Cu(I)‐catalyzed Green Synthesis of Propargyl Amines Decorated with Carbazole Moiety by A3 ‐Coupling

A series of novel N ‐alkylcarbazol–propargylamine hybrids were designed and synthesized by Cu^IBr ‐catalyzed A³ ‐coupling of N ‐octylcarbazol‐3‐carbaldehyde, amines, and alkynes. The tri‐substituted propargyl amines decorated with carbazole moiety were obtained under solvent‐free conditions in good to moderate yields. Furthermore, the scope of the method was studied, which was found to be applicable to primary aliphatic and aromatic amines. Also, a large variety of substituents both on alkynes and anilines are well tolerated.     

Stereoselective Synthesis of Trisubstituted Alkenes through Sequential Iron‐Catalyzed Reductive anti‐Carbozincation of Terminal Alkynes and Base‐Metal‐Catalyzed Negishi Cross‐Coupling

The stereoselective synthesis of trisubstituted alkenes is challenging. Here, we show that an iron‐catalyzed anti‐selective carbozincation of terminal alkynes can be combined with a base‐metal‐catalyzed cross‐coupling to prepare trisubstituted alkenes in a one‐pot reaction and with high regio‐ and stereocontrol. Cu‐, Ni‐, and Co‐based catalytic systems are developed for the coupling of sp‐, sp²‐, and sp³‐hybridized carbon electrophiles, respectively. The method encompasses a large substrate scope, as various alkynyl, aryl, alkenyl, acyl, and alkyl halides are suitable coupling partners. Compared with conventional carbometalation reactions of alkynes, the current method avoids pre‐made organometallic reagents and has a distinct stereoselectivity.     

Expeditious and highly efficient synthesis of propargylamines using a Pd‐Cu nanowires catalyst under solvent‐free conditions

A heterogeneous Pd‐Cu NWs‐catalyzed expeditious and solvent‐free synthesis of propargylamines via A³‐coupling of aldehydes, alkynes, and amines has been proposed. A wide range of aldehydes, alkynes and amine substrates undergo A³‐coupling to produce propargylamines in good to excellent yields with good functional tolerance, such as that towards alkoxy, hydroxy, C‐X (X = F, Cl, Br) as well as amide and C=C bonds. Furthermore, the catalyst could be recovered easily and reused for at least 5 cycles without showing significant loss of catalytic activity.     

Copper(I)‐catalyzed multicomponent reactions in sustainable media

Multicomponent reactions including Biginelli reaction and A³ coupling are useful synthetic methodologies as they can provide valuable intermediates and building blocks for the synthesis of bioactive natural compounds. The heterocyclic products of these transformations represent antibacterial, antitumor or anti‐inflammatory properties. In presented study, copper‐mediated protocols for Biginelli reaction and A³ coupling in sustainable solvents were reported. At first, charged NHC copper complexes were synthesized in few steps and characterized using spectroscopic methods followed by preliminary activity tests in sustainable media. Later in this study, Biginelli reaction and A³ coupling were proceeded using prepared copper catalytic systems under mild conditions. Desired nitrogen‐bearing products were obtained with moderate to very high yields. Some attempts to recycle one of the received NHC copper initiators were also investigated.     

Caffeine gold complex supported on magnetic nanoparticles as a green and high turnover frequency catalyst for room temperature A3 coupling reaction in water

A new heterogeneous catalyst derived from gold (III) and supported on caffeine‐coated magnetic nanoparticles, Fe₃O₄@Caff‐Au, has been prepared and characterized using different techniques. This magnetic gold composite shows high catalytic activity in A³ coupling reactions of terminal alkynes, aldehydes and secondary amines. Using this green catalyst, propargylamines are obtained in high turnover frequency in short reaction times using water as solvent at room temperature. This stable and ready accessible catalyst can be easily recycled magnetically for at least nine consecutive runs without significant loss of activity and with slight aggregation of Au species.     

Altering Copper‐Catalyzed A3 Couplings by Mechanochemistry: One‐Pot Synthesis of 1,4‐Diamino‐2‐butynes from Aldehydes,Amines, and Calcium Carbide

The ability of mechanochemistry to alter established chemical selectivity is demonstrated. A copper(I)‐catalyzed mechanochemical aldehyde/alkyne/amine coupling using calcium carbide as the acetylene source provides selective access to 1,4‐diamino‐2‐butynes, which contrasts classical approaches that provide propargylamine‐type products. Solventless milling conditions were found to be essential to unmask A³ coupling products with new compositions.     

