Aryl Alkynes Research Articles

Nickel-catalyzed switchable arylative/endo-cyclization of 1,6-enynes

Carbo- and heterocycles are frequently used as crucial scaffolds in natural products, fine chemicals, and biologically and pharmaceutically active compounds. Transition-metal-catalyzed cyclization of 1,6-enynes has emerged as a powerful strategy for constructing functionalized carbo- and heterocycles. Despite significant progress, the regioselectivity of alkyne functionalization is entirely substrate-dependent. And only exo-cyclization/cross-coupling products can be obtained, while endo-selective cyclization/cross-coupling remains elusive and still poses a formidable challenge. In this study, we disclose a nickel-catalyzed switchable arylation/cyclization of 1,6-enynes in which the nature of the ligand dictates the regioselectivity of alkyne arylation, while the electrophilic trapping reagents determine the selectivity of the cyclization mode. Specifically, using a commercially available 1,10-phenanthroline as a ligand facilitates trans-arylation/cyclization to obtain seven-membered ring products, while a 2-naphthyl-substituted bisbox ligand promotes cis-arylation/cyclization to access six-membered ring products. Diastereoselective cyclizations have also been developed for the synthesis of enantioenriched piperidines and azepanes, which are core structural elements of pharmaceuticals and natural products possessing important biological activities. Furthermore, experimental and density functional theory studies reveal that the regioselectivity of the alkyne arylation process is entirely controlled by the steric hindrance of the ligand; the reaction mechanism involves exo-cyclization followed by Dowd-Beckwith-type ring expansion to form endo-cyclization products.

A Simple Tool to Benchmark Reactivity in Asymmetric Catalysis

AbstractHerein, we report a simple and noninvasive experimental protocol in which a series of relative reaction rates may be obtained by way of single competition experiments. This approach permits a quantitative comparison of any given number of chiral catalysts relative to a ‘benchmarking’ chiral catalyst – a particularly useful tool since catalyst design and selection have remained largely dependent on chemical intuition. We apply this benchmarking approach towards an asymmetric N-heterocyclic carbene (NHC) catalyzed intramolecular Stetter reaction as a proof-of-concept study. In doing so, we demonstrate a rapid method to assess the complex interplay between catalyst reactivity and stereoelectronic effects – an analytical approach that has heretofore not been attempted for NHCs. To showcase the generality of this method, we apply it to an enantioselective Rh(I)-catalyzed [2+2+2] cycloaddition of alkenyl isocyanates and aryl alkynes for a series of chiral phosphoramidite ligands. The results described herein demonstrate that this inexpensive and easily adoptable protocol can reveal complex yet subtle steric and stereoelectronic effects of vastly different chiral catalyst structures, which can further aid with catalyst development and selection for a clearly defined application.

Ratiometric fluorescent sensing of pyrophosphate with sp³-functionalized single-walled carbon nanotubes

Inorganic pyrophosphate is a key molecule in many biological processes from DNA synthesis to cell metabolism. Here we introduce sp3-functionalized (6,5) single-walled carbon nanotubes (SWNTs) with red-shifted defect emission as near-infrared luminescent probes for the optical detection and quantification of inorganic pyrophosphate. The sensing scheme is based on the immobilization of Cu2+ ions on the SWNT surface promoted by coordination to covalently attached aryl alkyne groups and a triazole complex. The presence of Cu2+ ions on the SWNT surface causes fluorescence quenching via photoinduced electron transfer, which is reversed by copper-complexing analytes such as pyrophosphate. The differences in the fluorescence response of sp3-defect to pristine nanotube emission enables reproducible ratiometric measurements in a wide concentration window. Biocompatible, phospholipid-polyethylene glycol-coated SWNTs with such sp3 defects are employed for the detection of pyrophosphate in cell lysate and for monitoring the progress of DNA synthesis in a polymerase chain reaction. This robust ratiometric and near-infrared luminescent probe for pyrophosphate may serve as a starting point for the rational design of nanotube-based biosensors.

