Efficient Lewis Base for Mukaiyama Aldol Reaction with Ketones

Chemfiles Volume 10 Article 2

        Dr. Mark Redlich

Dr. Mark Redlich
Product Manager
Email:mark.redlich@sial.com

There have been few reported methods for the synthesis of tertiary aldols due to the low reactivity of the starting ketones and rapid retro-aldol reaction, even at low temperatures. Ishihara and coworkers recently reported the Lewis base-catalyzed Mukaiyama aldol reaction using a simple mixed sodium phenoxide–phosphine oxide catalyst.3 When the test reaction was run at a 100 mmol scale with 0.5 mol % of the catalyst under optimized conditions, a 97% yield of the tertiary aldol product was reported (Scheme 1).

Scheme 1(708836)


The catalyst is effective with a wide variety of TMS enolates and ketones, generally providing the tertiary aldol adducts in good to excellent yields. Two notable exceptions were when the phenyl ester enolate was used, the β-lactone was produced in >99% yield (entry 7), and when acetophenone was used, the aldol product was generated in 57% yield (entry 9). The low yield in the case of acetophenone is likely due to the interaction of the basic catalyst with the enolizable alpha proton on the substrate.

Surprisingly, the catalyst was also effective in Mannich-type reactions when protected aldimines were used as substrate (Scheme 2). No apparent deactivation was observed, despite the increased basicity of the products, and yields were generally good to excellent in all cases. Deprotection of the N-Boc product in entry 2 generated the primary amine in quantitative yield.

Scheme 2(708836)


Bis[1,2-bis(diphenylphosphine oxide)benzene] sodium phenoxide

 

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Materials

     

References

  1. Beaulieu, F. et al. Org. Lett. 2009, 11, 5050.
  2. (a) Haufe, G. J. Prakt. Chem. 1996, 338, 99. (b) McClinton, M. A. Aldrichimica Acta 1995, 28, 31. (c) Gatner, K. Pol. J. Chem. 1993, 67, 1155. (d) Franz, R. J. Fluorine Chem., 1980, 15, 423.
  3. Hatano, M. et al. Org. Lett. 2007, 9, 4527.

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