The development of iron catalysts for carbon–heteroatom bond formation, which has attracted strong interest in the context of green chemistry and nitrene transfer, has emerged as the most promising ...way to versatile amine synthetic processes. A diiron system was previously developed that proved efficient in catalytic sulfimidations and aziridinations thanks to an FeIIIFeIV active species. To deal with more demanding benzylic and aliphatic substrates, the catalyst was found to activate itself to a FeIIIFeIVL. active species able to catalyze aliphatic amination. Extensive DFT calculations show that this activation event drastically enhances the electron affinity of the active species to match the substrates requirements. Overall this process consists in a redox self‐adaptation of the catalyst to the substrate needs.
Self‐adaptive catalyst: An efficient diiron catalyst mediates nitrene transfer to sulfides through an FeIV active state but self‐activates to FeV when facing aliphatic substrates that are harder to oxidize.
Amines are ubiquitous in biology and pharmacy. As a consequence, introducing N functionalities in organic molecules is attracting strong continuous interest. The past decade has witnessed the ...emergence of very efficient and selective catalytic systems achieving this goal thanks to engineered hemoproteins. In this review, we examine how these enzymes have been engineered focusing rather on the rationale behind it than the methodology employed. These studies are put in perspective with respect to in vitro and in vivo nitrene transfer processes performed by cytochromes P450. An emphasis is put on mechanistic aspects which are confronted to current molecular knowledge of these reactions. Forthcoming developments are delineated.
Examples of nitrene transfer reactions catalyzed by natural and engineered hemoproteins. Display omitted
•Historical coverage of biological nitrene transfer by hemoproteins.•Mechanistic understanding of generation of the nitrenoid species from nitrene precursors.•Comprehension of the electronic aspects of nitrene transfer reactions.
The development of an automated process for Suzuki–Miyaura cross couplings is described, in which the complete reaction, workup, and product isolation are effected automatically with no user ...involvement, aside from loading of the starting materials and reaction capsule. This practical and simple method was successfully demonstrated to provide the desired biaryl products using a range of aryl bromides and boronic acids and is also effective for the late-stage functionalization of aryl halides in bioactive molecules.
Described herein is the development of an automated and reproducible process for the conversion of primary amines to organic azides utilizing prepacked capsules containing all the required reagents, ...including imidazole-1-sulfonyl azide tetrafluoroborate. Apart from manually loading the primary amine into the reaction vessel, the entire reaction and product isolation process can be achieved automatically, with no further user involvement, and delivers the desired organic azide in high purity. This practical and simple automated capsule-based method offers a convenient and safe way of generating organic azides without handling or exposure of potentially explosive reagents.
Aziridination has very recently been found to be catalyzed by heme and nonheme Fe enzymes, opening the way to biotechnological developments. However, its mechanism is not fully understood owing to ...the contrasting behaviors exhibited by several Fe catalysts. Indeed, whereas a few Fe catalysts exhibit an activity dominated by inductive effects, the activity of others reveal significant and even dominant radical delocalization. Therefore, no clear and general rationale of aziridination has yet emerged. Elaborating on our previous studies, we anticipated that replacing two pyridines of a pentanitrogen ligand by two quinolines would enhance the electron affinity of the corresponding imido FeIV active species and hence its aziridination activity. This proved to be the case, and Hammett correlations indicate an electrophilic active species and dominant inductive effects. The calculated reaction profile points to a two-step mechanism with the formation of the first C–N bond being rate-determining and involving a strong charge transfer in the transition state. The aziridine ring closure in the second step is almost barrierless. A clear correlation of aziridination yields with calculated EA for Fe-catalysts indicate that the dependence of aziridination efficacy on EA of active species is a quite general feature. To generalize this analysis, we reinvestigated a catalyst exhibiting a radical delocalization dominance. Indeed, a similar two-step mechanism was found, which involves a partial charge transfer in the C–N bond formation as all other cases. The interesting point is that owing to the strong steric hindrance of the catalyst substitution, the aziridine ring closure of the intermediate benzylic radical (second step) becomes rate-determining, thus explaining the dominance of the radical delocalization effect. Eventually, a general aziridination two-step mechanism has been rationalized, and EA thus appears as the key descriptor for Fe-based catalytic aziridination that can be used in a predictable way.
