Diethyl Azodicarboxylate (DEAD)

Chemfiles Volume 6 Article 2

Due to stricter safety regulations, shipment of diethyl azodicarboxylate (DEAD, Figure 4) as a dry reagent is prohibited in the United States. We have achieved full compliance with UN and U.S. DOT safety regulations, and is pleased to offer this extremely versatile reagent as a stable and safe 40% solution in toluene.

Diethyl Azodicarboxylate (DEAD)

Figure 4

The most widespread application of DEAD is as an activating reagent in the Mitsunobo reaction. Under the Mitsunobo protocol, numerous transformations are possible including stereochemical inversion of secondary alcohols, aminations, and macrolactonizations. For example, Fürstner’s total synthesis of (–)-balanol relied on the preparation of a chiral azide intermediate available from the corresponding stereoinverted alcohol (Scheme 38).1

Fürstner’s total synthesis of (–)-balanol relied on the preparation of a chiral azide intermediate available from the corresponding stereoinverted alcohol

Scheme 38

Keck utilized the DEAD-assisted Mitsunobo esterification to prepare a crucial intermediate in the synthesis of the antiviral alkaloid, 7-deoxypancratistatin (Scheme 39).2

Keck utilized the DEAD-assisted Mitsunobo esterification to prepare a crucial intermediate in the synthesis of the antiviral alkaloid, 7-deoxypancratistatin

Scheme 39

The azo-linkage in DEAD is also an active Michael acceptor. In the presence of a copper(II) salicylaldehydate catalyst, β-ketoesters add cleanly to DEAD, giving the corresponding hydrazine derivative (Scheme 40).3 In a similar fashion, copper(II) salts also catalyze the addition of boronic acids to DEAD in essentially quantitative yield.4

The azo-linkage in DEAD is also an active Michael acceptor. In the presence of a copper(II) salicylaldehydate catalyst, β-ketoesters add cleanly to DEAD, giving the corresponding hydrazine derivative

Scheme 40

In addition to C–O and C–N bond formation, DEAD can be used in the construction of C–C bonds. Optically active 3-aryl-3- substituted propanoic acids can be readily prepared in excellent enantiomeric excess from chiral secondary benzylic alcohols (Scheme 41).5

Optically active 3-aryl-3- substituted propanoic acids can be readily prepared in excellent enantiomeric excess from chiral secondary benzylic alcohols

Scheme 41

References

1.
Fürstner A, Thiel OR. 2000. Formal Total Synthesis of (−)-Balanol:  Concise Approach to the Hexahydroazepine Segment Based on RCM. J. Org. Chem.. 65(6):1738-1742. http://dx.doi.org/10.1021/jo991611g
2.
Keck GE, McHardy SF, Murry JA. 1999. Diastereoselective 6-exoRadical Cyclizations of Oxime Ethers:  Total Synthesis of 7-Deoxypancratistatin. J. Org. Chem.. 64(12):4465-4476. http://dx.doi.org/10.1021/jo9902042
3.
Comelles J, Moreno-Mañas M, Pérez E, Roglans A, Sebastián RM, Vallribera A. 2004. Ionic and Covalent Copper(II)-Based Catalysts for Michael Additions. The Mechanism. J. Org. Chem.. 69(20):6834-6842. http://dx.doi.org/10.1021/jo049373z
4.
Uemura T, Chatani N. 2005. Copper Salt Catalyzed Addition of Arylboronic Acids to Azodicarboxylates. J. Org. Chem.. 70(21):8631-8634. http://dx.doi.org/10.1021/jo051387x
5.
Hillier MC, Desrosiers J, Marcoux J, Grabowski EJJ. 2004. Stereoselective Carbon−Carbon Bond Formation via the Mitsunobu Displacement of Chiral Secondary Benzylic Alcohols. Org. Lett.. 6(4):573-576. http://dx.doi.org/10.1021/ol036380l