Tetra-n-propylammonium Perruthenate1


[114615-82-6]  · C12H28NO4Ru  · Tetra-n-propylammonium Perruthenate  · (MW 351.48)

(mild oxidant for conversion of multifunctionalized alcohols to aldehydes and ketones;1 can selectively oxidize primary-secondary diols to lactones;2 can cleave carbon-carbon bonds of 1,2-diols3)

Alternate Name: TPAP.

Physical Data: mp 165 °C (dec).

Solubility: sol CH2Cl2, and MeCN; partially sol C6H6.

Form Supplied in: dark green solid; commercially available.

Analysis of Reagent Purity: microanalysis.

Handling, Storage, and Precautions: stable at room temperature and may be stored for long periods of time without significant decomposition, especially if kept refrigerated in the dark. The reagent should not be heated neat, as small quantities decompose with flame at 150-160 °C in air.

General Procedures.

TPAP is a convenient, mild, neutral and selective oxidant of primary alcohols to aldehydes and secondary alcohols to ketones.1 These reactions are carried out with catalytic TPAP at rt in the presence of stoichiometric or excess N-Methylmorpholine N-Oxide (NMO) as a cooxidant. A kinetic study with 2-propanol as the substrate has shown that these oxidations are strongly autocatalytic.4 Turnovers of up to 250 are obtainable if activated powdered molecular sieves are introduced to remove both the water formed during oxidations and the water of crystallization of the NMO. Solvents commonly employed are dichloromethane and acetonitrile, or combinations of these. This reagent also works well on a small scale where other methods, such as those employing activated Dimethyl Sulfoxide reagents, are inconvenient.1 For large scale oxidations it is necessary to moderate these reactions by cooling and by slow portionwise addition of the TPAP. To achieve full conversion on a large scale, the NMO should be predried (by first treating an organic solution of NMO with anhydrous magnesium sulfate) and the use of 10% acetonitrile-dichloromethane as solvent is recommended.1

Oxidation of Primary Alcohols.

Primary alcohols can be oxidized in the presence of a variety of functional groups, including tetrahydropyranyl ethers (eq 1),1,5 epoxides (eq 2),1,6 acetals (eq 3),1,7 silyl ethers,1,8 peroxides,9 lactones,1,10 alkenes,1,11 alkynes,1,12 esters,1,13 amides,1,14 sulfones,1 and indoles.10 Oxidation of substrates with labile a-centers proceeds without epimerization.1

Oxidation of Secondary Alcohols.

In a similar fashion, multifunctional secondary alcohols are oxidized to ketones (eqs 4 and 5)9,15 in good yields.1,5-14

A particularly hindered secondary alcohol (an intermediate in the latter stages of the synthesis of tetronolide) resisted oxidation with activated DMSO, Pyridinium Chlorochromate, and activated Manganese Dioxide, yet stoichiometric TPAP afforded the ketone in 81% yield.16

Allylic Alcohols.

These alcohols are successfully oxidized to the corresponding enones and enals (eq 6).1,17

Oxidation of a primary allylic alcohol over a secondary allylic alcohol has been achieved.18 Oxidation of the homoallylic alcohol of cholesterol by TPAP and NMO under ultrasonication conditions gives the dienone cholest-4-ene-3,6-dione in 80% yield.19 This oxidation was subsequently carried out in the presence of a labile TBDMS enol ether group which remained intact, while with both PCC and activated DMSO this protecting group did not survive.19 Oxidation of homopropargylic alcohols leads to allenones, as with other common oxidants.20


Oxidations of lactols to lactones are facile and high yielding; several examples have been reported in the literature (eq 7).1,21

Selective Oxidations.

The selective oxidation of 1,4 and 1,5 primary-secondary diols to lactones is a valuable application of this reagent.2 Few general mild reagents for the chemoselective oxidation to the hydroxy aldehyde are available.22 The most widely known reagents are Pt and O2, and Dihydridotetrakis(triphenylphosphine)ruthenium(II).22 Hydroxy aldehydes, in their lactol form, are then oxidized further to lactones. The use of TPAP is advantageous in that it is commercially available, employs mild catalytic reaction conditions, and reacts with high selectivity in unsymmetrical cases (eq 8).2 Lactones have also been formed from primary-tertiary diols.23

Functional Group Compatibility.

The neutral conditions of these oxidations have been utilized to provide improved yields with acid sensitive substrates compared to the well established Swern method (eqs 9, 10).1,16

Highly sensitive alcohols have also been oxidized, albeit in low yield, when most other conventional methods, such as Dess-Martin periodinane (1,1,1-Triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one),24 PCC, Pyridinium Dichromate, and DMSO activated with Sulfur Trioxide-Pyridine have failed (eq 10).25

Oxidative Cleavage Reactions.

Among the numerous methods for 1,2-diol cleavage there exist only a few that involve catalytic ruthenium reagents, for example Ruthenium(III) Chloride with Sodium Periodate.22 Attempted selective monooxidation of a 1,2-diol to the hydroxy aldehyde with catalytic TPAP and NMO resulted in carbon-carbon bond cleavage to provide the aldehyde (eq 11).3 Furthermore, attempted oxidation of an anomeric a-hydroxy ester failed; instead, in this case decarboxylation/decarbonylation and formation of the lactone was observed (eq 12). However, Dimethyl Sulfoxide-Acetic Anhydride provided the required a-dicarbonyl unit.26 Retro-aldol fragmentations can also be a problem.27

Heteroatom Oxidation.

