Trifluoromethylation of aromatic compounds

Experiments were performed with various sulfoxylate radical anion precursors sodium dithionite, sodium hydroxymethanesulfinate or a mixture of sulfur dioxide with a reductant, such as zinc or sodium formate (refs. 29, 30).In contradistinction with the trifluoromethylation of aromatic compounds (Figs. 19,20), a stoiechiometric amount of the sulfoxylate radical anion precursor was necessary. In the disulfide case, there is no intermediate able to reduce back the sulfur dioxide which is formed in the medium (Fig. 22). 

Kobayashi, Y Kumadaki, I. Trifluoromethylation of aromatic compounds. Tetrahedron Lett. 1969, (47), 4095-4096. 

SCHEME 9.6 Overview of fluorination and trifluoromethylation of aromatic compounds. 

Aromatic Compounds. Nucleophilic trifluoromethylation of aromatic compounds containing nitro, fluoro, and trifluoromethyl... 

Sawada H, Nakayama M, Yoshida M, Yoshida T, Kamigata N (1990) Trifluoromethylation of aromatic compounds with bis(trifluoroacetyl) peroxide. J Fluor Chem 46 423-431... 

KobayashiY, Kumadaki I (1980) Studies on organic fluorine compounds. Part 27. Abnormal reactions in the trifluoromethylation of aromatic compounds with trifluoromethyl iodide and copper powder. J Chem Soc Perkin Trans 1 661-664... 

Yamakawa described an interesting iron-mediated oxidative trifluoromethylation of aromatic compounds using iodotrifluoromethane and an iron catalyst in the presence of hydrogen peroxide. The reaction was effective for an extensive range of (hetero)aromatic substrates, again with the production of regioisomers in some cases (Scheme 15.96). 

Valence Bond Isomers of Aromatic Compounds Stabilized by Trifluoromethyl Groups Kohayashi Y Kumadaki, I Acc Chem Res 14 76-82 46... 

Miscellaneous PTC Reactions The field of PTC is constantly expanding toward the discovery of new enantioselective transformations. Indeed, more recent applications have demonstrated the capacity of chiral quaternary ammonium salts to catalyze a number of transformations, including the Neber rearrangement (Scheme 11.19a), ° the trifluoromethylation of carbonyl compounds (Scheme 11.19b), ° the Mannich reaction (Scheme 11.19c), and the nucleophilic aromatic substitution (SnAt)... 

Trifluoromethyl-substituted aromatic compounds are obtained by reacting methyl arenecar-bodithioates with tetrabutylammonium dihydrogen trifluoride and l,3-dibromo-5.5-dimethyl-hydantoin. The use of /V-bromosuccinimide or A-iodosuccinimide instead of l,3-dibromo-5,5-dimethylhydantoin affords difluoro(methylsulfanyl)methyl-substitutcd aromatics.62... 

Valence Bond Isomers of Aromatic Compounds Stabilized by Trifluoromethyl Groups ... 

A procedure for alkylation of C=0 double bonds in the presence of (metal-free) organocatalysts and non-metallic nucleophiles has been reported by the Iseki group for trifluoromethylation of aldehydes and ketones [185]. On the basis of a previous study of the Olah group [186, 187] which showed the suitability of non-chiral phase-transfer catalysts for trifluoromethylation of carbonyl compounds, Iseki et al. investigated the use of N-benzylcinchonium fluoride, 182, as a chiral catalyst. The reaction has been investigated with several aldehydes and aromatic ketones. Trifluoromethyltrimethylsilane, 181, was used as nucleophile. The reaction was, typically, performed at —78 °C with a catalytic amount (10-20 mol%) of 182, followed by subsequent hydrolysis of the siloxy compound and formation of the desired alcohols of type 183 (Scheme 6.82). 

Cycloaddition reactions with trifluoromethyl-substituted alkynes provide good access to trifluoromethyl-substituted aromatic compounds,32"34 e.g. formation of 5.32... 

After a brief survey of the history of valence-bond isomers of aromatic compounds, new syntheses and the reactions of these isomers reported in the last decade are reviewed. In the second chapter, the valence-bond isomers of homoaromatic compounds, especially benzene derivatives, are described and in the third chapter those of heterocyclic compounds. Photoreactions of perfluoroalkylated aromatic compounds afford valence-bond isomers in high yields. These isomers are very stable and useful for the synthesis of highly strained compounds. Therefore, the emphasis is put on the chemistry of trifluoromethylated benzvalenes, Dewar thiophenes, and Dewar pyrroles. 

BTF belongs to an important group of trifluoromethyl-substituted aromatic compounds, which have broad applications as intermediates or building blocks for crop protection chemicals, insecticides and pharmaceuticals, as well as dyes. Related higher boiling compounds that are produced in multimillion pound quantities include 4-chlorobenzotrifluoride (PCBTF) and 3,4 dichlorobenzotri-fluoride (3,4-DCBTF). 

