What Is Fries Rearrangement?
The Fries rearrangement enables the conversion of aryl esters into valuable ortho- and para-hydroxyaryl ketones. Catalyzed by Lewis or Brønsted acids, or initiated photochemically, this acyl migration reaction offers a direct route to compounds prevalent in pharmaceuticals, agrochemicals, fragrances, and advanced materials.
- Reagents: Lewis acid catalysts; Brønsted acid catalysts.
- Reactants: Aryl esters.
- Products: o- and p-hydroxyaryl ketones.
- Reaction Type: Rearrangement reaction.
- Related Reactions: Friedel-Crafts acylation, Houben-Hoesch reaction.
Experimental Tips:
- Some reactions that cannot be carried out with AlCl3 catalysis or require a large excess of AlCl3 can be replaced with Sc(OTf)3 as a catalyst. Boron trifluoride ether complex can catalyze the rearrangement of hydroquinone diesters, and the product is an acetylated derivative of hydroquinone. The Fries rearrangement promoted by methanesulfonic acid can obtain excellent para-selectivity.
- Crucial for solubility, controlling reaction rate, and influencing ortho/para ratio. Common choices include nitrobenzene (good solvent for AlCl3, but toxic and hard to remove), dichloromethane, dichloroethane, carbon disulfide, chlorobenzene, o-dichlorobenzene. Solvent-free conditions are sometimes possible with molten reactants or using solid catalysts.
- Fries rearrangement can be induced by metalation of α-halogenated aromatic esters. This base-mediated Fries rearrangement reaction is used in the synthesis of the natural product rhein and the new inhibitor topoisomerase I. O-aryl carbamates can also undergo base-mediated Fries rearrangement.
- In addition, the Fries reaction rearrangement has been extended to the anionic N-Fries rearrangement and used in the synthesis of acridone and pyranoacridone alkaloids.
Fig 1. Fries rearrangement and its mechanism. [1]
Mechanism of Fries Rearrangement
The widely accepted mechanism for the catalyzed Fries rearrangement proceeds via an electrophilic aromatic substitution (SEAr) pathway:
Activation:
The Lewis acid catalyst (e.g., AlCl3) coordinates strongly with the carbonyl oxygen of the ester, generating a highly electrophilic acylium ion complex (aluminum phenolate, acylium ion). In Brønsted acid catalysis, protonation of the carbonyl oxygen achieves a similar activation, generating the electrophilic species R'C⁺=OH.
Intramolecular Acylation:
The highly electrophilic acylium ion (or equivalent) attacks the ortho or para position of the same aromatic ring (intramolecular electrophilic aromatic substitution). This step benefits from the proximity of the electrophile to the ring.
Deprotonation and Rearomatization:
Loss of a proton (H+) from the Wheland intermediate (arenium ion) restores aromaticity, yielding the hydroxyaryl ketone product.
Application Examples of Fries Rearrangement
- Example 1: Singam Naveen Kumar et al. developed a one-pot method involving sequential anionic Fries rearrangement, anionic Si → C alkyl rearrangement and Claisen-Schmidt condensation key steps to achieve an efficient synthesis of 2’-hydroxychalcones from phenyl diethylcarbamate, such as the synthesis of the anti-inflammatory natural product Lonchocarpin. [2]
- Example 2: Xiu-Hua Xu et al. first reported a NaH-mediated remote anionic 1,5-thia-Fries rearrangement reaction. It not only provides an efficient method for the synthesis of biologically active 3-indole triflones, but also for the synthesis of various 2-(2-hydroxyphenyl)-3-sulfonyl-1H-indoles. [3]
Fig 2. Synthetic examples via Fries rearrangement.
Related Products
References
- Jie Jack Li. Name Reactions-A Collection of Detailed Mechanisms and Synthetic Applications, Sixth Edition, 2021, 209-211.
- Kumar, Singam Naveen, et al. Organic letters, 2018, 20(17), 5362-5366.
- Xu, Xiu-Hua, et al. Organic Letters, 2013, 15(3), 686-689.
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