1-bromoprop-1-ene

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

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

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

Procedure: A mixture of 1.2 parts of bromo-1-propene, 3.26 parts of 9-[(4-fluorophenyl)methyl]-N-(4-piperidinyl)-9H-purin-8-amine, 1.5 parts of sodium hydrogen carbonate and 40 parts of ethanol was stirred for 1 hour at reflux temperature. The reaction mixture was filtered over diatomaceous earth while hot and the filtrate was evaporated. The residue was taken up in water and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 0.8 parts (22%) of 9-[(4-fluorophenyl)methyl]-N-[1-(2-propenyl)-4-piperidinyl)-9H-purin-8-amine; mp. 144.8° C. (compound 120). at reflux temperature The reaction mixture was filtered over diatomaceous earth while hot and the filtrate was evaporated the product was extracted with 4-methyl-2-pentanone The extract was dried filtered evaporated The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol The pure fractions were collected the eluent was evaporated The residue was crystallized from acetonitrile The product was filtered off dried

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

Procedure: A mixture of 1.2 parts of bromo-1-propene, 3.26 parts of 9-[(4-fluorophenyl)methyl]-N-(4-piperidinyl)-9H-purin-8-amine, 1.5 parts of sodium hydrogen carbonate and 40 parts of ethanol was stirred for 1 hour at reflux temperature. The reaction mixture was filtered over diatomaceous earth while hot and the filtrate was evaporated. The residue was taken up in water and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 0.8 parts (22%) of 9-[(4-fluorophenyl)methyl]-N-[1-(2-propenyl)-4-piperidinyl)-9H-purin-8-amine; mp. 144.8° C. (compound 120). at reflux temperature The reaction mixture was filtered over diatomaceous earth while hot and the filtrate was evaporated the product was extracted with 4-methyl-2-pentanone The extract was dried filtered evaporated The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol The pure fractions were collected the eluent was evaporated The residue was crystallized from acetonitrile The product was filtered off dried

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

Procedure: 12 g. of magnesium turnings were suspended under nitrogen in 250 ml. of dry tetrahydrofuran. Between 60° and 65°, 60 g. of 1-bromopropene dissolved in 50 ml. of tetrahydrofuran were added dropwise. During the addition, to prevent escaping of 1-bromopropene, the reflux condenser fitted on the reaction flask was cooled to -40°/-50°. When all Mg had reacted, the mixture was cooled to 20° and 76 g. of citral was added dropwise with cooling. After standing overnight, the mixture was poured into 1.5 liter of concentrated aqueous NH4Cl at 0°. The mixture was extracted 3 times with ether and the combined ether extracts treated as usual. After distillation, 6,10-dimethyl-4-hydroxy-2,5,9-undecatriene, b.p. 70°/0.1 Torr was obtained as a liquid with following constants : nD20 =1.4950; d420 =0.9145. Between 60° 65°, 60 g During the addition the reflux condenser fitted on the reaction flask was cooled to -40°/-50° When all Mg had reacted the mixture was cooled to 20° with cooling The mixture was extracted 3 times with ether the combined ether extracts treated as usual After distillation, 6,10-dimethyl-4-hydroxy-2,5,9-undecatriene b.p. 70°/0.1 Torr was obtained as a liquid with following constants

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

Procedure: 12 g. of magnesium turnings were suspended under nitrogen in 250 ml. of dry tetrahydrofuran. Between 60° and 65°, 60 g. of 1-bromopropene dissolved in 50 ml. of tetrahydrofuran were added dropwise. During the addition, to prevent escaping of 1-bromopropene, the reflux condenser fitted on the reaction flask was cooled to -40°/-50°. When all Mg had reacted, the mixture was cooled to 20° and 76 g. of citral was added dropwise with cooling. After standing overnight, the mixture was poured into 1.5 liter of concentrated aqueous NH4Cl at 0°. The mixture was extracted 3 times with ether and the combined ether extracts treated as usual. After distillation, 6,10-dimethyl-4-hydroxy-2,5,9-undecatriene, b.p. 70°/0.1 Torr was obtained as a liquid with following constants : nD20 =1.4950; d420 =0.9145. Between 60° 65°, 60 g During the addition the reflux condenser fitted on the reaction flask was cooled to -40°/-50° When all Mg had reacted the mixture was cooled to 20° with cooling The mixture was extracted 3 times with ether the combined ether extracts treated as usual After distillation, 6,10-dimethyl-4-hydroxy-2,5,9-undecatriene b.p. 70°/0.1 Torr was obtained as a liquid with following constants

