Extending the versatility of the Hemetsberger–Knittel indole synthesis through microwave and flow chemistry

Ranasinghe, Nadeesha; Jones, Graham B.

doi:10.1016/j.bmcl.2013.01.066

Cited by 16 publications

(12 citation statements)

References 12 publications

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“…The indole scaffold is a privileged structure widely applied in the quest for new biologically active compounds, due to its ability to bind to different targets, resulting in a wide range of medicinal applications . One of the most popular flow strategies to afford indole derivatives is the thermolysis reaction of methyl 2‐azido‐3‐phenylacrylate derivatives , …”

Section: Heterocyclic Synthesismentioning

confidence: 95%

Flow Chemistry: Towards A More Sustainable Heterocyclic Synthesis

2019

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Flow Chemistry is a revolutionary field in Organic Chemistry. By changing the conventional methods and apparatus applied in the chemical synthesis, flow chemistry emerges as a game changer for organic synthesis laboratories, in both academia and industries. Considered as a sustainable practice, flow processes play an important role in the development of fine chemical products and in drug discovery development pro- [a] The main advantages of flow chemistry are that it allows the reaction to be carried out safely with high selectivity, high reproducibility and reduced energy consumption/carbon footprint. These features make this emerging technology for organic synthesis desirable for green and sustainable chemical synthesis, giving the chemist time for work planning and design, instead of using it in repetitive tasks, [5b,12] as expressed by the CHEM21 project by awarding a green flag for continuousflow reactions, in opposition to an amber flag for those performed under batch conditions. [13] Pedro Brandão received his MSc in Pharmaceutical Sciences from the Faculty of Pharmacy -University of Porto, in 2011. Pursuing his passion on studies in the field of Drug Discovery and Development, he is currently undergoing his PhD studies in Chemistry, in the field of Catalysis and Sustainability. His main focus of work is the discovery of new drug candidates through sustainable techniques. Marta Pineiro received her Ph.D. in Organic Chemistry in 2003 in the University of Coimbra, Portugal, and since 2002 has been enrolled at the University of Coimbra, being at present Auxiliary Professor. Her research interests are in the area of sustainable organic synthesis, microwave-assisted organic synthesis and synthesis and biological applications of tetrapyrrolic macrocycles. Teresa M. V. D. Pinho e Melo studied Chemistry at the University of Coimbra, where she graduated in 1985, got her M. 7191CPBA) as the oxidizing agent, avoiding the handling of this expensive and explosive reagent. [25] Recently, Morodo et al. explored the synthesis of two very important oxiranes (epichlorohydrin and glycidol) from biobased glycerol, under flow conditions. As depicted in Scheme 1, and using pimelic acid as the catalyst (10 mol-%), a sequential hydrochlorination/dichlorination process allows high conversion of glycerol (> 99 %) into 1,3-dichloro-2-propanol, followed by the quantitative conversion into a separable mixture of glycidol and epichlorohydrin (2:3). The separation of these two products is performed by an in-line membrane separation system, which allows the first product to be collected in the aqueous phase, while the second is collected in MTBE. This heterocycle can be further used as a synthetic precursor to relevant APIs bearing -amino alcohol moieties (e.g., propranolol, alprenolol and naftopidil). [26] Scheme 1. Sequential flow setup for the preparation of glycidol and epichlorohydrin, important APIs synthetic intermediates.Scheme 3. Synthesis and inline purification of a bicyclic aziridine (SGMR = silicon-glass microfluidic react...

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Section: Heterocyclic Synthesismentioning

confidence: 95%

Flow Chemistry: Towards A More Sustainable Heterocyclic Synthesis

2019

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“…al. 36 described the design of a MW-assisted Hemetsberger-Knittel (HK) reaction of a series of azidoesters under a variety of conditions to produce a number of substituted indoles (Scheme 1). The azidoesters 30, readily obtained in one step, were directly cyclized into carboxylate indoles 31, or converted to their corresponding azidoesters 32.…”

Section: Indolementioning

confidence: 99%

“…In all cases, the microwave reaction time is just one twelh that of conventional methods and results in a yield up to 24% higher than that of conventional methods. 36…”

Section: Indolementioning

confidence: 99%

Benefits and applications of microwave-assisted synthesis of nitrogen containing heterocycles in medicinal chemistry

et al. 2020

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“…In this context, the authors carried out a scalable continuous flow thermolysis of azidoacrylates with the preparation of 8.5 g of 35, a precursor of a DAAO inhibitor, within 21 min (productivity of 2.5 mmol•min −1 ). In 2013, a comparative study between thermolysis, microwave irradiation, and flow approach for the preparation of indole-2-carboxylates via the Hemetsberger-Knittel reaction was presented by Jones [61]. By using microwave irradiation, indole-2-carboxylates were obtained in a higher yield and with a shorter reaction time (200 °C, 10 min) with respect to batch (140 °C, 2 h).…”

Section: Hemetsberger-knittel Indole Synthesis Under Continuous Flow mentioning

confidence: 99%

“…In 2013, a comparative study between thermolysis, microwave irradiation, and flow approach for the preparation of indole-2-carboxylates via the Hemetsberger–Knittel reaction was presented by Jones [ 61 ]. By using microwave irradiation, indole-2-carboxylates were obtained in a higher yield and with a shorter reaction time (200 °C, 10 min) with respect to batch (140 °C, 2 h).…”

Section: Synthesis Of Indole Ring Under Continuous Flow Conditionsmentioning

confidence: 99%

Continuous Flow Synthesis of Heterocycles: A Recent Update on the Flow Synthesis of Indoles

2020

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Indole derivatives are among the most useful and interesting heterocycles employed in drug discovery and medicinal chemistry. In addition, flow chemistry and flow technology are changing the synthetic paradigm in the field of modern synthesis. In this review, the role of flow technology in the preparation of indole derivatives is showcased. Selected examples have been described with the aim to provide readers with an overview on the tactics and technologies used for targeting indole scaffolds.

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Extending the versatility of the Hemetsberger–Knittel indole synthesis through microwave and flow chemistry

Cited by 16 publications

References 12 publications

Flow Chemistry: Towards A More Sustainable Heterocyclic Synthesis

Flow Chemistry: Towards A More Sustainable Heterocyclic Synthesis

Benefits and applications of microwave-assisted synthesis of nitrogen containing heterocycles in medicinal chemistry

Continuous Flow Synthesis of Heterocycles: A Recent Update on the Flow Synthesis of Indoles

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