Altering Copper‐Catalyzed A3 Couplings by Mechanochemistry: One‐Pot Synthesis of 1,4‐Diamino‐2‐butynes from Aldehydes,Amines, and Calcium Carbide

The ability of mechanochemistry to alter established chemical selectivity is demonstrated. A copper(I)‐catalyzed mechanochemical aldehyde/alkyne/amine coupling using calcium carbide as the acetylene source provides selective access to 1,4‐diamino‐2‐butynes, which contrasts classical approaches that provide propargylamine‐type products. Solventless milling conditions were found to be essential to unmask A³ coupling products with new compositions.     

Nafion?NR50 catalyzed A3-coupling for the synthesis of propargylamines via C-H activation

A one-pot, three-component coupling reaction of aldehydes, amines and alkyne (A³-coupling) via C-H activation using perflorinated resinsulphonic acid (Nafion?NR50) as a recyclable and environmentally benign catalyst for the synthesis of propargylamine derivatives is described. This protocol avoids the use of heavy metals, co-catalysts and produces the propargylamines in excellent yields.     

Palladium‐Catalyzed One‐Pot Three‐ or Four‐Component Coupling of Aryl Iodides,Alkynes, and Amines through CN Bond Cleavage: Efficient Synthesis of Indole Derivatives

An efficient synthesis of N‐substituted indole derivatives was realized by combining the Pd‐catalyzed one‐pot multicomponent coupling approach with cleavage of the C(sp³)?N bonds. Three or four components of aryl iodides, alkynes, and amines were involved in this coupling process. The cyclopentadiene–phosphine ligand showed high efficiency. A variety of aryl iodides, including cyclic and acyclic tertiary amino aryl iodides, and substituted 1‐bromo‐2‐iodobenzene derivatives could be used. Both symmetric and unsymmetric alkynes substituted with alkyl, aryl, or trimethylsilyl groups could be applied. Cyclic secondary amines such as piperidine, morpholine, 4‐methylpiperidine, 1‐methylpiperazine, 2‐methylpiperidine, and acyclic amines including secondary and primary amines all showed good reactivity. Further application of the resulting indole derivatives was demonstrated by the synthesis of benzosilolo[2,3‐b]indole.     

Iridium(III) Catalysts with an Amide‐Pendant Cyclopentadienyl Ligand: Double Aromatic Homologation Reactions of Benzamides by Fourfold C−H Activation

The synthesis, characterization, and catalytic performance of iridium(III) catalysts that bear an amide‐pendant cyclopentadienyl ligand ([Cp^AIrI₂]₂) is reported. These [Cp^AIrI₂]₂ catalysts were obtained from the complexation of a Cp^A ligand precursor with [Ir(cod)OAc]₂ followed by oxidation. Double aromatic homologation reactions of benzamides with alkynes by fourfold C?H activation proceeded in good to high yield with these [Cp^AIrI₂]₂ catalysts, demonstrating their superior catalytic performance in this challenging transformation.     

Identifying a Highly Active Copper Catalyst for KA2 Reaction of Aromatic Ketones

The well‐established A³ coupling reaction of terminal alkynes, aldehydes, and amines provides the most straightforward approach to propargylic amines. However, the related reaction of ketones, especially aromatic ketones, is still a significant challenge. A highly efficient catalytic protocol has been developed for the coupling of aromatic ketones with amines and terminal alkynes, in which Cu^I, generated in situ from the reduction of CuBr₂ with sodium ascorbate, has been identified as the highly efficient catalyst. Since propargylic amines are versatile synthetic intermediates and important units in pharmaceutical products, such an advance will greatly stimulate research interest involving the previously unavailable propargylic amines.     

