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Double C-alkylation
To a suspension of NaH (17.6 g, 60%) in DMF (150 mL) at ice-bath temperature with mechanical stirring was added over a one hour period a mixture of 4-chlorobenzyl cyanide (30.3 g) and 1,3-dibromopropane (22.3 mL, 44.5 g). The reaction mixture was stirred for an additional 1 hour, and isopropyl alcohol (10 mL) was added slowly to quench excess NaH. Water (150 mL) was added. The reaction mixture was extracted with MTBE (2 × 200 mL), and the combined extracts were washed with water (3 × 200 mL), brine, and dried over MgSO4. The solvent was removed in rotavapor and the final product was purified by column chromatography to give 1-(4-chlorophenyl)cyclobutanecarbonitrile (32.6 g, 85%) as a pale yellow oil. NMR complies.
Note: 1. The procedure was taken from US patent 6,974,838 B2. But we found anhydrous DMF (stored over molecular sieves) is a better solvent than DMSO in this case. 2. The reaction is very exothermic when the starting materials were added to NaH in DMF at 0 oC. The addition should be very slow in order to avoid foaming and overflow.
Selective cleavage of Arylacetates to Phenols
Morpholine (1.1 mL, 0.012 mol) was added to a solution of ethyl 4-(6-acetoxy-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)butanoate in 10 mL THF and the resulting mixture was refluxed for 1 h. The progress of the reaction was monitored by thin layer chromatography (TLC). The reaction mixture was evaporated, diluted with ethyl acetate, washed with water, dried over sodium sulfate and evaporated under reduced pressure to give ethyl 4-(6-hydroxy-3-oxo-2H-benzo[b][1,4]oxazin-4(3H)-yl)butanoate, isolated as a brown oil (1.2 g, 99% yield, NMR complies).
DIBAL Reduction of Ester to Alcohol
(E)-Ethyl 3-(2-chlorophenyl)acrylate (1.5 g, 0.007 mol) was dissolved in 15 mL of anhydrous dichloromethane, cooled to -78 oC and treated with a solution of di-iso-butylaluminum hydride (1.0 M solution in hexane, 21.4 mL, 0.021 mol) over a period of 20 minutes (the solution turned yellow in color). After 1.5 hours total at -78 oC, the reaction was quenched with methanol (15 mL) at -78 oC (the solution became colorless and then a white solid precipitated out), warmed to 23 oC (over 9 hrs) and treated with a saturated aqueous solution of NH4Cl (60 mL). The resulting mixture was extracted with dichloromethane (2 × 100 mL) (emulsion formed was filtered over Celite to remove white gummy precipitate). The combined extracts were dried (Na2SO4) and concentrated under vacuum to give (E)-3-(2-chlorophenyl)prop-2-en-1-ol which was purified by column chromatography (silica gel, 0-50% ethyl acetate in hexanes) as a pale brown oil (0.45 g, 37% yield, NMR complies). 0.8 g of starting ester was also recovered. Ref: WO2005/097744
Selective O-demethylation
A mixture of 2-((1-benzylpiperidin-4-yl)methyl)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one (3.4 g, 0.009 mol), sodium ethanethiolate (3.8 g, 0.045 mol) in 34 mL DMF was heated at 50 oC for overnight (12 h). The reaction mixture was cooled to rt and diluted with water (100 mL) and ethyl acetate (100 mL). The unreacted starting material was separated by extracting into the organic layer using 2 x 100 mL ethyl acetate. The pH of the aqueous layer was adjusted to pH = 7 by carefully adding 1 mL of saturated aqueous citric acid solution. A oil gets separated which soon becomes a white solid. The solid was filtered off, washed with water, redissolved in dichloromethane, dried over sodium sulfate to give 2-((1-benzylpiperidin-4-yl)methyl)-6-hydroxy-5-methoxy-2,3-dihydro-1H-inden-1-one as a white solid (2.4 g, 74% yield). NMR complies.
Ref. WO 2008/073452 A1, US 2008/0153878 A1
