Selective oxidations of primary alcohols

Compared with ketoreductases, the synthetic application of alcohol oxidases has been less explored. However, selective oxidation of primary alcohols to aldehydes is superior to the chemical methods in terms of conversion yields, selectivity, and environmental friendliness of reaction conditions. In addition, coupling of alcohol oxidase with other enzymes provides a tremendous opportunity to develop multi-enzyme processes for the production of complex molecules. Therefore, a growing impact of alcohol oxidases on synthetic organic chemistry is expected in the coming years. 

Scheme 30 Nitroxyl-radical-mediated selective oxidation of primary alcohols.

D. L. Wu, A. P. Wight, M. E. Davis, Shape Selective Oxidation of Primary Alcohols using Perruthenate-Containing Zeolites, Chem. Commun. 6 (2003) 758-759. 

Despite the extensive work reported in the area of the selective oxidation of primary alcohols, there is still a continuous need for developing efficient and... 

Aldehydes are prepared by the hydroboration-oxidation of alkynes (see Section 5.3.1) or selective oxidation of primary alcohols (see Section 5.7.9), and partial reduction of acid chlorides (see Section 5.7.21) and esters (see Section 5.7.22) or nitriles (see Section 5.7.23) with lithium tri-terr-butox-yaluminium hydride [LiAlH(0- Bu)3] and diisobutylaluminium hydride (DIBAH), respectively. 

Protecting groups, including very labile ones, withstand the action of Collins reagent. The very labile primary TMS ethers are transformed into the corresponding aldehydes.103 As secondary and tertiary TMS ethers resist the action of Collins reagent, a protocol involving per-silylation followed by Collins oxidation allows the selective oxidation of primary alcohols in the presence of secondary ones.104... 

Primary TMS and TES ethers205 are deprotected and transformed into the corresponding aldehydes under Swern conditions. Other less labile silyl ethers—such as TBS ethers as well as secondary TMS and TES ethers—, remain unaffected. This allows to perform selective oxidations of primary alcohols in the presence of secondary ones by persilylation of poliols by TMS or TES, followed by selective oxidation of the primary silyl ethers to aldehydes under Swern conditions. 

Although the selective oxidation of primary TMS and TES ethers, in the presence of secondary TMS and TES ethers, has been reported by several research groups, there is a contradictory report2050 showing that 2-octanol TMS ether is oxidized quicker than 1-octanol TMS ether. This rises the concern that the selective oxidation of primary TES and TMS ethers may be the result of a selective acidic hydrolysis, produced by adventitious HC1. This would lead to oxidations with low reproducibility. As the selective oxidation of primary alcohols is an important synthetic operation, this matter deserves a close scrutiny. 

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... 

Selective Oxidations of Primary Alcohols in Presence of Secondary Alcohols... 

Primary alcohols possess a substantially less crowded environment than secondary ones. Thus, in the absence of dominant electronic factors, many oxidants tend to react quicker with primary alcohols. These include many common oxidants, like TPAP,1 PCC,2 Parikh-Moffatt,3 Dess-Martin,4 IBX5 and Swern,6 that are sometimes able to perform selective oxidations of primary alcohols in useful yields, regardless of the fact that they were not devised for this purpose. 

It must be mentioned that IBX is particularly useful in selective oxidations of primary alcohols, leading to hydroxyaldehydes present as lactols. 

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. 

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... 

Systems involving oxoammonium salts, electrolitically generated from TEMPO19 or employed in stoichiometric amounts,8 can also show useful selectivities for the oxidation of primary alcohols. The use of stoichiometric oxoammonium salts is sometimes more satisfactory in the selective oxidation of primary alcohols than the employment of catalytic TEMPO... 

Selective Oxidation of Primary Alcohols via Silyl Ethers... 

Mainly iodine(v) reagents have been used for such oxidations, but some iodine(III) reagents have also been successfully applied. The radical TEMPO (2,2,6,6-tetramethyl-l-piperidinyloxyl) is necessary in the oxidation of alcohols with (diacetoxyiodo)benzene 3. With this combination highly selective oxidations of primary alcohols to the corresponding aldehydes in high yields are possible, Scheme 12. Secondary alcohols are not attacked under the reaction conditions providing a useful alternative to the widely used Dess-Martin reagent [71 ]. 

