6-Keto esters, acylation alkylation

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... 

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... 

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. 

The reaction between dialkyl phosphorocyanatidite and acyl cyanides in dichloro-methane at 0 °C parallels that between the same phosphite and 1,2-dicarbonyl compounds, and is probably initiated by attack of tervalent phosphorus on the carbonyl group the formation of O- and V-alkyl products, (30) and (29), is an indication of the probable nature (28) of an intermediate.25 The extension of the reaction (see Organophosphorus Chemistry , Vol. 7, pp. 108, 126) to include ethyl phosphorodicyanatidite and 1-keto-esters provides a route to the 5-phosphabicyclo-[3,2,0]heptanes (31) in high yields.26... 

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]. 

Hudson, B. E., and Ch. R. Hauser Condensations. XVI. Various Acylations and Alkylations of the Sodium Enolates of Aliphatic Esters. Methods for the Synthesis of a,a-Disubstituted j -Keto Esters and of Certain Other Compounds. J. Amer. chem. Soc. 63, 3156 (1941). 

Among isolable metal homoenolates only zinc homoenolates cyclize to cyclo-propanes under suitable conditions. Whereas acylation of zinc alkyls makes a straightforward ketone synthesis [32], that of a zinc homoenolate is more complex. Treatment of a purified zinc homoenolate in CDC13 with acid chloride at room temperature gives O-acylation product, instead of the expected 4-keto ester, as the single product (Eq. (22) [33]). The reaction probably proceeds by initial electrophilic attack of acyl cation on the carbonyl oxygen. A C-acylation leading to a 4-keto ester can, however, be accomplished in a polar solvent Eq. (44)-... 

The lower members of the homologous series of 1. Alcohols 2. Aldehydes 3. Ketones 4. Acids 5. Esters 6. Phenols 7. Anhydrides 8. Amines 9. Nitriles 10. Polyhydroxy phenols 1. Polybasic acids and hydro-oxy acids. 2. Glycols, poly-hydric alcohols, polyhydroxy aldehydes and ketones (sugars) 3. Some amides, ammo acids, di-and polyamino compounds, amino alcohols 4. Sulphonic acids 5. Sulphinic acids 6. Salts 1. Acids 2. Phenols 3. Imides 4. Some primary and secondary nitro compounds oximes 5. Mercaptans and thiophenols 6. Sulphonic acids, sulphinic acids, sulphuric acids, and sul-phonamides 7. Some diketones and (3-keto esters 1. Primary amines 2. Secondary aliphatic and aryl-alkyl amines 3. Aliphatic and some aryl-alkyl tertiary amines 4. Hydrazines 1. Unsaturated hydrocarbons 2. Some poly-alkylated aromatic hydrocarbons 3. Alcohols 4. Aldehydes 5. Ketones 6. Esters 7. Anhydrides 8. Ethers and acetals 9. Lactones 10. Acyl halides 1. Saturated aliphatic hydrocarbons Cyclic paraffin hydrocarbons 3. Aromatic hydrocarbons 4. Halogen derivatives of 1, 2 and 3 5. Diaryl ethers 1. Nitro compounds (tertiary) 2. Amides and derivatives of aldehydes and ketones 3. Nitriles 4. Negatively substituted amines 5. Nitroso, azo, hy-drazo, and other intermediate reduction products of nitro com-pounds 6. Sulphones, sul-phonamides of secondary amines, sulphides, sulphates and other Sulphur compounds... 

PdLX complex undergoing insertion of the coordinated double bond into the a-Pd-carbon bond to form a Pd-alkyl intermediate. With 1,4-penta-diene and 1,5-hexadiene, cyclic keto esters are formed in MeOH and a similar cyclic mechanism is suggested involving insertion of the coordinated double bond into the acyl Pd complex intermediate (16). Although CO pressures of 1000 atm were used, these cyclic ketones were produced also at 250 atm in the presence of p-toluene sulfonic acid, but no details were reported. 

A general convenient alkyl methyl ketone synthesis, which utilises the /7-keto ester system as an intermediate, involves the acylation of a malonate ester by way of the ethoxymagnesium derivative. Hydrolysis and decarboxylation to the ketone is accomplished by heating in acid solution the synthesis of cyclohexyl methyl ketone is the illustrative example (Expt 5.96). 

Keto acids and 2-alkyl- or 2-arylmalonic acids readily decarboxylate, and acylations with these proceed satisfactorily only at low temperatures. An alternative to direct acylation with /3-keto acids is thermolysis of acyl Meldrum s add (to generate an acylketene) in the presence of a nucleophile (Scheme 7.7). Esters of /J-keto acids can also be conveniently prepared from other keto esters by transesterification [27, 28],... 

A mild and efficient process for the acyl-alkylation of arynes to give ortho-substituted arenes has been reported (Scheme 63)." The transformation results in the formation of two new C-C bonds by the net insertion of an arene unit into the a,/3-single bond of a /3-keto ester. 

The over-all yields (R equals w-C,-Q, -C , and -C ) from the esters vary from 55% to 78%. Certain heterocyclic ketones, namely, 8-acetyl-quinoline and /3-acetylpyridine, have been prepared through a mixed ester condensation. (3) If acetoacetic ester is acylated in the form of its sodium enolate and carefully hydrolyzed, a new /3-keto ester is formed. Alkylation of this keto ester followed by hydrolysis gives ketones of the type RCOCH,R. ... 

Inverse electron demand hetero-Diels-Alder reactions of acyl phosphonates or a-keto ester heterodienes and enol ethers are also catalyzed by (5, iS )-t-Bu-box complexes. High levels of enantioselectivity are obtained with y-alkyl-, -aryl-, -alkoxy-... 

Stereoselective reduction of a-alkyl-3-keto acid derivatives represents an attractive alternative to stereoselective aldol condensation. Complementary methods for pr uction of either diastereoisomer of a-alkyl-3-hydroxy amides from the corresponding a-alkyl-3-keto amides (53) have been developed. Zinc borohydride in ether at -78 C gave the syn isomer (54) with excellent selectivity ( 7 3) in high yield via a chelated transition state. A Felkin transition state with the amide in the perpendicular position accounted for reduction with potassium triethylborohydride in ether at 0 C to give the stereochemi-cally pure anti diastereoisomer (55). The combination of these methods with asymmetric acylation provided an effective solution to the asymmetric aldol problem (Scheme 6). In contrast, the reduction of a-methyl-3-keto esters with zinc borohydride was highly syn selective when the ketone was aromatic or a,3-unsaturated, but less reliable in aliphatic cases. Hydrosilylation also provided complete dia-stereocontrol (Scheme 7). The fluoride-mediated reaction was anti selective ( 8 2) while reduction in trifluoroacetic acid favored production of the syn isomer (>98 2). No loss of optical purity was observed under these mild conditions. 

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