Cu-catalyzed Cascade Research Articles

Cu-catalyzed cascade difluoroalkylation/5-endo cyclization/β-fluorine cleavage of ynones.

A copper-catalyzed, redox-neutral cascade difluoroalkylation/5-endo annulation/β-fluorine cleavage of ynones is developed, providing a direct and stereoselective method to access synthetically important α-monofluoroalkenyl cyclopentanones. Mechanistic studies suggest an unprecedented CuII-assisted β-fluorine fragmentation, which may be valuable for the challenging but important C-F bond activation. Moreover, the in situ generated difluorocarbene was found to serve as an effective reductant for the regeneration of copper(I) catalyst, thus avoiding the addition of external reductants.

Direct synthesis of alkylated 4-hydroxycoumarin derivatives via a cascade Cu-catalyzed dehydrogenation/conjugate addition sequence.

An efficient approach for the direct synthesis of alkylated 4-hydroxycoumarin derivatives via a Cu-catalyzed cascade dehydrogenation/conjugate addition sequence starting from simple saturated ketones and 4-hydroxycoumarins has been developed. This protocol features excellent functional-group tolerance, easy scale-up, and a broad substrate scope including bioactive molecules. More importantly, a series of marketed drugs, such as warfarin, acenocoumarol, coumachlor, and coumafuryl, can be obtained by this method.

Cu2O-Promoted cascade reaction of O-halobenzoate and enaminones for the synthesis of isoquinolinone derivatives

A practical Cu-catalyzed cascade cyclization of o-halobenzoate with enaminones to construct isoquinolinone derivatives is described. The process involves a Cu-catalyzed intermolecular CC coupling and intramolecular azacyclization, wherein a wide range of enaminones could be tolerated.

Cu-catalyzed efficient construction of S (Se)-containing functional organosilicon compounds.

A Cu-catalyzed cascade reaction of four-membered silacyclobutanes (SCBs) and thiosulfonates to construct S (Se)-containing organosilicon compounds was developed. The protocol shows a wide range of substrate scope, high functional group compatibility and mild reaction conditions. New C-S (Se) and Si-O bonds were constructed in one step.

Copper-Catalyzed (4+1) Cascade Annulation of Terminal Alkynes with 2-(Tosylmethyl)anilines: Synthesis of 2,3-Disubstituted Indoles.

A novel strategy based on Cu-catalyzed (4+1) cascade annulation of terminal alkynes as one-carbon synthons with 2-(tosylmethyl)anilines has been developed for the expeditious synthesis of 2,3-disubstituted indoles, in which in situ generations of aza-o-quinone methides and alkynyl-copper(I) species are involved. This annulation provides an effective method for the assembly of synthetically and structurally interesting 2,3-disubstituted indoles.

Isoquinolone-4-Carboxylic Acids by Ammonia-Ugi-4CR and Copper-Catalyzed Domino Reaction.

Highly substituted isoquinolone-4-carboxylic acid is an important bioactive scaffold; however, it is challenging to access it in a general and short way. A Cu-catalyzed cascade reaction was successfully designed involving the Ugi postcyclization strategy by using ammonia and 2-halobenzoic acids as crucial building blocks. Privileged polysubstituted isoquinolin-1(2H)-ones were constructed in a combinatorial format with generally moderate to good yields. The protocol, with a ligand-free catalytic system, shows a broad substrate scope and good functional group tolerance toward excellent molecular diversity. Free 4-carboxy-isoquinolone is now for the first time generally accessible by a convergent multicomponent reaction protocol.

Cu-Catalyzed [1,3]-Alkoxy Rearrangement/Diels-Alder Cascade Reactions via in Situ Generation of Functionalized ortho-Quinol Imines.

A Cu-catalyzed cascade reaction between N-alkoxyanilines having an electron-donating functional group at the ortho position and dienophiles, such as N-methylmaleimide, styrene, and indene, proceeded via a dearomative [1,3]-alkoxy rearrangement followed by the Diels-Alder reaction, affording the corresponding ketimines with highly functionalized bicyclic skeletons in an efficient and stereoselective manner. Our mechanistic investigations indicated that the [1,3]-rearrangement is the rate-determining process, efficiently suppressing unfavorable side reactions.

