Phosphorus(V) Oxide-Methanesulfonic Acid1

P2O5-MeSO3H

[39394-84-8]  · CH4O8P2S  · Phosphorus(V) Oxide-Methanesulfonic Acid  · (MW 238.06) (P2O5)

[1314-56-3]  · O5P2  · Phosphorus(V) Oxide-Methanesulfonic Acid  · (MW 141.94) (MeSO3H)

[75-75-2]  · CH4O3S  · Phosphorus(V) Oxide-Methanesulfonic Acid  · (MW 96.12)

(acidic dehydrating agent used in cycloalkenone synthesis,1 Friedel-Crafts reactions,1 the Fischer indole synthesis,2 the Beckmann rearrangement,1 and other dehydrations; an alternative to polyphosphoric acid1)

Alternate Name: Eaton's reagent.

Physical Data: 7.5 wt% solution: bp 122 °C/1 mmHg; d 1.500 g cm-3.

Solubility: sol ether, alcohol, MeCN, CH2Cl2; insol toluene, hexane.2,3

Form Supplied in: 7.5 wt% solution is commercially available.

Preparative Method: prepared1 by adding Phosphorus(V) Oxide (P2O5, 36 g) in one portion to Methanesulfonic Acid (360 g) and stirring at rt3 until the P2O5 dissolves.4 Although Eaton recommends the use of freshly distilled methanesulfonic acid to allow for a clean workup and good yields,1 others report using the acid as purchased.5,6

Handling, Storage, and Precautions: Eaton's reagent is toxic and corrosive. Direct contact with this reagent should be avoided. The solution begins to yellow upon standing for long periods of time; however, this does not appear to affect the viability of the reagent.1 Use in a fume hood.

Reagent Description.

The reagent was conceived as an alternative to the widely used, but often inconvenient, Polyphosphoric Acid (PPA) (see also Polyphosphate Ester, PPE).1 Eaton's reagent successfully addresses the drawbacks of PPA's physical properties. It is much less viscous, and is, therefore, easier to stir. Organic compounds are generally soluble in Eaton's reagent, and the hydrolytic workup is less tedious.1 Reactions are run at ambient or slightly elevated temperatures. Standard aqueous workup is easy and clean. Eaton recommends quenching the reaction with water; quenching in ice may cause methanesulfonic anhydride to precipitate and be extracted into the organic layer; quenching in aqueous base may cause extensive foaming.1 In addition to its ease of handling, yields obtained with Eaton's reagent compare favorably with those obtained with PPA.7 Few modifications of Eaton's original procedure have appeared. A 1:5 by weight ratio has been reported to be as effective as a 1:10 ratio.8 It has been noted that, to avoid polymer formation, only the minimum amount of reagent needed to effect condensation should be used.9 The nature of the reagent has not been rigorously determined. It appears that the reactive or catalytic species may vary by reaction. In certain acid-catalyzed reactions, P2O5 has been found to be superfluous.10

Cycloalkenones.

P2O5/MeSO3H is used as a reagent in several reactions leading to cycloalkenones. First described in Eaton's original paper, the lactone-to-cyclopentenone rearrangement (eq 1)1 has since found wide use.11

In a related reaction, readily available nitroalkanoic acids cyclize to form cyclopentenones (eq 2).12 As illustrated in eq 3,13a vinylcyclobutanones undergo acyl migration to produce either cyclopentenones or cyclohexenones.13

Vinylcyclopentenones have undergone the Nazarov cyclization in good yield in the presence of Eaton's reagent (eq 4).14 However, other reagents may be more generally useful, since there are reports of Eaton's reagent not providing optimal results in this reaction.15

Friedel-Crafts Acylations of Aromatic Rings.

