Reduction Of Amides Research Articles

Highly Chemoselective Synthesis of α, α-Dideuterio Amines by the Reductive Deuteration of Thioamides Using Mild SmI2-D2O.

An efficient and chemoselective protocol for the single-electron-transfer (SET) reductive deuteration of thioamides using SmI2 and D2O is reported. This method uniquely produces α,α-dideuterio amines via a thio-ketyl radical intermediate without generating alcohol byproducts, distinguishing it from the SET reduction of amides. The inherent high reactivity of thioamides obviates the need for ligands like Et3N to improve the reducing power of SmI2, thereby enabling milder reaction conditions that are compatible with a broad range of sensitive functional groups. This protocol tolerates both primary and secondary aliphatic and aromatic thioamides, leading to the synthesis of 27 α,α-dideuterio amines and valuable deuterated nitrogen heterocycles with >95% deuterium incorporations.

A Tandem Catalysis for Isoindolinone Synthesis over Single-Atom Pd/TiO2 Catalyst.

Developing an efficient strategy to replace the conventional synthesis method for producing isoindolinone (IIO) scaffold, a crucial structural motif for constructing pharmaceutical molecules, remains to be a great challenge. Herein, a single-atom Pd/TiO2 tandem catalysis has been developed for the IIO scaffold synthesis by using readily available phthalic anhydride (PA), ammonia, and H2. The single-atom Pd/TiO2 catalyst demonstrates superior catalytic performance, achieving a PA conversion of 99 %, an IIO selectivity of 91 %, and a turnover frequency (TOF) up to 4807 h-1. This exceptional performance can be attributed to the tandem catalysis between TiO2 support and single-atom Pd. The TiO2 efficiently catalyzes the conversion of PA with ammonia to form phthalimide (PAM), subsequently transformed into IIO over TiO2 through the reaction of PAM with NH3 and the spillover hydrogen species derived from single-atom Pd. Notably, NH3 functions not only as a reactant but also as a promoter to accelerate the reduction of amides combined with the Pd/TiO2 catalyst. This tandem catalysis of a single-atom Pd/TiO2 catalyst provides a promising strategy for the synthesis of the crucial IIO platform molecules.

Nickel‐Catalyzed Reductive Amidation of Aryl Sulfonium Salts with Isocyanates for Amide Synthesis via C−S Bond Activation

AbstractA nickel‐catalyzed reductive amidation of aryl sulfonium salts with isocyanates for amide synthesis via C−S bond cleavage was developed. The reactions proceeded smoothly at ambient temperature in the presence of nickel catalyst and manganese metal in DMF to give a variety of amides in moderate to good yields with wide functional group tolerance.

Reduction of Carboxamides Into Amines Catalyzed by La[NH‐2,6‐iPr2‐4‐FcC6H2]3/HBpin

ABSTRACTReduction of carboxamides is an efficient approach to obtain the corresponding amines, albeit it is one of the most problematic. In this work, by use of pinacolborane (HBpin) as a reductant, the rare‐earth metal tris (arylamido) complex supported by a ferrocenyl‐modified arylamido ligand La[NH‐2,6‐iPr2‐4‐FcC6H2]3 was employed as a precatalyst for primary and secondary amide reductions. This catalyst system exhibited high activity toward hydroborative reduction of amides to amines under mild conditions, as well good tolerance for heteroatoms and functional groups in the reduction. A lanthanide hydride was experimentally verified as the active species and the reduction mechanism was proposed.

Azirine Weinreb amides: Preparation and use in the synthesis of 2-acylated aziridines and azirines

