P-Keto compound

Collomb, D., Deshayes, C., and Doutheau, A., Synthesis of functionalized phenolic derivatives via the benzannulation of dienylketenes formed by a thermal Wolff rearrangement of a-diazo-P-keto compounds. Tetrahedron, 52, 6665, 1996. 

Thus, ethylacetoacetate is an outcome of Claisen condensation of two molecules of ethyl acetate in the presence of alkali to form a P-keto compound. 

Keywords Aromatic aldehydes, cyclic 1,3-diketones, p-keto compounds, anmumium acetate, ceric ammonium nitrate (CAN), ethanol, room temperature, one-pot multicomponent synthesis, Hantzsch condensation, polyhydroquinohnes... 

A dried 10 mL round-bottomed flask was charged with aromatic aldehyde (1 1.0 mmol), cyclic 1,3-diketone (2 1,3-cyclohexanedione or 5,5-dimethyl-l,3-cyclohexanedione 1.0 mmol), p-keto compound (3 2,4-pentadione or acetoacetate derivatives 1.0 mmol), ammonium acetate (4 1.0 mmol), and ceric ammonium nitrate (CAN) (0.05 mmol 5 mol%) followed by 0.5 mL of ethanol. The mixture was then stirred at room temperature until the reaction was completed as monitored by TLC (25 min to 7 h). The resulting reaction mixture was treated with brine solution followed by extraction with ethyl acetate (2 x 20 mL). After evaporation of the solvent, the crude yellow product was recrystalhzed from ethanol to give a yellow or brown solid in good to excellent yield (64-98%). All the products were characterized from their detailed spectral studies including NMR, NMR, EIMS and HRMS. 

P Keto esters (t.g., ethyl ocetoacetate) are soluble in solutions of caustic alkalis but not in sodium carbonate solution. They give colours with freshly prepared ferric chloride solution a little alcohol should be added to bring the ester into solution. Sodium ethoxide solution reacts to yield sodio compounds, which usually crystallise out in the cold. Phenylhydrazine yields pyrazolones. They are hydrolysed by boiling sulphuric acid to the Corresponding ketones, which can be identified as usual (Section 111,74). 

These substances, as well as the parent compound, are p-keto esters and undergo hydrol3rtio cleavage in two directions. One type of cleavage, ketonlc hydrolysis, is effected by the action of dilute caustic alkali in the cold, followed by acidification and boiling the free acetoacetic acid produced has a carboxyl and carbonyl group on the same carbon atom and therefore readily undergoes decarboxylation to yield a ketone, for example ... 

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 ... 

In the presence of a double bond at a suitable position, the CO insertion is followed by alkene insertion. In the intramolecular reaction of 552, different products, 553 and 554, are obtained by the use of diflerent catalytic spe-cies[408,409]. Pd(dba)2 in the absence of Ph,P affords 554. PdCl2(Ph3P)3 affords the spiro p-keto ester 553. The carbonylation of o-methallylbenzyl chloride (555) produced the benzoannulated enol lactone 556 by CO, alkene. and CO insertions. In addition, the cyclobutanone derivative 558 was obtained as a byproduct via the cycloaddition of the ketene intermediate 557[4I0]. Another type of intramolecular enone formation is used for the formation of the heterocyclic compounds 559[4l I]. The carbonylation of the I-iodo-1,4-diene 560 produces the cyclopentenone 561 by CO. alkene. and CO insertions[409,4l2]. 

Before describing how p keto esters are used as reagents for organic synthesis we need to see how these compounds themselves are prepared The mam method for the prepa ration of p keto esters is the Claisen condensation... 

Michael condensation is the addition of a compound with an active methylene group to an a, p-unsaturated keto-compound... 

A structurally unrelated agent is tazadolene (40). The synthesis of tazadolene begins with P-keto ester 37 and subsequent enamine formation with 3-amino-1-propanol followed by hydrogenolysis to give 38. This phenylhydroxymethyl compound is then dehydrated with hydrochloride acid to form olefin 39. Treatment with bromine and triphenylphosphine effects cycliza-tion to form the azetidine ring of tazadolene [10]. 

