Ethers difluoromethylene

Miller et al. [9] hypothesized rules on the regioselectivity of addition from the study of the base-catalyzed addition of alcohols to chlorotnfluoroethylene. Attack occurs at the vinylic carbon with most fluorines. Thus, isomers of dichloro-hexafl uorobutene react with methanol and phenol to give the corresponding saturated and vinylic ethers The nucleophiles exclusively attack position 3 of 1,1-dichloro-l,2,3,4,4,4-hexafluoro-2-butene and position I of 4,4-dichloro-l,l,2,3,3,4-hexafluoro-1-butene [10]. In I, l-dichloro-2,3,3,4,4,4-hexafluoro-l-butene, attack on position 2 is favored [J/] (equation 5) Terminal fluoroolefms are almost invariably attacked at tbe difluoromethylene group, as illustrated by the reaction of sodium methoxide with perfluoro-1-heptene in methanol [/2J (equation 6). 

The addition of nucleophiles to cyclic fluoroolefins has been reviewed by Park et al. [2 ]. The reaction with alcohols proceeds by addition-elimination to yield the cyclic vinylic ether, as illustrated by tlie reaction of l,2-dichloro-3,3-di-fluorocyclopropene Further reaction results in cyclopropane ring opening at the bond opposite the difluoromethylene carbon to give preferentially the methyl and ortho esters of (Z)-3-chloro-2-fluoroacrylic acid and a small amount of dimethyl malonate [29] (equation 8). 

In another series of experiments, addition of phosphonyl radicals to carbohydrate gem-difluoroenol ethers was investigated as a route to new anomeric carbohydrate difluoromethylene phosphonates 261,262 Phosphonyl radicals could be produced from either diethyl phosphite in the presence of di-ferf-butyl peroxide in refluxing octane, or diethyl(phenylselenyl)phosphonate, on treatment with n-Bu3SnH (plus AIBN) added slowly to a benzene solution under reflux. With the first method,... 

Ethyl pentafluoroisopropenyl ether reacts in its resonance structure with sulfur trioxide in such a way that the sulfur atom of sulfur trioxide becomes attached to the terminal difluoromethylene group. The oxygen atom of sulfur trioxide combines with the methylene carbon of the ethyl group, and thus ethyl 2-oxopentafluoropropane-1 -sulfonate is formed. Its transesterification with trifluoroacetic acid affords 2-oxopentafluoropro-panesulfonic acid and ethyl trifluoroacetate [44],... 

The clue to the reaction is the polarity of the double bond. The lowest electron density is at the carbon linked to hydrogen, and is due to the strong inductive effect of the difluoromethylene groups and a slight effect of the vinylic chlorine. The attacking species, ethoxide anion, which is in an equilibrium with hydroxide ion in alcoholic potassium hydroxide, reacts in an SN2 reaction by joining the carbon bonded to hydrogen. The subsequent shift of the double bond facilitates ejection of fluorine as an anion and leads to an ether, compound O [77]. 

The methoxide anion joins the carbon of the difluoromethylene group and generates a carbanion that is protonated by methanol to afford E, 2,2-dichloro-l,l-difluoroethyl methyl ether and methoxide anion that perpetuates the reaction. 

Treatment of certain 1,3-diketones with sulfur tetrafluoride using diethyl ether as solvent leads to the formation of unsaturated /i-fluoro ketones and mixtures of E- and Z-isomers are obtained, e.g. I.8 In this case the monoenolic form of the 1,3-diketone is the substrate for sulfur tetrafluoride. When diethyl ether is not used, the expected conversion of one or two carbonyl groups into difluoromethylene groups occurs. 

Compounds carrying a trifluoroacetyl group, for example trifluoromethyl ketones and esters of trifluoroacetic acid, can be converted into the corresponding trimethylsilyl difluoroenol ethers [27] or into trimethylsilyldifluoroacetic acid esters [28] by reduction with magnesium metal in the presence of Me SiCl (Scheme 2.195). These readily accessible species are synthetically very useful as nucleophilic difluoromethylene equivalents. The same type of chemistry [29] can also be extended to trifluoromethyl imines [30]. 

Some difluoromethylene phosphonates have been prepared by phosphonyl radical addition to difluoroenol ethers, e.g. 11 gave 12. Treatment of unsaturated 1,6-anhydro sugar 13 with DAST has afforded 14, and the epoxide 15 was opened (KHF2, ethylene glycol) to give deoxyfluoro sugar 16. 

Brigaud and Portella et al. applied Yb(OTf)3 to aldol reaction of a,a-difluoroenol silyl ether (2) affording difluoromethylene ketones, a common structural motif of HlV-1 protease inhibitor [4], (2) was generated from acylsilane and trifluo-romethyltrimethylsilane and directly subjected to the aldol reaction with aldehydes with 10 mol% ofYb(OTf)3 in a one-pot procedure (Scheme 13.1). The same reaction with other Lewis acids such as TiCU or BF3-OEt2 required more than stoichiometric amount. 

Fluorinated derivatives play an important role in pharmaceutical and agrochemical compounds of interest. In fact, approximately 20% of the pharmaceuticals available in the market contain fluorine. The difluoromethylene group is isopolar and isosteric to the ethereal oxygen atom or the hydroxymethylene group, which are useful for the creation of biologically active compounds. 

Difluoromethylene compounds. Ethereal 20%-LiAlH4 added at -5 to 5 under dry Ng during 1.5 hrs. to a soln. of 3-chloro-3,3-difluoro-2-(trifluoromethyl)-prop-l-ene in anhydrous ether, and stirring continued 1 hr. at room temp. 

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