Alcohols oxidation with oxoammonium salts

During the oxidation of primary alcohols with oxoammonium salts, sometimes dimeric esters are formed.20a This can be minimized by increasing the quantity of TEMPO. 

The 2,2,6,6-tetramethylpiperidinoxyl (TEMPO) radical was first prepared in 1960 by Lebedev and Kazarnovskii by oxidation of its piperidine precursor. TEMPO is a highly persistent radical, resistant to air and moisture, which is stabilized primarily by the steric hindrance of the NO-bond. Paramagnetic TEMPO radicals can be used as powerful spin probes for investigating the structure and dynamics of biopolymers such as proteins, DNA, and synthetic polymers by ESR spectroscopy [7]. A versatile redox chemistry has been reported for TEMPO radicals. The radical species can be transformed by two-electron reduction into the respective hydroxyl-amine or by two-electron oxidation into the oxoammonium salt [8]. One-electron oxidations involving oxoammonium salts have also been postulated [9]. The TEMPO radical is usually employed under phase-transfer conditions with, e.g., sodium hypochlorite as activating oxidant in the aqueous phase. In oxidations of primary alcohols carboxylic acids are often formed by over-oxidation, in addition to the de-... 

As peracids react very sluggishly with alcohols, it was apparent that the presence of a nitroxide was playing an important role in the oxidation of the alcohol into a ketone. This seminal serendipitous observation led to the development of the first description of the oxidation of alcohols mediated by catalytic 2,2,6,6-tetramethylpiperidine-l-oxyl (TEMPO) (55), published almost simultaneously by Celia et al and Ganem.3 These authors presented two papers with remarkably similar contents, in which alcohols were oxidized by treatment with MCPBA in CH2CI2 at room temperature in the presence of a catalytic amount of TEMPO (55). In both papers, a plausible mechanism is presented, whereby m-chloroperbenzoic acid oxidizes TEMPO (55) to an oxoammonium salt 56. This oxoammonium salt 56, as detailed in Ganem s paper, can react with the alcohol producing an intermediate 57, which can deliver a carbonyl compound by a Cope-like elimination. 

As soon as, it was learnt that oxoammonium salts, which are unstable compounds, are very efficient in the oxidation of alcohols, and that they can be generated in situ by treating catalytic TEMPO, or related compounds, with MCPBA acting as a secondary oxidant, it became apparent that other secondary oxidants would be more practical than MCPBA in Synthetic Organic Chemistry. MCPBA is a very energetic oxidant that reacts with many functionalities including alkenes and ketones. 

Oxoammonium salts react with water resulting in the generation of hydrogen peroxide.14 This side reaction is minimized at 0°C. A substantial amount of heat is evolved in oxidations following Anelli s protocol therefore, on multigram scale reactions it may be very difficult to keep a temperature as low as 0°C. In such cases, an efficient oxidation can be achieved at 10-15°C, a temperature in which the decomposition of oxoammonium compounds does not compete substantially with the desired oxidation of alcohols.15... 

Among common alcohol oxidants, TEMPO-mediated oxidations have been the subject of a close scrutiny, aimed at finding optimum conditions for the selective oxidation of primary alcohols. In fact, TEMPO-mediated oxidations, that is oxidations in which an oxoammonium salt acts as a primary oxidant, have a great tendency to operate quicker with primary alcohols, regardless of the secondary oxidant employed and the exact experimental conditions. 

A scant look at the facts might suggest that the selective oxidation of primary alcohols in TEMPO-mediated oxidations can be explained solely on steric grounds. Things are not so simple, as it was found8 that the primary oxidants, that is oxoammonium salts, when used stoichiometrically, react quicker with primary alcohols when present as oxoammonium chlorides, while the reverse selectivity, that is selective oxidation of secondary alcohols, is observed when oxoammonium bromides are employed. 

Stable organic nitroxyl radicals are of relatively recent use as catalysts in the oxidation of alcohols. Nitroxyl radicals are compounds that contain the A ,A -disubstituted NO-group with one unpaired electron, and their uses have been reviewed.124 The most simple radical of this class is 2,2,6,6-tetramethylpiperidin-l-oxyl (43, TEMPO). It is generally assumed that the active oxidizing species, the oxoammonium salt (44), is formed in a catalytic cycle by a one-electron oxidation of the nitroxyl radical by a primary oxidant [two-electron oxidation of the hydroxylamine (45) is also possible, depending on the primary oxidant] (Scheme 21). 

For the sake of completeness we also note that oxygen transfer processes can be mediated by organic catalysts which can be categorized on the same basis as metal catalysts. For example, ketones catalyze a variety of oxidations with mono-peroxysulfate (KHS05) [14]. The active oxidant is the corresponding dkmrane and, hence, the reaction can be construed as involving a peroxometal pathway. Similarly, TEMPO-catalyzed oxidations of alcohols with hypochlorite [15, 16] involve an oxoammonium salt as the active oxidant, i.e. an oxometal pathway. 

