28 research outputs found
Aminocarbonylations Employing Mo(CO)<sub>6</sub> 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)<sub>6</sub> 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)<sub>6</sub>-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