6-Keto esters, acylation

The Claisen condensation of esters normally gives / -keto esters. Acylation of tricarboalkoxymethide ions also leads to reaction at the carbon atom. The aberration from the HSAB principle could be due to intervention of preequilibrium and rearrangement, respectively (98). 

Alkyl- and arylmercury(II) halides are used for the ketone formation[402]. When active methylene compounds. such as /f-keto esters or malonates are used instead of alcohols, acylated / -keto esters and malonates 546 are produced, For this reaction, dppf is a good ligand[403]. The intramolecular version of the reaction proceeds by trapping the acylpalladium intermediate with eno-late to give five- and six-membered rings smoothly. Formation of 547 by intramolecular trapping with malonate is an example[404]. 

Various organotin reagents react with acyl and aroyl halides under mild conditions without decarbonylation to give carbonyl compounds[390,39l]. Alkyl- or alkenyltin reagents react with acyl and aroyl chlorides to give ketones[548.733,734]. One example is the preparation of the a,/3-dnsaturated 7-keto esters 860 and 861, carried out under a CO atmosphere[735]. The reaction has been applied intramolecularly to the synthesis of the macrocyclic keto... 

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],... 

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... 

Acylation of ketones (Sec tion 21 4) Diethyl carbo nate and diethyl oxalate can be used to acylate ketone enolates to give p keto esters... 

In a reaction related to the mixed Claisen condensation, nonenolizable esters are used as acylating agents for ketone enolates. Ketones (via their enolates) are converted to p-keto esters by reaction with diethyl carbonate. 

It s reasonable to ask why one would prepare a ketone by way of a keto ester (ethyl acetoacetate, for example) rather than by direct alkylation of the enolate of a ketone. One reason is that the monoalkylation of ketones via their enolates is a difficult reaction to cany out in good yield. (Remember, however, that acylation of ketone enolates as described in Section 21.4 is achieved readily.) A second reason is that the delocalized enolates of (3-keto esters, being far- less basic than ketone enolates, give a higher substitution-elimination ratio when they react with alkyl halides. This can be quite important in those syntheses in which the alkyl halide is expensive or difficult to obtain. 

V. Acyl acetates. j8-Keto esters have proved useful for the preparation of pyrido[2,3-d]pyrimidin-7(8H)-ones bearing alkyl and aryl... 

The chiral BOX-copper(II) complexes are effective catalysts for enantioselective cycloaddition reactions of a,/ -unsaturated acyl phosphonates [48] and a,/ -unsaturated keto esters [38b, 49]. 

This sequence is equally applicable to keto esters. Thus, condensation of guanidine with ethyl acetoacetate gives the pyrimidone, 134. Elaboration as above gives the pyrimidine, IJ5 acylation with the sulfonyl chloride (88) followed by hydrolysis yields sulfamerazine (107). Reaction of guanidine with beta dicarbonyl compounds gives the pyrimidine directly. Condensation of the base with acetonyl acetone affords the starting amine for sulfadimidine (108). ... 

Strategy The Claisen condensation of an ester results in loss of one molecule of alcohol and formation of a product in which an acyl group of one reactant bonds to the a carbon of the second reactant. The product is a /3-keto ester. 

The mechanism of the Dieckmann cyclization, shown in Figure 23.6, is the same as that of the Claisen condensation. One of the two ester groups is converted into an enolate ion, which then carries out a nucleophilic acyl substitution on the second ester group at the other end of the molecule. A cyclic /3-keto ester product results. 

Step 4 of Figure 29.3 Chain Cleavage Acetyl CoA is split off from the chain in the final step of /3-oxidation, leaving an acyl CoA that is two carbon atoms shorter than the original. The reaction is catalyzed by /3-ketoacyl-CoA thiolase and is mechanistically the reverse of a Claisen condensation reaction (Section 23.7). In the forward direction, a Claisen condensation joins two esters together to form a /3-keto ester product. In the reverse direction, a retro-Claisen reaction splits a /3-keto ester (or /3-keto thioester) apart to form two esters (or two thioesters). 

Acid derivatives that can be converted to amides include thiol acids (RCOSH), thiol esters (RCOSR), ° acyloxyboranes [RCOB(OR )2]. silicic esters [(RCOO)4Si], 1,1,1-trihalo ketones (RCOCXa), a-keto nitriles, acyl azides, and non-enolizable ketones (see the Haller-Bauer reaction 12-31). A polymer-bound acyl derivative was converted to an amide using tributylvinyl tin, trifluoroacetic acid, AsPh3, and a palladium catalyst. The source of amine in this reaction was the polymer itself, which was an amide resin. 

Other carbanionic groups, such as acetylide ions, and ions derived from a-methylpyridines have also been used as nucleophiles. A particularly useful nucleophile is the methylsulfinyl carbanion (CH3SOCHJ), the conjugate base of DMSO, since the P-keto sulfoxide produced can easily be reduced to a methyl ketone (p. 549). The methylsulfonyl carbanion (CH3SO2CH2 ), the conjugate base of dimethyl sulfone, behaves similarly, and the product can be similarly reduced. Certain carboxylic esters, acyl halides, and DMF acylate 1,3-dithianes (see 10-10. )2008 Qxj(jatjye hydrolysis with NBS or NCS, a-keto aldehydes or a-... 

Basic Cleavage of P-Keto Esters and p-Diketones Hydro-de-acylation... 

In another procedure, acyl radicals derived from phenyl selenoesters ArCOSePh I by treatment of them with Bu3SnH) add to a,P-unsaturated esters and nitriles to give y-keto esters and y-keto nitriles, respectively. ... 

Hydroxymethy lene compounds are O-alkylated by potassium carbonate and an alkyl halide in acetone, but these conditions produce only the usual C-alkylation with /J-diketones or keto esters.423 Nitro-compounds have also been reported to give either O- or C-alkylation.424 While acylation of the sodium derivative of acetoacetic ester normally takes place on carbon, O-acylation is the result in pyridine. 

Although the synthesis of 3-isoxazolols from P-keto esters and hydroxylamine suffers from the formation of 5-isoxazolones as major products, treatment of acyl chlorides with Meldrum s acid 4 followed by aminolysis gave rise to p-keto hydroxamic acids 6 that cyclised to the corresponding 5-substituted 3-isoxazolols 7 without formation of any byproduct <00JOC1003>. Cyclisation of N-substituted salicylhydroxamic acids 9 under... 

P-Keto esters.2 In the presence of a trace of tertiary amine, an acid reacts with 1 in THF at 0° to form a 2-acyl-3,5,dioxo-l,2,4-oxadiazolidine (2). This activated form of an acid reacts with the lithium enolate of an ester in THF at - 75°... 

Halodeacylation. Reaction of a (3-keto ester or a p-diketone with NCS or NBS and a base (alkoxide or KOH) results in an a-halo ester or an a-halo ketone by replacement of an acyl group by halogen. 

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