Alkynylation Reaction Research Articles

Electrophile-Arene Affinity: An Energy Scale for Evaluating the Thermodynamics of Electrophilic Dearomatization Reactions.

Rational design and development of organic reactions are lofty goals in synthetic chemistry. Quantitative description of the properties of molecules and reactions by physical organic parameters plays an important role in this regard. In this Article, we report an energy scale, namely, electrophile-arene affinity (EAA), for evaluating the thermodynamics of electrophilic dearomatization reactions, a class of important transformations that can rapidly build up molecular complexity and structural diversity by converting planar aromatic compounds into three-dimensional cyclic molecules. The acquisition of EAA data can be readily achieved by theoretically calculating the enthalpy changes (ΔH) of the hypothetical reactions of various (cationic) electrophiles with aromatic systems (taking the 1-methylnaphthalen-2-olate ion as an example in this study). Linear correlations are found between the calculated ΔH values and established physical organic parameters such as the percentage of buried volume %VBur (steric effect), Hammett's σ or Brown's σ+ (electronic effect), and Mayr's E (reaction kinetics). Careful analysis of the ΔH values leads to the rational design of a dearomative alkynylation reaction using alkynyl hypervalent iodonium reagents as the electrophiles.

Zinc-Catalyzed Cyclization of Alkynyl Derivatives: Substrate Scope and Mechanistic Insights.

Novel alkyl zinc complexes supported by acetamidate/thioacetamidate heteroscorpionate ligands have been successfully synthesized and characterized. These complexes exhibited different coordination modes depending on the electronic and steric effects of the acetamidate/thioacetamidate moiety. Their catalytic activity has been tested toward the hydroelementation reactions of alkynyl alcohol/acid substrates, affording the corresponding enol ether/unsaturated lactone products under mild reaction conditions. Kinetic studies have been performed and confirmed that reactions are first-order in [catalyst] and zero-order in [alkynyl substrate]. DFT calculations supported a reaction mechanism through the formation of the catalytically active species, an alkoxide-zinc intermediate, by a protonolysis reaction of the Zn-alkyl bond with the alcohol group of the substrate. Based on the experimental and theoretical results, a catalytic cycle has been proposed.

Mechanistic Insights into the Copper‐Catalyzed Cross‐Dehydrogenative Allylic Alkynylation Reaction

AbstractAllylic functionalization reactions are an important tool for constructing many organic compounds, as they allow for the insertion of the versatile allyl group. Numerous catalytic processes have been developed, primarily utilizing noble metals such as palladium and pre‐functionalized substrates. Conversely, the copper‐catalyzed oxidative C−H derivatization route, whether thermal or photocatalyzed, remains relatively underdeveloped. This is mostly due to the lack of a general concept and corresponding mechanistic understanding. Here we present a comprehensive analysis of the mechanism of this transformation. We utilized a range of spectroscopic techniques, including UV‐Vis, NMR, and EPR, single crystal x‐ray diffraction, as well as cyclovoltammetry, and DFT calculations. We propose that there are no free organic radicals involved in this cross‐dehydrogenative coupling, and that the reaction pathway is analogous to the well‐known Karash‐Sosnovsky reaction.

Mitochondria-targeted ruthenium complexes can be generated in vitro and in living cells to target triple-negative breast cancer cells by autophagy inhibition

Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer, which owned severe resistance to platinum-based anticancer agents. Herein, we report a new metal-arene complex, Ru-TPE-PPh3, which can be synthesized in vitro and in living cells with copper catalyzed the cycloaddition reaction of Ru-azide and alkynyl (CuAAC). The complex Ru-TPE-PPh3 exhibited superior inhibition of the proliferation of TNBC MDA-MB-231 cells with an IC50 value of 4.0 μM. Ru-TPE-PPh3 could induce the over production of reactive oxygen species (ROS) to initiate the oxidative stress, and further damage the mitochondria both functionally and morphologically, as loss of mitochondrial membrane potential (MMP) and cutting the supply of adenosine triphosphate (ATP), the disappearance of cristae structure. Moreover, the damaged mitochondria evoked the occurrence of mitophagy with the autophagic flux blockage and cell death. The complex Ru-TPE-PPh3 also demonstrated excellent anti-proliferative activity in 3D MDA-MB-231 multicellular tumor spheroids (MCTSs), indicating the potential to inhibit solid tumors in living cells. This study not only provided a potent agent for the TNBC treatment, but also demonstrated the universality of the bioorthogonally catalyzed lethality (BCL) strategy through CuAAC reation.

