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ORIGINAL RESEARCH article
Front. Chem.
Sec. Green and Sustainable Chemistry
Volume 12 - 2024 |
doi: 10.3389/fchem.2024.1431382
This article is part of the Research Topic Green Processes for the Synthesis of Heterocycles View all 4 articles
A green Heck reaction protocol towards trisubstituted alkenes, versatile pharmaceutical intermediates
Provisionally accepted- 1 University of Pavia, Pavia, Italy
- 2 University of Naples Federico II, Naples, Campania, Italy
- 3 University of Barcelona, Barcelona, Catalonia, Spain
The Heck reaction is widely employed to build a variety of biologically relevant scaffolds and has been successfully implemented in the production of active pharmaceutical ingredients (APIs). Typically, the reaction with terminal alkenes gives high yields and stereoselectivity toward the transsubstituted alkenes product, and many green variants of the original protocol have been developed for such substrates. However, these methodologies may not be applied with the same efficiency to reactions with challenging substrates, such as internal olefins, providing trisubstituted alkenes. In the present work, we have implemented a Heck reaction protocol under green conditions, to access trisubstituted alkenes as final products or key intermediates of pharmaceutical interest. A set of preliminary experiments performed on a model reaction led to selecting a simple and green setup, based on a design of experiments (DoE) study. In such a way, the best experimental conditions (catalyst loading, equivalents of alkene, base and tetraalkylammonium salt, composition, and amount of solvent) have been identified. Then, a second set of experiments were performed, bringing the reaction to completion and considering additional factors. The protocol thus defined involves using EtOH as the solvent, microwave (mw) irradiation to achieve short reaction times, and the supported catalyst Pd EnCat®40, which affords an easier recovery and reuse. These conditions were tested on different aryl bromides and internal olefines to evaluate the substrate scope. Furthermore, with the aim to limit as much as possible the production of waste, a simple isomerization procedure was developed to convert the isomeric byproducts into the desired conjugated E alkene, which is also the thermodynamically favoured product.The approach herein disclosed represents a green, efficient, and easy-to-use handle towards different trisubstituted alkenes via the Heck reaction.
Keywords: Heck reaction, Trisubstituted alkenes, Green solvents, Microwaves, Catalysis, Design of Experiments, DOE
Received: 11 May 2024; Accepted: 11 Jun 2024.
Copyright: © 2024 Rossino, Marrubini, Brindisi, Zapata, Linciano, Rossi and Collina. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Giacomo Rossino, University of Pavia, Pavia, Italy
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Marc G. Zapata
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