Challenges and Breakthroughs in Selective Amide Activation

Angewandte Chemie International Edition, Journal Year: 2022, Volume and Issue: 61(49)

Published: Sept. 20, 2022

In contrast to ketones and carboxylic esters, amides are classically seen as comparatively unreactive members of the carbonyl family, owing their unique structural electronic features. However, recent decades have emergence research programmes focused on selective activation under mild conditions. past four years, this area has continued rapidly develop, with new advances coming in at a fast pace. Several novel strategies been demonstrated effective tools for amide activation, enabling transformations that once synthetically useful mechanistically intriguing. This Minireview comprises field, highlighting trends breakthroughs what could be called age activation.

Language: Английский

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meta-Nitration of Pyridines and Quinolines through Oxazino Azines

Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: 147(9), P. 7485 - 7495

Published: Feb. 24, 2025

meta-Nitration of azines (pyridines and quinolines) serves as a powerful method for the prompt construction derivatization several pharmaceuticals, agrochemicals, materials. However, due to inherent electronic properties pyridines, achieving direct selective meta-C-H nitration under mild conditions has been long-standing challenge in synthetic chemistry. Currently, there is no adequate strategy late-stage pyridine-containing drugs drug precursors. To address this void, we introduce practical protocol highly regioselective meta-nitration pyridines using dearomatization-rearomatization strategy. The introduced provides diversification platform at meta-position via radical pathway. This mild, open-air, one-pot, scalable, catalyst-free process employed pyridine containing drugs, precursors, ligands limiting reagents. Consecutive C3 C5 difunctionalization also achieved with complete regiocontrol relying on sequential addition, which further highlights potential presented work. Additionally, obtained products could be transformed into meta-amino azine other valuable building blocks. Incorporating N-heterocyclic amine structures through amidation ibuprofen significantly improved drug's clinical success, highlighting importance

Language: Английский

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Generation of Oxyphosphonium Ions by Photoredox/Cobaloxime Catalysis for Scalable Amide and Peptide Synthesis in Batch and Continuous‐Flow

Angewandte Chemie International Edition, Journal Year: 2021, Volume and Issue: 61(5)

Published: Nov. 16, 2021

Abstract Phosphine‐mediated deoxygenative nucleophilic substitutions, such as the Mitsunobu reaction, are of great importance in organic synthesis. However, conventional protocols require stoichiometric oxidants to trigger formation oxyphosphonium intermediates for subsequent additions. Through dual catalysis photoredox and cobaloxime, we realized a radical strategy catalytic acyloxyphosphonium ions that enables direct amidation. The protocol exhibits broad scope has been used late‐stage amidation drug molecules. In addition batch reactions, continuous‐flow reactor was developed, enabling rapid peptide synthesis on gram scale. successful assembly tetrapeptide solid support further demonstrated versatility this photocatalytic system. Moreover, experimental computational studies consistent with hypothesis being formed key intermediates.

Language: Английский

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Mechanistic Approach Toward the C4‐Selective Amination of Pyridines via Nucleophilic Substitution of Hydrogen

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: 63(24)

Published: April 9, 2024

Abstract The development of site‐selective functionalization N‐heteroarenes is highly desirable in streamlined synthesis. In this context, direct amination pyridines stands as an important synthetic methodology, with particular emphasis on accessing 4‐aminopyridines, a versatile pharmacophore medicinal chemistry. Herein, we report reaction manifold for the C4‐selective by employing nucleophilic substitution hydrogen (S N H). Through 4‐pyridyl pyridinium salt intermediates, 4‐aminopyridine products are obtained aqueous ammonia without intermediate isolation. notable regioselectivity was achieved electronic tuning external pyridine reagents along maximization polarizability proton elimination stage. Further mechanistic investigations provided guiding principle selective C−H pyridination additional N‐heteroarenes, presenting strategic avenue installation diverse functional groups.

Language: Английский

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Chiral Bisphosphine-Catalyzed Asymmetric Staudinger/aza-Wittig Reaction: An Enantioselective Desymmetrizing Approach to Crinine-Type Amaryllidaceae Alkaloids

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(20), P. 14136 - 14148

Published: April 20, 2024

An unprecedented chiral bisphosphine-catalyzed asymmetric Staudinger/aza-Wittig reaction of 2,2-disubstituted cyclohexane-1,3-diones is reported, enabling the facile access a broad range cis-3a-arylhydroindoles in high yields with excellent enantioselectivities. The key to success this work relies on first application bisphosphine DuanPhos reaction. effective reductive system has been established address challenging PV═O/PIII redox cycle associated catalyst. In addition, comprehensive experimental and computational investigations were carried out elucidate mechanism Leveraging newly developed chemistry, enantioselective total syntheses several crinine-type Amaryllidaceae alkaloids, including (+)-powelline, (+)-buphanamine, (+)-vittatine, (+)-crinane, have accomplished remarkable conciseness efficiency.

