Keto 1,3-diketones

This synthesis of the pyrrole ring system, due to Knorr, consists in the condensation of an a-aminoketone with a 1,3-diketone or the ester of a p-keto-acid, a-Aminoketones are unstable in the free state, readily undergoing self-condensation consequently they must be prepared, by the reduction of an a-nitroso (or oximino) ketone, in the presence of the 1,3-diketone or p-ketoester, to ensure rapid interaction. 

The synthesis will therefore normally produce a 2,4-substituted pyrrole, with in addition an ester group or an acyl group at the 3-position, if a keto ster or a diketone respectively has been employed, and an ester group or an alkyl (aryl) group at the 5-position, according to the nature of the amino-ketone. 

This reaction consists of the condensation of two molecular equivalents of a 1,3 diketone (or a J3-keto-ester) with one equivalent of an aldehyde and one of ammonia. Thus the interaction of ethyl acetoacetate and acetaldehyde and ammonia affords the 1,4-dihy dro-pyridine derivative (1), which when boiled with dilute nitric acid readily undergoes dehydrogenation and aromatisation" to gb e the diethyl ester of collidine (or 2,4,6-trimethyl-pyridine-3,5 dicarboxylic acid (II)). For the initial condensation the solid aldehyde-ammonia can conveniently be used in place of the separate reagents. 

Heating of -keto esters or of 1 3-diketones with an equivalent amount of phenylhydrazine often yields substituted pjrrazolones or pjrrazoles respectively. The latter may serve as derivatives of enols. 

Suggestions as to the methods for identifying the above classes of compounds will be found under Class Reactiona in Section XI,7. Some fimther remarks upon enolic compounds (see Table IV,1I4A) may be made here. Enols may be divided into (a) p-keto esters and (b) 1 3-diketones. With 5 per cent, sodium hydroxide solution, a p-keto ester yields the salt of the corresponding acid, which when heated with dilute hydrochloric acid is decarboxylated to a ketone ... 

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). 

Several 1,4-dicarbonyl compounds are prepared based on this oxidation. Typically, the 1,4-diketone 10 or the 1,4-keto aldehyde 12 can be prepared by the allylation of a ketone[24] or aldehyde[61,62], followed by oxidation. The reaction is a good annulation method for cyclopentenones (11 and 13). Syntheses of pentalenene[78], laurenene[67], descarboxyquadrone[79], muscone (14 R = Me)[80]) and the coriolin intermediate 15[71] have been carried out by using allyl group as the masked methyl ketone (facing page). 

No intennolecular reaction of malonate or /3-keto esters with halides has been reported, but the intramolecular reaction of /3-diketones such as 790 and malonates proceeds smoothly[652,653]. Even the simple ketone 791 can be arylated or alkenylated intramolecularly. In this reaction, slow addition of a base is important to prevent alkyne formation from the vinyl iodide by elim-ination[654]. 

The o -diketone 865 can be prepared by the coupling of the acylstannane 864 with acyl chlorides[738,739]. The a-keto ester 868 is prepared by the coupling of (a-methoxyvinyl)tributylstannane (866) with acyl chloride, followed by ozo-nization of the coupled product 867[740,741],... 

The decarboxylation of allyl /3-keto carboxylates generates 7r-allylpalladium enolates. Aldol condensation and Michael addition are typical reactions for metal enolates. Actually Pd enolates undergo intramolecular aldol condensation and Michael addition. When an aldehyde group is present in the allyl fi-keto ester 738, intramolecular aldol condensation takes place yielding the cyclic aldol 739 as a main product[463]. At the same time, the diketone 740 is formed as a minor product by /3-eIimination. This is Pd-catalyzed aldol condensation under neutral conditions. The reaction proceeds even in the presence of water, showing that the Pd enolate is not decomposed with water. The spiro-aldol 742 is obtained from 741. Allyl acetates with other EWGs such as allyl malonate, cyanoacetate 743, and sulfonylacetate undergo similar aldol-type cycliza-tions[464]. 

Active methylene or methine compounds, to which two EWGs such as carbonyl, alko.xycarbonyl, formyl, cyano, nitro, and sulfonyl groups are attached, react with butadiene smoothly and their acidic hydrogens are displaced with the 2,7-octadienyl group to give mono- and disubstituted compounds[59]. 3-Substituted 1,7-octadienes are obtained as minor products. The reaction is earned out with a /3-keto ester, /9-diketone, malonate, Q-formyl ketones, a-cyano and Q-nitro esters, cya noacetamide, and phenylsulfonylacetate. Di(octadienyl)malonate (61) obtained by this reaction is converted into an... 

When a bidentate phosphine is used as a ligand for the reaction of J-keto esters or /i-diketones, no dimerization takes place. Only a 2-butenyl group is introduced to give 68[49,62], Substituted dienes such as isoprene, 1,3-cyclohexa-diene, and ocimene react with carbon nucleophiles to give a mixture of possible regio- and stereoisomers of 1 1 adducts when dppp is used as a ligand[63,64]. 

