Diketones, acid catalyzed ketones

The most commonly used protected derivatives of aldehydes and ketones are 1,3-dioxolanes and 1,3-oxathiolanes. They are obtained from the carbonyl compounds and 1,2-ethanediol or 2-mercaptoethanol, respectively, in aprotic solvents and in the presence of catalysts, e.g. BF, (L.F. Fieser, 1954 G.E. Wilson, Jr., 1968), and water scavengers, e.g. orthoesters (P. Doyle. 1965). Acid-catalyzed exchange dioxolanation with dioxolanes of low boiling ketones, e.g. acetone, which are distilled during the reaction, can also be applied (H. J. Dauben, Jr., 1954). Selective monoketalization of diketones is often used with good success (C. Mercier, 1973). Even from diketones with two keto groups of very similar reactivity monoketals may be obtained by repeated acid-catalyzed equilibration (W.S. Johnson, 1962 A.G. Hortmann, 1969). Most aldehydes are easily converted into acetals. The ketalization of ketones is more difficult for sterical reasons and often requires long reaction times at elevated temperatures. a, -Unsaturated ketones react more slowly than saturated ketones. 2-Mercaptoethanol is more reactive than 1,2-ethanediol (J. Romo, 1951 C. Djerassi, 1952 G.E. Wilson, Jr., 1968). 

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)]." " ... 

Selective hydroxylation with osmium tetroxide (one equivalent in ether-pyridine at 0 ) converts (27) to a solid mixture of stereoisomeric diols (28a) which can be converted to the corresponding secondary monotoluene-sulfonate (28b) by treatment with /7-toluenesulfonyl chloride in methylene dichloride-pyridine and then by pinacol rearrangement in tetrahydrofuran-lithium perchlorate -calcium carbonate into the unconjugated cyclohepte-none (29) in 41-48 % over-all yield from (27). Mild acid-catalyzed hydrolysis of the ketal-ketone (29) removes the ketal more drastic conditions by heating at 100° in 2 hydrochloric acid for 24 hr gives the conjugated diketone (30). 

A key step in the approach to 3(2//)-furanone ring systems via the acid-catalyzed cyclization-dehydration of appropriately substituted a -hydroxy-l,3-diketones involves the acylation of a-hydroxy-ketone dianions 11141... 

An alternative new synthetic approach to chrysene 1,2-dihydro-diol based on Method IV has recently been developed (60). This method (Figure 12) entails synthesis of 2-chrysenol via alkylation of 1-1ithio-2,5-dimethoxy-1,4-cyclohexadiene with 2-(1-naphthyl) e-thyl bromide followed by mild acid treatment to ge nerate the diketone 12. Acid-catalyzed cyclization of 12 gave the unsaturated tetracyclic ketone 13 which was transformed to 2-chrysenol via dehydrogenation of its enol acetate with o-chloranil followed by hydrolysis. Oxidation of 2-chrysenol with Fremy s salt gave chrysene... 

Furans can be prepared by acid catalyzed cyclization of masked 1,4-diketones. /3-Chloroallyl ketones which are obtained by alkylation of enamines or enolate ions behave as masked 1,4-diketones and afford furans on treatment with acid (67JA4557). 2,4-Dialkyl-furans (40) have been prepared by cyclization of the 3-chloroallyl ketone (39), which may be obtained by acylation of allyl chlorides (73KGS1434). 

From a mechanistic point of view, the first step is an acid catalyzed aldol reaction to IX/18. Acetalization of the remaining ketone, IX/19, and cleavage of the one-atom-bridge led to IX/20. This reaction was applied to the synthesis of bulnesol, IX/22, using the diketone, IX/21, as a starting material [7]. 

They found that at room temperature using benzene as the solvent only 3% consisted of the diketone 25 and mainly the ring-contracted products were obtained 33% of keto aldehyde 24 and 28% of ketone 26. From an industrial point of view the desired compound is the keto aldehyde 24, which is an interesting intermediate for the synthesis of other cyclopentanone derivatives with floral and fruity smells. The acid catalyzed reaction mechanism leading to the synthesis of keto aldehyde 24 had been discussed earlier (25). Therefore, it is of interest whether the product distribution changes in the presence of a heterogeneous catalyst system and also whether the decarbonylation of the compound 24 to compound 26 can be suppressed. 

Reduction of enol ethers or enol esters of 1,3-diketones, followed by acid-catalyzed allylic rearrangement of the reduction product (see p. 85 in ref. 5) is a useful route to a,P-unsaturated ketones. Ali-phatic - and alicyclic enones have thus been prepared in good yields at low temperatures with NaAlH2(0CH2CH20Me)2.2 6... 

Complementary to the acylation of enolate anions is the acid-catalyzed acylation of the corresponding enols, where the regiochemistry of acylation can vary from that observed in base-catalyzed reactions. Although the reaction has been studied extensively in simple systems, it has not been widely used in the synthesis of complex molecules. The catalysts most frequently employed are boron trifluoride, aluminum chloride and some proton acids, and acid anhydrides are the most frequently used acylating agents. Reaction is thought to involve electrophilic attack on the enol of the ketone by a Lewis acid complex of the anhydride (Scheme 58). In the presence of a proton acid, the enol ester is probably the reactive nucleophile. In either case, the first formed 1,3-dicarbonyl compound is converted into its borofluoride complex, which may be decomposed to give the 3-diketone, sometimes isolated as its copper complex.164... 

Anthranilamides (43) and aldehydes (or their acetals) react when heated or oxidized to give quinazolones 85. The alkaloid dihydro-isoevodiamine (88) was obtained by the same sequence of reactions as evodiamine (57) [cf. Eq. (9)], using formaldehyde instead of formic acid. Ketones give the corresponding 2,2-disubstituted quinazolones (86), while diketones such as acetylacetone lead in an acid catalyzed reaction with anthranilamides (43) or thioanthranilamides to quinazolones of type 87, which are methaqualone analogs (Scheme 15). 

Scheme 8.14. A representation of the acid-catalyzed oxidation of a ketone (cyclohexanone) with selenium dioxide to the corresponding a-diketone (1,2-cyclohexanedione) (e.g., see Singh, K. I Anand, S. N. /. Indian Chem. Soc., 1979,56, 363).

Regio- and enantioselective reduction of diketones have been conducted successfully by biocafalysis. Examples for the reduction of diketones to hydroxyl ketones and diols are shown in Figure 11.11. Figure 11.11a shows the preparation of a key intermediafe for the synthesis of terpenoids by a baker s yeast-catalyzed reduction of a o-cyclohexanedione. DMSO (10%) was used to solubilize the substrate [67]. Figure 11.11b shows the reduction of 3,5-dioxo-6-(benzyloxy)hexanoic acid ethyl ester by Acinetobacter sp. SC 13874 to the corresponding si/n-(3R,5S)-diol, potential intermediates for die s)mthesis of HMG-CoA reducfase inhibitors, in 99.4% ee with 52-74% de depending on substrate concentrations (74% de in 2g/l and 52% de in lOg/1) [66]. After the reaction, XAD-16 resin was added to facilitate the recovery process by adsorbing the product. 

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