Lithium Diisopropylamide-Mediated Lithiations of Imines: Insights into Highly Structure-Dependent Rates and Selectivities
- 13 November 2003
- journal article
- Published by American Chemical Society (ACS) in Journal of the American Chemical Society
- Vol. 125 (49) , 15114-15127
- https://doi.org/10.1021/ja030409z
Abstract
Lithium diisopropylamide-mediated lithiations of N-alkyl ketimines derived from cyclohexanones reveal that simple substitutions on the N-alkyl side chain and the 2-position of the cyclohexyl moiety afford a 60,000-fold range of rates. Detailed rate studies implicate monosolvated monomers at the rate-limiting transition structures in all instances. Comparisons of experimentally derived regioselectivities and rates, taken in conjunction with density functional theory computational studies, reveal a number of factors that influence reactivities including: (a) axial versus equatorial disposition of the proton on the cyclohexane ring, (b) syn versus anti orientation of the lithiation relative to the N-alkyl group, (c) the presence or absence of a potentially chelating methoxy moiety on the N-alkyl group, (d) the presence of a 2-methyl substituent at the geminal or distal α-carbon, and (e) branching in the N-alkyl group. The isolated contributions are not large, yet they display a strong and predictable additivity leading to a kinetic resolution of imines derived from racemic 2-methylcyclohexanone.Keywords
This publication has 36 references indexed in Scilit:
- Synthesis and Reactivity of New β-Enamino Acid Derivatives: A Simple and General Approach to β-Enamino Esters and ThioestersThe Journal of Organic Chemistry, 1998
- Solvent- and substrate-dependent rates of imine metalations by lithium diisopropylamide: understanding the mechanisms underlying krelJournal of the American Chemical Society, 1993
- Metalation of imines by lithium diisopropylamide solvated by N,N,N',N'-tetramethylethylenediamine: evidence for solvent-free open dimer reactive intermediatesJournal of the American Chemical Society, 1993
- Determination of structures of solvated lithium dialkylamides by semiempirical (MNDO) methods. Comparison of theory and experimentJournal of the American Chemical Society, 1992
- (E,Z) Equilibria, 12. Differential NMR Shielding by Phenyl, Assigned from Chemical Labelling and (Z,E) EquilibrationEuropean Journal of Inorganic Chemistry, 1990
- 15N, 13C, 6Li NMR spectroscopic studies and colligative measurements of lithiated cyclohexanone phenylimine solvated by tetrahydrofuranJournal of the American Chemical Society, 1987
- Synthesis of N-glycosides. Formation of glucosylamine by reaction of 2,3,4,6-tetra-O-benzyl-D-glucopyranose with acetonitrile in the presence of trifluoromethanesulfonic anhydrideThe Journal of Organic Chemistry, 1981
- Stabilities of stereoisomeric imine anionsJournal of the American Chemical Society, 1980
- Complete syn selectivity in the alkylation of lithiated ketiminesJournal of the American Chemical Society, 1978
- Mechanism of interconversion of (Z)-and (E)-ketiminesJournal of the American Chemical Society, 1972