Preparation of phenyl alkynes from aryl iodides and terminal alkynes via the Sonogashira reaction

J. Med. Chem., 1993, 36, 3321-3332 (Sonogashira Reaction) Reagents: Phenyl iodide: 1 equivalent Alkyne: 1.2 equivalent bis(triphenylphosphine)palladium(II)chloride: 0.3 equivalent cupper iodide: 0.6 equivalent Triethylamine: excess, solvent Phenyl alkyne: >80% yield expected Procedure: To a dried flask containing triethylamine (3 mL/ mmol of phenyl iodide) under an argon atmosphere was added the phenyl iodide (1 equivalent), terminal alkyne (1.2 eq), (Ph3P)2PdCl2 catalyst (0.3 eq), and cupper iodide (0.6 eq). The resulting mixture was heated at 50 oC for 4 h. Upon cooling to room temperature, the reaction mixture was filtered, the solids were washed with Et2O, and the solvent was evaporated. The residue was diluted with Et2O, washed with... [Read More...]

Preparation of propargyl alcohol from dibromoethene or dibromovinyl using paraformaldehyde

J. Med. Chem. 1992, 35, 1550-1557 Reagents: Dibromoethene or dibromovinyl compound  : 1 equivalent n-BuLi in Hexanes (1.6 M): 2 eq Paraformaldehyde : 3 eq, excess THF (anhydrous) : solvent propargyl alcohol: expected yield 50-90% Procedure: To a solution of the dibromoethenyl compound in anhydrous THF cooled to -78 oC is added a solution of n-BuLi in hexane dropwise over a period of 5 min. After stirring at -78 oC for 50 min, powdered paraformaldehyde is added. The reaction mixture is allowed to gradually warm up to ambient temperature over a period of 16 h, and then it is quenched with saturated aqueous NaHCO3 solution.  The solvent is evaporated under reduced pressure and extracted with ETOAc (3x).  The organic layer is dried over MgSO4,... [Read More...]

Preparation of alpha beta unsaturated ketone via the Aldol Condensation

J. Med. Chem, 1992, 35, 1853 Aldol condensation Reagents: Methyl ketone : 1 equivalent Aldehdye : 1 eq Sodium methoxide : 1.2 eq Methanol : solvent Alpha beta unsaturated ketone : variable yield expected. Procedure: To a solution of the methyl ketone and aldehyde (1 eq) in methanol was added sodium ethoxide (1.2eq).  The solution was heated to reflux for 2 h, cooled to room temperature, diluted with water, acidified with 2 N HCl, and extracted with EtOAc (3x).  The combined extracts were washed with water, brine, dried over Na2SO4, filtered, and concentrated to give the alpha beta unsaturated ketone.  The product above was recrystallized from 2-propanol to give a pale-yellow solid.  Yield = 25%. NOTE: Low yield was probably due to low recovery... [Read More...]

Preparation of benzoic acid esters from carbonylation of triflates using palladium acetate and carbon monoxide

Reagents: Aryl triflate or aryl halide: 1 equivalent Carbon monoxide : excess Triethylamine : 0.3 mL/mmol of triflate Palladium acetate : 0.04 eq 1,3- bis(diphenylphosphino)-propane : 0.08 eq/mmol Anhydrous DMSO : solvent Anhydrous methanol : solvent Procedure: A mixture containing the aromatic halide or triflate, DMSO (3 mL/mmol), anhydrous methanol (2 mL/mmol), triethylamine (0.3 mL/mmol), Pd(OAc)2 (0.04 eq), and 1,3-bis(diphenylphosphino)-propane (0.08 eq/mmol) was purged with carbon monoxide for 5 minutes.  The carbonylation reaction was warmed to 75 oC under a carbon monoxide atmosphere (balloon) and stirred for 1 h.  After cooling, the reaction was filtered through a thin layer of Celite and concentrated.  The residue was dissolved... [Read More...]