Palladium-Catalyzed Difluorocarbene Transfer Enabled Divergent Synthesis of γ-Butenolides and Ynones from Iodobenzene and Terminal Alkynes.

Herein, we report a ligand-controlled palladium-catalyzed method that enables the synthesis of ynones and γ-butenolides with excellent regioselectivity from the same set of readily available aryl iodides, aryl acetylenes, and BrCF2CO2K. In this reaction, the [PdII]═CF2 does demonstrate electrophilicity and can generate CO readily when reacting with H2O. It is environmentally friendly and safe compared to traditional methods, and the current protocol enables us to afford ynones and γ-butenolides in high yields with excellent functionality tolerance. Moreover, esters can also be obtained with corresponding phenols and alcohols utilizing this strategy. The success of late-stage functionalization of bioactive compounds further illustrates the synthetic utility of this protocol in material development and drug discovery.

Synthesis of di/tri-substituted carbazoles involving Pd-mediated Sonogashira coupling of indolyltriflates with aryl acetylenes.

In this study, we present our preliminary findings on the synthesis of carbazole derivatives involving the Sonogashira coupling reaction of 2-(trimethylamino)methylindolyltriflates with aryl acetylenes followed by isomerization, thermal electrocyclization and 1,3-H shift, furnishing the respective di- and tri-substituted carbazoles.

Z-selective dimerization of terminal alkynes by a (PNNP)FeII complex.

A tetradentate bis(amido)bis(phosphine) FeII complex, (PNNP)Fe, is shown to activate the terminal C-H bond of aryl alkynes across its Fe-Namide bonds. (PNNP)Fe is also shown to catalytically dimerize terminal aryl alkynes to produce 1,3-enynes with Z : E ratios as high as 96 : 4 with yields up to 95% and loadings as low as 1 mol% at 30 °C in 2 h. A plausible metal-ligand cooperative mechanism invoking a vinylidene intermediate is proposed.

Dehydrative alkynylation of 3-hydroxyisoindolinones with terminal alkynes for the synthesis of 3-alkynylated 3,3-disubstituted isoindolinones.

A brand-new procedure for the synthesis of 3-alkynylated 3,3-disubstituted isoindolinones has been disclosed via a HOTf or Fe(OTf)3-catalyzed dehydrative alkynylation of 3-hydroxyisoindolinones with terminal alkynes. Aryl, alkenyl and alkyl terminal alkynes are suitable to couple with a broad range of 3-hydroxyisoindolinones to afford the desired products in moderate to good yields. This protocol features the use of an inexpensive catalyst, mild reaction conditions, broad substrate scope and easy elaboration of the products.

Synthesis and electronic properties of nitrogen-rich nanographene.

A polycyclic aromatic hydrocarbon displaying twelve edge nitrogen centers for a 42 π-electron system is reported. This compound was synthesized via Sonogashira coupling of pyrimidine precursors, [2+2+2] cycloaddition of bis(aryl) alkynes, and anionic cyclodehydrogenation. Spectroscopy, electrochemistry, and computational results suggest a narrowing of the HOMO-LUMO gap compared to the N-free analogue. Metal coordination affects the optical properties of the extended π system.

Unprecedented Mo3S4 cluster-catalyzed radical C-C cross-coupling reactions of aryl alkynes and acrylates.

A new method for the generation of benzyl radicals from terminal aromatic alkynes has been developed, which allows the direct cross coupling with acrylate derivatives. Our additive-free protocol employs air-stable diamino Mo3S4 cubane-type cluster catalysts in the presence of hydrogen. A sulfur-centered cluster catalysis mechanism for benzyl radical formation is proposed based on catalytic and stoichiometric experiments. The process starts with the cluster hydrogen activation to form a bis(hydrosulfido) [Mo3(μ3-S)(μ-S)(μ-SH)2Cl3(dmen)3]+intermediate. The reaction of various aromatic terminal alkynes containing different functionalities with a series of acrylates affords the corresponding Giese-type radical addition products.

Metal-free oxidative coupling of aryl acetylene with elemental sulphur and amines: facile access to α-ketothioamides.

