The in situ formed ruthenium catalytic system ([Ru]/L) was found to be highly selective for the dehydrogenative coupling reaction of 2-aminophenyl ketones with amines to form quinazoline products. The deaminative coupling reaction of 2-aminobenzamides with amines led to the efficient formation of quinazolinone products. The catalytic coupling method provides an efficient synthesis of quinazoline and quinazolinone derivatives without using any reactive reagents or forming any toxic byproducts. Quinazolines and quinazolinones are a privileged class of nitrogen heterocyclic scaffolds that have been found to exhibit a broad spectrum of pharmacological activities, including anti-inflammatory, antitubercular, and antiviral activities.(1) A number of quinazoline-based drugs such as prazocin and doxazosine have been approved to treat benign prostatic hyperplasia and post-traumatic stress disorder,(2) while both erlotinib and gefitinib have been used for the treatment of lung and pancreatic cancers (Figure 1).(3) Lapatinib, as an inhibitor for epidermal growth factor, has been shown to be effective in combination therapy for breast cancer.(4) Several quinazolinone-based drugs including idelalisib and fenquizone have been shown to exhibit a broad spectrum of antimicrobial, antitumor, antifungal, and cytotoxic activities.(5)
The catalytic system generated in-situ from the tetranuclear Ru–H complex with a catechol ligand (1/L1) was found to be effective for the direct deaminative coupling of two primary amines to form secondary amines. The catalyst 1/L1 was highly chemoselective for promoting the coupling of two different primary amines to afford unsymmetric secondary amines. The analogous coupling of aniline with primary amines formed aryl-substituted secondary amines. The treatment of aniline-d7 with 4-methoxybenzylamine led to the coupling product with significant deuterium incorporation on CH2 (18% D). The most pronounced carbon isotope effect was observed on the α-carbon of the product isolated from the coupling reaction of 4-methoxybenzylamine (C(1) = 1.015(2)). Hammett plot was constructed from measuring the rates of the coupling reaction of 4-methoxyaniline with a series of para-substituted benzylamines 4-X-C6H4CH2NH2 (X = OMe, Me, H, F, CF3). (ρ = −0.79 ± 0.1). A plausible mechanistic scheme has been proposed for the coupling reaction on the basis of these results. The catalytic coupling method provides an operationally simple and chemoselective synthesis of secondary amine products without using any reactive reagents or forming wasteful byproducts.
The
cationic Ru–H complex [(C6H6)(PCy3)(CO)RuH]+BF4
– (1) with 3,4,5,6-tetrachloro-1,2-benzoquinone (L1) was found to be a highly effective catalyst for the deaminative
coupling reaction of 2′-hydroxyaryl ketones with simple amines
to form 3-substituted flavanone products. The analogous deaminative
coupling reaction of 2-aminobenzamides with branched amines directly
formed 3,3-disubstituted quinazolinone products. The catalytic method
efficiently installs synthetically useful flavanone and quinazolinone
core structures without employing any reactive reagents.
The catalytic system formed in situ from the reaction of a cationic Ru−H complex with 3,4,5,6-tetrachloro-1,2-benzoquinone was found to mediate a regioselective deaminative coupling reaction of ketones with amines to form the α-alkylated ketone products. Both benzylic and aliphatic primary amines were found to be suitable substrates for the coupling reaction with ketones in forming the α-alkylated ketone products. The coupling reaction of PhCOCD 3 with 4-methoxybenzylamine showed an extensive H/D exchange on both α-CH 2 (41% D) and β-CH 2 (21%) positions on the alkylation product. The Hammett plot obtained from the reaction of acetophenone with para-substituted benzylamines p-X-C 6 H 4 CH 2 NH 2 (X = OMe, Me, H, F, Cl, CF 3 ) showed a strong promotional effect by the amine substrates with electron-releasing groups (ρ = −0.49 ± 0.1). The most significant carbon isotope effect was observed on the α-carbon of the alkylation product (C α = 1.020) from the coupling reaction of acetophenone with 4-methoxybenzylamine. The kinetics of the alkylation reaction from an isolated imine substrate led to the empirical rate law: rate = k[Ru][imine]. A catalytically active Ru−catecholate complex was synthesized from the reaction of the cationic Ru−H complex with 3,5-di-tert-butyl-1,2-benzoquinone and PCy 3 . The DFT computational study was performed on the alkylation reaction, which revealed a stepwise mechanism of the [1,3]-carbon migration step via the formation of a Ru(IV)-alkyl species with a moderate energy of activation (ΔG ‡ = 32−42 kcal/mol). A plausible mechanism of the catalytic alkylation reaction via an intramolecular [1,3]-alkyl migration of an Ru-enamine intermediate has been compiled on the basis of these experimental and computational data.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.