Keto esters reaction with heterocycles

The most useful procedure utilises a 1,4-keto-ester giving a dihydro-pyridazinone, which can be easily dehydrogenated to the fully aromatic heterocycle, often by C-bromination then dehydrobromination alternatively, simple air oxidation can often suffice. 6-Aryl-pyridazin-3-ones have been produced by this route in a number of ways using an a-amino nitrile as a masked ketone in the four-carbon component, or by reaction of an acetophenone with glyoxylic acid and then hydrazine. Friedel-Crafts acylation using succinic anhydride is an alternative route to 1,4-keto-acids, reaction with hydrazine giving 6-aryl-pyridazinones. Alkylation of an enamine with a phenacyl bromide prodnces 1-aryl-l,4-diketones, allowing synthesis of 3-aryl-pyridazines. ... 

Hydrazinopyridazines such as hydralazine have a venerable history as anti hypertensive agents. It is of note that this biological activity is maintained in the face of major modifications in the heterocyclic nucleus. The key intermediate keto ester in principle can be obtained by alkylation of the anion of pi peri done 44 with ethyl bromo-acetate. The cyclic acylhydrazone formed on reaction with hydrazine (46) is then oxidized to give the aromatized compound 47. The hydroxyl group is then transformed to chloro by treatment with phosphorus oxychloride (48). Displacement of halogen with hydrazine leads to the formation of endralazine (49). ... 

The recently reported (757) conversion of 5-pyrazolones directly to a,j8-acetylenic esters by treatment with TTN in methanol appears to be an example of thallation of a heterocyclic enamine the suggested mechanism involves initial electrophilic thallation of the 3-pyrazolin-5-one tautomer of the 5-pyrazolone to give an intermediate organothallium compound which undergoes a subsequent oxidation by a second equivalent of TTN to give a diazacyclopentadienone. Solvolysis by methanol, with concomitant elimination of nitrogen and thallium(I), yields the a,)S-acetylenic ester in excellent (78-95%) yield (Scheme 35). Since 5-pyrazolones may be prepared in quantitative yield by the reaction of /3-keto esters with hydrazine (168), this conversion represents in a formal sense the dehydration of /3-keto esters. In fact, the direct conversion of /3-keto esters to a,jS-acetylenic esters without isolation of the intermediate 5-pyrazolones can be achieved by treatment in methanol solution first with hydrazine and then with TTN. 

Heterocycles.—The phosphonium salt (59) is an effective three-carbon synthon, as demonstrated by its reaction with enolates of /9-keto-esters (Scheme 20) to give cyclopentenyl sulphides via an intramolecular Wittig reaction.63 Ylides are also intermediates in the synthesis of dihydrofurans (60) from the cyclopropylphos-phonium salt (61) and sodium carboxylates (Scheme 21).64 Cumulated ylides are very useful for the synthesis of heterocyclic compounds, e.g. (62), from molecules which contain both an acidic Y—H bond and a carbonyl or nitroso-function, as shown in Scheme 22.65... 

Reactions of this type are of value in the synthesis of 1,2,4-triazepines fused to various heterocyclic ring systems. Reactants of type (464) combine with /3-keto esters to give products such as (465) (75JHC661, 1095, 79LA639). Similarly compounds of type (466) react with /3-halogenoacyl halides, /3-diketones and /3-keto esters to give a variety of triazepines and triazepinones, e.g. (467) (77AJC2053). 

The problems involved are exemplified here by Knorr s pyrrole synthesis (A. Gossauer, 1974). It has been known for almost a century that a-aminoketones (C2N components) react with 1,3-dioxo compounds (C2 components) to form pyrroles (C4N-heterocycles). A side-reaction is the cyclodimerization of the a-aminoketones to yield dihydropyrazines (C4Nj), but this can be minimized by keeping the concentration of the ar-aminoketone low relative to the 1,3-dioxo compound. The first step in Knorr s pyrrole synthesis is the formation of an imine. This depends critically on the pH of the solution. The nucleophilicity of the amine is lost on protonation, whereas the carbonyl groups are activated by protons. An optimum is found around pH 5, where yields of about 60% can be reached. At pH 4 or 6 the yield of the pyrrole may approach zero. The ester groups of /7-keto esters do not react with the amine under these conditions. If a more reactive 1,3-diketone is used, it has to be symmetrical, otherwise mixtures of two different imines are obtained. The imine formed rearranges to an enamine, which cyclizes and dehydrates to yield a 3-acylpyrrole as the normal Knorr product (A. Gossauer, 1974 G.W. Kenner, 1973 B). 

The reaction of selenoamides and selenourea with aldehydes and ketones has been known to take place via the nucleophilic attack of the selenium atom and end up in the formation of a variety of selenium- and nitrogen-containing heterocycles [99]. For example, selenourea was treated with j0-keto ester in the presence of KOH to give selenouracil (Eq. 27) [100], and its biological activity has been tested [100b]. Very recently, Lewis acid mediated addition of primary selenoamides to a, -unsaturated ketones has been reported to give 1,3-selena-zines (Eq. 28) [99 f]. 

Van der Baan, J. L., Bickelhaupt, F. Knoevenagei reaction of malononitrile with cyclic P-keto esters. II. Mechanism of formation of heterocyclic reaction products. Tetrahedron 1974, 30, 2447-2453. 

Reutrakui, V., Kusamran, K., Wattanasin, S. Reaction of diethyi iithiosuccinate with carbonyi compounds Stobbe condensation of a-keto esters. Heterocycles 1977, 6, 715-719. 

Pyrazolones are prepared in quantitative yield by the reaction of hydrazine with / -keto esters R. H. Wiley and P. Wiley, in The Chemistry of Heterocyclic Compounds, A. Weissberger, Ed., Interscience. New York, Vol. 20 (1964). 

The mild, water-soluble Lewis acid, indium(III) chloride is finding increasing use in organic synthesis, including heterocyclic syntheses. An indium(III) chloride catalysed synthesis of a range of new dlbenzo[(f,/ [l,3]dioxepines 125 has been described based on the reaction of 2,2 -dihydroxybiphenyl 124 with ketones or P-keto esters capable of enolisation yields of the products 125 were low to moderate <04TL6909>. 

A great variety of methods is available for the ring synthesis of pyridines the most obvious approach is to construct a 1,5-dicarbonyl compound, preferably also having further unsaturation and allow it to react with ammonia, addition of which at each carbonyl group, with losses of water, producing the pyridine. 1,4-Dihydropyridines, which can easily be dehydrogenated to the fully aromatic system, result from the interaction of aldehydes with two mol equivalents of 1,3-diketones (or 1,3-keto-esters, etc.) and ammonia aldol and Michael reactions and addition of ammonia at the termini, produces the heterocycle. 

Tandem oxidation processes have also been applied to five-and six-membered heterocycle synthesis. New examples of six-membered rings include pyrimides and p)mdines. In one approach, an cK-arylpropargyl alcohol is oxidized to the corresponding ynone, which then reacts with ethyl a-aminocrotonate or an amidine to afford pyridines or p)Timidines, respectively (eqs 105 and 106). In both cases, the reactions were limited in scope, but the former was subsequently inproved by implementation of 8-keto esters and ammonium acetate in place of the a-amino cro-tonate s)mthon (eq 107). ... 

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