Methyl difluoro acetate

Acetate Methyl Difluoro-(heptade-cafluoro-octyloxy)- E10b2. 77 (CF2-SO,-F > COOH)... 

Direct trifluoromethylsulfuration of aryl halides can also be achieved by employing methyl difluoro(fluorosulfonyl)acetate in the presence of sulfur and copper iodide (see Table 5). ... 

Table 5. Reaction of Aryl Halide.s 4 with Methyl Difluoro(fluoro.sul-fonyl)acetate (5) in the Presence of Copper Iodide and Sulfur ...

Abramov nucleophilic addition of various phosphorus acid esters to nucleoside aldehyde derivatives yielded the phosphonate-based iso-polar, non-iso-steric 5 -nucleotide analogues (28) containing a geminal hydroxy phosphonate moiety on the 5 -carbon of the pentofuranose ring. The enantiomerically pure D- and l- 2, 3, 5 -trideoxy-4 -[(ethoxyphosphoryl) difluoromethyl] thymidine analogues(29) have been synthesized from (i 5)-( )-2-methyl-5-(4-methyl-phenyl-sulfinyl)pent-2-ene and ethyl 2-(diethoxyphosphoryl)-2,2-difluoro-acetate in 45% overall yield over seven steps. ... 

As described previously for trifluoromethyl ethers, Umemoto [23c] reported on the trifluoromethylation of thiols with -(trifluoromethyl) dibenzothiophenium triflate affording the corresponding trifluoromethyl thioethers in medium to good yield. Otherwise, trifluoromethyl phenyl thioethers and ring-substituted analogs are readily made from iodo- or bromoarenes, methyl difluoro(fluorosulfonyl)acetate and elemental sulphur in the presence of cuprous iodide in hexamethylphosphoric triamide (HMPA) or A-methylpyrrohdone (NMP) (Scheme 10). 

R = H, R =Br, R" =Et) was prepared by cyclization of aroylacetate 314 (R = H, R =Br, r2 = H, X = F) (OOMIPIO). 9,10-Difluoro-3(5)-methyl-7-oxo-7//-pyrido[l,2,3- /e]-l,4-benzoxazine-6-carboxylic acid and its racemic form were prepared in the reaction of ethyl 2-(2,3,4,5-tetrafluorobenzoyl)-2-ethoxymethyleneacetate and (R)- or (i ,5)-2-aminopropanol and subsequent hydrolysis of the ring closed tricyclic esters (98MI45). Cyclization of ethyl 2-(2,3-difluoro-5-iodobenzoyl)-2-[A-(2-hydroxyethyl)aminomethylene]acetate 315 in the presence of K2CO3 in DMF at 95 °C for 3.5 h yielded 9-iodo-7-oxo-2,3-dihydro-7//-pyrido[l,2,3- /e]-l,4-benzoxazine-6-carboxylate (01MIP2). 

After further working up there is obtained an oily crystalline residue which is subjected to chromatography on silica gel. The 16a-methyl-6a,9a-difluoro-A -pregnadien-11/3,21-diol-3,20-dione is eluated with ethyl acetatereacted with valeric acid chloride to give the valerate ester. 

Diethyl Ar,Af-dimethylaminomethylenemalonate was reacted with 7,8-difluoro-3-methyl-l,4-benzoxazine in acetic acid at 80-90°C for 5 hr to give (l,4-benzoxazin-4-yl)methylenemalonate (272) in 74.8% yield [86JAP(K)246172, 86J AP( K)246188]. 

Diethyl (7,8-difluoro-3-methyl-3,4-dihydro-2//-benzoxazin-4-yl)methy-lenemalonate was cyclized in boiling acetic anhydride on the action of boron trifluoride in THF to give a pyrido[l,2,3-de]-l,4-benzoxazine-6-... 

Ethyl 6-amino-4,5-difluoro-l-methyl-7-oxo-li/,7//-pyrido[3,2,l-i/]cinno-line-8-carboxylate (84, R = H) was prepared from the 6-benzylamino derivative 84 (R = CH2Ph) by catalytic debenzylation over Pd/C in a mixture of ethanol and acetic acid (92EUP470578,92MIP1). 

Difluoroacetic anhydride reacts similarly with alanine and this process affords 2-(difluoromethyl)-4-methyl-5(277)-oxazolone 7. Treatment of 7 with hydrogen bromide in acetic acid in the presence of ethanethiol yields 8 that was converted to 3,3-difluoroalanine 11 in several steps as shown in Scheme 7.3. ° This reaction opened the way to prepare p,(3-difluoro amino acids. 

Ishihara and coworkers have reported that the reaction of 2-[(trimethylsilyl)methyl]-3-chloro-3,3-difluoropropene couples regioselectively with a variety of carbonyl compounds in the presence of zinc-copper chloride or silver acetate to give 2,2-difluoro-3-(trimethylsilyl)methyl-3-buten-l-ol derivatives (equation 87)81. Note again that the difluo-roallyl zinc species generated in situ reacts exclusively on the difluoromethylene terminus. 

Acetate Methyl (8-Chloro-hcxade-cafluoro-octyloxy)-difluoro-E10b2. 77 (CF,-S02-F COOII)... 

