Dominique M. Roberge

Synthesis of 5‐Substituted 1H‐Tetrazoles from Nitriles and Hydrazoic Acid by Using a Safe and Scalable High‐Temperature Microreactor Approach

Interest in tetrazole chemistry over the past few years has been increasing rapidly, mainly as a result of the role played by this heterocyclic functionality in medicinal chemistry as a metabolically stable surrogate for carboxylic acid functionalities. Additional important applications for tetrazoles are found in coordination chemistry, materials science, and as intermediates in a variety of synthetic transformations. The most common synthetic approach to prepare 5-substituted 1H-tetrazole derivatives involves the addition of azide salts to organic nitriles in a temperature range of typically 100–150 8C (Scheme 1). A plethora of synthetic

Enabling Continuous‐Flow Chemistry in Microstructured Devices for Pharmaceutical and Fine‐Chemical Production

Microstructured devices offer unique transport capabilities for rapid mixing, enhanced heat and mass transfer and can handle small amounts of dangerous or unstable materials. The integration of reaction kinetics into fluid dynamics and transport phenomena is essential for successful application from process design in laboratory to chemical production. Strategies to implement production campaigns up to tons of pharmaceutical chemicals are discussed, based on Lonza projects.

Safe Generation and Synthetic Utilization of Hydrazoic Acid in a Continuous Flow Reactor

Hydrazoic acid (HN3) was used in a safe and reliable way for the synthesis of 5-substitued-1H-tetrazoles and for the preparation of N-(2-azidoethyl)acylamides in a continuous flow format. Hydrazoic acid was generated in situ either from an aqueous feed of sodium azide upon mixing with acetic acid, or from neat trimethylsilyl azide upon mixing with methanol. For both processes, subsequent reaction of the in situ generated hydrazoic acid with either organic nitriles (tetrazole formation) or 2-oxazolines (ring opening to β-azido-carboxamides) was performed in a coil reactor in an elevated temperature/pressure regime. Despite the explosive properties of HN3, the reactions could be performed safely at very high temperatures to yield the desired products in short reaction times and in excellent product yields. The scalability of both protocols was demonstrated for selected examples. Employing a commercially available benchtop flow reactor, productivities of 18.9 g/h of 5-phenyltetrazole and 23.0 g/h of N-(1-azido-2-methylpropan-2-yl)acetamide were achieved.

A Two-Step Continuous-Flow Synthesis of N-(2-Aminoethyl)acylamides through Ring-Opening/Hydrogenation of Oxazolines

