2,2-difluoro-1,3-benzodioxole

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

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

Procedure: A mixture of 15.8 grams (0.1 mole) of 2,2-difluoro-1,3-benzodioxole in 200 mL of carbon tetrachloride was stirred, and 2.8 grams (0.05 mole) of iron powder was added. The reaction mixture was cooled to 0° C., and 5.2 mL (0.1 mole) of bromine was added during a 20 minute period. Upon completion of addition the reaction mixture was cautiously warmed to 75° C. where it was stirred for one hour and then was allowed to cool to ambient temperature where it was stirred for 18 hours. The reaction mixture was taken up in 200 mL water and stirred for 20 minutes. The organic layer was separated and washed with water and then with two portions of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was distilled under high vacuum to yield 11.7 grams of 5-bromo-2,2-difluoro-1,3-benzodioxole. The nmr spectrum was consistent with the proposed structure. The reaction was repeated several times. Upon completion of addition the reaction mixture was cautiously warmed to 75° C. where it was stirred for one hour to cool to ambient temperature where it was stirred for 18 hours stirred for 20 minutes The organic layer was separated washed with water The organic layer was dried with magnesium sulfate filtered The filtrate was concentrated under reduced pressure to a residue The residue was distilled under high vacuum

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 12 g of 1-(2,2-difluoro-1,3-benzodioxol-4-yl)propanone are prepared by condensation of N,N-dimethylpropionamide with the lithiated anion of 2,2-difluoro-1,3-benzodioxole obtained according to the procedure described in patent EP 333658, are then dissolved in 14.6 ml (0.11 mol) of N,N-dimethylformamide dimethyl acetal and heated at 70° C. according to the procedure described in Example No. 1. 25 g (0.05 mol) of enaminone thus obtained are dissolved in 130 ml of acetic acid and then 3.3 ml (0.069 mol) of hydrazine hydrate are added. The crude product obtained is purified by trituration in pentane. obtained

Conditions: temp:70.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 12 g of 1-(2,2-difluoro-1,3-benzodioxol-4-yl)propanone are prepared by condensation of N,N-dimethylpropionamide with the lithiated anion of 2,2-difluoro-1,3-benzodioxole obtained according to the procedure described in patent EP 333658, are then dissolved in 14.6 ml (0.11 mol) of N,N-dimethylformamide dimethyl acetal and heated at 70° C. according to the procedure described in Example No. 1. 25 g (0.05 mol) of enaminone thus obtained are dissolved in 130 ml of acetic acid and then 3.3 ml (0.069 mol) of hydrazine hydrate are added. The crude product obtained is purified by trituration in pentane. obtained

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

Procedure: 2,2-Difluoro-1,3-benzodioxole (320 mg, 2.05 mmol) was dissolved in THF (2.5 mL) and cyclohexane (1.2 mL) and the resulting solution cooled down to −78° C. sec-BuLi 2M solution in cyclohexane (1.025 ml, 2.05 mmol) was added drop wise and the reaction mixture stirred for 2 hours at −78° C. Trimethylborate (230 mg, 2.25 mmol) was added and the mixture was allowed to warm slowly to room temperature. A 30% w/w aqueous solution of H2O2 (4.1 mmol) and NaOH (82 mg, 2.05 mmol) were added and the reaction mixture stirred for 18 hours at room temperature. The reaction was quenched with a 2N aqueous solution of HCl and diluted with ethyl acetate. Two phases were separated and the organic layer was washed twice with brine, dried over Na2SO4 and evaporated to dryness, affording the title compound (340 mg). was added drop wise to warm slowly to room temperature the reaction mixture stirred for 18 hours at room temperature The reaction was quenched with a 2N aqueous solution of HCl diluted with ethyl acetate Two phases were separated the organic layer was washed twice with brine dried over Na2SO4 evaporated to dryness

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

Procedure: 2,2-Difluoro-1,3-benzodioxole (960 mg, 6.1 mmol) was dissolved in THF (8 mL) and cyclohexane (4 mL) and the resulting solution cooled to −78° C. sec-BuLi 1.4M solution in cyclohexane (4.3 mL, 6.1 mmol) was added dropwise and the reaction mixture stirred for 1.5 hours at −78° C. Trimethylborate (694 mg, 6.75 mmol) was added and the mixture was allowed to warm slowly to −30° C. The reaction mixture was quenched with a 2N solution of HCl and diluted with ethyl acetate. Two phases were separated and the organic layer was washed twice with brine, dried over Na2SO4 and evaporated to dryness affording the title compound as yellow oil which was used in the next step without further purification. was added dropwise to warm slowly to −30° C The reaction mixture was quenched with a 2N solution of HCl diluted with ethyl acetate Two phases were separated the organic layer was washed twice with brine dried over Na2SO4 evaporated to dryness