Language: Английский

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Nickel‐Catalyzed Highly Selective Radical C−C Coupling from Carboxylic Acids with Photoredox Catalysis

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: 63(32)

Published: May 24, 2024

Controlling the cross-coupling reaction between two different radicals is a long-standing challenge due to process occurring statistically, which would lead three products, including homocoupling products and one product. Generally, selectivity achieved by persistent radical effect (PRE) that requires presence of transient radical, thus resulting in limited precursors. In this paper, highly selective alkyl with acyl construct C(sp

Language: Английский

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Photomediated reductive coupling of nitroarenes with aldehydes for amide synthesis

Chemical Science, Journal Year: 2022, Volume and Issue: 13(32), P. 9361 - 9365

Published: Jan. 1, 2022

In view of the widespread significance amide functional groups in organic synthesis and pharmaceutical studies, an efficient practical synthetic protocol that avoids use stoichiometric activating reagents or metallic reductants is highly desirable. A straight-forward pathway to access amides from abundant chemical feedstock would offer a strategic advantage complex amides. We herein disclose direct reductive amidation reaction using readily available aldehydes nitroarenes enabled by photo-mediated hydrogen atom transfer catalysis. It production toxic waste. While represent classic class electrophilic synthons, corresponding nucleophilic acyl radicals could be directly accessed photo catalysis, enabling polarity inversion. Our method provides orthogonal strategy conventional couplings, tolerating substituents such as free alcohols sensitive amines carbonyl formyl groups. The utilization this demonstrated late-stage modification biologically active molecules drug leflunomide lidocaine.

Language: Английский

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C2-Selective, Functional-Group-Divergent Amination of Pyrimidines by Enthalpy-Controlled Nucleophilic Functionalization

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(7), P. 2885 - 2892

Published: Feb. 9, 2022

Synthesis of heteroaryl amines has been an important topic in organic chemistry because their importance small-molecule discovery. In particular, 2-aminopyrimidines represent a highly privileged structural motif that is prevalent bioactive molecules, but general strategy to introduce the pyrimidine C2–N bonds via direct functionalization elusive. Here we describe synthetic platform for site-selective C–H affords pyrimidinyl iminium salt intermediates, which then can be transformed into various amine products situ. Mechanism-based reagent design allowed C2-selective amination pyrimidines, opening new scope functionalization. Our method compatible with broad range pyrimidines sensitive functional groups and access complex aminopyrimidines high selectivity.

Language: Английский

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Two-Component Redox Organocatalyst for Peptide Bond Formation

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(8), P. 3637 - 3643

Published: Feb. 21, 2022

Peptides are fundamental therapeutic modalities whose sequence-specific synthesis can be automated. Yet, modern peptide remains atom uneconomical and requires an excess of coupling agents protected amino acids for efficient amide bond formation. We recently described the rational design organocatalyst that operate on Fmoc acids─the standard monomers in automated (J. Am. Chem. Soc. 2019, 141, 15977). The catalytic cycle centered conversion carboxylic acid to selenoester, which was activated by a hydrogen bonding scaffold amine coupling. selenoester generated situ from diselenide catalyst stoichiometric amounts phosphine. Although prior system catalyzed oligopeptide solid phase, it had two significant requirements limited its utility as alternative agents─it depended phosphine required molecular sieves dehydrating agent. Here, we address these limitations with optimized method only no new utilizes two-component organoreductant/organooxidant-recycling strategy catalyze

Language: Английский

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Mechanistic Details of Asymmetric Bromocyclization with BINAP Monoxide: Identification of Chiral Proton-Bridged Bisphosphine Oxide Complex and Its Application to Parallel Kinetic Resolution

Journal of the American Chemical Society, Journal Year: 2022, Volume and Issue: 144(9), P. 3913 - 3924

Published: Feb. 28, 2022

The mechanism of our previously reported catalytic asymmetric bromocyclization reactions using 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP) monoxide was examined in detail by the means control experiments, NMR studies, X-ray structure analysis, and CryoSpray electrospray ionization mass spectrometry (ESI-MS) analysis. chiral BINAP transformed to a key catalyst precursor, proton-bridged bisphosphine oxide complex (POHOP·Br), presence N-bromosuccinimide (NBS) contaminating water. thus-formed POHOP further reacts with NBS afford dioxide molecular bromine (Br2) simultaneously equimolar amounts. While resulting Br2 is activated form more reactive brominating reagent (Br2─NBS), serves as bifunctional catalyst, acting both Lewis base that Br2─NBS agent (P═O+─Br) also Brønsted for activation substrate. By taking advantage this novel concerted Lewis/Brønsted catalysis dioxide, we achieved first regio- chemodivergent parallel kinetic resolutions (PKRs) racemic unsymmetrical bisallylic amides via bromocyclization.

Language: Английский

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