Palladium-catalyzed allylic alkylation via decarboxylative and retro-Claisen C-C cleavage methods

Abstract

Presented herein is the development of new methods for Pd-catalyzed allylic alkylation with a central focus on reactions that generate molecular complexity rapidly with little waste byproduct. With this simply stated, yet challenging goal in mind, we present the decarboxylative allylation (DcA) of nitroalkanes and the conceptually novel deacylative allylation (DaA, or retro-Claisen) reaction. The main unifying themes of this research are (a) Pd-catalyzed allylation, (b) in-situ generation of nucleophilic and electrophilic coupling partners, and (c) "green" synthetic methods. Regarding the former topic, DcA of nitroalkanes, we have developed methods for the synthesis of both tertiary and secondary allylated nitroalkanes using decarboxylation as a strategy. Carbon dioxide is the only byproduct and the organic building blocks prepared by this method are easily converted into nitrogen-containing heterocycles by functional group pairing. The conceptually new deacylative allylation (DaA) reaction has been shown to be a useful method for allylation of various in situ generated nucleophiles. The reaction leads to similar products as can be accessed by the DcA method, but has many added benefits. For example, both nucleophilic and electrophilic coupling partners are prepared in situ by a single retro-Claisen event. Furthermore, DaA substrate synthesis begins from commercial/readily available active methylene nucleophiles (β-dicarbonyl compounds) and can utilize robust methods previously developed for these compounds (e.g. Cu/Pd-catalzyed arylation, Tsuji-Trost allylation, etc.). The DaA reaction itself directly couples allylic alcohols, which is desirable due to their availability and reduced toxicity compared to other allylating agents. In terms of utility, DaA can rapidly construct 1,6-heptadienes (cycloisomerization substrates) via 1-pot 3-component coupling. We have also utilized the reaction to construct an important intermediate ¬en route ¬to the drug verapamil as well an asymmetric DaA reaction that allows formal access to (+)-hamigeran and other enantioenriched tetralone derivatives.