Efficient Palladium-Catalyzed Synthesis of 2-Aryl Propionic Acids

Neumann, Helfried; Sergeev, Alexey G.; Spannenberg, Anke; Beller, Matthias

doi:10.3390/molecules25153421

Cited by 5 publications

(3 citation statements)

References 24 publications

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“…To keep the number of experiments reasonable, we elected to screen all reactions with triethylamine as a common base. Three P 2 N 2 ligands with differing phosphine substituents (P Ph , P Cy , and P t Bu ) were chosen for study alongside 9 “gold standard” commercially available phosphine ligands that have been demonstrated to be optimal in related methodologies: dppp, , dppf, ,, JohnPhos, P t Bu 3 , PPh 3 , IMes, DavePhos, 1,10-phenanthroline, and XantPhos . Benzotrifluoroaniline-derived P 2 N 2 ligands were explored, as P 2 Cy N 2 ArCF3 was previously found to be highly effective in nickel-catalyzed cross-couplings. , …”

Section: Resultsmentioning

confidence: 99%

Controlling Reactivity and Selectivity in the Mizoroki–Heck Reaction: High Throughput Evaluation of 1,5-Diaza-3,7-diphosphacyclooctane Ligands

Isbrandt,

Chapple,

et al. 2024

J. Am. Chem. Soc.

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We report a high throughput evaluation of the Mizoroki−Heck reaction of diverse olefin coupling partners. Comparison of different ligands revealed the 1,5-diaza-3,7-diphosphacyclooctane (P 2 N 2 ) scaffold to be more broadly applicable than common "gold standard" ligands, demonstrating that this family of readily accessible diphosphines has unrecognized potential in organic synthesis. In particular, two structurally related P 2 N 2 ligands were identified to enable the regiodivergent arylation of styrenes. By simply altering the phosphorus substituent from a phenyl to tert-butyl group, both the linear and branched Mizoroki− Heck products can be obtained in high regioisomeric ratios. Experimental and computational mechanistic studies were performed to further probe the origin of selectivity, which suggests that both ligands coordinate to the metal in a similar manner but that rigid positioning of the phosphorus substituent forces contact with the incoming olefin in a π−π interaction (for P-Ph ligands) or with steric clash (for P-t Bu ligands), dictating the regiocontrol.

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Section: Resultsmentioning

confidence: 99%

Controlling Reactivity and Selectivity in the Mizoroki–Heck Reaction: High Throughput Evaluation of 1,5-Diaza-3,7-diphosphacyclooctane Ligands

Isbrandt,

Chapple,

et al. 2024

J. Am. Chem. Soc.

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“…The Mizoroki-Heck reaction (often referred to simply as Heck reaction) is one of the most popular Pd-catalysed cross-coupling reactions, allowing easy access to substituted alkenes ( Oestreich, 2009 ; Jagtap, 2017 ). This reaction is now an indispensable implement in the organic chemist’s toolbox, and it has been used in synthesizing a variety of active pharmaceutical ingredients (APIs), clinical candidates, natural products and fine chemicals ( Prashad, 2004 ; Bollikonda et al, 2015 ; Neumann et al, 2020 ; Zhang, 2021 ; Deng et al, 2022 ; Tabassum et al, 2022 ; Cai et al, 2023 ; Stanway-Gordon et al, 2023 ; Moschona et al, 2024 ). Some notable examples are reported in Figure 1 .…”

Section: Introductionmentioning

confidence: 99%

A green Heck reaction protocol towards trisubstituted alkenes, versatile pharmaceutical intermediates

Rossino,

Marrubini,

Brindisi

et al. 2024

Front. Chem.

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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 trans-substituted 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.

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“…With a personal view form the pharmaceutical industry, Blanco and Buskes review the most relevant contributions of Suzuki-Miyaura and Buchwald-Hartwig coupling reactions to the synthesis of bioactive compounds [31]. As a communication, Beller et al report the synthesis of aryl propionic acids, a common structural motif in medicinal chemistry, through combination of a palladium-catalyzed Heck coupling reaction with a rhodium-catalyzed hydroformylation [32].…”

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confidence: 99%