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

Procedure: In an atmosphere of nitrogen, a solution of 280 g. of 1-bromopropene in 430 ml. of tetrahydrofuran was added dropwise at 63°-65° into a suspension of 53.3 g. of magnesium turnings in 660 ml. of tetrahydrofuran. During the addition the reflux condenser fitting the reaction vessel was cooled to -40° to -50° in order to prevent escaping of the vapours of unreacted 1-bromopropene. The mixture was stirred for an additional 21/2 hours at 60°-62° after which it was cooled to 0°. A solution of 278 g. of β-cyclocitral in 350 ml. of tetrahydrofuran was then added dropwise between 0° and 7°. The mixture was allowed to stand overnight then it was poured onto a mixture of ice and saturated aqueous NH4Cl solution. The organic layer was removed and the aqueous phase extracted with petroleum-ether (b.p. 30°-50°). The combined extracts were washed as usual, dried and then evaporated under vacuum. The residue gave 350 g. of crude 2,6,6-trimethyl-1-[1-hydroxy-2-butenyl]-1-cyclohexene which was used without further purification. During the addition the reflux condenser was cooled to -40° to -50° in order was cooled to 0° to stand overnight The organic layer was removed the aqueous phase extracted with petroleum-ether (b.p. 30°-50°) The combined extracts were washed as usual, dried evaporated under vacuum The residue gave 350 g of crude 2,6,6-trimethyl-1-[1-hydroxy-2-butenyl]-1-cyclohexene which was used without further purification

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To Mg (143 mg, 5.8 mmol) in THF (4 mL) with trace of I2 was added α-bromopropene (583 μL) in order to maintain a 60° C. exotherm. After 30 minutes, a solution of ZnBr2 (1.31 g, 5.8 mmol) in THF (4 mL) was added. The reaction mixture was heated at 55° C. for 1 hour, cooled to r.t. and (Pd (dppf) CH2Cl2 (50 mg) was added followed by CuI (18.5 mg). After 5 minutes a solution of methyl (8-bromo-6-methoxy-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetate (Example 22, Step 5, 200 mg, 0.59 mmol) in THF (7 mL) was added and the mixture was refluxed for 1 hour, cooled, quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography to give the title compound (50 mg). The reaction mixture was heated at 55° C. for 1 hour cooled to r.t. the mixture was refluxed for 1 hour cooled quenched with saturated aqueous NH4Cl extracted with EtOAc The combined organic layers were dried over Na2SO4 concentrated The residue was purified by silica gel chromatography

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Alpha-bromopropene (514 μL, 5.2 mmol) was added portionwise, in order to maintain 55° C. exotherm, to Mg (126 mg, 5.2 mmol) (in THF 4 mL) and a trace of iodine. The mixture was heated and stirred for 30 minutes. Dried ZnBr2 (1.16 g, 5.2 mmol) in THF (4 mL) was added and the mixture was heated at 55° C. for 1 hour. The reaction mixture was cooled to room temperature, and Pd (dppf) CH2Cl2 (19 mg) was added followed by CuI (7 mg) after a further 5 minutes. The product of Step 1 (200 mg, 0.52 mmol) in 3 ml THF was then added. The reaction mixture was heated to 75° C. for 15 minutes. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography to give the title compound (130 mg). The mixture was heated the mixture was heated at 55° C. for 1 hour The reaction mixture was cooled to room temperature The reaction mixture was heated to 75° C. for 15 minutes The reaction was quenched with saturated aqueous NH4Cl extracted with EtOAc The combined organic layers were dried over Na2SO4 concentrated The residue was purified by silica gel chromatography

