Selective transformation of unactivated CH bonds is one of the notable advances in synthetic chemistry in last 20 years to streamline the synthesis of complex organic molecules. Transition metal catalysis has become a powerful tool to convert unreactive aliphatic CH bonds into an array of useful functionalities.1-3 Nonetheless, selective transformation of distal aliphatic CH bonds still presents a significant challenge, more so in absence of an exogenous directing group.4-5 In this context, aliphatic acids have been identified as the choice of substrates that could be functionalized without utilizing any extra directing group. However, the weak coordination of carboxylate group has been shown to activate mostly the methyl group at or position, limiting the scope and applicability of aliphatic acids.6-8 Herein, we have developed a ligand enabled palladium catalyzed protocol that activates the challenging methylene CH bond of aliphatic acids in presence of methyl CH bonds to form bicyclic lactones in an intramolecular manner (mid to large size). The reported protocol allows the reversal of the general selectivity in aliphatic CH bond activation. Computational mechanistic studies suggest that the CH activation in the cycloalkane ring of the starting material is followed by -hydride elimination to give Pd-coordinated cycloalkene, C-O cyclization, and another -hydride elimination to provide bicyclic unsaturated lactones. The scope of this previously unfamiliar reaction mode has been highlighted via dehydrogenative lactonization of mid to macro ring containing acids along with CH olefination reaction with olefin and allyl alcohol. Furthermore, synthesis of a variety of complex molecules via formal synthesis of natural products underscore the generality and significance of this reaction and suggestive of a new mode of CH activation reactions in aliphatic acids that could simplify the synthesis of bicyclic lactones, that are important features of numerous natural products as well as pharmacoactive molecules.
Access to Unsaturated Bicyclic Lactones by Overriding Conventional C(sp3)-H Site Selectivity