Lithiated heterocycles amines

F. Mixed Complexes between Chiral Lithium Amides containing Amines and Lithiated Heterocycles... 

Butyllithium is also used for the stereoselective a-lithiation of chiral sulfonyl compounds/ chiral 2-alkenyl carbamates, various heterocyclic amine derivatives with chiral auxiliaries appended on the nitrogen (e.g. oxazoline or formamidine groups) (eq 10)7 and chiral oxazolidinones derived from ben-zylamines (eq 11). These elegant reactions have been applied to the asymmetric syntheses of a number of natural products. ... 

The reductive ring opening of six-membered nitrogen-containing heterocycles was studied with A-phenyltetrahydroisoquinoline (391). Its lithiation with lithium and a catalytic amount of DTBB (4.5%) afforded the benzylic intermediate 392, which was allowed to react with electrophiles giving, after hydrolysis, functionalized amines 393 (Scheme 110) . It is noteworthy that in the reaction with carbon dioxide, instead of the corresponding lactam, amino acid 393 with X = CO2H was exclusively isolated. 

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. 

Propargylic carbonates are converted to substituted allenyllithium species but I -alkynylsilanols undergo dilithiation (with r-BuLi-HMPA) and the subsequent reaction with electrophiles at the propargylic position. The doubly lithiated A-methyl aminals can be used in the preparation of Si-N- and P-N-containing heterocycles. ... 

Two asymmetric syntheses of phenethylisoquinolines have been reported. Simple exchange between isoquinoline 125 and imine 126 gave the chiral formamidine 127. Methylation of 127 with /ert-butyllithium gave the lithiated formamidine, which was alkylated with 3,4-dimethoxyphenethyl iodide and hydrazinolyzed to give the (S)-(-)-isoquinoline 128 in 95% enantiomeric excess (e.e.) (74). The e.e. of 128 was determined by chiral-column HPLC analysis, as developed by Pirkle and applied to chiral N-heterocycles and other amines (75). 

One of the first uses of directed metalation as a route to heterocycles was the synthesis of phthalans (2,3-benzo-l,4-dihydrofurans) by the thermally induced cyclization of the methiodides of ortho-substituted di-methylbenzylamines (Reaction 37) (45). The amine was lithiated in the ortho position by n-butyllithium and condensed with benzaldehyde and benzophenone. The corresponding alcohols obtained upon aqueous work-up were converted to their respective methiodides. Heating the methiodides to 200°C for one hour under nitrogen gave the phthalans... 

Unlike lithiated tetrahydroisoquinolines, a-lithio derivatives of saturated heterocycles are configurationally stable [202-204] (review [163]), and they have a considerably higher kinetic barrier to deprotonation. Nevertheless, there have been a number of activating groups developed for the alkylation of a-lithio amines. In 1991, Beak showed that the complex of sparteine and sec-butyllithium enantioselectively deprotonates BOC-pyrrolidine, and that the derived organolithium is a good nucleophile for the reaction with several electrophiles, as shown in... 

Chiral cyclic allylic amines have also been utilized in lithiation-substitution reactions to access substitution a to nitrogen. Meyers and coworkers have demonstrated that lithiation of chiral formamidine-protected pyrroline 135 and tet-rahydropyridine 136 followed by substitution with electrophiles provides both the a and y-substituted heterocycles (Scheme 43) [97]. 

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