Hydroxymethyl ketones, formation

Ruthenium tetroxide can also be used in the oxidation of alkenes. Conditions that are selective for formation of ketols have been developed.36 Use of 1 mol % of RuC13 and five equivalents of KHS05 (Oxone ) in an ethyl acetate-acetonitrile-water mixture gives mainly hydroxymethyl ketones from terminal alkenes. 

In contrast to (diacetoxyiodo)benzene, [bis(trifluoroacetoxy)iodo]benzene, (BTI) reacts in aqueous solvents with both terminal and non-terminal alkynes affording eventually a-hydroxyketones and 1,2-diketones, respectively. The primary reaction of terminal alkynes leads to the formation of alkynyl phenyliodonium salts, which are not isolable under the experimental conditions but have been prepared by other routes (Section 9.1.3) these are hydrolysed in situ to a-hydroxymethyl ketones, through the intermediacy of their O-tri fluoroacetates, which sometimes may be isolated as by-products. 

The condensation of cyclohexanone (13) and cyclopentanone (14) with formaldehyde produced the corresponding tetrakis-(hydroxymethyl) -ketones in 37 and 90% yields, respectively. When the tetramethylolcyclohexanone was treated with cyclohexanone, a 77% yield of the model keto spiro ketal was formed. In this compound the carbonyl group located between the two quaternary carbon atoms is so hindered that no ketal formation apparently takes place. 

Hydroxymethylation of ketone (155) was followed by protection of the aliphatic hydroxy group (2-methoxypropyl ether) and addition of an a-benzyloxymethylene group at C-4. Acidic workup at the last stage of the reaction sequence produced (156). Its transformation to aldehyde (157) was carried out by successive treatment with methoxypropyl ether, acetic anhydride and pyridine, hydrochloric acid and methanol, and finally chromic acid, pyridine and hydrochloric acid. Dehydration of (157) led to the formation of (158) in 20% yield. Reagents other than the mentioned produced appreciable quantities of the cis A/B isomer. The butenolide (159) was finally synthesized by oxidation and hydrogenolysis. In order to complete the synthesis of triptolide it was necessary to introduce the... 

When the cyclopropene has a single carbomethoxy or aryl substitunt at the 3-position, the predominant stereoisomer of the enone obtained has the substituent cis-to the ketone 260 261). One possible explanation is the formation of a bicyclobutane by peracid attack from the side away from this substituent, followed by a stereocontrolled rearrangement. If the 3-substituent is hydroxymethyl, the reverse stereochemistry is observed in the enone, in agreement with a peracid attack directed by this group to the same face of the cyclopropene, followed again by rearrangement 262). 

In an analogous manner, treatment of 4-(2-haloethyl)-phenols and -l-naphthols " with bases produces spiro[2.5]octa-4,7-dien-6-ones and their benzo analogues, respectively. The basic treatments of jS-oxiranyl ketones , esters (equation 13) , nitriles , sulfones and alkynes affords 2-(hydroxymethyl) cyclopropyl derivatives, usually as the sole cyclization product. The cyclization occurs regiospecifically by the intramolecular attack of the anion on the y-carbon in the oxirane ring. Attack of the anion on the 5-carbon in the oxirane, which should lead to the formation of cyclobutanols, usually does not take... 

A very convenient hydroxymethylation process has been developed based on the Sml2-mediated Bar-bier-type reaction. Treatment of aldehydes or ketones with benzyl chloromethyl ether in the presence of Smh provides the alkoxymethylated products in good to excellent yields. Subsequent reductive cleavage of the benzyl ether provides hydroxymethylated products. Even ketones with a high propensity for enolization can be alkylated by this process in reasonable yields. The method was utilized by White and Soners as a key step in the synthesis of ( )-deoxystemodinone (equation 27). This particular ketone substrate resisted attack by many other nucleophilic reagents (such as methyllithium) owing to conpeti-tive enolate formation. 

Trost also found that treatment of these cyclobutanones with sodium methoxide and diphenyl disulfide leads to in situ bisulfenylation and ring cleavage (secosulfenylation). This was applied to the total synthesis of verrucarol, a complex tetrahydrochromanone substituted at the ring junction by a hydroxymethyl substituent. The synthetic strategy twice used the cyclobutanone formation from 1-lithiocyclo-propyl phenyl sulfide and a ketone, followed by the secosulfenylation process and Baeyer-Villiger type rearrangement of cyclobutanone. Only this part of the synthesis is described in Scheme 28. 

Hydroxymethylation of ketones.1 A ketone can be converted into the a-hydroxy-methyl derivative in two steps acylation with ethyl formate, followed by aluminum hydride reduction. The sequence is illustrated for the conversion of 4-/er/-butylcyclo-hexanone (1) into 2-hydroxymethyl-4-te rt-butylcyclohexanone (3). 

Metallation of TTF (5) has been accomplished at — 78°C by either lithium diisopropylamide or by -butyllithium (Scheme 82) <77CC161,79JOC1476>. It has been found that strict temperature control is essential for the success of these reactions, since at — 20°C a redistribution of product formation is observed <79J0C1476>. 1-Lithio-TTF (426) reacts at —70°C with a series of electrophiles to afford the corresponding alcohols, aldehydes, ketones, carboxylic acids, and esters as well as monoalkylated TTF <77CCi6i, 79JOCi476>. Improvement of this procedure allowed the synthesis of carboxy-TTF (427), formyl-TTF (428), and hydroxymethyl-TTF in 80-92% yield (Scheme 83) <94S489>. 

Enamines. In a synthesis of 19/3-norsteroids, Habermehl and Haaf1 found that the 19 -hydroxymethyl group of (1) is eliminated as formaldehyde on formation of the enamine (2). Thus, when (1) is heated to reflux with pyrrolidine in methanol, the enamine (2) separates within minutes. The enamine is hydrolyzed to the A4-3-ketone (3) by treatment with sodium acetate in acetic acid-methanol. Such an elimination had been observed previously by retroaldol... 

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