Diastereoselective palladium-catalyzed C(sp3)-H cyanomethylation of amino acid and carboxylic acid derivatives.

In this study, we report an efficient protocol for Pd-catalyzed methylene ß-C(sp3)-H cyanomethylation of 8-aminoquinoline-directed α-amino acids using inexpensive chloroacetonitrile. Iodoacetonitrile generated in situ from chloroacetonitrile reacts with methylene C(sp3)-H bonds of α-amino acids with excellent diastereoselectivity, enabling access to a wide range of important γ-cyano-α-amino acids. Our protocol works well with different amino acid and carboxylic acid derivatives with good chemical yields and high functional group tolerance.

Reactivity vs. selectivity of quinone methides: synthesis of pharmaceutically important molecules, toxicity and biological applications.

Quinone methides (QMs) are considered to be highly reactive intermediates because of their aromatization both in chemical and biological systems. Being highly accessible, quinone methides (QMs) have been widely exploited and their concurrent use has been manifested for the synthesis of tertiary and quaternary carbon centers of bioactives, drugs and drug-like molecules. In this feature article, the synthetic routes, structure-reactivity relationships and synthetic applications of quinone methides are discussed. Formation of the intermediates during bioactivation of different chemical entities and possible chemical manifestations leading to their toxicity in biological systems are also covered.

Synthesis and Antimalarial Activity of 4-Methylaminoquinoline Compounds against Drug-Resistant Parasite.

A series of novel 4-aminoquinoline analogues bearing a methyl group at 4-aminoquinoline moiety were synthesized via a new and robust synthetic route comprising in situ tert-butoxycarbonyl (Boc) deprotection-methylation cascade resulting in the corresponding N-methylated secondary amine using Red-Al and an efficient microwave-assisted strategy for the fusion of N-methylated secondary amine with 4-chloroquinoline nucleus to access the series of novel 4-N-methylaminoquinoline analogues. The new series of compounds were evaluated for their antimalarial activity in in vitro and in vivo models. Among 21 tested compounds, 9a-i have shown a half-maximal inhibitory concentration (IC50) value less than 0.5 µM (i.e., <500 nM) against both chloroquine-sensitive strain 3D7 and chloroquine-resistant strain K1 of Plasmodium falciparum with acceptable cytotoxicity. Based on the in vitro antimalarial activity, selected compounds were screened for their in vivo antimalarial activity against Plasmodium yoelii nigeriensis (a multidrug-resistant) parasite in Swiss mice. Most of the compounds have shown significant inhibition on day 4 post infection at the oral dose of 100 mg/kg. Compound 9a has shown 100% parasite inhibition on day 4, and out of five treated mice, two were cured till the end of the experiment. The present study suggests that 4-methylamino substitution is well tolerated for the antiplasmodial activity with reduced toxicity and therefore will be highly useful for the discovery of a new antimalarial agent against drug-resistant malaria.

Regioselective ß-Csp3-Arylation of ß-Alanine: An Approach for the Exclusive Synthesis of Diverse ß-Aryl-ß-amino Acids.

An approach for the synthesis of a variety of new ß-aryl-ß-amino acids has been developed via a palladium-catalyzed auxiliary-directed regioselective Csp3-H arylation of the unactivated ß-methylene bond of ß-alanine. The use of 8-aminoquinoline amide as an auxiliary efficiently directs the desired regioselective ß-Csp3-H functionalization. The developed protocol enables the easy and straightforward access to several high-value ß-aryl-ß-amino acids useful for peptide engineering, starting from inexpensive and readily available ß-alanine precursors in moderate to excellent yields.

Regioselective synthesis of dihydrothiophene and thiopyran frameworks via catalyst-controlled intramolecular Cγ/Cδ-S fusion of α-allyl-ß'-oxodithioesters.

A highly efficient and atom-economic dual reaction manifold has been developed to synthesize 4H-thiopyran and 4,5-dihydrothiophene frameworks via regioselective intramolecular C-S fusion of α-allyl-ß'-oxodithioesters. The ring size of the sulfur-heterocycles has been efficiently tuned by the use of two different catalytic systems. Palladium activates the Cδ-H of the allyl termini and facilitates the intramolecular Cδ-S coupling to furnish six-membered thiopyran skeletons exclusively. Conversely, the allylic double bond of the same substrate has been activated by BF3·Et2O to promote the Cγ-S cyclization leading to the formation of a five-membered dihydrothiophene nucleus.

Lewis acid promoted construction of chromen-4-one and isoflavone scaffolds via regio- and chemoselective domino Friedel-Crafts acylation/Allan-Robinson reaction.

A facile and efficient synthesis of chromen-4-one and isoflavone frameworks is achieved by the domino C-acylation/O-acylation/aldolization sequence. This operationally simple one-pot elegant strategy provides structurally unique chromen-4-ones and isoflavones directly from phenols via concomitant formation of multiple C-C and C-O bonds in a single operation. The outcomes of the buttressing effect, substituent dependence, and catalyst and solvent specificity during the course of the Friedel-Crafts acylation reactions are demonstrated and supported by fitting experiments.

Palladium catalyzed oxidative coupling of α-enolic dithioesters: a new entry to 3,4,5-trisubstituted 1,2-dithioles via a double activation strategy.

An operationally simple, facile, and convenient one-pot straightforward method for the construction of 3,4,5-trisubstituted 1,2-dithioles has been explored and developed via palladium catalyzed self-coupling of α-enolic dithioesters for the first time. Pd(0) efficiently catalyzes the activation and cleavage of S-H and C-S bonds to achieve cascade coupling, which results in the concomitant formation of new S-S and C-C bonds. Optimization data, substrate scope, and mechanistic insights are discussed.

Regioselective synthesis of tetrahydrothiochromen-5-ones via a one-pot three-component solvent-free domino protocol.

A highly efficient one-pot three-component regioselective synthesis of 4-aryl-3-aroyl-2-methylsulfanyl-4,6,7,8-tetrahydrothiochromen-5-ones has been developed by annulation of ß-oxodithioesters with aldehydes and cyclic 1,3-diketones under solvent-free conditions promoted by P(2)O(5). No cocatalyst or activator is needed in this protocol. The merit of this process is highlighted by its high efficiency of producing three new bonds and a stereocenter in one operation.