methyl 3-hydroxy-2,2-dimethyl-3-phenylpropanoate类似物合成

chem 48110 0

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methyl 3-hydroxy-2,2-dimethyl-3-phenylpropanoate (26b)
After 1.65 M solution of nBuLi in hexane (21.4 mL, 35.3 mmol) was added slowly to a stirred solution of iPr2NH (5.4 mL, 38.4 mmol) in dry THF (130 mL) at -78 ºC under N2 atmosphere, the solution was warmed to 0 ºC and stirred for 0.5 h. Then the resulting solution was cooled to -78 ºC and a solution of methyl isobutyrate (3.00 g, 29.4 mmol) in dry THF (20 mL) was added to the reaction mixture. After being stirred for 0.75 h at -78 ºC, benzaldehyde (3.6 mL, 35.2 mmol) was added. The solution was warmed to room temperature and stirred for 1.5 h, then sat. NH4Cl aq. was added to the reaction mixture, which was extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4. After removal of the solvent in vacuo, the residue was subjected to silica gel column chromatography using hexane/EtOAc (25:1) as the eluent to give the product 26b (4.98 g, 81%).

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Conditions: a) BH3-Me2S, THF; b) NaH, DMF, PMB-Cl; c) nBuLi, THF, DMF; d) (i) 1-
methylimidazole, ((1-methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane, LiCl, DMF, (ii)
NaOH, KHF2 , H2O, HCl;
e) 3-bromoprop-1-yne, NaH, DMF; f) DDQ, DCM/H2O

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Conditions: a) n-BuLi, DMF, THF b) NaH, PMBCl, DMF c) t-BuLi or n-BuLi, THF d) TiCl4 ,
DCM (or) (i) DBU, Cl3CCN, CH3CN; ii) Tf2NH, iii) DDQ, DCM/H2O
e) SOCl2, DCM f) R1 3H,
DIPEA, CH3CN; (or) R1 3H, NaH, DMF g) LiOH, MeOH, THF.

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To a solution of (1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)(3-(((4-
methoxybenzyl)oxy)methyl)-4-methylphenyl)methanol (15.0g, 35.9 mmol) in
dichloromethane (DCM) (250.0 mL) was added ((1-methoxy-2-methylprop-1-en-1-
yl)oxy)trimethylsilane (12.53 g, 71.9 mmol), then titanium tetrachloride (3.96 mL, 35.9 mmol) in DCM (20ml) was slowly dropped into the reaction at 0 °C under N2 protection. The reaction mixture was stirred at 0 °C for 30 min under N2 protection, then was warmed to ambient temperature and continuously stirred for an additional 4 h. Then the reaction mixture was poured into saturated NaHCO3 aqueous solution (100 mL) at 0 °C. The organic layer was separated and the aqueous layer was extracted with DCM (3 x 50 mL). The combined organic layer was washed with brine (100 mL) and dried over anhydrous Na2SO4 and concentrated. The residue was purified with a silica gel chromatography (petroleum ether/ethyl acetate=1:1) to obtain the title compound methyl 3-(1, 4-dimethyl-1H-benzo[d] [1,2, 3] triazol-5-yl)-3-(3-(hydroxymethyl)-4-methylphenyl)-2, 2-dimethylpropanoate (3.0 g, 7.63
mmol, 21.23 % yield) as a solid.

2,2,2-trichloroacetonitrile (4.23 ml, 42.2 mmol) and DBU (0.146 ml, 1.054 mmol) were added sequentially to a solution of (1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)(3-(((4-methoxybenzyl)oxy)methyl)-4-methylphenyl)methanol (8.8 g, 21.08 mmol) in acetonitrile (263 ml) at ambient temperature and stirred for 45 minutes. ((1-Methoxy-2-methylprop-1-en-1-yl)oxy)trimethylsilane (9.19 g, 52.7 mmol) followed by 1,1,1-trifluoro-N-
(0.593 g, 2.108 mmol) were then added and the solution stirred at ambient temperature for 2 h. The reaction was quenched with saturated sodium bicarbonate(10 mL) and extracted with DCM (3 x 15 mL), dried over sodium sulfate, filtered and concentrated. The residue was redissolved in dichloromethane (DCM) (263 mL). Water (15.19 mL, 843 mmol) was added and the solution was cooled to 0 ◦C, 4,5-dichloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile (9.57 g, 42.2 mmol) was added. The solution was stirred at 0 °C for 1 h. The reaction was quenched with saturated sodium bicarbonate (10 mL) and extracted with DCM (3 x 15 mL) and dried over sodium sulfate. The crude product was purified by flash chromatography on a silica gel
chromatography to give the title compound (6.9 g, 18.09 mmol, 86 % yield).



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