7-trifluoromethyl-substituted substrates

Trifluoromethyl-substituted olefins appear to also be problematic substrates for asymmetric hydrogenation as very long amounts of time and high pressures were required to achieve appreciable yields with ligand 10b (Scheme 9) [49]. Nevertheless, useful yields and excellent enantioselectivities were obtained for most examples. 

Based on the known substrate specificity of a-chymotrypsin, phenylalanine has been chosen as the amino acid at the Pi position (P-nomenclature according to Schechter and Berger) [55]. The a-proton at Pi has been substituted either by methyl or trifluoromethyl. Substitutions beyond Pi contain trifluoromethyl alanine or aminoisobutyric acid. Therefore, each fluorosubstitution can be compared to its natural as well as fluorine-free a-substituted analog, thereby enabling differentiation of the steric and electronic effects. Scheme 2 summarizes the amino acids that have been used in this study. 

A further dependence of the selectivity between different nucleophiles on the stability and reactivity of carbocations was found by Richard and Amyes in a study of reactions of alcohols and carboxylate anions with -substituted a-trifluoromethyl benzyl cations (75, X = Me, OMe, SMe, N(Me)CH2CF3, and NMe2) monitored using the azide clock.305 Apart from the methyl-substituted substrate, for which the reactions approached diffusion control,... 

Common methods for the furan ring construction were applied to preparation of trifluoromethyl-substituted benzofurans starting from the substrates bearing appropriately located CFs-group. Thus, 2-(trifluoropropynyl)-phenol 170 was cyclized into trifluoromethylbenzofuran 171 by heating with pyridine [118]. 

Alternatively, Shibata and coworkers first realized the catalytic enantioselective synthesis of trifluoromethyl-substituted 2-isoxazolines 69 in 2010 by developing a cinchona-alkaloid-catalyzed asymmetric conjugate addition/cyclization/dehydration cascade reaction with hydroxylamines 67 and enones 68 (Scheme 2.19). A wide range of substrates could be employed in this reaction to give the desired cyclized products with excellent enantioselectivities [33]. 

In 2013, a C-H activation route to dibenzopentalenes was discovered by the Itami group (Scheme 2.16) [49]. Through a series of electrophilic palladations and insertions, the diphenyldibenzopentalene 14i was constructed in 52% yield. Notably, this method obviates the need for ortho-functionalized precursors as in prior examples. Over the course of a mechanistic study, it was found that the first C-H palladation event was sensitive to the electronic nature of the substrate and the subsequent alkyne insertion proceeded irrespective of it. Electron-poor / -trifluoromethyl-substituted tolans were excellent substrates (14m, 79% yield), and /w-substituted tolans were decent as well (14n, 53% yield 14o, 66% yield) however, / -methoxy-substituted tolans provided no product. 

Trifluoromethyl groups are aminolyzed by ammonia to yield carbonitriles, which works especially well with electron-rich-substituted trifluoromethane derivatives (e.g., 7), even when aqueous ammonia is used.41 45 It has been proposed that these substrates might react via a fulvene-like intermediate, which could be formed via an ElcB mechanism. With less reactive substrates, sodium amide or liquid ammonia has to be used as reagent in order to achieve carbonitrile formation.3,46 49... 

Tetrafluorobenzyne, generally generated by the treatment of pentafluoro-benzene with butyllithium at -78 °C in ether in the presence of the substrate diene, is a versatile dienophile [9, 103, 104]. In an interesting study of the use of substituted benzynes to synthesize isoindoles, tetrafluorobenzyne, 4-fluorobenzyne, and 4-(trifluoromethyl)benzyne were shown to react in moderate yields with A7 (trimethylsiIyl)pyrroles, with the adducts being easily converted to the respective fluorinated isoindoles [705] (equation 87). 

Evidence for the tetrahedral intermediate includes a Hammett p constant of+2.1 for the deacylation reaction of substituted benzoyl-chymotrypsins and the formation of tetrahedral complexes with many inhibitors, such as boronates, sulfonyl fluorides, peptide aldehydes, and peptidyl trifluoromethyl ketones. In these last the chemical shift of the imidazole proton is 18.9 ppm, indicating a good low-barrier H-bond, and the pJQ of the imidazolium is 12.1, indicating that it is stabilized by 7.3 kcal mol 1 compared to substrate-free chymotrypsin. The imidazole in effect is a much stronger base, facilitating proton removal from the serine. 

Liquid-phase fluorination of methyl-substituted benzene derivatives depends strongly on the structure and concentration of the substrate, its molar ratio to xenon difluoride and the catalyst used (Scheme 32). HF-catalyzed fluorination of 1,2,4,5-tetramethylbenzene with an equimolar amount of xenon difluoride gave a small amount of 1,4-difluoro product, while reaction with two equivalents of xenon difluoride also gave the demethylated product l-fluoro-2,4,5-trimethylbenzene, which was also formed by HF-catalyzed fluorination of 1,3,4-trimethylbenzene34. In contrast, trifluoroacetic acid catalyzed fluorination is much more complex, and forms the four products l-(trifluoromethyl)-2,3,5,6-tetrametylbenzene, 2,4,5-trimethylbenzyl trifluoroacetate, l-fluoro-2,3,5,6-tetramethyl-benzene and l-(trifluoromethyl)-2,3,4,5-tetramethylbenzene, the distribution depending on the amount of trifluoroacetic acid used. Similar results were also observed in the fluorination of 1,2,3-trimethylbenzene and 1,3,5-trimethylbenzene34. 

It is possible to obtain reasonable yield of substitution product when the CF3 group is in position 6, even though this substrate generates an unhindered but poor electrophilic radical, whereas the substrate in which the CF3 group is in position 4 is not anticipated to be a useful substrate for synthesizing trifluoromethyl heterobiaryl derivatives188,2-Amino-... 

Fluorinated aromatic chlorides " or bromides are substrates for nucleophilic substitutions however, fluorine is preferentially substituted. This is demonstrated by the formation of compound 19j in good yield. - The trifluoromethyl and the trifluorometliylsulfonate groups are activating groups that are not readily displaced. Again, chlorine. - i5i.is4 bromine, or iodine are readily substituted by alcoholates. 

In the presence of tris(dimcthylamino)sulfonium difluorotrimethylsilicatc64 65 as a source of nonhydrated fluoride ion.66 trimethyl(trifluoromethyl)si]anc undergoes perfluoroalkylation of polyfluoroaromatic compounds.64 Fluorinated aromatic substrates such as perfluoropyridinc, perfluorotoluene, perfluorobenzonitrile, and perfluorobiphcnyl can be fluoroalkylated, but se-lcctivities are difficult to control and some multiple substitution takes place, resulting in modest yields of monoadducts 8 in the 30-50% range.64... 

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