Iron(III) Chloride-Acetic Anhydride1

FeCl3-Ac2O
(FeCl3)

[7705-08-0]  · Cl3Fe  · Iron(III) Chloride-Acetic Anhydride  · (MW 162.20) (Ac2O)

[108-27-7]  · C4H6O3  · Iron(III) Chloride-Acetic Anhydride  · (MW 102.10)

(Lewis acid cleaving ethers,2 gem-diacetates,8 imides11)

Alternate Name: ferric chloride-acetic anhydride.

Preparative Method: this reagent combination is used in situ via addition of anhydrous Iron(III) Chloride (6.2 mmol), to the substrate (35.5 mmol) and Acetic Anhydride (15 mL).2

Handling, Storage, and Precautions: reactions can be mildly exothermic. FeCl3 is hygroscopic and corrosive, inhalation or ingestion may be fatal. Acetic anhydride is moderately toxic by inhalation, ingestion, and skin contact. It is a skin and severe eye irritant. It can react vigorously with oxidizing agents, and will react vigorously with water.12 Use in a fume hood.

Cleavage of Ethers.2

Iron(III) chloride in acetic anhydride was first reported to cleave diethyl ether to ethyl acetate,3 and has been developed into a very useful ether-cleavage reagent.2a Iron(III) chloride is added to the substrate and acetic anhydride. For simple substrates the reaction may be heated on a steam bath, while for sensitive functionality it is best conducted at 0 °C and monitored by TLC. The acetate ester is obtained as the product (44-92%). The reaction can be performed using ethyl acetate2a or ether2b as cosolvent and detailed procedures are available.2 Reactions are usually worked up via extraction into hexane, and washing with water and sodium bicarbonate. Alternatively, saturated Na2HPO4 can be used to form FePO4, which can be filtered off prior to extraction. This system will cleave a wide range of ethers: n-alkyl, isopropyl, t-butyl, benzyl, and TBDMS. The reaction conditions are compatible with easily isomerized alkenes (eq 1). Optically active ethers usually afford racemic acetates; however, the synthesis of (R)-(+)-4-acetoxycyclopent-2-enone4 provides a notable exception (eq 2). The FeCl3-Ac2O procedure is the one of choice when an alcohol deprotection is to be followed by acylation with a hindered acid chloride.5 It also provides an excellent route to cyanohydrin esters from ketones (eq 3).6 Deprotection of ethers is covered extensively in the literature.1,7

gem-Diacetates from Aldehydes.8

Aldehydes are converted to geminal diacetates (63-93%) via addition of iron(III) chloride to a solution of aldehyde in acetic anhydride (eq 4). A wide range aldehydes react: aliphatic, aromatic, heteroaryl, and a,b-unsaturated aldehydes. Alternative reaction conditions include acid catalysis9 and Phosphorus(III) Chloride.10

Imides.11

a-t-Butoxy- or a-acetoxyacrylonitriles can be converted into imides with FeCl3-Ac2O (eq 5) via cleavage of the t-butyl ether and addition to the nitrile. However this reaction is limited to t-butoxy- and acetoxyacrylonitriles.


1. Bhatt, M. V.; Kulkarni, S. U. S 1983, 249.
2. (a) Ganem, B.; Small, V. R., Jr. JOC 1974, 39, 3728. (b) Alexakis, A.; Gardette, M.; Colin, S. TL 1988, 29, 2951.
3. Knoevenagel, E. LA 1914, 402, 133.
4. Eschler, B. M.; Haynes, R. K.; Ironside, M. D.; Kremmydas, S.; Ridley, D. D.; Hambley, T. W. JOC 1991, 56, 4760.
5. Sampson, P.; Roussis, V.; Drtina, G. J.; Koerwitz, F. L.; Wiemer, D. F. JOC 1986, 51, 2525.
6. Hiyama, T.; Oishi, H.; Saimoto, H. TL 1985, 26, 2459.
7. (a) Greene, T. W. Protective Groups in Organic Synthesis; Wiley: New York, 1981; p 29. (b) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis; Wiley: New York, 1991; pp 49, 156.
8. Kochar, K. S.; Balkrishna, S. B.; Deshapande, R. P.; Rajadhyaksha, S. N.; Pinnick, H. W. JOC 1983, 48, 1765.
9. Thiele, J.; Winter, E. LA 1960, 311, 355.
10. Michie, J. K.; Miller, J. A. S 1981, 824.
11. Diamond, P. M.; Dinizo, S. E.; Freerksen, R. W.; Haltiwanger, R. C.; Watt, D. S. CC 1977, 298.
12. Lewis, R. J., Sr. Hazardous Chemicals Desk Reference; Van Nostrand Reinhold: New York, 1991; p 8.

Andrew D. White

Parke-Davis Pharmaceutical Research, Ann Arbor, MI, USA



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