Radicalic Ethoxycarbonylation of 3-Iodopyridazines: An Efficient Access to Tri- and Tetrasubstituted Pyridazines

Abstract

Introduction of ester groups into positions 4 and 5 of 3-iodopyridazines (1,2) by redox decomposition of the oxyhydroperoxide of ethyl pyruvate in a sulfuric acid/toluene two-phase system affords trifunctional pyridazine building blocks (3,4a) in a single step. Iodoarenes and -hetarenes are known as useful synthons for C-C bond formation by palladium-catalyzed cross-coupling reactions. In the pyridazine series, a number of alkynyl and aryl derivatives have been prepared in good yields from iodo precursors, using this methodology, although in some cases also chloro-, bromo-, or trifluoromethanesulfonyloxypyridazines have been successfully employed as substrates for Pd-catalyzed introduction of carbon substituents. The limited availability of iodopyridazines other than the 3-iodo and easily accessible 6-substituted 3-iodo derivatives, however, restricts the scope of this reaction type for the synthesis of polyfunctional 1,2-diazines. In particular, only very few iodo-substituted pyridazinecarboxylic acid derivatives have been described so far. Here, we wish to report on a facile and convenient access to 3-iodo-4,5-pyridazinedicarboxylic acid diethyl ester and its 6-methyl congener, which were required in our laboratory as key intermediates for the construction of polycyclic condensed systems, by means of radicalic ethoxycarbonylation of the corresponding iodopyridazines. Since the pioneering work of Minisci, nucleophilic carbon-centered radicals, including alkyl, acyl, carbamoyl and alkoxycarbonyl radicals, have found wide application for substitution reactions in π* Dedicated with best wishes to Prof. Dr. F. Sauter on the occasion of his 70 birthday electron-deficient heteroaromatics. For instance, the introduction of ester groups into the pyridazine nucleus by Fe-induced redox decomposition of ethyl pyruvate oxyhydroperoxide in the presence of the protonated diazine has been investigated by Heinisch and Lotsch, who could achieve a significant selectivity enhancement by running the reaction in a sulfuric acid/dichloromethane two-phase system instead of the “standard” homogeneous solution. Thus, diethyl pyridazine-4,5-dicarboxylate had been obtained in 65% yield from pyridazine, and the formation of previously observed polysubstituted side products was almost completely suppressed under these conditions. So far, only one example of a halogen-containing pyridazine, namely 3-chloro-6-methylpyridazine has been subjected to radicalic alkoxycarbonylation. By this method, Dal Piaz had prepared diethyl 3-chloro-6-methylpyridazine-4,5dicarboxylate in approx. 40% yield. We now examined the possibility to introduce ester functionalities into 3-iodo-6-methylpyridazine (1) and 3-iodopyridazine (2). For the latter compound, we developed a new, convenient synthesis based on oxidative dehydrazination of 6-iodo-3-pyridazinylhydrazine which is easily available from the known 3,6-diiodopyridazine. Initial experiments showed that under two-phase conditions using dichloromethane as the organic layer, protonated compounds (1,2) indeed undergo radicalic ethoxycarbonylation in high conversion rates, as revealed by GC/MS and H-NMR analyses of the crude reaction mixtures. Moreover, we found that the yield of the corresponding diester can be optimized by using toluene instead of dichloromethane as the organic solvent in this process. By this method, diethyl 3-iodo-6-methylpyridazine-4,5-dicarboxylate (3) was obtained from compound (1) in excellent yield (94%).