Enantioselective Divergent Syntheses of Diterpenoid Pyrones.

Capitalizing a synergy between late-stage C(sp3)-H alkynylation and a series of transition metal-catalyzed alkyne functionalization reactions, we reported herein enantioselective divergent synthesis of 10 diterpenoid pyrones within 14-16 steps starting from chiral pool enoxolone, including the first enantioselective synthesis of higginsianins A, B, D, E, and metarhizin C. Our synthesis also highlights an unprecedented biomimetic oxidative rearrangement of α-pyrone into 3(2H)-furanone, as well as applications of Echavarren C(sp3)-H alkynylation reaction and Toste chiral counterion-mediated Au-catalyzed intramolecular allene hydroalkoxylation in natural product synthesis.

Ru(II)‐Catalyzed Selective C—H Alkynylation of Isoquinolones, Quinazolones and Phthalazinones with Bromoalkynes

Comprehensive SummaryA new, selective Ru(II)‐catalyzed alkynylation reaction of isoquinolones, quinazolones and phthalazinones with readily available bromoalkynes has been developed. This reaction enables the selective construction of a new C(sp2)‐C(sp) bond through C—H activation and C—Br functionalization, and offers an effective and selective route to synthesizing highly valuable alkynylated isoquinolone, quinazolone and phthalazinone derivatives with a wide substrate scope and high selectivity.

Cyclic Diaryl λ3‐Bromanes as a Precursor for Regiodivergent Alkynylation Reactions

AbstractRegiodivergent reactions are a fascinating tool to rapidly access molecular diversity while using identical coupling partners. We have developed a new approach for regiodivergent synthesis using the dual character of hypervalent bromines. In addition to the recently reported reactivity of hypervalent bromines as aryne precursors, the first transition metal‐catalyzed reaction is reported. Accordingly, the development of these two complementary transformations allows for the alteration of regioselectivity to furnish both ortho‐ and meta‐substituted alkynylation products. Mechanistic and computational studies show how these selectivities are controlled.

Cyclic Diaryl λ3-Bromanes as a Precursor for Regiodivergent Alkynylation Reactions.

Regiodivergent reactions are a fascinating tool to rapidly access molecular diversity while using identical coupling partners. We have developed a new approach for regiodivergent synthesis using the dual character of hypervalent bromines. In addition to the recently reported reactivity of hypervalent bromines as aryne precursors, the first transition metal-catalyzed reaction is reported. Accordingly, the development of these two complementary transformations allows for the alteration of regioselectivity to furnish both ortho- and meta-substituted alkynylation products. Mechanistic and computational studies show how these selectivities are controlled.

Rhodium‐Catalyzed Direct Enantioselective Alkynylation of Trifluoropyruvates with Terminal 1,3‐Diynes

AbstractA direct catalytic enantioselective alkynylation reaction of trifluoropyruvates with terminal 1,3‐diynes was achieved by using C2‐symmetric NCN pincer rhodium (III) complexes with bis(imidazolinyl)phenyl ligands. This protocol is effective for enantioselective synthesis of optically active trifluoromethylated tertiary alcohols with the diyne moiety. A variety of electronically and structurally diverse terminal 1,3‐diynes are well tolerated. Furthermore, the catalytic reaction is applicable to preparation of both enantiomers of the chiral CF3‐containing conjugated diynols with high enantioselectivity.

Copper-Catalyzed Benzylic Functionalization of Lignin-Derived Monomers.

