Aromatic compounds trifluoromethylation

FLUORINECOMPOUNDS,ORGANIC - FLUORINATED AROMATIC COMPOUNDS] (Volll) (+)-N-Methyl-g-[4-(trifluoromethyl)phenoxy]ben-zenepropanamine hydrochloride [54910-89-3]... 

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

Af-trifluoromethyl-AT-nitrosotrifluoroinethanesulfonamide is an effective trifluoromethylatmg agent for aromatic compounds under thermal or photocliemi cal conditions [163] (equation 140)... 

Bis(trifluoromethyl) peroxycarbonate, 705 Bis(trifluoromethyl) peroxydicarbonate, 705 Bis(trifluoromethyl) trioxide IR spectrum, 740 O NMR spectroscopy, 182 Bis(trifluoromethyl) tiioxydicarbonate, 740 Bis(trimethylsilyl) monoperoxysulfate Baeyer-Vilhger oxidation, 785 catalytic epoxidation, 791-2 Bis(trimethylsilyl) peroxide (BTSP) alcohol oxidation, 787-90 alkyne reactions, 800 aromatic compounds, 794-5 Baeyer-Vilhger ketone oxidation, 784-7 demethylation, 798... 

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. 

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... 

Partial Fluorination of (Trifluoromethyl)benzene29 and Aromatic Compounds 1-4 1... 

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

A particularly useful reaction of this type involves the direct formation of hexakis(trifluoromethyl)cyclopentadiene (71) (Scheme 31), or the corresponding cyclopentadienide (72), from the diene (38) by a fluoride ion induced reaction with pentafluoropropene [67-69]. Recent work [54] has shown that very active sources of fluoride ion can be generated by direct reaction of amines, especially TDAE (43), with perfluorinated alkenes or perfluorinated aromatic compounds and these essentially solventless systems promote both oligomerisations (see above) and polyfluoroalkylations. The absence of solvent makes recovery of product very easy, e.g. in high-yielding formation of (73), (74) or (75) (Scheme 32). 

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

Friedel-Crafts Alkylation Reactions. The activation of glyoxylate esters,trifluoromethyl pyruvate esters, and unsaturated a-ketoesters by catalyst 2 converts these materials into effective electrophiles for asymmetric Friedel-Crafts alkylation reactions with activated arenes (eqs 16 and 17). In fact, bis(triflate) (2) is far superior to tbe bis(hexafluoroantimonate) complex at catalyzing the enantioselective alkylation of benzene derivatives. Aniline and anisole derivatives both give the reaction, as do heterocyclic aromatic compounds such as indole and furan. 

Synthesis of trifluoromethylated compounds 152 has been achieved via ester-enolate [2,3]-Wittig and [3,3]-lreland-Claisen rearrangements. Perfluorocyclo-butane phosphonium ylides, e.g. 153, have been used as a masked fluoride anion source in their reactions with alcohols and carboxylic acids which lead to alkyl-and acyl-fluorides. Ylides 153 are also reported to cleave Si-C and Si-O bonds, cause dimerisation of fluoro-olefins, and also react with acid chlorides or other activated aromatic compounds under halogen exchange. ... 

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. 

Among perfluorinated aromatic compounds, only hexakis(trifluoromethyl)benzene was converted to benzvalene. Using an ultraviolet lamp of longer wavelength (307 nm), benzvalene was selectively obtained in high yield (12)14,1S). This benzvalene is very stable and relatively easy to handle. Its reactions will be discussed in Section 2.5. 

A similar method of activation of the perfluoroalkyl silane is used for nucleophilic addition or substitution of trifluoromethyl moieties to obtain electron-deficient fluorinated aromatic compounds [91] (Scheme 2.137). 

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). 

A very important consideration to the chemistry of BTFs is the stability of the CF3 group toward acid or base. The CF3 group of BTF is stable to strongly basic conditions. For example (Scheme 5), BTF can be treated with butyllithium/ potassium f-butoxide in tetrahydrofuran to prepare a lithiated aromatic compound, which yields 2-trifluoromethyl benzoic acid (TFMBA) upon treatment with CO2 [10]. 

Other electron-rich aromatic compounds can be employed as substrates. Pyrroles were trifluoromethylated regioselectively at the 2-position (ref. 27). Recently, the system trifluoromethyl iodide-zinc-sulfur dioxide in DMF at low temperature was used for the trifluoromethylation of aminonaphtalenes and aminoquinolines (ref. 28). Computational results support the mechanism in which the electrophilic trifluoromethyl radical intertact with the aromatic ring at the sites with the greatest electron density of the HOMO orbitals. 

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). 

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. ... 

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