AMMONIUM-15N CHLORIDE, 98 ATOM pound yen 15N

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

Procedure: A mixture of 72.8 ml. (0.146 mole) of 2 M n-butyllithium solution in hexane and 420 ml. of anhydrous tetrahydrofuran was stirred and cooled to -50° C. while 112 ml. of liquified methylacetylene was added dropwise from a dry ice cooled addition funnel. After the addition was complete, the reaction mixture was allowed to warm to reflux temperature (8° C.) (dry ice condenser) and stirred at this temperature for 1 hour. The white slurry was then cooled to 0° C. and stirred while a solution of 14 g. (0.0728 mole) of rac. 4-benzyloxy-3-methylbutanal in 125 ml. of anhydrous tetrahydrofuran was added dropwise. After stirring at 0° C. for 1 hour, the mixture was slowly warmed to 40° C. and stirred at this temperature for 1 hour whereupon the reaction mixture was treated with saturated aqueous ammonium chloride. The product was isolated by ether extraction and worked up as in Example 1. There was obtained 15.4 g. of crude material which was chromatographed on 400 g. of silica gel. Elution with 2:1 parts by volume and 1:1 parts by volume hexane: ether afforded rac. 1-benzyloxy-2-methylhept-5-yn-4-ol as a yellow oil. A mixture of 72.8 ml cooled addition funnel After the addition to warm The white slurry was then cooled to 0° C. stirred while a solution of 14 g After stirring at 0° C. for 1 hour the mixture was slowly warmed to 40° C. stirred at this temperature for 1 hour whereupon the reaction mixture There was obtained 15.4 g of crude material which was chromatographed on 400 g Elution with 2:1 parts by volume and 1:1 parts by volume hexane

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

Procedure: A solution of 5.8 g. (0.0307 mole) of rac. 4-benzyloxy-3-methylbutyronitrile in 290 ml. of hexane was stirred at -65° C. to -70° C. while 22.4 ml. (4.78 g.; 0.0337 mole) of 25% diisobutylaluminum hydride solution in toluene was added dropwise. The resulting solution was stirred at -65° C. to -70° C. for 0.5 hours then at room temperature for 5 hours whereupon 2.8 ml. of ethyl formate was added dropwise. The reaction mixture was then treated with 250 ml. of saturated aqueous ammonium chloride solution. Stirring was continued for 20 minutes at which point 125 ml. of 5% by weight aqueous sulfuric acid was added and stirring was continued for an additional 10 minutes. The organic layer was separated and the aqueous layer was extracted with ether. The organic solutions were combined and processed as in Example 1 giving 4.79 g. (81.3%) of rac. 4-benzyloxy-3-methylbutanal as a yellow oil. at room temperature for 5 hours whereupon 2.8 ml The reaction mixture was then treated with 250 ml Stirring was continued for 20 minutes at which stirring was continued for an additional 10 minutes The organic layer was separated the aqueous layer was extracted with ether

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

Procedure: A stirred suspension of 121.6 g (5.0 mol) of magnesium in 1-1 of anhydrous ether is treated with 0.6 g of mercuric chloride and about 100 jmg of iodine. After several minutes, 3 ml of propargyl bromide is added and if no exotherm is noted, a small amount of reacting propargyl bromide and magnesium in ether is added. When the reaction begins, a mixture of 5.0 mol of cyclohexanone and 595 g (5.0 mol) of propargyl bromide is added dropwise at a rate that produces vigorous refluxing of the solution. (The propargyl bromide must always be present in some excess otherwise the reaction will stop. If this happens, the addition of about 1 ml of propargyl bromide will restart the reaction.) After about half of the propargyl bromide-cyclohexanone mixture has been added, another 500-750 ml of ether is used to dilute the reaction mixture. At the end of the addition, the reaction mixture is refluxed for at least 0.5 hour, cooled and poured into 4 liters of saturated ammonium chloride during good stirring. The ethereal layer is separated and the aqueous layer is washed with ether several times and the combined extract is washed twice with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Evaporation of the ether yields 583 g (630 g theory) of a dark oil which is distilled giving purified 1-propargyl-1-hydroxycyclohexane. After several minutes is added dropwise at a rate that produces vigorous refluxing of the solution the reaction to dilute the reaction mixture At the end of the addition the reaction mixture is refluxed for at least 0.5 hour cooled The ethereal layer is separated the aqueous layer is washed with ether several times the combined extract is washed twice with saturated sodium chloride solution dried over anhydrous magnesium sulfate Evaporation of the ether yields 583 g (630 g theory) of a dark oil which is distilled giving purified 1-propargyl-1-hydroxycyclohexane

