Expedient Mukaiyama-Type Mannich Reaction Catalyzed by Lithium Chloride

Abstract

The Mannich reaction of methylsilyl enol ether with aryl­aldimine proceeded in the presence of a catalytic amount of lithium chloride in dimethylformamide at room temperature. The reaction was mild enough to apply to aldimines having the AcO, TBDMSO, or MeS group. Microwave irradiation accelerated the reaction substantially to reduce reaction time.

Keywords

Mannich reaction - aldimines - trimethylsilyl ketene acetal - microwave heating - lithium chloride

References and Notes

• 1 Green Chemistry: Theory and Practice   Anastas PT. Warner JC. Oxford University Press; Oxford: 1998. 
• For reviews on Mannich and Mannich-type reactions, see:
• 2a Kleinman EF. In Comprehensive Organic Synthesis   Vol. 2:  Trost BM. Fleming I. Oxford; Pergamon: 1991.  p.893 
• 2b Arend M. Westermann B. Risch N. Angew. Chem. Int. Ed.  1998,  37:  1045 
• 2c Kobayashi S. Ishitani H. Chem. Rev.  1999,  99:  1069 
• 3 Fujisawa H. Nagata Y. Sato Y. Mukaiyama T. Chem. Lett.  2005,  34:  842 ; and earlier references cited therein
• 4 Fujisawa H. Takahashi E. Mukaiyama T. Chem. Eur. J.  2006,  12:  5082 ; and earlier references cited therein
• For example:
• 5a Ojima I. Inaba S. Yoshida K. Tetrahedron Lett.  1977,  3643 
• 5b Ojima I. Inaba S. Nagai M. Synthesis  1981,  545 
• 6a Hagiwara H. Inoguchi H. Fukushima M. Hoshi T. Suzuki T. Tetrahedron Lett.  2006,  47:  5371 
• 6b Hagiwara H. Inoguchi H. Fukushima M. Hoshi T. Suzuki T. Synlett  2005,  2388 
• 7a Miura K. Tamaki K. Nakagawa T. Hosomi A. Angew. Chem. Int. Ed.  2000,  39:  1958 
• 7b Miura K. Nakagawa T. Hosomi A. J. Am. Chem. Soc.  2002,  124:  536 

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Typical Experimental Procedure
To a stirred solution of N-p-toluenesulfonyl-p-chlorophenyl-aldimine (1, 118 mg, 0.4 mmol) and LiCl (3.4 mg, 0.08 mmol) in DMF (1.5 mL) was added trimethylsilyl ketene acetal 2 (130 µL, 0.6 mmol) at r.t. under nitrogen atmosphere. After stirring for 13 h, the reaction was quenched by adding H₂O. The product was extracted with EtOAc twice and the combined organic layer was washed with H₂O and brine, and then evaporated to dryness. Column chromatography of the residue (eluent, EtOAc-n-hexane, 1:2) afforded β-amino ester 3 (145 mg, 91%).