Replacement of a benzene ring by its isostere, thiophene, is one of the more venerable practices in medicinal chemistry. Application of this stratagem to the NSAID piroxicam, gives tenoxicam, 136, a drug with substantially the same activity, nie synthesis of this compound starts by a multi-step conversion of hydroxy thiophene carboxylic ester 130, to the sulfonyl chloride 133. Reaction of that with N-methylglycinc ethyl ester, gives the sulfonamide 134. Base-catalyzed Claisen type condensation serves to cyclize that intermediate to the p-keto ester 135 (shown as the enol tautomer). The final product tenoxicam (136) is obtained by heating the ester with 2-aminopyridine [22]. 

No biosynthetic experiments have been reported for these compounds, but they probably all share the same biosynthetic mechanism. One possibility is that they are generated by cyclization of an a-amino-p-keto carboxyl intermediate that would arise from threonine (136) and sphingosine (131) for 139 and 130, respectively (Figure 11.23). Alternatively, cyclization may precede oxidation, with an aziridine intermediate being formed. 

Certain ketoximes can be converted to nitriles by the action of proton or Lewis acids. Among these are oximes of a-diketones (illustrated above), a-keto acids, a-dialkylamino ketones, a-hydroxy ketones, p-keto ethers, and similar compounds. These are fragmentation reactions, analogous to 17-25 and 17-26. For example, ot-dialkylamino ketoximes also give amines and aldehydes or ketones besides nitriles. 

Alternatively, Cushman has devised a facile route to pyrroles by the reaction of Boc-a-amino aldehydes or ketones 14 with the lithium enolates of ketones 15 to afford aldol intermediates 16 which cyclize to pyrroles 17 under mild acidic conditions <96JOC4999>. This method offers several advantages over the Knorr since it employs readily available Boc-a-amino aldehydes or ketones and utilizes simple ketones instead of the p-diketo compounds or p-keto esters normally used in the Knorr. 

Whilst azo compounds prepared from diazonium salts and phenolic or keto-enol coupling components are often depicted in the hydroxyazo form (4.11), an alternative tautomeric structure can be drawn for such compounds (Scheme 4.19). This ketohydrazone tautomer (4.21) can, in cases where the azo and hydroxy groups are located on adjacent carbon atoms, exhibit hydrogen bonding between the two groups as shown. Similar pairs of structures, but without hydrogen bonding, can be drawn for p-hydroxyazo compounds. 

The activated methylene compound (2 mmol), TEBA-Cl (46 mg, 0.2 mmol) and powdered K2C03 (0.55 g) in CH2Cl2 or PhH (10 ml) are stirred at room temperature for ca. 1 h. MeSS02Me (0.25 g, 2 mmol) in CH2C12 (3 ml) is added, and the mixture is stirred for 2-6 h and then filtered. The solid is washed with CH2C12 (20 ml) and the combined solutions are washed with H20 (2 x 20 ml), dried (MgS04), and evaporated to yield the methyl thioether ( a 1 1 mixture of CH2C12 and PhH is preferred for the p-keto sulphoxides). 

Alkylation of P-dicarbonyl compounds and p-keto esters occurs preferentially on the carbon atom, whereas acylation produces the 0-acyl derivatives (see Chapter 3). There are indications that C- and 0-alkylated products are produced with simple haloalkanes and benzyl halides, but only C-alkylated derivatives are formed with propargyl and allyl halides [e.g. 90]. Di-C-alkylation frequently occurs and it has been reported that the use of tetra-alkylammonium 2-oxopyrrolidinyl salts are more effective catalysts (in place of aqueous sodium hydroxide and quaternary ammonium salt) for selective (-90%) mono-C-alkylation of p-dicarbonyl compounds [91]. 

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