14 research outputs found
Direct Preparation of Nitriles from Carboxylic Acids in Continuous Flow
A continuous-flow
protocol for the preparation of organic nitriles
from carboxylic acids has been developed. The method is based on the
acidânitrile exchange reaction with acetonitrile, used as the
solvent, and takes place without any catalyst or additives under the
high-temperature/high-pressure conditions employed. At 350 °C
and 65 bar, where acetonitrile is in its supercritical state, the
transformation of benzoic acid to benzonitrile requires 25 min. The
protocol has been tested for a variety of nitriles, including aromatic
and aliphatic substrates
An Experimental and Computational Assessment of Acid-Catalyzed Azide-Nitrile Cycloadditions
The mechanism of the azideânitrile cycloaddition
mediated
by different Brønsted and Lewis acids has been addressed through
DFT calculations. In all cases activation of the nitrile substrate
by the Brønsted or Lewis acid catalyst was found to be responsible
for the rate enhancement. According to DFT calculations the cycloaddition
proceeds in a stepwise fashion involving the initial formation of
an open-chain imidoyl azide intermediate. Kinetic experiments performed
using <i>N</i>-methyl-2-pyrrolidone as solvent and sodium
azide as azide source demonstrate that all evaluated Brønsted
acids have the same efficiency toward cycloaddition with benzonitrile,
suggesting that hydrazoic acid is the actual dominant catalytic species
in these tetrazole syntheses. Lewis acids such as Zn or Al salts perform
in a similar manner, activating the nitrile moiety and leading to
an open-chain intermediate that subsequently cyclizes to produce the
tetrazole nucleus. The most efficient catalyst evaluated was 5-azido-1-methyl-3,4-dihydro-2<i>H</i>-pyrrolium azide, which can readily be generated in situ
from aluminum chloride, sodium azide in <i>N</i>-methyl-2-pyrrolidone.
The efficiency of this catalyst has been examined by preparation of
a series of 5-substituted-1<i>H</i>-tetrazoles. The desired
tetrazole structures were obtained in high yields within 3â10
min employing controlled microwave heating
Flash Flow Pyrolysis: Mimicking Flash Vacuum Pyrolysis in a High-Temperature/High-Pressure Liquid-Phase Microreactor Environment
Flash vacuum pyrolysis (FVP) is a gas-phase continuous-flow
technique
where a substrate is sublimed through a hot quartz tube under high
vacuum at temperatures of 400â1100 °C. Thermal activation
occurs mainly by moleculeâwall collisions with contact times
in the region of milliseconds. As a preparative method, FVP is used
mainly to induce intramolecular high-temperature transformations leading
to products that cannot easily be obtained by other methods. It is
demonstrated herein that liquid-phase high-temperature/high-pressure
(high-T/p) microreactor conditions (160â350 °C, 90â180
bar) employing near- or supercritical fluids as reaction media can
mimic the results obtained using preparative gas-phase FVP protocols.
The high-T/p liquid-phase âflash flow pyrolysisâ (FFP)
technique was applied to the thermolysis of Meldrumâs acid
derivatives, pyrrole-2,3-diones, and pyrrole-2-carboxylic esters,
producing the expected target heterocycles in high yields with residence
times between 10 s and 10 min. The exact control over flow rate (and
thus residence time) using the liquid-phase FFP method allows a tuning
of reaction selectivities not easily achievable using FVP. Since the
solution-phase FFP method does not require the substrate to be volatile
any more î¸a major limitation in classical FVPî¸the transformations
become readily scalable, allowing higher productivities and spaceâtime
yields compared with gas-phase protocols. Differential scanning calorimetry
measurements and extensive DFT calculations provided essential information
on pyrolysis energy barriers and the involved reaction mechanisms.
A correlation between computed activation energies and experimental
gas-phase FVP (moleculeâwall collisions) and liquid-phase FFP
(moleculeâmolecule collisions) pyrolysis temperatures was derived
Hydrazine-mediated Reduction of Nitro and Azide Functionalities Catalyzed by Highly Active and Reusable Magnetic Iron Oxide Nanocrystals
Iron
oxide (Fe<sub>3</sub>O<sub>4</sub>) nanocrystals generated <i>in situ</i> from an inexpensive and readily available iron source
catalyze the reduction of nitroarenes to anilines with unparalleled
efficiency. The procedure is chemoselective, avoids the use of precious
metals, and can be applied under mild reflux conditions (65 or 80
°C) or using sealed vessel microwave heating in an elevated temperature
regime (150 °C). Utilizing microwave conditions, a variety of
functionalized anilines have been prepared in nearly quantitative
yields within 2â8 min at 150 °C, in a procedure also successfully
applied to the reduction of aliphatic nitro compounds and azides.
The iron oxide nanoparticles are generated in a colloidal form, resulting
in homogeneous solutions suitable for continuous flow processing.
