618-42-8Relevant articles and documents
An efficient, economical and eco-friendly acylation of alcohols and amines by alum doped nanopolyaniline under solvent free condition
Behera, Satyaranjan,Patra, Braja N.
, (2021/08/06)
We report acylation of alcohols and amines employing acetic acid as an acylating agent in solvent free condition by using alum doped nanopolyaniline (NDPANI) as a catalyst. This environmentally benign method does not use corrosive acid anhydrides and acid chlorides for acylation and does not produce waste product. Also, a non-toxic potash alum was used for doping of polyaniline rather than corrosive acids. The reaction conditions represent an advance over established method not only in omitting the need for expensive catalysts or solvents but also in shortening the reaction time significantly. The advantages of this catalyst are non-hazardous, cheap, reusable, easy to prepare and handling.
Asymmetric Transfer Hydrogenation of α-Keto Amides; Highly Enantioselective Formation of Malic Acid Diamides and α-Hydroxyamides
Gediya, Shweta K.,Vyas, Vijyesh K.,Clarkson, Guy J.,Wills, Martin
supporting information, p. 7803 - 7807 (2021/10/20)
The asymmetric transfer hydrogenation (ATH) of α-keto-1,4-diamides using a tethered Ru/TsDPEN catalyst was achieved in high ee. Studies on derivatives identified the structural elements which lead to the highest enantioselectivities in the products. The α-keto-amide reduction products have been converted to a range of synthetically valuable derivatives.
Deconstructing Noncovalent Kelch-like ECH-Associated Protein 1 (Keap1) Inhibitors into Fragments to Reconstruct New Potent Compounds
Pallesen, Jakob S.,Narayanan, Dilip,Tran, Kim T.,Solbak, Sara M. ?.,Marseglia, Giuseppe,S?rensen, Louis M. E.,H?j, Lars J.,Munafò, Federico,Carmona, Rosa M. C.,Garcia, Anthony D.,Desu, Haritha L.,Brambilla, Roberta,Johansen, Tommy N.,Popowicz, Grzegorz M.,Sattler, Michael,Gajhede, Michael,Bach, Anders
, p. 4623 - 4661 (2021/05/07)
Targeting the protein-protein interaction (PPI) between nuclear factor erythroid 2-related factor 2 (Nrf2) and Kelch-like ECH-associated protein 1 (Keap1) is a potential therapeutic strategy to control diseases involving oxidative stress. Here, six classes of known small-molecule Keap1-Nrf2 PPI inhibitors were dissected into 77 fragments in a fragment-based deconstruction reconstruction (FBDR) study and tested in four orthogonal assays. This gave 17 fragment hits of which six were shown by X-ray crystallography to bind in the Keap1 Kelch binding pocket. Two hits were merged into compound 8 with a 220-380-fold stronger affinity (Ki = 16 μM) relative to the parent fragments. Systematic optimization resulted in several novel analogues with Ki values of 0.04-0.5 μM, binding modes determined by X-ray crystallography, and enhanced microsomal stability. This demonstrates how FBDR can be used to find new fragment hits, elucidate important ligand-protein interactions, and identify new potent inhibitors of the Keap1-Nrf2 PPI.
Environmentally benign decarboxylative: N-, O-, and S-Acetylations and acylations
Ghosh, Santanu,Purkait, Anisha,Jana, Chandan K.
supporting information, p. 8721 - 8727 (2020/12/30)
An operationally simple and general method for acetylation and acylation of a wide variety of substrates (amines, alcohols, phenols, thiols, and hydrazones) has been reported. Meldrum's acid and its derivatives have been used as an air-stable, non-volatile, cost-effective, and easy to handle acetylating/acylating agent. Easily separable byproducts (CO2 and acetone) allowed the isolation of analytically pure acetylated products without the requirement of work-up and any chromatography. This journal is
Direct amide formation in a continuous-flow system mediated by carbon disulfide
Orsy, Gy?rgy,Fül?p, Ferenc,Mándity, István M.
, p. 7814 - 7818 (2020/12/28)
Amide bonds are ubiquitous in nature. They can be found in proteins, peptides, alkaloids, etc. and they are used in various synthetic drugs too. Amide bonds are mainly made by the use of (i) hazardous carboxylic acid derivatives or (ii) expensive coupling agents. Both ways make the synthetic technology less atom economic. We report a direct flow-based synthesis of amides. The developed approach is prominently simple and various aliphatic and aromatic amides were synthetized with excellent yields. The reaction in itself is carried out in acetonitrile, which is considered as a less problematic dipolar aprotic solvent. The used coupling agent, carbon disulfide, is widely available and has a low price. The utilized heterogeneous Lewis acid, alumina, is a sustainable material and it can be utilized multiple times. The technology is considerably robust and shows excellent reusability and easy scale-up is carried out without the need of any intensive purification protocols.
N-acetylation of amines in continuous-flow with acetonitrile—no need for hazardous and toxic carboxylic acid derivatives
Fül?p, Ferenc,Mándity, István M.,Orsy, Gy?rgy
, (2020/04/29)
A continuous-flow acetylation reaction was developed, applying cheap and safe reagent, acetonitrile as acetylation agent and alumina as catalyst. The method developed utilizes milder reagent than those used conventionally. The reaction was tested on various aromatic and aliphatic amines with good conversion. The catalyst showed excellent reusability and a scale-up was also carried out. Furthermore, a drug substance (paracetamol) was also synthesized with good conversion and yield.
