Refined Synthesis of 5-Substituted Dipyrromethanes

5-Substituted dipyrromethanes are important precursors for the synthesis of meso-substituted porphyrins,1 expanded porphyrins, and porphyrin analogues.2 Several one-flask methods have been reported for the synthesis of 5-substituted dipyrromethanes by the condensation of an aldehyde and pyrrole using various combinations of acids and solvents.3-14 We previously reported a one-flask synthesis of dipyrromethanes in which an aldehyde is dissolved in a 40-fold excess of pyrrole with a catalytic amount of an acid at room temperature in the absence of any other solvent.8 This method has afforded good yields of 5-substituted dipyrromethanes bearing many types of functional groups.15 However, purification of the product is typically achieved by flash column chromatography, restricting application to the small-scale preparation of dipyrromethanes. Our objective in this study was to eliminate the use of chromatography during purification, thereby removing the major bottleneck to the synthesis of multigram quantities of dipyrromethanes. Upon examining the crude reaction mixture from the acid-catalyzed condensation of benzaldehyde in excess pyrrole, we found that the principal reaction products consist of the dipyrromethane (1), the N-confused dipyrromethane (2,3′-dipyrromethane) (2) and the tripyrrane (3) (Scheme 1). The presence of the N-confused dipyrromethane was surprising as this species had not been detected previously.8 Using GC we have examined the distribution of these products as a function of the pyrrole:benzaldehyde ratio and the acid catalyst. We have developed a purification process based on bulb-to-bulb distillation followed by recrystallization that affords analytically pure dipyrromethanes in multigram quantities. The condensation of pyrrole and benzaldehyde upon heating without added acids has also been examined.