Petasis reaction
| Petasis reaction | |
|---|---|
| Named after | Nicos A. Petasis |
| Reaction type | Coupling reaction |
| Identifiers | |
| Organic Chemistry Portal | petasis-reaction |
| RSC ontology ID | RXNO:0000232 |
The Petasis reaction (alternatively called the Petasis borono–Mannich (PBM) reaction) is the chemical reaction of an amine, aldehyde, and vinyl- or aryl-boronic acid to form substituted amines.
Reported in 1993 by Nicos Petasis as a practical method towards the synthesis of a geometrically pure antifungal agent, naftifine, the Petasis reaction can be described as a variation of the Mannich reaction. Rather than generating an enolate to form the substituted amine product, in the Petasis reaction, the vinyl group of the organoboronic acid serves as the nucleophile. In comparison to other methods of generating allyl amines, the Petasis reaction tolerates a multifunctional scaffold, with a variety of amines and organoboronic acids as potential starting materials. Additionally, the reaction does not require anhydrous or inert conditions. As a mild, selective synthesis, the Petasis reaction is useful in generating α-amino acids, and is utilized in combinatorial chemistry and drug discovery.
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.
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