Trifluoromethyl enol ether

The carbonyl of trifluoroacetates is reactive enough to react with phosphoranes and to yield trifluoromethyl enol ethers (the reaction must be conducted without lithium salts i.e., the phosphorane must be generated without a nonlithiated base). In the same way, trifluoroacetamides and trifluorothioacetates afford, respectively, trifluoromethyl enamines and vinyl thioethers (Figure 2.44). " ... 

Figure 2.44 Preparation and reactivity of trifluoromethyl enol ethers. -...

Dehydrobromination of bromotrifluoropropene affords the more expensive trifluoropropyne [237], which was metallated in situ and trapped with an aldehyde in the TIT group s [238]synthesis of 2,6-dideoxy-6,6,6-trifluorosugars (Eq. 77). Allylic alcohols derived from adducts of this type have been transformed into trifluoromethyl lactones via [3,3] -Claisen rearrangements and subsequent iodolactonisation [239]. Relatively weak bases such as hydroxide anion can be used to perform the dehydrobromination and when the alkyne is generated in the presence of nucleophilic species, addition usually follows. Trifluoromethyl enol ethers were prepared (stereoselectively) in this way (Eq. 78) the key intermediate is presumably a transient vinyl carbanion which protonates before defluorination can occur [240]. Palladium(II)-catalysed alkenylation or aryla-tion then proceeds [241]. 

A variety of functional groups that can be tolerated at positions R R, R andR as shown in Table 1. In the case of the trifluoromethyl enol ether (Table 1, entry 6), despite a successful RCM reaction, the subsequent aromatization was not possible. This can be attributed to the electron-withdrawing effect of the CF3 group destabihzing the cation formed during the... 

In 1959 Carboni and Lindsay first reported the cycloaddition reaction between 1,2,4,5-tetrazines and alkynes or alkenes (59JA4342) and this reaction type has become a useful synthetic approach to pyridazines. In general, the reaction proceeds between 1,2,4,5-tetrazines with strongly electrophilic substituents at positions 3 and 6 (alkoxycarbonyl, carboxamido, trifluoromethyl, aryl, heteroaryl, etc.) and a variety of alkenes and alkynes, enol ethers, ketene acetals, enol esters, enamines (78HC(33)1073) or even with aldehydes and ketones (79JOC629). With alkenes 1,4-dihydropyridazines (172) are first formed, which in most cases are not isolated but are oxidized further to pyridazines (173). These are obtained directly from alkynes which are, however, less reactive in these cycloaddition reactions. In general, the overall reaction which is presented in Scheme 96 is strongly... 

Silyl enol ethers have also been used as a trap for electrophilic radicals derived from a-haloesters [36] or perfluoroalkyl iodides [32]. They afford the a-alkylated ketones after acidic treatment of the intermediate silyl enol ethers (Scheme 19, Eq. 19a). Similarly, silyl ketene acetals are converted into o -pcriluoroalkyl esters upon treatment with per fluoro alkyl iodides [32, 47]. The Et3B/02-mediated diastereoselective trifluoromethylation [48,49] (Eq. 19b) and (ethoxycarbonyl)difluoromethylation [50,51] of lithium eno-lates derived from N-acyloxazolidinones have also been achieved. More recently, Mikami [52] succeeded in the trifluoromethylation of ketone enolates... 

Experimental Procedure 4.2.10. Cycloaddition of an Acylcarbene Complex to an Enol Ether Ethyl 5-Ethoxy-2-trifluoromethyl-4,5-dihydro-3-furoate [1417]... 

A semiempirical AMI study of the inverse-electron-demand Diels-Alder reaction of 4-substituted 6-nitrobenzofurans with enol ethers and enamines favours a stepwise mechanism involving short-lived diradical intermediates. The inverse-electron-demand intermolecular Diels-Alder reactions of 3,6-bis(trifluoromethyl)-l,2,4,5-tetra-zine with acyclic and cyclic dienophiles followed by the elimination of N2 produce 4,5-dihydropyridazines, which cycloadd further to yield cage compounds. The preparation of jS-carbolines (90) via an intramolecular inverse-electron-demand Diels-Alder... 

Monoalkyl ethers of (R,R) 1,2-bis[3,5-bis(trifluoromethyl)phenyl]ethanediol, 24, have been examined for the enantioselective protonation of silyl enol ethers and ketene disilyl acetals in the presence of SnCU (Scheme 12.21) [25]. The corresponding ketones and carboxylic acids have been isolated in quantitative yield. High enantioselectivities have been observed for the protonation of trimethylsilyl enol ethers derived from aromatic ketones and ketene bis(trimethylsilyl)acetals derived from 2-arylalkanoic acids. 

The compounds obtained in these reactions, especially enol ethers, are interesting building blocks they can give rise to many other trifluoromethyl molecules. For... 

Fluoral hydrate and hemiacetals are industrial products. They are stable liquids that are easy to handle, and they react as fluoral itself in many reactions. Thus, in the presence of Lewis acids, they react in Friedel-Crafts reactions. They also react very well with organometallics (indium and zinc derivatives) and with silyl enol ethers.Proline-catalyzed direct asymmetric aldol reaction of fluoral ethyl hemiac-etal with ketones produced jS-hydroxy-jS-trifluoromethylated ketones with good to excellent diastereo- (up to 96% de) and enantioselectivities. With imine reagents, the reaction proceeds without Lewis acid activation. The use of chiral imines affords the corresponding 8-hydroxy ketones with a 60-80% de (Figure 2.49). ° ... 

