C), 159.7 (3-C). EIMS: m/z 206 [M]·+ (73), 191 (41), 151 (100), 150 (25), 138 (17), 121 (27). HREIMS: m/z 206.1307 (calculated for C13H18O2 206.1307). 1,3-dimethoxy-5-methyl-2-(3’-methylbut-2’-en-1’-yl)benzene (3.3). This compound was isolated from the same reaction mixture generating 3.2 as a viscous yellow oil (51%, 26 mg, 0.12 mmol).181H
NMR (400 MHz, CD3OD): δ 1.62 (3H, s, 4’-H), 1.72 (3H, s, 5’-H), 2.29 (3H, s, 5-Me), 3.23 (2H, d, J= 7.1 Hz, 1’-H), 3.76 (6H, s, 1,3-OMe), 5.10 (1H, t, J= 7.1 Hz, 2’-H), 6.39 (2H, s, 4,6-H). 13C NMR (100 MHz, CD3OD): δ 17.8 (5’-C), 22.0 (5-Me), 22.8 (1’-C), 25.9 (4’-C), 1 3 5 OH OMe 1' 3' 5' 1 3 5 OMe OMe 1' 3' 5'
56.1 (1,3-OMe), 105.7 (4,6-C), 116.2 (2-C), 124.8 (2’-C), 130.9 (3’-C), 137.9 (5-C), 159.2 (1,3-C). EIMS: m/z 220 [M]·+ (81), 205 (100), 189 (22), 165 (29), 152 (36), 135 (16). ESIMS:
m/z 243 [M+Na]+ (66), 221 (35), 167 (41), 153 (100), 149 (60), 113 (45). HREIMS: m/z
220.1465 (calculated for C14H20O2 220.1463). HRESIMS: m/z 243.1360 (calculated for
C14H20O2Na 243.1361).
5-methyl-4-(3’-methylbut-2’-en-1’-yl)benzene-1,3-diol (3.4). A solution of compound 3.35 (118 mg, 0.72 mmol) in anhydrous trimethylethylene solution (2M in THF, 100 eq., 36 mL, 72 mmol) was added to a oven-dried and air-free 2-neck round bottom flask, the solution at 0 °C was then exposed to a stream of argon. After that, Grubb’s 2nd generation catalyst (10%,
61 mg, 0.07 mmol) was added, the reaction mixture was stirred at room temperature under an argon atmosphere. The reaction was monitored by TLC and GC-MS, and was continued until the starting material was consumed. The reaction mixture was concentrated in vacuo and the residue was subjected to flash column chromatography on silica using 40% EtOAc in petroleum ether as eluent to return the title compound as a viscous green oil (94%, 130 mg, 0.67 mmol).441H NMR (400 MHz, CD3OD): δ 1.66 (3H,
s, 4’-H), 1.74 (3H, s, 5’-H), 2.14 (3H, s, 5-Me), 3.22 (2H, d, J= 6.5 Hz, 1’-H), 5.04 (1H, t, J= 6.5 Hz, 2’-H), 6.11 (1H, d, J= 2.1 Hz, 6-H), 6.13 (1H, d, J= 2.1 Hz, 2-H). 13C NMR (100 MHz,
CD3OD): δ 17.9 (5’-C), 20.0 (5-Me), 25.6 (1’-C), 25.9 (4’-C), 101.2 (2-C), 109.4 (6-C), 119.3
(4-C), 125.1 (2’-C), 130.8 (3’-C), 139.2 (5-C), 156.4 (1-C), 156.8 (3-C). EIMS: m/z 192 [M]·+
(40), 177 (29), 138 (28), 137 (100), 124 (28). HREIMS: m/z 192.1152 (calculated for C12H16O2 192.1150).