Azirine Weinreb amides (N-methoxy-N-methyl-2H-azirine-2-carboxamides) were synthesized in yields of 35–94 % by the reaction of N,O-dimethylhydroxylamine with 2H-azirine-2-carbonyl chlorides, formed by the catalytic isomerization of 5-chloroisoxazoles. Red-Al reduction of azirine Weinreb amides affects only the azirine CN bond and leaves the C(O)NMeOMe group unaffected, forming stereoselectively 1-unprotected 3-substituted cis-N-methoxy-N-methylaziridine-2-carboxamides. The developed approach is a stereo-complementary addition to the previously proposed method for preparing unprotected trans-N-methoxy-N-methyl-3-phenylaziridine-2-carboxamide. The Weinreb amide group in the synthesized cis-N-methoxy-N-methylaziridine-2-carboxamides was used to prepare cis-2-acyl-3-arylaziridines by reaction with organometallic compounds. The reaction of organomagnesium compounds with azirine Weinreb amides allow the stereoselective preparation of 3-aryl-3-aryl/hetary/alkyl-N-methoxy-N-methylaziridine-2-carboxamides; which, in turn, were used to obtain the corresponding aziridinyl ketones. The reaction of azirine Weinreb amides with bulky substituents in the 3-position of azirine with organometallic compounds occurs only at the C(O)NMeOMe group with retention of the azirine CN bond with the formation of 2-acyl-2H-azirines.

Nickel-Catalyzed Reductive Amidation of Aryl Fluorosulfates with Isocyanates: Synthesis of Amides via C-O Bond Cleavage.

With the assistance of nickel as catalyst, 2,2'-bipyridine (bpy) as ligand, and manganese as reducing metal, the reductive amidation of isocyanates with readily accessible aryl fluorosulfates could be successfully accomplished. The reactions proceeded effectively via C-O bond activation in DMF at room temperature, enabling the facile synthesis of a range of structurally diverse amides in moderate to high yields with broad functionality compatibility. In addition, the synthetic usefulness of the method was further demonstrated by applying the reaction in scale-up synthesis and the late-stage functionalization of complex molecules with biological activities.

Intramolecular Reductive Amidation of Unactivated Esters with Nitroarenes: A Telescoped Synthesis of Tetrahydropyrrolo/Pyrido[1,2-a]quinoxalinones.

A reductive amidation of unactivated esters with nitroarenes, a key step in the telescopic synthesis of tetrahydropyrrolo[1,2-a]quinoxalinones and tetrahydropyrido[1,2-a]quinoxalinones, is reported. The process involves an intermolecular base-mediated SNAr reaction, followed by intramolecular reductive amidation employing sodium dithionite. The substrate scope coupled with the demonstration of the synthesis of pharmaceuticals is reported. The key features include nitro reduction at room temperature, easy purification without chromatography, amidation of unactivated esters without any externally added activating agent, and a telescopic process.

A Novel Approach of Electrocatalytic Deamination From Aromatic Amide to Diarylimide on Ni-PTFE Modified Electrode.

A hydrophobic Ni-PTFE modified electrode has been prepared by constant current and cathodic electroplating with a nickel sheet as substrate in a PTFE suspension. Then the Ni-PTFE modified electrode was used for electroreduction from aromatic amide to diarylimide. The electrochemical characterizations such as cyclic voltammogram, EIS, polarization curves, and electrode stability have been carried out by electrochemical workstation. The structure of the electroreduction product diarylimide was characterized by 1HNMR, FT-IR, MS(Mass Spectrum), and EA(Elemental Analyzer). Based on the hydrophobicity of the electrode, an approach suggested that the phenyl ketone radical may be formed by electroreductive deamination at the cathode. With the construction of C-N bond by the radical coupling, the electrocatalytic reduction may be comprised of a one-electron process including an ECC (Electrochemical-Chemical-Chemical) process. The electroreduction of aromatic amide to diarylimide may be controlled by both charge migration and concentration polarization. Electrocatalytic reduction of aromatic amides on Ni-PTFE modified electrodes is all well conversion ratio.

Counterintuitive chemoselectivity in the reduction of carbonyl compounds.

The reactivity of carbonyl functional groups largely depends on the substituents on the carbon atom. Reversal of the commonly accepted order of reactivity of different carbonyl compounds requires novel synthetic approaches. Achieving selective reduction will enable the transformation of carbon resources such as plastic waste, carbon dioxide and biomass into valuable chemicals. In this Review, we explore the reduction of less reactive carbonyl groups in the presence of those typically considered more reactive. We discuss reductions, including the controlled reduction of ureas, amides and esters to aldehydes, as well as chemoselective reductions of carbonyl groups, including the reduction of ureas over carbamates, amides and esters; the reduction of amides over esters, ketones and aldehydes; and the reduction of ketones over aldehydes.

