N,N-diethylbenzamide

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:80.01; pressure:0.00; stir:

Procedure: In an argon filled glove box, a 5.0 mL wheaton microreactor was charged with [Ir(cod)(OMe)]2 (1.98 mg, 1.5 mol%), L1 ligand (2.1 mg, 3.5 mol%), B2pin2 (50.8 mg, 1.0 equiv.), KOtBu (1.0 mg, 4.5 mol%), and dry THF (1.0 mL). The reaction mixture was stirred for 2 minutes at room temperature. To this mixture, N,N-diethylbenzamide (35.5 mg, 0.2 mmol) was added. The microreactor was capped with a teflon pressure cap and placed into pre-heated aluminum block at 80 oC. The reaction mixture was stirred for 12 h. After completion (judged by GC/MS), THF was removed under reduced pressure and chromatographic separation with silica gel (15% ethylacetate in hexane) gave the meta-borylated product 4b (46.7 mg, 77%) as white solid.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The mixture of benzhydrylpiperazine epimers (7.6 g, 14.9 mmol) was dissolved in 50 mL of dry tetrahydrofuran with 1.6 mL (18.6 mmol) of allyl bromide and 5.1 g (36.9 mmol) of sodium carbonate and stirred at room temperature under nitrogen for 2 days. The reaction solution was poured into ice water/ethyl acetate and separated. The organic layer was dried over sodium sulfate, and concentrated in vacuo. The residue was dissolved in a small amount of dichloromethane and placed on a column of silica gel. The diastereomers were separated by elution with a stepwise gradient of ethanol in dichloromethane. The first isomer was eluted with 1.3% ethanol in dichloromethane, and the second isomer was obtained with 1.6% ethanol in dichloromethane. Fractions containing the second isomer were combined and the solvent removed in vacuo to give 1.44 g of 4-(αR)-α-((2R,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-(tert-butyldimethylsilyloxy)benzyl)-N,N-diethylbenzamide as a brown oil. separated The organic layer was dried over sodium sulfate concentrated in vacuo The residue was dissolved in a small amount of dichloromethane The diastereomers were separated by elution with a stepwise gradient of ethanol in dichloromethane The first isomer was eluted with 1.3% ethanol in dichloromethane the second isomer was obtained with 1.6% ethanol in dichloromethane Fractions containing the second isomer the solvent removed in vacuo

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:-78.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of 1.28 g of N,N,N',N'-tetramethylethylene-diamine in 25 ml of tetrahydrofuran was added 10.5 ml of 1.05 M cyclohexane solution of sec-butyl lithium under a nitrogen gas atmosphere, and a solution of 1.77 g of N,N-diethylbenzamide in 15 ml of tetrahydrofuran was added to the solution at -78° C. After stirring for 10 minutes at -78° C., a solution of 2.24 g of 4-dimethylaminobenzaldehyde in 10 ml of tetrahydrofuran was added to the mixture. After stirring at -78° C. for 1.5 hours, the temperature was gradually elevated to 5° C. and the reaction mixture was concentrated under reduced pressure. To the residue were added 50 ml of water and 50 ml of ethyl ether, and pH of the mixture was adjusted to 0.5 with 4N-hydrochloric acid. After shaking, the organic layer was discarded and 50 ml of methylene chloride was added to the aqueous layer. The pH was adjusted to 12 with 10N-sodium hydroxide solution. After shaking, the aqueous layer was discarded and the organic layer was washed with saturated aqueous sodium chloride solution. After drying over anhydrous sodium sulfate, the organic layer was concentrated under reduced pressure. The crude product obtained was subjested to silica gel column chromatography (eluting solvent, ethyl acetate:hexane:triethylamine=50:50:5). A fraction eluted secondly was concentrated under reduced pressure and the concentrate was tritylated with methyl alcohol to give 0.54 g of 3-(4-dimethylaminophenyl)-1,3-dihydro-isobenzofuran-1-one (Compound A). After stirring at -78° C. for 1.5 hours was gradually elevated to 5° C. the reaction mixture was concentrated under reduced pressure To the residue were added 50 ml of water and 50 ml of ethyl ether, and pH of the mixture After shaking 50 ml of methylene chloride was added to the aqueous layer After shaking the organic layer was washed with saturated aqueous sodium chloride solution After drying over anhydrous sodium sulfate the organic layer was concentrated under reduced pressure The crude product obtained was subjested to silica gel column chromatography (eluting solvent, ethyl acetate:hexane:triethylamine=50:50:5) A fraction eluted secondly was concentrated under reduced pressure

