prop-2-ynoxymethylbenzene

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

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

Procedure: To a solution of benzyloxy prop-2-yne (2.3 g, 16 mmol) in dry THF (25 ml) at −78° C. was added n-BuLi in hexane (10.7 ml, 16 mmol) and the mixture stirred for 20 min. Borontrifluoride etherate (2 ml, 16 mmol) was then added to the solution and stirring continued. for 20 min. at −78° C. A TEF solution of (S)-glycidol-4-fluorophenyl ether (1.8 g, 10.7 mmol) was added and after stirring for 1 h at −78° C., the reaction was quenched by adding aqueous NH4Cl. The organic materials were extracted with ethyl acetate, dried (Na2SO4) and concentrated under vacuum. The crude product was purified on a silica gel column using EtOAc-light petroleum (1:4) as eluent to give (2S)-6-benzyloxy-1-(4-fluorophenoxy)-hex-4-yn-2-ol (2 g, 65%) as a yellow colour liquid. TLC:ethyl acetate-light petroleum (1:3), Rf=0.4. 1H NMR (CDCl3, 200 MHz): 8 2.65 (m, 2H), 3.95-4.10 (m, 2H), 4.13-4.21 (m, 3H), 4.6 (s, 2H), 6.8-7.02 (m, 4H), 7.30-7.38 (m, 5H) stirring for 20 min. at −78° C after stirring for 1 h at −78° C. the reaction was quenched by adding aqueous NH4Cl The organic materials were extracted with ethyl acetate dried (Na2SO4) concentrated under vacuum The crude product was purified on a silica gel column

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

Procedure: To a solution of benzyloxy prop-2-yne (2.3 g, 16 mmol) in dry THF (25 ml) at −78° C. was added n-BuLi in hexane (10.7 ml, 16 mmol) and the mixture stirred for 20 min. Borontrifluoride etherate (2 ml, 16 mmol) was then added to the solution and stirring continued for 20 min. at −78° C. A THF solution of (S)-glycidol-4-fluorophenyl ether (1.8 g, 10.7 mmol) was added and after stirring for 1 h at −78° C., the reaction was quenched by adding aqueous NH4Cl. The organic materials were extracted with ethyl acetate, dried (Na2SO4) and concentrated under vacuum. The crude product was purified on a silica gel column using EtOAc-light petroleum (1:4) as eluent to give (2S)-6-benzyloxy-1-(4-fluorophenoxy)-hex-4-yn-2-ol (2 g, 65%) as a yellow colour liquid. TLC:ethyl acetate-light petroleum (1:3), Rf=0.4. 1H NMR (CDCl3, 200 MHz): 82.65 (m, 2H), 3.95-4.10 (m, 2H), 4.13-4.21 (m, 3H), 4.6 (s, 2H), 6.8-7.02 (m, 4H), 7.30-7.38 (m, 5H). stirring continued for 20 min. at −78° C after stirring for 1 h at −78° C. the reaction was quenched by adding aqueous NH4Cl The organic materials were extracted with ethyl acetate dried (Na2SO4) concentrated under vacuum The crude product was purified on a silica gel column

