Lithiating reagents

The enantioselectivity is due to the retention of the chiral sparteine in the lithiated reagent. The adducts have been used to synthesize a number of pyrrolidine and piperidine derivatives. 

Coupling of certain lithiated reagents with aryl and vinyl halides is also possible.82 These reactions probably proceeds by a fast halogen-lithium exchange, generating the alkyl halide, which then undergoes substitution. This reaction has been applied to P-lithiobenzamides.83... 

In addition to applications as nucleophiles, the lithium reagents have enormous importance in synthesis as bases and as lithiating reagents. The commercially available methyl, n-butyl, s-butyl, and f-butyl reagents are used frequently in this context. 

Acceptor-substituted allenes can be prepared from the corresponding propargyl precursors by prototropic isomerization (see Section 7.2.2). Conversely, such allenes can also be used to synthesize propargyl compounds. For example, treatment of the sulfoxides 417 with 1 equivalent of a lithiation reagent leads to the intermediates 418, which furnish propargyl sulfoxides 419 by hydrolysis (Scheme 7.55) [101]. If the electrophiles used are not protons but primary alkyl halides or carbonyl compounds, the products 420 or 421, respectively, are formed by C,C linkage. 

Stoichiometric, irreversible formation of enolates from ketones or aldehydes is usually performed by addition of the carbonyl compound to a cold solution of LDA. Additives and the solvent can strongly influence the rate of enolate formation [23]. The use of organolithium compounds as bases for enolate formation is usually not a good idea, because these reagents will add to ketones quickly, even at low temperatures. Slightly less electrophilic carbonyl compounds, for example some methyl esters [75], can, however, be deprotonated by BuLi if the reactants are mixed at low temperatures (typically -78 °C), at which more metalation than addition is usually observed. A powerful lithiating reagent, which can sometimes be used to deproto-nate ketones at low temperatures, is tBuLi [76],... 

However, as also observed in germanium chemistry, a mixture of dihydride with an excess of lithiated reagent behaves as a stannyldianion in reactions with organic halides, polyformaldehyde or epoxides (Scheme 7)29, and it thus appears as an interesting synthetic reagent. 

The reaction was extended to 1,3-dienyltins, giving the corresponding lithiated reagents, both in terminal633-635 or internal636 position, which can be substituted by alkoxy groups637. Recently, a 1,3,5-trienyl lithium carbanion was prepared in a similar way from 22 and used for a further synthesis (equation 48)638. 

In the reaction of 1/7-indol-l-ylsilylamine 256 and lithium amide the latter acts as the lithiation reagent for the more basic nitrogen atom of the heteroaromatic system. The products are 1-lithium indolide and amine 253 (R = Bu"). For this reason a reverse synthetic strategy is necessary to obtain compound 256 (Scheme 53) <1996JOM(524)203>. 

The Wittig-Horner reaction of protected 3-formylindazoles with iV-(benzyloxycarbonyl)-a-phosphonoglycine trimethyl ester has been developed as a new practical synthesis of dehydro 2-azatryptophans and amino acid derivatives <2007TL2457>. Nucleophilic addition of Grignard or lithiated reagents of 3-A -methoxy-A -methyl-amides of indazole afforded a library of 3-keto and 3-formylindazoles <2007T419>. 

AT-Methylimidazole was converted into the 2-lithio-imidazole upon treatment with a stoichiometric amount of lithium in the presence of isoprene as catalyst (20mol%) in THF at room temperature with near quantitative yield <2005T11148>. The same lithioimidazole was obtained in high yield when butyllithium <2005H(66)263> or methyllithium <2002EJI2015> were used as lithiating reagents (Schemes 79 and 80). 

C-Lithiation (to give 71) of the 1,3-benzazaphospholes 70 was achieved with /-BuLi and the C-lithiated reagents proved to be synthetically very useful, reacting with a variety of electrophiles to produce 2-substituted derivatives 72 as indicated in Scheme 8 < 20020M912>. 

The reaction of (1)2 with /BuLi leads to a metalation of the phosphanide substituent and the elimination of LiCl. Another equivalent of the lithiation reagent yields LiCl, butane, and the tetramer [HGaPSi[Pg.150]

Scheme 1. Pathways of the reaction of ketones with a lithiated reagent and a difluorosilane.

The silyl group stabilizes the enol form and the fluorosilyl-enolethers are isolable. The formation of the silyl-enoleth depends on the lithiated reagent. 

The addition of the alkyl group om the lithiated reagent to the carbonyl carbon is affected by the dimensitm of the alkyl group. Sterically undemanding groups favm- the addition reaction and prevent the formation of the silyl-molethers. 

Eq. 4. Synthesis of different fluorosilyl-ethers by changing the lithiated reagent. 

The silyl-ethers were synthesized with the ketones 3,3-dimethyl-2-butanone and phenyl-methylketone, the lithiated reagents n-butyllithium and phenyllithium and with different fluorosilanes. Further fluorosilyl-ethers were isolated in the reaction of the ketone 2,4-dimethyl-3-pentanone and rert-butyllithium as lithiated reagent. 

Sn/Li exchange. After reaction of the lithiated reagents with electrophiles the carbamates... 

Lithiation occurs ortho to —OCH OCHj because the lithiating reagent complexes better with this group rather than with OCH,. It may be noted that acid catalysed electrophilic substitution on the resorcinol ethers occurs only at 4-position . ... 

There are plenty of other groups which are known to be ortho-directors. The halogens can behave as ort/w-dircctors and fluorine is perhaps the best (which is why it is in a box in the figure). However, if you were attempting to use either bromine or iodine as an ortho-director then you d better watch out. It would be essential not to use butyl lithium as the lithiating reagent—they... 

Lithio-benzothiophenes can be generated, and reacted with electrophiles, if the temperature is kept low. ° Direct deprotonation of benzothiophenes follows the usual pattern for flve-membered heterocycles and takes place adjacent to the heteroatom,"" and in concord with this pattern, metal-halogen exchange processes favour a 2- over a 3-halogen the sequence below shows how this can be utilised to develop substituted benzothiophenes. 2-Lithiated reagents react with electrophiles for example with p-toluenesulfonyl cyanide, 2-cyano derivatives are produced and similarly, 2-trimethylstannylbenzofuran and -benzothiophene and benzofuran-2- and benzothiophene-2-boronic acids can be prepared. 

One of the earliest descriptions of an asymmetric lithiating reagent was reported by Nozaki and co-workers in 1968 (35). (—)-Sparteine was used to coordinate n-butyllithium, and this complex stereoselectively added to several carbonyl compounds (Reaction 32). Moreover, the Skattebol-Moore method (which consists of dehalogenating gem-dihalo-cyclopropanes with an alkyllithium complex) by Nozaki to synthesize allenes gave optically active products when the n-butyllithium/ ( —)-sparteine complex was used (36). 

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