5-methoxy-3-methyl-2-(3’-methylbut-2’-en-1’-yl)phenol (3.5). A solution of compound 3.4 (146 mg, 0.76 mmol) in anhydrous acetone (25 mL) was added to a oven-dried 2-neck round bottom flask. Then potassium carbonate (1.3 eq., 137 mg, 0.99 mmol) was added to the flask. After that dimethylsulfate (1.3 eq., 94 μl, 0.99 mmol) was added to a dropping funnel contaning 10 mL anhydrous acetone, and added dropwise to the flask, and the reaction mixture was stirred and refluxed under an argon atmosphere. The reaction was monitored by TLC and GC-MS, and was continued until the starting material was consumed. The reaction mixture was concentrated in vacuo, the residue was suspended in water and acidified by 0.1 M HCl, then extracted with EtOAc three times. The
5' 3' 1' OH OH 5 3 1 5' 3' 1' OH OMe 3 1 5
combined organic layer was washed with deionised water, dried over Na2SO4 and
concentrated in vacuo, the residue was subjected to flash column chromatography on silica using 25% EtOAc in petroleum ether as eluent to return the title compound as a viscous yellow oil (7%, 11 mg, 0.06 mmol).451H NMR (400 MHz, CD3OD): δ 1.66 (3H, s,
4’-H), 1.75 (3H, s, 5’-H), 2.18 (3H, s, 3-Me), 3.24 (2H, d, J= 6.7 Hz, 1’-H), 3.69 (3H, s, 5- OMe), 5.04 (1H, t, J= 6.7 Hz, 2’-H), 6.22 (2H, brs, 4,6-H). 13C NMR (100 MHz, CD3OD): δ
17.9 (5’-C), 20.1 (3-Me), 25.6 (1’-C), 25.9 (4’-C), 55.4 (5-OMe), 99.9 (6-C), 107.8 (4-C), 120.4 (2-C), 124.8 (2’-C), 131.0 (3’-C), 139.3 (3-C), 156.8 (1-C), 159.4 (5-C). ESIMS: m/z
245 [M+K]+ (8), 229 [M+Na]+ (14), 221 (23), 207 (100), 205 (12), 183 (47), 165 (13).
HRESIMS: m/z 245.0945 (calculated for C13H18O2K 245.0944), 229.1205 (calculated for
C13H18O2Na 229.1204).
3-methoxy-5-methyl-4-(3’-methylbut-2’-en-1’-yl)phenol (3.6). This compound was isolated from the same reaction mixture generating 3.5 as a viscous yellow oil (22%, 34 mg, 0.17 mmol).
1H NMR (400 MHz, CD3OD): δ 1.65 (3H, s, 4’-H), 1.74 (3H, s, 5’-H), 2.16 (3H, s, 5-Me), 3.22 (2H, d, J= 6.9 Hz, 1’-H), 3.73 (3H, s, 3-OMe), 4.98 (1H, t, J= 6.9 Hz, 2’-H), 6.20 (1H, d, J= 2.0 Hz, 6-H), 6.25 (1H, d, J= 2.0 Hz, 2-H). 13C NMR (100 MHz, CD3OD): δ 17.9 (5’-C), 19.9 (5-Me), 25.5 (1’-C), 25.9 (4’-C), 55.9 (3-OMe), 97.6 (2-C), 109.9 (6-C), 120.6 (4-C), 124.9 (2’-C), 130.9 (3’-C), 138.9 (5-C), 156.9 (1-C), 159.6 (3-C). EIMS: m/z 206 [M]·+ (84), 192 (53), 191 (100), 177 (19), 151 (50), 138 (52), 121 (31). HREIMS: m/z 206.1309 (calculated for C13H18O2 206.1307). 1,5-dimethoxy-3-methyl-2-(3’-methylbut-2’-en-1’-yl)benzene
(3.7). This compound was isolated from the same reaction mixture generating 3.5 as a viscous yellow oil (34%, 57 mg, 0.26 mmol). 1H NMR (400 MHz, CD3OD): δ 1.64 (3H, s, 4’-H), 1.74 (3H, s, 5’-H), 2.21 (3H, s, 3-
Me), 3.24 (2H, d, J= 6.7 Hz, 1’-H), 3.73 (3H, s, 5-OMe), 3.75 (3H, s, 1-OMe), 4.98 (1H, t,
J= 6.7 Hz, 2’-H), 6.31 (1H, d, J= 2.2 Hz, 4-H), 6.33 (1H, d, J= 2.2 Hz, 6-H). 13C NMR (100
MHz, CD3OD): δ 17.9 (5’-C), 20.1 (3-Me), 25.6 (1’-C), 25.9 (4’-C), 55.6 (5-OMe), 55.9 (1-
OMe), 97.0 (6-C), 107.9 (4-C), 121.9 (2-C), 124.6 (2’-C), 131.1 (3’-C), 138.9 (3-C), 159.5 (1-C), 159.8 (5-C). ESIMS: m/z 259 [M+K]+ (5), 243 [M+Na]+ (13), 221 (11), 188 (44), 153