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...]

alpha Alkylation of esters using alkyl halide and sodium hydride or sodium ethoxide

J. Med. Chem, 1994, 37, 1339. Reagents : Ester : 1 equivalent Sodium : 1.1 eq Anhydrous ethanol : solvent Alkyl halide : 1 eq Alkyl ester product : 60 – 80% expected yield Procedure: A solution of sodium ethoxide is prepared by adding sodium hydride (1.1 eq) to anhydrous ethanol(solvent) at 0 oC.  The solution of freshly prepared sodium ethoxide is added dropwise to a cold (0 oC) solution of ethyl N-(diphenylmethylene)-glycinate ester (1 eq) in anhydrous ethanol.  The solution becomes yellow-orange in color.  After stirring the solution for 20 minutes at 0 oC, the alkyl halide (1eq) is added and the reaction mixture is stirred for 5 h at room temperature (longer time may be necessary).  The ethanol is evaporated in vacuo and the residue... [Read More...]

Alkylation of malonate ester with alkyl halides and sodium hydride

J. Med. Chem, 1994, 37, 1339. Reagents: Diethyl acetamidomalonate :1 eq Sodium hydride : 1.1 eq Absolute ethanol : solvent Alkyl halide : 1 eq Alkyl malonate ester product : 60 – 80% expected yield Procedure: To a solution of Na (1.1 eq) in absolute ethanol (3 mL/mmol of sodium) at 0 oC is added a solution of diethyl acetamidomalonate (1 eq) and after 20 minutes of stirring the alkyl halide (1 eq) is also added.  The orange-yellow solution should turn light or less intense in color.  The mixture is stirred at room temperature for 4h (or longer and warming to higher temperature may be need).  The solvent is concentrated in vacuo and the residue is dissolved with ethyl acetate and water.  The organic layer is separated and washed with... [Read More...]

alpha alkylation of esters with alkyl halide and lithium diisopropylamine (LDA)

Reagents: Ester : 1 equivalent Lithium diisopropylamine (LDA) : 1.1 eq Alkyl halide : 1 equivalent Anhydrous THF : solvent Alkylated ester product : 70-90 % expected yield Procedure: To a cooled solution of the alkyl ester in dry THF (1 mL/mmol) at -78 oC is added dropwise a solution of lithium diisopropylamine (LDA, 1.1 eq) in dry THF (1 mL/mmol) and the yellow-orange solution is let to stir for 20-30 minutes.  The alkyl halide (alkylating agent) is added (decoloration takes place) and the reaction mixture is stirred at room temperature for 4 h.  The reaction is quenched at 0 oC by the dropwise addition of water.  The reaction solution is concentrated in vacuo.  The residue is taken up in ethyl acetate and 1 N HCl.  The separated organic... [Read More...]

Alkylation of malonate ester using alkyl mesylate

J. Med. Chem, 1993, 36, 205. Reagents: Alkyl mesylate : 1 equivalent Sodium hydride : 3 eq to mesylate diethyl malonate : 3 eq to mesylate Alkylated malonate ester : 60 – 80% expected yield Anhydrous THF : solvent Procedure: To a suspension of NaH (60%, 3 eq to mesylate) in anhydrous THF (1 mL/mmol of NaH) is added slowly diethyl malonate (3 eq to mesylate) at room temperature.  The reaction mixture is stirred for 30 minutes at room temperature, and a solution of the alkyl mesylate in anhydrous THF (1 mL/2 mmol) is added and then refluxed for 18 h.  The reaction mixture is cooled to room temperature and poured into saturated aqueous NH4Cl.  The alkylated diethyl malonate is extracted with CH2Cl2 (3x).  The combined organic extract is... [Read More...]

Arylation via phenyl organocopper reagents

J. Med. Chem, 1993, 36, 2300. Reagents: Copper cyanide (CuCN) : 1 eq Phenylmagnesium bromide : 1.2 eq or excess Arylated product : > 80% expected yield Procedure A mixture of CuCN (1 eq) is added to a solution of butadiene monoxide (1 eq) in anhydrous THF (2 mL/mmol), and the mixture is cooled to -78 oC.  A phenylmagnesium bromide solution in ether (1.2 eq) is added dropwise to this mixture.  The reaction mixture is warmed to 0 oC and is stirred until the reaction mixture becomes homogeneous.  The reaction mixture is cooled to -78 oC, and a second portion of phenylmagnesium bromide (1.1 eq) solution in ether is added dropwise over 30 minutes.  The reaction mixture is allowed to warm to room temperature with stirring and then quenched... [Read More...]

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