光/电催化喹喔啉酮官能团化反应研究进展

喹喔啉酮作为重要的含氮杂环骨架,广泛应用于抗菌化合物、抗肿瘤药物、半导体材料中.因此,开发新方法合成不同官能团化喹喔啉酮以丰富其结构多样性在近年来广受关注.在众多合成方法中,喹喔啉酮的直接C–H官能团化是一类步骤经济性较高、简便高效地构建喹喔啉酮衍生物的重要方法.近年来,光催化、电催化和光电催化技术已发展成为现代有机合成中强有力的绿色合成工具,可以有效利用光能或者电能促进有机化学转化,减少传统有机反应中的高能耗.过去几年,化学工作者在光/电催化喹喔啉酮的直接C–H官能团化反应方面进行了大量研究,开发了系列不同官能团化喹喔啉酮的绿色合成方法.本文系统总结了喹喔啉酮的光/电催化官能团化研究最新进展,重点讨论了光/电催化下自由基历程的喹喔啉酮C–H键直接官能团化反应,反应类型主要包括喹喔啉酮的3-芳基化、3-烷基化、3-氟烷基化、3-烷氧基化、3-酰化、3-氨基化、3-膦酰化、3-巯基化、3-硅烷基化和环化反应等方面,这将有助于理解光/电催化喹喔啉酮官能团化反应.反应在温和条件下可以成功产生各种碳中心或杂原子为中心的自由基,这些自由基进一步与喹喔啉酮的3-位进行加成反应,进而开发出众多有效的方法来合成不同官能团化的喹喔啉酮.这些条件温和的反应方法已经有部分成功应用于合成具有重要生物活性的喹喔啉酮化合物.此外,药物中常见的一些重要官能团,例如三氟甲基和二氟甲基等可以顺利地引入到喹喔啉酮骨架结构,这些研究为喹喔啉酮衍生物的生物活性相关研究奠定了基础.本文还对当前光/电催化喹喔啉酮官能团化反应所面临的挑战和未来发展作了展望和总结,期待在不久的将来,有机合成工作者能基于喹喔啉酮的C–H键直接官能团化开发更多不同类型的新反应.另一方面,需要进一步开发新型的非均相可见光催化剂,实现光催化剂的回收与再利用,进一步降低反应成本,促进其在药物开发、功能材料合成等应用方面的发展.     

Molecular oxygen-mediated selective hydroxyalkylation and alkylation of quinoxalin-2(1H)-ones with alkylboronic acids

Herein, an efficient molecular oxygen-mediated method for the selective hydroxyalkylation and alkylation of quinoxalin-2(1H)-ones with alkylboronic acids under transition-metal free conditions has been developed. This strategy demonstrates a broad scope of quinoxalin-2(1H)-ones and alkylboronic acids, giving 3-hydroxyalkylquinoxalin-2(1H)-ones and 3-alkylquinoxalin-2(1H)-ones in moderate-to-good yield. Control experiments reveal that a radical pathway is involved.     

Visible-light-initiated 4CzIPN catalyzed multi-component tandem reactions to assemble sulfonated quinoxalin-2(1H)-ones

A mild and efficient photochemical multi-component tandem reaction of quinoxalin-2(1H)-ones, alkenes and sulfinic acids is reported. This tandem reaction could be conveniently carried out at room temperature by employing 4CzIPN as the metal-free photocatalyst and dioxygen (air) as the environmentally benign oxidant. A number of sulfonated quinoxalin-2(1H)-ones were obtained in satisfactory yields with favorable functional group tolerance. Radical trapping experiment and fluorescence quenching experiments were performed to elucidate this visible-light mediated radical reaction process.     

