With TPAP

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. ... 

R. Ciriminna, S. Campestrini and M. Pagliaro, Fluorinated Silica Gels Doped with TPAP as Effective Aerobic Oxidation Catalysts in Dense Phase Carbon Dioxide, Adv. Synth. Catal., 2004, 346, 231. 

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). 

The commonest solvent for TPAP in organic oxidations is CH Clj (DCM), normally in conjunction with 4 A powdered molecular sieves (PMS) to remove water formed during the oxidation. Addition of CH3CN, as in many Ru-catalysed oxidations, makes reactions with TPAP/NMO more effective [59], and occasionally CH3CN is used as the only solvent [159]. Ionic liquids, e.g. [emim](PF )/PMS [479] and [bmim](BF )/PMS [480] have been used with TPAP/NMO. It has also been used in supercritical CO [457]. 

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. 

Fig. 2.3 Formation of an aldehyde intermediate with TPAP in the synthesis of irisquinone [95]...

For the total synthesis of the anti-cancer drug taxol (paclitaxel) the system was used in three steps, two of primary alcohols to aldehydes (with TPAP/NMO/PMS/ CH Clj and one of a secondary alcohol to ketones by TPAP/NMO/PMS/CH Cl -CHjCN... 

Diols were converted to lactols by TPAP/NMO/PMS/CHjCN [352] or TPAP/NMO/ PMS/CH Clj-CHjCN [353] oxidation of a keto hemi-ketal by TPAP/NMO/PMS/ CH Cl in an avermectin synthesis yielded a lactol, via an intermediate retro-aldol [354], The 1,4-diols in Fig. 2.19 (R=C3H, Ph) produced lactones with TPAP/ NMO/PMS/CHjClj as did the 1,5-diol HO(CH3) C(OH)C5H, [46]. 

Cyclic secondary amines with pyrrolo[2,l-c][l, 4]-benzodiazepine rings were oxidised with TPAP/NMO/PMS/CH3CN to the corresponding imines. Thns (llaS)-1,2,3,10,ll,lla-hexahydro-5H-pyrrolo[2,l-c][l, 4]-benzodiazepine-5-one gave (llaS)-l,2,3,lla-tetrahydro-5H-pyrrolo[2,l-c][l, 4]benzo-diazepine-5-one [23]. 

It is open to speculation whether the same mechanism would apply to the more common oxidations with TPAP, in which the perruthenate ion operates in an apolar environment. 

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... 

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... 

Hydroxylamines are efficiently oxidized to nitrones with TPAP.91 Although aromatic nitrocompounds resist the action of TPAP,92 aliphatic nitrocompounds can suffer oxidation.93... 

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. 

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. 

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. 

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. 

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. 

In a similar manner, 2-propanol is oxidized to 2-propanone and cyclobutanol to cyclobu-tanone. N-Methylmorpholine-N-oxide (NMO) or oxygen may be used to reoxidize the expensive TPAP catalyst. The water formed in the reaction is removed by molecular sieves, which prevents further oxidation of the aldehyde to the carboxylic acid. The presence of water increases an equilibrium concentration of the aldehyde hydrate, which can undergo further oxidation to carboxylic acid. The oxidation of 7.21 with TPAP in the presence of NMO gave 7.22 in good yield. ... 

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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