Diketones, acid catalyzed acids

In an intramolecular aldol condensation of a diketone many products are conceivable, since four different ends can be made. Five- and six-membered rings, however, wUl be formed preferentially. Kinetic or thermodynamic control or different acid-base catalysts may also induce selectivity. In the Lewis acid-catalyzed aldol condensation given below, the more substituted enol is formed preferentially (E.J. Corey, 1963 B, 1965B). 

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). 

The course of the acid catalyzed dehydration of 1,4-diketones to furans, known as the Paal-Knorr method (1884CB2756), entails the formal addition of the enol of one carbonyl group to the other carbonyl. Examples which illustrate some of the routes used to make the necessary 1,4-diketones are shown in Scheme 13. Few examples are known of the preparation of the other heterocycles by this general approach using isolated intermediates, although some of the ring closures discussed in Section 3.03.3.1.1 are mechanistically equivalent. One example of the preparation of a hydroxypyrrole is included in Scheme 13 <59AC(R)2075). 

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). 

Ibers used the Paal-Knorr furan synthesis to prepare a key intermediate for the synthesis of novel porphyrin-like aromatic macrocycles. Bis yrolyljfuran 27 was available in good yield via the acid catalyzed condensation of diketone 26. ... 

The mercaptals obtained by the acid catalyzed reaction of J3-ketoesters, e.g., ethyl acetoacetate, with methyl thioglycolate (73) undergo the Dieckmann cyclization with alcoholic potassium hydroxide at lower temperatures to give ethyl 3-hydroxy-5-methyl-2-thiophenecarboxylate (74) in 75% yield. ° Besides ethyl acetoacetate, ethyl a-ethylacetoacetate, ethyl benzoyl acetate, and ethyl cyclopentanonecarboxylate were also used in this reaction/ It is claimed that /8-diketones, hydroxy- or alkoxy-methyleneketones, or /8-ketoaldehyde acetals also can be used in this reaction. From acetylacetone and thioglycolic acid, 3,5-dimethyl-2-thiophenecarboxyl-ic acid is obtained. ... 

For the latter case an acid-catalyzed decomposition of intermediate 4 is assumed to give the carbonyl products 2 and 3, or a diketone as shown above, without going through a cyclic intermediate ... 

As in the [22]porphyrin(3.1.3.1) series, the cyclohexene moieties being part of the bridges originate from the preparation of the dimers from dimethylpyrrole and a hydronaphthalene diketone by acid-catalyzed condensation. The synthetic approach developed by Franck2b has the advantage over the foregoing method that more stable conventional pyrroles and dipyrryl-methanes can be used to form the macrotetracycle in a stepwise manner. 

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... 

The functionalized [4]radialene 86 offers opportunities for further transformations by hydrolytic cleavage of the O-silylenol moieties and by oxidative desilylation (Scheme 16). Base- and acid-catalyzed hydrolyses lead to different products (130 and 131, respectively)60. By analogy with the formation of 1,4-diketones by oxidative coupling of two siloxyalkene molecules, treatment of 86 with the iodonium salt Phl+—O—+I—Ph BF4 in dichloromethane leads to 132 which is immediately... 

The diketone (291) could also undergo acid catalyzed ring cleavage to provide the keto-acid (292), which possesses the structural feature of a propellane100). 

Acid-catalyzed condensation of anilines and P-diketones to assemble quinolines. Cf. Conrad-Limpach reaction. 

The preparation of 620, a tricyclic intermediate suited for elaboration into quadrone, has been reported by Monti and Dean Following introduction of the proper C5, stereochemistry by alkylation of 618 under kinetically controlled conditions, diketone 619 was subjected to acid-catalyzed rearrangement. After functional group manipulation, a tandem intramolecular aldol-pinacol rearrangement gave 620. 

A similar type of acid-catalyzed condensation of aldehydes with 4-methylene-2-oxetanone (diketene), giving 4-oxo-6-methyl-l,3-dioxins, has been patented (73GEP2149650). However, other work has established that <5-hydroxy-/3-keto acids or unsaturated keto acids are formed as the principal products (equation 24) (78CPB3877, 78CL409). The latter reaction probably involves electrophilic attack of the protonated aldehyde on the nucleophilic exocyclic methylene carbon atom of the diketone. A closely related reaction of acetals with diketene, catalyzed by titanium tetrachloride, gives the corresponding <5-alkoxy-/3-keto esters (74CL1189). 

Diketones are synthetically quite versatile, but they have found only modest use in the syntheses of heterophanes. When 1,3-cyclohexadecanedione (53) is treated with hydrazine hydrate or phenylhydrazine, pyrazolophane (54) or (55), respectively, is obtained (78TL2821). Reaction of dione (56) with hydroxylamine, followed by acid-catalyzed cyclization of the intermediate monoxime, gives the [3,5]isoxazolophane (57) (79TL1875). 

The facile acid-catalyzed elimination of the elements of water from the carbinols derived from 2-methylindole and 1,3-dicarbonyl compounds, such as ethyl acetoacetate or pentane-2,4-dione, yields the 3-vinylindole derivatives (122) (B-70MI30500). Pyrroles tend to form 2 1 adducts with 1,3-diketones. For example, cyclohexane-1,3-dione produces the bispyrrolyl derivatives (121) (B-77MI30502). 

The preparation of furans by acid catalyzed dehydration of 1,4-diketones followed by cyclization of the monoenol has been comprehensively reviewed (69RCR389). This method of furan preparation is useful for all 1,4-diketones which are not sterically hindered with the highly hindered l,4-bis(2,4,6-triisopropylphenyl)-l,4-butanedione no cyclization occurs (50JA5754). Although sulfuric acid is normally used for cyclization, hydrochloric acid was employed in the conversion of a 1,2-diacylethylene to a furylacrylic acid derivative (59MIP31200). Other reagents used for this purpose include polyphosphoric acid, phosphorus trichloride, zinc chloride and DMSO. Both DMSO and phosphoric esters provide neutral... 

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). 

An efficient general synthesis of a variety of 3(2i/)-furanones has been developed. Aldol condensation of aldehydes with the enolate derived from 3-methyl-3-(trimethylsiloxy)-2-butanone (183) followed by Collins oxidation afforded 1,3-diketones (184). Acid catalyzed cyclodehydration leads to the corresponding 3(2//)-furanones (185) (Scheme 43)... 

This observation led to the development of a general route to 4/f-pyrans, in which the acid-catalyzed condensation of unsaturated carbonyl compounds with 1,3-dicarbonyl compounds is used to generate 1,5-diketones, which spontaneously cyclize to the pyran (equation 3) (69JOC3169). The moderate yields are compensated by the ready availability of the... 

Hydrolysis of Pd(MeCOCHMe)2 in aqueous methanol is considered to involve Pd(0,0-MeCOCHCOMe)(0-MeCOCHCOMe)(MeOH) as an intermediate from which the monodentate acetylacetonate ligand is then solvolyzed.221 Subsequent studies on Lewis base complexes of palladium bis(diketonate) complexes provide ample support for the proposed intermediate. A pulse radiolysis study of the kinetics of aquation of M(MeCOCHCOMe) " (M = Cr, Co) indicates that an 17,-172 equilibrium involving one or more of the acetylacetonate ligands occurs, associated with an acid-catalyzed removal of the monodentate ligand.222 Treatment of Cu(MeCOCHCOMe)2 with picric acid in moist dichloromethane affords a partially hydrolyzed material, Cu(MeCOCHC-0Me)(H20)2[C6H2(N02)30], proposed to contain square pyramidal five-coordinate copper with the oxygen atom from the picrate moiety at the apex.223... 

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