Isolation and Characterization of Regioisomers of Pyrazole-Based Palladacycles and Their Use in α-Alkylation of Ketones Using Alcohols

Abstract

Regioisomers of 3,5-diphenyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrazole-based palladacycles (1 and 2) were synthesized by the aromatic C−H bond activation of N/3-aryl ring. The application of these regioisomers as catalysts to enable the formation of α-alkylated ketones or quinolines with alcohols using a hydrogen borrowing process is evaluated. Experimental results reveal that palladacycle 2 is superior over palladacycle 1 to catalyze the reaction under similar reaction conditions. The reaction mechanisms for the palladacycles 1 and 2 catalyzed α-alkylation of acetophenone were studied using density functional theoretical (DFT) methods. The DFT studies indicate that palladacycle 2 has an energy barrier lower than that of palladacycle 1 for the alkylation reaction, consistent with the better catalytic activity of palladacycle 2 seen in the experiments. The palladacycle−phosphine system was found to tolerate a wide range of functional groups and serves as an efficient protocol for the synthesis of α-alkylated products under solvent-free conditions. In addition, the synthetic protocol was successfully applied to prepare donepezil, a drug for Alzheimer's disease, from simple starting materials.

Palladium on carbon-catalyzed α-alkylation of ketones with alcohols as electrophiles: Scope and mechanism

“…With regard to the nature of the hydrogen-borrowing catalysis, there are two possibilities: 1) heterogeneous catalysis by palladium nanoparticles or 2) leaching of catalytically active homogeneous species. [45,46] To distinguish between these possibilities, a hot filtration experiment was performed (Scheme 1). In the experiment, inhibition of the catalytic activity occurred when the solid catalyst was removed from the reaction mixture despite the addition of fresh K3PO4 (1.5 equiv).…”

Ruthenium-Catalyzed β-Alkylation of Secondary Alcohols and α-Alkylation of Ketones via Borrowing Hydrogen: Dramatic Influence of the Pendant N-Heterocycle

“…The borrowing hydrogen methodology, also called hydrogen autotransfer, has been developed rapidly in recent years, because it is regarded as an environmentally friendly and an atom-ecomonic tactic. , For example, many β-alkylated secondary alcohols and α-alkylated ketones were synthesized by following this strategy, and H 2 O was the only byproduct. − Direct β-alkylation of secondary alcohols with primary alcohols has been applied under ruthenium, , iridium, palladium, copper, manganese, and cobalt catalysis or under transition metal-free conditions . Similarly, various catalysts were also applicable for α-alkylation of ketones with primary alcohols. ,,− Currently, ruthenium complex A containing 6,6′-dihydroxy-2,2′-bipyridine is the most effective catalyst for β-alkylation of secondary alcohols, which was reported by Kundu et al, showing TOFs up to 797.6 h –1 (Figure , A ) . While for α-alkylation of ketones, the most active catalyst is an iridium N -heterocyclic carbene complex developed by Gülcemal’s group, revealing TOF values up to 970 h –1 (Figure , B )…”

Nickel‐catalyzed α‐alkylation of ketones with benzyl alcohols

“…[ 3 ] The alkylation reaction of ketones is environmentally friendly process by using the hydrogen borrowing strategy result in high atom economy. In previous studies, the α‐alkylation of ketone with alcohols was well developed with noble‐metal catalysts, such as Ir, [ 4 ] Pd, [ 5 ] Rh, [ 6 ] and Ru [ 7 ] complexes (Scheme 1a). Despite substantial progress was achieved in precious metal catalysis, utilizing earth‐abundant, inexpensive, and nonprecious transition‐metal catalysts in α‐alkylation of ketone with alcohols is a long‐term goal and challenge.…”