Ethers difluoroenol

More stable difluoroenol ethers were prepared in four steps from ethyl chlorodifluoroacetate by the Taguchi group (Eq. 127). Lewis acid-mediated additions to aldehydes [330], and to -acyliminium species [331], were described. The choice of Lewis acid was critical for the success of these reactions, particularly in the former case where Lewis acids capable of activity in SET processes were effective, whereas more conventional agents such as trimethylsilyl triflate were not. 

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,... 

As may be seen from Table n, the stereochemistry found for the products resulting from the addition of a phosphonyl radical to a difluoroenol ether double... 

As depicted in Equation (97), oxidative cross-coupling of a-aryl-/3,/3-difluoroenol silyl ether with unfunctionalized benzo[ ]furan 82 in the presence of Cu(OTf)2 in wet acetonitrile proceeded smoothly to give benzo[/ ]furan difluoromethyl aryl ketone in 50% yield <2004OL2733>. 

If the reaction between enol silyl ethers and a,/ -unsaturated ketones is attempted in the presence of a titanium Lewis acid, the mode of the reaction switches to 1,4-addition with reference to the unsaturated ketone [109-113]. The reaction of an enol silyl ether is shown in Eq. (30) [114]. Ketene silyl acetals react with a,j8-unsaturated ketones in similar 1,4-fashion, as exemplified in Eq. (31) [115]. Acrylic esters, which often tend to polymerize, are also acceptable substrates for a, -unsaturated carbonyl compounds [111]. A difluoroenol silyl ether participated in this cationic reaction (Eq. 32) [116], and an olefinic acetal can be used in place of the parent a-methylene ketone [111] to give the 1,5-diketone in good yield (Eq. 33) [117]. More results from titanium-catalyzed 1,4-addition of enol silyl ethers and silyl ketene acetals to a,f -unsaturated carbonyl compounds are summarized in Table 4. 

Motherwell, W B, Ross, B C, Tozer, M J, Some radical reactions of exocyclic carbohydrate difluoroenol ethers, Synlett, 68-70, 1989. 

Herpin, T.E, Houlton, J.S., Motherwell, W.B., Roberts, B.P., and Weibel, J.-M., Preparation of some new anomeric carbohydrate difluoromethylenephosphonates via phosphonyl radical addition to gem-difluoroenol ethers, J. Chem. Soc., Chem. Commun., 613, 1996. 

Difluoroenol ethers are synthetically equivalent to nucleophilic gem-difluoromethy-lene building blocks [24] which can be derivatized in their a-positions by a wide range of structures [25]. Similarly to their non-fluorinated analogs, they react with a variety of different electrophiles or radicals [26] and afford particularly convenient access to fluorinated analogs of natural products and other bioactive compounds. 

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]. 

Trimethylsilyl difluoroenol ethers and their imine analogs react with a variety of different electrophiles [29] (Schemes 2.196 and 2.197). They have, for example, been used for the synthesis of fluorinated amino acids [30] and anti-malarials [31]. 

Scheme 2.197 Synthesis of a di-fluoromethylene ketone-derivatized I j artemisinine by use of a difluoroenol silyl ether [31].

Another inexpensive and readily accessible precursor to difluoroenol ethers is trifluoroethanol. Several 0-substituted derivatives of trifluoroethanol have been converted into 1-lithio 2,2-difluoroenolates by elimination of hydrogen fluoride and subsequent metalation with LDA [36]. These building blocks have the advantage... 

Difluoroenol ethers are also available from esters and lactones by a Wittig-like reaction with CF2Br2/P(NMe2)3 in the presence of a reducing agent [38, 39] (Scheme 2.202). 

Scheme 2.202 Synthesis of difluoroenol ethers from esters and lactones [38, 39].

Scheme A.20 Reaction of trimethylsilyl difluoroenol ethers with aldehydes [26].

In particular, defluorination brought about by the Mg-TMSCl-DMF system is reliable for the purpose [11]. Difluoroenol silyl ethers [12], enamines [13], phenyl-1,1-difluoroacetate [14], difluorinated Danishefsky diene [15], and trimethylsilyldifluoromethyl benzenes [16] can be prepared in good to excellent yields. The one-pot synthesis of 22 from 21 is of great interest. Defluoro-dechlorinative double silylation occurs under very mild conditions to afford compound 22, a useful synthetic intermediate, in which two different silyl groups can be replaced with various electrophiles in a stepwise manner [17]. Highly functionalized a-iminoesters (27) can be synthesized via 25 and 26 in excellent yields as shown in Scheme 2.15. 

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. 

Scheme 13.1 Aldol reaction of a,a-difluoroenol silyl ether catalyzed by ytterbium triflate.

Biphenyl derivatives. A biphenol-based chiral phosphoric acid (218) catalysed the asymmetric Mannich-type reaction of iV-Boc protected imine (214) with difluoroenol silyl ethers (215) in the presence of 3 A moleculear sieves in THF to afford p-amino-i ,l -difluoroketones (216) in good yields and with excellent enantioselectivities (up to 94% ee). Optically pure 3,3-difluoroazetidin-2-one (217) was readily synthesised from the Mannich-adduct (216) (Scheme 57), ... 

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