P-Keto-acid

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 thermal decarboxylation of p keto acids is the last step in a ketone synthesis known as the acetoacetic ester synthesis The acetoacetic ester synthesis is discussed in Section 21 6... 

Section 19 17 11 Dicarboxylic acids (malonic acids) and p keto acids undergo thermal decarboxylation by a mechanism m which a p carbonyl group assists the departure of carbon dioxide... 

The carbon-carbon bond forming potential inherent m the Claisen and Dieckmann reac tions has been extensively exploited m organic synthesis Subsequent transformations of the p keto ester products permit the synthesis of other functional groups One of these transformations converts p keto esters to ketones it is based on the fact that p keto acids (not esters ) undergo decarboxylation readily (Section 19 17) Indeed p keto acids and their corresponding carboxylate anions as well lose carbon dioxide so easily that they tend to decarboxylate under the conditions of their formation... 

The sequence begins with a Claisen condensation of ethyl pentanoate to give a p keto ester The ester is hydrolyzed and the resulting p keto acid decarboxylates to yield the desired ketone... 

Section 21 5 Hydrolysis of p keto esters such as those shown m Table 21 1 gives p keto acids which undergo rapid decarboxylation forming ketones... 

P-Keto acid Enol form of ketone Ketone... 

Here too there is an enol that tautomerizes to the product. The mechanism is illustrated for the case of P-keto acids, ° but it is likely that malonic acids, a-cyano acids, a-nitro acids, and P,y-unsaturated acids behave similarly, since similar six-membered transition states can be written for them. Some a,P-unsaturated acids are also decarboxylated by this mechanism by isomerizing to the p,y-isomers before... 

For a review of the mechanism of the decarboxylation of P-keto acids, see Jencks, W.P. Catalysis in Chemistry and Enzjnology, McGraw-Hill NY, 1969, p. 116. 

Wasserman, H.H. in Newman Steric Effects in Organic Chemistry, Wiley NY, 1956, p. 352. See also Buchanan, G.L. Kean, N.B. Taylor, R. Tetrahedron, 1975, 31, 1583. StericaUy hindered P-keto acids decarboxylate more slowly Meier, H. Wengenroth, H. Lauer, W. Krause, V. Tetrahedron Lett., 1989, 30, 5253. 

The COOH group of a P-keto acid is replaced by an allylic group when the acid is... 

A bifnnctional enol-CoA hydratase and 3-hydroxyacetyl-CoA dehydrogenase are used in the degradation of CoA-alkenoic esters to the p-keto acid. This is then degraded to acetyl-CoA and the lower alkanoate ester by 3-ketoacetyl CoA thiolase and acetyl-CoA thiolase. 

The RuClj/aq. HCl system is effective for hydration of phenylpropiolic acid to give acetophenone and carbon dioxide via the P-keto acid (Eq. 6.53) [86]. 

P-keto acid X = alkyl or aryl = ketone substituted malonic acid X=OH = substituted acetic acid... 

Figure 5.8 Examples of formation and cleavage of carbon-carbon bonds (a) aldol condensation, (b) Claisen ester condensation and (c) decarboxylation of a P-keto acid. (From Voet and Voet, 2004. Reproduced with permission from John Wiley Sons., Inc.)...

The signal molecule, 30,C6-HSL and number of its analogues, with variations in the acyl chain and the hetero-ring, have been prepared [15,56,57] to investigate the mechanism of induction of carbapenem and luminescence in Erwinia carotovora and V.fischeri respectively. Essentially, the acylation of l-HSL with 3-oxoalkanoic acid by the same method as outlined for the preparation of AT-acyl-L-HSL delivers the desired derivatives. However, as the p-keto acids are thermally labile, these were prepared from the corresponding p-keto ester after the initial protection of the p-keto function as ethylene glycol ketal (route a, Scheme 6). 

The mechanistic steps can be deduced by inspection of structures and conditions. Enolate anion formation from diethyl malonate under basic conditions is indicated, and that this must attack the epoxide in an Sn2 reaction is implicated by the addition of the malonate moiety and disappearance of the epoxide. The subsequent ring formation follows logically from the addition anion, and is analogous to base hydrolysis of an ester. Ester hydrolysis followed by decarboxylation of the P-keto acid is then implicated by the acidic conditions and structural relationships. 

Decarboxylation is the loss of Ccirbon dioxide, which happens easily because of the stability of CO2. Heating P-keto acids to between 100 and 150 degrees Celsius is one example of a decarboxylation reaction. The mechanism for the decarboxylation of a P-keto acid is in Figure 12-43. 

P-Keto acids 34 can be converted into 5,6-dialkyl-4-hydroxypyran-2-ones by thermolysis of the Meldrumls acid derivatives 35. A Fries rearrangement of the derived enol acylates and reduction of the resulting 3-acylpyranone with EtjSiH provides a route to the 3,6-dialky Ipyranones 36 (Scheme 17) <99T4783>. 

The majority of publications on transesterification catalyzed by solid acids have focused on the reaction of 3-keto esters. Transesterification provides an alternative route to synthesize these kinds of esters since direct preparation from P-keto acids is not a good option given that they can easily undergo decarboxylation. Table 11 provides a review of results in the literature relating to the transesterification of P-keto esters with alcohols. 

We have previously seen (0-96) that dianions of carboxylic acids can be alkylated in the a position. These ions can also be acylated on treatment with a carboxylic ester1705 to give salts of p-keto acids. As in 0-96, the carboxylic acid can be of the form RCH2COOH or RR"CHCOOH. Since p-keto acids are so easily converted to ketones (2-40), this is also a method for the preparation of ketones R COCHiR and R COCHRR", where R can be primary, secondary, or tertiary alkyl, or aryl. If the ester is ethyl formate, an a-formyl carboxylate salt (R = H) is formed, which on acidification spontaneously de-carboxylates into an aldehyde.1706 This is a method, therefore, for achieving the conversion RCH2COOH — RCH2CHO, and as such is an alternative to the reduction methods discussed in 0-83. When the carboxylic acid is of the form RR CHCOOH. better yields are obtained by acylating with acyl halides rather than esters.1707... 

Sterically hindered p-keto acids decarboxylate more slowly Meier Wengenroth Laucr Krause Tetrahedron... 

For a review of p-keto acids, sec Oshry Rosenfcld Org. Prep. Proced. lnt. 1982, 14. 249-264. 

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