1,2-Aryl Migration Induced by Amide C-N Bond-Formation: Reaction of Alkyl Aryl Ketones with Primary Amines Towards α,α-Diaryl β,γ-Unsaturated γ-Lactams.

Rearrangement reactions incorporated into cascade reactions play an important role in rapidly increasing molecular complexity from readily available starting materials. Reported here is a Cu-catalyzed cascade reaction of α-(hetero)aryl-substituted alkyl (hetero)aryl ketones with primary amines that incorporates an unusual 1,2-aryl migration induced by amide C-N bond formation to produce a class of structurally novel α,α-diaryl β,γ-unsaturated γ-lactams in generally good-to-excellent yields. This cascade reaction has a broad substrate scope with respect to primary amines, allows a wide spectrum of (hetero)aryl groups to smoothly undergo 1,2-migration, and tolerates electronically diverse α-substituents on the (hetero)aryl ring of the ketones. Mechanistically, this 1,2-aryl migration may stem from the intramolecular amide C-N bond formation which induces nucleophilic migration of the aryl group from the acyl carbon center to the electrophilic carbon center that is conjugated with the resulting iminium moiety.

Pyrrole synthesis through Cu-catalyzed cascade [3 + 2] spiroannulation/aromatization of oximes with azadienes

We disclose an efficient synthetic protocol for the assembly of poly-substituted pyrroles through cascade [3 + 2] spiroannulation/aromatization of oximes with azadienes.

Cu-Catalyzed Cascade Reaction of Isoxazoles with Diaryliodonium Salts for the Synthesis of Acridines

A straightforward and efficient synthesis of acridine derivatives via a copper-catalyzed cascade reaction among isoxazoles and diaryliodonium salts is achieved. Various mono-, multi-substituted and 9-substituted acridine derivatives could be obtained in moderate to good yields. The process has gone through tandem double arylation and Friedel-Crafts reactions.

Iron- or copper-catalyzed cascade chloromethylation of activated alkenes: Efficient access to chlorinated oxindoles

An efficient and versatile Fe- or Cu-catalyzed cascade chloromethylation of activated alkenes has been developed for the synthesis of chloro-substituted oxindoles. The reaction proceeds via the C(sp3)-halogen activation of readily available trichloro- and tetrachloro-reagents using an oxidant-free catalytic system with broad substrate scope and wide functional group tolerance.

Modular Synthesis of 2,8-Dioxabicyclo[3.2.1]octanes by Sequential Catalysis

A modular synthesis of 2,8-dioxabicyclo[3.2.1]octane (2,8-DOBCO) ketals is realized by sequential catalysis. The key intermediates, e-hydroxyl-β,γ-unsaturated ketones, are readily available by Ni-catalyzed three-component coupling of 1,3-dienes, aldehydes, and acylzirconocene reagents. These polyfunctionalized ketones can undergo a V-catalyzed cascade of epoxidation and ring rearrangement to provide access to 6-hydroxyl-2,8-DOBCOs. Mechanistic studies indicate that the V(V) species, generated under epoxidation conditions, promotes the ring rearrangement in a stereospecific manner. Meanwhile, the e-hydroxyl-β,γ-unsaturated ketones are transformed into 6-amino-2,8-DOBCOs by a Cu-catalyzed cascade of aziridination and ring rearrangement. In the end, the one-pot approach toward 6-hydroxyl- or 6-amino-2,8-DOBCOs from 1,3-diene, aldehydes, and acylzirconocene reagents is more favorable.

Copper-Catalyzed Oxidative Reaction of β-Keto Sulfones with Alcohols via C-S Bond Cleavage: Reaction Development and Mechanism Study.

A Cu-catalyzed cascade oxidative radical process of β-keto sulfones with alcohols has been achieved by using oxygen as an oxidant. In this reaction, β-keto sulfones were converted into sulfinate esters under the oxidative conditions via cleavage of C-S bond. Experimental and computational studies demonstrate that a new pathway is involved in this reaction, which proceeds through the formation of the key four-coordinated CuII intermediate, O-O bond homolysis induced C-S bond cleavage and Cu-catalyzed esterification to form the final products. This reaction provides a new strategy to sulfonate esters and enriches the research content of C-S bond cleavage and transformations.

Cu-Catalyzed Synthesis of Fluoroalkylated Isoxazoles from Commercially Available Amines and Alkynes.

