Catalytic Addition of Homoenolates to Imines - The Homo-Mannich Reaction

Abstract

For the first time, homo-Mannich reactions with unmasked homoenolates have been achieved by adding homoenolate precursor 1 and imines 5. The key to this reaction is the right choice of the Lewis acids - Cu(OTf)₂ proved to be most suitable for preparing the homoenolate and activation of the imine. An asymmetric catalytic version of this reaction is provided by using chiral, non-­racemic phenyl-derived bisoxazolidine as ligand for the Lewis acid.

asymmetric catalysis - amino acids - Lewis acids - homoenolates - Mannich reaction

References

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<A NAME="RG21304ST-11">11</A>

Experimental Procedures;
Procedure for the Cu(OTf) ₂ -Catalyzed Homoenolate Addition to Imine 5.
In an inert atmosphere [(1-ethoxycyclopropyl)oxy]tri-methylsilane (1, 250 µL, 1.21 mmol, 1.3 equiv) was added to a stirred mixture of Cu(OTf)₂ (37 mg, 0.7 mmol) in THF (3 mL) at -78 °C. Imine 5 (207 mg, 1.0 mmol) was dissolved in 1.0 mL of THF and added to the reaction mixture. Stirring was continued for 18 h at r.t. The reaction was quenched with EtOH (1-2 mL), concentrated, the residue dissolved in CH₂Cl₂ (2 mL) and filtered over a small bed of silica gel using CH₂Cl₂ (20 mL) as eluent. Evaporation of the solvent under reduced pressure afforded the crude reaction product 6, which was purified by column chromatography. R _f = 0.6 (silica gel, petrol ether-EtOAc, 1:1, TLC developed twice).
The separation of the enantiomers was carried out with a Daicel Chiralcel OD-H column (hexane-i-PrOH, 8:2; c _analyt 0.1 mg/mL; flow rate 0.5 mL/min, λ 254 nm); t _R1 = 14.87 min; t _R2 = 16.28 min.
Procedure of the BOX-Catalyzed Reaction.
In an oven dried 50 mL flask equipped with a magnetic stirring bar, Cu(OTf)₂ (35.5 mg, 0.1 mmol) and (S,S)-2,2-isopropylidene-bis-(4-phenyl-2-oxazoline) (8, 38 mg, 0.11 mmol) were added. The mixture was stirred under high vacuum for 2 h and then filled with dry argon. Dry THF (5 mL, distilled over Na and LiAlH₄) was added and the solution was stirred for 4 h. Imine 5 (207 mg, 1.0 mmol) was dissolved in 1-2 mL of dry THF and added dropwise followed by hemiacetal 1 (250 µL, 1.21 mmol) at -78 °C. Stirring was continued for 72 h at r.t. and then the reaction was quenched with EtOH (1-2 mL), concentrated and the residue dissolved in CH₂Cl₂ (2 mL), filtered over a small pad of silica gel using CH₂Cl₂ (20 mL) as eluent. Evaporation of the solvent under reduced pressure afforded the crude product 6, which was purified by column chromatography (silica gel, n-hexane-EtOAc, 1:1).