Within the field of lignin biorefining, significant research effort has been dedicated to the advancement of catalytic methods for lignocellulose depolymerization. However, another key challenge in lignin valorization is the conversion of the obtained monomers into higher value-added products. To address this challenge, new catalytic methods that can fully embrace the inherent complexity of their target substrates are needed. Here, we describe copper-catalyzed reactions for benzylic functionalization of lignin-derived phenolics via intermediate formation of hexafluoroisopropoxy masked para-quinone methides (p-QMs). By controlling the rates of copper catalyst turnover and p-QM release, we have developed copper-catalyzed allylation and alkynylation reactions of lignin-derived monomers to install various unsaturated fragments amenable to further synthetic applications.

Enantioselective Synthesis of N-N Atropisomers by Palladium-Catalyzed C-H Functionalization of Pyrroles.

The catalytic asymmetric construction of N-N atropisomeric biaryls remains a formidable challenge. Studies of them lag far behind studies of the more classical carbon-carbon biaryl atropisomers, hampering meaningful development. Herein, the first palladium-catalyzed enantioselective C-H activation of pyrroles for the synthesis of N-N atropisomers is presented. Structurally diverse indole-pyrrole atropisomers possessing a chiral N-N axis were produced with good yields and high enantioselectivities by alkenylation, alkynylation, allylation, or arylation reactions. Furthermore, the kinetic resolution of trisubstituted N-N heterobiaryls with more sterically demanding substituents was also achieved. Importantly, this versatile C-H functionalization strategy enables iterative functionalization of pyrroles with exquisite selectivity, expediting the formation of valuable, complex, N-N atropisomers.

Enantioselective Synthesis of N‐N Atropisomers by Palladium‐Catalyzed C−H Functionalization of Pyrroles

AbstractThe catalytic asymmetric construction of N−N atropisomeric biaryls remains a formidable challenge. Studies of them lag far behind studies of the more classical carbon‐carbon biaryl atropisomers, hampering meaningful development. Herein, the first palladium‐catalyzed enantioselective C−H activation of pyrroles for the synthesis of N−N atropisomers is presented. Structurally diverse indole‐pyrrole atropisomers possessing a chiral N−N axis were produced with good yields and high enantioselectivities by alkenylation, alkynylation, allylation, or arylation reactions. Furthermore, the kinetic resolution of trisubstituted N−N heterobiaryls with more sterically demanding substituents was also achieved. Importantly, this versatile C−H functionalization strategy enables iterative functionalization of pyrroles with exquisite selectivity, expediting the formation of valuable, complex, N−N atropisomers.

Gold(I)‐Catalyzed Alkynylation of N,O‐Acetals: An Access to Alkynylated Saturated N‐heterocycles

AbstractA synthetic route for the preparation of alkynylated saturated N‐heterocycles via a sequential combination of a Shono oxidation and a gold(I)‐catalyzed alkynylation reaction has been developed. The electrochemical Shono oxidation allowed an efficient access to a variety of N,O‐acetals via a direct C−H bond functionalization of cyclic amines. The reaction conditions were amenable with functionalized pyrrolidine, tetrahydroisoquinoline and pyrrolidine‐cyclopropyl fused bicyclic skeletons. The gold‐catalyzed process allowed the introduction of aryl acetylene partners bearing electron‐donating and moderate electron‐withdrawing. The efficiency of the gold process is remarkable and could be scaled up to 5 mmol of N,O‐acetal. Post‐functionalization reactions were performed based on the reactivity of the alkyne, showing the broad interest of our methodology. Promising preliminary results on an asymmetric version were obtained (e.r. up to 84.5:15.5).magnified image

Recent Developments in Copper(I)‐Catalyzed Enantioselective Alkynylation Reactions via a Radical Process

Comprehensive SummaryAlkynes are one of the most significant functional groups in organic chemistry and great efforts have been made to explore efficient approach for the construction of chiral alkynes. The asymmetric C(sp3)–C(sp) cross‐coupling provides a significant complementary strategy through radical‐initiated process. However, the stereocontrol of highly reactive and unstable radical intermediate has been a challenge for decades. To address this problem, a variety of chiral ligands are developed for initiating the reaction and achieving enantiocontrol of alkyl radicals. This review summarizes recent developments in copper‐catalyzed enantioselective alkynylation of prochiral alkyl radicals and their brief mechanistic studies.

Highly Diastereoselective Synthesis of Oxindoles Containing Vicinal Quaternary and Tertiary Stereocenters by a Domino Heck/Decarboxylative Alkynylation Sequence.