Conditions: temp:55.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Alpha-bromopropene (514 μL, 5.2 mmol) was added portionwise, in order to maintain 55° C. exotherm, to Mg (126 mg, 5.2 mmol) (in THF 4 mL) and a trace of iodine. The mixture was heated and stirred for 30 minutes. Dried ZnBr2 (1.16 g, 5.2 mmol) in THF (4 mL) was added and the mixture was heated at 55° C. for 1 hour. The reaction mixture was cooled to room temperature, and Pd (dppf) CH2Cl2 (19 mg) was added followed by CuI (7 mg) after a further 5 minutes. The product of Step 1 (200 mg, 0.52 mmol) in 3 ml THF was then added. The reaction mixture was heated to 75° C. for 15 minutes. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography to give the title compound (130 mg). The mixture was heated the mixture was heated at 55° C. for 1 hour The reaction mixture was cooled to room temperature The reaction mixture was heated to 75° C. for 15 minutes The reaction was quenched with saturated aqueous NH4Cl extracted with EtOAc The combined organic layers were dried over Na2SO4 concentrated The residue was purified by silica gel chromatography

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

Procedure: 32 g of 4,6,6-trimethyl-1,3-cyclohexadiene-1-carbaldehyde [prepared according to A. F. Thomas et al., Helv. Chim. Acta, 59 (1976), p. 2261-7] in 80 ml of THF were added dropwise to a Grignard compound which had been prepared beforehand from 6 g of magnesium turnings and 32 g of 1-bromo-1-propene in 120 ml of THF. The temperature was maintained at 20° with a water bath during the addition, after which the mixture was heated and kept at reflux over 30 minutes. The reaction mixture was poured into an ice/water ixture and then extracted with ether. The organic phase was washed to neutrality, dried and concentrated. The crude product was then oxidized with 210 g of activated manganese dioxyde (see Houben Weyl, Vol. 7, 1, page 178, 1951; E. M. Goldman, Org. Chem., 34, 1979, 1969) in 200 ml of petroleum ether. The temperature was maintained at 20° with a water bath during the addition after which the mixture was heated at reflux over 30 minutes extracted with ether The organic phase was washed to neutrality dried concentrated

Conditions: temp:65.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Bromo-1-propene (0.78 mL, 9.0 mmol) was added dropwise under argon to a stirred mixture of fluorescein 16 (3.0 g, 9.0 mmol) and K2CO3 (1.24 g, 9.0 mmol) in dry DMF (40 mL). The resulting mixture was stirred for 4 h at 65° C. The mixture was concentrated, diluted with ethyl acetate, washed with 10% NaHCO3, brine, dried with anhydrous Na2SO4, and evaporated. The residue was purified by column chromatography (ethyl acetate/hexane=2:1) to give 21 as a brown solid (0.70 g, 21%). 1H NMR (CDCl3, 500 MHz) δ 4.42 (d, J=6.0 Hz, 2H, CH2), 5.06 (m, 2H, 2CH), 5.53 (m, 1H, CH), 6.81 (m, 2H), 6.88 (m, 2H), 6.98 (m, 2H), 7.32 (d, J=7.5 Hz, 1H), 7.68 (t, J=7.5 Hz, 1H), 7.74 (t, J=7.5 Hz, 1H), 8.26 (d, J=7.5 Hz, 1H). 13C NMR (CDCl3, 125 MHz) δ 66.26, 103.90, 115.01, 119.49, 122.30, 130.02, 130.51, 130.65, 131.00, 131.38, 132.77, 134.48, 155.89, 158.06, 165.08, 175.84. ESIMS calcd for C23H17O5 [M+H]+ 373.1. Found 373.2. The mixture was concentrated diluted with ethyl acetate washed with 10% NaHCO3, brine dried with anhydrous Na2SO4 evaporated The residue was purified by column chromatography (ethyl acetate/hexane=2:1)