2-Oxazolines are a readily available class of heterocycles that are easily generated from aminoalcohols and carboxylic acids, or through alternative synthetic procedures starting from alkenes or epoxides as substrates. The oxazoline moiety is very resistant against a range of reagents, such as nucleophiles, bases, or radicals, and is, therefore, heavily used as protecting and/or directing group, or as a powerful source of chirality in asymmetric synthesis. Under acidic conditions, however, oxazolines are susceptible to nucleophilic ring-opening. Thus, the SN2 attack of a nucleophile at the ether carbon C5 of the ring leads to b-substituted carboxamides as products. This reaction is extensively employed in glycoside synthesis, whereby an anomeric oxazoline is used as the glycopyranosyl donor. Importantly, the ring-opening of oxazolines with an azide source is a key step in the synthesis of neuraminic acid analogues (e.g., neuraminidase inhibitors, such as Zanamivir and Oseltamivir) and may attain equal importance for the preparation of other pharmaceutically active compounds that contain the N-(2-aminoethyl)acylamide scaffold. Here, the oxazoline 1 is first ring-opened with the azide ion as nucleophile, and the ensuing azide 2 is subsequently reduced to the monoacylated 1,2-diamine 3 (Scheme 1). The azide source is usually TMSN3 in a high-boiling alcohol, such as tBuOH. For example, the corresponding oxazoline-ring-opening reaction with TMSN3 in tBuOH to introduce the N-(2-aminoethyl)acylamide moiety in the neuraminidase inhibitor Zanamivir (Scheme 1) was performed at 80 8C for 10.5 h on up to 600 g scale. It should be noted that TMSN3 rapidly releases volatile hydrazoic acid (HN3, b.p. 37 8C) in the presence of protic solvents, such as alcohols. HN3 is an extremely explosive and toxic material and, hence, these batch protocols are hardly suitable for reactions on scale. Therefore, alternative strategies that avoid the use of TMSN3 to introduce the N-(2-aminoethyl)acylACHTUNGTRENNUNGamide moiety have been developed. Recently, we have described a general and scalable method for the synthesis of 5-substituted-1H-tetrazoles through cycloaddition of organic nitriles with HN3 by using continuous-flow technology. Key to this protocol is the in situ generation of HN3 from an aqueous solution of NaN3 and AcOH inside a microreactor environment by using a two-feed concept. Driven by the ever increasing demand for cost-effective and safe chemical processes, the interest in continuous-flow and microreactor technology in the fine chemical industry increased tremendously in recent years. A continuous-flow approach generally allows more drastic reaction conditions (e.g., high temperatures/ pressures) to be used, even when hazardous reagents or intermediates are involved. Heat and mass transfer is very fast at the scales used in flow systems (channel or capillary diameters of 50–1000 mm), and the volumes processed at any time are kept very small. Synthetic intermediates can be generated and consumed in situ in a closed system by combining multiple reagent streams, which eliminates the need to handle or store toxic, reactive, or explosive intermediates. A further important advantage of microreaction technology is the ease with which reaction conditions can be scaled to production scale capacities, for example, through the operation of multiple systems in parallel or related strategies. As an extension of our earlier HN3 microreactor work, [9] we herein report the ring-opening of various 2-oxazolines 1 to the corresponding b-azido carboxamides 2 with in situ [a] B. Gutmann, Prof. Dr. C. O. Kappe Christian Doppler Laboratory for Microwave Chemistry (CDLMC) and Institute of Chemistry Karl-Franzens-University Graz Heinrichstrasse 28, A-8010 Graz (Austria) Fax: (+43) 316-380-9840 E-mail : oliver.kappe@uni-graz.at [b] Dr. J.-P. Roduit, Dr. D. Roberge Microreactor Technology, Lonza AG CH-3930 Visp (Switzerland) E-mail : dominique.roberge@lonza.com Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201102772. Scheme 1. Two-step synthesis of selectively monoacylated 1,2-diamines starting from 2-oxazolines.

Shifting Chemical Equilibria in Flow—Efficient Decarbonylation Driven by Annular Flow Regimes

To efficiently drive chemical reactions, it is often necessary to influence an equilibrium by removing one or more components from the reaction space. Such manipulation is straightforward in open systems, for example, by distillation of a volatile product from the reaction mixture. Herein we describe a unique high-temperature/high-pressure gas/liquid continuous-flow process for the rhodium-catalyzed decarbonylation of aldehydes. The carbon monoxide released during the reaction is carried with a stream of an inert gas through the center of the tubing, whereas the liquid feed travels as an annular film along the wall of the channel. As a consequence, carbon monoxide is effectively vaporized from the liquid phase into the gas phase and stripped from the reaction mixture, thus driving the equilibrium to the product and preventing poisoning of the catalyst. This approach enables the catalytic decarbonylation of a variety of aldehydes with unprecedented efficiency with a standard coil-based flow device.

Transitional Flow and Related Transport Phenomena in Curved Microchannels

In microchannels with typical dimensions from 10 μm to a few hundreds of micrometers, the flow is dominated by viscous forces, often leading to laminar flow conditions. At the entrance or in bends and curves, where the flow changes its velocity or direction, inertial forces generate transverse flow velocities. Due to continuity, vortex pairs, such as Dean flow in circular bends, are generated, which are still laminar, steady, and showing no statistically distributed fluctuations typical for turbulent flow. This deviation from straight laminar conditions is called transitional flow, often occurring in channels larger than 500 μm at higher flow rates. Transitional flow phenomena include the first occurrence of flow bifurcation, pulsating vortices, period doubling of vortex pairs, and regularly fluctuating wake flow or vortex shedding. Chaotic flow phenomena are the first evidence of turbulence. Transitional flow augments the transport characteristics in microchannels for enhanced heat and mass transfer and for performing chemical reactions in microreactors. The profound understanding of how to generate and control vortices in microchannels guides the design of advanced microstructured devices for various applications.

