Chemical Synthesis

Diethyl Azodicarboxylate

Diethyl azodicarboxylate (DEAD), a widely used reagent, is now available again from Sigma-Aldrich. Due to increased safety regulations, domestic shipment of DEAD as a dry reagent is prohibited. Sigma-Aldrich recently achieved full compliance with UN and US DOT safety regulations and is proud to offer this versatile reagent for your research needs as a stable and safe 40% solution in toluene.

DEAD is most popularly known from association with the Mitsunobu reaction. The Mitsunobu reaction proceeds with clean inversion, which makes reaction with secondary alcohols a powerful method for the inversion of stereogenic centers in natural product synthesis. The Mitsunobu protocol has been applied in aminations, cyclodehydrations, dexoygenations, and dehydrative alkylations, allowing for formation of many different functional groups, and is an effective method of creating new carbon-carbon bonds. DEAD can also function as a dienophile in [4+2] cycloadditions,1 an activating agent in silylations of alcohols,2 as a Michael acceptor,3 and can be used in the aza-Baylis-Hillman reaction with α,ß-unsaturated ketones, acrylates, and acrylonitrile.4

Recently, DEAD was also applied in a ring-expansion reaction of methylenecyclopropanes in the presence of zirconium triflate to form cyclobutanones in moderate to high yields (Scheme 1).5



Scheme 1

The one-pot synthesis of functionalized ß-amino alcohols from aldehydes and ketones can be achieved using DEAD and L-Proline (Scheme 2).6

Scheme 2

DEAD has been used in the asymmetric construction of quaternary stereocenters with catalytic amounts of copper-Ph-BOX (Scheme 3)7 or ß-isocupreidine8 catalysts.



Scheme 3



 
Diethyl azodicarboxylate, 40% solution in toluene 563110
Diethyl azodicarboxylate, polymer-bound, 1% DVB, 100-200 mesh 561851


References:

  1. (a) Kuethe, J. T. and Davies, I. W. Tetrahedron Lett. 2004, 45, 4009
    (b) Ellis, J. M. and King, S. B. Tetrahedron Lett. 2002, 43, 5833.
  2. Hayashi, M. et al. Tetrahedron Lett. 2004, 45, 1409.
  3. Comelles, J. et al. J. Org. Chem. ,2004, 69, 6834.
  4. Shi, M. and Zhao, G-L. Tetrahedron. 2004, 60, 2083.
  5. Shao, L-X. and Shi, M. Eur. J. Org. Chem. 2004, 426.
  6. Chowdari, N. S. et al. Org. Lett. 2003, 5, 1685.
  7. Marigo, M. et al. Angew. Chem. Int. Ed. 2003, 42, 1367.
  8. Saaby, S. et al. J. Am. Chem. Soc. 2004, 126, 8120.