Eaton's reagent has been used widely and very effectively16a to catalyze Friedel-Crafts acylations.16 One of the few potential drawbacks is the deprotection of an aryl ether. The examples shown below compare the utility of Eaton's reagent vs. PPA with regard to this deprotection problem. In eq 5, although the cyclization proceeds with an undesired protecting group exchange, the cyclization fails in PPA.17 Deprotection of an aryl methyl ether is avoided by using Eaton's reagent in place of PPA in one case (eq 6),18 but not in another.19 Intramolecular Friedel-Crafts acylations have been observed to occur without the addition of P2O5.10 A comparative study found this observation to be generally applicable to intramolecular acylations, but not intermolecular acylations.10b,20

Friedel-Crafts Alkylations.

P2O5/MeSO3H compares favorably with other reagents in the Friedel-Crafts alkylation reaction.21 Mechanistic aspects of this reaction have been discussed.21b Eq 7 shows an alkene-initiated alkylation that provides (+)-O-methylpodocarpate selectively.22

Dehydration.

Alcohols have been dehydrated to alkenes with Eaton's reagent (eq 8).23 In a formal dehydration, a cyclopentenone has been transformed into a diene (eq 9).24

Fischer Indole Synthesis.

The use of Eaton's reagent as the acid catalyst in the Fischer indole reaction results in unprecedented regiocontrol favoring 2-substituted indoles (eq 10).2 In cases where the harshness of the reagent results in low yields of indoles, dilution of the reaction mixture in sulfolane or CH2Cl2 attenuates the problem. Mechanistic studies indicate that the catalytic species, in this reaction, is MeSO3H. The role of P2O5 is to act as a drying agent. Further experiments indicate that for the Friedel-Crafts acylation this is not the case; a mixed anhydride is the catalytic species.2

Heterocycle Preparation.

Various heterocycles have been prepared through P2O5/MeSO3H-mediated cyclizations. Condensation, and subsequent dehydration, of aminothiophenol and the appropriate acid provides benzothiazoles (eq 11).25

Oxadiazoles can be prepared from diacylhydrazines (eq 12).26 Furans are formed from the cyclodehydration of a phenolic ketone (eq 13).27

Butenolides have been prepared by cyclization of keto esters (eq 14)28 or by elimination of H2O from a preformed hydroxy butenolide (eq 15).29

Yields in the synthesis of thiadiazolo[3,2-a]pyrimidin-5-ones have been greatly improved by using Eaton's reagent in the place of PPA (eq 16).8b

Eaton's reagent is superior to PPA in the addition of an amide across a double bond (eq 17).30 In another synthesis of lactams, 3-alkenamides reacted stereoselectively with benzaldehyde to provide lactams containing three contiguous stereogenic centers (eq 18).31

Beckmann Rearrangement.

Eaton's disclosure of P2O5/MeSO3H as an alternative to PPA compared the two reagents' ability to effect the Beckmann rearrangement.1 Eaton's reagent has been reported to be superior to other reagents at inducing stereospecific rearrangement of the (E)- and (Z)-oximes of phenylacetone.4 However, this is not a general finding. Rearrangement of the oxime in eq 19 does not provide the product expected from an anti-migration process.32


