PEPPSI™-IPent for Demanding Cross-Coupling Reactions

Introduction

Professor Mike Organ and co-workers have developed the PEPPSI™ (Pyridine-Enhanced Precatalyst Preparation Stabilization and Initiation) precatalysts for palladium-catalyzed cross-coupling reactions. PEPPSI™ palladium precatalysts have become a choice alternative to palladium phosphine complexes, as they are comprised of a bulky N-heterocyclic-carbene (NHC) ligand bonded to palladium and a s-donating 3-chloropyridine ligand for stability. The PEPPSI™-IPent (732117) further advances the agility of cross-coupling reactions by being air-stable and thus increasing user-friendliness. We are proud to offer the most active of the PEPPSI™ series, PEPPSI™-IPent, in collaboration with the Organ Research Group.¹

Advantages

• PEPPSI™-IPent is bench stable: no need for a glovebox
• Poisoning of Pd has not been observed
• Higher pyrrole-based cross-coupling reactions success
• Consistently superior coupling yields over PEPPSI™-IPr
• Effective and versatile catalyst for difficult, sterically-demanding reactions²

Representative Applications

Under relatively mild conditions, PEPPSI™-IPent is a highly effective catalyst in challenging Suzuki–Miyaura and Negishi cross-coupling reactions. This produces tetra-ortho-substituted (hetero)biaryl compounds in high yields, especially when compared to the use of PEPPSI™-IPr. Bulky and acidic substituents were observed to be well tolerated.^1,2

Negishi cross-coupling reactions of secondary alkyl zinc halides with aryl halides utilize PEPPSI™-IPent, boasting higher selectivity than PEPPSI™-IPr. The desired branched product was obtained in higher yields than that of the linear product.^1,3

Buchwald–Hartwig–Yagupol’skii aryl aminations typically use strong bases to aid the rate-limiting step, creating conditions that functional groups poorly tolerate. In contrast, using mildly basic conditions and PEPPSI™-IPent, a variety of demanding aryl chlorides were successfully coupled to secondary amines. In addition, PEPPSI™-IPent facilitated the coupling of electron-deficient anilines with electron-rich aryl chlorides. In these reactions, the highly reactive PEPPSI™-IPent consistently outperformed PEPPSI™-IPr.^1,4,5

In Stille–Migita cross-couplings of heteroaryl stannanes with aryl halides, PEPPSI™-IPent allowed for lower reaction temperatures below 100 ºC for thermally sensitive cross-coupling partners. Organ and co-workers observed successful coupling within in the range of 30–80 ºC while maintaining consistent yields.^1,6

High temperatures frequently used for carbon-sulfur bond formation were circumvented with PEPPSI™-IPent, featuring mild conditions for the formation of thiol ethers by metal-catalyzed sulfinations. Successful reactions have included the sulfination of (hetero)aryl halides with aryl sulfides, alkyl thiols, and also sterically hindered substrates.^1,7

References

1. Valente C, Çalimsiz S, Hoi KH, Mallik D, Sayah M, Organ MG. 2012. The Development of Bulky Palladium NHC Complexes for the Most-Challenging Cross-Coupling Reactions. Angew. Chem. Int. Ed.. 51(14):3314-3332. https://doi.org/10.1002/anie.201106131

2. Organ MG, Calimisiz S, Sayah M, Hoi K, Lough A. 2009. Angew. Chem. Int. Ed.. 482283–7.

3. Çalimsiz S, Organ MG. 2011. Negishi cross-coupling of secondary alkylzinc halides with aryl/heteroaryl halides using Pd?PEPPSI?IPent. Chem. Commun.. 47(18):5181. https://doi.org/10.1039/c0cc04835f

4. Hoi KH, Çalimsiz S, Froese RDJ, Hopkinson AC, Organ MG. 2011. Amination with Pd?NHC Complexes: Rate and Computational Studies on the Effects of the Oxidative Addition Partner. Chem. Eur. J.. 17(11):3086-3090. https://doi.org/10.1002/chem.201002988

5. Hoi KH, Çalimsiz S, Froese RDJ, Hopkinson AC, Organ MG. 2012. Amination with Pd?NHC Complexes: Rate and Computational Studies Involving Substituted Aniline Substrates. Chem. Eur. J.. 18(1):145-151. https://doi.org/10.1002/chem.201102428

6. Dowlut M, Mallik D, Organ M. 2010. An Efficient Low-Temperature Stille-Migita Cross-Coupling Reaction for Heteroaromatic Compounds by Pd-PEPPSI-IPent. Chem. Eur. J.. 16(14):4279-4283. https://doi.org/10.1002/chem.200903337

7. Sayah M, Organ MG. 2011. Carbon-Sulfur Bond Formation of Challenging Substrates at Low Temperature by Using Pd-PEPPSI-IPent. Chem. Eur. J.. 17(42):11719-11722. https://doi.org/10.1002/chem.201102158