Reformatsky Reaction: Mechanism, Variations & Applications

The term “Reformatsky reaction” is named in honor of the Russian chemist Sergey Nikolaevich Reformatsky, who first discovered this reaction in 1887. This chemical reaction involves the interaction between an alpha‐haloester and a carbonyl compound, which can be an aldehyde, ketone, or ester. Zinc is commonly employed as a catalyst in the presence of which this reaction occurs predominantly.

This chemical change is accomplished through the utilization of metallic zinc as a reagent, followed by subsequent acid treatment. Commonly, inert solvents such as diethyl ether or tetrahydrofuran (THF) are chosen as suitable reaction mediums.

Reformatsky Reaction

The Reformatsky reaction is a versatile organic transformation utilized to convert a ketone or aldehyde, in conjunction with an α-halo ester, into a β-hydroxy ester.

An advantageous aspect of this reaction is that it eliminates the need for isolating the organozinc compound. Within the course of the reaction, a fresh carbon-carbon connection is established, accompanied by the generation of an organozinc halide.

Additionally, the introduction of mild acids can prompt decomposition as part of the process.

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Enhanced Yields

Enhanced yields in the Reformatsky reaction are often achieved through a two-step approach:

In the initial step, the transformation of the alpha bromo ester into an organozinc bromide occurs.
This conversion is facilitated by reacting the compound with zinc under controlled conditions in a pure and dry dimethoxyethane solvent.

Structure of the Reagent

The Reformatsky reagents, namely tert-butyl bromozincacetate and ethyl bromozincacetate, form cyclic dimers with eight members within the solid state. However, they exhibit distinct stereochemical characteristics.

Mechanism of Reformatsky reaction

Research involving spectroscopic and crystallographic investigations of Reformatsky reagents, which are generated from α-halo esters, has unveiled that the enolate predominantly adopts the C-enolate configuration. Particularly, in the presence of ether solvents, these reagents tend to form dimers. Conversely, enolates originating from α-halo ketones tend to favor the O-metal enolate configuration.

Theoretical calculations have led to the assumption that zinc enolate dimers undergo dissociation through the influence of carbonyl compounds. This process leads to the conversion of these dimers into the corresponding O-zinc enolates. Subsequently, the reaction progresses through a six-membered chair-like transition state.

Variations

Boron-mediated Reformatsky reaction:

Diastereoselective Reformatsky reaction:

Synthetic Applications

1. Synthesis of C₁₆, C₁₈-bis-epi-cytochalasin D

Cytochalasins, which are cyclic natural compounds with diverse biological effects, have been of significant interest. In the synthesis of C₁₆, C₁₈-bis-epi-cytochalasin D, E. Vedejs and colleagues utilized the Reformatsky reaction to close a twelve-membered cyclic structure. This reaction was triggered using finely dispersed zinc metal, produced by reducing ZnCl₂ with sodium naphthalide.

The cyclization was performed at room temperature, with the substrate gradually added to the metal suspension. The product was subsequently treated with 10% H₂SO₄ during the work-up process to eliminate the hydroxyl group and hydrolyze the methyl enol ether subunit.

Following additional steps, C₍₁₆₎, C₍₁₈₎-bis-epi-cytochalasin D was formed, and its structure was confirmed through spectroscopic techniques and X-ray crystallography.

2. Highly Efficient Synthesis of a Decacyclic Ciguatoxin

In the laboratory of M Sakasi, a highly efficient synthesis of a decacyclic ciguatoxin model was achieved. To establish the fused oxononane ring structure, researchers utilized a SmI₂-mediated intramolecular Reformatsky reaction.

The reaction was executed in THF at a temperature of -78 °C, leading to the formation of the desired oxacyclic ring with excellent yield and as a singular diastereomer. Following the reaction, the resultant hydroxyl group was protected in situ by forming an acetate ester.

3. CuCl₂-Mediated Reformatsky Reaction for C₁-C₆ Fragment Synthesis of Epothilones

Wessjohn and colleagues effectively employed the CuCl₂-mediated Reformatsky reaction to synthesize the C₁-C₆ fragment of epothilones. They integrated the Evans (R)-4-benzyl-oxazolidinone chiral auxiliary in their strategy to control the absolute stereochemistry.

Through the chromium-Reformatsky reaction between (R)-4-benzyl-3-(2-bromoacetyl)-oxazolidinone and 2,2-dimethyl-3-oxo-pentanal, they achieved complete chemoselectivity, yielding the desired product with 63% yield and as a sole diastereomer.

4. Facilitated Reformatsky Reaction for Dolaproine Synthesis

R. Pettit and colleagues employed an innovative tetrakis(triphenylphosphine)cobalt(0)-facilitated Reformatsky reaction to synthesize a Boc-protected form of dolaproine, which constitutes a unit of dolastatin 10.

Advantages

This reaction offers several noteworthy benefits:

The Reformatsky mechanism can be readily adapted for intramolecular aldol reactions.
The organozinc halide reagents employed in this reaction are notably stable and are readily accessible through commercial sources.
The reaction’s outcome involves the isolation of beta-hydroxy esters.
Another advantage lies in its convenience, as the Reformatsky reaction serves as an alternative to the reaction of an aldehyde or ketone with the preferred lithium enolate of an ester.
Enhanced yields in the Reformatsky reaction can be achieved by using freshly prepared zinc powder, a heated column of zinc dust, copper-zinc couple, acid-washed zinc, and trimethylchlorosilane.

Key points

The Reformatsky reaction occurs when an alpha-haloester interacts with a carbonyl compound, which could be an aldehyde, ketone, or ester.
Zinc is commonly employed to promote this reaction. Furthermore, this reaction also illustrates the extension of reactions between carbonyl compounds and dialkylzinc or alkyl zinc halides.
An advantageous aspect of the Reformatsky reaction is the omission of the need to isolate the organozinc product.
The reaction leads to the formation of a new carbon-carbon bond, accompanied by the generation of an organozinc halide. This transformation is influenced by the presence of dilute acids.
The resulting product, α-hydroxy esters, holds significant importance in the synthesis of natural compounds and pharmaceuticals.

Concepts Berg

What are the typical conditions for carrying out a Reformatsky reaction?

The typical conditions for a Reformatsky reaction involve mixing the α-halo ester or ketone with metallic zinc and a halogen source in a suitable solvent, often in the presence of a base like sodium hydroxide (NaOH) or sodium amide (NaNH₂).

What is the mechanism of the Reformatsky reaction?

The Reformatsky reaction involves the formation of an organozinc intermediate, which subsequently reacts with a carbonyl compound to form a β-hydroxy ester or ketone through nucleophilic addition.

What are some applications of the Reformatsky reaction?

The Reformatsky reaction is used in organic synthesis to construct complex molecules, such as natural products and pharmaceuticals. It is particularly valuable for introducing a β-hydroxy group into a molecule.

What are some limitations or challenges associated with the Reformatsky reaction?

Some limitations of the Reformatsky reaction include issues with regioselectivity, the sensitivity of the reaction to moisture and air, and the limited scope of compatible functional groups in the starting materials. Additionally, the use of toxic or expensive reagents, such as certain halogens, can be a drawback.

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

References link

An Article (en.wikipedia.org)
An Article (chem.libretexts.org)
An Article (byjus.com)

Reformatsky Reaction: Mechanism, Variations & Applications