N-Methylmorpholine N-Oxide1

[7529-22-8]  · C5H11NO2  · N-Methylmorpholine N-Oxide  · (MW 117.17)

(used as a co-oxidant with OsO42 and ruthenates;3 acts a mild oxidizing agent4)

Alternate Name: NMO.

Physical Data: mp 75-76 °C (as monohydrate)

Solubility: sol water, acetone, alcohol, ether.

Form Supplied in: colorless deliquescent crystals; available commercially.

Purification: crystallize from ethanol.

Handling, Storage, and Precautions: refrigerate; hygroscopic; irritant; handle in a fume hood using gloves; avoid skin contact and inhalation; in case of contact, rinse immediately with water.

Co-oxidation Reagent.

N-Methylmorpholine N-oxide is commonly used as a mild co-oxidant. The stoichiometric use of Osmium Tetroxide to cis-dihydroxylate alkenes is avoided by using NMO as a reoxidant (eq 1).1,2,5 This reagent is preferred over other cis-dihydroxylation reagents such as Potassium Permanganate, Iodine-Silver Acetate, or Osmium Tetroxide in the presence of barium perchlorate or Hydrogen Peroxide, since these reagents give poor yields, require cumbersome workups, or are prohibitively expensive for large-scale glycolization reactions.2,5 See also Osmium Tetroxide-N-Methylmorpholine N-Oxide.

Oxidation of allylic alcohols using NMO/OsO4 occurs with high stereoselectivity. The relative stereochemistry of the incoming hydroxy group is erythro to the hydroxy, alkoxy, or methyl group in the allylic position of the product (eq 2).6 Similar results are obtained using this procedure to oxidize higher-carbon sugars containing allylic alcohols.7

Asymmetric dihydroxylation is accomplished by using NMO in the presence of OsO4 and dihydroquinidine p-chlorobenzoate (eq 3).8 This procedure works well for a variety of alkenes but gives the best results for those alkenes with aromatic directing groups. The method is insensitive to scale, moisture, and can be run with very low concentrations of OsO4.

A kinetic study using Trimethylamine N-Oxide in place of NMO as a reoxidant has been reported.9 Crystallographic analysis of an isolated intermediate using NMO (eq 4) has provided mechanistic evidence for osmate ester intermediates in tertiary amine N-oxide oxidation systems.1,10

Intermediate cis-diols generated by NMO/OsO4 oxidation can be cleaved to give the corresponding dialdehydes by periodate oxidation (eq 5).11

a-Hydroxyaldehydes and their tautomeric hydroxymethyl ketones can be conveniently prepared using NMO/OsO4 or KMnO4 to cis-hydroxylate enol phosphonates (eq 6).12 The oxidation step is accomplished in high yields and the overall synthesis requires only three steps from a ketone.

The NMO/OsO4 oxidation system efficiently oxidizes terminal alkenes. However, this reagent may be replaced in some cases by Potassium Ferricyanide/OsO4 to give comparable yields of the corresponding 1,2-diol (eq 7).13

Besides OsO4, other oxidants can be used catalytically in the presence of NMO. For example, epoxides are left intact when oxidizing a primary alcohol with NMO in the presence of catalytic Tetra-n-propylammonium Perruthenate (TPAP) (eq 8) and when oxidizing a secondary alcohol using catalytic tetra-n-butylammonium perruthenate (TBAP) (eq 9).3 This reagent will also oxidize 1,4- and 1,5-primary/secondary diols to lactones.14

NMO along with a catalytic amount of RuCl2(PPh3)3 will oxidize alcohols to aldehydes and ketones; RuCl2(PPh3)3/NMO efficiently oxidizes (+)-carveol to (+)-carvone in 94% yield at rt after 2 h.15 This reagent system will also oxidize sulfides and phosphines to their respective oxides.16

Mild Oxidant.

Activated halides can efficiently be converted to aldehydes or ketones under mild conditions using NMO. For example, cinnamyl bromide is converted to cinnamaldehyde by stirring the activated halide with NMO in acetonitrile.4 This reagent will oxidize a halide in the presence of a double bond (eq 10).

NMO can also be used as a reoxidant in the Pauson-Khand reaction for the synthesis of cyclopentenones.17 This reaction typically is run at elevated temperatures (60-110 °C) or with ultrasound at 45 °C. Milder conditions are used with NMO, thus allowing for higher stereoselectivity in cycloadditions involving dicobalt hexacarbonyl complexes of alkynes (eq 11).

Peptide synthesis can be performed using NMO as a mild oxidizing agent in the presence of the peptide hydrochloride, Diphenyl Diselenide and Tri-n-butylphosphine at 60 °C.18 The phosphine and selenide act as a reductant and oxidant respectively. NMO inhibits the formation of byproducts by oxidizing selenophenol produced in the reaction mixture (eq 12) (see also Trimethylamine N-Oxide).

1. Albini, A. S 1993 263.
2. VanRheenen, V.; Cha, D. Y.; Hartley, W. M. OS 1978, 58, 43.
3. Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D. CC 1987, 1625.
4. Griffith, W. P.; Jolliffe, J. M.; Ley, S. V.; Springhorn, K. F.; Tiffin, P. D. SC 1992, 22, 1967.
5. VanRheenen, V.; Kelly, R. C.; Cha, D. Y. TL 1976, 1973.
6. Cha, J. K.; Christ, W. J.; Kishi, Y. TL 1983, 24, 3943.
7. (a) Brimacombe, J. S.; Hanna, R.; Kabir, A. K. M. S.; Bennett, F.; Taylor, I. D. JCS(P1) 1986, 815. (b) Brimacombe, J. S.; Hanna, R.; Kabir, A. K. M. S. JCS(P1) 1986, 823.
8. (a) McKee, B. H.; Gilheany, D. G.; Sharpless, K. B. OS 1992, 70, 47. (b) Jacobsen, E. N.; Markó, I.; Mungall, W. S.; Schröder, G.; Sharpless, K. B. JACS 1988, 110, 1968.
9. Erdik, E.; Matteson, D. S. JOC 1989, 54, 2742.
10. Sivik, M. R.; Gallucci, J. C.; Paquette, L. A. JOC 1990, 55, 391.
11. Reedich, D. E.; Sheridan, R. S. JOC 1985, 50, 3535.
12. Waszkuć, W.; Janecki, T.; Bodalski, R. SC 1984, 1025.
13. (a) Minato, M.; Yamamoto, K.; Tsuji, J. JOC 1990, 55, 766. (b) Gurjar, M. K.; Joshi, S. V.; Sastry, B. S.; Rama Rao, A. V. SC 1990, 20, 3489.
14. Bloch, R.; Brillet, C. SL 1991, 829.
15. Sharpless, K. B.; Akashi, K.; Oshima, K. TL 1976, 2503.
16. Caroling, G.; Rajaram, J.; Kuriacose, J. C. JIC 1989, 66, 632.
17. Shambayati, S.; Crowe, W. E.; Schreiber, S. L. TL 1990, 31, 5289.
18. Singh, U.; Ghosh, S. K.; Chadha, M. S.; Mamdapur, V. R. TL 1991, 32, 255.

Mark R. Sivik

Procter & Gamble, Cincinnati, OH, USA

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