TBAI/H2O-cooperative electrocatalytic decarboxylation coupling-annulation of quinoxalin-2(1H)-ones with N-arylglycines

The first example of TBAI/H₂O cooperative electrocatalytic coupling-annulation of quinoxalin-2(1H)-ones with N-arylglycines was developed. A broad range of tetrahydroimidazo[1,5-a]quinoxalin-4(5H)-ones were obtained in good to excellent yields with exclusive chemoselectivities and excellent regioselectivities. The H-hydrogen bond served as a key factor for the electrocatalytic production of aminomethyl radical at lower oxidative potential.     

Convenient synthetic method for 3-(3-substituted indol-2-yl)quinoxalin-2-ones as VEGF inhibitor

It has already been reported that 3-(indol-2-yl)quinoxalin-2-ones have a potent inhibitory effect on the growth of tumor cells based on anti-angiogenesis activity. We have also carried out a structure-activity relationship (SAR) study of 3-(indol-2-yl)quinoxalin-2-ones, which showed a potent inhibitory activity toward the vascular endothelial growth factor (VEGF)-induced proliferation of human mesangial cells and the VEGF-induced auto-phosphorylation of human umbilical vein endothelial cells. Moreover, one of these compounds has a potent medicinal effect based on anti-angiogenic action, by oral administration (Chart 1, 9). However, since the existing synthetic methods for the preparation of 3-(indol-2-yl)quinoxalin-2-ones consist of multiple steps some of which require strict anhydrous conditions, a convenient and simple synthetic method in place of the existing method is desirable. As a result of the investigations into the synthetic procedures, 3-(3-substituted indol-2-yl)quinoxalin-2-ones can be easily prepared by the condensation of 3-substituted indoles with quinoxalin-2-ones in the presence of trifluoroacetic acid (TFA). Herein, we report the examination of these reaction conditions and the application of this new synthetic method to the synthesis of the derivatives as VEGF inhibitors.     

Rearrangement in the series of 3-(2-aryl-2-oxoethyl)-3,4-dihydroquinoxalin-2(1H)-ones

4-Acetyl- and 4-succinyl-3-(2-aryl-2-oxoethyl)-3,4-dihydroquinoxalin-2(1H)-ones undergo the rearrangement into (Z)-2-(3-arylquinoxalin-2-ylidene)acetic acids accompanied by the elimination of the acyl groups. The nitration of 3-(2-oxo-2-phenylethyl)-3,4-dihydro-quinoxalin-2(1H)-one affords 5-nitro- and 7-nitro-2-carboxymethylidenequinoxalines. The bromination of quinoxalin-2-ones in AcOH gives 3-aryl-2-carboxymethylidenequinoxalines and the corresponding 7-bromo derivatives, with the former products predominating.     

Visible-Light-Induced Photocatalytic C3-Trifluoroethylation of Quinoxalin-2-(1H)-ones

A visible-light-induced Rose bengal catalyzed C3-trifluoroethylation of quinoxalin-2-(1H)-ones is reported. A wide range of quinoxalin-2-(1H)-ones was compatible, which led to the corresponding products in moderate to good yields. A gram-scale reaction proceeded well and afforded an efficient route to prepare C3-trifluoroethylated quinoxalin-2-(1H)-ones.     

Five-membered 2,3-dioxoheterocycles: LXXIII. Synthesis and thermolysis of 3-acylpyrrolo[1,2-a]quinoxaline-1,2,4(5H)-triones

Reactions of (Z)-3-(phenacylidene-2-oxo)-3,4-dihydroquinoxalin-2(1H)-ones and (Z)-3-(3,3-dimethyl-2-oxobutylidene)-3,4-dihydroquinoxalin-2(1H)-one with oxalyl chloride led to the formation of 3-acyl-1Hpyrrolo[1,2-a]quinoxaline-1,2,4(5H)-triones that at the thermal decarbonylation generated acyl(3-oxoquinoxalin-2-yl)ketenes which underwent the intramolecular stabilization giving 3-acylfuro[3,2-b]quinoxalin-2(4H)-ones.     

