Selectivity in β-Enamino Ketone Anion Generation and Alkylation

Article abstract of DOI:10.1021/jo00336a002

The regioselectivity of anion generation from β-alkoxy- and β-(dialkylamino)-α,β-unsaturated ketones was probed by use of (13)C NMR spectroscopy and alkylation techniques.Results indicate that the kinetic anions of these systems can be formed selectively from the parent ketones by using excess lithium diisopropylamide as the base at -78 deg C and diethyl ether or tetrahydrofuran as the solvent.The kinetic anion in these systems is the one resulting from deprotonation at the α'-carbon.Alkylation occurs at this center in synthetically useful yields.Equilibration to produce the thermodynamically more stable extended γ-enolate anion occurs when less than 1 equiv of lithium diisopropylamide is present and at elevated temperatures (>-20 deg C).The rate of equilibration is sensitive to the solvent employed, occurring much more rapidly in tetrahydrofuran than in diethyl ether.A synthetically more practical method for formation and alkylation of the thermodynamic anions of β-(dialkylamino)-α,β-unsaturated ketones utilizes excess lithium bis(trimethylsilyl)amide as the base in tetrahydrofuran as the solvent at -78 deg C followed by quenching with the alkylating agent.Methods for regioselective generation of dianions from β-(alkylamino)-α,β-unsaturated ketones have been explored.Analysis of products produced by methylation suggest that the N,α'- and N,γ-dianions can be produced independently by use of the respective kinetic and thermodynamic anion-producing conditions described above.However, all attempts to identify these dianions by spectroscopic methods failed due to the exceedingly low solubilities of these substances in solvent systems compatible with the technique.Likewise, dialkylation or acyclation-alkylation of the N,γ-dianions, in attempts to develope one-step procedures for fused-bicyclic pyrrolidine synthesis, was unsuccessful.