Allylic Trifluoromethyl Groups

A phenyl substituent or an additional conjugated double bond at the /1-position does not affect the chemical shift any differently than does an alkyl substituent. 

The carbon spectrum is wonderfully discernable, with all three carbons appearing as quartets in the same general region, with the highly split (270 Hz) trifluoromethyl carbon at 122.8 ppm, the C2 carbon at 126.4 ppm with 34 Hz coupling, and the Cl carbon absorbing at 123.6 ppm with 6.9 Hz coupling. 

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Allylic trifluoromethyl groups that are of the type CF3CR=C appear at higher field than those of the CF3CH=C type, which is consistent with our knowledge of the effect of branching on chemical shift (Scheme 5.34). 

Trifluoromethyl groups are very resistant to hydrolysis, unless they are allylic or benzylic, or vicinal to a carbon linked to hydrogen. In the last case, elimination of hydrogen fluonde leads to the formation of a difluoromethylene group which is key to additional reactions... 

Such rearrangements are common during attempted allylic halogen exchange reactions, especially when the stable trifluoromethyl group results.6,7... 

The substitution of a trifluoromethyl group at C4 in ether 57 (substitution at position 1 on the allyl fragment) leads to no rate acceleration in comparison with allyl vinyl ether, which is in sharp contrast with a 3.5 kcal moP 1 lower Ea for the C4 cyano compound. This indicates that it is not the electron-withdrawing capacity of the substituent at C4, but its ability to stabilize radical character, which is important in stabilizing the transition state/ ... 

The palladium-catalyzed cyclization of ( )-3-alkynyl-3-trifluoromethyl allylic alcohols proceeds via a favourable 6-endo-dig cyclization due to the electron withdrawing properties of the trifluoromethyl group to afford 4-trifluoro-methyl-27/-pyrans (Equation 8) <2000TL7727>. 

In all cases it was reported that the trifluoromethyl group enhances the interaction in the prochiral ion pair, resulting in higher ee. The exception appears to be the asymmetric synthesis of a-amino acids via alkylation of the benzophenone Schiff base of glycine alkyl esters with allyl bromide, which produced a 56% ee with the trifluoromethyl-substituted catalyst compared to 66% with the unsubstituted catalysts TY-benzylcinchoninium chloride (3) or TY-benzylcinchonidinium chloride (4) (eq 5). ... 

The only example of an N-sulfonyl ketimine participating in an ene reaction involves the tosyl imine of trifluoroacetone 266 [90] [Eq.(62)]. When heated with a terminal olefin such as allyl benzene (265) in refluxing xylene, imine 266 leads to ene product 267 in moderate yields. However, internal alkenes gave significantly lower yields of ene products. The inefficiency of the ene process with more highly substituted olefins was ascribed to unfavorable steric effects due to the bulky trifluoromethyl groups. Interestingly, with /J-methyl styrene and allyl thiophenyl ether, [2+2]-cycloadducts were detected rather than ene products. 

The fluorine atom adjacent to a trifluoromethyl group in the furan ring shown below could be replaced under mild conditions by various nucleophiles. Consequently, the reaction of 2-fluoro-3-trifluoromethylfuran with allyl alcohol followed by a Claisen rearrangement led to the formation of trifluoromethyl substituted butenolides <01TL1657>. 

This reaction was initially reported by Finkelstein in 1910. It is a preparation of alkyl iodide from alkyl bromide or chloride with potassium or sodium iodide in acetone. Therefore, this reaction is generally known as the Finkelstein reaction. Occasionally, it is also referred to as the Finkelstein halide exchange, Finkelstein displacement, or Conant-Finkelstein reaction. Mechanistically, this reaction is a simple nucleophilic substitution (often via Sn2), as iodide is a stronger nucleophile than bromide or chloride. The yield of this reaction is very high and can be quantitative if occurs in DMF. It was found that the trifluoromethyl group retards the displacement of bromide when it presents as an a- or /3-substituent but accelerates the reaction as a substituent in an allylic chloride. Under normal conditions, this type of halide displacement does not occur for aryl halides. For dihalides, unsaturated or cyclic compounds may form via carbocation intermediates, which form transient covalent iodides or are reduced directly by iodide to free radicals. However, the aromatic halide exchange reacts smoothly when 10% Cul is present in the reaction... 

In 2011, Jiang and co-workers [133a] and Shibata and co-workers [133b] reported independently an enantioselective trifluoromethylation of BH carbonate at the allylic position by employing 74 as the catalyst and Rupert-Prakash reagent as the source of trifluoromethyl group (entry 12). 

In this way any intermediate anion is stabilized by inductive withdrawal by the trifluoromethyl groups, as well as gaining allylic stabilization if its lifetime permits 90° rotation of the terminal orbital into alignment with theTr-bond. 

Following the biosynthetic mechanism, initial ionization of GDP to the cation followed by the subsequent addition of the IDP unit forms the FDP cation in a reaction that is catalyzed by FPPS prenyltransferase (Scheme 7.1) [2]. The mechanism is based on the findings that the enzyme, which normally catalyzes the addition of GDP to IDP, is also able to catalyze the hydrolysis of GDP [3]. Deuterium experiments of this hydrolysis process either with D O or with (1S)-[1- H] GDP indicated that C—O bond was broken and the chirality of the C-1 carbon of GDP was inverted in this process. In addition, when trifluoromethyl group was present at the C-3 position or fluoro atom at the C-2 position of the allylic substrate, destabilization of the cation has been witnessed as observed on the retard of enzyme reaction [4]. In the elimination step (Scheme 7.1) hydrogen is removed from C-2 of IDP part with simultaneous formation of a double bond. The formation of a trans or cis double bond during the FPPS reaction depends on the spatial orientation of IDP relative to the elongating FDP. In the tranx-prenyltransferases, the GDP... 

Kawatsura M, Hrrakawa T, Tanaka T, Dceda D, Hayase S, Itoh T. Regioselective synthesis of trifluoromethyl group substituted allylic amines via palladium-catalyzed allylic amination. Tetrahedron Lett. 2008 49 2450-2453. 

Hirakawa T, Ikeda K, Tanaka T, Ogasa H, Kawatsura M, Itoh T. Regioselective synthesis of trifluoromethyl group containing allylic amines by palladium-catalyzed aUyUc amination and sequential isomerization. Tetrahedron 2011 67 8238 247. 

Clearly allylic trifluoromethylation is an important topic with several other groups reporting in the area these methods are summarised in Scheme 15.110. ... 

The thus prepared /l-trifluoromethylated 0,S-acetal 4 allows us to make a carbon-carbon bond via a carbocation at the -position to the CF 3 group as shown in Scheme 6.9 [48]. Interestingly, Lewis acid-mediated allylation and cyanation can be achieved efficiently only when electrogenerated acids (EGA) are employed. 

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