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

Procedure: To a Grignard solution preapred from 1.05 g (0.41 moles) of magnesium and 6.2 g (0.435 moles) of methyl iodide in 30 ml of dry ether under argon is added dropwise 10 g of 1-iodo-1-octen-3-one (Example 183) in 45 ml of ether. The resulting solution is stirred at ambient temperature for one hour. After the addition of 75 ml of saturated ammonium chloride the ether layer is separated and the aqueous layer is separated and the aqueous layer is extracted several times with ether. The combined ether extracts are washed successively with ammonium chloride and water, dried and taken to dryness to give 9.24 g of product as an oil; λ max 2.89, 3.23, 6.24 and 10.5. is separated the aqueous layer is separated the aqueous layer is extracted several times with ether The combined ether extracts are washed successively with ammonium chloride and water dried

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

Procedure: Acetylene gas, dried by passing through a trap containing sulfuric acid, is bubbled at a moderate rate, through 5 ml of vigorously stirred tetrahydrofuran, for 15 minutes. To this acetylenic solution, is then added dropwise, with continued passage of acetylene, 3.5 ml of a 2.4M solution of n-butylmagnesium chloride in tetrahydrofuran (8.4 mmoles) over 45 minutes. The mixture is stirred a further 15 minutes, and a solution of 580 mg (3.9 mmoles) of p-fluorophenoxy acetaldehyde (Example 156) in 3 ml of tetrahydrofuran is added dropwise over 15 minutes. This solution is stirred for 2 more hours, with passage of acetylene, poured into 50 ml of a saturated solution of ammonium chloride, extracted twice with 50 ml of ether, washed with 10 ml of ammonium chloride solution, dried with magnesium sulfate, filtered, and evaporated. The crude subject product is purified by sublimation at 75° C. (0.1 mm) for 5 hours to give 330 mg (48%) of white crystals, mp 46°-47° C. Acetylene gas, dried by passing through a trap containing sulfuric acid is bubbled at a moderate rate, through 5 ml of vigorously stirred tetrahydrofuran, for 15 minutes extracted twice with 50 ml of ether washed with 10 ml of ammonium chloride solution dried with magnesium sulfate filtered evaporated is purified by sublimation at 75° C. (0.1 mm) for 5 hours

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

Procedure: Ethyl 2-(4-bromo-2-nitroanilino)-5-ethyl-thiophene-3-carboxylate (0.4 g, 0.001 mol) was added to powdered zinc (0.4 g) and ammonium chloride (0.4 g) in water (10 ml) and stirred at 50° C. for 24 hours. The reaction mixture was filtered and the recovered solid washed successively with water and ethyl acetate. The organic phase was separated, washed with water, dried (MgSO4) and evaporated in vacuo to give the title compound. The reaction mixture was filtered the recovered solid washed successively with water and ethyl acetate The organic phase was separated washed with water dried (MgSO4) evaporated in vacuo

