PEPPSI

The aforementioned PEPPSI-IPr pre-catalyst 16 has also been used in the Suzuki-Miyaura reaction. This pre-catalyst allowed the easy preparation of hindered biaryls and drug-like heteroaromatic compounds in good to excellent yields (Scheme 6.27). 

Research is active to produce precatalysts that are stable in air, highly active, well-defined, and possess a broad spectrum of activity. One such precatalyst is complex 68, which consists of Pd complexed with a sterically hindered NHC carbene (Section 10-1-1). Also present is a substituted pyridine ligand (a so-called throw-away ligand). Complex 68 is a member of the PEPPSI (pyridine-enhanced precatalyst preparation, stabilization, and mtitiation) family... 

Pd-PEPPSI-SIMes 29. Pd-PEPPSI-IPent 33. [Pd(IMes)(allyl)CI] 39. [Pd(SIPr)(cln)CI]... 

Scheme 4 Reactivity of Pd-PEPPSI-SIPr (26) and Pd-PEPPSI-IPr (27) in KTC coupling...

Figure 6 Structures of some Pd-PEPPSI complexes used in this study. Rate of formation of 67 by using catalysts 29 ( ), 63 (m), 64 (a.) and PdCI (y control). Conversion was determined by using GC/MS against a calibrated internal standard (undecane)...

Later in 2014, Benhamou et also reported the synthesis of chiral biaryl products using the new bulky chiral PEPPSI pre-catalyst 83 (Figure 10). The combination... 

A year later. Organ et reported the synthesis and characterization of well-defined NHC-Pd pre-catalysts 23,24, and 27. Pd-PEPPSI-IPr (27) was found to be the most active, successfully coupling all combinations of alkyl and aryl centers (i.e., sp —sp sp —sp sp —sp sp2—sp2) (Scheme 28). Since the o-donor abilities of IMes and IPr carbenes are similar, improvements in catalyst performance were attributed to the increased steric bulk around the metal centre. Organohalides (i.e.. Cl, Br, I) and pseudohalides (i.e., triflates, tosylates, mesylates) were used in this study and proved to be excellent oxidative addition partners, all resulting in high yield of the... 

In 2010, Organ and co-workers investigated the activity of Pd-PEPPSI-IPr (27) and Pd-PEPPSI-IPent (29) in the synthesis of di-, tri-, and tetra-ort/io-substituted biaryl and heterobiaryl products. With a few exceptions, 29 was found to be the optimal pre-catalyst system, generating various biaryl and heterobiaryl products possessing a variety of functional groups and/or orf/io-substituents (Scheme 29). In particular, a number of tetra-ort/jo-substituted biaryl compounds were synthesized in excellent... 

Unfortunately, despite the good yields on small scale, scale-up proved challenging due to the water sensitivity of the vinyl aluminum and vinyl Zn species. In addition, we were not able to reduce the catalyst load below 3 mole% of the PEPPSI catalyst making the cost of the catalyst a significant percentage of the cost of the API. So once more, an elegant reaction in the laboratory does not appear to be commercially viable. 

The PEPPSI (pyridine-enhanced, precatalyst, preparation, stabilization and initiation) precatalyst 20 is a very versatile catalyst for Kumada couphngs of highly hindered substrates and heterocycles at ambient temperature (Equation 2.64) [106]. 

Orfho-disubstituted aryl iodides as representative examples of sterically hindered substrates are more challenging in palladium-catalyzed coupling reactions. In this respect it is interesting to note that Martin et al. reported a synthesis of sterically hindered aryl ketones by using the NHC palladium complex PEPPSI-iPr [34]. Several diaryl ketones were produced in moderate to good yields by this method (Scheme 4.18). 

It has been found that the reaction at the C-Br or the C-Cl bond of l-bromo-4-chlorobutane can be controlled by changing the solvent for the reaction. For instance, the regiospeciflcity at the C-Br bond in the S 2 alkylation reaction with RZnBr in the presence of a Pd-PEPPSI-/-Pr catalyst when the DMI/THF ratio is 1/2 is 12.2 1 or 92%. DMI is dimethylimidazolidinone with an e = 37.6, whereas THF has an e = 7.5. However, when the DMI/THF = 2/1, the reaction occurs at the C—Cl bond. This means that the two reactions can be performed in one pot that is, one RZnBr reagent is used to displace bromine and, when this reaction is complete, the solvent composition is changed and a different RZnBr reagent is used to displace chlorine. Both reactions occur at room temperature, with yields of 70%. 

B,4 )-isomer 1 was shown to be at least 10 by using 0.001 mol% of PEPPSI (Pyridine-Enhanced Precatalyst Preparation Stabilization and Initiation) [105]. 

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