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

Procedure: A solution of 3-benzyloxy-1-propyne (1 molar equivalent) in dry ether is added dropwise to a stirred solution of ethylmagnesium bromide (1 molar equivalent) in ether at ambient temperature under a nitrogen atmosphere. Upon completing the addition, the reaction mixture is stirred at ambient temperature until gas evolution (ethane generation) ceases, then is cooled to 0° to 5° C. and treated with cyclohexanone (1 molar equivalent) added dropwise at such a rate as to prevent the reaction mixture from attaining room temperature. After completing the addition, the reaction mixture is allowed to warm to room temperature, then is heated at reflux for 1 hour. In vacuo evaporation of the reaction mixture at 40° C. provides a gelatinous residue which is treated with anhydrous tetrahydrofuran and acetic anhydride (1 molar equivalent) and then heated at reflux under a nitrogen atmosphere for 1/2 hour. After cooling to 0° to 5° C., the reaction mixture is slowly diluted with cold 2 N hydrochloric acid, stirred at 0° to 5° C. for 15 minutes and allowed to warm to room temperature. The resulting turbid reaction mixture is extracted several times with ether. The combined organic extract is washed with water (until washings are neutral to Litmus paper) and saturated aqueous brine, dried over sodium sulfate, and filtered. Evaporation (in vacuo at 40° C.) of the filtrate provides the title compound as an essentially colorless oil. the addition is cooled to 0° to 5° C. added dropwise at such a rate as from attaining room temperature the addition is heated at reflux for 1 hour In vacuo evaporation of the reaction mixture at 40° C. provides a gelatinous residue which heated at reflux under a nitrogen atmosphere for 1/2 hour After cooling to 0° to 5° C. to warm to room temperature The resulting turbid reaction mixture is extracted several times with ether The combined organic extract is washed with water (until washings are neutral to Litmus paper) and saturated aqueous brine dried over sodium sulfate filtered Evaporation (in vacuo at 40° C.) of the filtrate

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Tetrabutylammonium bromide (19.34 g, 600 mmol) was added to a solution of benzylbromide (71.3 ml, 600 mmol) and propargyl alcohol (35.5 ml, 600 mmol) in 270 ml of toluene and the mixture was heated to 50° C. A solution of sodium hydroxide (24 g, 600 mmol) in 55 ml of water was then added dropwise over a period of 1 hour and stirring was continued for another 3 hours. The reaction mixture was then cooled to 25° C. and transferred into a separatory funnel. The aqueous layer was removed and the organic layer was washed three times with 150 ml of brine. Residual water was removed by repeated azeotropic distillation using toluene. A pale yellow liquid was obtained. Yield: 81.9 g (93.4 %). The reaction mixture was then cooled to 25° C. transferred into a separatory funnel The aqueous layer was removed the organic layer was washed three times with 150 ml of brine Residual water was removed distillation A pale yellow liquid was obtained

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

Procedure: To a solution of benzyloxy prop-2-yne (2.3 g, 16 mmol) in dry THF (25 ml) at −78° C. was added n-BuLi in hexane (10.7 ml, 16 mmol) and the mixture stirred for 20 min. Borontrifluoride etherate (2 ml, 16 mmol) was then added to the solution and stirring continued. for 20 min. at −78° C. A TEF solution of (S)-glycidol-4-fluorophenyl ether (1.8 g, 10.7 mmol) was added and after stirring for 1 h at −78° C., the reaction was quenched by adding aqueous NH4Cl. The organic materials were extracted with ethyl acetate, dried (Na2SO4) and concentrated under vacuum. The crude product was purified on a silica gel column using EtOAc-light petroleum (1:4) as eluent to give (2S)-6-benzyloxy-1-(4-fluorophenoxy)-hex-4-yn-2-ol (2 g, 65%) as a yellow colour liquid. TLC:ethyl acetate-light petroleum (1:3), Rf=0.4. 1H NMR (CDCl3, 200 MHz): 8 2.65 (m, 2H), 3.95-4.10 (m, 2H), 4.13-4.21 (m, 3H), 4.6 (s, 2H), 6.8-7.02 (m, 4H), 7.30-7.38 (m, 5H) stirring for 20 min. at −78° C after stirring for 1 h at −78° C. the reaction was quenched by adding aqueous NH4Cl The organic materials were extracted with ethyl acetate dried (Na2SO4) concentrated under vacuum The crude product was purified on a silica gel column