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

Procedure: A solution of 1.88 g. of 7-[8-nitromethyl-7-(3-oxo-1-octenyl)-1,4-dioxaspiro[4.4]non-6-yl]-5-heptenoic acid in 80 ml. of tetrahydrofuran was treated at -0° C. with 6.6 ml. of 3M phenyl magnesium bromide in tetrahydrofuran and was stirred at 0° C. for one hour. The reaction mixture was added to aqueous ammonium chloride solution, acidified with acetic acid and extracted with ether. After washing with water and drying with magnesium sulfate, the extract was evaporated and the residue chromatographed on silica. Elution with 30% ethyl acetate in hexane gave 0.90 g. of the title product as an oil, λmaxfilm 3.00 (shoulder), 3.50, 5.88, 6.28, 6.47, 6.95, 7.25, 13.30, 14.35μ . NMR: δ3.93 (S, 4, ketal), 4.35 (M, 2, --CH2NO2), 5.15-6.05 (M, 4, olefinic --H), 5.88 (S, 2, --OH) 7.45 (M, 5, aromatic-HO ppm. Mass spectrum: M+ at m/e 515 (theory 515 (theory 515), M+ -H2O at m/e 497.2776 (theory 497/2776. extracted with ether After washing with water drying with magnesium sulfate the extract was evaporated the residue chromatographed on silica Elution with 30% ethyl acetate in hexane gave 0.90 g

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

Procedure: A solution of 1.72 g. of 7-[8-nitromethyl-7-(3-oxo-1-octenyl)-1,4-dioxaspiro[4.4]non-6-yl]-5-heptenoic acid in 80 ml. of tetrahydrofuran was treated at -10° C. with 9.7 ml. of 3M methyl magnesium bromide in tetrahydrofuran and was stirred at 0° C. for one hour. The reaction mixture was added to aqueous ammonium chloride solution, acidified with acetic acid and extracted with ether. After washing with water and drying over magnesium sulfate, the extract was evaporated and the residue chromatographed on silica. Elution with 30% ethyl acetate in hexane gave 0.26 g. of the title product as an oil, 80max film 3.00 (shoulder), 3.45, 5.80 (shoulder), 5.85, 6.45, 7.25, 10.30μ . NMR: δ1.32 (S, 15-methyl), 4.01 (S, 4, ketal), 4.40 (M, 2, CH2NO2), 5.22 (M, 2, 5 and 6-H), 5.63 (M, 2, 13 and 14-H) ppm. Mass spectrum: M+ at m/e 453), (theory 453), M+ --H2O at m/e 435.2571 (theory 435.2620). extracted with ether After washing with water drying over magnesium sulfate the extract was evaporated the residue chromatographed on silica Elution with 30% ethyl acetate in hexane gave 0.26 g

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

Procedure: A stirred suspension of 121.6 g (5.0 mol) of magnesium in 1-1 of anhydrous ether is treated with 0.6 g of mercuric chloride and about 100 mg of iodine. After several minutes, 3 ml of propargyl bromide is added and if no exotherm is noted, a small amount of reacting propargyl bromide and magesium in ether is added. When the reaction begins, a mixture of 5.0 mol of cyclohexanone and 595 g (5.0 mol) of propargyl bromide is added dropwise at a rate that produces vigorous refluxing of the solution. (The propargyl bromide must always be present in some excess otherwise the reaction will stop. If this happens, the addition of about 1 ml of propargyl bromide will restart the reaction.) After about half of the propargyl bromide-cyclohexanone mixture has been added, another 500-750 ml of ether is used to dilute the reaction mixture. At the end of the addition, the reaction mixture is refluxed for at least 0.5 hour, cooled and poured into 4 liters of saturated ammonium chloride during good stirring. The ethereal layer is separated and the aqueous layer is washed with ether several times and the combined extract is washed twice with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Evaporation of the ether yields 583 g (630 g theory) of a dark oil which is distilled giving purified 1-propargyl-1-hydroxycyclohexane. After several minutes is added dropwise at a rate that produces vigorous refluxing of the solution the reaction to dilute the reaction mixture At the end of the addition the reaction mixture is refluxed for at least 0.5 hour cooled The ethereal layer is separated the aqueous layer is washed with ether several times the combined extract is washed twice with saturated sodium chloride solution dried over anhydrous magnesium sulfate Evaporation of the ether yields 583 g (630 g theory) of a dark oil which is distilled giving purified 1-propargyl-1-hydroxycyclohexane

