Buchwald catalysts of C–C and C–N cross-coupling reactions are widely used in modern organic chemistry to synthesize compounds for medicinal and agrochemistry. The catalysts of this type developed up to date can be classified into several generations, which differ by the structure of the palladocycle and the nature of the anion. In particular, the G3, G4 and G5 pre-catalysts contain the fragments of 2-aminobiphenyl, N-methyl-2-aminobiphenyl and N-phenyl-2-aminobiphenyl, respectively, and form carbazole, N-methylcarbazole and N-phenylcarbazole upon activation. Despite the large number of publications dealing with these catalysts, information allowing to perform a comparison of their catalytic activity is scarce, and proper selection of the most efficient catalyst for certain reactions often requires much effort.
In this study, the catalytic activity of RuPhos G3, G4 and G5 in N-arylation of morpholine by 1-chloro-4-fluorobenzene (Figure 1) was evaluated by the dependency of product yield on time. The composition of the reaction mixture was monitored by ¹⁹F NMR. While (RuPhos)Pd G3 was almost not active in this reaction (product yield ca. 3%), the use of (RuPhos)Pd G5 led to 40% conversion of 1-chloro-4-fluorobenzene to 4-(4-fluorophenyl)morpholine (27% yield; fluorobenzene was the by-product). (RuPhos)Pd G4 was the most active in this series of catalysts. Its use led to 81% conversion of 1-chloro-4-fluorobenzene (the yield of C-N coupling product was 55%). Termination of the reaction at achieving 55% and 27% yields in the case of G4 and G5 catalysts was caused by their deactivation. The addition of new portions of pre-catalysts to the reaction mixtures led to recommencement of the product formation.
The difference between the studied G3, G4 and G5 catalysts can include deactivation of the catalytically active Pd0(Phos) species because of the coordination of carbazole in the G3 system, and different efficiency of Pd0(Phos) formation in the process of the pre-catalyst activation. All these reasons will be discussed in the presentation.

Figure 1. Reaction of morpholine and 1-chloro-4-fluorobenzene C-N coupling at the presence of Buchwald catalysts

Artem Mishchenko

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