Tertiary Amine Oxidation using HOF ⋅ CH3CN: A Novel Synthesis of N-Oxides

Abstract

HOF◊CH 3 CN, probably the best oxygen transfer agent organic chemistry has to offer, is easily made by bubbling diluted fluorine (10-15%) through aqueous acetonitrile solution. Used as formed without any isolation or purification, it reacts with various tertiary amines such as pyridine derivatives, polyaromatic nitrogen containing compounds and aliphatic and alicyclic ones to form the corresponding N-oxides. When two nitrogen atoms are present it is possible to make both the N-monoxides and the N,N-dioxides. The reaction times are short (a few minutes), conditions are very mild (0-25°C) and the yields range from good to excellent (70-95%).Tertiary amine N-oxides are a class of compounds which assumes increasing importance. They are used in a variety of processes as well as final products such as fiber preparation, 1 hair tonics, 2 topical pharmaceuticals, 3 and cellulose solvents. 4 The increased attention these compounds are receiving encouraged us to examine their preparation by using one of the best oxygen transfer agents organic chemistry has to offer, the HOF◊CH 3 CN complex.The preparation of this reagent, first introduced by us some years ago, 5 is quite simple. Its solution is formed in good yields by passing nitrogen-diluted fluorine through aqueous acetonitrile. The HOF◊CH 3 CN complex is used as obtained and does not require any isolation or purification. It is able to transfer an oxygen atom under mild conditions even to very weak nucleophiles. In the past we have demonstrated its ability to epoxidize normal 6 and very electron deficient alkenes, 7 oxidize amines, 8 ethers, 9 a variety of sulfides, 10 and much more. 11 We report here yet another of its fast and efficient reactions, this time with tertiary amines forming the corresponding N-oxides. It should be noted that although some of the N-oxides had been previously prepared, the combination of the very mild conditions and short reaction times gave in most cases better results than those reported in the literature. 12Pyridines react quickly at temperatures ranging from 0 to 25°C to produce the N-oxide compounds in good yields. Pyridine (1) itself was transformed into its N-oxide derivative 2 in 85% yield within less than five minutes. Similarly 3-and 4-methylpyridines 3 and 4 were converted to the corresponding N-oxides 5 and 6 in high yields. Rings substituted with strong electron-donating groups such as 2-methoxypyridine 13 (7) or with electron-withdrawing ones such as 2-cyano-(8), 3-acetyl-(9) and 2-chloropyridine (10) also proved to be excellent substrates producing the respective N-oxides 11-14 in good yields. Although we had already demonstrated that double bonds react with HOF◊CH 3 CN to form epoxides 11 the nitrogen atom of the pyridine is activated first. Thus 4-vinylpyridine (15) was converted in 70% yield to the corresponding N-oxide 16 without affecting the alkene. Another interesting example is 4-(N,N-dimethylamino)pyridine (17) with its two tertiary nitrogen atoms. Under the mild reaction conditions applied, only the ring-nitrogen at...

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