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 acid–nitrile 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

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 400–1100 °C. Thermal activation occurs mainly by molecule–wall 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 (160–350 °C, 90–180 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 “flash flow pyrolysis” (FFP) technique was applied to the thermolysis of Meldrum’s 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 a major limitation in classical FVPthe transformations become readily scalable, allowing higher productivities and space–time 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 (molecule–wall collisions) and liquid-phase FFP (molecule–molecule collisions) pyrolysis temperatures was derived

An Experimental and Computational Assessment of Acid-Catalyzed Azide-Nitrile Cycloadditions

The mechanism of the azide–nitrile 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 3–10 min employing controlled microwave heating

Hydrazine-mediated Reduction of Nitro and Azide Functionalities Catalyzed by Highly Active and Reusable Magnetic Iron Oxide Nanocrystals

Iron oxide (Fe₃O₄) 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 2–8 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% HNO₃ (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 liquid–liquid 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

Continuous Flow α‑Trifluoromethylation of Ketones by Metal-Free Visible Light Photoredox Catalysis

A continuous-flow, two-step procedure for the preparation of α-CF₃-substituted carbonyl compounds has been developed. The carbonyl substrates were converted <i>in situ</i> into the corresponding silyl enol ethers, mixed with the CF₃ 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

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 Ti­(<i>i</i>PrO)₄, cyclocondensation of <b>3</b> with thioamide <b>4</b> to form thiol <b>5</b>, and aminolysis using ammonia and Zn­(OAc)₂, allowing the target building block <b>6</b> to be accessed in 47% overall yield

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