Imine anions isomerization

Ironically, species such as (89 M Li) are also the major isomers obtained when unsymmetrical ke-timines are deprotonated with LDA at -78 There is a kinetic preference for deprotonation anti to the substituent on nitrogen. At very low temperatures, deprotonations with LDA occur at the less-substituted carbon atom via the less stable (Z)-imine. Rearrangements then occur to the syn, less-substituted imine, which is in turn alkylated. On the other hand, deprotonations conducted at -23 to 0 C with LDA are faster than imine isomerization and the imine anion mixture composition reflects the ( ) (Z) ratio of the starting imine. Anti-syn imine anion isomerization occurs to give predominately the more-substituted fyn-metallated imine (cf. 90), which then undergoes alkylation. These results are summarized in Scheme 46 using the f-butylimine of 2-butanone as an example. 

Imines derived from benzylamine and a,3-unsaturated ketones which represent 1-azadiene systems can be isomerized to the corresponding 2-azadienes with potassium t-butoxide. Addition of r-butyl-lithium occurs smoothly to afford simple imine anions that undergo alkylation in the usual fashion. 3S The two examples provided in Scheme 17 illustrate the power of this method to provide either a,a- or a,a -substitution. On the other hand, reaction of similar 1-azadiene systems with Grignard reagents results in addition to form the imine anion directly (equation 44). This example represents one of the early contributions to asymmetric induction in this area and will be elaborated in Section 4.1.3.5. 

A number of investigators have examined the ease of isomerization about the formal carbon-carbon bond in imine anions. " Bergbreiter and Newcomb determined an energy barrier of approximately 17 kcal mol" for rotation about this bond in both the lithium imine anions derived from cyclohexyl- and f-butyl-amine addition to acetaldehyde. The barrier for rotation for the corresponding anion derived... 

Lithium aldimine (131), an acyl anion equivalent derived from an isocyanide and an organolithium reagent, adds to aldehydes giving, after quenching with water, a-amino ketones (134) via the Amadori rearrangement (Scheme 33)." The a-amino ketone (134) results from a double tautomerization of a-hydroxy imine (132), formed initially after quenching with water. Thus, the imine (132) isomerizes to enolamine (133), which in turn tautomerizes to the observed product (134). 

Anions derived from the aldimine of tiglaldehyde (14) react with carbonyl compounds preferentially at the a-position under conditions of kinetic control to give adducts (15), but products (16) derived from 7-attack are obtained under equilibrating conditions (Scheme 4). Addition of HMPA to the reaction or adduct mixture is required to promote isomerization of the initially formed a-adduct to the 7-product. There is also an increasing preference for 7-capture of the unsaturated imine anion as the degree of substitution a to the carbonyl function increases as in a-branched aldehydes and ketones (Table 2). Efforts to isomerize the initial a-adduct formed from reaction of the aldimine derived from crotonaldehyde with cyclohexanecarbaldehyde gave complicated mixtures. 

Imine anions obtained by isomerization of heterocyclic, secondary allylic amines with n-butyllithium add to benzophenone (Schemes 9 and lO). However, the generality of this process with respect to the allylamine starting material and the carbonyl partner remains to be established. 

Base catalyzed nitrile hydrolysis involves nucleophilic addition of hydroxide ion to the polar C=N bond to give an imine anion. Protonation then gives a hydroxy imine, which isomerizes to an amide. The mechanism is shown in Figure 15.3. 

Only in 1961 did Woodward and Olofson succeed in elucidating the true mechanism of this interesting reaction by making an extensive use of spectroscopic methods. The difficulty was that the reaction proceeds in many stages. The isomeric compounds formed thereby are extremely labile, readily interconvertible, and can be identified only spectroscopically. The authors found that the attack by the anion eliminates the proton at C-3 (147) subsequent cleavage of the N—0 bond yields a -oxoketene imine (148) whose formation was established for the first time. The oxoketene imine spontaneously adds acetic acid and is converted via two intermediates (149, 150) to an enol acetate (151) whose structure was determined by UV spectra. Finally the enol acetate readily yields the W-acyl derivative (152). 

Attempts to achieve an asymmetric 1,3-proton shift reaction of (/ )-33, obtained from ethyl 3,3,3-trifhioro-2-oxopropanoate and (f )-l-phenylethanamine in 81 % yield, resulted in conversion into 34 in 89% yield, but without any reliably delectable enantiomeric excess.26 Even at 10% conversion, the Shiff base 34 formed is completely racemic. Imine 34 undergoes isotopic exchange in triethylamine/methanoI-r/4 at a rate 10 times slower than the isomerization of 33 to 34. The authors reason that if a 1.3-proton shift mechanism is operating, some enantiomeric excess would have to be observable in product 34 at low conversion. Since this is not the ease, a 1,5-proton shift to the carbonyl oxygen, via stabilized anion 37, to form achiral intermediate enol 38, was proposed.26... 

---