N-Methylmorpholine oxide-Hydrogen peroxide

N-Methylmorpholine Oxide-Hydrogen Peroxide Oxidation. The preparation of A-methylmorpholine oxide-hydrogen peroxide is described in Reagents for Organic Synthesis by L. Fieser and M. Fieser. 

N-methylmorpholine oxide-hydrogen peroxide, 184, 221, 223 4-Methyl-19-nortestosterone, 89 16/3-Methyl-l 6a, 17a-oxidopregn-4-ene-... 

The reagent is prepared by slow addition of 34 g. (0.5 mole) of 50% hydrogen peroxide to 26 g. (0.25 mole) of N-methylmorpholine in 100 ml. of t-butanol while maintaining the temperature at 30-35° with a water bath. The mixture is diluted with 170 ml. of t-butanol and allowed to stand for 48 hrs. to complete the oxidation of N-methylmorpholine. The solution may be titrated for peroxide content and used as such for the oxidation of olefins, or dried with magnesium sulfate and the volatile materials distilled in vacuo to leave the crystalline N-methylmorpholine oxide —hydrogen peroxide complex, which is triturated with acetone and collected. 

The very sensitive ether peroxide test strips (Merckoquant, Art. No. 10011), available from E. Merck, Darmstadt, are used. If the test is still positive at this point, an additional 0.2 ml. of N-methyl morpholine is added. Stirring and heating at 75° are continued for another 5 hours. Remaining peroxide renders the work-up and drying of the product potentially hazardous. N-Methylmorpholine N-oxide (1) and hydrogen peroxide form a strong 1 1 complex. In the reaction with osmium tetroxide, this complex produces conditions similar to those of the Milas reaction,7 and some ketol formation may result. 

Since Os04 is volatile, toxic and expensive, considerable effort has been devoted to the catalytic application of the cis dihydroxylation of alkenes in the presence of excess cooxidant.57-290 Previous procedures used metal chlorate (Hoffman reagent),339 or hydrogen peroxide (Milas reagent)350 as cooxidant, usually in Bu OH or acetone.290 Recent procedures utilize t-butyl hydroperoxide in conjunction with ammonium salts (Et4NOH or Et4NOAc)57,351 or N-methylmorpholine N-oxide,352 and are generally more selective. 

For the oxidation of alkenes, osmium tetroxide is used either stoichiometrically, when the alkene is precious or only small scale operation is required, or catalytically with a range of secondary oxidants which include metal chlorates, hydrogen peroxide, f-butyl hydroperoxide and N-methylmorpholine A -oxide. The osmium tetroxide//V-methylmorpholine A -oxide combination is probably the most general and effective procedure which is currently available for the syn hydroxylation of alkenes, although tetrasubstituted alkenes may be resistant to oxidation. For hindered alkenes, use of the related oxidant trimethylamine A -oxide in the presence of pyridine appears advantageous. When r-butyl hydroperoxide is used as a cooxidant, problems of overoxidation are avoided which occasionally occur with the catalytic procedures using metal chlorates or hydrogen peroxide. Further, in the presence of tetraethylam-monium hydroxide hydroxylation of tetrasubstituted alkenes is possible, but the alkaline conditions clearly limit the application. 

Many different co-oxidants can be used in conjunction with osmium tetroxide for the catalytic dihydroxylation reaction. The most popular is A -methylmorpholine N-oxide (NMO) the use of NMO with less than one equivalent of osmium tetroxide is often referred to as the Upjohn conditions. Other oxidants, such as [K3Fe(CN)6], tert-hutyl hydroperoxide, hydrogen peroxide or bleach are effective. In these reactions, the intermediate osmate ester is oxidized to an osmium(VIII) species that is then hydrolysed with regeneration of osmium tetroxide to continue the cycle. For example, less than 1 mol% of osmium tetroxide is needed for the dihydroxylation of the alkene 74 (5.80). 

Most frequently, iodosylbenzene (PhlO) or sodium hypochlorite (NaOCl) are used as the stoichiometric oxidant, althoi alternative reagents have been used, including hydrogen peroxide, periodate,dimethyldioxirane, and an mCPBA/N-methylmorpholine-N-oxide combination which allows the use of a lower temperature and provides higher enantioselectivities. ... 

The oxidized electron transfer mediator (ETMox). namely the peroxo complexes of methyltrioxorhenium (MTO) and vanadyl acetylacetonate [VO(acac)2] and flavin hydroperoxide, generated from its reduced form (Figure 1.1) and H2O2, recycles the N-methylmorpholine (NMM) to N-methylmorpholine N-oxide (NMO), which in turn reoxidizes the Os(VI) to Os(VIII). While the use of hydrogen peroxide as oxidant without any electron transfer mediators is inefficient and nonselective, various alkenes were oxidized to diols in good to excellent yields employing this mild triple catalytic system (Scheme 1.2). 

---