Microwave-assisted synthesis of non-substituted tripyrrane, tetrapyrrane and pentapyrrane Irena Saltsman and Zeev Gross * Schulich Faculty of Chemistry, Technion, Israel Institute of Technology, Haifa 32000, Israel Received 17 September 2007; revised 7 November 2007; accepted 14 November 2007 Available online 19 November 2007 Abstract—The microwave-assisted one-step condensation of aqueous formaldehyde with pyrrole was successfully applied for the preparation of non-substituted tri-, tetra- and pentapyrranes with reasonable yields. All three compounds are important precursors to advanced porphyrins and porphyrin analogs. The advantages of this method are short reaction times, clean reaction mixtures and work in the non-toxic and environment friendly solvent—water. Ó 2007 Elsevier Ltd. All rights reserved. The most straightforward synthesis of symmetrically- substituted porphyrinoids, such as triarylcorroles, tetrarylporphyrins and expanded porphyrins, relies on cyclocondensation of pyrrole and aldehydes. However, there is also large demand for derivatives where non- identical substituents occupy the methine bridges between the pyrrole rings (called meso-carbon atoms), as well as for porphyrinoids that are not meso-substi- tuted. Efficient methods for the preparation of methyl- ene-bridged oligopyrroles (called dipyrromethanes for the simplest molecule, but tripyrrane, tetrapyrrane, etc. for the other cases) are hence desirable, as these com- pounds can be applied as precursors for the synthesis of many new derivatives. 1–4 Previous reports have mainly focused on one-flask methods for the synthesis of meso-substituted oligopyrranes. 5–8 The procedures usually involve acid-catalyzed condensation of an alde- hyde with pyrrole, where the polymerization process is suppressed by using a very large excess of pyrrole. Unsubstituted dipyrromethane and tripyrrane (3) were also reported and applied, but not any of the larger oligo- mers. 9,10 One interesting outcome is that water was found to be the best solvent for the preparation of tripyrrane 3, as well as of its synthetic precursor 2,5- bis(hydroxymethyl)pyrrole. Since water is also an ideal solvent for microwave-assisted synthesis, 11 we decided to examine the utility of microwave irradiation with regard to affecting the reaction between aqueous formaldehyde and pyrrole. We here report the microwave-assisted condensation of aqueous formaldehyde with pyrrole as a very convenient approach for the synthesis of non-substituted tri-, tetra- and penta-pyrranes (Scheme 1). 12 An open to air mix- ture consisting of 5 mL of 1.4 M formalin (1) (6.2 mmol) and 1.7 mL of (24.6 mmol) pyrrole (2) was heated in a microwave oven (240 W power) for 40 s. 13 The brownish oil obtained from extraction of the reaction mixture by dichloromethane was purified by column chromato- graphy on silica gel (n-hexane/ethyl acetate = 17/3). Single column chromatography was sufficient for separating the desired components of the reaction in reasonable yields: tripyrrane (3)—11%, tetrapyrrane (4)—17% and pentapyrrane (5)—19%. The compounds were found to be sensitive to light and air, but were stable for extended periods when stored in a freezer under an inert atmosphere. Tetrapyrrane 4 is a potential precursor to the parent (and still unknown) macrocyclic and aromatic corrole 6 (Scheme 2). Large efforts devoted to preparing 6 from 4 were not met with any real success: small amounts of porphine (the parent porphyrin) and biliverdin-like compounds were obtained instead. On the other hand, oxidation of pentapyrrane 5 using p-chloranil resulted in the formation of the meso-pyrrole-substituted por- phine 7 (Scheme 3) as a single product in a respectable 47% yield. Compound 7 was recently obtained (and fully characterized) in 7% yield from the condensation of 3 with 2-formyl-pyrrole. 14 Microwave-assisted condensation of formalin and pyrrole in aqueous solution is a very convenient 0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2007.11.082 * Corresponding author. Tel.: +972 4 829 3954; fax: +972 4 829 5703; e-mail: chr10zg@tx.technion.ac.il Available online at www.sciencedirect.com Tetrahedron Letters 49 (2008) 247–249