Small Molecule Library Synthesis Using Segmented Flow

Thompson, Christina; Poole, Jennifer L.; Cross, Jeffrey L.; Akritopoulou‐Zanze, Irini; Djurić, Stevan W.

doi:10.3390/molecules16119161

Cited by 35 publications

(15 citation statements)

References 19 publications

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“…Inline analytics allow immediate evaluation of the reaction's outcome and combination with smart algorithms [machine learning, artificial intelligence, and design of experiments (DoE)] enables self-optimization protocols [72,73], reducing the number of experiments necessary to optimize complex systems. Many of these systems are based on segmented flow strategies, where droplets (segments) of the reaction mixture (each with its own unique reaction conditions) are pushed through the reactor, alternated by inert gases or solvents to avoid cross-contamination ( Figure 4A) [69,[74][75][76].…”

Section: Automated Screening Platforms For Flow Photochemistrymentioning

confidence: 99%

Flow Photochemistry: Shine Some Light on Those Tubes!

Sambiagio

Noël

2020

Trends in Chemistry

316

223

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Continuous-flow chemistry has recently attracted significant interest from chemists in both academia and industry working in different disciplines and from different backgrounds. Flow methods are now being used in reaction discovery/methodology, in scale-up and production, and for rapid screening and optimization. Photochemical processes are currently an important research field in the scientific community and the recent exploitation of flow methods for these methodologies has made clear the advantages of flow chemistry and its importance in modern chemistry and technology worldwide. This review highlights the most important features of continuous-flow technology applied to photochemical processes and provides a general perspective on this rapidly evolving research field. Microflow Technology and Photochemistry: A Perfect MatchThe use of light to promote chemical reactions has been exploited since the 18th century, but only recently a resurgence has been observed in synthetic organic chemistry, in particular due to the development of visible-light photoredox catalysis [1-5]. All transformations involving light (e.g., Figure 1A-D) must consider, besides classical chemical parameters (i.e., reaction conditions), the photophysical aspects of the sensitizer (see Glossary)/photocatalyst (when used), and the reactor design. The latter, although often neglected by chemists, is a critical aspect for the outcome of the studied chemical transformation. This includes, for example, the size, shape, and material of the reaction vessel, the characteristics and positioning of the light source(s), and heat-transfer properties, particularly when high-intensity lamps are used [6,7]. The engineering and technological aspects of photochemical processes are often at the basis of the irreproducibility and non-scalability of such transformations.According to the Beer-Lambert law, light transmittance decreases exponentially with the distance from the light source ( Figure 1F). For a standard batch reactor (diameter at least in the centimeter range), light intensity decreases considerably from the flask walls to the middle of the reaction mixture, resulting in slow reactions and nonhomogeneous irradiation of the reaction mixture. Performing photochemical reactions in microchannels (ID < 1 mm) allows a higher and more homogeneous photon flux, resulting in shorter reaction times and consequently less side-product formation due to over-irradiation, often observed in batch [8,9]. Another advantage of microflow chemistry, correlated with the large surface:volume ratio, is improved heat and mass transfer, with the possibility to perform mass-transfer-limited multiphasic reactions efficiently [10]. Reactive chemicals and intermediates can be handled more safely in flow than in batch, as no accumulation of dangerous components occurs within the confined reactor volume due to the continuous nature of the process. Together, these result in often faster, safer, and higher-yielding reactions, with the possibility to perform reactions under condition...

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Section: Automated Screening Platforms For Flow Photochemistrymentioning

confidence: 99%

Flow Photochemistry: Shine Some Light on Those Tubes!

