New Route to ABCD-Porphyrins via Bilanes Dilek Kiper Dogutan, Syeda Huma H. Zaidi, Patchanita Thamyongkit, and Jonathan S. Lindsey* Department of Chemistry, North Carolina State UniVersity, Raleigh, North Carolina 27695-8204 jlindsey@ncsu.edu ReceiVed June 18, 2007 A new strategy for preparing porphyrins that bear up to four different meso-substituents (ABCD-porphyrins) relies on two key reactions. One key reaction entails a directed synthesis of a 1-protected 19-acylbilane by acid-catalyzed condensation at high concentration (0.5 M) of a 1-acyldipyrromethane and a 9-protected dipyrromethane-1-carbinol (derived from a 9-protected 1-acyldipyrromethane). Three protecting groups (X) were examined, including thiocyanato, ethylthio, and bromo, of which bromo proved most effective. The bilanes were obtained in 72-80% yield, fully characterized, and examined by 15 N NMR spectroscopy. The second key reaction entails a one-flask transformation of the 1-protected 19-acylbilane under basic, metal-templating conditions to give the corresponding metalloporphyrin. The reaction parameters investigated for cyclization of the bilane include solvent, metal salt, base, concentration, temperature, atmosphere, and time. The best conditions entailed the 1-bromo-19-acylbilane at 100 mM in toluene containing DBU (10 mol equiv) and MgBr 2 (3 mol equiv) at 115 °C exposed to air for 2 h, which afforded the magnesium porphyrin in 65% yield. The magnesium porphyrin is readily demetalated to give the free base porphyrin. A stepwise procedure (which entailed treatment of the 1-(ethylthio)-19- acylbilane to oxidation, metal complexation, desulfurization, carbonyl reduction, and acid-catalyzed condensation) was developed but was much less efficient than the one-flask process. The new route to ABCD-porphyrins retains the desirable features of the existing “2 + 2” (dipyrromethane + dipyrromethane- 1,9-dicarbinol) method, such as absence of scrambling, yet has significant advantages. The advantages include the absence of acid in the porphyrin-forming step, the use of a metal template for cyclization, the ability to carry out the reaction at high concentration, the lack of a quinone oxidant, avoidance of use of dichloromethane, and the increased yield of macrocycle formation to give the target ABCD- metalloporphyrin. Introduction Porphyrins bearing four different meso substituents provide versatile building blocks for use in biomimetic and materials chemistry. The existing method for the synthesis of such ABCD- porphyrins is shown in Scheme 1. The porphyrin-forming reaction entails acid-catalyzed condensation of a dipyrromethane- 1,9-dicarbinol (I) + a dipyrromethane (II), which is believed to proceed via a bilanecarbinol (III) and a porphyrinogen (IV) with competing formation of polypyrromethanes (V). Treatment of the reaction mixture with an oxidant gives the porphyrin (VI). 1,2 This “2 + 2” method enables synthesis of ∼1g quantities of variously substituted ABCD-porphyrins with low or no detectable scrambling. In developing access to ABCD-porphyrins, we have attempted to meet the following criteria: (1) no scrambling at any stage of the synthesis, (2) limited reliance on chromatography, (3) scalable syntheses affording at least 1 g of porphyrin, (4) (1) Rao, P. D.; Dhanalekshmi, S.; Littler, B. J.; Lindsey, J. S. J. Org. Chem. 2000, 65, 7323-7344. (2) Zaidi, S. H. H.; Fico, R. M., Jr.; Lindsey, J. S. Org. Process Res. DeV. 2006, 10, 118-134. 10.1021/jo701294d CCC: $37.00 © 2007 American Chemical Society J. Org. Chem. 2007, 72, 7701-7714 7701 Published on Web 09/07/2007