Selected examples of anilines of industrial importance have been prepared
in a continuous regime using this protocol
Continuous Flow Synthesis of a Key 1,4-Benzoxazinone Intermediate via a Nitration/Hydrogenation/Cyclization Sequence
The
preparation of a functionalized 4H-benzo-[1,4]-oxazin-3-one
was completed via a three-step nitration/hydrogenation/cyclization
sequence. The unstable nature of the nitro and amino intermediates,
in addition to the hazards associated with the nitration of organic
compounds in general, makes this procedure exceedingly difficult to
perform on industrial scale. To overcome these limitations, we have
developed a fully integrated continuous protocol in which the aromatic
starting material (2,2-difluoro-2-(3-fluorophenoxy)-<i>N</i>,<i>N</i>-dimethylacetamide) is subjected to an initial
continuous flow dinitration using 20% oleum in combination with 100%
HNO<sub>3</sub> (2.5 equiv) using a microstructured device heated
to 60 °C. This was followed directly by continuous flow hydrogenation
of the dinitrointermediate over a Pd/C fixed bed catalyst at 45 °C.
The resulting air-sensitive diamino derivative was then directly cyclized
to the desired 6-amino-2,2,7-trifluoro-4H-benzo-[1,4]-oxazin-3-one
target compound via an acid-catalyzed cyclization step at 80 °C
using a tubular reactor. Uninterrupted continuous flow processing
was achieved by integrating liquidâliquid membrane separation
technology and the inline removal of excess of hydrogen gas using
gas permeable tubing into the process. The overall product yield for
the continuous flow process was 83%, a significant increase compared
to yield reported for the batch process (67%)
Benchmarking Immobilized Di- and Triarylphosphine Palladium Catalysts for Continuous-Flow Cross-Coupling Reactions: Efficiency, Durability, and Metal Leaching Studies
Leaching resistance and recyclability,
in addition to efficiency,
are key parameters which constrain the choice of a catalyst for performing
metal-catalyzed cross-coupling reactions in continuous-flow mode.
Comparison of commercially available immobilized catalysts is often
difficult because literature data are typically obtained under a wide
range of reaction conditions. Here we present a comparative investigation
on some of the most common immobilized phosphine-based Pd catalysts,
namely Pd Tetrakis (polymer bound), FiberCat 1001, EnCat TPP30, and
SiliaCat DPP-Pd. The efficiency, recyclability, and leaching resistance
of each of the catalysts has been carefully investigated under a standard
set of conditions as well as a selection of literature-based protocols.
The data presented herein enable a direct comparison of these catalysts
and provide further insights into the leaching phenomena of these
types of ligand-based palladium catalysts
Scaling-up Electroorganic Synthesis Using a Spinning Electrode Electrochemical Reactor in Batch and Flow Mode
Technology for the rapid scale-up of synthetic organic
electrochemistry
from milligrams to multigrams or multi-100 g quantities is highly
desirable. Traditional parallel plate flow electrolysis cells can
produce large quantities of material, but transfer from batch to this
flow technology requires reoptimization of the reaction conditions
and fully homogeneous reaction mixtures. Moreover, single-pass processing
is often difficult to accomplish due to gas generation and the low
flow rates typically used in continuous mode. Herein we present a
novel reactor design, based on a rotating cylinder electrode concept,
that enables seamless scale up from small scale batch experimentation
to gram and even multikilogram per day quantities. The device can
operate in batch and flow mode, and it is able to easily process slurries
without clogging of the system or fouling of the electrodes. Continuous
operation is also demonstrated using three reactors in series that
act as a continuous stirred electrochemical reactor cascade, providing
kilogram per day productivities in a single pass
Process Intensification and Integration Studies for the Generation of a Key Aminoimidazole Intermediate in the Synthesis of Lanabecestat
An improved synthetic procedure for
the multistep synthesis of
aminoimidazole <b>6</b>, a key intermediate in the preparation
of lanabecestat (AZD3293/LY3314814), is described. Under intensified
conditions (high temperature and elevated pressure), the overall processing
time and required amounts of reagents could be significantly reduced,
thus potentially minimizing manufacturing costs and improving the
sustainability footprint. Process integration of three sequential
steps starting from ketone intermediate <b>2</b> has been attempted
to set the stage for a potential multistep continuous manufacturing
route. The process consists of initial formation of imine <b>3</b> by treatment of ketone <b>2</b> with ammonia and TiÂ(<i>i</i>PrO)<sub>4</sub>, cyclocondensation of <b>3</b> with
thioamide <b>4</b> to form thiol <b>5</b>, and aminolysis
using ammonia and ZnÂ(OAc)<sub>2</sub>, allowing the target building
block <b>6</b> to be accessed in 47% overall yield
Continuous Flow ÎąâTrifluoromethylation of Ketones by Metal-Free Visible Light Photoredox Catalysis
A continuous-flow,
two-step procedure for the preparation of Îą-CF<sub>3</sub>-substituted
carbonyl compounds has been developed. The carbonyl
substrates were converted <i>in situ</i> into the corresponding
silyl enol ethers, mixed with the CF<sub>3</sub> radical source, and
then irradiated with visible light using a flow reactor based on transparent
tubing and a household compact fluorescent lamp. The continuous protocol
uses Eosin Y as an inexpensive photoredox catalyst and requires only
20 min to complete the two reaction steps
A Continuous-Flow Protocol for Light-Induced Benzylic Fluorinations
A continuous-flow protocol for the
light-induced fluorination of
benzylic compounds is presented. The procedure uses Selectfluor as
the fluorine source and xanthone as an inexpensive and commercially
available photoorganocatalyst. The flow photoreactor is based on transparent
fluorinated ethylene propylene tubing and a household compact fluorescent
lamp. The combination of xanthone with black-light irradiation results
in very efficient fluorination. Good to excellent isolated yields
were obtained for a variety of substrates bearing different functional
groups applying residence times below 30 min