Lithiation nitrogen compounds

Phosphorus-nitrogen compounds have numerous interesting applications, which cannot be covered here. Only a few are mentioned. Thus, the lithiated phosphorane imine Ph3P=NLi is a usefiil synthetic reagent in organic chemistry for the preparation of various nitriles. ... 

Alkylation can also be carried out, in certain compounds, at positions a to other heteroatoms, for example, at a position a to the nitrogen of tertiary amines. Alkylation a to the nitrogen of primary or secondary amines is not generally feasible because an NH hydrogen is usually more acidic than a CH hydrogen. a-Lithiation of... 

After a fluorine/chlorine exchange, a lithiated aminochlorosilane is obtained. Lithium is bound to nitrogen, the strongest Lewis base in this compound. The SiN bond is enlarged (164.2 pm) and the SiNC angle of 138.7° shows the character of the amine.17,18... 

In contrast to the rich chemistry of alkoxy- and aryloxyallenes, synthetic applications of nitrogen-substituted allenes are much less developed. Lithiation at the C-l position followed by addition of electrophiles can also be applied to nitrogen-containing allenes [10]. Some representative examples with dimethyl sulfide and carbonyl compounds are depicted in Scheme 8.73 [147, 157]. a-Hydroxy-substituted (benzotriazo-le) allenes 272 are accessible in a one-pot procedure described by Katritzky and Verin, who generated allenyl anion 271 and trapped it with carbonyl compounds to furnish products 272 [147]. The subsequent cyclization of 272 leading to dihydro-furan derivative 273 was achieved under similar conditions to those already mentioned for oxygen-substituted allenes. 

Only the most reactive organolithium compound, e.g. f-BuLi, is able to attack the carbon-nitrogen triple bond at temperatures below —20°C. For the other less reactive species, namely PhLi and n-BuLi, higher temperatures in ordinary solvents like pentane would be more appropriate to synthesize their lithiated Schiff bases. Flowever, for their detection IR spectroscopy seems to be unsuitable, since the relevant C=N stretching mode will be hidden by strong CH deformation modes of the solvent. 

The diastereoselectivity of Ugi s lithiation can be improved upon by replacing the methyl group a to nitrogen by isopropyl . Complete (>99 1) selectivity is observed in the lithiation of 291 (R = i-Pr). Attempts to hthiate compounds 291 with even bigger O -substituents (and avoid the need for a resolution in the synthesis of the enantiomerically pure starting material) failed. 

A particular case for the generation of a y-substimted organolithium compound, derived from an imine, was used for the synthesis of 2-substituted pyrrolidines. DTBB-catalyzed (5%) lithiation of y-chloro imines 196 yielded, after hydrolysis, 2-substituted pyrrolidines 198, including nomicotine (R = H, R = 3-pyridyl). The corresponding y-nitrogenated organolithium intermediate 197 was probably involved (Scheme 68). ... 

Lithiation of heteroaromatic compounds, especially nitrogen-containing systems, is an important methodology, because the lithiated intermediates can be easily functionalized in a regioselective manner by reaction with electrophiles. This process can be performed by deprotonation only at the ortho position of the heteroatom, but obviously the reaction is not possible at other positions . 

Although the generation of the corresponding a-nitrogen-substituted compound can be achieved in general in a highly enantioselective manner, a complication can result from the observation that the stereochemical outcome of the reaction with electrophiles (i.e. retention or inversion) depends on the nature of the electrophile and is not always uniform. The chemistry of lithiated carbamates has been reviewed in a comprehensive manner. ... 

The synthesis of oxygen- and nitrogen-containing heterocyclic compounds by anionic cyclization of unsaturated organolithium compounds has been reviewed recently. " Broka and Shen reported the first intramolecular reaction of an unstabilized a-amino-organolithium compound using reductive lithiation of an A,5-acetal derived from a homoaUylic secondary amine (Scheme 21). Just one example was reported treatment with lithium naphthalenide gave the pyrrolidine product, predominantly as the cis isomer. 

If the mesomeric stabilization is provided by a double bond, the lithiated species is a homoenolate synthon, as shown in Scheme 44a. Reaction with an electrophile typically occurs at the y-position, yielding an enamine, which can then be hydrolyzed to a carbonyl compound. An important application of this approach is to incorporate a chiral auxiliary into the nitrogen substituents so as to effect an asymmetric synthesis. 2-AzaaUyl anions (Scheme 44b), which are generated by tin-lithium exchange, can be useful reagents for inter- and intramolecular cycloaddition reactions. ... 

Examples of the direct 5-metalation of nonfused compounds containing heterocyclic sp3-nitrogen are quite limited, often because of competing side-reactions such as benzylic deprotonation. However, with the appropriate substitution pattern 8-metalation can occur even in those cases where benzylic deprotonation is a possibility. Examples of successful 8-lithiation include the imidazolidine 172 and 2-methyloxazolidine 173 (91G249), as well as the tetrahydroisoquinoline derivative 174 [69CI(L)621], although in this latter case subsequent steps resulted in only a 10% yield of the desired product 175. 

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