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Synlett 2005(3): 473-476  
DOI: 10.1055/s-2005-862378
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Muhammad Abbasa, Christiane Neuhausa, Birte Krebsb, Bernhard Westermann*a,b
a Leibniz-Institute of Plant Biochemistry, Department of Bioorganic Chemistry, Weinberg 3, 06120 Halle (Saale), Germany
Fax: +49(345)55821309; e-Mail: bwesterm@ipb-halle.de;
b University of Paderborn, Department of Chemistry, 33095 Paderborn, Germany
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Publication History

Received 24 June 2004
Publication Date:
04 February 2005 (online)

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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.

Key words

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

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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).