Whereas the lithium enolates of acetate and propionate esters of difluoroallylic alcohols are known to fragment rapidly, methoxy- and benzyloxy-acetates have been found151 to form chelated enolates which undergo a smooth [3,3]-sigmatropic rearrangement as their silyl ketene acetals to afford highly functionalized difluoro compounds (see Scheme 33). Allenic silyl ketene acetals (117) have been used152 to prepare 2-substituted methyl 3,4-dienoates (118). 

The combined extracts were washed with water, dried over anhydrous sodium sulfate and concentrated to approximately 35 ml. The solution was chromatographed over 130 g of Florisil anhydrous magnesium silicate. The column was developed with 260 ml portions of hexanes (Skellysolve B) containing increasing proportions of acetone. There was thus eluted 6a,9a-difluoro-lip, 17a,21-trihydroxy-16a-methyl-l,4-pregnadiene-3,20-dione-21-acetate which was freed of solvent by evaporation of the eluate fractions. 

Simultaneously, 6 g of 16a-methyl-6a,9a-difluoro-84-pregnene-lip,21-diol-3,20-dione-21-acetate in 200 cc of dimethylformamide are added and the fermentation is continued for 50 hours under the same conditions. 

A solution of the 6a,9a-difluoro-lip-hydroxy-16a-methyl-3-oxo-17a-propionyloxyandrosta-l,4-diene-17p-carboxylic acid (500 mg) and sodium iodide (1.874 g) in acetone (15 ml) was stirred and heated under reflux for 6.5 h. Ethyl acetate (75 ml) was then added and the solution was washed successively with water, 10% sodium thiosulfate solution, 5% sodium hydrogen carbonate solution and water, dried and evaporated to give an off-white foam (525 mg). PLC in chloroform-acetone (6 1) to give an off-white foam (478 mg) which was crystallised from acetone without being heated above room temperature to give colourless crystals of the S-iodomethyl-6a,9a-difluoro-lip-hydroxy-16a-methyl-3-oxo-17a-propionyloxyandrosta-l,4-diene-17p-carbothioate (241 mg) m.p. 196-197°C, [a]D = -32° (c 1.01). 

A solution of S-iodomethyl-6a,9a-difluoro-lip-hydroxy-16a-methyl-3-oxo-17a-propionyloxyandrosta-l,4-diene-17p-carbothioate (310 mg) in acetonitrile (10 ml) was stirred with silver fluoride (947 mg) for 3 days at room temperature in the dark. Ethyl acetate (100 ml) was added and the mixture was filtered through kieselguhr. The filtrate was washed successively with 2 N hydrochloric acid, water, saturated brine, then dried. The solvent was removed and the residue was subjected to column chromatography in chloroform then chloroform-acetone (19 1). The product was eluted with ethyl acetate and crystallised on concentration of the solution to give S-fluoromethyl 6a,9a-difluoro-lip-hydroxy-16a-methyl-3-oxo-17a-propionyloxyandrosta-l,4-diene-17p-carbothioate (0.075 g) melting point 272-273°C (dec.), [a]D= +30° (c 0.35). 

BF3OEt2 (0.060 ml, 0.48 mmol as a solution of 48% in BF3) and phenylselenol (0.064 ml, 0.60 mmol) were added to a stirred solution of methyl 4,6-di-O-benzoyl-2,3-dideoxy-3,3-difluoro-a-D-erythro-hexopyranoside (100 mg, 0.24 mmol) in anhydrous dichlormethane (2 ml). The solution was heated to reflux for 3 h, neutralized by dropwise addition of pyridine and evaporated to dryness. The residue was purified by column chromatography (hexane/ethyl acetate 10/1) to afford 92 mg (72%) of phenyl 4,6-di-0-benzoyl-2,3-dideoxy-3,3-difluoro-l-seleno-a-D-erythro-hexopyranoside as an anomeric mixture. 

To 1.13 g of (-)-7,8-difluoro-2,3-dihydro-3-methyl-4H-[l,4]benzoxazine was added 1.58 g of diethyl ethoxymethylenemalonate, and the mixture was stirred at 130-140°C for 70 min. The reaction mixture was subjected to column chromatography using 50 g of silica gel and eluted with chloroform to obtain 2.47 g of diethyl [(-)-7,8-difluoro-3-methyl-2,3-dihydro-4H-[l,4] benzoxazin-4-yl]methylenemalonate. This product was dissolved in 5 ml of acetic anhydride, and 10 ml of a mixture of acetic anhydride and concentrated sulfuric acid (2/1 by volume) with stirring under ice-cooling, followed by stirring at 50-60°C for 40 min. To the reaction mixture were added ice and an aqueous solution of sodium bicarbonate, and the product was extracted three times with 150 ml portions of chloroform. The combined extract was washed with water, dried over anhydrous sodium sulfate and concentrated. The precipitate was washed with a small amount of diethyl ether to yield 1.32 g of (-)-ethyl 9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[l,2,3-de][l,4] benzoxazine-6-carboxylate. 

In 12 ml of acetic acid was dissolved 1.20 g of the resulting compound, and 25 ml of concentrated hydrochloric acid was added, followed by refluxing at 120-130°C for 90 min. Upon allowing the reaction mixture to stand at room temperature, colorless crystals were precipitated, which were collected by filtration and washed successively with a small amount of water, ethanol and diethyl ether to obtain 0.96 g of (-)-9,10-difluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[l,2,3-de][l,4]benzoxazine-6-carboxylic acid. 

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