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

Procedure: 50 mmol of 5-butyliminomethyl)-2,2-difluoro-1,3-benzodioxole and 50 mmol of methyl acetoacetate are added simultaneously to 80 ml of acetic anhydride and, after brief warming, the mixture is left to stand at room temperature for 24 hours. It is then hydrolyzed with 1 l of ice-water and the oil which has separated out is separated off, diluted with a little methylene chloride, dried and subsequently used as the crude product. after brief warming, the mixture is left hydrolyzed with 1 l of ice-water and the oil which has separated out is separated off diluted with a little methylene chloride dried

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

Procedure: 50 mmol of 5-butyliminomethyl)-2,2-difluoro-1,3-benzodioxole and 50 mmol of methyl acetoacetate are added simultaneously to 80 ml of acetic anhydride and, after brief warming, the mixture is left to stand at room temperature for 24 hours. It is then hydrolyzed with 1 l of ice-water and the oil which has separated out is separated off, diluted with a little methylene chloride, dried and subsequently used as the crude product. after brief warming, the mixture is left hydrolyzed with 1 l of ice-water and the oil which has separated out is separated off diluted with a little methylene chloride dried

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

Procedure: 39.3 g (339 mmol) of N,N,N',N'-tetramethylethylenediamine are added dropwise under a nitrogen atmosphere at from -15° to -10° C. to 137.8 g (409 mmol) of n-butyllithium solution (19.0% in toluene). The resulting reaction mixture is added dropwise at from -15° to -10° C. under a nitrogen atmosphere to a solution of 53.3 g (337 mmol) of 2,2-difluoro-1,3-benzodioxole in 46 ml of toluene, n-butane being formed in addition to the title compound. The resulting reaction mixture

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

Procedure: 94.0 g (272 mmol) of n-butyllithium (18.5% in toluene) are added dropwise under a nitrogen atmosphere at from -15° to -10° C. to 29.5 g (254 mmol) of N,N,N',N'-tetramethylethylenediamine and 40.0 g (253 mmol) of 2,2-difluoro-1,3-benzodioxole in 35 ml of toluene, n-butane being formed in addition to the title compound.

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

Procedure: 94.0 g (272 mmol) of n-butyllithium (18.5% in toluene) are added dropwise under a nitrogen atmosphere at from -15° to -10° C. to 29.5 g (254 mmol) of N,N,N',N'-tetramethylethylenediamine and 40.0 g (253 mmol) of 2,2-difluoro-1,3-benzodioxole in 35 ml of toluene, n-butane being formed in addition to the title compound.

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

Procedure: 15.8 g (100 mmol) of 2,2-difluoro-1,3-benzodioxole are metallated according to Example 2, at -20° C., with 70 ml (110 mmol) of n-butyllithium (1.58M in hexane) and 12.8 g (110 mmol) of TMEDA in 120 ml of hexane. To the white suspension there is added dropwise at -100° C., over a period of 5 minutes, a solution of 10.4 g (100 mmol) of trimethyl borate in 50 ml of diethyl ether. When the reaction mixture has warmed up and has been stirred for 30 minutes at room temperature, there are added to the precipitated dimethoxy-(2,2-difluoro-1,3-benzodioxol-4-yl)borane, while cooling with ice, 35 ml of 3N sodium hydroxide solution, immediately followed by the addition, over a period of 10 minutes, of 32 ml (~310 mmol) of 30% hydrogen peroxide solution. The yellow-orange emulsion is adjusted to pH 3 with 10% HCl. The aqueous phase is extracted three times with 150 ml of diethyl ether each time. The organic solutions are washed three times with 100 ml of 2N FeSO4 solution each time, then twice with 100 ml of 20% sodium bisulfite solution each time and finally with 50 ml of brine, dried over MgSO4 and concentrated in a vacuum rotary evaporator. Upon distillation of the residue, 8.4 g (48%) of the product distil over in the form of a pale yellow oil at boiling point (b.p.) 135°-139° C./25 mbar. To the white suspension there is added dropwise at -100° C., over a period of 5 minutes When the reaction mixture has warmed up The aqueous phase is extracted three times with 150 ml of diethyl ether each time The organic solutions are washed three times with 100 ml of 2N FeSO4 solution each time twice with 100 ml of 20% sodium bisulfite solution each time and finally with 50 ml of brine, dried over MgSO4 concentrated in a vacuum rotary evaporator Upon distillation of the residue, 8.4 g (48%) of the product distil over in the form of a pale yellow oil at boiling point (b.p.) 135°-139° C./25 mbar