Metal-Free Synthesis of Heteroaryl Amines or Their Hydrochlorides via an External-Base-Free and Solvent-Free C–N Coupling Protocol

Fan, Guang-Gao; Jiang, Bowen; Sang, Wei; Cheng, Hua; Zhang, Rui; Yu, Baoyi; Yuan, Ye; Cheng, Chen; Verpoort, Francis

doi:10.1021/acs.joc.1c01467

Cited by 7 publications

(2 citation statements)

References 60 publications

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“…Reported methods for coupling five-membered heteroaryl halides with secondary amines are largely limited to small classes of privileged substrates (Scheme A). The heteroarenes investigated, with few exceptions, are generally restricted to either arenes that contain a single heteroatom (e.g., thiophene, indole) ,, or activated 2-halo-1,3-azoles, , the latter of which readily undergo S N Ar reactions in the absence of Pd. , The scope of the amine coupling partner is similarly constrained. Several examples of relatively acidic primary nitrogen nucleophiles, such as anilines , and amides, have been reported using weak bases, yet comparatively few studies have demonstrated coupling reactions of simple aliphatic amines, , especially α-branched , or acyclic secondary amines.…”

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confidence: 99%

Pd-Catalyzed Amination of Base-Sensitive Five-Membered Heteroaryl Halides with Aliphatic Amines

et al. 2023

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We report a versatile and functional-group-tolerant method for the Pd-catalyzed C–N cross-coupling of five-membered heteroaryl halides with primary and secondary amines, an important but underexplored transformation. Coupling reactions of challenging, pharmaceutically relevant heteroarenes, such as 2-H-1,3-azoles, are reported in good-to-excellent yields. High-yielding coupling reactions of a wide set of five-membered heteroaryl halides with sterically demanding α-branched cyclic amines and acyclic secondary amines are reported for the first time. The key to the broad applicability of this method is the synergistic combination of (1) the moderate-strength base NaOTMS, which limits base-mediated decomposition of sensitive five-membered heteroarenes that ultimately leads to catalyst deactivation, and (2) the use of a GPhos-supported Pd catalyst, which effectively resists heteroarene-induced catalyst deactivation while promoting efficient coupling, even for challenging and sterically demanding amines. Cross-coupling reactions between a wide variety of five-membered heteroaryl halides and amines are demonstrated, including eight examples involving densely functionalized medicinal chemistry building blocks.

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confidence: 99%

Pd-Catalyzed Amination of Base-Sensitive Five-Membered Heteroaryl Halides with Aliphatic Amines

et al. 2023

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“…In 2021, our group reported the synthesis of secondary and tertiary amines between heteroaryl halides ( 54 ) and amines under metal‐, external‐base‐ and solvent‐free conditions (Scheme 11a) [39c] . Using this protocol, various heteroaromatic amines and their HCl forms ( 55 ) were obtained in up to 97 %yields.…”

Section: Carbon‐nitrogen Bond Formation Without Transition Metalsmentioning

confidence: 99%

Recent Advances in Carbon‐Nitrogen/Carbon‐Oxygen Bond Formation Under Transition‐Metal‐Free Conditions

Zhang

Song

Shi

et al. 2023

The Chemical Record

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Carbon‐heteroatom bond formation under transition‐metal free conditions provides a powerful synthetic alternative for the efficient synthesis of valuable molecules. In particular, C−N and C−O bonds are two important types of carbon‐heteroatom bonds. Thus, continuous efforts have been deployed to develop novel C−N/C−O bond formation methodologies involving various catalysts or promoters under TM‐free conditions, which enables the synthesis of various functional molecules comprising C−N/C−O bonds in a facile and sustainable manner. Considering the significance of C−N/C−O bond construction in organic synthesis and materials science, this review aims to comprehensively present selected examples on the construction of C−N (including amination and amidation) and C−O (including etherification and hydroxylation) bonds without transition metals. Besides, the involved promoters/catalysts, substrate scope, potential application and possible reaction mechanisms are also systematically discussed.

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Dual Activation of Carboxylic Acid Functionality by Protic Ionic Liquid: Solvent and Metal Free Strategy for Selective Esterification of Alcohols and Acylation of Aromatic Amines

Das

Majumdar

2022

ChemistrySelect

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Highly efficient and chemoselective esterification of alcohols and acylation of aromatic amines with carboxylic acids using imidazolium based protic ionic liquid, 1-butyl-imidazolium trifluoroacetate ([HBIm]TFA) as activator has been realized under organic volatile solvent free condition. The protic ionic liquid played dual role for activation of carboxylic acid which was proved by NMR study. A very interesting aspect of the present protocol is the acylation of less basic aromatic amines than the more reactive aliphatic amines as the later one forms salt with carboxylic acid. Our methodology offers several advantages like high yield, fast, efficient, chemo-selectivity, metal and other coupling agent free procedure, recyclability of ionic liquid used and formation of water as the only byproduct.

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Metal-Free Synthesis of Heteroaryl Amines or Their Hydrochlorides via an External-Base-Free and Solvent-Free C–N Coupling Protocol

Cited by 7 publications

References 60 publications

Pd-Catalyzed Amination of Base-Sensitive Five-Membered Heteroaryl Halides with Aliphatic Amines

Pd-Catalyzed Amination of Base-Sensitive Five-Membered Heteroaryl Halides with Aliphatic Amines

Recent Advances in Carbon‐Nitrogen/Carbon‐Oxygen Bond Formation Under Transition‐Metal‐Free Conditions

Dual Activation of Carboxylic Acid Functionality by Protic Ionic Liquid: Solvent and Metal Free Strategy for Selective Esterification of Alcohols and Acylation of Aromatic Amines

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