Darzens Reaction: Mechanism, Variations & Applications

In the Darzens Reaction, a carbonyl compound and α-halo ester react in the presence of a base to form α, β-epoxy esters, often called “glycidic esters.” This transformation, also known as the Darzens glycidic ester reaction, results from the condensation of aldehydes and ketones with α-halo esters.

Introduction

Initially reported by E. Erlenmeyer, G. Darzens later developed and popularized the reaction, finding sodium ethoxide (NaOEt) to be an effective condensing agent. Sodium amide and other bases can also facilitate the reaction.

The generality of the reaction allows aromatic and aliphatic aldehydes and ketones, α,β-unsaturated, and cyclic ketones to react smoothly, yielding the desired glycidic esters. The use of α-chloro esters is preferred for higher yields.

The variations extend the reaction to α-halo sulfones, nitriles, ketones, ketimines, thiol esters, or amides, leading to corresponding glycidic derivatives. An extension of the process, the aza-Darzens reaction, produces aziridines from imines.

Glycidic esters are valuable synthetic intermediates, amenable to the nucleophilic opening of the epoxide, and, upon heating, undergo decarboxylation to yield one carbon homolog of the starting aldehyde or ketone.

Mechanism

In the initial step of the mechanism, an aldol reaction takes place: a base abstracts a proton from the α-halo ester in a step that governs the rate (RDS – Rate determining step). This generates a carbanion (enolate) that subsequently attacks the carbonyl group of the aldehyde or ketone reactant. This leads to the formation of a halohydrin intermediate.

In the subsequent step, an SNi (substitution nucleophilic internal) reaction occurs, resulting in the formation of an epoxide ring.

The stereoselectivity of the Darzens condensation generally favors the trans glycidic derivative. However, manipulating solvents, bases, and substituents can yield either cis or trans diastereomers.

The product’s stereochemistry is influenced by the original enolate geometry and the steric demands of the transition state. After deprotonation, the α-halo ester reacts with the carbonyl compound, leading to the creation of syn and anti-diastereomers.

In the following stage, an intramolecular SN₂ reaction generates the epoxide. The cis-to-trans ratio for epoxide formation usually ranges from 1:1 to 1:2.

Variations

A simple variation:

Stereoselective Darzens Reaction Governed by Substrate.

Enantioselective Darzens Reaction of Isatin and Diazoacetamide.

Darzens Condensation Linked with Friedel-Crafts Alkylation Cascade.

Enantioselective Vinylogous Aza-Darzens Strategy for Vinyl Aziridine Synthesis.

Enantioselective aza-Darzens reaction.

Synthetic Applications

1. Enantioselective Total Synthesis of (–)-Coriolin

In the enantioselective total synthesis of (–)-coriolin, I. Kuwajima and colleagues employed a Darzens-type reaction to create the spiro epoxide section on the triquinane skeleton. Notably, the typical Darzens condensation of α-bromoketone with paraformaldehyde led to a bromohydrin with the hydroxymethyl group added from the concave side of the molecule.

Treating this bromohydrin with DBU resulted in undesired stereochemistry at C3 (as seen in 3-epi-coriolin). To correct this, the substituents were added in reverse.

To increase enolate reactivity with potassium pinacolate, a reactive potassium enolate was formed in the presence of NIS. The in situ-generated iodohydrin subsequently underwent cyclization to form the spiro epoxide, now possessing the desired stereochemistry at C3. This approach allowed for the successful construction of (–)-coriolin while effectively managing stereochemistry challenges.

2. Concise Five-Step Synthesis of (±)-Epiasarinin

In P.G. Steel’s laboratory, a concise five-step synthesis of (±)-epiasarinin from piperonal was established. This synthesis prominently featured three key reactions: the Darzens condensation, alkenyl epoxide-dihydrofuran rearrangement, and a cyclization facilitated by a Lewis acid.

The synthesis began by reacting (E)-methyl-4-bromocrotonate and piperonal with LDA (lithium diisopropylamide), forming a vinyl epoxide intermediate. This intermediate was then treated with a mild acid (NH4Cl) to halt the reaction. These strategic steps enabled the efficient synthesis of (±)-epiasarinin, showcasing the effective utilization of these reactions in a concise sequence.

3. Enantioselective Synthesis of Diltiazem-Like Calcium Channel Blockers

A. Schwartz and co-workers accomplished the enantioselective synthesis of calcium channel blockers belonging to the diltiazem group. This was achieved through an auxiliary-induced asymmetric Darzens glycidic ester condensation. By condensing p-anisaldehyde with an enantiopure α-chloro ester, a pair of diastereomeric glycidic esters was produced, differing significantly in solubility.

The main product, a major diastereomer, was directly crystallized from the reaction mixture with a yield of 54%, and it exhibited nearly enantiopure characteristics. This predominant glycidic ester was subsequently transformed into diltiazem over a few additional synthetic steps.

In essence, this work demonstrated a successful enantioselective route to synthesizing diltiazem-like calcium channel blockers by utilizing an auxiliary-induced asymmetric Darzens glycidic ester condensation as a key transformation.

Concepts Berg

What is the significance of the α-halo carbonyl compound intermediate in Darzens’ Reaction?
The α-halo carbonyl compound is a key intermediate that is formed before the epoxide is generated. It is a reactive species in the reaction.

Can Darzens’ Reaction be used for asymmetric synthesis?
Yes, asymmetric versions of Darzens’ Reaction have been developed using chiral reagents or catalysts, allowing for the synthesis of optically active epoxides.

Is Darzens’ Reaction regioselective or stereoselective?
Darzens’ Reaction is typically regioselective, meaning it selectively forms epoxides at one specific position within the molecule. However, the stereoselectivity can vary depending on the reaction conditions and reactants used.

What are some alternatives to Darzens’ Reaction for epoxide synthesis?
Alternatives include the use of peroxy acids, peroxides, and other reagents to form epoxides. Epoxide synthesis can also be achieved through other methods like the Prilezhaev reaction and Sharpless epoxidation.

Can Darzens’ Reaction be used for the synthesis of cyclic epoxides?
Yes, Darzens’ Reaction can be applied to cyclic ketones and aldehydes to produce cyclic epoxides, contributing to the synthesis of various cyclic organic compounds.

Are there any safety considerations when working with Darzens’ Reaction reagents?
Yes, some of the reagents used in Darzens’ Reaction, such as chloroform and chlorosulfuric acid, can be hazardous. Proper safety precautions, including the use of appropriate protective equipment and a well-ventilated workspace, are essential.

References Books

A Textbook of Strategic Applications of Named Reactions in Organic Synthesis book by Laszlo Kurti and Barbara Czako
A Textbook of Name Reactions: A Collection of Detailed Mechanisms and Synthetic Applications book by Jie Jack Li

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