A simple and efficient oxidative coupling of aromatic alkynes with elemental sulphur and secondary amines has been reported. The iodine/DMSO system easily promoted the transformations, affording thioglyoxamides via C-S, C-O, and C-N bond formations. In this context, acetylenic C-H bond oxidation has occurred through iodination, leading to the desired products. Moreover, this metal-free, one-pot protocol is accomplished by using readily available starting materials, without external oxidants, and under aerobic conditions, providing a variety of α-ketothioamide compounds in moderate to good yields.

Water as a key ingredient in the synthesis of platinum H‐phosphonate complexes and catalytic cascade reactions involving the hydration of alkynes and hydrogen/deuterium exchange reaction

Several platinum (II) complexes bearing heteroatom‐substituted phosphine oxides ligand H(O)P(OCMe2CMe2O) were obtained. The H‐phosphonate was synthesized in an alternative, one‐pot procedure with the use of water from hexamethylphosphorus triamide and pinacol. In the presence of H(O)P (OCMe2CMe2O) ligand, [PtCl2(cod)] was converted into three new complexes: [PtCl2{P(OH)(OCMe2CMe2O)}2] [Pt1], [PtCl{P(O)(OCMe2CMe2O)}{P(OH)(OCMe2CMe2O)}2] [Pt2], and [Pt{P(OH)(OCMe2CMe2O)}4]Cl2 [Pt3]. When [PtCl2(PPh3)2] was utilized as the substrate, [PtCl(PPh3)2{P(OH)(OCMe2CMe2O)}]Cl [Pt4] and [PtCl(PPh3)2{P(O)(OCMe2CMe2O)}] [Pt5] complexes were obtained, as the results of reaction with H(O)P(OCMe2CMe2O) and HP(OCMe2CMe2O)(OCH2CMe2NH) ligands. The structural features of all complexes were characterized by physicochemical and spectroscopic methods as well as single X‐ray diffraction studies. Complex [Pt1] was found to promote cascade reaction, the addition of water to triple bond, and hydrogen/deuterium exchange reaction. The hydration reaction of substituted terminal aryl alkynes gave exclusively Markovnikov products and tolerated different functional groups. Various aryl ketones were synthesized in good to excellent yield. H/D exchange reaction was exemplified by the model reaction of acetophenone in deuterium containing methanol. Factors influencing the effectiveness of the hydrogen/deuterium exchange reaction of the methyl group were determined. The cascade procedure bears the potential to overcome the limitations of conventional synthesis and unlocks practical use in the synthesis of deuterium‐labeled pharmaceuticals.

Copper(I) complexes of 1,2-bis(diphenylphosphino)benzene as efficient catalysts for alkyne hydroamination and azide-alkyne cycloaddition

This paper reports the synthesis of a small group of three copper(I) complexes using 1,2-bis(diphenylphosphino)benzene, abbreviated as dppbz, and their utilization as catalyst for CN bond formation reactions. Reaction of dppbz has been carried out with three different copper(I) sources. While reaction with [Cu(CH3CN)4]ClO4 affords [CuI(dppbz)2]ClO4 (complex 1), that with CuI and CuSCN affords di-copper complexes [{CuI(dppbz)I}2] and [{CuI(dppbz)(SCN)}2] (complexes 2 and 3) respectively. Bulk characterization on the complexes has been done by elemental (C, H, N) analysis, magnetic susceptibility measurement, and spectroscopic (IR, NMR and UV–vis) methods. Crystal structures of all three complexes have been determined. In [CuI(dppbz)2]ClO4, copper(I) is having a highly distorted tetrahedral CuP4 core. In [{CuI(dppbz)I}2] and [{CuI(dppbz)(SCN)}2], the tetrahedral CuP2I2 and CuP2SN cores are relatively less distorted. These copper complexes have been found to serve as efficient catalyst precursors for two types of CN bond formation reactions, viz. hydroamination and click reaction. Hydroamination of aryl alkynes with aryl amines has afforded selectively imine products of a single type (Markownikov product) in good yields under relatively mild condition. However, similar hydroamination with benzyl amines or alkyl amines has afforded selectively anti-Markownikov imine products. Click reaction between aryl alkynes and aryl azides yielding the cycloaddition products has also been brought about successfully with remarkable catalytic efficiency.