Thus far, TPAP has only been used to oxidize sulfur. Oxidation of an oxothiazolidine S-oxide to the corresponding S,S-dioxide gave only poor results in comparison to the standard RuO2 with NaIO4 conditions.28 However, oxidation of sulfides to sulfones in the presence of isolated double bonds has been investigated. The yields with TPAP/NMO range from 61-99% which are higher than to those obtained with m-Chloroperbenzoic Acid, Potassium Monoperoxysulfate (Oxone®), or Hydrogen Peroxide-Acetic Acid.29

1. (a) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. CC 1987, 1625. (b) Griffith, W. P.; Ley, S. V. Aldrichim. Acta 1990, 23, 13. (c) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. S 1994, 639.
2. Bloch, R.; Brillet, C. SL 1991, 829.
3. Queneau, Y.; Krol, W. J.; Bornmann, W. G.; Danishefsky, S. J. JOC 1992, 57, 4043.
4. Lee, D. G.; Wang, Z.; Chandler, W. D. JOC 1992, 57, 3276.
5. Guanti, G.; Banfi, L.; Ghiron, C.; Narisano, E. TL 1991, 32, 267.
6. (a) Stürmer, R.; Ritter, K.; Hoffmann, R. W. AG(E) 1993, 32, 101. (b) Kim, G.; Chu-Moyer, M. Y.; Danishefsky, S. J. JACS 1990, 112, 2003.
7. (a) Anthony, N. J.; Armstrong, A.; Ley, S. V.; Madin, A. TL 1989, 30, 3209. (b) Romeyke, Y.; Keller, M.; Kluge, H.; Grabley, S.; Hammann, P. T 1991, 47, 3335.
8. (a) Ley, S. V.; Maw, G. N.; Trudell, M. L. TL 1990, 31, 5521. (b) Rosini, G.; Marotta, E.; Raimondi, A.; Righi, P. TA 1991, 2, 123.
9. (a) Hu, Y.; Ziffer, H. J. Labelled Comp. Radiopharm. 1991, 29, 1293.
10. Linz, G.; Weetman, J.; Hady, A. F. A.; Helmchen, G. TL 1989, 30, 5599.
11. (a) Cole, P. A.; Bean, J. M.; Robinson, C. H. PNA 1990, 87, 2999. (b) Piers, E.; Roberge, J. Y. TL 1991, 32, 5219.
12. Desmaële, D.; Champion, N. TL 1992, 33, 4447.
13. Hori, K.; Hikage, N.; Inagaki, A.; Mori, S.; Nomura, K.; Yoshii, E. JOC 1992, 57, 2888.
14. Guanti, G.; Banfi, L.; Narisano, E.; Thea, S. SL 1992, 311.
15. Sulikowski, M. M.; Ellis Davies, G. E. R.; Smith, A. B., III JCS(P1) 1992, 979.
16. Takeda, K.; Kawanishi, E.; Nakamura, H.; Yoshii, E. TL 1991, 32, 4925.
17. (a) Ninan, A.; Sainsbury, M. T 1992, 48, 6709. (b) Rychnovsky, S. D.; Rodriguez, C. JOC 1992, 57, 4793. (c) Kang, H.-J.; Ra, C. S.; Paquette, L. A. JACS 1991, 113, 9384. (d) Schreiber, S. L.; Kiessling, L. L. TL 1989, 30, 433.
18. Hitchcock, S. A.; Pattenden, G. TL 1992, 33, 4843.
19. Moreno, M. J. S. M.; Melo, M. L. S.; Neves, A. S. C. TL 1991, 32, 3201.
20. Marshall, J. A.; Robinson, E. D.; Lebreton, J. JOC 1990, 55, 227.
21. Paquette, L. A.; Kang, H-J.; Ra, C. S. JACS 1992, 114, 7387.
22. COS 1991, 7.
23. (a) Mehta, G.; Karra, S. R. TL 1991, 32, 3215. (b) Mehta, G.; Karra, S. R. CC 1991, 1367.
24. Yamashita, D. S.; Rocco, V. P.; Danishefsky, S. J. TL 1991, 32, 6667.
25. Tokoroyama, T.; Kotsuji, Y.; Matsuyama, H.; Shimura, T.; Yokotani, K.; Fukuyama, Y. JCS(P1) 1990, 1745.
26. Watanabe, T.; Nishiyama, S.; Yamamura, S.; Kato, K.; Nagai, M.; Takita, T. TL 1991, 32, 2399.
27. Shih, T. L.; Mrozik, H.; Holmes, M. A.; Arison, B. H.; Doss, G. A.; Waksmunski, F.; Fisher, M. H. TL 1992, 33, 1709.
28. White, G. J.; Garst, M. E. JOC 1991, 56, 3177.
29. Guertin, K. R.; Kende, A. S. TL 1993, 34, 5369.

Steven V. Ley & Joanne Norman

University of Cambridge, UK

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