Jones oxidation alcohols

An important task remaining is the stereocontrolled introduction of a methyl group at C-8. When a cold (-78 °C) solution of 14 in THF is treated successively with LDA and methyl iodide and then warmed to -45 °C, intermediate 24 admixed with minor amounts of the C-8 epimer is formed in a yield of 95 %. The action of LDA on 14 generates a lactone enolate which is alkylated on carbon in a diastereoselective fashion with methyl iodide to give 24. It is of no consequence that 24 is contaminated with small amounts of the unwanted C-8 epimer because hydrolysis of the mixture with lithium hydroxide affords, after Jones oxidation of the secondary alcohol, a single keto acid (13) in an overall yield of 80%. Apparently, the undesired diastereoisomer is epimerized to the desired one under the basic conditions of the saponification step. 

Namely, allyl alcohol is successively treated with diethylzinc, (R,R) dipropyl tartrate, and 4-methoxybenzohydroximinoyl chloride (163) to afford the enantiomeric isoxazoline alcohol 166, which under the Jones oxidation conditions affords the corresponding carboxylic acid derivative (167). Treatment of compound 167 with hydroxylamine-O-triflate followed by tri-fluoroacetic acid gives rise to the desired enantiomeric 165 in high excess enantiomeric yield. The synthesis of other isosteric analogues of 165 was reported in the same paper. None of the isosteric analogues exhibits LpxC inhibitory and antibacterial activities [103]. 

This preparation illustrates a general and convenient way of oxidizing secondary alcohols to ketones in high deld. This procedure, usually called the Jones oxidation or oxidation by use of the Jones reagent, offers the advantage of almost instantaneous... 

Chromium(VI) oxide is used for chromium plating copper stripping as an oxidizing agent for conversion of secondary alcohols into ketones (Jones oxidation) as a corrosion inhibitor in purification of oil and in chromic mixtures for cleaning laboratory glassware. 

The last synthesis to evolve which is due to Ito and his coworkers is interesting in that it relies on a stereospecific skeletal rearrangement of a bicyclo[2.2.2]octane system which in turn was prepared by Diels-Alder methodology (Scheme XLVIII) Heating of a toluene solution of cyclopentene 1,2-dicarboxylic anhydride and 4-methylcyclohexa-l,4-dienyl methyl ether in the presence of a catalytic quantity of p-toluenesulfonic acid afforded 589. Demethylation was followed by reduction and cyclization to sulfide 590. Desulfurization set the stage for peracid oxidation and arrival at 591. Chromatography of this intermediate on alumina induced isomerization to keto alcohol 592. Jones oxidation afforded diketone 593 which had earlier been transformed into gymnomitrol. 

The diacetate of 711 has also been produced in stereoselective fashion via a route beginning with dicyclopentadiene (Scheme LXXVI) Ketone 712 was transformed into dimethylated alcohol 713 whose ozonolysis provided 714. Following Jones oxidation, decarboxylation with concomitant introduction of a double bond was realized by application of Kochi s prowdure. A lengthy quence of steps to adjust functionality led up to annulation by a modified Wichterle sequence. The conversion of 715 to 716 was accomplish by standard reactions. 

The synthesis of pyrazolo[3,4-. ]pyridines can be achieved by reaction of 2,6-dichloro-3-lithiopyridine with 5-bromo-2-methoxybenzaldehyde 138 to provide the alcohol, which after Jones oxidation gave ketone 139. Treatment of the ketone with hydrazine furnished the desired pyrazolo[3,4-3]pyridine 140 (Scheme 8) <2006BML262>. 

The Diels-Alder reaction of 3-methoxyfuran with octyl vinyl ketone took place at room temperature in quantitative yield to afford exclusively the endo cycloadduct (27) (81CC221). Reduction of the carbonyl group with lithium tri-r-butoxyaluminum hydride produced a single alcohol (28). Ozonolysis of the double bond followed by Jones oxidation yielded the lactone ester (29). Hydrolysis of the ester and lead tetraacetate oxidation gave the lactone acetate. This was converted by further hydrolysis and Jones oxidation to the bis-lactone (30), a known intermediate in the synthesis of ( )-isoavenaciolide (Scheme 6). 

JONES OXIDATION. The oxidation of primary and secondary alcohols to acids and ketones by the addition of the calculate amount of chromic anhydride in dilute sulfuric acid to a solution of the alcohol in acetone. This procedure dues not attack triple bonds or shift douhle bonds into conjugation with the ketone formed in the oxidation. 

