Poly(ethylene) glycols and mechanochemistry for the preparation of bioactive 3,5-disubstituted hydantoins

International audienceMechanochemistry was effective for the preparation of 3,5-disubstituted hydantoins from a-amino methyl esters, using either 1,1 0-carbonyldiimidazole (CDI) or alkyl isocyanates. The preparation of the antimicrobial additives, 3-allyl-5,5 0-dimethyl hydantoin (ADMH) and 1-chloro-3-ethyl-5,5 0-dimethyl hydantoin (CEDMH) were performed by grinding. A chlorination reaction, never described before by mechanochemistry was achieved by Ca(ClO) 2 , while the preparation of the bioactive anticonvulsant marketed drug ethotoin was achieved by a novel approach based on poly(ethylene) glycol (PEGs) assisted grinding

Organic mechanosynthesis : kinetic study of the Diels-Alder reaction and synthesis of 1,2,4-triazoles with biological activities

Ce projet de thèse vise à développer des procédés verts en utilisant la mécanochimie pharmaceutique. Il comporte deux volets imbriqués. Tout d’abord, le mécanisme de la réaction de Diels-Alder par mécanochimie en comparaison avec la réaction en milieu liquide a été étudié. L’impact des paramètres du procédé pour un broyeur vibrant a été évalué. Le matériau, la taille et la masse de la bille de broyage ont été étudiés, ainsi que la température de broyage, ce qui a permis le calcul de l’énergie d’activation apparente (Ea). Par ailleurs, différentes voies de synthèses de dérivés 1,2,4-triazoles par mécanochimie ont été développées. Les activités biologiques de ces composés contre M. Tuberculosis ont été évaluées. Cette thèse vise à poser les bases de futurs changement d’échelle de procédés verts mécanochimiques, en approfondissant les mécanismes, afin d'énoncer des règles de portée générale. Cette thèse bénéficiant d'une aide de la Région Occitanie s'appuie sur la synergie de compétences complémentaires des laboratoires RAPSODEE (Albi) et SPCMIB (Toulouse).This thesis project aims at developing green processes by medicinal mechanochemistry. It contains two parts. First, the Diels-Alder reaction mechanism using mechano-chemistry in comparison with the reaction in solvent medium was studied. The impact of process parameters for a vibratory ball mill was assessed. Grinding material, size and mass of the balls were studied, as well as the temperature of the milling media, providing apparent activation energy (Ea). In addition, different pathways for the synthesis of 1,2,4-triazole derivatives using mechanochemistry were developed. The biological activities of these compounds against M. Tuberculosis were evaluated. This thesis aims to lay the foundations for future scaling-up of green mechanochemical processes, analyzing the mechanisms, in order to formulate rules of general scope. This thesis, supported by the Occitanie Region, is based on the synergy of complementary skills of RAPSODEE (Albi) and SPCMIB (Toulouse) laboratories

Mécanosynthèses organiques : étude cinétique de la réaction de Diels-Alder et synthèses de 1,2,4-triazoles à activités biologiques

This thesis project aims at developing green processes by medicinal mechanochemistry. It contains two parts. First, the Diels-Alder reaction mechanism using mechano-chemistry in comparison with the reaction in solvent medium was studied. The impact of process parameters for a vibratory ball mill was assessed. Grinding material, size and mass of the balls were studied, as well as the temperature of the milling media, providing apparent activation energy (Ea). In addition, different pathways for the synthesis of 1,2,4-triazole derivatives using mechanochemistry were developed. The biological activities of these compounds against M. Tuberculosis were evaluated. This thesis aims to lay the foundations for future scaling-up of green mechanochemical processes, analyzing the mechanisms, in order to formulate rules of general scope. This thesis, supported by the Occitanie Region, is based on the synergy of complementary skills of RAPSODEE (Albi) and SPCMIB (Toulouse) laboratories.Ce projet de thèse vise à développer des procédés verts en utilisant la mécanochimie pharmaceutique. Il comporte deux volets imbriqués. Tout d’abord, le mécanisme de la réaction de Diels-Alder par mécanochimie en comparaison avec la réaction en milieu liquide a été étudié. L’impact des paramètres du procédé pour un broyeur vibrant a été évalué. Le matériau, la taille et la masse de la bille de broyage ont été étudiés, ainsi que la température de broyage, ce qui a permis le calcul de l’énergie d’activation apparente (Ea). Par ailleurs, différentes voies de synthèses de dérivés 1,2,4-triazoles par mécanochimie ont été développées. Les activités biologiques de ces composés contre M. Tuberculosis ont été évaluées. Cette thèse vise à poser les bases de futurs changement d’échelle de procédés verts mécanochimiques, en approfondissant les mécanismes, afin d'énoncer des règles de portée générale. Cette thèse bénéficiant d'une aide de la Région Occitanie s'appuie sur la synergie de compétences complémentaires des laboratoires RAPSODEE (Albi) et SPCMIB (Toulouse)

