Design and Synthesis of Multipurpose Derivatives for N‐Hydroxyimide and NHPI‐based Catalysis Applications**

Caruso, Manfredi; Petroselli, Manuel; Cametti, Massimo

doi:10.1002/slct.202103792

Cited by 13 publications

(3 citation statements)

References 60 publications

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“…In the past two decades, the pharmaceutical industry and the U.S. Food and Drug Administration (FDA) have recognized continuous manufacturing as an economically and environmentally transformative means of drug production. While continuous manufacturing develops as a plausible alternative to batch processes, another point of intervention related to sustainability should be considered for the future of industrial catalysis, i.e., the replacement of transition metals by greener systems [40]. We hope that this work will encourage academic scientists to explore the hitherto less developed organocatalytic processes in industry, with the aim of overcoming the limitations of metal-catalyzed reactions in terms of cost and residue generation.…”

Section: Discussionmentioning

confidence: 99%

Iridium- and Palladium-Based Catalysts in the Pharmaceutical Industry

López

Padrón

2022

Catalysts

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Transition metal catalysts play a vital role in a wide range of industrial organic processes. The large-scale production of chemicals relying on catalyzed organic reactions represents a sustainable approach to supply society with end products for many daily life applications. Homogeneous (mainly for academic uses) and heterogeneous (crucial in industrial processes) metal-based catalysts have been developed for a plethora of organic reactions. The search for more sustainable strategies has led to the development of a countless number of metal-supported catalysts, nanosystems, and electrochemical and photochemical catalysts. In this work, although a vast number of transition metals can be used in this context, special attention is devoted to Ir- and Pd-based catalysts in the industrial manufacture of pharmaceutical drugs. Pd is by far the most widely used and versatile catalyst not only in academia but also in industry. Moreover, Ir-based complexes have emerged as attractive catalysts, particularly in asymmetric hydrogenation reactions. Ir- and Pd-based asymmetric reductions, aminations, cross-coupling reactions, and C–H activation are covered herein in the production of biologically active compounds or precursors; adaptation to bulk conditions is particularly highlighted.

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Section: Discussionmentioning

confidence: 99%

Iridium- and Palladium-Based Catalysts in the Pharmaceutical Industry

López

Padrón

2022

Catalysts

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“…968 To develop a more easily recyclable nitroxide catalyst, NHPI derivatives were immobilized on polystyrene 969,970 or on silica, 971 and also, readily separable imidazolium-based NHPI derivatives were developed. 972 Enantioselective radical C−H activation was investigated using chiral imidoxyl radicals. However, the enantioselectivity for the hydroxylation of ethylbenzene was low.…”

Section: Oxidations Of C Nucleophilesmentioning

confidence: 99%

Organic Synthesis Using Nitroxides

Leifert

Studer

2023

Chem. Rev.

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Nitroxides, also known as nitroxyl radicals, are long-lived or stable radicals with the general structure R 1 R 2 N−O • . The spin distribution over the nitroxide N and O atoms contributes to the thermodynamic stability of these radicals. The presence of bulky N-substituents R 1 and R 2 prevents nitroxide radical dimerization, ensuring their kinetic stability. Despite their reactivity toward various transient C radicals, some nitroxides can be easily stored under air at room temperature. Furthermore, nitroxides can be oxidized to oxoammonium salts (R 1 R 2 N�O + ) or reduced to anions (R 1 R 2 N−O − ), enabling them to act as valuable oxidants or reductants depending on their oxidation state. Therefore, they exhibit interesting reactivity across all three oxidation states. Due to these fascinating properties, nitroxides find extensive applications in diverse fields such as biochemistry, medicinal chemistry, materials science, and organic synthesis. This review focuses on the versatile applications of nitroxides in organic synthesis. For their use in other important fields, we will refer to several review articles. The introductory part provides a brief overview of the history of nitroxide chemistry. Subsequently, the key methods for preparing nitroxides are discussed, followed by an examination of their structural diversity and physical properties. The main portion of this review is dedicated to oxidation reactions, wherein parent nitroxides or their corresponding oxoammonium salts serve as active species. It will be demonstrated that various functional groups (such as alcohols, amines, enolates, and alkanes among others) can be efficiently oxidized. These oxidations can be carried out using nitroxides as catalysts in combination with various stoichiometric terminal oxidants. By reducing nitroxides to their corresponding anions, they become effective reducing reagents with intriguing applications in organic synthesis. Nitroxides possess the ability to selectively react with transient radicals, making them useful for terminating radical cascade reactions by forming alkoxyamines. Depending on their structure, alkoxyamines exhibit weak C−O bonds, allowing for the thermal generation of C radicals through reversible C−O bond cleavage. Such thermally generated C radicals can participate in various radical transformations, as discussed toward the end of this review. Furthermore, the application of this strategy in natural product synthesis will be presented.

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“…A possible decomposition route of the reactive intermediate, phthalimide-N-oxyl radical (PINO), is the ring-opening of imide moiety, which was proposed by Masui and coworkers based on mass spectrometric analysis of decomposition products (Figure 1b). [24] While heterogeneous support, [25][26][27][28][29][30][31][32] use of ionic liquid, [33][34][35][36][37] phase-transfer conditions, [38,39] supercritical CO 2 , [40] combination with other redox mediators, [41][42][43] and the combination of these techniques [37] have been suggested to address the lifetime issue, NHPI derivatives with intrinsic long lifetime are highly desirable. For aerobic oxidation of hydrocarbons, one of the examples superior to NHPI is lipophilic NHPI A reported by Ishii and coworkers (Figure 2a).…”

Section: Introductionmentioning

confidence: 99%

Lipophilic N‐Hydroxyimide Derivatives: Design, Synthesis, and Application to Aerobic Alkane Oxidation Under Neat Conditions

et al. 2022

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This work reports the design and synthesis of a series of 5membered and 6-membered N-hydroxyimides flanked by lipophilic alkyl groups adjacent to carbonyl groups, aiming to endow lipophilicity and tolerance toward ring opening degradation. Their solubility in cyclohexane was 5-20 times higher than those of unsubstituted N-hydroxyphthalimide (NHPI) and even 3-10 times higher than a formerly known lipophilic NHPI analog bearing a long alkyl ester. UV-Vis spectroscopy determined the rate constants of first-order decay of N-oxyls, which revealed enhanced stability of 3,5-di-tert-butyl-NHPI and Nhydroxyglutarimide flanked by spiro-cyclohexanes compared with that of NHPI. Their bond dissociation energies were assessed by EPR spectroscopy and DFT calculation, suggesting these lipophilic N-hydroxyimides catalyzed aerobic cyclohexane oxidation under neat conditions with up to 60 turnovers, which is the highest among hitherto reported reactions under neat conditions.

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Design and Synthesis of Multipurpose Derivatives for N‐Hydroxyimide and NHPI‐based Catalysis Applications**

Cited by 13 publications

References 60 publications

Iridium- and Palladium-Based Catalysts in the Pharmaceutical Industry

Iridium- and Palladium-Based Catalysts in the Pharmaceutical Industry

Organic Synthesis Using Nitroxides

Lipophilic N‐Hydroxyimide Derivatives: Design, Synthesis, and Application to Aerobic Alkane Oxidation Under Neat Conditions

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