Unusual behavior in the reactivity of 5-substituted-1H-tetrazoles in a resistively heated microreactor

Summary The decomposition of 5-benzhydryl-1H-tetrazole in an N-methyl-2-pyrrolidone/acetic acid/water mixture was investigated under a variety of high-temperature reaction conditions. Employing a sealed Pyrex glass vial and batch microwave conditions at 240 °C, the tetrazole is comparatively stable and complete decomposition to diphenylmethane requires more than 8 h. Similar kinetic data were obtained in conductively heated flow devices with either stainless steel or Hastelloy coils in the same temperature region. In contrast, in a flow instrument that utilizes direct electric resistance heating of the reactor coil, tetrazole decomposition was dramatically accelerated with rate constants increased by two orders of magnitude. When 5-benzhydryl-1H-tetrazole was exposed to 220 °C in this type of flow reactor, decomposition to diphenylmethane was complete within 10 min. The mechanism and kinetic parameters of tetrazole decomposition under a variety of reaction conditions were investigated. A number of possible explanations for these highly unusual rate accelerations are presented. In addition, general aspects of reactor degradation, corrosion and contamination effects of importance to continuous flow chemistry are discussed.

Liquid–Liquid Test Reactions to Characterize Two-Phase Mixing in Microchannels

Multiphase flow is often found in chemical engineering, food processing, or analytical devices. First contacting and droplet generation as well as coalescence and redispersion are important for the flow characteristics. In all processes, the channel geometry, fluid properties, and flow velocity determine the flow regime, droplet size, and interfacial area. The hydrolysis of alkyl acetates in organic phase with sodium hydroxide NaOH in the aqueous phase is investigated as flexible test reaction for mass transfer and interfacial area determination. The alkyl group is chosen from ethyl, isopropyl, or n-butyl, which differ in water solubility, diffusivity, and rate constant, for adequate design of the characteristic time for mass transfer. The consumption of NaOH is used for calculation of specific area and related mass transfer coefficient. Different channel geometries are characterized and design considerations are derived.

Control of Hazardous Processes in Flow: Synthesis of 2-Nitroethanol

After a short section of safety aspects related to 2-nitroethanol, the paper describes a powerful methodology for developing flow processes based on a proof of concept (1), an optimization and modeling analysis (2), and a long run study in a mini-plant (3). The proof of concept is the initial stage where the solubilities and concentrations are fixed, taking into account the rough kinetics with a mass transfer understanding. It is followed by a complete kinetic analysis including activation energy to model the reaction under various conditions to optimize different targets (yield not being the only driver!). The last section shows the operation of a mini-plant including a microreactor and work-up unit operations. The approach is extremely powerful as it enables the study at laboratory scale of all the features that are usually associated with a pilot plant namely: stability over time on stream, solvent recirculation, model prediction, and robustness.

Continuous Flow Homolytic Aromatic Substitution with Electrophilic Radicals ‐ A Fast and Scalable Protocol for Trifluoromethylation

We report an operationally simple and rapid continuous flow radical C-C bond formation under Minisci-type reaction conditions. The transformations are performed at or below room temperature employing hydrogen peroxide (H2 O2 ) and dimethylsulfoxide (DMSO) as reagents in the presence of an FeII catalyst. For electron-rich aromatic and heteroaromatic substrates, C-C bond formation proceeds satisfactorily with electrophilic radicals including . CF3 , . C4 F9 , . CH2 CN, and . CH2 CO2 Et. In contrast, electron-poor substrates exhibit minimal reactivity. Importantly, trifluoromethylations and nonafluororobutylations using CF3 I and C4 F9 I as reagents proceed exceedingly fast with high conversion for selected substrates in residence times of a few seconds. The attractive features of the present process are the low cost of the reagents and the extraordinarily high reaction rates. The direct application of the protocol to dihydroergotamine, a complex ergot alkaloid, yielded the corresponding trifluoromethyl ergoline derivative within 12 seconds in a continuous flow microreactor on a 0.6 kg scale. The trifluoromethyl derivative of dihydroergotamine is a promising therapeutic agent for the treatment of migraines.