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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.

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

Materials
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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
Para hydroxybenzophenone

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:

Oxa Michael Addition Reaction

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 Cs2.5H0.5PW12O40 (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
Dimethoxyquinone

Figure 4.Dimethoxyquinone

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

Figure 5.Phenyl Acetate

Materials
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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
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