Nitroxide-mediated oxidation based on oxoammonium salts is a very common application of nitroxides in organic synthesis. In addition to a variety of alcohol oxidations, applications using oxoammonium species as one-electron oxidants have been utilized with a number of different substrates [30]. 

Oxidation of primary and secondary alcohols by oxoammonium salts derived from nitroxides has become very popular because of the very mild and chemoselective reaction conditions available (Scheme 13). The stoichiometric oxidant can often be an inexpensive reagent, such as hypochlorite (bleach), O2 with a metal catalyst, electrochemical anodic oxidation, peracid, or bromine. The oxoammonium salt can be either pre-formed and used stoichiometrically or generated catalytically from the nitroxide in situ. The mechanism of the reactions is pH dependent strongly acidic conditions chemoselectively oxidize secondary alcohols with accelerated rates over primary alcohols, whereas basic or mildly acidic conditions provide chemoselective oxidation of primary alcohols in the presence of secondary alcohols. A compre-... 

Treatment of nitroxides with strong acids such as toluenesulfonic acid or perchloric acid facilitates disproportionation to form one oxoammonium salt in situ for every two equivalents of starting nitroxide. Under strongly acidic conditions, secondary alcohols are efficiently oxidized to ketones, whereas primary alcohols are much slower to react [33]. The reaction mechanism [31] is most likely that shown in Scheme 15. A kinetic isotope effect [kn/ku = 3.1) supports deprotonation of the alpha hydrogen as the rate limiting step [34]. The use of an additional oxidant such as bleach (NaOCl) or hypobromous acid (HOBr) or hypochlorous acid (HOCl) generated in situ from bromide or chloride ion [35] can facilitate the reaction by rapidly reforming the oxoammonium species under the reaction conditions. This allows the nitroxide to be utilized in catalytic amounts. Recently, Bobbitt [36] has... 

There is extensive history on the use of stoichiometric and catalytic organic nitroxyls for alcohol oxidation, wherein the key step involves a reaction between the alcohol and an JV-oxoammonium salt (Scheme 15.5, featuring TEMPO) [18, 20]. The JV-oxoammonium salt can be formed in situ from the corresponding nitroxyl radical using various oxidants, such as NaOCl or NO2 (Scheme 15.5, top left), or by acid-induced disproportionation of the nitroxyl into N-oxoammonium and hydroxylamine species (Scheme 15.5, bottom left) [21]. Stable Af-oxoammonium salts have also been isolated and used directly as reagents or catalysts for alcohol oxidation [22]. The pH-dependent mechanism of the reaction of the Af-oxoammonium salt with alcohols has been studied... 

Different heteroaromatic rings (e.g., pyridine, furan and thiophene) and carbon-carbon double bonds are well tolerated under the reaction conditions. Moreover, reagent 130 can be easily recycled from the reaction mixture and reused. The mechanism of this reaction includes initial homolytic cleavage of the I—Cl bond providing a chlorine atom and the iodanyl radical 132, which is in equilibrium with the benzoyloxy radical 133. TEMPO (134) is oxidized by the chlorine atom to oxoammonium salt 135, which then oxidizes the alcohol 129 to the corresponding carbonyl compound 131 and is itself reduced to hydroxylamine 136. The benzoyloxy radical 133 accomplishes the regeneration of TEMPO 134 from hydroxylamine 136, giving rise to 2-iodobenzoic acid and the catalytic cycle is complete (Scheme 3.55) [158]. 

On the other hand, however, trimethylsilyl-protected catalyst 18 was suitable for the asymmetric bromination of aldehydes, and the resulting a-bromoaldehydes can be diastereoselectively transformed into the corresponding bromohydrin in one-pot (Scheme 7.31) (54). An additional utility of catalyst 18 was highlighted by application to the development of the direct aminoxylation of aldehydes with an oxoammonium salt generated from 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) by in situ oxidation with benzoyl peroxide, allowing for the highly enantioselective synthesis of stable a-aminoxy aldehydes, which could subsequently be reduced to the corresponding alcohol (55). 

The olefin metathesis of 3-hydroxy-4-vinyl-l,2,5-thiadiazole 112 and a McMurry coupling reaction (Ti3+ under reductive conditions) of the aldehyde 114 were both unsuccessful <2004TL5441>. An alternative approach via a Wittig reaction was successful. With the use of the mild heterogenous oxidant 4-acetylamino-2,2,6,6-tetramethyl-piperidine-l-oxoammonium perfluoroborate (Bobbitt s reagent), the alcohol 113 was converted into the aldehyde 114. The phosphonium salt 115 also obtained from the alcohol 113 was treated with the aldehyde 114 to give the symmetrical alkene 116 (Scheme 16) <2004TL5441>. 

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