David Cantillo

Continuous‐Flow Technology—A Tool for the Safe Manufacturing of Active Pharmaceutical Ingredients

In the past few years, continuous-flow reactors with channel dimensions in the micro- or millimeter region have found widespread application in organic synthesis. The characteristic properties of these reactors are their exceptionally fast heat and mass transfer. In microstructured devices of this type, virtually instantaneous mixing can be achieved for all but the fastest reactions. Similarly, the accumulation of heat, formation of hot spots, and dangers of thermal runaways can be prevented. As a result of the small reactor volumes, the overall safety of the process is significantly improved, even when harsh reaction conditions are used. Thus, microreactor technology offers a unique way to perform ultrafast, exothermic reactions, and allows the execution of reactions which proceed via highly unstable or even explosive intermediates. This Review discusses recent literature examples of continuous-flow organic synthesis where hazardous reactions or extreme process windows have been employed, with a focus on applications of relevance to the preparation of pharmaceuticals.

In Situ Generated Iron Oxide Nanocrystals as Efficient and Selective Catalysts for the Reduction of Nitroarenes using a Continuous Flow Method

Functionalized anilines are industrially important intermediates in the preparation of pharmaceuticals, agrochemicals, dyes, and pigments. The most commonly used method for the synthesis of anilines is the reduction of aromatic nitro compounds. [1] While traditional non-catalytic reduction processes (that is using Fe/HCl) generate large amounts of undesirable waste; catalytic hydrogenation using heterogeneous transition-metal catalysts is a well-established technique and often the method of choice for the reduction of nitroarenes to anilines. [2, 3] However, selectivity problems in the presence of other common functional groups can occur, [4] often requiring the use of carefully selected and expensive precious metal catalysts (for example, Pd, Pt, or Ru). [3] Therefore, significant efforts have been made to develop more efficient and sustainable methods to achieve the selective reduction of nitroarenes to anilines. Apart from the use of hydrogen, several other stoichiometric reducing agents such as ammonium salts, [5] silanes, [6] boranes, [7] sodium borohydride, [8] formic acid, [9] and hydrazine, [10] have been used in combination with a number of different metal catalysts. [5–10] Hydrazine, specifically the less hazardous hydrazine hydrate (N2H4·H2O), is a particularly good reagent because it generates only N2 as a side product and is comparatively safe to handle. In the past few years, interest in the use of iron-based catalysts in organic synthesis has increased dramatically. [11] Iron is an abundant, eco-friendly, relatively nontoxic, and inexpensive element, and thus the development of catalysts based on this metal is highly desirable. Several Fe-catalyzed procedures for the hydrazine-mediated reduction of nitroarenes have been reported. [10a–g] In the general context of

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

Iron oxide (Fe3O4) nanocrystals generated in situ 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 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 in situ 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.

Immobilized Transition Metals as Catalysts for Cross‐Couplings in Continuous Flow—A Critical Assessment of the Reaction Mechanism and Metal Leaching

In the not too distant future many industrially important chemicals (including pharmaceuticals) will probably be manufactured using continuous flow technology. For a significant number of synthetic steps involved in these protocols transition metal (mostly palladium)‐catalyzed carbon–carbon or carbon–heteroatom bond forming reactions (“cross‐coupling chemistry”) will play an important role. Designing a process for continuous cross‐coupling chemistry involves either the use of a homogeneous or of a heterogeneous (immobilized) catalyst/ligand system. In the latter case, the catalyst/ligand system is typically in the form of a packed‐bed reactor, through which the reaction mixture is pumped, employing an appropriate temperature regime and residence time. Although this approach has been widely popular during the past 15 years, there is growing evidence that suggests that the use of immobilized transition metal catalysts for performing cross‐coupling chemistry in continuous flow is, in fact, not very practical. As demonstrated in this review, significant leaching of the transition metal out of the packed‐bed catalyst will almost inevitably occur, leading to decreased catalyst activity and contamination of the product with transition metal. This is a consequence of the well‐known fact that the reaction mechanism for these kinds of transformations is (quasi)homogeneous and involves the transformation of a Pd0 species into a (soluble) PdII species. Using an immobilized catalyst in a batch protocol the transient leaching of palladium will not be immediately obvious, as, after completion of the catalytic cycle, Pd0 will typically redeposit onto the support. In contrast, in continuous flow mode, the palladium metal will progressively be “chromatographed” through the packed‐bed catalyst until, ultimately, all palladium will be removed from the support. This effect typically will become only evident when long run experiments are performed. The preferred alternative, in particular for larger scale experiments, is to use a homogeneous (pre)catalyst in combination with an appropriate catalyst recycling technology.