Recent advances and perspectives on the synthesis and C–H bond functionalization of quinoxalin-2(1H)-one

Abstract

Over the past few decades, quinoxalin-2(1H)-one derivatives are serving as active components in diverse families of drugs such as antimicrobial, anticancer, antithrombotic agents and protein kinase inhibitor. Previously, significant attention has been marked for its synthesis and recent years have also observed an upsurge in the modification of this scaffold as well as its functionalization. This review (2008–2020) focused on selective C–H bond functionalization namely arylation, amination, acylation, amidation, alkylation, benzylation, alkoxycarbonylation, cyanoalkylation and phosphorylation etc. at C-3 position of quinoxalin-2(1H)-one. Additionally, alternative complimentary route (radical cyclization protocol) for its synthesis part is well elaborated herein. We also briefly summarized the mechanistic pathway of the C–H bond functionalization approach.     

Visible-light-induced chemoselective reactions of quinoxalin-2(1H)-ones with alkylboronic acids under air/N2 atmosphere

A visible-light-induced chemoselective reactions of quinoxalin-2(1H)-ones with alkylboronic acids in the presence of air (O₂) and N₂ atmosphere was developed under transition-metal free conditions, providing 3-alkylquinoxalin-2(1H)-ones and 3,4-dihydroquinoxalin-2(1H)-ones, respectively. The overall strategy accommodates a broad scope of substituted quinoxalin-2(1H)-ones and alkylboronic acids with good to excellent product yields.     

Visible-light-induced three-component reaction of quinoxalin-2(1H)-ones,alkenes and CF3SO2Na leading to 3-trifluoroalkylated quinoxalin-2(1H)-ones

A facile and metal-free visible-light-enabled three-component reaction of quinoxalin-2(1 H)-ones,alkenes and CF₃SO₂Na has been developed under air at room temperature.This photocatalytic tandem reaction using 4 CzIPN as the photocatalyst and air as the green oxidant,provides a mild and environmentally friendly approach to access a series of 3-trifluoroalkylated quinoxalin-2(1 H)-ones.     

Electro-reductive C-H cyanoalkylation of quinoxalin-2(1H)-ones

Herein, we report a practical electro-reductive protocol for the direct C–H cyanoalkylation of quinoxalin-2(1H)-ones via iminyl radical-mediated ring opening. These mild reactions proceed under metal-, reductant-, and reagent-free conditions to provide synthetically useful cyanoalkylated quinoxalin-2(1H)-ones.     

Mn(OAc)3*2H2O promoted addition of arylboronic acids to quinoxalin-2-ones

A simple method has been developed for the synthesis of 3-aryl quinoxalin-2-one derivatives through an oxidative cross-coupling of arylboronic acids with quinoxalin-2-ones using a readily available oxidant Mn(III) acetate dihydrate. This method provides 3-aryl quinoxalin-2-one scaffolds with a broad substrate scope.     

An efficient synthesis of 3-(indol-3-yl)quinoxalin-2-ones with TfOH-catalyzed Friedel-Crafts type coupling reaction in air

An efficient one-pot synthetic approach to access a variety of 3-(indol-3-yl)quinoxalin-2-ones from various quinoxalin-2-ones and very wide scope of indoles through TfOH-catalyzed Friedel-Crafts type coupling reaction in DMF has been developed. Only 10 mol % Brønsted acid as a catalyst, air as an oxidizer, and very wide range of substrates are the prominent advantages of this method.     

A facile method for building fused quinoxaline-quinolinones via an acidless post-Ugi cascade reaction

A series of quinolino[3,4-b]quinoxalin-6(5H)-ones have been synthesized using an Ugi/deprotection/cyclization(UDC) strategy, followed by a nucleophilic aromatic substitution reaction. This facile microwave-assisted method provided good yields and could potentially be used for the construction of a diverse library of quinolino[3,4-b]quinoxalin-6(5H)-ones for high-throughput screening in medicinal chemistry.     

