Temperature‐Controlled Mechanochemistry Unlocks the Nickel‐Catalyzed Suzuki–Miyaura‐Type Coupling of Aryl Sulfamates at Different Scales

Reynes, Javier Fernandez; Garcı́a, Felipe

doi:10.1002/anie.202215094

Cited by 11 publications

(10 citation statements)

References 17 publications

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“…Next, a mechanochemical procedure was applied to perform a nucleophilic aromatic substitution (S N Ar) between fluorinated derivatives 2a-2l and anhydrous piperazine to obtain final compounds 3a-3l. The advantages of using temperature-controlled mechanochemical procedures have been recently demonstrated for different organic reactions [33][34][35][36]. In line with those findings, heating of a 10 mL SS jar containing intermediate 2a (1 eq) and anhydrous piperazine (1 eq) at 50 • C for 1.5 h by using a temperaturecontrolled heat gun pre-set at 90 • C enabled the formation of the product 3a (55% of conversion).…”

Section: Mechanochemical Synthesis Of Compounds 3a-3lsupporting

confidence: 64%

1-(Arylsulfonyl-isoindol-2-yl)piperazines as 5-HT6R Antagonists: Mechanochemical Synthesis, In Vitro Pharmacological Properties and Glioprotective Activity

et al. 2022

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In addition to the canonical Gs adenylyl cyclase pathway, the serotonin type 6 receptor (5-HT6R) recruits additional signaling pathways that control cognitive function, brain development, and synaptic plasticity in an agonist-dependent and independent manner. Considering that aberrant constitutive and agonist-induced active states are involved in various pathological mechanisms, the development of biased ligands with different functional profiles at specific 5-HT6R-elicited signaling pathways may provide a novel therapeutic perspective in the field of neurodegenerative and psychiatric diseases. Based on the structure of SB-258585, an inverse agonist at 5-HT6R-operated Gs and Cdk5 signaling, we designed a series of 1-(arylsulfonyl-isoindol-2-yl)piperazine derivatives and synthesized them using a sustainable mechanochemical method. We identified the safe and metabolically stable biased ligand 3g, which behaves as a neutral antagonist at the 5-HT6R-operated Gs signaling and displays inverse agonist activity at the Cdk5 pathway. Inversion of the sulfonamide bond combined with its incorporation into the isoindoline scaffold switched the functional profile of 3g at Gs signaling with no impact at the Cdk5 pathway. Compound 3g reduced the cytotoxicity of 6-OHDA and produced a glioprotective effect against rotenone-induced toxicity in C8-D1A astrocyte cell cultures. In view of these findings, compound 3g can be considered a promising biased ligand to investigate the role of the 5-HT6R-elicited Gs and Cdk5 signaling pathways in neurodegenerative diseases.

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Section: Mechanochemical Synthesis Of Compounds 3a-3lsupporting

confidence: 64%

1-(Arylsulfonyl-isoindol-2-yl)piperazines as 5-HT6R Antagonists: Mechanochemical Synthesis, In Vitro Pharmacological Properties and Glioprotective Activity

et al. 2022

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“…Their protocol allowed efficient cross‐couplings of insoluble aryl halides with large polyaromatic structures that hardly react under conventional conditions in solution to produce a series of organic pigments [72] . The combination of mechanochemistry with other energy sources has recently taken the spotlight since they enable a new level of solid‐state reactivity [75, 76, 78, 111] …”

Section: Upscaling Mechanochemistrymentioning

confidence: 99%

“…This limitation has been partially circumvented with custom‐made reactors, which allow temperature control in ball‐milling systems and commercial equipment with temperature control for both batch and continuous processes, addressing and/or mitigating some of the above‐mentioned challenges with traditional mechanochemical processes [32, 51, 73–78] …”

Section: Introductionmentioning

confidence: 99%

Tinkering with Mechanochemical Tools for Scale Up

2023

Self Cite

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Mechanochemistry provides an environmentally benign platform to develop more sustainable chemical processes by limiting raw materials, energy use, and waste generation while using physically smaller equipment. A continuously growing research community has steadily showcased examples of beneficial mechanochemistry applications at both the laboratory and the preparative scale. In contrast to solution‐based chemistry, mechanochemical processes have not yet been standardized, and thus scaling up is still a nascent discipline. The purpose of this Minireview is to highlight similarities, differences and challenges of the various approaches that have been successfully applied for a range of chemical applications at various scales. We hope to provide a discussion starting point for those interested in further developing mechanochemical processes for commercial use and/or industrialisation.

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“…However, the implementation of mechanochemistry (both in batch and continuous) in manufacturing processes for covalent bond forming reactions has not reached yet the industrial era. The biggest challenge is especially in the manufacturing of Active Pharmaceutical Ingredients (APIs), [19a–d] needing to solicit inquisitiveness in developing green‐by‐design chemical processes during early‐stage development activities in laboratories, KiloLab or pilot plant of chemical companies [20] . Such an approach does not include only green metrics [8a–b,21] or life‐cycle assessment (LCA) [9] but also by implementing emerging technologies such as mechanochemistry, currently underserved in chemical industries.…”

Section: Introductionmentioning

confidence: 99%

Sustainable Beckmann Rearrangement using Bead‐Milling Technology: The Route to Paracetamol

Geib,

Colacino,

Gremaud

2024

ChemSusChem

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To address the growing demand for more sustainable and greener chemistry, mechanochemical methodologies are emerging as key players. However, to date there has been little data highlighting the benefits of these rising mechanochemical technologies with regard to process scale‐up activities or implementation in commercial production scale. Herein, we report the first application of bead‐mill technology (Dyno®‐mill) for the sustainable mechanochemical synthesis of Acetaminophen, known under the brand name Paracetamol. Using the Beckmann rearrangement, the optimized solvent‐free methodology delivered a final product on a scale of several tens of grams. In comparison to current production solvent‐based process, the proposed process achieves a higher yield while also allowing the removal of solvents in the chemical reaction, hereby reducing one of the extensive drivers to waste generation. The mechanochemical approach was compared to solvent‐based process using a combination of green metrics and EcoScale score. The mechanochemical synthesis of paracetamol scores the highest for all the metrics over currently used solution‐based processes.

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Temperature‐Controlled Mechanochemistry Unlocks the Nickel‐Catalyzed Suzuki–Miyaura‐Type Coupling of Aryl Sulfamates at Different Scales

Cited by 11 publications

References 17 publications

1-(Arylsulfonyl-isoindol-2-yl)piperazines as 5-HT6R Antagonists: Mechanochemical Synthesis, In Vitro Pharmacological Properties and Glioprotective Activity

1-(Arylsulfonyl-isoindol-2-yl)piperazines as 5-HT6R Antagonists: Mechanochemical Synthesis, In Vitro Pharmacological Properties and Glioprotective Activity

Tinkering with Mechanochemical Tools for Scale Up

Sustainable Beckmann Rearrangement using Bead‐Milling Technology: The Route to Paracetamol

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