Phosphonium coupling is a chemical reaction in organic chemistry for organic synthesis. It is a mild, efficient, chemoselective and versatile methodology for the direct C–C, C–N, C–O, and C–S bond formations of unactivated and unprotected tautomerizable heterocycles.
History
Originally reported in 2004, phosphonium coupling proceeds via C–OH bond activation of a tautomerizable heterocycle with a phosphonium salt (PyBroP, PyBOP, BroP, or BOP), and subsequent functionalization with either a nucleophile through SNAr displacement or an organometallic through transition metal catalyzed cross coupling reaction.
As the first direct bond formation via C–OH bond activation, phosphonium coupling offers a powerful and practical methodology for chemical synthesis that features operational simplicity, functionality compatibility, and broad substrate scope. Its attractive protecting group free direct bond formation involving a domino multiple-step process in a single step provides unique and facile access to many biologically important heterocycles.
The concept of in situ activation of the C-OH bond in phosphonium coupling has also been applied to cross coupling reactions of tautomerizable heterocycles and arenols using other types of activating reagents. The phosphonium salts have been traditionally used for peptide synthesis. Recently, besides their novel uses in phosphonium coupling, they have also found similar utilities in certain cross coupling reactions.
Phosphonium coupling generates in situ a pseudo aryl or heteroaryl halide (the intermediate phosphonium species), and subsequently reacts with the other coupling partners under the suitable conditions. Therefore, as a new addition to the modern chemical methodology toolbox, it can be applied to many classical reactions involving aryl or heteroaryl halides.