Lithium ester enolates, condensation with imines

More recently, a study pertaining to the condensation of lithium ester enolates with substituted imines has appeared (eq. [66]) (79). Although monosubstituted enolates (Rj = H R2 = Ph, N=C(OLi)Ph] afforded moderate yields (35-45%) of trans-lactam 87, disubstituted enolates (Rj = OLi, CH3 R2 = Ph, CH3) afforded good yields (66-91%) of lactam products. The authors concluded from their study that the condensation step was probably reversible. 

Lithium ester enolate-imine condensation has been used for the preparation of / -lactam rings via addition at the imine moiety <1996H(43)1057>. But treatment of imino derivatives of the pyridazine 293 with the lithium enolate of ethyl a,a-dimethylacetate 294 in THE led to the formation of the pyrido[3,4-r/ pyridazine 295 and its oxidized form 296. Compound 295 was obtained by nucleophilic attack of the carbanion species at C-5 of the pyridazine ring followed by cyclization (Equation 24) <1996JHC1731>. 

A comprehensive review article on 3-lactam formation via the ester enolate-imine condensation has been written by Hart and Ha. Achiwa and coworkers have published a full paper detailing their work on the synthesis of N-benzyloxy-3-lactams utilizing the reaction of N-benzyloxyimines with silylketene acetals in the presence of TMS-OTf, or with lithium ester enolates. ... 

A substoichiometric version of this ester enolate-imine condensation could be developed shortly later the tridentate ligand 383 catalyzed the condensation of lithium enolate 378 with imines 381 derived from aromatic and aliphatic aldehydes to give P-lactams 382 in excellent chemical yield and substantial. 

The one-pot condensation of an ester enolate with an imine is a very powerful synthetic procedure toward azetidin-2-ones (Equation 183). Various types of esters and imines can be utilized. Although in the vast majority the reactions have been mediated by lithium, various other metals mediate the reaction as well. Some examples include zinc, aluminium, tin, boron, indium, and titanium <1996MI119>. Theoretical studies on these reactions have been reviewed <1998JCC1826>. 

Attempts to prepare homochiral -lactams using chiral reactants under Reformatsky conditions described above gave poor results.Good diastereoselectivities are observed in the reaction of lithium enolates with imines bearing a chiral group on either a nitrogen (equation 46)or carbon atom (equation 47). Esters derived from isobomeol-lO-diisopropylsulfonamide give enolates which condense with cinnamaldimines to yield cis -lactams with excellent enantioselectivity (equation 48). ... 

In one approach, an imine moiety was generated in situ by reaction of a methoxy carbamate with lithium diisopropylamide. This imine was then condensed with an ester enolate to give the amino-ester, protected as a carbamate. Reaction of 4,70 with lithium diisopropylamide gave imine 4.71, for example. Subsequent reaction with... 

Stevens and co-workers have also attempted to develop a fundamentally different approach to the tricyclic amino ketone 463 which is used in the Fischer cyclization approach to the Aspidosperma skeleton (240). Condensation of the aldehyde-ester 553 with protected keto amine 554 gave an imine (555) which, upon heating with ammonium chloride at 160°, afforded the 2-pyrroline ester 556 in 70% yield. Treatment with dry hydrochloric acid gas in ether was followed by acid hydrolysis of the ketal, and base-catalyzed cyclization produced a mixture of two enol ethers (557 and 558) the latter predominating. The major isomer was reduced with lithium aluminum hydride and the hydroxy enol ether dehydrated in hot... 

The lithium enolate of t-amyl acetate exists as a doubly chelated dimer in the presence of TMEDA (A,A,A, At -tetramethylethylenediamine). Reaction with a simple aldimine such as pflra-F-C6H4-CH=N-Ph gives an iV-lithiated -amino ester as a monomer, observed by Li- and i N-NMR. Kinetic studies by i F-NMR give a reaction order consistent with a TS of stoichiometry [(ROLi)2(TMEDA)2(imine)], supported by DPT calculations. That such aza-aldol condensations involve dimeric mechanistic routes runs counter to many claims that monomers are more reactive. 

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