Pyridinium trifluoroacetate, oxidation

The most intensively studied oxidizing system is that developed by Pfitzner and Moflatt in which the oxidation is carried out at room temperature in the presence of dicyclohexylcarbodiimide (DCC) and a weak acid such as pyridinium trifluoroacetate or phosphoric acid. The DCC activates the DMSO which in turn reacts with the carbinol to give an oxysulfonium intermediate. This breaks down under mild base catalysis to give the desired ketone and dimethyl sulfide. 

The use of dichloroacetic acid instead of pyridinium trifluoroacetate increases the rate of oxidation considerably. This acid has been used in one case to obtain an optimum yield of the 11-ketoestrone (8) from the corresponding 1 la-hydroxy compound. ... 

Pyridinium trifluoroacetate in oxidation of cholane-24-ol with dimethyl sulfoxide and dicyclohexylcar-bodiimide, 47,25... 

Acetic acid,127 pyridinium trifluoroacetate (PTFA)121 or pyridinium tosylate (PPTS)128 are often added in order to speed up PDC oxidations. Acetic acid, which is described as superior127a and very easy to remove, is used most often. Although this precludes the advantages of using an almost neutral PDC medium, it provides a very useful substantial acceleration of the oxidations. The combined employment of molecular sieves and an acid can provide a synergistic accelerating effect.127a... 

Moffatt et al. found that the optimized reaction conditions developed for the oxidation of testosterone (14), worked ideally in the oxidation of other alcohols. Later, researchers tended to apply, on reactions run at room temperature on very diverse alcohols, these optimized conditions involving 3 equivalents of DCC or other carbodiimide, 0.5 equivalents of pyridinium trifluoroacetate with some extra pyridine added, and neat DMSO or a mixture of DMSO and benzene as solvent. The only substantial changes to this standard protocol involve the growing use of the water-soluble carbodiimide EDC,17 instead of DCC, in order to facilitate the work-ups, and the occasional employment of dichloroacetic acid,18 which proved very effective in the oxidation of some complex polar alcohols, instead of pyridinium trifluoroacetate. 

Very often more than 0.5 equivalents of pyridinium trifluoroacetate (MW — 191.1) are added. This practice is not advisable, as it can lead to a substantial decrease in the yield of the aldehyde or ketone. For instance, during the oxidation of testosterone (14), Moffatt el al. found that on changing from 0.5 to 2.0 equivalents of pyridinium trifluoroacetate, a decrease of ca. 20% occurs.14b On the other hand, the quantity of pyridinium trifluoroacetate can be diminished to 0.1 equivalents with no erosion of the yield, although leading to a slower reaction. 

If the substrate possesses a basic site, like an amine, this can neutralize the pyridinium trifluoroacetate and prevent the oxidation. In such cases, 1.5 equivalents of pyridinium trifluoroacetate must be added. 

During the oxidation of greatly hindered alcohols, it can be advisable to use 0.5 equivalents of ortophosphoric acid (MW = 98.0) (solid phosphoric acid) instead of pyridinium trifluoroacetate. This causes an acceleration of the oxidation, although it normally leads to greater amounts of side compounds. On some highly polar compounds, the use of 0.5 equivalents of dichloroacetic acid (DCAA) (MW = 128.9, d = 1.47) can provide best results. 

Homoallylic alcohols are oxidized, in the presence of pyridinium trifluoroacetate, with no migration of the alkene into conjugation with the carbonyl, even in cases in which such migration can occur under very mild acidic catalyses. On the other hand, the stronger acid H3PO4 is able to produce such isomerizations.14b... 

C-(w-propyl)-N-phenylnitrone to N-phenylmaleimide, 46, 96 semicarbazide hydrochloride to ami-noacetone hydrochloride, 45,1 tetraphenylcyclopentadienone to diphenyl acetylene, 46, 44 Alcohols, synthesis of equatorial, 47, 19 Aldehydes, aromatic, synthesis of, 47,1 /8-chloro-og3-unsaturated, from ketones and dimethylformamide-phosphorus oxychloride, 46, 20 from alkyl halides, 47, 97 from oxidation of alcohols with dimethyl sulfoxide, dicyclohexyl carbodiimide, and pyridinium trifluoroacetate, 47, 27 Alkylation, of 2-carbomethoxycyclo-pentanone with benzyl chloride, 45, 7... 

Initially, Corey and Schmidt found that by addition of pyridinium trifluoroacetate (0.4 equiv.) to their reactions, there was an increase in rate and the amount of PDC needed for complete oxidation diminished. Subsequently, several other techniques have been devised to improve the rate and efficacy of PDC oxidations (most frequently in the field of carbohydrate research). 

