Dicarbonyl compounds 8-Keto esters

Keto amides (see Dicarbonyl compounds) Keto esters (see Dicarbonyl compounds) Ketones (see also Dicarbonyl compounds, Unsaturated carbonyl compounds) From alcohols by oxidation... 

Michael additions of active methylene compounds (e.g. 1,3-dicarbonyls, /3-keto-esters, and malonates) to a,/3-unsaturated esters, leading to 5-keto-ester derivatives, can be effected very efficiently and under near neutral conditions by using Ni(acac)2 as catalyst. The Michael addition of O-silyl ester enolates to cycloalkenones to give 5-keto-esters can be carried out in the absence of a catalyst if the two reactants are simply heated together in acetonitrile (Scheme 20) Yields with simple models are 90% not only is this method a... 

Analysis Another lactone FGl reveals the true TM (A). Our normal discormection a of an a,p-unsaturated carbonyl compound gives us the 1,5-dicarbonyl compound (B) and the ketone (C) clearly derived from phenol. Alternatively we could disconnect bond b to the keto-ester (D) with the further discormection shown ... 

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). ... 

When a hydrogen atom is flanked by two carbonyl groups, its acidity is enhanced even more. Table 22.1 thus shows that compounds such as 1,3-dikotoncs (/3-diketoncs). 3-oxo esters (/3-keto esters), and 1,3-diesters are more acidic than water. This enhanced acidity of jS-dicarbonyl compounds is due to the stabilization of the resultant enolate ions by delocalization of the negative charge over both carbonyl groups. The enolate ion of 2,4-pentanedione, for instance,... 

The best Michael reactions are those that take place when a particularly stable enolate ion such as that derived from a /i-keto ester or other 1,3-dicarbonyl compound adds to an unhindered a,/3-unsaturated ketone. Tor example, ethyl acetoacetate reacts with 3-buten-2-one in the presence of sodium ethoxide to yield the conjugate addition product. 

A Michael reaction involves the conjugate addition of a stable enolate ion donor to an o,/3-unsaturated carbonyl acceptor, yielding a 1,5-dicarbonyl product. Usually, the stable enolate ion is derived from a /3-diketone, jS-keto ester, malonic ester, or similar compound. The C—C bond made in the conjugate addition step is the one between the a carbon of the acidic donor and the (3 carbon of the unsaturated acceptor. 

KetO Adds, Aldehydes, and Esters see also Dicarbonyl Compounds)... 

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]. 

The Claisen condensation is one method of synthesizing (3-dicarbonyl compounds, specifically a (3-keto ester. This reaction begins with an ester and occurs in two steps. In the first step, a strong base, such as sodium ethoxide, removes a hydrogen ion from the carbon atom adjacent to the carbonyl group in the ester. (Resonance stabilizes the anion formed from the ester.) The anion can then attack a second molecule of the ester, which begins a series of mechanistic steps until the anion of the (3-dicarbonyl compound forms, which, in the second reaction step (acidification), gives the product. 

The most used route to pyridines is called the Hantzsch synthesis. This uses a 1,3-dicarbonyl compound, frequently a 1,3-keto ester [ethyl ace-toacetate (ethyl 3-oxobutanoate)], and an aldehyde, which are heated together with ammonia (Scheme 2.18). At the end of the reaction the dihydropyridine is oxidized to the corresponding pyridine with nitric acid (or another oxidant such as Mn02). The normal Hantzsch procedure leads to symmetrical dihydropyridines. Two different 1,3-dicarbonyl compounds may not be used as two enoiate anions might form, giving mixed products when reacted with the aldehyde. The aldehyde itself should preferably be non-enolizable, otherwise the chance of aldoliza-tion exists, but with care this can be avoided. 

Much more studied is the reaction of /8-dicarbonyl compounds with 2-amino-2-deoxyaldoses in particular, with 2-amino-2-deoxy-D-glu-cose (55), both in neutral and alkaline medium. In neutral methanol or aqueous acetone, 2-amino-2-deoxy-D-glucose reacts with 2,4-pen-tanedione to give52 54 3-acetyl-2-methyl-5-(D-arabino-tetrahydroxy-butyl)pyrrole (56a), and, with ethyl acetoacetate,55 the pyrrole 56b. Similar (tetrahydroxybutyl)pyrroles have been prepared from other /3-keto esters, such as ethyl 3-oxohexanoate, ethyl thiolacetoacetate, and diethyl 3-oxopentanedioate.53,56,56a... 

An important pyrrole synthesis, known as the Knorr synthesis, is of the cyclizative condensation type. An a -amino ketone furnishes a nucleophilic nitrogen and an electrophilic carbonyl, while the second component, a /3-keto ester or similar /3-dicarbonyl compound, furnishes an electrophilic carbonyl and a nucleophilic carbon. The initial combination involves enamine formation between the primary amine and the dicarbonyl compound. Subsequent cyclization occurs as a result of the nucleophilic jg-carbon of the enamine adding to the electrophilic carbonyl group of the a-amino ketone (equation 76). Since a-amino... 

