Arenes trifluoromethylation

Transition metal-catalyzed arene trifluoromethylation 12CJO1380. 

MacMillan reported a photoredox catalyst induced arene trifluoromethylation approach emplo3dng triflylchloride as the CF3 source. In this instance, treatment of the parent C-H compound with a ruthenium(ii) or iridium(iii) catalyst under irradiation from a 26 W household lightbulb resulted in the direct trifluoromethylation of 5- and 6-membered heterocycles as well as benzenoid systems (Scheme 15.94). Again, as with other innate C-H methods, some examples did lead to the formation of regioisomers. 

Scheme 15.95 MacMillan s photocatal rzed arene trifluoromethylation of Lipitor.

Aromatic thio orthoesters are successfully converted into trifluoromethyl arenes by treatment with a pyridinium polyhydrogen fluoride-A -halo imide reagent. The reactions are conducted at -30 to -20 °C, and the nature of A-halo imide is critical both 1,3-dibromo-5,5-dimethylhydantoin and A-bromosuccin-imide give similar yields of trifluoromethyl compounds [5] (equation 7)... 

An unprecedented carbene insertion reaction was observed on reaction of the cationic re-arene ruthenium amidinates with trimethylsilyldiazo-methane (Scheme 145, TFPB = tetrakis[3,5-bis(trifluoromethyl)phenyl]borate). 

Trifluoromethyl groups that are bound to sp2 carbons of alkenes, arenes, or heterocyclic compounds are slightly deshielded compared to the saturated counterparts, but the influence is relatively small (Scheme 5.32). 

Since these methoxylated and acetoxylated sulfides have an acetal structure, it is expected that Lewis acid catalyzed demethoxylation should generate a carbocation intermediate which is stabilized by the neighboring sulfur atom. In fact, nucleophilic substitution with arenes has been successfully achieved as shown in Scheme 6.7 [43], This procedure is useful for the preparation of trifluoroethyl aromatics. As already mentioned, generation of carbocations bearing an a-trifluoromethyl group is difficult due to the strong electron-withdrawing effect. Therefore, this carbon-carbon bond formation reaction is remarkable from both mechanistic and synthetic aspects. 

Lachwa, J. et al.. Changing from an unusual high-temperature demixing to a UCST-type in mixtures of l-alkyl-3-methylimidazolium bis (trifluoromethyl) sulfonyljamide and arenes. Green Chem., 8, 262, 2006. 

It was recognized in the 1930s that Swarts work on (trifluoromethyl)benzene opened the way to the synthesis of many side-chain-fluorinated arenes. Aryl trichloromethyl groups were found to be readily converted to trifluoromethyl groups by anhydrous hydrogen fluoride, and systematic work in the area was initiated. This included commercial investigations, and patents were filed on potential uses of both side chain and nuclear fluorinated arenes. 

The methods that are known for introducing trifluoromethoxy groups into arenes are generally not effective. An interesting onc-pot O-alkylation of phenols followed by halogen exchange to form trifluoromethyl ethers 6 has been described227 (see also Houben-Weyl, Vol. E4, pp 626-627). 

Arenecarbodithioates are also converted into (trifluoromethyl)arenes using bromine trifluoride (3.5 equiv of bromine trifluoride, trichlorofluoromethane, 0 C). In this way XC6H4CF3 (X = 4-CN, 2-C1, 3-Br) can be obtained in 70-75% yield.63... 

Table 4. Conversion of Arenepolycarboxylic Acids into Poly(trifluoromethyl)arenes...

Carboxylic acid fluorides, intermediates in the pathway to trifluoromethyl derivatives, are readily formed in reactions of all types of carboxylic acids with sulfur tetrafluoride derivatives (see Section 8.2.4.). Little attention has been paid to fluorination of other carboxylic acid halides. Aroyl chlorides are converted into aroyl fluorides by treatment with sulfur tetrafluoride, e.g. formation of l,41 or to (trifluoromethyl)arenes, e.g. 2 and 3. in the presence of hydrogen fluoride.45 Chlorination of the aromatic ring occurs in some cases.41... 

Trifluoromethyl)-3//-diazirin-3-yl]arenes, e.g. 36 (R1 = CF3), were introduced as photophores by Brunner et alJ116 to provide a more favorable carbene than the one produced from diazoesters[117 or from aryldiazirines. 118 Both 3//-diazirin-3-ylarenes I8-1201 and the [(3-tri-fluoromethyl)-3//-diazirin-3-yl]arenes (e.g., 36, R = H, CF3, respectively) 116 are more stable in acid than most diazoesters, and photolyze at around 360 nm to generate highly reactive carbenes such as 37. However, these diazirines can photo-isomerize to some extent to the... 

Scheme 11 Photolysis Reactions of [3-(Trifluoromethyl)-3//-diazirin-3-yl]arenes and 3/f-Diazirin-3-ylarenes171...

The syntheses of 4-[3-(trifluoromethyl)-3//-diazirin-3-yl]arene-containing peptides are carried out in a straightforward manner. In solid-phase syntheses, H-Phe(4-Tmd)-OH [Tmd = 3-(trifluoromethyl)-3//-diazirin-3-yl] is incorporated as the Fmoc-Phe(4-Tmd)-OH (Table 4).[i23,130-133] Solution-phase syntheses of [Phe4(4-Tmd)J-Leu-enkephalin and [Phe2(4-Tmd)J-aspartame employ Boc-Phe(4-Tmd)-OH and are carried out by the mixed anhydride method.1122 Apparently Phe(4-Tmd) is stable in TFA/CH2C12 (1 1) for 30 min at rt 122 or even in neat TFA for 15 min at 0°CJ134] A post-synthetic modification of a free peptide has been carried out by the mixed anhydride mediated coupling of 4-[3-(trifluoromethyl)-3/7-diazirin-... 

Bis(trifluoromethyl) nitroxide abstracts aldehydic hydrogen atoms from perfluorobenzaldehyde with great case, to give the ( [bis(trifluoromethyl)amino]oxyjcarbonyl)arene in almost quantitative yields.188 The reaction has also been extended to other classes of compounds (vide infra).189... 

Schlosser and co-workers have reported the shift of lithium in lithiated l-bromo-3-(tri-fluoromethyl)benzene 2,fa Quenching at — 100 C gives exclusively the product derived from 2, whereas after 2 hours at — 75 C, arene 2 is completely converted into less basic 3. A lithium-iodine exchange takes place in lithiated 2-chloro-3-iodo-6-(trifluoromethyl)pyridine 4, which at —85 C is totally converted into the less basic isomer 5.7 These rearrangements have been discussed in terms of a base-catalyzed halogen dance or halogen-shuffling mechanism. 

Bis-[1-hydroxy-2,2,2-trifluoro-l-trifluoromethyl-ethyl]- VI/la2, 1357 (Ketone + Arene)... 

Trifluoromethylation of arenes.1 Arenes are trifluoromethylated by CF3Br on irradiation (315-440 nm) in acetonitrile. This photochemical reaction with uracil provides 5-trifluoromethyluracil in 11% yield. 

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