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Related Reactions
Corey-Chaykovsky Reaction
De Kimpe Aziridine Synthesis
Prilezhaev Reaction
Sharpless Epoxidation
Synthesis of aziridines
Synthesis of epoxides

Darzens Reaction
Darzens Condensation

The Darzens Reaction is the condensation of a carbonyl compound with an α-halo ester in the presence of a base to form an α,β-epoxy ester.

Mechanism of the Darzens Reaction

After deprotonation, the α-halo ester adds to the carbonyl compound to give syn and anti diastereomers:

In the subsequent step, an intramolecular SN2 reaction forms the epoxide:

Typically, the cis:trans ratio of the epoxide formation lies between 1:1 and 1:2.

In the past, Darzens methodology was primarily used for the synthesis of aldehydes and ketones, as a homologation reaction without any consideration of stereocontrol in the epoxide formation. For this sequence, saponification of the α,β-epoxy ester followed by decarboxylation gives the substituted carbonyl compound:

Darzens methodology for the construction of epoxides can also be used for α-halo carbonyl compounds, or similar compounds that can undergo deprotonation and bear electron-withdrawing groups. In addition, the reaction can be carried out with diazoacetate, where N2 is the leaving group, or with a sulphur ylide with SR2 as the leaving group (see Corey Chaykovsky).

In the following specific substitution pattern, the outcome of the reaction depends on the energy of the transition states of the addition, the rotation and the ring closure, as described by Aggarwal. Although explanations for the diastereoselectivity have been given, the enantioselectivity that is induced by the camphor-derived sulphonium group is not yet fully understood:

V. K. Aggarwal, G. Hynd, W. Picoul, J.-L. Vasse, J. Am. Chem. Soc., 2006, 128, 2105-2114. DOI

Another concept for highly diastereoselective and enantioselective transformations was developed by Arai:

S. Arai, Y. Shirai, T. Ishida, T. Shioiri, Tetrahedron, 1999, 55, 6375-6386.

In this system, the chiral phase transfer catalyst (PTC) is able to recognize one aldolate selectively. There is an equilibrium between syn- and anti-aldolates via retro-aldol addition, and the formation of a stable, chelated lithium salt blocks the non-catalyzed subsequent reaction from yielding the epoxide product:

The following aza-Darzens reaction, in which a preformed lithium α-bromoenolate reacts with a sulphinimine to give an aziridine, features a six-membered transition state that accounts for the high diastereoselectivity:

F. A. Davies, H. Liu, P. Zhou, T. Fang, G. V. Reddy, Y. Zhang, J. Org. Chem., 1999, 64, 7559-7567. DOI

The development of enantioselective methods remains challenging. In principle, any of the methods that are used for stereoselective aldol additions can also be tested in the Darzens Reaction, as the first step is an aldol addition.

Recent Literature

The Brønsted Acid-Catalyzed Direct Aza-Darzens Synthesis of N-Alkyl cis-Aziridines
A. L. Williams, J. N. Johnston, J. Am. Chem. Soc., 2004, 126, 1612-1613.

Bi(OTf)3-[Bmim]PF6: A novel and Reusable Catalytic System for the Synthesis of cis-Aziridine Carboxylates
J. S. Yaday, B. V. S. Reddy, P. N. Reddy, M. Shesha Rao, Synthesis, 2003, 1387-1389.

Phase-transfer-catalyzed asymmetric Darzens reaction
S. Arai, Y. Shirai, T. Ishida, T. Shioiri, Tetrahedron, 1999, 55, 6375-6386.

Highly Enantioselective Darzens Reaction of a Camphor-Derived Sulfonium Amide to Give Glycidic Amides and Their Applications in Synthesis
V. K. Aggarwal, G. Hynd, W. Picoul, J.-L. Vasse, J. Am. Chem. Soc., 2002, 124, 9964-9965.