A New Color of the Synthetic Chameleon Methoxyallene: Synthesis of Trifluoromethyl-Substituted Pyridinol Derivatives: An Unusual Reaction Mechanism, a Remarkable Crystal Packing, and First Palladium-Catalyzed Coupling Reactions

Abstract

An unexpected route to pyridines was discovered while studying the reactions of lithiated alkoxyallenes with nitriles. Successive treatment of nitriles with lithiated methoxyallene, trifluoroacetic acid, and trimethylsilyl triflate (TMSOTf) gives 6-trifluoromethyl-substituted pyridinols in good overall yield (see scheme). These pyridinols are of interest as building blocks for introduction into potentially biological active compounds and as construction elements for supramolecular arrangements. Addition of lithiated methoxyallene to pivalonitrile afforded after aqueous workup the expected iminoallene 1 in excellent yield. Treatment of this intermediate with silver nitrate accomplished the desired cyclization to the electron-rich pyrrole derivative 2 in moderate yield. Surprisingly, trifluoroacetic acid converted iminoallene 1 to a mixture of enamide 3 and trifluoromethyl-substituted pyridinol 4 (together with its tautomer 5). A plausible mechanism proposed for this intriguing transformation involves addition of trifluoroacetate to the central allene carbon atom of an allenyl iminium intermediate as crucial step. Enamide 3 is converted to pyridinol 4 by an intramolecular aldol-type process. A practical direct synthesis of trifluoromethyl-substituted pyridinols 4, 10, 11, and 12 starting from typical nitriles and methoxyallene was established. Pyridinol 10 shows an interesting crystal packing with three molecules in the elementary cell and a remarkable helical supramolecular arrangement. Trifluoromethyl-substituted pyridinol 4 was converted to the corresponding pyridyl nonaflate 13, which is an excellent precursor for palladium-catalyzed reactions leading to pyridine derivatives 14–16 in good to excellent yields. The new synthesis of trifluoromethyl-substituted pyridines disclosed here demonstrates a novel reactivity pattern of lithiated methoxyallene which is incorporated into the products as the unusual tripolar synthon B.