A Series of Analogues to the AT2R Prototype Antagonist C38 Allow Fine Tuning of the Previously Reported Antagonist Binding Mode

We here report on our continued studies of ligands binding to the promising drug target angiotensin II type 2 receptor (AT₂R). Two series of compounds were synthesized and investigated. The first series explored the effects of adding small substituents to the phenyl ring of the known selective nonpeptide AT₂R antagonist C38 , generating small but significant shifts in AT₂R affinity. One compound in the first series was equipotent to C38 and showed similar kinetic solubility, and stability in both human and mouse liver microsomes. The second series was comprised of new bicyclic derivatives, amongst which one ligand exhibited a five-fold improved affinity to AT₂R as compared to C38 . The majority of the compounds in the second series, including the most potent ligand, were inferior to C38 with regard to stability in both human and mouse microsomes. In contrast to our previously reported findings, ligands with shorter carbamate alkyl chains only demonstrated slightly improved stability in microsomes. Based on data presented herein, a more adequate, tentative model of the binding modes of ligand analogues to the prototype AT₂R antagonist C38 is proposed, as deduced from docking redefined by molecular dynamic simulations.     

High-speed heck reactions in ionic liquid with controlled microwave heating

Palladium-catalyzed Heck arylations in the polar and robust ionic liquid, 1-butyl-3-methylimidazolium hexafluorophosphate (bmimPF(6)), have for the first time been accomplished under microwave irradiation. The couplings were efficiently performed in sealed tubes within 5-45 min of heating. Without significant reductions in yield, a phosphine-free ionic catalyst phase could be recycled in five successive 20 min reactions at 180 degrees C. The product was easily removed from the reaction medium by distillation.     

Arylboronic acids as versatile coupling partners in fast microwave promoted oxidative Heck chemistry

The useful and selective reactivity of arylboronic acids makes them favourite building blocks for many modern organic chemistry applications like the metal-mediated formation of C-C, C-O, C-N, and C-S bonds. This report describes oxidative Heck coupling reactions of arylboronic acids and olefins, which were conveniently and rapidly (5-30 min) carried out under air with temperature-controlled microwave heating. Different reaction conditions were investigated with regard to both microwave heating capability and chemical productivity. Copper(II) acetate was identified as a microwave compatible reoxidant of Pd(0). The scope and limitations of this high-speed chemistry protocol with diverse olefins and organoboronic acids are discussed.     

Highly selective palladium-catalyzed synthesis of protected alpha,beta-unsaturated methyl ketones and 2-alkoxy-1,3-butadienes. High-speed chemistry by microwave flash heating

A selective and mild procedure is described for the direct synthesis of 2-alkene-2-methyl-1,3-dioxolanes via regiocontrolled Heck vinylation of commercially available 2-hydroxyethyl vinyl ether. The procedure permits chemoselective transformation of a vinylic triflate or bromide into a blocked alpha,beta-unsaturated methyl ketone. Furthermore, a significantly improved and highly regioselective synthesis of 2-alkoxy-1,3-butadienes has been developed. Flash heating by microwave irradiation promotes the palladium-catalyzed reactions, and the starting materials are fully converted after reaction times of 5-7 min.     

Increasing rates and scope of reactions: sluggish amines in microwave-heated aminocarbonylation reactions under air

Commercially available molybdenum hexacarbonyl serves as a convenient and solid carbon monoxide source in palladium-catalyzed aminocarbonylations of aryl bromides and iodides. This improved microwave protocol, relying on DBU as base and THF as solvent, enables rapid couplings using otherwise sluggish anilines, tert-butylamine, and free amino acids. In addition, Cr(CO)(6) and W(CO)(6) were found to be useful alternative CO-releasing reagents. Altogether, 16 different aromatic amides were synthesized under air in 35-95% yield after only 15 min of controlled microwave irradiation.     

Development of Stereocontrolled Palladium(II)-Catalyzed Domino Heck/Suzuki β,α-Diarylation Reactions with Chelating Vinyl Ethers and Arylboronic Acids

A stereoselective and 1,4-benzoquinone-mediated palladium(II)-catalyzed Heck/Suzuki domino reaction involving metal coordinating cyclic methylamino vinyl ethers and a number of electronically diverse arylboronic acids has been developed and studied. Diastereomeric ratios up to 39:1 and 78 % isolated yields were obtained. The stereoselectivity of the reaction was found to be highly dependent on the nature of the arylboronic acid and the amount of water present in the reaction mixture. Thus, a domino β,α-diarylation–reduction of chelating vinyl ethers can now be accomplished and stereochemically controlled, given that optimized conditions and an appropriate chiral auxiliary are used. To the best of our knowledge, this represents the first example of a stereoselective, oxidative Heck/Suzuki domino reaction in the literature.     

Direct palladium(II)-catalyzed synthesis of arylamidines from aryltrifluoroborates

A fast and convenient synthesis of arylamidines starting from readily available potassium aryltrifluoroborates and cyanamides is reported. The coupling was achieved by Pd(II)-catalysis in a one step 20 min microwave protocol using Pd(O(2)CCF(3)), 6-methyl-2,2'-bipyridyl, TFA, and MeOH, providing the corresponding arylamidines in moderate to excellent yields.     

Palladium-catalyzed carbonylative synthesis of N-cyanobenzamides from aryl iodides/bromides and cyanamide

A novel and convenient protocol for the synthesis of N-cyanobenzamides starting from readily available aryl halides and cyanamide via palladium-catalyzed aminocarbonylation has been developed. The protocol utilizes Mo(CO)₆ as the CO source or CO(gas) and affords the desired N-cyanobenzamides in moderate to good yields.     

Synthesis of Styrenes by Palladium(II)‐Catalyzed Vinylation of Arylboronic Acids and Aryltrifluoroborates by Using Vinyl Acetate

One Heck of a reaction : Treatment of arylboronic acids or aryltrifluoroborates with vinyl acetate by using a palladium(II) catalyst gives the corresponding styrenes (see scheme). No palladium reoxidant is needed and the vinylation is performed under non‐inert conditions