Multicomponent reactions are attracting strong interest because they contribute to develop more efficient synthetic chemistry. Understanding their mechanism at the molecular level is thus an ...important issue to optimize their operation. The development of integrated experimental and theoretical approaches has very recently emerged as most powerful to achieve this goal. In the wake of our recent investigation of amidine synthesis, we used this approach to explore how an Fe-catalyzed aziridination can lead to an imidazoline when run in acetonitrile. We report that the synthesis of imidazoline by combination of styrene, acetonitrile, an iron catalyst and a nitrene precursor occurs along a new kind of multicomponent reaction. The formation of imidazoline results from acetonitrile interception of a benzyl radical styrene aziridination intermediate within Fe coordination sphere, as opposed to classical nucleophilic opening of the aziridine by a Lewis acid. Comparison of this mechanism to that of amidine formation allows a rationalization of the modes of intermediates trapping by acetonitrile according to the oxidation state Fe active species. The molecular understanding of these processes may help to design other multicomponent reactions.
Integrated experimental and computational studies reveal a new mechanism for Fe-catalyzed imidazoline synthesis through combined nitrene transfer and acetonitrile attack of a styrenyl radical intermediate.
2‐iminothiazolidines are important scaffold for pharmaceutical drugs. Herein, we describe a fast and easy procedure for their synthesis by a telescoping reaction integrating an iron‐catalyzed nitrene ...transfer under mild conditions. The aziridination reaction of olefins is followed by the domino ring‐opening cyclization (DROC) of the aziridine intermediates with organic isothiocyanates catalyzed by a Lewis acid leading to the desired product. This new synthetic route allows time, step and purification economies, which is in agreement with the development of more efficient processes for the synthesis of small molecules.
In this work, iron‐catalyzed aziridination (nitrene transfer) is combined in a single process to aziridine ring opening (DROC) to produce 2‐iminothiazolidines which constitute interesting cores of pharmaceuticals.
Les amines sont des composés essentiels en biologie, pharmacie et agriculture. La synthèse directe de tels composés constitue un enjeu majeur dans le domaine de la chimie. Le travail présenté dans ce ...manuscrit porte sur l’étude et le développement de synthèses intégrant le transfert de nitrène par des catalyseurs de fer pour l’obtention de composés aminés. Dans une première partie, nous avons étudié la réaction d’aziridination par plusieurs catalyseurs à base de fer sur différentes oléfines. Nous rapportons ici, comment des études mécanistiques couplées à des investigations des structures électroniques et des profils réactionnels, par des méthodes quantiques de type DFT, peuvent conduire à une complète compréhension du mécanisme, ainsi qu’au développement rationnel de nouveaux catalyseurs de fer pour la réaction d’aziridination. Nous avons pu établir que l’affinité électronique joue un rôle majeur dans ce type de transformation. Dans une seconde partie, nous avons étudié la possibilité d’intégrer la catalyse de transfert de nitrène de fer dans des processus multi-séquentiels. Nous avons pu obtenir des amidines et imidazolidines dans des réactions multicomposants via la réaction entre un substrat, un donneur de nitrène et un nitrile, le tout catalysé par le fer. Les calculs DFT ont pu confirmer le mécanisme proposer expérimentalement. Une seconde étude a pu mettre en lumière les réactions monotopes à travers la synthèse de 2-iminothiazolidines via l’ouverture de cycle d’une aziridine suivie de l’insertion d’un isothiocyanate avec de bons rendements. Ces deux types de réactions ont démontré le fort potentiel du transfert de nitrène dans des réactions multi-séquentielles et ouvrent la porte au développement de nouvelles voies de synthèses efficaces dans une chimie durable.
