Unified Approach to the Chemoselective α-Functionalization of Amides with Heteroatom Nucleophiles

Journal of the American Chemical Society, Год журнала: 2019, Номер 141(46), С. 18437 - 18443

Опубликована: Ноя. 12, 2019

Functionalization at the α-position of carbonyl compounds has classically relied on enolate chemistry. As a result, generation new C–X bond, where X is more electronegative than carbon requires an oxidation event. Herein we show that, by rendering amides electrophilic through mild and chemoselective umpolung transformation, broad range widely available oxygen, nitrogen, sulfur, halogen nucleophiles can be used to generate α-functionalized amides. More 60 examples are presented establish generality this process, calculations mechanistic aspects underline fragmentation pathway that accounts for broadness methodology.

Язык: Английский

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Direct Amidation of Esters by Ball Milling**

Angewandte Chemie International Edition, Год журнала: 2021, Номер 60(40), С. 21868 - 21874

Опубликована: Авг. 6, 2021

The direct mechanochemical amidation of esters by ball milling is described. operationally simple procedure requires an ester, amine, and substoichiometric KOtBu was used to prepare a large diverse library 78 amide structures with modest excellent efficiency. Heteroaromatic heterocyclic components are specifically shown be amenable this protocol. This synthesis platform has been applied the active pharmaceutical ingredients (APIs) agrochemicals as well gram-scale pharmaceutical, all in absence reaction solvent.

Язык: Английский

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Highly Chemoselective Transamidation of Unactivated Tertiary Amides by Electrophilic N−C(O) Activation by Amide‐to‐Acyl Iodide Re‐routing

Angewandte Chemie International Edition, Год журнала: 2022, Номер 61(24)

Опубликована: Март 31, 2022

The challenging transamidation of unactivated tertiary amides has been accomplished via cooperative acid/iodide catalysis. Most crucially, the method provides a novel manifold to re-route reactivity N,N-dialkyl through reactive acyl iodide intermediates, thus reverting classical order carboxylic acid derivatives. This direct route amide-to-amide bond interconversion with excellent chemoselectivity using equivalent amounts amines. combination and identified as essential factor activate amide C-N electrophilic catalytic activation, enabling production new desired transamidated products wide substrate scope both amines, including late-stage functionalization complex APIs (>80 examples). We anticipate that this powerful activation mode bonds will find broad-ranging applications in chemical synthesis.

Язык: Английский

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Classes of Amides that Undergo Selective N–C Amide Bond Activation: The Emergence of Ground-State Destabilization

The Journal of Organic Chemistry, Год журнала: 2022, Номер 88(19), С. 13371 - 13391

Опубликована: Сен. 2, 2022

Ground-state destabilization of the N–C(O) linkage represents a powerful tool to functionalize historically inert amide bond. This burgeoning reaction manifold relies on availability bond precursors that participate in weakening nN → π*C=O conjugation through N–C twisting, N pyramidalization, and electronic delocalization. Since 2015, acyl activation ground-state has been achieved by transition-metal-catalyzed oxidative addition bond, generation radicals, transition-metal-free addition. Perspective summarizes contributions our laboratory development new ground-state-destabilized enabled twist synthetic utility amides cross-coupling reactions reactions. The use as electrophiles enables plethora previously unknown transformations such coupling, decarbonylative radical coupling forge C–C, C–N, C–O, C–S, C–P, C–B bonds. Structural studies activated catalytic systems developed past decade enable view change from "traditionally inert" "readily modifiable" functional group with continuum reactivity dictated destabilization.

Язык: Английский

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Ni‐Catalyzed Divergent Synthesis of 2‐Benzazepine Derivatives via Tunable Cyclization and 1,4‐Acyl Transfer Triggered by Amide N‐C Bond Cleavage

Angewandte Chemie International Edition, Год журнала: 2022, Номер 61(25)

Опубликована: Апрель 6, 2022

Abstract Ligand‐directed divergent synthesis can transform common starting materials into distinct molecular scaffolds by simple tuning different ligands. This strategy enables the rapid construction of structurally rich collection small molecules for biological evaluation and reveals novel modes catalytic transformation, representing one most sought‐after challenges in synthetic chemistry. We herein report a Ni‐catalyzed ligand‐controlled tunable cyclization/cross‐couplings pharmacologically important 2‐benzazepine frameworks. The bidentate ligand facilitates nucleophilic addition aryl halides to amide carbonyl, followed 1,4‐acyl transfer cross‐coupling obtain 2‐benzazepin‐5‐ones benzo[c]pyrano[2,3‐e]azepines. tridentate promotes selective 7‐ endo cyclization/cross‐coupling access 2‐benzazepin‐3‐ones. protocol operates under mild reaction conditions with cyclization patterns that be easily modulated through backbone.