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

Procedure: To a solution of benzyloxy prop-2-yne (2.3 g, 16 mmol) in dry THF (25 ml) at −78° C. was added n-BuLi in hexane (10.7 ml, 16 mmol) and the mixture stirred for 20 min. Borontrifluoride etherate (2 ml, 16 mmol) was then added to the solution and stirring continued for 20 min. at −78° C. A THF solution of (S)-glycidol-4-fluorophenyl ether (1.8 g, 10.7 mmol) was added and after stirring for 1 h at −78° C., the reaction was quenched by adding aqueous NH4Cl. The organic materials were extracted with ethyl acetate, dried (Na2SO4) and concentrated under vacuum. The crude product was purified on a silica gel column using EtOAc-light petroleum (1:4) as eluent to give (2S)-6-benzyloxy-1-(4-fluorophenoxy)-hex-4-yn-2-ol (2 g, 65%) as a yellow colour liquid. TLC:ethyl acetate-light petroleum (1:3), Rf=0.4. 1H NMR (CDCl3, 200 MHz): 82.65 (m, 2H), 3.95-4.10 (m, 2H), 4.13-4.21 (m, 3H), 4.6 (s, 2H), 6.8-7.02 (m, 4H), 7.30-7.38 (m, 5H). stirring continued for 20 min. at −78° C after stirring for 1 h at −78° C. the reaction was quenched by adding aqueous NH4Cl The organic materials were extracted with ethyl acetate dried (Na2SO4) concentrated under vacuum The crude product was purified on a silica gel column

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

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

Procedure: To a solution of benzyloxy prop-2-yne (2.3 g, 16 mmol) in dry THF (25 ml) at −78° C. was added n-BuLi in hexane (10.7 ml, 16 mmol) and the mixture stirred for 20 min. Borontrifluoride etherate (2 ml, 16 mmol) was then added to the solution and stirring continued. for 20 min. at −78° C. A TEF solution of (S)-glycidol-4-fluorophenyl ether (1.8 g, 10.7 mmol) was added and after stirring for 1 h at −78° C., the reaction was quenched by adding aqueous NH4Cl. The organic materials were extracted with ethyl acetate, dried (Na2SO4) and concentrated under vacuum. The crude product was purified on a silica gel column using EtOAc-light petroleum (1:4) as eluent to give (2S)-6-benzyloxy-1-(4-fluorophenoxy)-hex-4-yn-2-ol (2 g, 65%) as a yellow colour liquid. TLC:ethyl acetate-light petroleum (1:3), Rf=0.4. 1H NMR (CDCl3, 200 MHz): 8 2.65 (m, 2H), 3.95-4.10 (m, 2H), 4.13-4.21 (m, 3H), 4.6 (s, 2H), 6.8-7.02 (m, 4H), 7.30-7.38 (m, 5H) stirring for 20 min. at −78° C after stirring for 1 h at −78° C. the reaction was quenched by adding aqueous NH4Cl The organic materials were extracted with ethyl acetate dried (Na2SO4) concentrated under vacuum The crude product was purified on a silica gel column

