0-Keto esters preparation

P-Keto esters —> enoates.1 The cnolates of /3-keto esters, prepared with lithium hcxamethyldisilazane in DME, on reaction with the Schwartz reagent (1 cquiv.) at 0-20° arc converted into enoates in 55-70% yield. 

B. 2-Methylcyclopenlane-l,3,5-trione hydrate. A mixture of 200 g. (0.89 mole) of the keto ester prepared above, 910 ml. of water, and 100 ml. of 85% phosphoric acid is healed under reflux for 4 hours and then cooled in an ice-salt bath to —5°. The trione mixed with oxalic acid separates and is collected by filtration and dried under reduced pressure. The dried material is extracted with boiling ether (250-300 ml.) under reflux, and the ethereal extract is separated from the undissolved oxalic acid. The original aqueous filtrate is also extracted with ether in a continuous extractor. The two extracts are combined, and ether is removed by distillation. The crude trione separates as a dark brown solid and is crystallized from ca. 250 ml. of hot water. The once-crystallized, faintly yellow product weighs 95-105 g. (74-82%), m.p. 70-74°. This product is used in the next step without further purification. A better specimen, m.p. 77-78°, which is almost colorless, can be obtained by recrystallization from hot water after treatment with Norit activated carbon. 

A combination of self-condensation, condensation with diethyl carbonate, and alkylation of keto-esters prepared by one of these means will allow us to make most P keto-esters that we are likely to want Look out for all the usual problems of enolate chemistry. 

Keto esters, preparation—Continued by carbethozylation of ketones, 488... 

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). 

The main use of organocadmium compounds is for the preparation of ketones and keto-esters, and their special merit lies in the fact that they react vigorously with acid chlorides of all types but add sluggishly or not at all to multiple bonds (compare addition of Grignard reagents to carbonyl groups). Some t3rpical syntheses are ... 

The success of the last reaction depends upon the inertness of the ester carbonyl groups towards the organocadmium compound with its aid and the use of various ester acid chlorides, a carbon chain can be built up to any reasonable length whilst retaining a reactive functional group (the ester group) at one end of the chain. Experimental details are given for l-chloro-2-hexanone and propiophenone. The complete reaction (formation of ketones or keto-esters) can be carried out in one flask without isolation of intermediates, so that the preparation is really equivalent to one step. 

The aryl- and heteroarylfluorosilanes 541 can be used for the preparation of the unsymmetrical ketones 542[400], Carbonylation of aryl triflate with the siloxycyclopropane 543 affords the 7-keto ester 545. In this reaction, transme-tallation of the siloxycyclopropane 543 with acylpalladium and ring opening generate Pd homoenolate as an intermediate 544 without undergoing elimination of/3-hydrogen[401],... 

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],... 

The most widely used method for the preparation of carboxylic acids is ester hydrolysis. The esters are generally prepared by heterocyclization (cf. Chapter II), the most useful and versatile of which is the Hantzsch s synthesis, that is the condensation of an halogenated a- or /3 keto ester with a thioamide (1-20). For example ethyl 4-thiazole carboxylate (3) was prepared by Jones et al. from ethyl a-bromoacetoacetate (1) and thioformamide (2) (1). Hydrolysis of the ester with potassium hydroxide gave the corresponding acid (4) after acidification (Scheme 1). 

We 11 begin by describing the preparation and properties of p keto esters proceed to a discussion of their synthetic applications continue to an examination of related species and conclude by exploring some recent developments m the active field of synthetic car banion chemistry... 

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... 

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. 

Some weak electrophilic reagents, which are usually inert toward azoles, also react with quaternized azoles. Diazonium salts yield phenylhydrazones (Scheme 48) in a reaction analogous to the Japp-Klingemann transformation of /S-keto esters into phenylhydrazones in the dithiolylium series illustrated the product has bicyclic character. Cyanine dye preparations fall under this heading (see also Section 4.02.1.6.5). Monomethine cyanines are formed by reaction with an iodo quaternary salt, e.g. Scheme 49. Tri- and penta-methinecar-bocyanines (384 n = 1 and 2, respectively) are obtained by the reaction of two molecules of a quaternary salt with one molecule of ethyl orthoformate (384 n = 1) or/S-ethoxyacrolein acetal (384 n =2), respectively. 

Generalized methods of preparation include the reaction of /3-keto esters (or amides) with hydroxylamine, a-alkynic and a,/3-unsaturated esters (or amides) with hydroxylamine (real or generated in situ), hydroxylamine and nitrile oxides, and /3-keto and a-alkynic nitriles with hydroxylamine (62HC(l7)l, pp. 3,7). 

This procedure illustrates a new method for the preparation of 6-alkyl-a,g-unsaturated esters by coupling lithium dialkylcuprates with enol phosphates of g-keto esters. The procedure for the preparation of methyl 2-oxocyclohexanecarboxylate described in Part A Is based on one reported by Ruest, Blouin, and Deslongcharaps. Methyl 2-methyl-l-cyc1ohexene-l-carboxylate has been prepared by esterification of the corresponding acid with dlazomethane - and by reaction of methyl 2-chloro-l-cyclohexene-l-carboxyl ate with lithium dimethylcuprate. -... 

The formation of g-alkyl-a,g-unsaturated esters by reaction of lithium dialkylcuprates or Grignard reagents in the presence of copper(I) iodide, with g-phenylthio-, > g-acetoxy-g-chloro-, and g-phosphoryloxy-a,g-unsaturated esters has been reported. The principal advantage of the enol phosphate method is the ease and efficiency with which these compounds may be prepared from g-keto esters. A wide variety of cyclic and acyclic g-alkyl-a,g-unsaturated esters has been synthesized from the corresponding g-keto esters. However, the method is limited to primary dialkylcuprates. Acyclic g-keto esters afford (Zl-enol phosphates which undergo stereoselective substitution with lithium dialkylcuprates with predominant retention of stereochemistry (usually > 85-98i )). It is essential that the cuprate coupling reaction of the acyclic enol phosphates be carried out at lower temperatures (-47 to -9a°C) to achieve high stereoselectivity. When combined with they-... 

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. 

Another improvement was reported by Leonard et al. in their preparation of a promising antimalarial, Endochin. The improvement was the alkylation of intermediate enamino-ester 28 by reaction with NaOEt followed by alkylation with an alkyl bromide, rather than forming 29 by reaction of 27 and a suitable P-keto-ester. This provided the important intermediate 29 required for cyclization to Endochin (30). Endochin was first reported by German scientists but was not publicly disclosed until the Department of Commerce made this information available after World War II.Leonard was able to improve upon the chemistry reported by Andersag and Salzer in 1940 and isolated Endochin in 40% overall yield from m-anisidine (27). 

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... 

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