Aniline derivatives trifluoromethylation

The reactivity of aromatic molecules in fluorination reactions with trifluoromethyl hypofluorite has been studied in detail, and in the case of aniline derivatives the effect of the substituent on nitrogen on the relative reactivity and ortho/para ratio in various aprotic nonpolar, aprotic polar and protic solvents has been determined.5... 

The synthesis of aniline derivatives can also be realized by direct addition of the NH2 unit, if the arene ring is made more electrophilic through activation by a trifluoromethyl group. For example, in the case of p-trifluoromethykhlorobenzenetricarbonylchromium complex 47, the aniline derivative 48 can be obtained in 32 % yield using NaNH2/NH3 in HMPT (Scheme 22) [11]. 

Trifluoromethyl hypofluorite reacts with a variety of aromatic systems, with the ease and extent of substitution dependent on the nature of the substituent already present. At low conversion (41%). benzene is converted into a mixture of fluorobenzene (93%) and (tri-fluoromethoxy)benzene(5%) when the conversion is increased, multifluorinated products become significant impurities. The fluorinations of aromatics containing alky] substituents, e.g. toluene, with trifluoromethyl hypofluorite yield complex mixtures of products with poor material balance. TV-Substituted aniline derivatives 11 react with trifluoromethyl hypofluorite to give high yields of ortho- and / ara-monosubstituted fluoro derivatives. 

Finally, a few miscellaneous compounds which were identified in the Delaware River and which have not been previously reported as water contaminants will be discussed Chloro (trifluoromethyl) aniline and chloro (trifluoromethyl) nitrobenzene (no. 55 and 56) were identified in the water, they had maximum concentrations at river mile 78. Both compounds represent common sub-structures in various pesticide and dye molecules, and several of the companies located along the river have patents using these compounds (30-32j. It is possible that these compounds are actually present in the river water as such, but it is also possible that they are formed in the GC injection port by pyrolytic degradation of larger pesticide or dye molecules (see above). All three binaphthyl-sulfone isomers (no. 92) were identified in the river water near Philadelphia. Product literature for one of the companies in the area indicates production of condensed sulfonated polymers derived from naphthalene sulfonic acid and maleic anhydride. It seems likely that the binaphthylsulfones are formed as by-products during preparation of this commercial product. 

Jouannetaud and co-workers229 have explored electrophilic trifluoromethylation under superacidic conditions of aniline derivatives229 and /V-heterocycles. Methyl-substituted anilines and substituted acetanilides [Eq. (5.85)] react with the CC13+ cation generated from CC14 in HF-SbF5 followed by fluorination to yield the corresponding trifluoromethyl derivatives. Under similar conditions, indolines are transformed to the 6-triluoromethyl derivatives, whereas substituted indoles yield 5-triluoromethyl derivatives.230... 

Aromatic primary amines are not only binucleophiles at the amino group, but they also exhibit the properties of C,N-binucleophiles. Their reactions with internal perfluoroolefins lead to quinoline derivatives (98JFC(88)169, 94JCS(CC)134, 98T4949). Thus the reaction of aniline with 2//-heptafluorobut-2-ene yields phenyl(2-trifluoromethylquinolin-4-yl) amine (00ZOR109) when the reaction is carried out with the tetrafluoro-ethylene trimer, it leads to 2-trifluoromethyl-3-(l-N-phenylimino-2,2,2-trifluoroethyl)-4-(N-phenylamino)quinoline (98JFC(88)169). 

If the nucleophile is very reactive, the preferred agent for trifluoromethylation is the dimethyl derivative 229b, which is not very powerful. Less reactive substrates were trifluoromethylated in reasonably good yields by the more powerful dinitro salt 230. The unsubstituted salt 229a is intermediate in its trifluoromethylating power. Carbanions, enamines, enol trimethylsilyl ethers, aniline, phenol, and pyrrole have all been successfully trifluoromethylated at their respective nucleophilic carbon atoms (Equations 112-117). 

Bis(trifluoromethyl)phenyl derivatives with meta substitution of the trifluoromethyl groups can be converted into phosphanes via regioselective lithiation. Thus, Af,fV-dimethyl-3,5-bis(tri-fluoromethyl)aniline (9) can be treated with butyllithium/W,Af,Af. .V -tctramcthylethylene-diamine or with methyllithium alone to yield isomers 10 or 11, respectively. ... 

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. 

A wide range of nucleophilic substrates of different reactivity were trifluoromethylated with these reagents. The substrates include carbanions, activated aromatics, heteroaromatics, enol silyl ethers, enamines, phosphines, thiolate ions and iodide anions. " (Scheme 3.8) The least reactive substrates, such as triphenylphosphine, aniline and phenols, require the use of the most reactive dinitro derivative. Most of the reactions can be conveniently performed with the unsubstituted 5-trifluoromethyl dibenzothiophenium salt (35). The least reactive sulfonium salts are the acyclic sulfonium compounds which reacted only with the sodium thiolates.55,59... 

Both inductive and resonance effects are involved. The favored reaction proceeds through the most stabilized (or least destabilized) intermediate carbocation. Study carefully the resonance forms pictured for the possible cations derived from electrophilic attack on methylbenzene and (trifluoromethyl)benzene (Section 16-2), and on benzenamine (aniline), benzoic acid, and a halobenzene (Section 16-3). Notice the types of groups that fall into the different categories in Table 16-1. In particular, notice the following two general trends ... 

In addition, Schiff bases can also be applied as intermediates of quinoline formation. Thus, Schiff bases derived from 2-(trifluoromethyl) aniline and a methyl naphthone, mediated by lithium 2-(dimethylamino)-ethylamide, were used to furnish a series of substituted 2-(2-naphthyl)quinolines designed to target DNA. ... 

An even more striking illustration can be seen in the following reaction. When the ortho derivative 1 is treated with sodium amide, the only organic product obtained is w -(trifluoromethyl)aniline ... 

Jiang B, Si YG (2002) Zn(II)-mediated alkynylation-cyclization of o-trifluoroacetyl anilines one-pot synthesis of 4-trifluoromethyl-substituted quinoline derivatives. J Org Chem 67 9449-9451... 

Cyclizations of alkynyl derivatives proved to be a synthetically convenient way to 2-(trifluoromethyl)quinolines. Indeed, the intramolecular cyclization of N-(a-trifluoromethyl)propargyl anilines 89 takes place with the gold(I) catalyst under extremely mild conditions to afford 2-trifluoromethylquinolines 90 (Scheme 36). The reaction mechanism has been suggested to involve cyclization and oxidation steps [57],... 

Strekowski L, Janda L, Lee H (1997) Synthesis of Bis(2-arylquinolin-4-yl)amines by lithium Bis(trimethylsilyl)amide-mediated cyclization of ketimines derived from 2-(trifluoromethyl) anilines and aryl methyl ketones. J Org Chem 62 4193 197... 

A group of methods for the preparation of fluoroalkyl-substituted pyrimidines relied on CNCh-CCN connection of the aromatic ring. A variety of fluorinated 1,3-dielectrophiles was used for the annulations of CNC triade to CCN binucleophiles (i.e. anilines, enamines and electron-rich amino heterocycles). The most widely used among such 1,3-CNC-dielectrophiles are functionalized heterocumulenes 845-847 (Fig. 26) trifluoromethyl substituted imine derivatives 848, 849 and 850 can be also mentioned. 

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