1. Eaton, P. E.; Carlson, G. R.; Lee, J. T. JOC 1973, 38, 4071.
2. This paper reports that in the preparation of 2-substituted indoles Eaton's reagent is superior to PPA, H2SO4, and PPSE: Zhao, D.; Hughes, D. L.; Bender, D. R.; DeMarco, A. M.; Reider, P. J. JOC 1991, 56, 3001.
3. These authors report the presence of a finely-divided solid after stirring for 6 h. It was removed by filtration under nitrogen.
4. Alternatively, the solution may be heated during dissolution of the P2O5. See: Stradling, S. S.; Hornick, D.; Lee, J.; Riley, J. J. Chem. Educ. 1983, 60, 502.
5. Akhtar, S. R.; Crivello, J. V.; Lee, J. L. JOC 1990, 55, 4222.
6. Corey, E. J.; Boger, D. L. TL 1978, 5.
7. Examples of exceptions: (a) PPA is superior to either Eaton's reagent or H2SO4 in a Friedel-Crafts acylation: Hormi, O. E. O.; Moisio, M. R.; Sund, B. C. JOC 1987, 52, 5272. (b) PPA is superior to Eaton's reagent, BF3.OEt2, HCO2H, ZnCl2, CF3CO2H, p-TsOH, and H2SO4 in a Friedel-Crafts alkylation: Maskill, H. JCS(P1) 1987, 1739. (c) PPA is superior to Eaton's reagent or CF3CO2H/(CF3CO)2O/BF3.OEt2 in a Friedel-Crafts acylation: Hands, D.; Marley, H.; Skittrall, S. J.; Wright, S. H. B.; Verhoeven, T. R. JHC 1986, 23, 1333. (d) PPA is superior to Eaton's reagent in a Friedel-Crafts acylation: Bosch, J.; Rubiralta, M.; Domingo, A.; Bolos, J.; Linares, A.; Minguillon, C.; Amat, M.; Bonjoch, J. JOC 1985, 50, 1516. (e) PPA is superior to Eaton's reagent or PPE in a Friedel-Crafts acylation: Jilek, J.; Holubek, J.; Svatek, E.; Schlanger, J.; Pomykacek, J.; Protiva, M. CCC 1985, 50, 519. (f) In a Friedel-Crafts acylation, where PPA or Eaton's reagent fails to give satisfactory results, the corresponding acid chloride is cyclized using AlCl3: Barco, A.; Benetti, S.; Pollini, G. P. OPP 1976, 8, 7.
8. (a) Eaton, P. E.; Mueller, R. H.; Carlson, G. R.; Cullison, D. A.; Cooper, G. F.; Chou, T.-C.; Krebs, E.-P. JACS 1977, 99, 2751. (b) Tsuji, T.; Takenaka, K. BCJ 1982, 55, 637.
9. Parish, W. W.; Stott, P. E.; McCausland, C. W.; Bradshaw, J. S. JOC 1978, 43, 4577.
10. (a) Leon, A.; Daub, G.; Silverman, I. R. JOC 1984, 49, 4544. (b) Premasagar, V.; Palaniswamy, V. A.; Eisenbraun, E. J. JOC 1981, 46, 2974.
11. (a) Jacobson, R. M.; Lahm, G. P.; Clader, J. W. JOC 1980, 45, 395. (b) Inouye, Y.; Fukaya, C.; Kakisawa, H. BCJ 1981, 54, 1117. (c) Murthy, Y. V. S.; Pillai, C. N. T 1992, 48, 5331. (d) Eaton, P. E.; Srikrishna, A.; Uggeri, F. JOC 1984, 49, 1728. (e) Pohmakotr, M.; Reutrakul, V.; Phongpradit, T.; Chansri, A. CL 1982, 687. (f) Baldwin, J. E.; Beckwith, P. L. M. CC 1983, 279. (g) Mundy, B. P.; Wilkening, D.; Lipkowitz, K. B. JOC 1985, 50, 5727. (h) Mehta, G.; Karra, S. R. TL 1991, 32, 3215. (i) Ho, T.-L.; Yeh, W.-L; Yule, J.; Liu, H.-J. CJC 1992, 70, 1375.
12. Ho, T.-L. CC 1980, 1149.