Conditions: temp:50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A Schlenk flask is charged with CuI (19 mg, 0.1 mmol), Pd(PhCN)2Cl2 (39 mg, 0.1 mmol), piperidine (28 mL), and [2-(5-bromo-1H-indol-3-yl)-ethyl]-dimethyl-amine (Example 3) (2.70 g, 10 mmol). The mixture is degassed, and then 0.4 mL of a solution of P(tBu)3 in hexane (0.2 mmol) is added. The stirred yellow solution is warmed to 50° C., and a solution of benzyl propargyl ether (2.65 g, 20 mmol) in piperidine (2 mL) is added during a 5 hour period. The yellow reaction mixture is left stirring for another 15 hours when HPLC indicates complete conversion of the 5-bromotryptamine. The mixture is diluted with ethyl acetate, washed with brine (4 times 10%, 3 times saturated), and dried. After removal of the solvent, the residue is triturated with 20 mL hexane/O(i-Pr)2 (1:1). The crystals which form are filtered off, washed with 4 mL of the same solvent mixture and dried in vacuo. Yield of the title compound: 2.70 g (75%), mp.=93-95° C. 1H-NMR (CDCl3, 300 MHz) δ 2.36 (s, 6, N(CH3)2); 2.63-2.70 (m, 2, CH2NMe2); 2.90-2.97 (m, 2, Indol-CH2); 4.46 (s, 2, CH2-alkin); 4.72 (s, 2, CH2Ph); 6.94 (d, 1, J=2.2 Hz, H-2); 7.18 (dd, 1, J=8.4 Hz, J=0.7 Hz, H-7); 7.26 (dd, 1, J=1.4 Hz, H-6); 7.32, 7.37, 7.41 (m, 5, Ph p-, m-, o-H); 7.76 (d, 1, H-4); 8.63 (br s, 1, NH). 13C-NMR (CDCl3, 75 MHz) δ 23.89 (indole-CH2); 45.73 (N(CH3)2); 58.55 (CH2CC); 60.48 (CH2NMe2); 71.90 (CH2Ph); 82.69 (CH2CC); 88.57 (CH2CC); 111.45 (C-7); 113.15 (C-5); 114.64 (C-3); 122.90 (C-2); 123.21 (C-4); 125.79 (C-6); 127.53 (C-9); 128.02, 128.40, 128.64 (Ph p, m, o-C); 136.34 (C-8); 137.90 (Ph ipso-C). The mixture is degassed The yellow reaction mixture is left washed with brine (4 times 10%, 3 times saturated) dried After removal of the solvent the residue is triturated with 20 mL hexane/O(i-Pr)2 (1:1) The crystals which form are filtered off washed with 4 mL of the same solvent mixture dried in vacuo

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4.6 g (192 mmol) of sodium hydride was charged in a 200 ml three-necked flask provided with a 100 ml dropping funnel with a bypass and vacuum-dried in nitrogen stream. Then, thereto was added 100 ml of tetrahydrofuran, followed by cooling to 0° C. Furthermore, 11.2 ml (192 mmol) of propargyl alcohol diluted with 100 ml of tetrahydrofuran was gradually added thereto. After stirring at this temperature for 30 minutes, 22.3 ml (160 mmol) of chloromethylbenzyl ether diluted with 20 ml of tetrahydrofuran was added dropwise, followed by stirring for 30 minutes. After further stirring for 1 hour at room temperature, the reaction was stopped by saturated aqueous ammonium chloride solution and the reaction mixture was rendered weakly acidic with 3N aqueous hydrochloric acid solution and extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by vacuum distillation and then the ether (1) was obtained by vacuum distillation. Boiling point: 80-83° C./ 0.5 mmHg, Yield: 90% provided with a 100 ml vacuum-dried in nitrogen stream Then, thereto was added 100 ml of tetrahydrofuran was gradually added was added dropwise by stirring for 30 minutes After further stirring for 1 hour at room temperature extracted with methylene chloride The organic layer was dried over anhydrous magnesium sulfate The solvent was removed by vacuum distillation

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

Procedure: Propargyl alcohol is allowed to react with chloromethylbenzyl ether to obtain 1-benzyloxy-2-propyne (1). Then, this is allowed to react with Grignard reagent and a trifluoroacetic acid ester to obtain 5-benzyloxy-1,1,1-trifluoro-3-pentyne-2-one (2). Then, this is allowed to react with hydride of boron or aluminum to obtain 5-benzyloxy-1,1,1-trifluoro-3-pentyne-2-ol (3). This is acetylated or isobutylated and thereafter lipase or lipase-producing microorganism is allowed to act thereon to obtain optically active (R)-5-benzyloxy-1,1,1-trifluoro-3-pentyne-2-ol [(R)-(3)] and optically active (S)-5-benzyloxy-1,1,1-trifluoro-2-acetoxy (or butoxy)-3-pentyne [(S)-(4)].