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The product of Example 42 was followed using thiomorpholine and cyclobutanecarbonyl chloride giving the desired product as a solid, mp 39°-40° C.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The product of Example 42 was followed using thiomorpholine and cyclobutanecarbonyl chloride giving the desired product as a solid, mp 39°-40° C.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The product of Example 42 was followed using 2-thiopheneacetyl chloride and diethylamine giving the desired product as an oil.

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred solution of 2.5 g of diethylamine and 3.5 g of triethylamine in 30 ml of methylene chloride was cooled in an ice bath while 4.9 g of benzoyl chloride was added dropwise. The cooling bath was removed and the mixture stirred at ambient temperature for 18 hours. The insolubles were removed by filtration followed by methylene chloride washing. The combined filtrates were washed with water and brine, dried and evaporated to a yellow oil which was distilled in a Kugelrohr still to give 5.91 g of the desired product as a colorless oil, 70°/300 mm. was added dropwise The cooling bath was removed The insolubles were removed by filtration The combined filtrates were washed with water and brine dried evaporated to a yellow oil which was distilled in a Kugelrohr still

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A stirred solution of 2.5 g of diethylamine and 3.5 g of triethylamine in 30 ml of methylene chloride was cooled in an ice bath while 4.9 g of benzoyl chloride was added dropwise. The cooling bath was removed and the mixture stirred at ambient temperature for 18 hours. The insolubles were removed by filtration followed by methylene chloride washing. The combined filtrates were washed with water and brine, dried and evaporated to a yellow oil which was distilled in a Kugelrohr still to give 5.91 g of the desired product as a colorless oil, 70°/300 mm. was added dropwise The cooling bath was removed The insolubles were removed by filtration The combined filtrates were washed with water and brine dried evaporated to a yellow oil which was distilled in a Kugelrohr still

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: The crude 4-(N,N-diethylcarbamoyl)benzhydryl chloride (125 mmol) was dissolved in acetonitrile (300 mL). Sodium iodide (18.64 g, 125 mmol), diisopropylethylamine (32.65 mL, 187 mmol), and (+)-(2S,5R)-1-allyl-2,5-dimethylpiperazine (19.23 g, 125 mmol, prepared by the method described in Example 1 for (−)-(2R,5S)-1-allyl-2,5-dimethylpiperazine, but using di-p-toluoyl-L-tartaric acid as the resolving agent) were added. The mixture was stirred at reflux, under nitrogen, for 3 hours. The acetonitrile was removed under reduced pressure, the reaction mixture was poured into ethyl acetate (500 mL) and potassium carbonate solution (150 mL of a 2M aqueous solution), and shaken. The organic phase was separated, washed with water and brine, dried over solid potassium carbonate, and concentrated in vacuo to give 55.35 g (100% crude yield) of 4-((αR and αS)-α-((2R,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)benzyl)-N,N-diethylbenzamide as a 1:1 mixture of isomers, epimeric at the benzhydryl carbon. were added at reflux, under nitrogen, for 3 hours The acetonitrile was removed under reduced pressure the reaction mixture was poured into ethyl acetate (500 mL) and potassium carbonate solution (150 mL of a 2M aqueous solution), and shaken The organic phase was separated washed with water and brine dried over solid potassium carbonate concentrated in vacuo