Lithium trifluoromethyl derivatives

More recently Ito and Mikami observed" that the titanium reagent is not indispensable in the case of highly basic lithium enolates derived from cyclic ketones or silyl enolates, for which the reactions are very fast (ending in ca Is to 5 min) and afford high yields of the a-trifluoromethylation products. A tentative radical mechanism has been proposed for these processes" involving reaction of the Mef free radical with the enolate to give a radical intermediate which reacts with another MefI molecule to afford Mef and the a-trifluoromethylation product (equation 42). 

The reaction of the lithium enolate of 2-methyl-1-indanone with the thiophenium salt (35) leading to the 2-trifluoromethyl derivative in 51% yield is an exception. With all other in situ generated enolates of ketones, no trifluoromethylation was observed. To moderate the reactivity of the enolates, a boron Lewis acid (40) was added to form the boron complexes. This made a regio-, diastereo- and enantio-selective trifluoromethylation possible in good to high yields. ... 

Silyl enol ethers have also been used as a trap for electrophilic radicals derived from a-haloesters [36] or perfluoroalkyl iodides [32]. They afford the a-alkylated ketones after acidic treatment of the intermediate silyl enol ethers (Scheme 19, Eq. 19a). Similarly, silyl ketene acetals are converted into o -pcriluoroalkyl esters upon treatment with per fluoro alkyl iodides [32, 47]. The Et3B/02-mediated diastereoselective trifluoromethylation [48,49] (Eq. 19b) and (ethoxycarbonyl)difluoromethylation [50,51] of lithium eno-lates derived from N-acyloxazolidinones have also been achieved. More recently, Mikami [52] succeeded in the trifluoromethylation of ketone enolates... 

Chiral derivatives of hemiacetal from fluoral have been prepared by adding an alcohol to fluoral in the presence of (l )-BlNOL— Ti(0—iPr)2 or by HPLC resolution of the racemate. The displacement of the sulfonate moiety from the tosyl derivative, by an alkyl lithium aluminate, affords the trifluoromethyl ether with inversion of configuration and an excellent chirality transfer (Figure 2.49). ° ... 

Only a few reports have appeared of reactions of substituted 1,8-phenanthrolines. From spectroscopic evidence it has been established that 4-hydroxy-2-trifluoromethyl-l,8-phenanthroline exists as the 4-oxo tautomer.38 It is converted with phosphorus bromides into 4-bromo-2-trifluoromethyl-l,8-phenanthroline. The bromo group has been replaced by lithium with w-butyl lithium and the lithio derivative converted into 4-carboxy-2-trifluoromethyl-l,8-phenanthroline with carbon dioxide.215... 

The bromine group in 4-bromo-5-methoxy-2-trifluoromethyl-l,10-phenanthroline has been replaced by lithium with w-butyllithium and the lithio derivative reacted with pyridine 2-aldehyde.215... 

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. 

Only the trifluoromethyl group has been subjected to reduction in this class of compound. Although not reduced by zinc in acetic acid or by sodium in ethanol, diethyl 2-methyl-4-(tri-fluoromethyl)-1//-pyrrole-3,5-dicarboxylate (1) is reduced at the trifluoromethyl group with an excess of lithium aluminum hydride to give the corresponding tetramethyl derivative 2 sodium borohydridc in ethanol is quite inefficient.104... 

The lithium benzamidinates 8 can be obtained analytically pure by recrystallization from hexane. Unsolvated 8 (R = CF3) is especially remarkable in that it sublimes readily at room temperature and dissolves freely in nonpolar solvents such as toluene or even hexane. Although the molecular structures of 8 (R = CF3) has not been determined by X-ray diffraction, it is highly likely that the 2,4,6-tris(trifluoromethyl)phenyl substituent is responsible for the remarkable properties of this particular lithium benzamidinate. It has been demonstrated that the stabilizing influence of the 2,4,6-tris(trifluoromethyl)phenyl substituent can be traced back to a combination of steric and electronic effects [42]. In addition, this ligand allows the characterization of its derivatives by 19F NMR spectroscopy. 

Trimethyltrifluoromethylsilane, which is now generally referred to as Ruppert s reagent [92], has been widely investigated [93-96] as an intermediate for transferring the trifluoromethyl group as a nucleophile, thus compensating for the deficiencies of poly-fluoroalkyl Grignard or lithium derivatives. This approach also complements other methods for transfer of trifluoromethide ion. A variety of procedures have now been developed for the synthesis of this compound but the electrochemical procedure [93]... 

Analogous to epoxides, aziridines can be prepared by the methylenation of imines. In this case, ethyl diazoacetate is the most common source of carbenes. For example, the imine derived from p-chlorobenzaldehyde 148 is converted to the c/j-aziridinyl ester 149 upon treatment with ethyl diazoacetate in the presence of lithium perchlorate <03TL5275>. These conditions have also been applied to a reaction medium of the ionic liquid l-n-butyl-3-methylimidazolium hexafluorophosphate (bmimPFe) with excellent results <03TL2409>. An interesting enantioselective twist to this protocol has been reported, in which a diazoacetate derived from (TJ)-pantolactone 150 is used. This system was applied to the aziridination of trifluoromethyl-substituted aldimines, which were prepared in situ from the corresponding aminals under the catalysis of boron trifluoride etherate <03TL4011>. 

C-Trifluoromethylation of titanium enolates by CF3I was recently compared to that of lithium enolates. Given that CF3 derivatives do not undergo substitution reactions by either Sn 1 or Sn2 reactions, a chain reaction involving CF3 and/or CF3U has been suggested. To understand this, thermochemical considerations include the strengths of Ti—I and Li—I bonds, and barriers for loss of Ti(III) and Li(0) from ketyl radicals. 

Scheme 2.166 Addition of sterically demanding tert-butyl lithium to trifluoromethyl acetylene derivatives leads to difluorocyclopropenes [48]. The driving force of the cyclization reaction is energetically favorable extrusion of lithium fluoride from the vinyl lithium intermediate.

However, a source of the non-natural 9S isomer (2) was first required. The ready availability of natural crinitol made a racemization/resolution route, as illustrated in Scheme 1, attractive. Racemization was accomplished by Collins oxidation (16,25) to the dicarbonyl compound (14), followed by lithium aluminum hydride (LAH) reduction to give the racemic mixture (1 + 2). Resolution via diastereomeric derivatives seemed plausible. Esterification with enantiomerically pure a-methoxy-a-(trifluoromethyl) phenylacetic acid (MTPA) (17), followed by separation of diastereomers by recycle-HPLC (R-HPLC), had earlier been used to purify enantiomers of ipsenol and ipsdienol (26). A model system, the resolution of -3-nonen-2-ol, a secondary allylic alcohol naturally occurring in Rooibos tea (16,27), also worked satisfactorily. Therefore, the route using the bis-(MTPA) esters was selected for crinitol. 

Commercially available in 75% ee, trifluoromethyloxirane (34) can be obtained optically pure by enantioselective hydrolysis." " It has been elaborated via its lithium salt into a wide variety of derivatives incorporating quaternary chiral carbon centers. Treatment with butyllithium at about — 100°C generates the trifluoromethyl-stabilized anion (35), which is stable for an hour at —78°C. It reacts with such electrophiles as aldehydes, ketones, and halides with retention of configuration, often in very good yield, to give products that are useful as synthetic intermediates. As an example, anion 35 reacts with a Weinreb amide to afford ketone 36." ... 

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. ... 

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