Rational or statistical routes from 1-acyldipyrromethanes to meso-substituted porphyrins.: Distinct patterns, multiple pyridyl substituents, and amphipathic architectures

New methodology is described for the synthesis of porphyrins bearing four (A(4), cis-A(2)B(2), cis-ABC(2), trans-A(2)B(2)) or fewer (A, cis-AB, cis-A(2), trans-A(2)) meso substituents. The method entails condensation of two 1-acyldipyrromethanes in the presence of a metal salt (MgBr(2), 3 mol equiv) and a noncoordinating base (DBU, 10 mol equiv) in a noncoordinating solvent (toluene) with heating (conventional or microwave irradiation) and exposure to air. The rational synthesis of trans-A(2)B(2)- or trans-A(2)-porphyrins was achieved via condensation of two identical 1-acyldipyrromethanes. The statistical synthesis of various mesosubstituted porphyrins was achieved via condensation of two nonidentical 1-acyidipyrromethanes. Both routes possess attractive features including (1) no scrambling, (2) good yield (up to 60%) at high concentration (100 mM) for the macrocycle-forming step, (3) reasonable scope (aryl, heteroaryl, alkyl, or no substituent), (4) short reaction time (similar to 2 h) via microwave irradiation, (5) magnesium porphyrins as the products, which easily undergo demetalation, and (6) facile chromatographic purification. A key advantage of the statistical route is to obtain a cis-substituted porphyrin without the corresponding trans isomer. For example, reaction of an A/B-substituted 1-acyldipyrromethane and the fully unsubstituted 1-formyldipyrromethane gave the magnesium chelates of three porphyrins: the trans-A(2)B(2)-porphyrin, the hybrid cis-AB-porphyrin, and porphine (no trans-AB-porphyrin can form), which were readily demetalated and separated as the free base species. Altogether 26 1-acyldipyrromethanes and 26 target porphyrins have been prepared, including many with two different pyridyl substituents. One set of amphipathic porphyrins includes cis-A(2)B(2)- or cis-A(2)BC-porphyrins wherein A = pentyl and B/C = pyridyl (o-, m-, p-). Taken together, the rational and statistical routes enable facile conversion of readily available 1-acyldipyrromethanes to diverse porphyrins bearing 1-4 meso substituents for which access is limited via other methods.