13. (a) Matz, J. R.; Cohen, T. TL 1981, 22, 2459. (b) For a related ring expansion of 1-alkenylcyclopropanols to cyclopentenones, see: Barnier, J.-P.; Karkour, B.; Salaun, J. CC 1985, 1270.
14. Paquette, L. A.; Stevens, K. E. CJC 1984, 62, 2415.
15. (a) This paper reports obtaining Nazarov cyclization products in 8-10% yield with either Eaton's reagent or FeCl3. A silicon assisted Nazarov was also explored: Cheney, D. L.; Paquette, L. A. JOC 1989, 54, 3334. (b) PPA is superior to Eaton's reagent or methanesulfonic acid in effecting cyclization of 1,1-dicyclopentenyl ketone: Eaton, P. E.; Giordano, C.; Schloemer, G.; Vogel, U. JOC 1976, 41, 2238. (c) Many other reagents including HCO2H/H3PO4, HCl, H2SO4, SnCl4, and TsOH have been used in this type of Nazarov cyclization. For a review of the Nazarov cyclization, see: Santelli-Rouvier, C.; Santelli, M. S 1983, 429.
16. Examples: (a) McGarry, L. W.; Detty, M. R. JOC 1990, 55, 4349. (b) Grunewald, G. L.; Sall, D. J.; Monn, J. A. JMC 1988, 31, 433. (c) Russell, R. K.; Rampulla, R. A.; van Nievelt, C. E.; Klaubert, D. H. JHC 1990, 27, 1761. (d) Ye, Q.; Grunewald, G. L. JMC 1989, 32, 478. (e) Kelly, T. R.; Ghoshal, M. JACS 1985, 107, 3879. (f) Eck, G.; Julia, M.; Pfeiffer, B.; Rolando, C. TL 1985, 26, 4723. (g) Kitazawa, S.; Kimura, K.; Yano, H.; Shono, T. JACS 1984, 106, 6978. (h) Stott, P. E.; Bradshaw, J. S.; Parish, W. W.; Copper, J. W. JOC 1980, 45, 4716. (i) Cushman, M.; Abbaspour, A.; Gupta, Y. P. JACS 1983, 105, 2873. (j) Acton, D.; Hill, G.; Tait, B. S. JMC 1983, 26, 1131. (k) Miller, S. J.; Proctor, G. R.; Scopes, D. I. C. JCS(P1) 1982, 2927.
17. Cushman, M.; Mohan, P. JMC 1985, 28, 1031.
18. Inouye, Y.; Uchida, Y.; Kakisawa, H. BCJ 1977, 50, 961.
19. Falling, S. N.; Rapoport, H. JOC 1980, 45, 1260.
20. For an example of an intermolecular acylation of cyclohexenone, see: Cargill, R. L.; Jackson, T. E. JOC 1973, 38, 2125.
21. (a) Fox, J. L.; Chen, C. H.; Stenberg, J. F. OPP 1985, 17, 169. (b) Davis, B. R.; Hinds, M. G.; Johnson, S. J. AJC 1985, 38, 1815.
22. Hao, X.-J.; Node, M.; Fuji, K. JCS(P1) 1992, 1505.
23. Ziegler, F. E.; Fang, J.-M.; Tam, C. C. JACS 1982, 104, 7174.
24. Scott, L. T.; Minton, M. A.; Kirms, M. A. JACS 1980, 102, 6311.
25. Boger, D. L. JOC 1978, 43, 2296.
26. Rigo, B.; Couturier, D. JHC 1986, 23, 253.
27. Cambie, R. C.; Howe, T. A.; Pausler, M. G.; Rutledge, P. S.; Woodgate, P. D. AJC 1987, 40, 1063.
28. Schultz, A. G.; Yee, Y. K. JOC 1976, 41, 561.
29. Schultz, A. G.; Godfrey, J. D. JACS 1980, 102, 2414.
30. Tilley, J. W.; Clader, J. W.; Wirkus, M.; Blount, J. F. JOC 1985, 50, 2220.
31. Marson, C. M.; Grabowska, U.; Walsgrove, T.; Eggleston, D. S.; Baures, P. W. JOC 1991, 56, 2603.
32. Jeffs, P. W.; Molina, G.; Cortese, N. A.; Hauck, P. R.; Wolfram, J. JOC 1982, 47, 3876.

Lisa A. Dixon

The R. W. Johnson Pharmaceutical Research Institute, Raritan, NJ, USA



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