One of the most reactive electrophilic alkenes is l,l-dicyano-2,2-bis(trifluoromethyl)ethene which undergoes cycloadditions with enol ethers, thioenol ethers, ketene acetals and thioacetals even at temperatures as low as — 78 °C. The cyclobutancs are formed as the sole products of the reaction.37-38 The reactions arc regiospecific and highly stereoselective even though evidence for zwitterionic intermediates have been obtained. 

In the presence of copper(I) chloride, FC-113a adds to silyl enol ethers affording adducts which can be transformed into the /1-chloro-/i-trifluoromethyl enones in moderate yields [100]. The carbon-carbon bond is formed via a free radical addition reaction (Eq. 28). Free radical addition mediated by iron pentacarbonyl was also described recently during a synthesis of a modified pyrethroid [101]. 

Bromination of the enol ether product with two equivalents of bromine followed by dehydrobromination afforded the Z-bromoenol ether (Eq. 79) which could be converted to the zinc reagent and cross-coupled with aryl halides [242]. Dehydrobromination in the presence of thiophenol followed by bromination/dehydrobromination affords an enol thioether [243]. Oxidation to the sulfone, followed by exposure to triethylamine in ether, resulted in dehydrobromination to the unstable alkynyl sulfone which could be trapped with dienes in situ. Alternatively, dehydrobromination of the sulfide in the presence of allylic alcohols results in the formation of allyl vinyl ethers which undergo Claisen rearrangements [244]. Further oxidation followed by sulfoxide elimination results in highly unsaturated trifluoromethyl ketonic products (Eq. 80). 

When ketones, aldehydes and esters are transformed to silyl enol ethers, further reaction with trifluoromethyl hypofluorite gives a-fluoro carbonyl products 16 in good to excellent yield.31... 

Reaction of enol ether 1 a with sodium methoxidc or ethoxide. or 1 b with sodium methoxide, gives ketene acetals, which rearrange in the presence of triethylamine to give esters 3.3 The phosphorus ylide trimethoxy[2,2,2-trilluoro-l-(trifluoromethyl)cthylidene]-A ,-phosphane f(CF3)2C = P(OMc),] rearranges readily to dimethyl f2.2,2-trifluoro-1-mcthyl-l-(trifluoro-mcthyi)ethyl]phosphonate [(CF,)2C(Me)PO(OMe)2] in a similar 1.3-shift.5-0... 

In the abstract of a symposium paper22 Nakai and Co-workers briefly reported the synthesis of allyl 1-(trifluoromethyl)vinyl ethers 66 from the corresponding trifluoromethyl ketone enolates followed by Claisen rearrangement to trifluoromethyl ketones 67 under very mild conditions (40 C for 66a, 60 C for 66b22,24). 

Trifluoromethyl ketones can also be synthesized from 1-trifluoromethyl-substituted enol ethers, which are readily prepared from aldehydes via a Wittig reaction (Scheme 9). Similar to Ruppert s procedure (Section 15.1.4.3.4), this method has thus far only been used to prepare trifluoromethyl compounds. The a-amino trifluoromethyl ketones produced in the reaction scheme are much less stable than the corresponding a-amino ketones, which leads to the formation of byproducts (a-hydroxy ketones) during attempts to purify the a-amino trifluoromethyl ketones by chromatography on silica gel. 35 ... 

The synthesis (Scheme 9) begins with the appropriate 1-trifluoromethyl-substituted enol ether 43, where R1 is an amino acid side chain or another appropriate carbon chain. The enol ether undergoes reaction with MCPBA in CH2C12 to give the corresponding epoxy ether 44. The epoxy ether is cleaved by reaction of a wide variety of secondary amines to give the a-amino trifluoromethylated ketone 45. Only a few compounds have been synthesized by this method. 35,36 ... 

Carbonyl Addition Diethylzinc has been added to benzaldehyde at room temperature in the presence of an ephedra-derived chiral quat (8) to give optically active secondary alcohols, a case in which the chiral catalyst affords a much higher enantioselectivity in the solid state than in solution (47 to 48, Scheme 10.6) [30]. Asymmetric trifluoromethylation of aldehydes and ketones (49 to 50, Scheme 10.6 [31]) is accomplished with trifluoromethyl-trimethylsilane, catalyzed by a quaternary ammonium fluoride (3d). Catalyst 3d was first used by the Shioiri group for catalytic asymmetric aldol reactions from silyl enol ethers 51 or 54 (Scheme 10.6) [32]. Various other 1,2-carbonyl additions [33] and aldol reactions [34] have been reported. 

Fluoride ion-catalysed addition of trifluoromethyltrimethylsilane to acyl silanes occurs to give l,l-difluoro-2-trimethylsilyloxyalkenes (silyl enol ethers of difluoromethyl ketones), through nucleophilic addition of trifluoromethyl anion, Brook rearrangement and loss of fluoride. These compounds could be isolated when tetrabutylammonium difluorotriphenylstannate was used as a catalyst use of tetrabutylammonium fluoride gave the product corresponding to subsequent aldol reaction with the difluoromethyl ketone (Scheme 78)m. 

Dihydropyran derivatives (339) have also been obtained by the hetero Diels-Alder reaction between electron-rich olefins such as enol ethers 338 and amino ketones 337 bearing electron-withdrawing groups such as methoxycarbonyl, trifluoromethyl or... 

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