Diketone formation double carbonylation

G. DIKETONE FORMATION FROM PALLADIUM-PROMOTED DOUBLE CARBONYLATION... 

Thioketals are readily formed by acid-catalyzed reaction with ethane-dithiol. Selective thioketal formation is achieved at C-3 in the presence of a 6-ketone by carrying out the boron trifluoride catalyzed reaction in diluted medium. Selective protection of the 3-carbonyl group as a thioketal has been effected in high yield with A" -3,17-diketones, A" -3,20-diketones and A" -3,l 1,17-triones in acetic acid at room temperature in the presence of p-toluenesulfonic acid. In the case of thioketals the double bond remains in the 4,5-position. This result is attributed to the greater nucleophilicity of sulfur as compared to oxygen, which promotes closure of intermediate (66) to the protonated cyclic mercaptal (67) rather than elimination to the 3,5-diene [cf. ketal (70) via intermediates (68) and (69)]." " ... 

The double bonds in certain heterocyclic compounds, such as furans, Af-acylpyrroles and A-acylindoles are also susceptible to photoaddition of carbonyl compounds to form oxetanes (equation 106) (77JHC1777). A wide range of carbonyl compounds can be used, including quinones, a-diketones, acyl cyanides, perfluorinated aldehydes and ketones and esters. A remarkable case of asymmetric induction in oxetane formation has been reported from optically active menthyl phenylglyoxylate and 2,3-dimethyl-2-butene the oxetane product obtained after hydrolysis of the ester group had an optical purity of 53% (79AG(E)868). 

Ordinarily, p-diketones are acidic because they can form enolates that can be stabilized by delocalization over both carbonyl groups. In this case, loss of the proton at the bridgehead carbon doesn t occur because the strained ring system doesn t allow formation of the bridgehead double bond. Instead, enolization takes place in the opposite direction, and the diketone resembles acetone, rather than a P-diketone, in it pKa and degree of dissociation. 

The reductive coupling of carbonyl compounds with formation of C-C double bonds was developed in the early seventies and is now known as McMurry reaction [38, 39]. The active metal in these reactions is titanium in a low-valent oxidation state. The reactive Ti species is usually generated from Ti(IV) or Ti(III) substrates by reduction with Zn, a Zn-Cu couple, or lithium aluminum hydride. A broad variety of dicarbonyl compounds can be cyclized by means of this reaction, unfunctionalized cycloalkenes can be synthesized from diketones, enolethers from ketone-ester substrates, enamines from ketone-amide substrates [40-42], Cycloalkanones can be synthesized from external keto esters (X = OR ) by subsequent hydrolysis of the primary formed enol ethers (Scheme 9). 

In the absence of activation, the carbonyl group (aliphatic ketones and aldehydes) is too weak an electrophore to exhibit a specific reduction in aqueous media. Moreover, aldehydes may lead to hydrates, the reduction of which is even more difficult. On the contrary, activation by a double bond(s) or an aromatic ring in the a position allows one to reduce carbonyl groups. Thus, in acidic media one observes a one-electron step (reduction of the protonated form of carbonyl) that affords the formation of dimers a mixture of pinacols with aromatic ketones or coupling in s-diketones with c/./l-elbylenic ketones. 

It seems a logical extension to use a 1,5-diketone to make substituted pyridines but there is a slight problem here as we will introduce only two of the required three double bonds when the two enamines are formed. To get the pyridine by enamine formation we should need a double bond somewhere in the chain between the two carbonyl groups. But here another difficulty arises—it will have to be a cis (Z) double bond or cyclization would be impossible. 

The formation of equilibrium between carbonyl compounds and alcohols is general for this reaction, except for the reduction of trifluoromethyl phenyl ketone. The Meerwein-Ponndorf-Verley reduction has advantages of chemoselectivity, mild reaction conditions, operational simplicity, low cost, and scalability." " In addition, this reaction does not affect other double bonds or triple bonds as well as other enolizable carbonyl compounds (e.g., j8-keto ester, j8-diketone). The catalysts suitable for this reaction include aluminum alkoxide and some transition-metal alkoxides (e.g., zirconium," " iron, ... 

More recently (2004), Joule proposed a novel synthetic route to access the akuammiline scaffold with reports from his group s synthetic efforts toward realizing this plan. Retrosynthetically, they envisioned akuammiline (1) to result from late stage imine formation of ketone 247 (Scheme 32). The functionality at position 16 would then be elaborated from a carbonyl contained in diketone 248, which in turn was planned to be obtained via an intramolecular Claisen condensation and double bond isomerization of enamine 249, the latter the product of an aza-Diels—Alder cycloaddition involving cyclic 1-aza-1,3-diene 250 and an acrylate 251. To access azadiene 250 they planned an oxidative ring opening of bicyclic pyrrole 252. 

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