What Is Favorskii Rearrangement?
The Favorskii rearrangement is a reaction in which α-haloketones react with nucleophiles in the presence of a base to form carboxylic acids or carboxylic acid derivatives. The Favorskii rearrangement is widely used in organic synthesis and has become an important method for synthesizing cyclic or multi-branched non-cyclic carboxylic acids or their derivatives and cage compounds. It is also important in the synthesis of certain natural products.
- Reagents: Strong bases.
- Reactants: α-Haloketones.
- Products: Carboxylic acid derivatives.
- Reaction Type: Base-induced molecular rearrangement.
- Related Reactions: Wolff rearrangement, Arndt-Eistert homologation.
Mechanism of Favorskii Rearrangement
- For ketones containing α-H, it is generally believed that the rearrangement reaction mechanism is through a cyclopropanone intermediate. This reaction mechanism through a cyclopropanone intermediate is supported by isotope labeling experiments.
- For ketones without α-H, the corresponding Favorskii rearrangement products can also be obtained. This reaction is different from the classic Favorskii rearrangement and is called the quasi-Favorskii rearrangement. Obviously, this reaction does not go through a cyclopropanone intermediate. It is generally believed that the reaction is similar to the Benzi rearrangement (benzilic acid rearrangement) reaction, also known as the semi-benzilic mechanism.
Fig 1. Favorskii rearrangement of cyclic α-haloketones and its mechanism. [1]
Favorskii Rearrangement of Cyclic α-Haloketones
Cyclic α-haloketones are widely used in Favorskii rearrangement. Generally, cyclic α-haloketones are rearranged to give condensed homologues, i.e., cycloalkane carboxylic acids or their derivatives with one less carbon. Favorskii rearrangement is an important method for synthesizing cage compounds, which are a class of strained fused ring molecules.
α,α'-dihalogenated cyclic ketones are used in Favorskii rearrangement, which is an effective method for synthesizing cycloalkenyl carboxylic acids or their derivatives. The reaction involves a series of reactions such as base deprotonation to form cyclobutanone, nucleophilic attack on the keto group, and ring opening to form a stable carbon anion, and finally elimination of hydrogen halide to form a carbon-carbon double bond.
Favorskii Rearrangement of Chain α-Haloketones
Open-chain α-haloketones are a typical Favorskii rearrangement substrate. Under the action of base, chain α-haloketones are deprotonated to form cyclobutanone derivatives, which are then attacked by nucleophiles to obtain alkyl migration products. α,α'-Dihaloketones are another important Favorskii rearrangement substrate.
The main product of the Favorskii rearrangement of α,α'-dihaloketones is a,β-unsaturated carboxylic acid or its derivatives. It is worth noting that the reaction has a certain stereoselectivity, and the product obtained by rearrangement is a cis (olefin) product.
In addition, using optically active starting materials, chiral cyclic intermediates can be formed through asymmetric Favorskii rearrangement, and applied to the synthesis of certain natural products.
Fig 2. Favorskii rearrangement of chain α-haloketones and its mechanism. [1]
Application Examples of Favorskii Rearrangement
- Example 1: Hua Xu et al. reported a safe, stable and scalable practical synthetic route for entecavir pilot production. Starting from (S)-(+)-carvone, the route includes a series of highly efficient reactions, such as Favorskii rearrangement-elimination-diastereomerization reaction, Baeyer-Villiger oxidation/rearrangement reaction, etc. [2]
- Example 2: Viju Balachandran Kammath et al. conducted a detailed investigation into how ring size influences the photo-Favorskii ring contraction reaction in hydroxybenzocycloalkanonyl acetate and mesylate esters. Their findings revealed that cycloalkanones containing seven or eight carbon atoms experienced efficient photo-Favorskii rearrangement, with the ring contraction aligning with the photochemical behavior of p-hydroxyphenacyl esters. [3]
Fig 3. Synthetic examples via Favorskii rearrangement.
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References
- Jie Jack Li. Name Reactions-A Collection of Detailed Mechanisms and Synthetic Applications, Sixth Edition, 2021, 186-189.
- Xu, Hua, et al. Organic Process Research & Development, 2018, 22(3), 377-384.
- Kammath, Viju Balachandran, et al. The Journal of organic chemistry, 2013, 78(5), 1718-1729.
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