A palladium-catalyzed domino Heck/decarboxylative alkynylation reaction of trisubstituted alkenes or enamines is reported. For two different types of substrates, the current domino reaction employing different solvents and bases led to 3,3-disubstituted oxindoles and hydropyrimidinyl spirooxindoles containing vicinal quaternary and tertiary stereocenters in moderate to good yields, respectively. The general applicability of this method was shown by gram-scale syntheses and diverse transformations of the reaction products. The enantioselective version for this domino process was also studied.

Silylium‐Catalyzed Alkynylation and Etherification Reactions of Benzylic Acetates

AbstractAddition of catalytic amounts of bistriflimide triggers useful coupling reactions of benzyl acetates with trimethyl(alkynyl)silanes and trimethyl(alkoxy)silanes to afford propargyl arenes and benzyl alkyl ethers, respectively. The added acid assists the release of reactive trimethylsilylium ion into the reaction media, which were found to act as the ultimate catalytic species responsible for the C−C and the C−O forming steps. The cationic nature of these coupling processes is documented.

Progress in Catalytic Decarboxylative Oxidative C-H Alkynylation

Abstract:Alkyne carboxylic acid derivatives are stable, non-toxic, inexpensive, and commercially available. They are prevalent intermediates for various synthetic transformations. In recent years, decarboxylative oxidative alkynylation reactions involving direct C−H bond activation of diverse carbo- and hetero-cycles with alkyne carboxylic acid have attracted more and more interest from the synthetic community. The joy and challenges of direct oxidative decarboxylative alkynylation have been discussed in detail to enlighten this highly emerging area. More emphasis is being placed on the fascinating implementation and advancement of various methods for the formation of C(SP2)-C(SP) bonds. This short review mainly focuses on developments of the decarboxylative oxidative alkynylation reaction, considering the uniqueness of each protocol by highlighting the substrate scope, selectivity, and yields in conjunction with mechanistic insights.

Synthesis of 5‐Alkynyl and 2,5‐Dialkynyl‐L‐histidines

AbstractSynthesis of previously unknown 5‐alkynyl‐L‐histidines and 2,5‐dialkynyl‐L‐histidines is reported. Fully protected 5‐iodo‐ and 2,5‐diiodo‐L‐histidines obtained upon electrophilic iodination underwent cross‐coupling alkynylation reaction with terminal alkynes in the presence of palladium‐copper co‐catalytic system to afford ring‐modified histidines in 62–85 % yield. The method is also successfully utilized to late‐stage alkynylate a 5‐iodohistidine residue containing peptide.

Reaction kinetics of phenyl + phenylacetylene at combustion-relevant intermediate temperatures

The reaction between phenyl radical and phenylacetylene is a prototype for the reactions of aryl radicals and alkynyl peri‑condensed aromatic hydrocarbons (PCAHs), which may help explain the dimerization of PCAHs by covalent bond with acetylene assistance. In this work, we have experimentally and theoretically investigated reaction kinetics of phenyl radical and phenylacetylene. Gas chromatography-mass spectrometry (GC–MS) is applied to separate and identify molecular structures of reaction products in a jet-stirred reactor (JSR). Diphenylacetylene is observed as the major product of this reaction, which shows dominant concentration near 1000 K. Formation of phenanthrene increases with temperature, while 9-methylene-fluorene is a minor product, and 2-ethynyl-biphenyl is negligible. The potential energy surface and rate coefficients of phenyl and phenylacetylene reaction are calculated by quantum chemistry and transition state theory. 1,2-Diphenylvinyl is the only resonance-stabilized radical (RSR) among the adducts formed via all six possible addition reaction channels. Its formation reaction channel has a much lower energy barrier and deeper potential well and, therefore, it wins the competition in the reaction of phenyl and phenylacetylene at combustion-relevant intermediate temperatures.

Gold-catalysed synthesis of phosphonate-substituted oxetan-3-ones – an easy access to highly strained HWE reagents

Gold-catalysed reaction of alkynyl phosphonates to attain alkenyl substituted oxetan-3-ones via subsequent HWE reaction.