Trifluoromethylation allylic substitution

Nagasawa and co-workers reported the use of a chiral bis-thiourea catalyst (108) for the asymmetric MBH reactions of cyclohexenone with aldehydes [95]. Since others had already shown that thioureas form hydrogen bonds with both aldehydes and enones, it was hypothesized that the inclusion of two thiourea moieties in close proximity on a chiral scaffold would organize the two partners of the MBH reaction and lead to enantiofacial selectivity. Initial studies showed that the achiral 3,5-bis-(trifluoromethyl)phenyl-substituted urea increased the rate of MBH reaction between benzaldehyde and cyclohexenone. These authors then showed that chiral 1,2-cyclohexyldiamine-linked bis-thiourea catalyst 108, used at 40 mol% loading in the presence of 40 mol% DMAP, promoted the MBH reactions of cyclohexenone with various aliphatic and aromatic aldehydes (40) to produce allylic alcohols in moderate to high yields (33-99%) and variable enantio-selectivities (19-90% ee Table 6.33). 

As illustrated in the following scheme, trifluoromethyl-substituted furans were generated in high yields by cyclization of ethynyl trifluoromethyl allyl alcohol in the presence of AgOTf as catalyst <07EJO3916>. The starting material can be obtained easily from 1,2-unsaturated trifluoromethyl ketones. 

A large number of different a,(o-bis[(trifluoromethyl)sulfonyloxy]-substituted organosilicon compounds can be obtained by relatively simple methods from the corresponding amino-, allyl-, or phenylsilanes. Moreover, it is remarkable that these silyl triflate derivatives are often easily formed, when the synthesis of the corresponding chloro- or bromosilanes is difficult or does not appear to have been attempted. Eq. 2 and Eq. 3 show selected examples of this synthesis [10-12]. The products were prepared in high purities and yields. The resulting triflates should be used for the polycondensation without further purification, because they often cannot be destilled without decomposition. 

Planar chiral phosphaferrocene-oxazolines (379) constitute another family of complexes that are usefiil as ligands in asymmetric catalysis. Preparation of these takes advantage of a modified Friedel-Crafts acylation of (373) and an unusual conversion of the resulting trifluoromethyl ketone into an amide that is then cyclized to an oxazoline. The diastereomeric complexes thus formed are chromatographically separable and are used in a palladium-catalyzed asymmetric allylic substitution. Modification of this complex by using the anion derived from 3,4-dimethyl-2-phenylphosphole gives more... 

The a-substituted 1-methyl allyl vinyl ether was shown to isomerize with a strong preference for the irons product (i.e., 95 % irons, 5 % cfe) . This corresponds to a conformational preference for equatorial methyl (as opposed to axial) in the chair transition state of about 2.4 kcal.mole . The identical value was calculated from the irons product preference in the allyl ester Claisen rearrangements (see a-methyl allyl acetate and a-trifluoromethyl allyl trifluoroacetate). 

Ichikawa, J., Nadano, R. and Ito, N. (2006) 5-endo Heck-type cyclization of 2-(trifluoromethyl)allyl ketone oximes synthesis of 4-difluoromethylene-substituted... 

Fluorinated analogues of biologically active molecules have received, in the past twenty years, an increasing interest. The Claisen-Johnson rearrangement applied to fluoro-substituted allylic alcohols appeared rapidly as a method of choice for the synthesis of various fluoro-polyfunctionalized compounds. Claisen rearrangement and Claisen-Johnson rearrangement of trifluoromethyl allylic alcohols 533 developed by Ishikawa [131] afforded selectively the anticipated esters 534 and 535. Z,syn-config-... 

Stereochemical results were similar to previous studies, with a predominance of anti products observed for the allylation of aromatic and alkyl aldehydes using y-substituted allylic bromides. In the same paper, the system was also used for the allylation of unprotected carbohydrates, a use that is particularly advantageous for such water-soluble substrates. As with aldehydes that possess functional groups at the a-position that is Lewis basic, a five-membered chelation transition state was proposed to account for the proportion of syn products. The group extended this work to the synthesis of P-trifluoromethylated allylic alcohols [32], and the effects of chelation control was again demonstrated in dramatic stereochemical reversal from minor structural changes in the aldehyde (Figure 8.13). 

For other allylic substitution reaction of CFs-substituted allylic alcohol derivatives, see Okano T, Matsubara H, Kusukawa T, Fujita M. The polar effect on the regiochemis-try of nucleophilic substitution of trifluoromethylated ju-allylpaUadium complex. J. Org. Chem. 2003 676 43-48. 

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. 

Trifluoromethyl-substituted 1,3-dipoles of the allyl type. Trifluoromethyl-substituted azomethine imines ate readily available on reaction of hexafluo-... 

Two convenient methods have been developed for the preparation of trifluoro-methyl-substituted alkoxyallenes. Reductive elimination of allylic acetates 30 with samarium diiodide leads to 31 (Scheme 8.11) [38], whereas reaction of Wittig cumu-lene 32 with phenyl trifluoromethyl ketone (33) and thermolysis of the intermediate 34 provides 35 (Scheme 8.12) [39]. 

The anti-SN2 substitution of allylic aziridines (see Section 10.5.2.1.3.2) has been extended to the synthesis of the methyl-substituted D-Ala-Ala alkene isostere 153 (Scheme 33)J91 For the corresponding (trifluoromethyl) alkene isostere, the aziridine precursor could not be formed. Instead, allylic SN2 displacement (see Section 10.5.2.1.3.1) of the mesylate 154 occurred readily to provide the Ala-D-Ala isostere 155. 

Andreev and co-workers have undertaken extensive studies on the reactions of allyl, crotyl, and propargyl alcohols with 2-substituted pentafluoropropenes 14.11 Allyl and crotyl alcohol react at 5-20 C with various 2-substituted pentafluoropropenes 14 in the presence of potassium fluoride in dimethylformamide to give -substituted a-(trifluoromethyl) esters 16. Saponification yields the corresponding acids. 

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/ ... 

A wide variety of a-trifluoromethyl-substituted amino acids are now available from the reaction of 5-fluoro-4-trifluoromethyl-l,3-oxazoles with allylic alcohols and benzyl alcohols. The reaction sequence involves a low-temperature Claisen rearrangement or a radical 1,3-benzyl shift from oxygen to carbon, respectively [88AG(E)848 89S850] (Scheme 86). 

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). ... 

Grellepois, F., Chorki, F., Ourevitch, M., et al. (2002) Allylic bromination of anhydrodihydroartemisinin and of its 10-trifluoromethyl analogue a new access to 16-substituted artemisinin derivatives. Tetrahedron Lett., 43, 7837-7840. 

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