Dicarbonyl compounds Diacids

When reviewed in CHEC-I some examples of cyclization y to the heteroatom had been described for the synthesis of pyridazines, but the method was of most importance in the synthesis of cinnolines. Examples of pyridazine syntheses included cyclization of ketazines with EDA, and intramolecular Wittig reactions of phosphoranes derived from phosphacumuleneneylides and the hydrazones produced from 1,3-dicarbonyl compounds and aryldiazonium salts. Synthetically useful approaches to cinnolines given include the intramolecular Friedel-Crafts acylation of the diacid chlorides derived from the condensation products of aryldiazonium salts and diethyl malonate to give 4(l//)-cinnolinones, and thermal cyclization of iminium hydrazones obtained from enamine esters and aryldiazonium salts. 

Aldol reactions of this type, involving 2-acetamido-2-deoxyaldohexoses, have been studied in connection with the chemical synthesis of A -acetyl-neuraminic acid (50) and related substances, and, for this reason, the choice of the dicarbonyl compound has thus far been limited to oxalacetic acid and its esters. Oxalacetic acid condenses readily with 2-acetamido-2-deoxyaldohexoses in aqueous solution at pH 11. Under these conditions, acetamido sugars partially epimerize, and the aldol reaction takes place for both of the 2-acetamido-2-deoxyaldohexoses present. The complexity of the reaction is further increased by the formation of asymmetric centers at carbon atoms 3 and 4 of the condensation products, namely, diacids (45) and (48), and this can result in the formation of four diastereo-isomers from each sugar. The reaction using 2-acetamido-2-deoxy-o-rnannose (47) has been the one most extensively studied. In this... 

Dicarbonyl compounds condense with thiodiacetates (or thiobismethyleneke-tones) to give thiophene-2,5-diacids (-diketones). 

Two consecutive aldol condensations between a 1,2-dicarbonyl compound and diethyl thiodiacetate give thiophenes. The immediate product is an ester-acid, produced " by a Stobbe-type mechanism, but the reactions are often worked up via hydrolysis to afford an isolated diacid. 

The venerable Hinsberg synthesis (e.g. Scheme 42) [71] involves two consecutive aldol cmidensations between a 1,2-dicarbonyl compound and diethyl 2,2 -thiobisacetate and produces thiophenes carrying ester and carboxylic acid groups at the 2- and 5-positi(Mis, respectively, via a Stobbe-type mechanism [72]. Reactions are often worked up via hydrolysis to afford a diacid as the isolated product. Scheme 43 indicates a reasonable sequence for the condensation and explains the formation of an acid-ester product. 

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