Fused Polycyclic Nitrogen-Containing Heterocycles: IX. Oxidative Fusion of Imidazole Ring to 3-Benzoylquinoxalin-2-ones

3--Chlorobenzyl- and 3-benzoylquinoxalin-2-ones react with benzylamine in DMSO to give intermediate 3-(-benzyliminobenzylidene)quinoxalin-2-one which is capable of existing in several tautomeric forms. The subsequent oxidative cyclocondensation leads to imidazo[1,5-a]quinoxalin-4-one. This new procedure for building up imidazo[1,5-a]quinoxalin-4-one system has been applied to the synthesis of various bis(imidazo[1,5-a]quinoxalin-4-ones).     

A facile synthesis of novel triazoloquinoxahnones and triazinoquinoxalinones

A series of 1-aryl-s-triazolo[4,3-a]quinoxalin-4-ones, 3 , were synthesized via the pyrolysis of the corresponding hydrazones, 6 . Thus, the cyclodehydrogenation occurred by refluxing them in an inert solvent (e.g. ethylene glycol) to give the triazoloquinoxalin-4-ones in a satisfactory yield. Using DMSO as a solvent for the above transformation afforded as a minor by-product an S-ylid. In contrast to earlier findings, annelation of a six-membered ring was successful and achieved through the pyrolysis of the pyruvate hydrazones derived of the quinoxalin-4-ones at ?230° to give the as-triazino[4,3-a]quinoxalin-5-ones, 4 . The reaction of 5 with acetylacetone afforded 3-(3′,5′-dimethylpyrazol-1-yl)-2(1H)-quinoxalinone, 10 . The structural assignments for the new compounds were based on their elemental analysis and spectroscopic data as well as an independent synthesis.     

Direct benzylation reactions from benzyl halides enabled by transition-metal-free photocatalysis

An S_N2-based photochemical strategy using dithiocarbamate anion as catalyst was developed for the activation of benzyl halides, which are extremely challenging to be applied as radical precursors in visible light photocatalysis. With this transition-metal-free and oxidant-free protocol, the benzylation(or cyanomethylation) of various heterocycles including quinoxalin-2(1H)-ones, coumarin, 2-phenyl-2H-indazole, 1-methyl-5-phenylpyrazin-2(1H)-one, 1-(fluoromethyl)cinnolin-4(1H)-one, and...     

Combined Photoredox and Carbene Catalysis for the Synthesis of Ketones from Carboxylic Acids**

As a key element in the construction of complex organic scaffolds, the formation of C−C bonds remains a challenge in the field of synthetic organic chemistry. Recent advancements in single-electron chemistry have enabled new methods for the formation of various C−C bonds. Disclosed herein is the development of a novel single-electron reduction of acyl azoliums for the formation of ketones from carboxylic acids. Facile construction of the acyl azolium in situ followed by a radical–radical coupling was made possible merging N-heterocyclic carbene (NHC) and photoredox catalysis. The utility of this protocol in synthesis was showcased in the late-stage functionalization of a variety of pharmaceutical compounds. Preliminary investigations using chiral NHCs demonstrate that enantioselectivity can be achieved, showcasing the advantages of this protocol over alternative methodologies.     

Combined Photoredox and Carbene Catalysis for the Synthesis of Ketones from Carboxylic Acids

As a key element in the construction of complex organic scaffolds, the formation of C?C bonds remains a challenge in the field of synthetic organic chemistry. Recent advancements in single‐electron chemistry have enabled new methods for the formation of various C?C bonds. Disclosed herein is the development of a novel single‐electron reduction of acyl azoliums for the formation of ketones from carboxylic acids. Facile construction of the acyl azolium in situ followed by a radical–radical coupling was made possible merging N‐heterocyclic carbene (NHC) and photoredox catalysis. The utility of this protocol in synthesis was showcased in the late‐stage functionalization of a variety of pharmaceutical compounds. Preliminary investigations using chiral NHCs demonstrate that enantioselectivity can be achieved, showcasing the advantages of this protocol over alternative methodologies.