Synthesis of 1,4‐Disubstituted and 1‐Substituted β‐Carbolines via 3‐Substituted 2‐Acylindoles

Abstractβ‐Carbolines represent a large class of bioactive natural products, whereby most of these alkaloids bear residues at C1, and occasionally at C3, and only limited examples of 1,4‐disubstituted β‐carbolines are known. In this project we worked out a novel approach to 1,4‐disubstituted β‐carbolines and performed a comprehensive analysis of the scope and limitations of this methodology. The 1,4‐disubstituted β‐carbolines were synthesized via 3‐substituted 2‐acylindoles, for which effective synthesis procedures were developed. Our studies revealed that a broad range of target compounds with electron‐withdrawing substituents at C4 are accessible. Limitations of this method arose from competing CH and NH acidities of precursors. Nevertheless, the work described herein provides a unique approach to highly substituted β‐carbolines. In addition, intermediates from this route opened a novel approach to 1‐substituted β‐carbolines utilizing a chemoselective Mo(CO)6‐catalyzed amide reduction with tetramethyldisiloxane.

Revealing the crucial role of cuticular wax components in postharvest water loss in passion fruit (Passiflora edulis Sims.)

Passion fruit (Passiflora edulis Sims.) is highly prone to water loss and shrinkage after harvesting. The fruit cuticle serves as a crucial barrier to prevent non-stomatal water loss. However, the impact of cuticle on water loss in passion fruit remains unclear. Therefore, the present study primarily focuses on the influence of the cuticle on postharvest water loss of passion fruit, specifically emphasizing the changes in cuticular wax components. Our results showed that both the thickness and content of cutin decreased during storage. The degradation of wax components exhibited a similar trend to fruit water loss. At the end of the storage, n-triacontane content was stored at 25 °C retained 2.8% of that at 7 °C. Follwed by stearic acid, palmitate, and so on, with amounts at 25 °C are 9.3% and 13.8% at 7 °C, respectively. Interestingly, the reduction of amides, erucamide and hexadecanamide lead to water loss in fruit. So far as we know, this is the first report demonstrating that cuticle amides influence water loss in fruit. This study provides new insights into the role of cuticle in the water loss of passion fruit.

Direct Synthesis of α-Ketoamides via Copper-Catalyzed Reductive Amidation of Nitroarenes with α-Oxocarboxylic Acids.

Nitroarenes are known for their stability, low toxicity, easy availability, and cost-effectiveness, making them one of the most fundamental chemical feedstocks. The direct utilization of nitroarenes as nitrogen sources in amidation reactions offers significant advantages over using arylamines. Herein, we disclose a streamlined method for constructing α-ketoamides through the direct coupling of nitroarenes with α-oxocarboxylic acids. This transformation obviates the need for preparing, isolating, and purifying arylamines, leading to improved efficiency, cost-effectiveness, and time savings.

Development of the Synthetic Route to PF-06878031 Part 2: Amide Reduction Route

Development of the Synthetic Route to PF-06878031 Part 2: Amide Reduction Route

Total Synthesis of Daphniphyllum Alkaloids: (+)-Daphlongamine E, (+)-Calyciphylline R, and (–)-10-Deoxydaphnipaxianine A

AbstractHere, we wish to describe our detailed efforts in the total synthesis of three calyciphylline A-type alkaloids, namely (+)-daphlongamine E, (+)-calyciphylline R, and (–)-10-deoxydaphnipaxianine A. Important steps in our approach include a Pt-catalyzed nitrile hydration, a Babler–Dauben rearrangement, a novel selective amide reduction tactic, and an oxidative Nazarov cyclization via an unfunctionalized tertiary divinyl carbinol (TDC).

Cobalt-catalyzed synthesis of amides from alkenes and amines promoted by light.

