Reaction Mechanism
The mechanism of the Petasis reaction is not fully understood; however, it is similar to the Mannich reaction at its early stage. In the Mannich reaction, an imine or iminium salt serves as the electrophile to which the nucleophile adds; however, in the Petasis reaction it is not clear which intermediate serves as the electrophile. Petasis proposes that the reaction is characterized by a complex equilibrium among the three starting materials and various intermediates, and the final product is formed via a rate-determining and irreversible C-C bond formation step. The condensation between amine 1 and carbonyl 2 forms hemiaminal 4, which is in a complex equilibrium with iminium ion 3 and aminal 5. Boronic acid 6 react with hemiaminal 4 and aminal 5 in a reversible fashion via intermediate 7 and 8 respectively, forming again electrophilic iminium ion 3, this time accompanied by nucleophilic boronate 3’. Note that there are no evidences suggesting that boronic acid alone can directly react with iminium ions: In addition to needing acid for an appreciable amount of iminium salt to be generated, it has been shown that vinyl boronic acids do not react efficiently with preformed iminium salts (like Eschenmoser’s salt). The irreversible C-C bond migration between 3 and 3’then follows, furnishing desired product 9 with loss of boric acid. All intermediates will ultimately lead to the final product, as the reaction between 3 and 3’ is irreversible, pulling the equilibrium of the entire system towards the final product.
Density Functional Theory (DFT) studies have been performed to study the mechanism of Petasis reaction. Starting with the Petasis reaction between glyoxylic acid, dimethylamine and phenylboronic acid, Gois et al. reported that the migration of the boronic acid substituent (phenyl group) of the “ate complex” A incurs an energy barrier of 10kcal/mol and a five-membered transition state B. Formation of quaternary boron salts during the reaction has been experimentally confirmed by Hansen and coworkers. They reported that, in the absence of amine, an upfield 11B shift is observed after the addition of glyoxylic acid to a solution of phenylboronic acid. This is presumably due to the formation of electron rich boronate species.
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