Fries Rearrangement

The Reaction

The Fries rearrangement reaction is an organic name reaction which involves the conversion of phenolic esters into hydroxyaryl ketones on heating in the presence of a catalyst. Suitable catalysts for this reaction are Brønsted or Lewis acids such as HF, AlCl₃, BF₃, TiCl₄, or SnCl₄. The Fries rearrangement reaction is an ortho, para-selective reaction, and is used in the preparation of acyl phenols.¹ This organic reaction has been named after German chemist Karl Theophil Fries.

Figure 1. German Chemist Karl Theophil Fries

The photo-Fries rearrangement involves a similar conversion of phenolic esters into hydroxy ketones in the presence of UV light without catalyst.¹

The thia-Fries rearrangement involves the conversion of aryl triflinates to trifluoromethanesulfinyl phenols in the presence of aluminum chloride in dichloromethane.²

The anionic phospho-Fries rearrangement involves the conversion of an aryl phosphate ester [ArOP(=O)(OR)₂] into an ortho-hydroxyarylphosphonate [o-HO-Ar-P(=O)(OR)₂]. This rearrangement yields phenols with an ortho C-P bond.³

Applications

The Fries rearrangement has found application in the following areas:

• The use of an ionic melt [1-butyl-3-methylimidazolium chloroaluminate, ([BMIm]Cl·xAlCl₃)] as both solvent and Lewis acid catalyst was investigated. The reaction with phenyl benzoate yields ortho- and para‑hydroxybenzophenone.⁴

Figure 2. Para hydroxybenzophenone

• Synthesis of o- and p-hydroxyacetophenones (useful intermediates in the manufacture of pharmaceuticals).⁵
• Total synthesis of α-tocopherol (vitamin E).⁶
• Regioselective synthesis of ortho-acylhydroxy[2.2]paracyclophanes, via TiCl₄-catalyzed Fries rearrangement and direct regioselective acylation reaction.⁷
• Synthesis of drug and agrochemical intermediates, thermographic materials, and effective antiviral agents.⁸
• Synthesis of hydroxynaphthyl ketones, via scandium trifluoromethanesulfonate catalyzed Fries rearrangement of acyloxynaphthalenes.⁹
• Photochemical one-pot synthesis of 5-, 6-, and 7-substituted chroman-4-ones from aryl 3-methyl-2-butenoate esters, via a photo-Fries rearrangement and a base-catalyzed intramolecular oxa-Michael addition reaction.¹⁰

Scheme of the above syntheses:

Figure 3. Oxa Michael Addition Reaction

Recent Research and Trends

• Thia–Fries rearrangement of aryl sulfonates in solvent-free conditions under microwave dielectric heating has been studied.⁸
  Photoreactive liquid crystalline polymer films were reported to undergo axis-selective photo-Fries rearrangement, and exhibited photoinduced optical anisotropy when exposed to linearly polarized ultraviolet (LPUV) light.¹
• Fries rearrangement has been employed in the key steps in the total synthesis of muricadienin, the unsaturated putative precursor in the biosynthesis of trans- and cis-solamin.¹⁰
• The anionic phospho-Fries rearrangement of chiral ferrocenyl phosphates yields diastereomeric enriched 1,2-P,O-phosphonates, which can then be converted into an enantiomerically pure phosphane.¹³
• Liquid-phase Fries rearrangement of aryl esters catalyzed by heteropoly acid H₃PW₁₂O₄₀ (PW) supported on silica or its salt Cs_2.5H_0.5PW₁₂O₄₀ (CsPW) has been reported.¹⁴
• Anionic phospho-Fries rearrangement has been successfully applied to investigate ferrocene chemistry.¹⁵
• Fries rearrangement is employed for the synthesis of the antiviral flavonoid lead ladanein, starting from 2,6-dimethoxyquinone.¹⁶

Figure 4. Dimethoxyquinone

• Heteropoly acid H₃PW₁₂O₄₀ has been reported as an efficient and environmentally benign catalyst for the Fries rearrangement of phenyl acetate.¹⁷

