Synthesis of allylic phenols from phenyl allyl ethers via Claisen rearrangement

J. Med. Chem, 1992, 35, 1597. REDUCTIVE CLAISEN REARRANGEMENT Reagents: Phenyl allyl ether : 1 equivalent Sodium dithionite : 2 eq to vinyl ether DMF : solvent Water : solvent Allyl-phenol product : 60-80% expected yield Procedure: To a solution of DMF-H2O (1-1, 50 mL/mmol of allyl phenyl ether) is added sodium dithionite (2 eq to ether) and the phenyl allyl ether.  The solution is heated to 70 oC under nitrogen.  Several pellets (1 pellet/mmol) of solid sodium hydroxide are added, and the resulting bright orange solution is stirred under nitrogen at 70 oC for 2 h.  The solution is oxygenated with a steady stream of oxygen for 30 minutes, then poured into water (30 mL/mmol), and acidified with HCl.  In the example above, the allylic phenol... [Read More...]

Pyridine hydrochloride cleavage of phenyl methyl ether to phenol alcohols

J. Med. Chem., 1993, 36, 3015 A mixture of the methyl ether and a large excess of pyridine hydrochloride is warmed to 180o C and stirred for 15 min.  The clear yellow solution is cooled to room temperature and concentrated in vacuo.  The residue is taken up in EtOAc and 1 N HCl (1/1, v/v).  The organic phase is separated and washed again with 1 N HCl, followed by water, brine, dried over MgSO4 and filtered.  Concentration in  vacuo affords the crude product.  Yield: Good.  Read More →

Hydrogenation of benzyl ethers with palladium on carbon and cyclohene to alcohols

J. Med. Chem., 1993, 36, 205 To a solution of the benzyl ether in EtOH[1] (6 mL/mmol) is added 20% palladium hydroxide on carbon followed by cyclohexene (4 mL/mmol of benzyl ether).  The reaction mixture is heated to reflux for 24 h[2].  The progress of the reaction is checked by TLC.  The catalyst is filtered off and washed with EtOH.  The combined filtrate is evaporated in vacuo to give the crude alcohol.  Yield: Good. [1] MeOH, iPr-OH, EtOAc, THF, and DMF are compatible solvents.  Up to 50% AcOH may be employed as a co-solvent. [2] Less reaction time may be required.  Read More →

Using ammonium formate (hydrogenation) to deprotect of benzyl ethers to alcohols

J. Med. Chem., 1993, 36, 4172 A mixture of the benzyl ether, 10% Pd/C (60mg/mmol), and ammonium formate (60mg/mmol ether) as the source of hydrogen in THF/MeOH (1/1, v/v)[1] (2mL/mmol ether) is stirred under nitrogen for approximately 1h[2].  The progress of the reaction is checked by TLC.  The mixture is filtered and concentrated in vacuo.  The residue is taken up with EtOAc and water.  The organic layer is washed with brine, dried over MgSO4 and concentrated to give the crude alcohol.  Yield: Good. [1] MeOH, iPr-OH, EtOAc, THF, or DMF are compatible solvents.  Up to 50% AcOH may be employed as a co-solvent. [2] Longer reaction time may be required.  Read More →

Deprotection of benzyl ethers with hydrogenation to alcohols

The benzyl ether is dissolved in EtOH[1] (2mL/mmol) containing catalytic amounts of Pd/C (1% eq).  Hydrogen gas is bubbled into the stirring flask for several hours[2].  The progress of the reaction is checked by TLC.  The palladium is filtered through a bed of Celite using ethanol.  Evaporation of the solvent in vacuo affords the alcohol.  Yield: Good. [1] EtOH, MeOH, iPr-OH, THF, EtOAc are compatible solvents.  AcOH may also be used as a co-solvent to help solubilize the starting material. [2] Longer reaction times may be required.  Read More →

Toluene sulfonic acid deprotection of trityl ethers to alcohols

J. Med. Chem., 1994, 37, 4118 The protected alcohol is dissolved in methanol/toluene[1] (2/1).  Amberlite IR-120 (plus) (H-form)[2] was added and the mixture is stirred at 25o C for 5 h or until TLC analysis indicates that the deprotection is completed[3].  The mixture is filtered to remove the resin, and the filtrate is concentrated in vacuo to give the crude alcohol.  Yield:  Fair. [1] THF, DCM, EtOAc, DMF may also be used.  However, MeOH or EtOH must be added to trap the resulting trytil cation. [2] p-Toluenesulfonic acid, acetic acid, or aqueous HCl may be used as the acid catalyst. [3] Reflux conditions may be required.  Read More →

HBr cleavage of methyl phenyl ethers to phenols alcohols

J. Med. Chem., 1995, 38, 318 A solution of the phenyl methyl ether in 48% HBr[1] (5mL/mmol) is heated at reflux for 2 h, under a nitrogen atmosphere[2].  The progress of the reaction is monitored by TLC[3].  After removal of the solvent, the residue taken up in EtOAc and water.  The organic phase is separated and washed with, brine, dried over MgSO4, filtered, and concentrated to give the crude alcohol.  Yield: Fair-Good. [1] 37% HBr in acetic acid may also be used. [2] Longer reaction time may be required. [3] A TLC sample is prepared by placing an aliquot of the reaction into a vial.  An equal volume of EtOAc is added and the solution is mixed.  Upon sitting, the organic will separate to the top.  The sample is taken from the organic... [Read More...]

ammonium tetrafluoride cleavage of silyl ethers with to alcohols

J. Med. Chem., 1993, 36, 2973 Tetrabutylammoniun fluoride (1.5 eq) is added to a solution of the silyl ether in THF[1] (1 mL/mmol) at 0o C.  The solution is stirred for 5 minutes at 0o C and then 15 min at room temperature[2].  The progress of the reaction is checked by TLC[3]. The THF is evaporated and replaced with EtOAc.  The EtOAc is washed with brine, dried over MgSO4, filtered and concentrated to give the crude alcohol.  Yield: Good. [1] Ethyl ether, dimethoxyethane, dimethylformamide, or ethyl alcohol are suitable solvents for this reaction. [2] Longer reaction time or reflux conditions may be required. [3] A TLC sample may be prepared by placing a small aliquot of the reaction in a vial and adding water. EtOac is added to extract... [Read More...]

Boron tribromide cleavage of methyl phenyl ethers to alcohols

J. Med. Chem., 1994, 37, 4079 J. Med. Chem., 1993, 36, 2335 A solution of the methoxy compound in dry CH2Cl2 (15mL/mmol) is cooled to -78o C and a solution of BBr3 (3-5 eq) in dry CH2Cl2 is added under nitrogen.  After stirring at -78o C for 1 h, the reaction is stirred for an additional 4 h at room temperature[1].  The progress of the reaction is monitored by TLC[2].  Hydrolysis is carried out by cooling the reaction in an ice-bath followed by the dropwise addition of MeOH (10 eq to BBr3) and stirring for 30 min.  The solvent is evaporated and the residue is extracted with EtOAc.  Evaporation of the combined organic fractions affords the crude product.  Yield: Good. [1] Longer reaction time or reflux conditions may be required. [2]... [Read More...]