A User-Friendly, All-Purpose Pd-NHC (NHC=N-Heterocyclic Carbene) Precatalyst for the Negishi Reaction: A Step Towards a Universal Cross-Coupling Catalyst

• Published in: Chemistry : a European journal 2006-06, Vol.12 (18), p.4749-4755
• Main Authors: Organ, Michael G., Avola, Stephanie, Dubovyk, Igor, Hadei, Niloufar, Kantchev, Eric Assen B., O'Brien, Christopher J., Valente, Cory
• Format: Article
• Language: English
• Subjects: alkanes; biaryls; CC coupling; heterocycles; palladium
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.200600206

We have developed the first user‐friendly Negishi protocol capable of routinely cross‐coupling all combinations of alkyl and aryl centers. The use of an easily synthesized, air stable, highly active, well‐defined precatalyst PEPPSI‐IPr (1; PEPPSI=pyridine‐enhanced precatalyst preparation, stabilization and initiation; IPr=diisopropylphenylimidazolium derivative) substantially increases the scope, reliability, and ease‐of‐use of the Negishi reaction. All organohalides and routinely used pseudohalides were excellent coupling partners, with the use of chlorides, bromides, iodides, triflates, tosylates, and mesylates resulting in high yield of the coupled product. Furthermore, all reactions were performed by using general laboratory techniques, with no glove‐box necessary as the precatalyst was weighed and stored in air. Utilization of this methodology allowed for the easy synthesis of an assortment of sterically encumbered biaryls and druglike heteroaromatics, demonstrating the value of the PEPPSI‐IPr system. Furthermore, this is also the first time Pd–NHC (NHC=N‐heterocyclic carbene) methodology has surpassed the related phosphine‐ligated Negishi processes both in activity and use. Take the PEPPSI challenge: Mix and match any carbon centers sp3–sp3, sp3–sp2, sp2–sp3, and sp2–sp2, PEPPSI‐IPr will couple them all (PEPPSI=pyridine‐enhanced precatalyst preparation, stabilization, and initiation; IPr=diisopropylphenylimidazolium derivative). The stability, ease of activation, and high reactivity of the catalyst allows easy synthesis of functionalized alkanes, sterically encumbered biaryls, and druglike heteroaromatics by the Negishi reaction in a few hours (see scheme).