Investigation of Alkyne Regioselectivity in the Ni‐Catalyzed Benzannulation of Cyclobutenones

A Ni‐catalyzed benzannulation reaction of cyclobutenones and alkynes provides a rapid synthesis of heavily substituted phenols. The regioselectivity of this reaction can be modulated by variation of substituents on the alkyne. Though the incorporation of Lewis basic donors provides modest selectivities, the use of aryl substituents can provide high levels of regiocontrol. Finally, alkynylboronates derived from alkyl‐substituted acetylenes provide both high yields and regioselectivities. This study suggests that alkynes bearing one sp²‐ and one sp³‐based substituent can undergo benzannulation with high levels of regiocontrol whereby the sp³‐based group is incorporated ortho‐to the phenolic OH.     

3‐(Diphenylphosphino)propanoic acid: an efficient ligand for the Pd/Cu‐catalyzed homo‐coupling of terminal alkynes in the presence of oxygen at room temperature

A simple, yet efficient system for PdCl₂/CuI to catalyze the homo‐coupling reactions of various terminal alkynes has been developed using 3‐(diphenylphosphino)propanoic acid as ligand in the presence of oxygen. The alkynes, including aromatic, heteroaromatic and aliphatic alkynes, were transformed at room temperature into the corresponding 1,3‐diynes in moderate to excellent yields. The turnover number was up to 1.04 × 10³. Copyright © 2015 John Wiley & Sons, Ltd.     

2,4‐Dinitrophenol‐Catalyzed α‐C(sp3)−H and C(sp)−H Bond Functionalization of Cyclic Amines and Alkynes: Highly Regio‐/Diastereoselective Synthesis of α‐Alkynyl‐3‐Amino‐2‐Oxindoles

A transition‐metal‐ and oxidant‐free DNP (2,4‐dinitrophenol)‐catalyzed atom‐economical regio‐ and diastereoselective synthesis of monofunctionalized α‐alkynyl‐3‐amino‐2‐oxindole derivatives by C?H bond functionalization of cyclic amines and alkynes with indoline‐2,3‐diones has been developed. This cascade event sequentially involves the reductive amination of indoline‐2,3‐dione by imine formation and cross coupling between C(sp³)?H and C(sp)?H of the cyclic amines and alkynes. This reaction offers an efficient and attractive pathway to different types of α‐alkynyl‐3‐amino‐2‐oxindole derivatives in good yields with a wide tolerance of functional groups. The salient feature of this methodology is that it completely suppresses the homocoupling of alkynes. To the best of our knowledge, this is the first example of a DNP‐catalyzed metal‐free direct C(sp³)?H and C(sp)?H bond functionalization providing biologically active α‐alkynyl‐3‐amino‐2‐oxindole scaffolds.     

Microwave‐Assisted,Rhodium(III)‐Catalyzed N‐Annulation Reactions of Aryl and α,β‐Unsaturated Ketones with Alkynes

New Rh^III‐catalyzed, one‐pot N‐annulation reactions of aryl and α,β‐unsaturated ketones with alkynes in the presence of ammonium acetate have been developed. Under microwave irradiation conditions, the processes lead to rapid formation of the respective isoquinoline and pyridine derivatives with efficiencies that are strongly dependent on the steric nature of the aryl ring and enone substituents. By employing this protocol, a variety of isoquinoline and pyridine derivatives were prepared in high yields. In addition, a new one‐pot approach to the synthesis of pyridines, involving four‐component reactions of ketones, formaldehyde, NH₄OAc, and alkynes, has been uncovered. This process takes place through a route involving initial aldol condensation of the ketone with formaldehyde to generate a branched α,β‐unsaturated ketone that then undergoes Rh^III‐catalyzed N‐annulation with NH₄OAc and the alkyne.     

Efficient Sonogashira and A3 coupling reactions catalyzed by biosynthesized magnetic Fe3O4@Ni nanoparticles from Euphorbia maculata extract

In this work, biosynthesized Fe₃O₄@Ni nanoparticles using Euphorbia maculata aqueous have been used as effective catalysts in the synthesis of 2,3-disubstituted benzo[b]furan derivatives using three component coupling of aldehydes, secondary amines and alkynes (A³ coupling reaction). Using novel nanoscale materials, the current green, practical and economical method leads to short reaction times and high yields. The biosynthesized catalyst was also successfully employed in the Sonogashira cross-coupling reactions of various aryl halides with phenylacetylene. The best performance was observed using just 20 mg of the catalyst and ethanol as a green solvent. The developed protocol provides easy workup, short reaction times and good to excellent product yields. Furthermore, since the composite is highly stable, an external permanent magnet can be easily used for separating the catalyst. Thus, the catalyst can be recycled several times without considerable loss of catalytic activity.     