A one-pot protocol for the construction of fluoroalkylated isoxazoles directly from commercially available amines and alkynes is described. The reaction is scalable, operationally simple, regioselective, mild, and tolerant of a broad range of functional groups. As such, it could be viewed as a "click synthesis" of fluoroalkylated isoxazoles. Preliminary mechanistic investigations reveal that the transformation involves an unprecedented Cu-catalyzed cascade sequence involving RfCHN2.

Cu-Catalyzed switchable synthesis of functionalized pyridines and pyrroles.

Herein, we describe a high yielding and switchable synthesis of a range of functionalized pyridines and pyrroles via Cu-catalyzed cascade reactions with alkynes and N-sulfonyl azadienes which are readily available from saccharin. Both unsymmetrical 2,4,6-trisubstituted pyridines and multi-substituted pyrroles could be transformed into some bioactive compounds and chiral ligands.

Copper-catalyzed cascade reaction: synthesis of pyrimido[4,5-b]quinolinones from 2-chloroquinoline-3-carbonitriles with (aryl)methanamines

Cu-catalyzed cascade reaction of 2-chloroquinoline-3-carbonitriles with benzyl amines using sodium hydroxide in aerobic atmosphere has been developed for the synthesis of pyrimido[4,5-b]quinoline-4-ones.

Dioxygen Activation via Cu-Catalyzed Cascade Radical Reaction: An Approach to Isoxazoline/Cyclic Nitrone-Featured α-Ketols

A facile, mild, and efficient dioxygen activation for the synthesis of isoxazoline/cyclic nitrone-featured α-ketols has been achieved by Cu-catalyzed trifunctionalization of internal unactivated alkynes of unsaturated ketoximes at room temperature. 18O isotope tracing and DFT calculation reveal that a cascade iminoxyl radical dichotomous 5-exo-dig cyclization/oxygen activation/peroxy radical 4-endo-trig cyclization process was involved in the reaction.

Cu-Catalyzed Cascade Annulation of Diaryliodonium Salts and Nitriles: Synthesis of Nitrogen-Containing Heterocycles

Developing versatile methodologies to construct various nitrogen­-containing heterocycles is a crucially significant part of contemporary organic chemistry. This review summarizes recent developments on the formation of nitrogen-containing heterocycles triggered by diaryliodonium salts. Diaryliodonium salts, as electrophilic arylating agents in the presence of catalytic copper salts, can react with nitriles to give N-arylnitrilium cations, which are highly reactive species. These species can efficiently react with nucleophiles, including C-, N- and O-nucleophiles, to give the corresponding products. This strategy is not only efficient and convenient, but also enables the synthesis of diverse nitrogen-containing heterocycles such as quinolines, quinazolines, and phenanthridines.1 Introduction2 Strategies and Mechanisms3 Cascade Annulations3.1 Cascade Annulation of Diaryliodoniums, Nitriles and C-Nucleo­philes3.2 Cascade Annulation of Diaryliodoniums, Nitriles and N-Nucleo­philes3.3 Cascade Annulation of Diaryliodoniums, Nitriles and O-Nucleo­philes4 Summary and Outlook

Copper-Catalyzed Borylative Cyclization of in Situ Generated o-Allenylaryl Nitriles with Bis(pinacolato)diboron

A Cu-catalyzed cascade borylcupration/cyclization of in situ generated allene-nitriles with B2pin2 has been developed, which provides highly substituted 3-boryl-1-naphthylamines with excellent regioselectivity and wide functional group compatibility. It has been shown that, for the first time, the catalytically generated allylcopper species can be captured by a cyano group from a normal nitrile to furnish a carbocycle.

Synthesis of Quinoline Derivatives via Cu-Catalyzed Cascade Annulation of Heterocumulenes, Alkynes, and Diaryliodonium Salts.

CuOTf-catalyzed substituent-controlled cascade [2 + 2 + 2] and [4 + 2] annulation reactions among heterocumulenes, alkynes, and diaryliodonium salts were achieved. Various quinoline derivatives could be obtained in good yields with excellent selectivity. This methodology provided a novel pathway to activate heterocumulenes via a unique highly reactive cationic intermediate. The reaction process was well elucidated by density functional theory calculations.