Anelli oxidation

Figure 5.13 Yields in the Montanari-Anelli oxidation of 1-nonanol to give nonanal in the presence of silica-supported TEMPO (SG-TMP-O, front row), and in the presence of sol gel ORMOSIL doped with TEMPO [SG-TEMPO-1 is 25% and SG-TEMPO-2 is 100% methylated (middle and back row, respectively)]. (Reproduced from ref. 25, with permission.)...

One of the most efficient methods for oxidation of primary alcohols to either aldehydes or carboxylic acids is the one, commonly known as the Anelli oxidation. This reaction is carried out in a two-phase (CH2Cl2/aq.buffer) system utilizing TEMPO/NaBr as a catalyst and NaOCl as the terminal oxidant The new system described here is an extension of the Anelli oxidation, but surprisingly, does not require the use of any organic solvents and replaces the KBr co-catalyst with the more benign, Na2B40y (Borax). The use of the new cocatalyst reduces the volume of the buffer solution and eliminates completely the need of a reaction solvent. The new system was successfully applied in the industrial synthesis of the 3,3-Dimethylbutanal, which is a key intermediate in the preparation of the new artificial sweetener Neotame. 

Oxidations Mediated by TEMPO and Related Stable Nitroxide Radicals (Anelli Oxidation)... 

The Anelli oxidation of alcohols to aldehydes and ketones has been accomplished using polymer-supported nitroxyl radical catalysts. The practicality of removing polymer-supported reagents by filtration to simplify product purification is highlighted by these examples. Bolm and coworkers11 demonstrated that a silica-supported nitroxyl catalyst is easily filtrated after use from the reaction solution, recovered and recycled, and the residual inorganic salts present in the reaction mixture are separated from the organic product by aqueous extraction (Table II, entry 7). 

As an extension to this synthetic method, Yasuda and Ley12 performed the Anelli oxidation with a polystyrene-supported nitroxyl radical and a polymer-supported chlorite (entry 8). The latter is incorporated in the reaction to oxidize the intermediate aldehydes to carboxylic acids. The choice of reagents and reaction design affords pure carboxylic acids in high yields. 

A convenient procedure for the oxidation of primary and secondary alcohols was reported by Anelli and co-workers (8,9). The oxidation was carried out in CH2CI2 with an aqueous buffer at pH 8.5-9.5 utilizing 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO, 1) as the catalyst and KBr as a co-catalyst. The terminal oxidant in this system was NaOCl. The major disadvantage of using sodium hypochlorite or any other hypohalite as a stoichiometric oxidant is that for each mole of alcohol oxidized during the reaction one mole of halogenated salt is formed. Furthermore,... 

P. L. Anelli, F. Montanan, S. Quid, Organic Syntheses CV8. 367. A number of other primary alcohol oxidations are reported. 

Pier Lucio Anelli, Fernando Montanan, and Silvio Quid 212 A GENERAL SYNTHETIC METHOD FOR THE OXIDATION OF PRIMARY ALCOHOLS TO ALDEHYDES (S)-(+)-2-METHYLBUTANAL... 

Anelli s protocol for the TEMPO-mediated oxidation of alcohols... 

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... 

Anelli s TEMPO-mediated oxidation can be accelerated by the addition of a quaternary ammonium salt, like Aliquat 336, acting as a phase transfer catalyst. This can be advisable in the oxidation of hindered secondary alcohols but can encourage the over-oxidation of primary alcohols to carboxylic acids.16... 

One important limitation of TEMPO-mediated oxidations, under Anelli s conditions, originates from competing reactions produced by HOC1, generated in situ from NaOCl. This problem can be solved by the use of [bis(acetoxy)iodo]benzene (BAIB) as a secondary oxidant following the protocol of Piancatelli and Margarita27 which has proved to be particularly efficient in difficult substrates,34 and it is a highly recommended alternative to Anelli s procedure when oxidations with oxoammonium salts are desired. 

Interestingly, using Anelli s protocol for the oxidation of alcohols allows quite selective oxidation of primary alcohols in the presence of secondary ones, which is effective in both transforming primary alcohols into aldehydes36, 37 and having a complete oxidation of primary alcohols into carboxylic adds.38... 

General Procedure for Oxidation of Alcohols with TEMPO-NaOCI (Anelli s Protocol)... 

Although TEMPO-mediated oxidations under Anelli s protocol are routinely performed at a slightly basic pH of 8.6 9.8,10 obtained by buffering the bleach solution with NaHCX>3, sometimes, in order to avoid base-induced side reactions, it is advisable to adjust the pH at 6.5-7.5 by adding an acid.13 A proper adjustment of the pH for example allows to obtain carbonyl compounds without a-epimerization in difficult substrates in which other common oxidants fail.42... 

The most serious limitation of TEMPO-mediated oxidations under Anelli s conditions is posed by the presence of HOC1—generated in situ— as a secondary oxidant, a quite reactive chemical that adds to olefins and produces electrophilic chlorination in many electron-rich substrates. 

Anelli s protocol is not generally compatible with the presence of olefins,10 although the less reactive olefins conjugated with electron-with-drawing groups, like carbonyls, are not affected,45 and occasional examples in which normal olefins remain unchanged during the oxidation of alcohols are found in the literature.13... 

Side reactions caused by the presence of HOC1 during Anelli s oxidations can be avoided by using a different secondary oxidant. For instance, the experimental conditions of Piancatelli and Margarita, employing PhI(OAc)2 as a secondary oxidant, are compatible with the presence of olefins.46... 

In variance with Anelli s conditions, TEMPO-mediated-oxidations—under the protocol of ... 

A sulfide is selectively oxidized under Anelli s conditions with no reaction on the secondary... 

Diols may suffer an oxidative C-C bond breakage under Anelli s oxidation, unless the quantity of NaOCl is carefully controlled. 

The HOC1 used as secondary oxidant under Anelli s conditions can add to olefins10 and react as an electrophilic chlorinating agent. 

Selective oxidations of primary alcohols can also be achieved employing less common variants of the Anelli s protocol, such as those involving silica-supported TEMPO11 and polymer-immobilized TEMPO.12... 

Under mildly acidic or basic conditions, primary alcohols are oxidized much more rapidly than secondary alcohols. A variety of stoichiometric oxidants and additives have been utilized. A very popular set of conditions is that developed by Anelli [37], which utilizes bleach as the stoichiometric oxidant, and requires only... 

The oxoammonium is generated in situ from its precursor, 2,2, 6,6 -tetramethyl-piperidine-N-oxyl (TEMPO), or derivatives thereof, which is used in catalytic quantities (see Figure 5.2). Various oxidants can be applied as the final oxidant [7-12]. In particular, the TEMPO-bleach protocol using bromide as co-catalyst introduced by Anelli et al. is finding wide application in organic synthesis [7]. TEMPO is used in amounts as low as 1 mol% relative to the substrate, and full conversion of substrates can commonly be achieved within 30 min. 

Anelli PL, Biffi C, Montanan F, Quici S. Fast and selective oxidation of primary alco-hob to aldehydes or to carboxylic acids and of secondary alcohols to ketones mediated by oxoammonium salts under two-phase conditions. J Org Chem. 1987 52 2559-2562. 

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