Язык: Английский

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Direct Catalytic Amidations from Carboxylic Acid and Ester Derivatives: A Review

Catalysts, Год журнала: 2023, Номер 13(2), С. 366 - 366

Опубликована: Фев. 7, 2023

The prevalence of amides in biological systems and chemical fields such as polymers, materials natural products drives continuous research on novel procedures to obtain these ubiquitous functional groups. Currently, efforts this purpose are mainly focused around the discovery direct catalytic methods that more atom economic, safe practical for diversified applications (e.g., organic, medicinal peptide chemistries, material polymer purposes, etc.), accordance with green chemistry principles. field amide synthesis has attained a level significance number reviews articles addressing it grown exponentially last decade. Rather than providing general overview amidation methods, which have been described broadly well recent literature, review is highlight formation bonds from amines carboxylic acids or esters. goal emphasize mechanistic aspects, but also discuss substrate tolerance racemization issues (when applicable).

Язык: Английский

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Diversification of Acrylamide Polymers via Direct Transamidation of Unactivated Tertiary Amides

Journal of the American Chemical Society, Год журнала: 2024, Номер 146(2), С. 1627 - 1634

Опубликована: Янв. 8, 2024

Postpolymerization modification offers a versatile strategy for synthesizing complex macromolecules, yet modifying acrylamide polymers like poly(N,N-dimethylacrylamide) (PDMA) is notoriously challenging due to the inherent stability and low reactivity of amide bonds. In this study, we unveil novel approach direct transamidation PDMA, leveraging recent advances in unactivated tertiary substrates. By exploiting photoiniferter polymerization, extended ultrahigh-molecular-weight (UHMW) showcasing unprecedented postpolymerization synthetic exceeding 106 g/mol. We also designed copolymers comprising both moderately reactive N-methyl-N-phenyl amides, along with less reactive, fully alkyl-substituted N,N-dimethyl amides PDMA. This disparate enabled sequential, chemoselective by initially targeting more pendant aryl nucleophilic aromatic amines, second, transamidating untouched moieties aliphatic yielding uniquely diversified copolymer. work not only broadens scope strategies pioneering but provides robust platform design intricate particularly realm UHMW polymers.

Язык: Английский

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Metal-Free Transamidation of Secondary Amides by N–C Cleavage

The Journal of Organic Chemistry, Год журнала: 2019, Номер 84(18), С. 12091 - 12100

Опубликована: Авг. 20, 2019

Transamidation reactions represent a fundamental chemical process involving conversion of one amide functional group into another. Herein, we report facile, highly chemoselective method for transamidation N-tert-butoxycarbonylation (N-Boc) activated secondary amides that proceeds under exceedingly mild conditions in the absence any additives. Because this reaction is performed metals, oxidants, or reductants, tolerates large number useful functionalities. The compatible with diverse and nucleophilic amines, affording products excellent yields through direct addition to bond. utility methodology highlighted synthesis Tigan, commercial antiemetic, directly from We expect new metal-free will have broad implications development transformations bond as key step.

Язык: Английский

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Electrochemically Enabled Double C–H Activation of Amides: Chemoselective Synthesis of Polycyclic Isoquinolinones

Organic Letters, Год журнала: 2019, Номер 21(24), С. 9841 - 9845

Опубликована: Дек. 12, 2019

We developed an electrochemically enabled dehydrogenative annulation reaction of amides and alkynes for the synthesis antitumor polycyclic isoquinolinones through a double C-H activation route. No external oxidant is required in this reaction, electricity used Ru catalyst circulation. The most remarkable feature effective improvement product regioselectivity under mild electrolytic conditions comparison with previously set strong conditions.

Язык: Английский

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KO^tBu-Promoted Transition-Metal-Free Transamidation of Primary and Tertiary Amides with Amines

Organic Letters, Год журнала: 2019, Номер 21(17), С. 6690 - 6694

Опубликована: Авг. 20, 2019

This work discloses transamidation of primary and tertiary amides with a range aryl, heteroaryl, aliphatic amines using potassium tert-butoxide. The reaction proceeds at room temperature under transition-metal-free conditions providing secondary in high yields. Moreover, cyclopropyl amine ring-opening to provide rapid access enamides.

Язык: Английский

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