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

Procedure: To a Grignard solution prepared from 1.05 g (0.41 moles) of magnesium and 6.2 g (0.435 moles) of methyl iodide in 30 ml of dry ether under argon is added dropwise 10 g of 1-iodo-1-octen-3-one (Example 183) in 45 ml of ether. The resulting solution is stirred at ambient temperature for one hour. After the addition of 75 ml of saturated ammonium chloride the ether layer is separated and the aqueous layer is separated and the aqueous layer is extracted several times with ether. The combined ether extracts are washed successively with ammonium chloride and water, dried and taken to dryness to give 9.24 g of product as an oil; λ max 2.89, 3.23, 6.24 and 10.5. is separated the aqueous layer is separated the aqueous layer is extracted several times with ether The combined ether extracts are washed successively with ammonium chloride and water dried

Conditions: temp:100.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of 4,4″-Dichloro-[1,1′;3′,1″]terphenyl-5′-carbonitrile (50 mg, 0.15 mmol), sodium azide (20 mg, 0.31 mmol) and ammonium chloride (16 mg, 0.31 mmol) in DMF (1 mL) was heated at 100° C. for 16 h. The reaction mixture was acidified with 1M HCl solution poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried (Na2SO4) and the solvent was removed in vacuo to give 5-(4,4″-dichloro-[1,1′;3′,1″]terphenyl-5′-yl)-1H-tetrazole yield 36 mg (64%) as an off-white solid. 1H NMR (DMSO) δ 7.49 (d, 2H), 7.23 (t, 1H), 7.17 (s br, 1H), 6.96-6.99 (m, 4H), 6.71-6.74 (m, 4H), LCMS method A R.T. 3.5 extracted with ethyl acetate The organic layer was washed with brine dried (Na2SO4) the solvent was removed in vacuo

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

Procedure: A solution of LDA (0.18 mL of 1.8 M in THF, 0.31 mmol) was added dropwise to a stirred solution of (4,4″-dichloro-[1,1′;3′,1″]terphenyl-5′-yl)-acetic acid methyl ester (100 mg, 0.26 mmol) in THF (10 mL) at −78° C. The reaction mixture was stirred for 30 minutes at −78° C. before iodopropane (0.035 mL, 0.31 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature overnight. A saturated aqueous solution of ammonium chloride (10 mL) was carefully added and the residue was partitionned between EtOAc and water. The aqueous layers were extracted with EtOAc (×3). The combined organic layers were washed with water, brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (EtOAc:petroleum ether) yield 70 mg (66%) 1H NMR (CDCl3) δ 7.60 (t, 1H), 7.55 (d, 4H), 7.48 (d, 2H), 7.42 (d, 4H), 3.65-3.72 (m, 4H), 2.11-2.23 (m, 1H), 1.78-1.89 (m, 1H), 1.28-1.40 (m, 4H), 0.94 (t, 3H) was added dropwise The aqueous layers were extracted with EtOAc (×3) The combined organic layers were washed with water, brine dried (MgSO4) filtered concentrated under reduced pressure The residue was purified by flash column chromatography (EtOAc:petroleum ether) yield 70 mg (66%) 1H NMR (CDCl3) δ 7.60 (t, 1H), 7.55 (d, 4H), 7.48 (d, 2H), 7.42 (d, 4H), 3.65-3.72 (m, 4H), 2.11-2.23 (m, 1H), 1.78-1.89 (m, 1H), 1.28-1.40 (m, 4H), 0.94 (t, 3H)