Trifluoromethylated pyridines basicity

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. 

The basicity of trifluoromethylated pyridines differs significantly depending on the position of CF3-group in the cycle. Timperley et al. recently demonstrated that both 3- and 4-trifluoromethyl pyridines in reaction with CH3I at 70°C form the corresponding pyridinium salts 98 and 99 in 72 and 39% yield. However,... 

Iodopyridine, recrystallized from light petroleum, 3-(trifluoromethyl)pyridine and 4-(trifluoromethyl)pyridine passed through a column of freshly activated basic aluminium oxide. 

Similar to the Dakin-West procedure previously mentioned, the Henry nitro-aldol condensation reaction is most widely used to synthesize trifluoromethyl ketones, although there are many examples of a,a-difluoroalkyl ketones synthesized by this method (Table 6)JU 12271 The method for a,a-difluoroalkyl and trifluoromethyl ketone synthesis is identical except for the final oxidation although fluoroalkyl and a,a-difluoroalkyl ketones are easily oxidized by the Sarett method (Cr03/pyridine),[12 the corresponding trifluoromethyl ketones can only be oxidized under basic conditions (0.3 M NaOH) with KMn04Jul Also, in some of the syntheses of a,a-difluoroalkyl ketones, the nitro alcohol intermediate was protected by si-lylation with /ert-butylchlorodimethylsilane. The silyl group was later removed by TosOH prior to oxidation. The full details of this method are given in Section 15.1.4.3.2. 

Two aspects of ligand-exchange reactions are under active study at present. The first of these areas is the development of the chemistry of the bis(trifluoromethyl)zinc adducts. Like the cadmium compound, (CF3)2Zn is isolatable only if complexed by 2 mol of base. The (CF3)2Zn 2 pyridine species (101), however, exchanges ligands only at a sluggish rate (113). The adducts of the less basic solvents examined to date yield complexes that are exceedingly reactive but very difficult to purify. 

Since Cd(CF3)2DME is ordinarily vastly superior to Hg(CF3)2 as a tii-fluoromethylating agent, it seems only reasonable to assume that trifluoromethyl zinc compounds might well be even more effective. Diligand Zn(CF3)2 complexes have been prepared by a number of routes, including the reactions of Zn(CH3)2 with Hg(CF3)2 (87) orCF3I (88) in basic solvents like pyridine, dimethoxyethane, and acetonitrile. 

Although early F NMR studies appeared to indicate that (CFj)2Hg and (CH3)2Cd undergo ligand exchange reactions in basic solvents like pyridine, no products from the reaction had been isolated." The procedure that follows depends upon the observation that the methyl, trifluoromethyl, and mixed methyl-... 

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