Alkyl, aryl and hetaryl acetylenes - highly reactive multifunctional compounds (a review)

The author’s data (2000-2022) on synthesis methods, reactivity and applied aspects of aryl- and hetarylacetylenes were summarized. The specificity of alkynylarenes (hetarenes) associated with the activation of the triple bond by acceptor groups were noted. Particular attention was paid to fundamentally important new reactions of heterocyclization and complete soft cleavage of the triple bond. The prospects for the use of alkynylarenes and -hetarenes and their modification products were reflected. The results of screening of the synthesized compounds were presented.

Cu-mediated enantioselective C–H alkynylation of ferrocenes with chiral BINOL ligands

A wide range of Cu(II)-catalyzed C–H activation reactions have been realized since 2006, however, whether a C–H metalation mechanism similar to Pd(II)-catalyzed C–H activation reaction is operating remains an open question. To address this question and ultimately develop ligand accelerated Cu(II)-catalyzed C–H activation reactions, realizing the enantioselective version and investigating the mechanism is critically important. With a modified chiral BINOL ligand, we report the first example of Cu-mediated enantioselective C–H activation reaction for the construction of planar chiral ferrocenes with high yields and stereoinduction. The key to the success of this reaction is the discovery of a ligand acceleration effect with the BINOL-based diol ligand in the directed Cu-catalyzed C–H alkynylation of ferrocene derivatives bearing an oxazoline-aniline directing group. This transformation is compatible with terminal aryl and alkyl alkynes, which are incompatible with Pd-catalyzed C–H activation reactions. This finding provides an invaluable mechanistic information in determining whether Cu(II) cleaves C–H bonds via CMD pathway in analogous manner to Pd(II) catalysts.

Reaction Environment Design for Multigram Synthesis via Sonogashira Coupling over Heterogeneous Palladium Single-Atom Catalysts.

Single-atom heterogeneous catalysts (SACs) attract growing interest in their application in green chemistry and organic synthesis due to their potential for achieving atomic-level precision. These catalysts offer the possibility of achieving selectivity comparable to the traditionally applied organometallic complexes, while enhancing metal utilization and recovery. However, an understanding of SAC performance in organic reactions remains limited to model substrates, and their application as drop-in solutions may not yield optimal activity. Here, we investigate the previously unaddressed influence of the reaction environment, including solvent, base, cocatalyst, and ligand, on the performance of a palladium SAC in Sonogashira-Hagihara cross-couplings. By examining the effects of different solvents using the established criteria, we find that the behavior of the SAC deviates from trends observed with homogeneous catalysts, indicating a distinct interplay between heterogeneous systems and the reaction environment. Our results illustrate the satisfactory performance of SACs in cross-couplings of aryl iodides and acetylenes with electron-withdrawing and -donating groups, while the use of bromides and chlorides remains challenging. Extending the proof-of-concept stage to multigram scale, we demonstrate the synthesis of an intermediate of the anticancer drug Erlotinib. The catalyst exhibits high stability, allowing for multiple reuses, even under noninert conditions. Life-cycle assessment guides the upscaling of the catalyst preparation and quantifies the potential environmental and financial benefits of using the SAC, while also revealing the negligible impact of the PPh3 ligand and CuI cocatalyst. Our results underscore the significant potential of SACs to revolutionize sustainable organic chemistry and highlight the need for further understanding the distinct interplay between their performance and the reaction environment.

Nickel-Catalyzed Hydroalkynylation of 1,3-Dienes with Simple Alkynes

AbstractA hydroalkynylation reaction of 1,3-dienes with simple alkynes, facilitated by an efficient nickel catalyst system with the 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (Xantphos) ligand, is presented. This reaction displays a broad substrate range for alkynes, encompassing both aryl alkynes and alkyl alkynes, thereby overcoming previous constraints in 1,3-diene hydroalkynylation. The method offers a convenient and direct means for obtaining allylic alkynes with high atom and step economy.