Iridium(III) Catalysts with an Amide-Pendant Cyclopentadienyl Ligand: Double Aromatic Homologation Reactions of Benzamides by Fourfold C−H Activation

The synthesis, characterization, and catalytic performance of iridium(III) catalysts that bear an amide-pendant cyclopentadienyl ligand ([Cp^AIrI₂]₂) is reported. These [Cp^AIrI₂]₂ catalysts were obtained from the complexation of a Cp^A ligand precursor with [Ir(cod)OAc]₂ followed by oxidation. Double aromatic homologation reactions of benzamides with alkynes by fourfold C−H activation proceeded in good to high yield with these [Cp^AIrI₂]₂ catalysts, demonstrating their superior catalytic performance in this challenging transformation.     

Facilitating polymer conjugation via combination of RAFT polymerization and activated ester chemistry

The synthesis of block copolymers via polymer conjugation of well‐defined building blocks offers excellent control over the structures obtained, but often several coupling strategies need to be explored to find an efficient one depending on the building blocks. To facilitate the synthesis of polymers with adjustable functional end‐groups for polymer conjugation, we report on the combination of activated ester chemistry with RAFT polymerization using a chain transfer agent (CTA) with a pentafluorophenyl ester (PFP‐CTA), which allows for flexible functionalization of either the CTA prior to polymerization or the obtained polymer after polymerization. Different polymethacrylates, namely PMMA, P(t‐BuMA) and PDEGMEMA, were synthesized with an alkyne‐CTA obtained from the aminolysis of the PFP‐CTA with propargylamine, and the successful incorporation of the alkyne moiety could be shown via ¹H and ¹³C NMR spectroscopy and MALDI TOF MS. Further, the reactive α‐end‐groups of polymers synthesized using the unmodified PFP‐CTA could be converted into azide and alkyne end‐groups after polymerization, and the high functionalization efficiencies could be demonstrated via successful coupling of the resulting polymers via CuAAC. Thus, the PFP‐CTA allows for high combinatory flexibility in polymer synthesis facilitating polymer conjugation as useful method for the synthesis of block copolymers. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2010     

Cobalt‐Catalyzed Annulation of Salicylaldehydes and Alkynes to Form Chromones and 4‐Chromanones

A unique cobalt(I)–diphosphine catalytic system has been identified for the coupling of salicylaldehyde (SA) and an internal alkyne affording a dehydrogenative annulation product (chromone) or a reductive annulation product (4‐chromanone) depending on the alkyne substituents. Distinct from related rhodium(I)‐ and rhodium(III)‐catalyzed reactions of SA and alkynes, these annulation reactions feature aldehyde C?H oxidative addition of SA and subsequent hydrometalation of the C=O bond of another SA molecule as common key steps. The reductive annulation to 4‐chromanones also involves the action of Zn as a stoichiometric reductant. In addition to these mechanistic features, the Co^I catalysis described herein is complementary to the Rh^I‐ and Rh^III‐catalyzed reactions of SA and internal alkynes, particularly in the context of chromone synthesis.     

Gold‐Catalyzed C(sp3)?H/C(sp)?H Coupling/Cyclization/Oxidative Alkynylation Sequence: A Powerful Strategy for the Synthesis of 3‐Alkynyl Polysubstituted Furans

In sharp contrast to the gold‐catalyzed reactions of alkynes/allenes with nucleophiles, gold‐catalyzed oxidative cross‐couplings and especially C H/C H cross‐coupling have been under represented. By taking advantage of the unique redox property and carbophilic π acidity of gold, this work realizes the first gold‐catalyzed direct C(sp³) H alkynylation of 1,3‐dicarbonyl compounds with terminal alkynes under mild reaction conditions, with subsequent cyclization and in situ oxidative alkynylation. A variety of terminal alkynes including aryl, heteroaryl, alkenyl, alkynyl, alkyl, and cyclopropyl alkynes all successfully participate in the domino reaction. The protocol offers a simple and region‐defined approach to 3‐alkynyl polysubstituted furans.