Mechanistic Insights on Azide−Nitrile Cycloadditions: On the Dialkyltin Oxide−Trimethylsilyl Azide Route and a New Vilsmeier−Haack-Type Organocatalyst

The mechanism of the azide-nitrile cycloaddition mediated by the known dialkylltin oxide-trimethylsilyl azide catalyst system has been addressed through DFT calculations. The catalytic cycle for this tin/silicon complex-based mechanism has been thoroughly examined, disclosing the most plausible intermediates and the energetics involved in the rate enhancement. In addition, a new catalyst, 5-azido-1-methyl-3,4-dihydro-2H-pyrrolium azide, is presented for the formation of tetrazoles by cycloaddition of sodium azide with organic nitriles under neutral conditions. The efficiency of this organocatalyst, generated in situ from N-methyl-2-pyrrolidone (NMP), sodium azide, and trimethylsilyl chloride under reaction conditions, has been examined by preparation of a series of 5-substituted-1H-tetrazoles. The desired target structures were obtained in high yields within 15-25 min employing controlled microwave heating. An in depth computational analysis of the proposed catalytic cycle has also been addressed to understand the nature of the rate acceleration. The computed energy barriers have been compared to the dialkylltin oxide-trimethylsilyl azide metal-based catalyst system. Both the tin/silicon species and the new organocatalyst accelerate the azide-nitrile coupling by activating the nitrile substrate. As compared to the dialkylltin oxide-trimethylsilyl azide method, the organocatalytic system presented herein has the advantage of higher reactivity, in situ generation from inexpensive materials, and low toxicity.

A Unified Mechanistic View on the Morita−Baylis−Hillman Reaction: Computational and Experimental Investigations

The thermodynamic properties and reaction mechanism of the Morita-Baylis-Hillman (MBH) reaction have been investigated through experimental and computational techniques. The impossibility to accelerate this synthetically valuable transformation by increasing the reaction temperature has been rationalized by variable-temperature experiments and MP2 theoretical calculations of the reaction thermodynamics. An increase in temperature results in a switching of the equilibrium to the reactants occurring at even moderate temperature levels. The complex reaction mechanism for the MBH reaction has been investigated through an in-depth analysis of the suggested alternative pathways, using the M06-2X computational method. The results provided by this theoretical approach are in agreement with all the experimental/kinetic evidence such as reaction order, acceleration by protic species (methanol, phenol), and autocatalysis. In particular, the existing controversy about the character of the key proton transfer in the MBH reaction (Aggarwal versus McQuade pathways) has been resolved. Depending on the specific reaction conditions both suggested pathways are competing mechanisms, and depending on the amount of protic species and the reaction progress (early or late stage) either of the two mechanisms will be favored.

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.

A Scalable Procedure for Light-Induced Benzylic Brominations in Continuous Flow

A continuous-flow protocol for the bromination of benzylic compounds with N-bromosuccinimide (NBS) is presented. The radical reactions were activated with a readily available household compact fluorescent lamp (CFL) using a simple flow reactor design based on transparent fluorinated ethylene polymer (FEP) tubing. All of the reactions were carried out using acetonitrile as the solvent, thus avoiding hazardous chlorinated solvents such as CCl4. For each substrate, only 1.05 equiv of NBS was necessary to fully transform the benzylic starting material into the corresponding bromide. The general character of the procedure was demonstrated by brominating a diverse set of 19 substrates containing different functional groups. Good to excellent isolated yields were obtained in all cases. The novel flow protocol can be readily scaled to multigram quantities by operating the reactor for longer time periods (throughput 30 mmol h(-1)), which is not easily possible in batch photochemical reactors. The bromination protocol can also be performed with equal efficiency in a larger flow reactor utilizing a more powerful lamp. For the bromination of phenylacetone as a model, a productivity of 180 mmol h(-1) for the desired bromide was achieved.

Can electromagnetic fields influence the structure and enzymatic digest of proteins? A critical evaluation of microwave-assisted proteomics protocols.

This study reevaluates the putative advantages of microwave-assisted tryptic digests compared to conventionally heated protocols performed at the same temperature. An initial investigation of enzyme stability in a temperature range of 37–80 °C demonstrated that trypsin activity declines sharply at temperatures above 60 °C, regardless if microwave dielectric heating or conventional heating is employed. Tryptic digests of three proteins of different size (bovine serum albumin, cytochrome c and β-casein) were thus performed at 37 °C and 50 °C using both microwave and conventional heating applying accurate internal fiber-optic probe reaction temperature measurements. The impact of the heating method on protein degradation and peptide fragment generation was analyzed by SDS-PAGE and MALDI-TOF-MS. Time-dependent tryptic digestion of the three proteins and subsequent analysis of the corresponding cleavage products by MALDI-TOF provided virtually identical results for both microwave and conventional heating. In addition, the impact of electromagnetic field strength on the tertiary structure of trypsin and BSA was evaluated by molecular mechanics calculations. These simulations revealed that the applied field in a typical laboratory microwave reactor is 3–4 orders of magnitude too low to induce conformational changes in proteins or enzymes.