Iridium-catalyzed selective para-C-alkylation of anilines/phenols with aryl alkynes

The general protocol for site-specific alkylation of anilines and phenols would provide an ideal strategy for affording densely functionalized aniline and phenol derivatives. Herein, we disclose a new iridium-catalyzed and acid-promoted process for selective para-alkylation of anilines and phenols using aryloxy or alkoxy aryl alkynes as the alkylated sources, delivering a wide range of para-C-alkylated phenols and anilines in good to excellent yields. The low catalyst loading (up to 0.05 mol%), scale-up of synthesis, operation under air conditions, as well as recycling of catalyst (5 times without deactivation) evidenced the promising application in organic synthesis.

Distinguishing between Linear and Non-Linear (Cooperative) Substrate Activation Mechanisms in the Sonogashira Reaction under “Ligand-Free” and “Copper-Free” Conditions

The results are presented on the comparative studies of the differential selectivity patterns in the Sonogashira reaction with a pair of competing aryl acetylenes in the “ligand-free” and “copper-free” conditions when varying the nature and concentration of aryl halides and base. The revealed sensitivity of the differential selectivity of competing aryl acetylenes to aryl halide nature unambiguously indicated that the substrates were activated through linear mechanism from kinetic view. An absence of any influence of the nature and concentration of the base on the differential selectivity of competing aryl acetylenes indicated the irreversible character of the step of their activation.

Catalyst‐Controlled Divergent Generations and Transformations of α‐Carbonyl Cations from Alkynes**

Abstractα‐Carbonyl cations are the umpolung forms of the synthetically fundamental α‐carbonyl carbanions. They are highly reactive yet rarely studied and utilized species and their precursors were rather limited. Herein, we report the catalyst‐controlled divergent generations of α‐carbonyl cations from single alkyne functionalities and the interception of them via Wagner–Meerwein rearrangement. Two chemodivergent catalytic systems have been established, leading to two different types of α‐carbonyl cations and, eventually, two different types of products, i.e. the α,β‐ and β,γ‐unsaturated carbonyl compounds. Broad spectrum of alkynes including aryl alkyne, ynamide, alkynyl ether, and alkynyl sulfide could be utilized and the migration priorities of different groups in the Wagner–Meerwein rearrangement step was elucidated. Density functional theory calculations further supported the intermediacy of α‐carbonyl cations via the N−O bond cleavage in both the two catalytic systems. Another key feature of this methodology was the fragmentation of synthetically inert tert‐butyl groups into readily transformable olefin functionalities. The synthetic potential was highlighted by the scale‐up reactions and the downstream diversifications including the formal synthesis of nicotlactone B and galbacin.

Catalyst-Controlled Divergent Generations and Transformations of α-Carbonyl Cations from Alkynes.

α-Carbonyl cations are the umpolung forms of the synthetically fundamental α-carbonyl carbanions. They are highly reactive yet rarely studied and utilized species and their precursors were rather limited. Herein, we report the catalyst-controlled divergent generations of α-carbonyl cations from single alkyne functionalities and the interception of them via Wagner-Meerwein rearrangement. Two chemodivergent catalytic systems have been established, leading to two different types of α-carbonyl cations and, eventually, two different types of products, i.e. the α,β- and β,γ-unsaturated carbonyl compounds. Broad spectrum of alkynes including aryl alkyne, ynamide, alkynyl ether, and alkynyl sulfide could be utilized and the migration priorities of different groups in the Wagner-Meerwein rearrangement step was elucidated. Density functional theory calculations further supported the intermediacy of α-carbonyl cations via the N-O bond cleavage in both the two catalytic systems. Another key feature of this methodology was the fragmentation of synthetically inert tert-butyl groups into readily transformable olefin functionalities. The synthetic potential was highlighted by the scale-up reactions and the downstream diversifications including the formal synthesis of nicotlactone B and galbacin.