Sambiagio

Noël

2020

Trends in Chemistry

316

223

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“…In fact, when 1-phenylpropargylamine 1b and the allyl isothiocyanate 2a were reacted in DCE at 130 °C a mixture of 4d and 5d in a 1:2 ratio was unexpectedly obtained (Table 2, entry 5). However, heating the mixture to 160 °C in DMF led to 4d 17 as a single product (Table 2, entry 6). No traces of 5d or the corresponding imidazole derivative were observed.…”

Section: Letter Syn Lettmentioning

confidence: 99%

Microwave-Assisted Domino Reactions of Propargylamines with Isothiocyanates: Selective Synthesis of 2-Aminothiazoles and 2-Amino-4-methylenethiazolines

Scalacci

Pelloja

Radi

et al. 2016

Synlett

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General Methods. Nuclear Magnetic Resonance (NMR) spectra were recorded on a 400 MHz spectrometer. 1 H and 13 C spectra were referenced relative to the solvent residual peaks and chemical shifts (δ) reported in ppm downfield of trimethylsilane (CDCl 3 δ H: 7.26 ppm, δ C: 77.0 ppm; CD 3 OD δ H: 3.31 ppm, δ C: 49.05 ppm; DMSO-d6 δ H: 2.50 ppm, δ C: 39.52 ppm). Coupling constants (J) are reported in Hertz and rounded to 0.5 Hz. Splitting patterns are abbreviated as follows: singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), broad (br) or some combination of these. Low resolution mass spectra were recorded by staff at the Northumbria University Newcastle and King's College London. Positive and negative electrospray ionisation spectrometry (ESI-MS) were conducted using a Thermo LCQ Advantage mass spectrometer by direct injection. GC-MS analyses were performed on a Thermo Electron Co. Focus GC coupled to a Thermo DSQ1 mass spectrometer and an AI3000 Auto Injector. Aliquots of the compound dissolved in DCM (5 μL) were injected onto a DB-5MS (30 m × 0.25 mm i.d. × 0.15 μm film thickness) column at 250 °C. The oven temperature was set at 40 °C for 4 min and raised at 15 °C/min to 135 °C, then at 5 °C/min to 250 °C and holded at 250°C for 5 minutes. The carrier gas flow was 1.0 mL/min. The mass spectrometer was operated in the full scan mode. The transfer line and ion source temperatures were 250 °C and 200 °C, respectively. Thin layer chromatography (TLC) was performed using commercially available pre-coated plates (Macherey-Nagel alugram. Sil G/UV254) and visualized with UV light at 254 nm; K 2 MnO 4 or Ninhydrin dips were used to reveal the products. Flash column chromatography was carried out using Fluorochem Davisil 40-63u 60Å. Petrol refers to the fraction of light petroleum ether boiling between 40 and 65 °C. All other solvents and commercially available reagents were used as received. All chemicals and solvents were used as supplied, unless noted otherwise.

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“…Reactions were performed in 10 min with a flow rate of 146 μL min −1 , which resulted in a throughput of 48‐member libraries in less than five days 40. Access to druglike thiazoles and pyrazoles with a mesoscale flow reactor has also been reported 41. Coil reactors may be incorporated as part of an intricate platform for performing key reactions.…”

Section: Application To Bioactive Chemical Agentsmentioning

confidence: 99%

Accessing New Chemical Entities through Microfluidic Systems

Rodrigues

Schneider

2014

Angew Chem Int Ed

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Flow systems have been successfully utilized for a wide variety of applications in chemical research and development, including the miniaturization of (bio)analytical methods and synthetic (bio)organic chemistry. Currently, we are witnessing the growing use of microfluidic technologies for the discovery of new chemical entities. As a consequence, chemical biology and molecular medicine research are being reshaped by this technique. In this Minireview we portray the state-of-the-art, including the most recent advances in the application of microchip reactors as well as the micro- and mesoscale coil reactor-assisted synthesis of bioactive small molecules, and forecast the potential future use of this promising technology.

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Small Molecule Library Synthesis Using Segmented Flow

Cited by 35 publications

References 19 publications

Flow Photochemistry: Shine Some Light on Those Tubes!

Flow Photochemistry: Shine Some Light on Those Tubes!

Microwave-Assisted Domino Reactions of Propargylamines with Isothiocyanates: Selective Synthesis of 2-Aminothiazoles and 2-Amino-4-methylenethiazolines

Accessing New Chemical Entities through Microfluidic Systems

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