In addition to preparation of arylhydrazones from the carbonyl compounds and an arylhydrazine, the Japp-Klingemann reaction of arenediazonium ions with enolates and enamines is an important method for preparation of arylhydrazones. This method provides a route to monoarylhydrazones of a-dicarbonyl compounds from /3-keto acids and to the hydrazones of pyruvate esters from / -keto esters. Enamines also give rise to monoarylhydrazones of a-diketones. Indolization of these arylhydrazones provides the expected 2-acyI-or 2-alkoxycarbonyl-indoles (equations 95-97). 

Substituted coumarins arise from the use of 2-substituted 1,3-dicarbonyl compounds. The synthesis of a number of such keto esters has been described together with their conversion into the coumarin (65JOC4114). The use of hydrogen fluoride in place of sulfuric acid as condensing agent was found to be very advantageous. 

Diazocarbonyl compounds can be prepared on insoluble supports by diazo group transfer with sulfonyl azides or by diazotization of primary amines. Diazo group transfer from sulfonyl azides to 1,3-dicarbonyl compounds proceeds on cross-linked polystyrene as smoothly as in solution (Table 10.19). When 3-keto esters or amides are... 

The compounds described in this section are diketones keto acids and keto esters, which may also be classified as dicarbonyl compounds, are considered in Section 5.14.3, p. 735. The relative location of the two carbonyl groups in the carbon chain may be designated numerically or by letters of the Greek alphabet. The alkyl groups may be the same or different the formulae below also represent keto aldehydes and dialdehydes when one or both of the residues (R), are hydrogen. 

The preparation of (83) (Expt 8.29) is an example of the Hantzsch pyridine synthesis. This is a widely used general procedure since considerable structural variation in the aldehydic compound (aliphatic or aromatic) and in the 1,3-dicarbonyl component (fi-keto ester or /J-diketone) is possible, leading to the synthesis of a great range of pyridine derivatives. The precise mechanistic sequence of ring formation may depend on the reaction conditions employed. Thus if, as implied in the retrosynthetic analysis above, ethyl acetoacetate and the aldehyde are first allowed to react in the presence of a base catalyst (as in Expt 8.29), a bis-keto ester [e.g. (88)] is formed by successive Knoevenagel and Michael reactions (Section 5.11.6, p. 681). Cyclisation of this 1,5-dione with ammonia then gives the dihydropyridine derivative. Under different reaction conditions condensation between an aminocrotonic ester and an alkylidene acetoacetate may be involved. 

When pyrimidinone 3 is allowed to react with 1,3-dicarbonyl compounds 19 in the presence of piperidine, polyfunctionalized pyridones 12 are prepared (Table 12) [62], In the present reaction, /3-keto esters 19b and 19i, diester 19k and cyanoacetate 191 are usable as the reagent to give corresponding pyridones 12, however /J-dikc tones 19c and 19j affords no RTF product, which is due to further decomposition of produced pyridones 12c and 12j under the employed conditions. 

The conjugate addition of carbonyl anions catalysed by thiazolium salts (via umpol-ung) that is fully operative under neutral aqueous conditions has been accomplished. The combination of a-keto carboxylates (157) and thiazolium-derived zwitterions (e.g. 160) in a buffered protic environment (pH 7.2) generates reactive carbonyl anions that readily undergo conjugate additions to substituted o /3-unsaturated 2-acylimidazoles (158) to produce (159). The scope of the reaction has been examined and found to accommodate various a-keto carboxylates and /3-aryl-substituted unsaturated 2-acylimidazoles. The optimum precatalyst for this process is the commercially available thiazolium salt (160), a simple analogue of thiamine diphosphate. In this process, no benzoin products from carbonyl anion dimerization were observed. The resulting 1,4-dicarbonyl compounds (159) can be efficiently converted into esters and amides by way of activation of the A-methylimidazole ring via alkylation.181... 

A highly enantioselective Michael addition of 1,3-dicarbonyl compounds to nitroalkenes has been reported that employs a newly developed Ni(II)-(bis)diamine-based catalyst (174). The reaction scope includes substituted and unsubstituted malonates, /3-keto esters, and nitroalkenes bearing aromatic and aliphatic residues.202... 

When we come to 1,3-dicarbonyl compounds 4 the principle is the same but we now have a choice the keto-ester 35 could be disconnected 35b to the enolate 36 of acetone and diethyl carbonate 37 and this synthesis would work but we prefer 35a as that gives us the enolate of ethyl acetate 34 and ethyl acetate itself 33—another self condensation. 

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