Parikh oxidation

Amine opening of lactone 308 generated hydroxyamide 310, which was chosen as the diverting point of the synthesis. The first series started with a Parikh oxidation of the primary alcohol. The resulting aldehyde ring closed to a hemi-aza-acetale, which after acetylation on treatment with boron trifluoride suffered elimination to the iminium-intermediate 311. This cydized stereoselectively from the convex side of the bicyclic intermediate (see 311) to afford an unsaturated lactam. Standard operations transformed it into indohzidine diol 309. 

The first oxidations of alcohols by stoicheiometric RuO /H O were reported in 1958, of primary alcohols to aldehydes or carboxyhc acids and secondary alcohols to ketones [1]. The first Ru-catalysed oxidation of an alcohol was reported in 1965 when Parikh and Jones used RuO /aq. Na(IO )/CCl (Table 2.3) [2] to oxidise secondary alcohol groups in carbohydrates. 

Peptide aldehydes 1 can be synthesized effectively by the oxidation of peptide alcohols 15, which are readily available without racemization by reduction of peptide esters 9 with sodium borohydride-lithium chloride (Scheme 5). The peptide alcohols 15 can be readily oxidized to afford enantiomerically pure aldehydes using Parikh-Doering or Dess-Martin reagents. This route is less popular than the previously described reductive methods due to (1) the sensitivity of the aldehydes to further oxidation, (2) racemization under the reaction conditions, and (3) instability of the products under the reaction conditions. 

Popular oxidation reactions of peptide alcohols such as the Parikh-Doering or Dess-Martin in addition to older oxidation reactions such as Collins, pyridinium chlorochromate, or Swern oxidation afford racemization free productsJ9121415 37-39 Oxidations using pyridinium dichromate results in racemization and low yields of product.[l3 Oxidation reactions have also been utilized in semisynthetic pathways of peptide aldehydes (1) peptide aldehydes are obtained through the enzymatic acylation of a peptide ester to an amino alcohol with subsequent oxidation of the peptide alcohol to afford the aldehyde, and (2) peptide aldehydes can also be obtained by direct enzymatic oxidation of the peptide alcohol by alcohol de-hydrogenaseJ40 41 ... 

The mechanism of the Parikh-Doering oxidation involves formation of O-di-methylsulfoxonium sulfate from the reaction of DMSO with S03. Displacement on the sulfur by the alcohol gives the alkoxysulfonium salt intermediate, which undergoes base-catalyzed elimination to afford the dimethyl sulfide and the aldehyde. This reaction must be carried out so the hydrogen sulfate of the alcohol is not formed first, otherwise no oxidation would occur. 1143 44 ... 

This oxidation that proved troublesome under a variety of conditions, like Swern, PCC, Dess-Martin and Parikh-Doering, succeeded under Pfitzner-Moffatt conditions. 

Parikh-Doering Oxidation (Sulfur Trioxide-Mediated Moffatt Oxidation)... 

Parikh and Doering in 1967 described80 that DMSO can be activated for the oxidation of alcohols, using sulfur trioxide that can be conveniently added to the reaction mixture as complex with pyridine. According to the original... 

These results suggest that the Parikh-Doering oxidation should be routinely tried at 0-10°C, rather than at room temperature, as described in the original paper. 

The Parikh-Doering oxidation is conveniently carried out at room temperature or moderately cool temperature. The activator—SO3 Py— generates side compounds that are very easily removed during the workup. In variance with other oxidations involving activating DMSO, the Parikh-Doering oxidation rarely delivers substantial amounts of methylthiomethyl ether side compounds.93 Unlike the Swern oxidation, no chlorinated side compounds are possible. 

This oxidation presented a serious challenge, because of the tendency of the substrate to suffer dehydration, or oxidative breakage at the benzylic positions. It succeeded under Parikh-Doering conditions, provided that scrupously dry conditions are used, and the reaction of SO3 Py with DMSO precedes the interaction with the diol, in order to avoid the formation of a sulfate ester. Thus, the solution of SO3 Py in DMSO was prepared 5 min in advance of its use. The application of the closely related Albright-Goldman oxidation led to erratic yields, the diol acetate being the main side product. 

After considerable experimentation, it was found that the Parikh-Doering oxidation provides a good and reproducible yield. Under Swern conditions, yields are erratic with substantial quantities of a product, arising from opening of the epoxide by attack of a chloride ion being formed. PCC did not afford a good yield of alcohol. 

While the Parikh-Doering oxidation succeeds, a Swern oxidation produces chlorination at the activated 3-position of the indole. ... 

During the oxidation, an acid-catalyzed cyclization of the product by attack of the nitrogen atoms on the ketone, leading to three different aminals, must be avoided. A Parikh-Doering oxidation gives a good yield of the desired ketone, while PCC, Dess-Martin reagent and Jones oxidation deliver diverse amounts of aminals. 

Functional Group and Protecting Group Sensitivity to Parikh-Doering Oxidation... 

There is a published instance, in which the Parikh-Doering oxidation is made with no interference from a secondary amine.100... 

The Parikh-Doering oxidation provides a very high regioselectivity for the oxidation of alcohols. Oxidation-sensitive functionalities, like indoles,99a,c sulfides,109 and selenides 110 as well as oxidation-sensitive protecting groups, like dithioacetals,111 PMB104 and dimethoxybenzyl ethers109b, do not react. 

It must be mentioned that sensitive compounds, like alkyl silanes,112 alkyl stannanes113 and vinyl stannanes,114 are not affected under the conditions of the Parikh-Doering oxidation. 

In a properly performed Parikh-Doering oxidation, the complex SO3 Py must not interfere, because it must be completely consumed by reaction with DMSO before the substrate is added. In practice, it can be difficult to avoid the presence of minor amounts of S03 Py, that can react with nucleophilic sites in the molecule, including alcohols. 

For an example of isolation of a methylthiomethyl ether in a Parikh-Doering oxidation see Takano, S. Sato, N. Akiyama, M. Ogasawaia, K. Heterocycles 1985,23, 2859. 

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. 

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