Amines are essential compounds in biology, pharmacy and agriculture. Therefore, their direct synthesis is a major issue in chemistry. The work presented in this manuscript focuses on the study and development of syntheses integrating nitrene transfer by iron catalysts in order to obtain amines. In a first part, we studied the aziridination reaction with several iron catalysts on different olefins. We report here, how mechanistic studies coupled with investigations of electronic structures and reactivity profiles, by quantum methods of DFT type, can lead to a complete understanding of the mechanism, as well as to the rational development of new iron catalysts for the aziridination reaction. We have been able to establish that electron affinity plays a major role in this type of transformation. In a second part, we studied the possibility to integrate iron-catalyzed nitrene transfer in multi-sequential processes. We have been able to obtain amidines and imidazolidines in multicomponent reactions via the reaction between a substrate, a nitrene donor, a nitrile and an iron catalyst. The DFT calculations were able to confirm the mechanism proposed experimentally. A second study was to highlight telescoping reactions through the synthesis of 2-iminothiazolidines via the ring opening of an aziridine followed by the insertion of an isothiocyanate with good yields. These two types of reactions have shown the strong potential of nitrene transfer in multi-sequential reactions and open the way to the development of new efficient synthesis routes in the context of green chemistry.
Multicomponent reactions are attracting strong interest as they contribute to the development of more efficient synthetic chemistry. Understanding their mechanism is thus an important issue to ...optimize their operation. However, it is also a challenging task owing to the complexity of the succession of molecular events involved. Computational methods have recently proven to be of utmost interest to help decipher some of these processes, and the development of integrated experimental and theoretical approaches thus appears as the most powerful means to understand these mechanisms at the molecular level. A good example is given by the synthesis of amidines which are important pharmaceutical compounds. Their synthesis requires the association of three components, often an alkyne, a secondary amine, and an organic azide as the nitrene precursor. We found that an alternative way is offered by an Fe-catalyzed combination of a hydrocarbon, a nitrile, and a nitrene which gives amidines in good yields under mild conditions. The efficiency of the transformation and the paucity of mechanistic information on these reactions prompted us to thoroughly investigate its mechanism. Several mechanistic scenarios were explored using experimental techniques, including radical trap and 15N labeling studies, combined with density-functional theory (DFT) calculations of reaction profiles. This allowed us to show that the amidination reaction involves the trapping of an intermediate substrate cation by an Fe-released acetonitrile molecule pointing to a true multicomponent reaction occurring exclusively within the cage around the metal center. Moreover, the calculated energy barriers of the individual steps explained how amidination outweighs direct amination in these reactions. The perfect consistency between DFT results and specific experiments to validate them strongly supports these mechanistic conclusions and highlights the potency of this combined approach.
In recent years, the therapeutically beneficial degradation of proteins using PROteolysis Targeting Chimeras (PROTACs) has become an increasingly popular approach in drug discovery. However, the ...preparation of these larger than average, heavily functionalised molecules can be synthetically challenging and time-consuming, and experience in making and handling the final PROTACs and their precursors is not yet widespread. To overcome these challenges, an existing capsule-based automated synthesis console has been adapted and employed for the automated synthesis of PROTAC-like molecules. Reagent capsules containing a partial PROTAC reagent plus the reagents required for conjugation of the partial PROTAC to the target protein binder, as well as the materials for product isolation, were prepared in order to accelerate the process and simplify PROTAC synthesis. The use of these capsules, in combination with the automated synthesis console, has enabled the safe, automated preparation of a range of different PROTAC-like molecules bearing different linker and E3 ligase functionalities.
Adaption of an easy to use, automated, capsule-based synthesis approach for the rapid preparation of PROTAC-like molecules.
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