PEPPSI catalyst

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. 

Scheme 4.35 Pd-catalyzed cross-coupling of arylzinc reagents in the presence of PEPPSI catalysts [138].

The carbonylative coupling of an alkynyl zinc reagent 4.18 with a highly substituted, electron-rich aryl iodide 4.17 was used in a short synthesis of luteolin 4.20, a flavanoid natural product (Scheme 4.11). After the coupling, employing the PEPPSI catalyst, selective crr/tc-deprotection and 6-endo cyclization yielded the natural product."... 

Figure 1.35 The application of Pd-PEPPSI catalysts developed by Organ et af. [54,116].

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). 

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... 

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]. 

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%. 

Much recent attention has been paid to the development of new ligand systems providing enhanced reactivity. As for nickel, catalytic systems of interest can be obtained with bulky NHC ligands. The family of PEPPSI (pyridine-enhanced precatalyst, preparation, stabilization, and initiation) precatalysts is well suited for crowded or poorly reactive electrophiles such as aromatic chlorides 67 (Scheme 5.12) [53]. As illustrated with the formation of 69 from biaryhnagnesium bromide 68, in the presence of PEPPSI-IPr (70) (2 mol%), reactions take place with high yields at room temperature in THF. It has been proposed that the pyridine attaches to and detaches from the Pd(0) complex in solution and therefore slows down the rate of palladium black formation and deactivation of the catalyst... 

Palladium complexes of monophosphine hgands such as PCyj or NHC ligands (PEPPSI-IPr catalyst 70) are efficient catalysts for the more challenging alkylations... 

Navarro and coworkers reported the synthesis of (NHC)PdCl2(TEA) (TEA = triethylamine) complexes 6 [12]. These complexes exhibited higher activity at lower temperature than the PEPPSI analogs. It was proposed that this increased activity resulted from either an easier departure of the throw away ligand, a higher tendency for TEA to recoordinate to the Pd° species, prolonging the life of the active catalyst in solution, or a combination of the two. 

Further invention of pyridine-enhanced precatalyst preparation stabilization and initiation (PEPPSI) ligands has led to a remarkable improvement in palladium-catalyzed C—S coupling [159, 160]. This catalyst effectively couples the less reactive aryl chlorides even at room tempauture [161]. Recently, NHC-based catalyst, [Pd(IPr )(cin)Cl] 18, has been developed for the coupling of aryl halides with aliphatic or aromatic thiols (Scheme 20.53) [162]. 

Figure 1.38 (a) The PEPPSI-type-triazol-5-ylidene Pd catalyst reported by Huang et al. [121], (b) by Azua et al. under ultrasound conditions in glycerol [122], and (c) the 4-hydroxyacetophenone oxime-derived pal-ladacycle reported by Alacid and Najera [123]. 

In 2013, Feringa s group [182] reported the application of hindered aryllithium reagents as substrates (or intermediates) in palladium-catalyzed cross-coupling, this in fact allowed access to tri- and tetra-ortfio-substituted products. This group used the Pd-PEPPSI-IPent catalyst for this transformation. 

In a 2013 paper. Organ s group [23] reported another PEPPSI-type catalyst with two chlorines in the backbone (Figure 2.3). This catalyst performed very well in the arylation of monosubstituted and... 

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