A catalytic system, based on TEMPO and Cu(II), has been developed for the selective oxidation of primary alcohols to aldehydes under very mild conditions. Cu(II) is generated in situ by oxidation of elemental copper and chelated by means of 2,2 -bipyridine. The reaction is dependent on pH. New insights into the currently accepted mechanism have been discussed.76 Allylic and benzylic alcohols are selectively oxidized with trimethylamine N-oxide in the presence of cyclohexa-1,3-dieneiron carbonyl.77... 

The selective oxidation of primary alcohols is notoriously difficult to achieve selectively as further oxidation of the product to the respective carboxylic acid occurs rapidly, as depicted in Scheme 50. Wiles et al. (2006) therefore proposed that it should be possible to isolate either the aldehyde or the carboxylic acid, depending on the reaction times employed. To demonstrate this, the authors constructed a packed-bed reactor [3 mm (i.d.)x 5.0 cm (long)] containing silica-supported Jones reagent (0.15 g, 0.15 mmol), a Cr(VI)-based oxidant, and by exploiting the high surface to volume ratio obtained within continuous flow reactors, the... 

In contrast, if a single aqueous liquid phase is used, and if the aldehyde product has a tendency to be hydrated, the reaction proceeds smoothly to the carboxylic acid salt (413,414). It is believed that the RC(OH)2 hydration product of the aldehyde is the actual reagent. This reaction is highly useful for the selective oxidation of primary alcohol groups in sugars such as methyl-a-D-glucopyranoside to the uronic salt ... 

The oxidation of primary alcohols with K2Cr207 in aqueous solution to nothing but the aldehyde, (i.e., without further oxidation to the carboxylic acid) is possible only if a volatile aldehyde results and is distilled off as it is formed. This is the only way to prevent the further oxidation of the aldehyde in the (aqueous) reaction mixture. Selective oxidations of primary alcohols to aldehydes with the Jones reagent succeed only for allylic and benzylic alcohols. Otherwise, the Jones reagent directly converts alcohols into carboxylic acids (see above). 

Other ruthenium-based catalysts for the aerobic oxidation of alcohols have been described where it is not clear if they involve oxidative dehydrogenation by low-valent ruthenium, to give hydridoruthenium intermediates, or by high-valent oxoruthenium. Masutani et al. [107] described (nitrosyl)Ru(salen) complexes, which can be activated by illumination to release the NO ligand. These complexes demonstrated selectivity for oxidation of the alcoholic group versus epoxidation, which was regarded as evidence for the intermediacy of Ru-oxo moieties. Their excellent alcohol coordination properties led to a good enantiomer differentation in the aerobic oxidation of racemic secondary alcohols (Fig. 19) and to a selective oxidation of primary alcohols in the presence of secondary alcohols [108]. 

Denooy, A. E. J., Besemer, A. C., and Vanbekkum, H., Selective oxidation of primary alcohols mediated by nitroxyl radical in aqueous-solution - Kinetics and mechanism. Tetrahedron 1995, 51 (29), 8023-8032. 

PS has also been used in the copper catalysed aerobic oxidation of primary alcohols (Scheme 9.3). The selective oxidation of primary alcohols into aldehydes can be complicated by overoxidation to carboxylic acids or even decomposition products. These side reactions were not observed in PS, and a high turnover frequency (>31 h ) was achieved. The product could be easily isolated by extraction into -pentane and the PS catalyst-containing phase could be recycled three times. 

Oxidation. Potassium ferrate (VI) is a reagent for selective oxidation of primary alcohols and amines to aldehydes and of secondary alcohols to ketones. Double bonds, aldehyde functions, tertiary hydroxyl groups, and tertiary amino groups are resistant to oxidation. The reaction is carried out at room temperature either in water or in aqueous solvents. In fact water is essential for oxidation. The reaction is carried out at an initial pH of 11.5 the final pH is 13.5. In a typical procedure K.2pe04 (0.(X)2 mole)... 

The only moderate selectivity is irrelevant because in the following step, 28 is oxidized to the 1,3-diketo compound 17 using pyridinium-chlorochromate (PCC). PCC has been developed particularly for the selective oxidation of primary alcohols to aldehydes, but it also works well for the oxidation of secondary alcohols. 

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