Aminocarbonylations Employing Mo(CO)₆ and a Bridged Two-Vial System: Allowing the Use of Nitro Group Substituted Aryl Iodides and Aryl Bromides

A bridged two-vial system aminocarbonylation protocol where Mo­(CO)₆ functions as an external <i>in situ</i> solid source of CO has been developed. For the first time both nitro group containing aryl/heteroaryl iodides and bromides gave good to excellent yields in the Mo­(CO)₆-mediated and palladium(0)-catalyzed conversion to benzamides, while the identical one-vessel protocol afforded extensive reduction of the nitro functionality. The above-mentioned bridged two-compartment protocol furnished good results with both primary amines and secondary amines and sluggish aniline nucleophiles at 65–85 °C reaction temperatures

Microwave Heated Continuous Flow Palladium(II)-Catalyzed Desulfitative Synthesis of Aryl Ketones

A protocol for Pd­(II)-catalyzed desulfitative synthesis of aryl ketones from sodium aryl sulfinates and nitriles in continuous flow has been developed. The reactions proceed with microwave heating using microwave transparent tube reactors, affording the desired aryl ketones in fair to good yields. Microwave transparent aluminum oxide reactors were identified as a safe and thermostable alternative to borosilicate glass reactors

Palladium(0)-Catalyzed Carbonylative One-Pot Synthesis of N‑Acylguanidines

A convenient synthetic strategy toward <i>N</i>-acylguanidines via a sequential one-pot multicomponent carbonylation/amination reaction has been developed. The compounds were readily obtained via an <i>N</i>-cyanobenzamide intermediate formed from the Pd(0)-catalyzed carbonylative coupling of cyanamide and aryl iodides or bromides. Subsequent amination with a large variety of amines provided the final <i>N</i>-acylguanidines, with the overall formation of one C–C and two C–N bonds, in moderate to excellent yields. The substrate scope was found to be wide and the methodology was used to produce over 50 compounds, including 29 novel molecules. Furthermore, three separate nitrogen-containing heterocycles were prepared from the <i>N</i>-acylguanidines synthesized using the developed multicomponent, carbonylative method

Virtual Screening for Transition State Analogue Inhibitors of IRAP Based on Quantum Mechanically Derived Reaction Coordinates

Transition state and high energy intermediate mimetics have the potential to be very potent enzyme inhibitors. In this study, a model of peptide hydrolysis in the active site of insulin-regulated aminopeptidase (IRAP) was developed using density functional theory calculations and the cluster approach. The 3D structure models of the reaction coordinates were used for virtual screening to obtain new chemical starting points for IRAP inhibitors. This mechanism-based virtual screening process managed to identify several known peptidase inhibitors from a library of over 5 million compounds, and biological testing identified one compound not previously reported as an IRAP inhibitor. This novel methodology for virtual screening is a promising approach to identify new inhibitors mimicking key transition states or intermediates of an enzymatic reaction

Microwave Promoted Transcarbamylation Reaction of Sulfonylcarbamates under Continuous-Flow Conditions

Successful conditions for the transcarbamylation/transesterification reaction of sulfonylcarbamates with alcohols by microwave heating under continuous-flow conditions were developed. After optimization of the processes, two series of <i>O</i>-alkylsulfonylcarbamates were obtained in high yields and purities using microwave transparent borosilicate tube reactors. In order to also illustrate the usefulness of the protocol in a medicinal chemistry context, the methodology was used for the synthesis of three angiotensin II type 2 receptor ligands

Continuous Flow Synthesis under High-Temperature/High-Pressure Conditions Using a Resistively Heated Flow Reactor

A cheap, easy-to-build, and effective resistively heated reactor for continuous flow synthesis at high temperature and pressure is herein presented. The reactor is rapidly heated directly using an electric current and is capable of rapidly delivering temperatures and pressures up to 400 °C and 200 bar, respectively. High-temperature and high-pressure applications of this reactor were safely performed and demonstrated by selected transformations such as esterifications, transesterifications, and direct carboxylic acid to nitrile reactions using supercritical ethanol, methanol, and acetonitrile. Reaction temperatures were between 300 and 400 °C with excellent conversions and good to excellent isolated product yields. Examples of Diels–Alder reactions were also carried out at temperatures up to 300 °C in high yield. No additives or catalysts were used in the reactions

One-Pot, Two-Step, Microwave-Assisted Palladium-Catalyzed Conversion of Aryl Alcohols to Aryl Fluorides via Aryl Nonaflates

A convenient procedure for converting aryl alcohols to aryl fluorides via aryl nonafluorobutylsulfonates (ArONf) is presented. Moderate to good one-pot, two-step yields were achieved by this nonaflation and microwave-assisted, palladium-catalyzed fluorination sequence. The reductive elimination step was investigated by DFT calculations to compare fluorination with chlorination, proving a larger thermodynamic driving force for the aryl fluoride product. Finally, a key aryl fluoride intermediate for the synthesis of a potent HCV NS3 protease inhibitor was smoothly prepared with the novel protocol

Synthesis of 4‑Quinolones via a Carbonylative Sonogashira Cross-Coupling Using Molybdenum Hexacarbonyl as a CO Source

A palladium-catalyzed CO gas-free carbonylative Sonogashira/cyclization sequence for the preparation of functionalized 4-quinolones from 2-iodoanilines and alkynes via two different protocols is described. The first method (A) yields the cyclized products after only 20 min of microwave (MW) heating at 120 °C. The second method (B) is a gas-free one-pot two-step sequence which runs at room temperature, allowing the use of sensitive substituents (e.g., nitro and bromide groups). For both protocols, molybdenum hexacarbonyl was used as a solid source of CO

Regio- and Stereoselective Synthesis of Functionalized Cyclopentene Derivatives via Mizoroki–Heck Reactions

Pd­(0)-catalyzed Mizoroki–Heck alkenylations and arylations of protected aminocyclopentenes, prepared in a few steps from Vince lactam, afforded functionalized cyclopentenes in high yields and stereoselectivities. DFT calculations were performed to rationalize the high diastereoselectivities. Functionalized cyclopentene products were transformed into valuable chiral building blocks, such as cyclic γ-amino acids and carbocyclic nucleoside precursors

Theoretical and Experimental Investigation of Palladium(II)-Catalyzed Decarboxylative Addition of Arenecarboxylic Acid to Nitrile

The reaction mechanism of palladium­(II)-catalyzed decarboxylative addition of 2,6-dimethoxybenzoic acid to acetonitrile was investigated by means of density functional theory (DFT) calculations. Calculations of the free energy profile for decarboxylation and carbopalladation indicated carbopalladation as the rate-determining step of the reaction. Investigation of the free energy profile for a series of experimentally evaluated nitrogen-based bidentate palladium ligands revealed that higher energy is required for decarboxylation and carbopalladation employing the experimentally least efficient ligand. The DFT investigation also showed that the relative free energies of the transition states were lowered in polar solvent, and preparative experiments confirmed that a nonoptimal ligand could be greatly improved by addition of water to the reaction system