Jones reagent is used to oxidize the aldehyde here to an acid. In general only the first two reagents listed in the Tips oxidi/e aldehydes to acids. TPAP can be used for oxidation of alcohols to aldehydes, ketones, or acids. The others are used for oxidizing alcohols to aldehydes or ketones.27... 

Although Cr03 is soluble in some organic solvents, like tert-butyl alcohol, pyridine or acetic anhydride, its use in such solvents is limited, because of the tendency of the resulting solutions to explode.2,3 Nevertheless, acetone can safely be mixed with a solution of chromium trioxide in diluted aqueous sulfuric acid. This useful property prompted the development of the so-called Jones oxidation, in which a solution of chromium trioxide in diluted sulfuric acid is dropped on a solution of an organic compound in acetone. This reaction, first described by Jones,13 has become one of the most employed procedures for the oxidation of alcohols, and represents a seminal contribution that prompted the development of other chromium (VI) oxidants in organic synthesis. 

Although Jones oxidation is very useful for the transformation of secondary alcohols into ketones, it can be difficult to stop the oxidation of primary alcohols at the intermediate aldehyde stage. 

In 1946, Jones discovered that secondary alcohols could be efficiently oxidized to ketones by pouring a solution of chromium trioxide in diluted sulfuric acid over a solution of the alcohol in acetone.13 This procedure, which has proved to be quite safe, allows a sufficient contact of the alcohol with chromium oxide derivatives for a reaction to take place. Jones oxidation marked the beginning of the highly successful saga of chromium-based oxidants. 

Jones oxidation is carried out under very convenient experimental conditions with no need to employ a dry environment or an inert atmosphere. It is very useful for the oxidation of secondary alcohols, while it rarely succeeds in the transformation of primary alcohols into aldehydes due to its tendency to cause over-oxidation to carboxylic acids (see page 2). 

General Procedure for Transformation of Alcohols to Ketones by Jones Oxidation... 

Only very acid-sensitive protecting groups are hydrolyzed under the conditions of the Jones oxidation. When free alcohols result from the hydrolysis of very acid-sensitive protecting groups, they are in situ oxidized to ketones or carboxylic acids. 

Alkoxyalkyl protected alcohols remain unchanged under Jones oxidation, except those protected with the very acid-sensitive THP group.26,27b... 

Table 1.1. Sensitivity of Alcohol Protecting Groups to Jones Oxidation...

Alcohols protected as esters, and diols protected as cyclic acetals resist Jones oxidation. 

Aldehydes are oxidized to carboxylic acids by Jones oxidation although, in certain cases, the oxidation of primary alcohols can be stopped at the aldehyde stage (see page 12). 

The sensitivity of some alcohol protecting groups to the acidic conditions of Jones oxidation allow the operation of one-pot reactions, in which deprotection of alcohols is followed by in situ oxidation to ketones. Some interesting synthetic applications of this principle are listed bellow ... 

Jones oxidation is generally not useful for the transformation of primary alcohols into aldehydes. This is due to the equilibrium of the aldehydes with the corresponding hydrates in the aqueous media, leading to the subsequent oxidation of the aldehyde hydrates into carboxylic acids. In fact, kinetic studies support the assumption that chromic acid oxidizes aldehydes into carboxylic acids via the corresponding aldehyde hydrates.5... 

Nevertheless, in those cases in which the proportion of hydrate in equilibrium with the aldehyde is low, it is possible to obtain a useful yield of aldehyde.60,61 Electron donating groups,68,69 conjugation with alkenes and aromatic rings5 and steric hindrance69 decrease the proportion of hydrates in equilibrium with aldehydes. This explains the fact that alcohols successfully transformed into aldehydes by Jones oxidation, normally belong to the allyl,70 benzyl71 or neopentyl kind.72... 

Alcohols, possessing substituents able to stabilize carbocations at the (3 position, may suffer a carbon-carbon bond breakage as in Equation below (route b), competing with the normal transformation to ketones on Jones oxidation (route a).75... 

As the oxidative carbon-carbon bond breakage of alcohols, leading to a stable carbocation, depends not only on the stability of the resulting carbocation but also on very exacting stereoelectronic factors, many cases are known in which alcohols are successfully oxidized to ketones, regardless of apparently easy oxidative carbon-carbon bond breakages. In fact, in synthetic experimental practice, it is recommended not to fail in trying a Jones oxidation because of fear of such side reactions. 

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