(100), 108 (13). HRESIMS: m/z 259.1103 (calculated for C14H20O2K 259.1100), 243.1361
(calculated for C14H20O2Na 243.1361). 5' 3' 1' OMe OH 5 3 1 5' 3' 1' OMe OMe 3 1 5
methyl 2,4-dihydroxy-6-methylbenzoate (3.38). A solution of orsellinic acid (1.50 g, 8.92 mmol) in acetone (50 mL) was added to a round bottom flask. Then potassium carbonate (0.5 eq., 616 mg, 4.46 mmol) and methyl iodide (10.0 eq., 5.55 mL, 89.2 mmol) were added to the solution, the reaction mixture was stirred and refluxed overnight. The reaction mixture was concentrated in vacuo, the residue was suspended in a saturated NaHCO3 aqueous
solution and extracted with EtOAc three times. The combined organic layer was washed with deionised water, dried over Na2SO4 and concentrated in vacuo without further
purification to return the title compound as white crystals (99%, 1.62 g, 8.92 mmol).24 1H NMR (400 MHz, CDCl3): δ 2.49 (3H, s, 6-Me), 3.93 (3H, s, 1-COOCH3), 5.27 (1H, s, 4-
OH), 6.23 (1H, s, 3-H), 6.27 (1H, s, 5-H), 11.73 (1H, s, 2-OH). 13C NMR (100 MHz, CDCl3):
δ 24.4 (6-Me), 52.0 (1-COOCH3), 101.4 (3-C), 105.9 (1-C), 111.5 (5-C), 144.2 (6-C), 160.3
(2-C), 165.5 (4-C), 172.3 (1-COOCH3). EIMS: m/z 182 [M]·+ (51), 151 (36), 150 (100), 122
(59), 94 (17). HREIMS: m/z 182.0586 (calculated for C9H10O4 182.0579).
methyl 4-(allyloxy)-2-hydroxy-6-methylbenzoate (3.39). A solution of compound 3.38 (392 mg, 2.15 mmol) in acetone (30 mL) was added to a round bottom flask. Then potassium carbonate (1.0 eq., 297 mg, 2.15 mmol) and allyl bromide (1.0 eq., 182 μl, 2.15 mmol) were added to the solution, and the reaction mixture was stirred and refluxed overnight. The reaction mixture was diluted in 200 mL DCM, then filtered. The filtrate was concentrated in vacuo, and the residue was subjected to flash column chromatography on silica using 20% EtOAc in petroleum ether as eluent to return the title compound as a white solid (99%, 472 mg, 2.13 mmol). 1H NMR (400 MHz, CDCl3): δ 2.49 (3H, s, 6-Me), 3.92 (3H, s, 1- COOCH3), 4.53 (2H, d, J= 5.3 Hz, 1’-H), 5.29-5.43 (2H, m, 3’-H), 5.97-6.07 (1H, m, 2’-H), 6.31 (1H, s, 5-H), 6.33 (1H, s, 3-H), 11.75 (1H, s, 2-OH). 13C NMR (100 MHz, CDCl3): δ 24.5 (6-Me), 52.0 (1-COOCH3), 68.8 (1’-C), 99.6 (3-C), 105.5 (1-C), 111.8 (5-C), 118.2 (3’-C), 132.6 (2’-C), 143.3 (6-C), 163.0 (4-C), 165.6 (2-C), 172.3 (1-COOCH3). EIMS: m/z 222 [M]·+ (37), 190 (100), 175 (28), 162 (75), 121 (26), 91 (24). HREIMS: m/z 222.0893 (calculated for C12H14O4 222.0892).
methyl 3-allyl-4,6-dihydroxy-2-methylbenzoate (3.40). A solution of compound 3.39 (105 mg, 0.47 mmol) in N,N-diethylaniline (1 mL) was added to a reaction vessel. Then the solution was heated
5 3 1 OH OH COOMe 5 3 1 O OH COOMe 1' 3' 3 5 1 OH OH COOMe 1' 3'
up to 250 °C by microwave followed by the procedure (250 W, ramp 5 min) and kept 250 °C for 20 min. The reaction mixture was diluted by EtOAc (50 mL) after cooling down to the room temperature, then washed with 1 M HCl twice. The organic layer was washed with brine and dried over Na2SO4 before concentration in vacuo, the residue