IrIII-Catalyzed direct syntheses of amides and esters using nitriles as acid equivalents: A photochemical pathway
Talukdar, Ranadeep
supporting information, p. 5303 - 5308 (2020/04/17)
An unprecedented IrIII[df(CF3)ppy]2(dtbbpy)PF6-catalyzed simple photochemical process for direct addition of amines and alcohols to the relatively less reactive nitrile triple bond is described herein. Various amides and esters are synthesized as the reaction products, with nitriles being the acid equivalents. A mini-library of different types of amides and esters is made using this mild and efficient process, which uses only 1 mol% of photocatalyst under visible light irradiation (λ = 445 nm). The reaction strategy is also efficient for gram-scale synthesis.
Synthesis of diverse libraries of carboxamides via chemoselective N-acylation of amines by carboxylic acids employing Br?nsted acidic IL [BMIM(SO3H)][OTf]
Savanur, Hemantkumar M.,Malunavar, Shruti S.,Prabhala, Pavankumar,Sutar, Suraj M.,Kalkhambkar, Rajesh G.,Laali, Kenneth K.
supporting information, (2019/09/30)
Chemoselective N-acylation of amines with carboxylic acids as acyl electrophiles and Br?nsted acidic IL [BMIM(SO3H)][OTf] as promoter is reported under both thermal and microwave irradiation to produce libraries of carboxamides in good to excellent yields after a simple workup. The protocol is compatible with structurally diverse 1° and 2° amines and works in the presence of sensitive functional groups such as thiols and phenols. The potential for recycling and reuse of the IL is also demonstrated.
Frustrated Lewis Pair Catalyzed Hydrogenation of Amides: Halides as Active Lewis Base in the Metal-Free Hydrogen Activation
Sitte, Nikolai A.,Bursch, Markus,Grimme, Stefan,Paradies, Jan
supporting information, p. 159 - 162 (2019/01/04)
A method for the metal-free reduction of carboxylic amides using oxalyl chloride as an activating agent and hydrogen as the final reductant is introduced. The reaction proceeds via the hydrogen splitting by B(2,6-F2-C6H3)3 in combination with chloride as the Lewis base. Density functional theory calculations support the unprecedented role of halides as active Lewis base components in the frustrated Lewis pair mediated hydrogen activation. The reaction displays broad substrate scope for tertiary benzoic acid amides and α-branched carboxamides.
Providing a New Aniline Bioisostere through the Photochemical Production of 1-Aminonorbornanes
Staveness, Daryl,Sodano, Taylor M.,Li, Kangjun,Burnham, Elizabeth A.,Jackson, Klarissa D.,Stephenson, Corey R.J.
supporting information, p. 215 - 226 (2019/01/21)
Recent years have witnessed an increasing focus on saturated substructures within drug development as a result of the pharmacokinetic and toxicological benefits correlated with higher saturation content. However, the synthetic challenges presented by densely functionalized saturated architectures generally prohibit their evaluation. The abundance of anilines within high-throughput screening libraries is demonstrative of these competing needs. Anilines are prone to adverse metabolic processing, commonly necessitating re-engineering of a given drug lead to ameliorate CYP450 inhibition and/or glutathione adduction issues, but the ease with which these systems are prepared outweighs the toxicity risks. This article contributes to the need for aniline bioisosteres through the development of a robust, photochemical methodology that supplies 1-aminonorbornanes, saturated bicyclic ring systems that offer similar spatial occupancy to anilines while improving metabolic stability. The chemistry provided herein details an efficient and flexible route toward architecturally distinctive 1-aminonorbornanes through the use of visible-light photoredox catalysis. The incorporation of readily diversifiable functional handles (e.g., -OH, -CO2Me, -NHBoc, -NHCbz) illustrates the potential utility of these 1-aminonorbornanes within drug-discovery programs. Additionally, these motifs offer improved metabolic stability relative to that of their aniline congeners (as demonstrated through microsomal stability assays and metabolite identification efforts), indicating applicability of 1-aminonorbornanes as aniline bioisosteres. This report describes the photochemical conversion of aminocyclopropanes into 1-aminonorbornanes via formal [3 + 2] cycloadditions initiated by homolytic fragmentation of amine radical cation intermediates. Aligning with the modern movement toward sp3-rich motifs in drug discovery, this strategy provides access to a diverse array of substitution patterns on this saturated carbocyclic framework while offering the robust functional-group tolerance (e.g., -OH, -NHBoc) necessary for further derivatization. Evaluating the metabolic stability of selected morpholine-based 1-aminonorbornanes demonstrated a low propensity for oxidative processing and no proclivity toward reactive metabolite formation, suggesting a potential bioisosteric role for 1-aminonorbornanes. Continuous-flow processing allowed for efficient operation on the gram scale, providing promise for translation to industrially relevant scales. This methodology only requires low loadings of a commercially available, visible-light-active photocatalyst and a simple salt; thus, it stays true to sustainability goals while readily delivering saturated building blocks that can reduce metabolic susceptibility within drug development programs.
