A Scalable and Resource-Saving Synthesis of Dipyrromethanes and Tetrapyrroles via Geminal Diethers: Minimal Polymer Formation and Facile Purification

The reported syntheses of dipyrromethanes and tetrapyrroles suffer from accompanying polymerization processes lowering yields and necessitating a laborious workup. Here we present the reaction of geminal dimethoxyethers (i.e., acetals or ketals) with pyrrolic nucleophiles under mild conditions solving those problems. The observed minimal polymerization enables greatly simplified purification procedures. This is possible, because under anhydrous, mildly acidic conditions, geminal dimethoxyethers are more reactive than their carbonyl counterparts. The reaction of geminal dimethoxyethers with pyrrolic nucleophiles proceeds smoothly and selectively at 0°C. Computational studies suggest that geminal dimethoxyethers react readily, while unfeasibly high intermediate energies hamper the reaction of carbonyl compounds under the same conditions. We demonstrate a high functional group tolerance and high yields by the preparation of 27 dipyrromethanes, one porphyrin, and 20 calix[4]pyrroles, many of which include synthetic anchor points for facile postfunctionalization. The method was scaled up to a 500 mmol scale for a dipyrromethane and a 252 mmol scale for a two-walled calix[4]pyrrole, without loss in yield or purity.