The method was applied to the synthesis of (-t-)-l9-nortestosterone by the following sequence of reactions. Michael addition of the bisannulation reagent 124 to the optically active keto ester 129 and decarboxylation afforded 130, and subsequent aldol condensation gave 131. Selective Pd-catalyzed oxidation of the terminal double bond afforded the diketone 132 in 78% yield. Reduction of the double bond and aldol condensation gave ( + )-19-nortestosterone (133)[114]. 

A 1 3 arrangement of two carbonyl groups (compounds called P diketones) leads to a situation m which the keto and enol forms are of comparable stability... 

Even though ketones have the potential to react with themselves by aldol addition recall that the position of equilibrium for such reactions lies to the side of the starting materials (Section 18 9) On the other hand acylation of ketone enolates gives products (p keto esters or p diketones) that are converted to stabilized anions under the reaction conditions Consequently ketone acylation is observed to the exclusion of aldol addition when ketones are treated with base m the presence of esters... 

Diketones and tetraketones derived from aromatic compounds by conversion of two or four SCH groups into keto groups, with any necessary rearrangement of double bonds to a quinonoid structure, are named by adding the suffix -quinone and any necessary affixes. 

Titanium chelates are formed from tetraalkyl titanates or haUdes and bi- or polydentate ligands. One of the functional groups is usually alcohoHc or enoHc hydroxyl, which interchanges with an alkoxy group, RO, on titanium to Hberate ROH. If the second function is hydroxyl or carboxyl, it may react similarly. Diols and polyols, a-hydroxycarboxyflc acids and oxaUc acid are all examples of this type. P-Keto esters, P-diketones, and alkanolamines are also excellent chelating ligands for titanium. 

Diehlorotriphenylantimony has been suggested as a flame retardant (177,178) and as a catalyst for the polymerization of ethylene carbonate (179). Dihromotriphenylantimony has been used as a catalyst for the reaction between carbon dioxide and epoxides to form cycHc carbonates (180) and for the oxidation of a-keto alcohols to diketones (181). 

AEyl chloride reacts with sodamide in Hquid ammonia to produce benzene when sodamide is in excess, hexadiene dimer is the principal product, with some trimer and tetramer (C24, six double bonds). AEylation at carbon atoms alpha to polar groups is used in the preparation of a-aEyl-substituted ketones and nittiles. Preparation of P-diketone derivatives, methionic acid derivatives, and malonic ester, cyanoacetic ester, and P-keto-ester derivatives, etc, involving substitution on an alpha carbon between two polar carbonyl groups, is particularly facEe. 

Though the dialdehyde-tropinone synthesis does not succeed when the dialdehyde is replaced by a diketone, Blount and Robinson have shown that 1-methyltropinone (XXXV) can be obtained by the interaction of the keto-aldehyde, laevulinaldehyde. Me. CO. CH. CH. CHO, with methylamine and calcium acetonedicarboxylate, and from this by reduction to 1-methyl- -tropine and benzoylation, 1-methyl tropacocaine (b.p. 210°/15 mm. picrate, m.p. 163-4°) has been prepared. 

A solution of bismuth trioxide in hot glacial acetic acid provides a specific method for the oxidation of acyloins. " The reaction rate is dependent on the steric accessibility of the ketol system. A 2,3-ketol requires less than one hour for completion but an 11,12-ketol is not yet fully oxidized in thirty hours." The reaction is highly selective as a-keto acids, hydrazines and phenols are not oxidized. In a direct comparison with cupric acetate, this procedure is somewhat superior for the preparation of a 2,3-diketone from a 2-keto-3-hydroxy steroid. ... 

Photochemical processes provide an alternative approach to 10(54)n6eo-3,5-diketones. Thus, irradiation of saturated or l,2-unsaturated-4,5-epoxy-3-keto steroids such as (129) and (130) produces 3,5-dioxo-10(54)<3Z)eo-... 

Fluorinated esters may also act as electrophiles in reactions with nonfluori-nated ketones [28] (equation 23) or malononitrile [29] (equation 24). Unfortunately, the yields of -diketones may be modest, but those of p-keto nitnles are excellent (Table 9)... 

Difunctional electrophiles such as diethyl carbonate and diethyl oxalate also react with perfluorooctyllithium and perfluoroalkyletherlithium compounds to yield ketones, diketones, and keto esters [39, 79] (equations 38 1). 

One of the most actively investigated aspects of enamine chemistry has been the acylation process (i). Initial intensive studies by Hiinig (373-375) showed the ease of preparing a variety of 9-diketones and particularly the synthetic potential of acylated cyclic ketones as intermediates in the preparation of aliphatic keto acids, keto dicarboxylic acids and diketo dicarboxylic acids (376-378). 

The Combes reaction is a sequence of the following reactions (a) condensation of an arylamine 1 with a 1,3-diketone, keto-aldehyde or dialdehyde 2 providing enamine 3, and (b) cyclodehydration to provide quinoline 4. 

In the 1880s, Pinner found that the amidine derivative 2 reacted with acetoacetic ester (4) to furnish 2-substituted-6-hydroxy-4-methylpyrimidine 5. The condensation of amidine derivative 2 with other (l-keto esters, malonic esters, and (l-diketones proceeded similarly (see the following pages for examples). ... 

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