Addition of small quantities of anhydrous acetic acid and fireshly activated sieves to oxidations of carbohydrates has also been found to increase the rate of oxidation. In comparison to the addition of pyridinium trifluoroacetate, reaction times were reduced from days to minutes (Scheme 1). The acetic acid and sieves appear to have a synergistic effect, since both are required to give the dramatic rate enhancement. 

The behavior of PDC in CH2CI2 is considerably different. Primary alcohols are oxidized only to aldehydes. Oxidation of secondary alcohols is also satisfactory and can be catalyzed by addition of pyridinium trifluoroacetate. Allylic alcohols are oxidized readily. ... 

Dimethyl sulfoxide (DMSO), which is successfully used to dehydrogenate primary alcohols to aldehydes, converts secondary alcohols into ketones in very high yields and under very gentle conditions. The mechanism is discussed in a previous section. Dehydrogenation and Oxidation of Primary Alcohols to Aldehydes (equation 217). The first oxidations were carried out in the presence of dicyclohexylcarbodiimide and an acid catalyst such as pyridinium trifluoroacetate [1016], which protonates the diimide and facilitates the attack by dimethyl sulfoxide (equation 259). 

The Moffatt oxidation was utilized in the endgame of the total synthesis of (+)-paspalicine by A.B. Smith et al. The advanced intermediate hexacyclic homoallylic alcohol was subjected to the Moffatt oxidation conditions using pyridinium trifluoroacetate as the acid catalyst. Under these conditions, the desired p,y-unsaturated ketone and the rearranged a,p-unsaturated ketone (paspalicine) were formed in a 5 1 ratio. The final step was the Rh-catalyzed isomerization of the p,y-unsaturated ketone to the natural product. 

Jones and Wigfield411 used the combination DMSO-DCC-PTFA (pyridinium trifluoroacetate, m.p. 78°, obtained in quantitiative yield by reaction of pyridine with trifluoroacetic acid in dry ether). They found the reagent useful for the oxidation of steroid Afl-3/3-alcohols to A5-3-ketones. 

Corrigan it was not exploited synthetically until Corey prepared the reagent by addition of pyridine to neutral chromium trioxide solutions and used it for the oxidation of alcohols to aldehydes, ketones, and acids.xhe reagent is not acidic and the neutral conditions required for the oxidation are superior for the oxidation of allylic alcohols. In dichloromethane (nonaqueous workup) the oxidation is similar to that of PCC. Addition of catalytic amounts of pyridinium trifluoroacetate in dichloromethane significantly increases the rate of oxidation. Allylic alcohols are oxidized faster than aliphatic alcohols, making PDC the reagent of choice for this transformation. Cyclohexenol, for example, is oxidized 10 times faster than cyclohexanol with... 

The initial reaction with DMSO is usually fast but overall oxidation is quite slow unless mineral acids or strong organic acids such as dichloroacetic acid or trifluoroacetic acid are added to the reaction. The pyridinium salts of strong acids are also good catalysts, exemplified by the pyridinium salts of orthophos-phoric acid and trifluoroacetic acid. Reagents formed in the presence of these acid gave clean and rapid oxidation of primary and secondary alcohols in the Moffatt oxidation. o-Phosphoric acid, dichloroacetic acid, and pyridinium trifluoroacetate are the most common acids used in this oxidation. 0 ... 

Moffatt oxidation has several problems associated with it. One is formation of the urea product 64, which can be very difficult to remove. Treatment with oxalic acid is the most common method employed for the removal of the last vestiges of the dicyclohexylurea byproduct. Oxidation of homoallylic alcohols is sometimes accompanied by isomerization of the double bond into conjugation with the carbonyl group. This can be minimized or prevented by addition of pyridinium trifluoroacetate. A threefold excess of DCC and an excess of DMSO are usually required for Moffatt oxidation and these must be removed from the product. The... 

However, the separation of the ketone from the dicyclohexylurea formed in the reaction is frequently a serious experimental problem. Use of phosphoric, phosphorous, or cyanoacetic acid in lieu of pyridinium trifluoroacetate gave inferior yields. Limited investigation of the dimethyl sulfoxide-acetic anhydride reagent has shown it to be superior in oxidations of triphenylsilyl-methylcarbinol, triphenylsilylethylcarbinol, and l,l-diphenylsila-2-cyclo-hexanol, giving the corresponding ketones in 60-70% yields (17, 24) since no separation problems are encountered. 

The oxidation of several monohydric alcohols to the corresponding aldehydes and ketones by bis(quinuclidine)bromine(I) bromide in chloroform and in the presence of pyridinium trifluoroacetate has a two-step mechanism in which transfer of hydride ion from the substrate to the oxidant is rate-determining. The proposed mechanism is supported by the thermodynamic parameters, deuterium kinetic isotope effect, and Hammett reaction constants of the reaction. ... 

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