Functionalization methods lithiation reactions

Similarly, polysulfone has been sulfophenylated by lithiation and anionic reaction with 2-sulfobenzoic acid cyclic anhydride (Figure 12). This provides another method to modify polysulfones by attaching pendant sulfonated phenyl groups via ketone links. It would be interesting to see if the phase separation in these materials was affected by the additional functionality of the ketone or the pendant attachment of the sulfonic acid, as opposed to direct attachment of ionic groups to the aromatic polymer backbone. 

Finally, an unprecedented functionalized ytterbium silsesquioxane was obtained as outlined in Scheme 31. Trisilanol 3 was lithiated in situ using an excess of LiN(SiMe3)2, followed by treatment of the reaction mixture with anhydrous ytterbium trichloride. " The resulting colorless crystals of 95 were fully characterized by spectroscopic and analytical methods as well as an X-ray crystal structure... 

Eaton and co-workers also reported the synthesis of 1,3,5-trinitrocubane and 1,3,5,7-tetranitrocubane (39) ° The required tri- and tetra-substituted cubane precursors were initially prepared via stepwise substitution of the cubane core using amide functionality to permit ort/jo-lithiation of adjacent positions. The synthesis of precursors like cubane-1,3,5,7-tetracarboxylic acid was long and inefficient by this method and required the synthesis of toxic organomercury intermediates. Bashir-Hashemi reported an ingenious route to cubane-1,3,5,7-tetracarboxylic acid chloride (35) involving photochemical chlorocarbonylation of cubane carboxylic acid chloride (34) with a mercury lamp and excess oxalyl chloride. Under optimum conditions this reaction is reported to give a 70 8 22 isomeric mixture of 35 36 37... 

The metalation of vinyl ethers, the reaction of a-lithiated vinyl ethers obtained thereby with electrophiles and the subsequent hydrolysis represent a simple and efficient method for carbonyl umpolung. Thus, lithiated methyl vinyl ether 56 and ethyl vinyl ether 54, available by deprotonation with t- or n-butyllithium, readily react with aldehydes, ketones and alkyl halides. When the enol ether moiety of the adducts formed in this way is submitted to an acid hydrolysis, methyl ketones are obtained as shown in equations 72 and 73 . Thus, the lithiated ethers 56 and 54 function as an acetaldehyde d synthon 177. The reactivity of a-metalated vinyl ethers has been reviewed recently . 

By the analogous reaction, the doubly lithiated sulphur substituted vinyllithium compound 126 was generated by Brandsma, Maercker and coworkers, starting from tellura-cycle 125. An interesting pathway to functionalized heteroatom-substituted polylithium compounds has been introduced by this method (Scheme 46). 

This isomerization was confirmed by means of a detailed kinetic NMR study (90T633), but is not detrimental to the synthesis of substituted 1,2,4-triazoles, because in all cases removal of the protecting group leads to a tautomeric mixture of 3- and 5-substituted products. The methods available for removal of the animal function actually depend upon the nature of the added C-5 substituent, with acid hydrolysis occurring only in some cases. More commonly, treatment with NaBH in refluxing ethanol is the method of choice (90T633). Lithiation and derivatization of the SEM protected compound (entry 6) can be achieved without the isomerization shown by the animal derivative, and deprotection can be achieved with either aqueous acid or anhydrous fluoride ion [92H(34)303], However, overall reaction yields are not as high as those for the aminal system. 

Polymeric supports can also be used with advantage to form monofunctional moieties from difunctional (Hies. Leznoff has used this principal in the synthesis of sex attractants on polymer supports (67). Starting from a sheap symmetrical diol he blocked one hydroxyl group by the polymer. Functionalization of cross-linked polymers is mostly performed by chloromethylation (65). A very promising method to introduce functional groups into crosslinked styrene-divinylbenzene copolymers is the direct lithiation with butyllithium in presence of N,N,N, N -tetramethyl-ethylenediamine (TMEDA) (69, 70). Metalation of linear polystyrene with butyl-lithium/TMEDA showed no exchange of benzylic hydrogen and a ratio of attack at m/p-position of 2 1 (71). In the model reaction of cumene with amylsodium, a kinetic control of the reaction path is established. After 3h of treatment with amyl-sodiuni, cumene is metalated 42% in a-, 39% m-, and 19% p-position. After 20h the mixture equilibrates to affort 100% of the thermodynamically more stable a-prod-uct (72). 

Another key reaction of lithiated epoxides is tt-elimination to form carbene intermediates. This reactivity has been developed to be a highly effective method for the functionalization of organic molecules. 

The pioneering work of Stork and coworkers and Wittig and coworkers on the metallation of ketimines, and their subsequent reaction with a variety of electrophiles, has proven extremely useful for controlled aldol condensation and also for regioselective functionalization of ketones Recently, reactions of chiral lithiated ketimines and aldimines have been established as an important method of asymmetric synthesis, producing chiral ketones in optical yields as high as 95%... 

Evans and co-workers developed a regioselective lithiation protocol of 2-methyl-4-substituted oxazoles 945 during their synthesis of phorboxazoles. In particular, the authors required a general method to generate regioselectively a 2-(lithiomethyl)oxazole and to functionalize the intermediate without competitive lithiation and reaction at C(5). Among the bases investigated, lithium diethylamide was particularly effective and selective for the required transformation (Scheme 1.253, p. 206). 

Ortiz [47] recently described the ortho-directed lithiation of R,R-diphenylami-nophosphazenes 64 followed by electrophilic quenching as an efficient process for the preparation of / -chiral ort/io-functionahzed P-chirogenic amidophosphinates 65 in good yields and diastereoselectivities. The usefulness of the method was shown with the preparation under mild reaction conditions of a variety of functionalized P-chiral compounds 66 in high yield and excellent stereoselectivity, including phosphinic esters, amides, thioamides, phosphine oxides, and (2-aminophenyl)phosphine boranes (Scheme 21). 

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