Alcohols oxidation with TPAP

S. Campestrini, M. Carraro, U. Tonellato, M. Pagliaro and R. Ciriminna, Alcohols oxidation with hydrogen peroxide promoted by TPAP-doped ormosils, Tetrahedron Lett., 2004, 45, 7283. 

Hydroboration occurred from the less hindered top face of rac-29 and resulted in the formation of alcohol rac-30. After a three-step sequence which included oxidation with tetrapropylammonium perruthenate (TPAP), methyl lithium addition and repeated oxidation with TPAP, ketone rac-31 was isolated. Finally, epimerization of the stereogenic center at C-7 to the correct configuration and methylenation with the Lombardo reagent led to the formation of racemic kelsoene (rac-1). 

Alcohols can be oxidized with TPAP in the presence of tertiary amines.88 Secondary amines are transformed into imines under the action of TPAP.89 At the time of writing, the scientific literature contains no data regarding the possibility of performing selective oxidation of alcohols in the presence of secondary or primary amines, with the exception of the following example in which a secondary amine is trapped by reaction with an aldehyde, resulting from the selective oxidation of a primary alcohol.90... 

It is possible to oxidize alcohols with TPAP in the presence of free phenols.95 Although, there is one instance in which it has been published that, unless a phenol is acetylated, an oxidation with TPAP fails.73 Oxidation-prone heterocycles, such as pyrroles96 and indoles,97 are not affected by TPAP during the oxidation of alcohols. 

A primary alcohol is transformed into an aldehyde in the presence of two secondary alcohols with 90% yield in a complex substrate. An attempted selective oxidation with TPAP/NMO failed because of reaction at the thiazole ring. 

Campestrini S, Carraro M, Ciriminna R et al (2005) A mechanistic study on alcohol oxidations with oxygen catalysed by TPAP-doped ormosils in supercritical carbon dioxide. Adv Synth Catal 347(6) 825-832... 

The effective oxidant in the TPAP oxidation of alcohols is the perruthenate ion, a Ru(VII) compound. This compound is employed only in catalytic amounts hut is continuously replenished (see below). The mechanism of the alcohol — aldehyde oxidation with TPAP presum-... 

The effective oxidant in the TPAP oxidation of alcohols is the perrathenate ion, a Ru(VII) compound. This compound is employed in catalytic amounts only but is continuously replenished (see below). The mechanism of the alcohol —> aldehyde oxidation with TPAP presumably corresponds to the nonradical pathway of the same oxidation with Cr(VI) (Figure 14.10, top). Accordingly, the key step of the TPAP oxidation is a /3-elimination of the ruthenium(VII) acid ester B. The metal is reduced in the process to ruthenium(V) acid. 

Nicolaou and co-workers established the severely strained A-ring oxazole (21) in their total synthesis of antitumor agent diazonamide A through initial oxidation of the hindered alcohol of intermediate 20 with TPAP and subsequent Robinson-Gabriel cyclodehydration of the resultant ketoamide with a mixture of POCI3 and pyridine (1 2) at 70°C. ... 

There are few reported oxidations of this type with TPAP in organic solvents, one of the advantages of the reagent being that the alcohol-to-aldehyde oxidation rarely proceeds further. One natural product which did involve such a step is antascomicin B using TPAP/NMO/PMS/CH Cl [85], In aqueous base however [RuO ] is a much more powerful oxidant than TPAP in organic media, perhaps because oxidation of aldehydes to carboxylic acids may proceed via an aldehyde hydrate, the formation of which is inhibited by the molecular sieves used in catalytic TPAP systems. 

The oxidation is first order with respect to catalyst and alcohol, while the order with respect to NMO is fractional. A rate expression was derived and formation of a catalyst snbstrate complex proposed [500]. Oxidation of 2-propanol to acetone (and other secondary alcohols) by stoich. TPAP/CH Cl may be anto-catalytic the initial redaction product (RuO ) may form an adduct [Ru0. nRu02] with [RuO ]. The initially slow rate of oxidation by TRAP accelerated sharply as the concentration of product built up and then decreased near the end of the reaction because of the lower concentration of reactants, giving a bell-shaped curve typical of autocatalytic reactions [501]. 

Griffith, Ley et al.n discovered that, in variance with the instability and complex behaviour of perruthenate and ruthenate ions in aqueous solution, TPAP in organic media is quite stable and behaves as a very good oxidant for alcohols. Normally, it is employed in catalytic quantities in dry CH2CI2 with addition of TV-methylmorpholine /V-oxide (NMO) as the secondary oxidant. Catalytic TPAP in the presence of NMO is able to oxidize alcohols to adehydes and ketones under very mild conditions in substrates adorned by complex functionalities, and it has become one of the routine oxidants for alcohols in most Synthetic Organic Chemistry laboratories. 

General Procedure for Oxidation of Alcohols with TPAP... 

TPAP oxidizes lactols to lactones.85 Treatment of 1,4- and 1,5-diols with TPAP, in which one of the alcohols is a primary one, leads to an intermediate hydroxyaldehyde that normally is transformed into a lactone86 via an intermediate lactol. No transformation into lactone occurs when the formation of the intermediate lactol is not permited by geometric constraints.87... 

Bringing together the reaction mixture, resulting from the oxidation of an alcohol with TPAP, with a solution containing a non-stabilized phosphorous ylide allows to perform a Wittig reaction with no need to isolate an intermediate aldehyde. 

When ultrasounds are applied in order to accelerate the oxidation of homoallylic alcohols with TPAP, over-oxidation to conjugated enediones can occur.73,67... 

In rare cases, ketones obtained by the oxidation of alcohols with TPAP suffer an in situ over-oxidation, resulting in the introduction of an alkene conjugated with the ketone.106 For example, this happens when thermodynamics are greatly favored by aromatization. 

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. 

Modern variations include the in situ, and thus catalytic, use of this high-valent selective reagent, not only for alcohols but also for ethers (see later). Ru(VII) (perruthenate) in the compounds tetra-n-butylammonium perruthenate (TBAP) and tetra-n-propylammonium perruthenate (TPAP) has found wide application in alcohol oxidation. Ru-oxo complexes with valence states of IV to VI are key intermediates in, for example, the selective oxygen transfer to alkenes, leading to epoxides. On the other hand 16-electron Ru(II) complexes can be used to catalyse hydrogen transfer thus these are excellent catalysts for oxidative dehydrogenation of alcohols. A separate section is included to describe the different mechanisms in more detail. 

Oxidation of the alcohol 10-[3 -methoxy-2 -(methoxymethoxy)phenyl]decan-l-ol (7.19) with TPAP [(C3H7)4NRu04] afforded the aldehyde 10-[3 -methoxy-2 -(methoxymethoxy)phenyl] decan-1-al (7.20) in quantitative yield. The reagent TPAP is known as Ley-Griffith s reagent. 

Mechanism The mechanism of the oxidation of alcohols with TPAP corresponds to the non-radical Cr(VI) oxidation. The perruthenate ion reacts with alcohols to form the ester of ruthenium(VII) acid A, which on elimination gives an aldehyde and reduced ruthe-nium(V) acid B (Scheme 7.10). It is believed that NMO reoxidizes the ruthenium(V) acid to perruthenate faster than the ruthenium(V) acid could attack on alcohol molecule. 

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