Figure 5. Phenyl Acetate

References

1. Bansal R K. 1996. Synthetic Approaches in Organic Chemistry. Jones & Bartlett Learning.

2. Chen X, Tordeux M, Desmurs J, Wakselman C. 2003. Thia-Fries rearrangement of aryl triflinates to trifluoromethanesulfinylphenols. Journal of Fluorine Chemistry. 123(1):51-56. https://doi.org/10.1016/s0022-1139(03)00106-4

3. Taylor C, Watson A. 2004. The Anionic Phospho-Fries Rearrangement. COC. 8(7):623-636. https://doi.org/10.2174/1385272043370717

4. Harjani JR, Nara SJ, Salunkhe MM. 2001. Fries rearrangement in ionic melts. Tetrahedron Letters. 42(10):1979-1981. https://doi.org/10.1016/s0040-4039(01)00029-6

5. Jayat F, Picot MJS, Guisnet M. 1996. Solvent effects in liquid phase Fries rearrangement of phenyl acetate over a HBEA zeolite. Catal Lett. 41(3-4):181-187. https://doi.org/10.1007/bf00811488

6. Termath AO, Velder J, Stemmler RT, Netscher T, Bonrath W, Schmalz H. 2014. Total Synthesis of (2RS)-?-Tocopherol through Ni-Catalyzed 1,4-Addition to a Chromenone Intermediate. Eur. J. Org. Chem.. 2014(16):3337-3340. https://doi.org/10.1002/ejoc.201402240

7. Rozenberg V, Danilova T, Sergeeva E, Vorontsov E, Starikova Z, Lysenko K, Belokon .Y. Eur J. 2000. Org. Chem. 193295.

8. Moghaddam FM, Dakamin MG. 2000. Thia-Fries rearrangement of aryl sulfonates in dry media under microwave activation. Tetrahedron Letters. 41(18):3479-3481. https://doi.org/10.1016/s0040-4039(00)00402-0

9. Kobayashi S, Moriwaki M, Hachiya I. 1995. The catalytic Fries rearrangement of acyloxy naphthalenes using scandium trifluoromethanesulfonate as a catalyst. J. Chem. Soc., Chem. Commun..(15):1527. https://doi.org/10.1039/c39950001527

10. Iguchi D, Erra-Balsells R, Bonesi SM. 2014. Expeditious photochemical reaction toward the preparation of substituted chroman-4-ones. Tetrahedron Letters. 55(33):4653-4656. https://doi.org/10.1016/j.tetlet.2014.06.081

11. Uraoka H, Kondo M, Kawatsuki N. 2014. Influence of End Groups in Photoinduced Reorientation of Liquid Crystalline Polymer Films Based on Axis-Selective Photo-Fries Rearrangement. Molecular Crystals and Liquid Crystals. 601(1):79-87. https://doi.org/10.1080/15421406.2014.940508

12. Adrian J, Stark CBW. 2014. Total Synthesis of Muricadienin, the Putative Key Precursor in the Solamin Biosynthesis. Org. Lett.. 16(22):5886-5889. https://doi.org/10.1021/ol502849y

13. Korb M, Lang H. 2014. Planar Chirality from the Chiral Pool: Diastereoselective Anionic Phospho-Fries Rearrangements at Ferrocene. Organometallics. 33(22):6643-6659. https://doi.org/10.1021/om500953c

14. Kozhevnikova E. 2004. Fries rearrangement of aryl esters catalysed by heteropoly acid: catalyst regeneration and reuse. Applied Catalysis A: General. 260(1):25-34. https://doi.org/10.1016/j.apcata.2003.10.008

15. Korb M, Schaarschmidt D, Lang H. 2014. Anionic Phospho-Fries Rearrangement at Ferrocene: One-Pot Approach to P,O-Substituted Ferrocenes. Organometallics. 33(8):2099-2108. https://doi.org/10.1021/om5002827

16. Martin-Benlloch X, Elhabiri M, Lanfranchi DA, Davioud-Charvet E. 2014. A Practical and Economical High-Yielding, Six-Step Sequence Synthesis of a Flavone: Application to the Multigram-Scale Synthesis of Ladanein. Org. Process Res. Dev.. 18(5):613-617. https://doi.org/10.1021/op4003642

17. Kozhevnikova EF, Derouane EG, Kozhevnikov IV. 2002. Heteropoly acid as a novel efficient catalyst for Fries rearrangement. Chem. Commun..(11):1178-1179. https://doi.org/10.1039/b202148j