The role of the milling environment on the copper-catalysed mechanochemical synthesis of tolbutamide

We provide a systematic investigation of the role of atmospheric oxygen and choice of milling assembly (i.e., the milling jar and ball materials) on a prototypical medicinal mechanochemistry reaction: the copper-catalysed coupling of isocyanate and sulfonamide to form the sulfonylurea tolbutamide. Using in-house developed equipment for work under controlled-atmosphere milling conditions, we reveal that the reaction is in fact catalysed by Cu(ii) species, with the conventionally used CuCl acting as a pre-catalyst, which becomes activated via aerobic oxidation during milling. Unexpectedly, the choice of milling jar material was found to have a profound effect on the coupling, with aluminium jars effectively “shutting down” reactivity, most likely by preventing CuCl oxidation. Hence, opposite to direct mechanocatalysis, a term used to describe reactions promoted by the milling jar or ball material, this observation reveals the possibility of direct mechanoinhibition – i.e., the inhibition of a mechanochemical reaction by the jar. These results highlight the importance of systematic investigations of both the milling assembly, as well as atmosphere, in understanding and controlling organic mechanochemical transformations

Synthesis of Biologically Relevant 1,2,3-and 1,3,4-Triazoles: From Classical Pathway to Green Chemistry: Review

International audienceGreen Chemistry has become in the last two decades an increasing part of research interest. Nonconventional «green» sources for chemical reactions include micro-wave, mechanical mixing, visible light and ultrasound. 1,2,3-triazoles have important applications in pharmaceutical chemistry while their 1,2,4 counterparts are developed to a lesser extent. In the review presented here we will focus on synthesis of 1,2,3 and 1,2,4-triazole systems by means of classical and « green chemistry » conditions involving ultrasound chemistry and mechanochemistry. The focus will be on compounds/scaffolds that possess biological/pharmacophoric properties. Finally, we will also present the formal cycloreversion of 1,2,3-triazole compounds under mechanical forces and its potential use in biological systems

Resonant Acoustic Mixing (RAM) for Efficient Mechanoredox Catalysis without Grinding or Impact Media

Resonant acoustic mixing (RAM) enables mechanoredox catalysis with BaTiO3 as the piezoelectric catalyst on model diazonium coupling reactions. RAM proceeds without formal grinding or impact media, is faster than the analogous ball-milling strategy, and is readily scalable to gram-scale. Combined X-ray diffraction and spectroscopy indicate that reusability of BaTiO3 as a mechanoredox catalyst might be limited by unwanted boration

Direct mechanocatalysis using Resonant Acoustic Mixing (RAM)

We demonstrate the first example of direct mechanocatalysis by Resonant Acoustic Mixing (RAM), an emerging mechanochemical methodology that eliminates the need for bulk solvent and milling media. By using a simple copper coil as a catalyst, RAM enables the effective one-pot, 2-step synthesis of triazoles via a combination of benzyl azide formation and copper-catalyzed alkyne-azide click-coupling (CuAAC), on a wide scope of reagents, providing excellent control over reaction stoichiometry, and enabling a simple synthesis of the anticonvulsant drug Rufinamide

Metal-catalyzed organic reactions by Resonant Acoustic Mixing

We introduce catalytic organic synthesis by Resonant Acoustic Mixing (RAM): a mechanochemical methodology that does not require bulk solvent or milling media. Using as model reactions ruthenium-catalyzed ring-closing metathesis, ene-yne metathesis and copper-catalyzed sulfonamide-isocyanate coupling, we demonstrate RAM-based mechanochemical synthesis that is faster and operationally simpler than conventional ball milling. Moreover, the method can be readily scaled-up, as demonstrated by straightforward catalytic synthesis of the antidiabetic drug Tolbutamide from hundreds of milligrams to at least 10 grams, without any significant changes in reaction conditions

Study of the Two Steps and One-Pot Two-Step Mechanochemical Synthesis of Annulated 1,2,4-Triazoles

International audienceThe mechanochemical synthesis of 1,2,4-triazoles by using a planetary ball-mill is studied starting from hydralazine hydrochloride. Excellent conditions were found for achieving total conversion to intermediate hydrazones in a few minutes in the presence of pyrogenic S13 silica as grinding auxiliary. The conversion to annulated 1,2,4-triazoles was optimal with iodobenzene diacetate (IBD) when using nonphenolic hydrazones, while SeO2 was found to be efficient for phenolic compounds. The one-pot two-step synthesis was also successfully conducted for the first time leading to annulated 1,2,4-triazoles. Finally, green metrics showed the efficiency of the method in comparison to the conventional syntheses of hydrazone 10 and triazole 13