Method for fluoromethylation of alcohols via halogenative decarboxylation
A technology of fluoromethylation and alkylation, which is applied in the direction of organic chemical methods, chemical instruments and methods, and the preparation of organic compounds, and can solve the problems of low yield of fluorinated products, expensive, and affecting reversible regulation
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Embodiment 1
[0044] α-(hexafluoroisopropoxy)acetic acid was synthesized according to the manner shown in Reaction Scheme I.
[0045] Reaction scheme I
[0046]
[0047] To a flame-dried 250 mL round bottom flask was added dry sodium hydride (2.4 g, 100 mmol) and 100 mL of anhydrous tetrahydrofuran. The resulting slurry was maintained under nitrogen atmosphere while cooling to 0 °C in an ice bath. To this slurry was added 1,1,1,3,3,3-hexafluoroisopropanol (11.6 mL, 110 mmol) dropwise while stirring. The pre-formed alkoxide was stirred for an additional 15 minutes before ethyl bromoacetate (11.1 mL, 100 mmol) was added in one portion. The mixture was allowed to gradually warm to room temperature while stirring overnight. The reaction mixture was filtered and concentrated in vacuo. The resulting crude ester was heated at reflux in water (100 mL) for 2 hours and 1 equivalent of LiOH (4.2 g, 100 mmol) was added. The reaction mixture was cooled, and 1N aqueous KOH ...
Embodiment 2
[0049] As shown in Reaction Scheme II, sevochlorane was synthesized by decarboxyhalogenation as follows (according to the method of Kochi, J.K.J Am. Chem. Soc. 1965, 87, 1811).
[0050] Reaction Scheme II
[0051]
[0052] To a solution of α-(hexafluoroisopropoxy)acetic acid (4.90 g, 21.7 mmol) in anhydrous benzene (43 mL) was added lead tetraacetate (10.11 g, 21.7 mmol), followed by lithium chloride (919 mg, 21.7 mmol ), the mixture was bubbled with dry nitrogen for 10 minutes. The degassed reaction mixture was heated at reflux for 20 minutes until the initially cloudy yellow slurry became a clear solution with a white gummy precipitate and gassing ceased. GC / MS analysis of the crude reaction mixture showed sevochlorane as the major product mixed with a small amount of methyl chloride and minor impurities. The product was distilled directly from the reaction mixture as a co-distillate of benzene at 77-78°C. The product solution was then used directl...
Embodiment 3
[0054] As shown in Reaction Scheme III, sevoflurane was synthesized in the following manner.
[0055]
[0056] The sevochlorane / benzene distillate from the previous method (Example 2) was mixed with PEG-400 (43 mL) and 5 equivalents of KF (6.3 g, 0.11 mol) and heated at 100-110 °C for 2 hours. The product was directly distilled from the reaction flask to yield 1.2 g (28% over two steps) of sevoflurane.
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