For many years now, the reactivity of trifluoromethyl bromide has been underestimated. During the past decade the major breakthrough in this area has been the realisation that trifluoromethylation of organic compounds with this halide can be induced by mild reductants such as thiolates, zinc or sulfoxylate radical anion. Nowadays, a great variety of fluorinated products are available by these new methods sodium triflinate and triflic acid, trifluoromethylated alcohols, trifluoromethyl-containing aromatic compounds, ethyl trifluoropyruvate, trifluoromethylsulfides. ... 

The reactions of trifluoromethyl radicals with a wide variety of aromatic compounds has been an active area of investigation for some time. The studies have not included determinations of the isomer distributions of the products, so that the rate coefficients quoted in the table below are actually composite ones for attack on all of the positions on the ring. A pair of rate studies for the CClFj radical are appended to the end of Table 62. 

Valence-bond isomers of aromatic compounds (both 6-membered and 5-mem-bered) that are stabilized by trifluoromethyl groups are reviewed, and it is concluded that both steric and electronic effects contribute to the stabilizing influence of the CF3 group. A fascinating example is provided of a substituted Dewar benzene (1) that is more stable thermodynamically than the isomeric... 

Yagupolskii, L., Bystrov, V., Stepanyants, A., and Fiatkov, Y., Influence of substituents with trifluoromethyl group on the reactivity of aromatic compounds, Z. Obshchei Khimii, 34, 3682-3690, 1964. 

Reactions with Carhonyl Compounds and Related Derivatives. Since the original procedure for the trifluoromethylation of carbonyl compounds with TMSCF3 was reported (enploying catalytic TBAF as initiator in THF as solvent), several improved protocols have appeared over the years. Thus, removal of residual water by pre-drying the TBAF solution over activated 4 A molecular sieves, in combination with non-polar aprotic solvents, made possible the trifluoromethylation of less reactive substrates such as hindered ketones and aliphatic or aromatic esters (eq 10). Other anhydrous sources of fluoride anions have been successfully applied, including CsF, tetramethylammonium fluoride... 

The F-C reactions of aromatic compounds can provide a practical synthetic route for chiral a-trifluorobenzylalcohols of synthetic importance (Scheme 1). In previous asymmetric syntheses of a-trifluorobenzylalcohols, the asymmetric reductions of trifluoromethyl ketone were used as a key step 30-34). In this F-C reaction, the catalytic activity and enantioselectivity of BINOL-Ti catalysts (55-57) were found to be critically influenced by the substituents of BINOL derivatives (Table I). 1) (i )-6,6 -Br2-BINOL-Ti catalyst was the most effective catalyst. This F-C reaction did not proceed easily as compared with the carbonyl-ene reaction (7,8) or the Mukaiyama-aldol reaction (7) with fluoral. Therefore, the role of the electron-witiidrawing group at the 6,6 -position of BINOL is very important for increasing the Lewis acidity (runs 1 3). Relatively high enantio-... 

Although the sulfur trifluoride compounds are generally useful as selective agents for conversion of carbonyl and carboxyl groups to difluoromethylene and trifluoromethyl groups, variations in reaction conditions are often necessary.7 Thus the reaction of aromatic ketones requires heating at 150°. Since the reaction with aliphatic aldehydes and ketones is exothermic, it is advan-... 

The synthesis of fluorinated aliphatic compounds is the main topic of this chapter. Indeed, numerous aromatic fluorinated products are available commercially. Moreover, in contrast to aliphatic molecules, their synthesis has not undergone significant evolution in the last few years. The synthesis of highly fluorinated compounds is also not considered here, since these compounds are much more involved in the formulation sciences than in medicinal chemistry. In this chapter, the synthesis of fluorinated compounds is dealt with in the following order monofluorinated, then difluoro-methylated, and finally trifluoromethylated molecules. 

In most of cases, the fluorine atom(s) or the CF3 group(s) is borne by aromatic rings. Synthesis of these compounds for the optimization of hits as well as for parallel synthesis is done using the numerous fluoro aromatic or heterocyclic compounds that are commercially available. These latter compounds generally come from aromatic fluorination or trifluoromethylation reactions (especially the Balz-Schiemann reaction) and from heterocyclization reactions. However, fluoroaliphatic chains and fluorofunctionalities are more and more present, because of their pharmacological properties. Some examples are given in this section. 

Other fluoroaromatic compounds such as fluorobenzene, trifluorotoluene and their derivatives may be elaborated to more complex aromatic compounds by directed metallation reactions (in itself, the subject of another large review [322-324]). Wakselman and co-workers described the conversion of 3-tri-fluoromethylphenol into 2-(trifluoromethyl)-l,3-cyclopentadienone, an intermediate they used to synthesise angularly trifluoromethylated steroid analogues [325]. The reaction, which involved an interesting ring contraction reaction, occurred with rather low efficiency (Eq. 122) [326]. 

In most aromatic compounds of interest to topics in this review, the fluorine, trifluoromethyl or similar substituents attached to the nucleus play the role of a highly electronegative ligand, strongly bonded to the nucleus and not participating in chemical reactions. A substantial modification of some physical properties of the molecule is effected by the introduction of such ligands, this also possibly influences their toxicity, as compared with nonfluorinated analogs. 

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