Lithium diisopropylamide-mediated lithiations of imines: insights into highly structure-dependent rates and selectivities.
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 alpha-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.
Liao
Songping
S
Department of Chemistry and Chemical Biology, Baker Laboratory, Cornell University, Ithaca, New York 14853-1301, USA.
Collum
David B
DB
D003512:Cyclohexanones / Q000737:chemistry; D007097:Imines / Q000737:chemistry*; D007700:Kinetics; D008094:Lithium / Q000737:chemistry*; D008958:Models, Molecular; D008968:Molecular Conformation; D011437:Propylamines / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013816:Thermodynamics
D003512:Cyclohexanones; D007097:Imines; D011437:Propylamines; D008094:Lithium; C007442:diisopropylamine