Catalytic methods to couple alkene and amine feedstocks are valuable in synthetic chemistry. The direct carbonylative coupling of alkenes and amines holds promise as a perfectly atom-economical approach to amide synthesis, but general methods remain underdeveloped. Herein, we report an alkene hydroaminocarbonylation catalyzed by unmodified, inexpensive cobalt carbonyl under mild conditions and low pressure promoted by light. Silane addition after the reaction enables sequential cobalt-catalyzed amide reduction, constituting a formal alkene hydroaminomethylation. These methods exhibit exceptional scope across both alkene and amine components with high chemo- and regioselectivity and proceed efficiently even in the absence of solvent. The formation of a hydridocobalt through photodissociation of a carbonyl ligand is proposed to enable catalytic activity under mild conditions, which addresses a long-standing challenge in catalysis.

Triflic acid-promoted post-Ugi condensation for the assembly of 2,6-diarylmorpholin-3-ones.

We report a two-step one-pot synthesis of the 2,6-diarylmorpholin-3-one core based on the Ugi reaction of 2-oxoaldehyde with 2-hydroxycarboxylic acid, a primary amine and tert-butyl isocyanide followed by a triflic acid-promoted intramolecular condensation accompanied by the loss of the isocyanide-originated amide moiety. The overall transformation proceeds with complete retention of stereoconfiguration at the 2-hydroxycarboxylic acid-derived chiral center, allowing the target morpholin-3-ones to be obtained in an enantiopure form. Subsequent double bond hydrogenation and amide reduction allow the degree of unsaturation to be reduced, providing a convenient entry to the cis-2,6-diphenylmorpholine motif.

TiF4-mediated, one-pot, reductive amination of carboxylic acids with borane-ammonia.

A facile one-pot, two-step, reductive alkylation of amines with carboxylic acids has been achieved with BH3-NH3 as an air- and moisture-stable reductant in the presence of TiF4. The catalyst is effective for both amidation and reduction steps, and the product amines are isolated in high yields as either the free amines, for those products containing an arylamine, or the borane-complexes. The free amine can be separated from these complexes using BF3-Et2O, followed by hydrolysis. The amide reduction has been demonstrated for primary, secondary, and tertiary amides, as well as lactams, and the reductive amination is applicable to a wide variety of aromatic and aliphatic acids as well as amines.

Machine Learning Directed Discovery and Optimisation of a Platinum-Catalysed Amide Reduction

The discovery and optimisation of reaction conditions leading to the reduction of amides, a fundamental large-scale industrial reaction, is achieved using a machine learning (ML) platform and a platinum catalyst....

Iron-Mediated Reductive Amidation of Triazine Esters with Nitroarenes.

A reductive amidation of triazine esters with nitroarenes by using cheap iron as a reducing metal in the presence of TMSCl in DMF was developed. The reactions proceeded efficiently under transition metal-free conditions to give the corresponding amides in moderate to good yields with good functional group compatibility. Preliminary mechanistic investigations indicated that nitrosobenzene, N-phenyl hydroxylamine, azoxybenzene, azobenzene, aniline, and N-arylformamide possibly served as the intermediates of the reaction.

Semi-rational engineering an aldo–keto reductase for stereocomplementary reduction of α-keto amide compounds

Enantio-pure α-hydroxy amides are valuable intermediates for the synthesis of chiral pharmaceuticals. The asymmetric reduction of α-keto amides to generate chiral α-hydroxy amides is a difficult and challenging task in biocatalysis. In this study, iolS, an aldo–keto reductase from Bacillus subtilis 168 was exhibited as a potential biocatalyst, which could catalyze the reduction of diaryl α-keto amide such as 2-oxo-N, 2-diphenyl-acetamide (ONDPA) with moderate S-selectivity (76.1%, ee) and 60.5% conversion. Through semi-rational engineering, two stereocomplementary variants (I57F/F126L and N21A/F126A) were obtained with ee value of 97.6% (S) and 99.9% (R) toward ONDPA (1a), respectively, delivering chiral α-hydroxy amide with > 98% conversions. Moreover, the excellent S- and R-preference variants displayed improved stereoselectivities toward the other α-keto amide compounds. Molecular dynamic and docking analysis revealed that the two key residues at 21 and 126 were identified as the “switch”, which specifically controlled the stereopreference of iolS by regulating the shape of substrate binding pocket as well as the substrate orientation. Our results offer an effective strategy to obtain α-hydroxy amides with high optical purity and provide structural insights into altering the stereoselectivity of AKRs.Graphical