Alkyne Insertion Research Articles

Combining Trifunctionalization of Alkynoic Acids, Arene ortho C-H Functionalization and Amination: An Approach to Unsymmetrical 2,3-Diaryl Substituted Indoles.

Here we report a simultaneous construction of two C-C and two C-N bonds in a unified procedure that incorporates alkynoic acid trifunctionalization, ortho C-H functionalization, and amination cascade. In an ordered process, the regioselective alkyne insertion reaction is favored over the decarboxylation process. The presence of the carboxyl group in alkynoic acid ensures the high regioselectivity in the carbopalladation process, paving the way for a novel method to synthesize unsymmetrically 2,3-diaryl substituted indole scaffolds with excellent regioselectivity. The protocol is demonstrated to be suitable for gram-scale synthesis.

Palladium-Catalyzed Synthesis of Substituted Phenanthrenes via a C-H Annulation of 2-Biaryl Triflates with Alkynes.

A new palladium-catalyzed efficient method for the synthesis of substituted 9,10-phenanthrenes from 2-biaryl triflates with alkynes has been developed. This method provides a great opportunity to prepare various symmetrical and unsymmetrical phenanthrene derivatives in good yields. This reaction proceeds via C-OTf bond cleavage and alkyne insertion followed by C-H annulation.

Asymmetric Total Synthesis of Naturally Occurring (R)-2'-Methoxydihydroartemidin, (R)-(E)-3'-Hydroxyartemidin, and Its Structural Congeners: Method Optimization and Mechanistic Analysis.

Asymmetric total synthesis of naturally occurring 3-substituted isocoumarins, 2'-methoxydihydroartemidin, (E)-3'-hydroxyartemidin, and two structural congeners is reported in this article. Enantiopure 3-alkylisocoumarin core present in those target molecules was accessed through an atom-economical and regiodefined 6-endo-dig cyclization from properly substituted 2-halobenzoic acids and chiral terminal alkynes through ligand-free Cu(I) catalysis. A detailed mechanistic investigation was carried out through control experiments, and density functional theory (DFT) analysis reveals that solvent directed a non-Sonogashira pathway through direct insertion of alkyne through a regiodefined way is operating. The synthesized 3-alkylisocoumarins are synthetically manipulated into various small molecular entities.

Rhodium(III)-Catalyzed Atroposelective Indolization to Access Planar-Chiral Macrocycles.

Macrocycles incorporating conformationally defined indoles are widely found in bioactive natural products. However, the catalytic enantioselective synthesis of planar-chiral indoles via indolization involving macrocyclization remains elusive. Herein, we present the first rhodium(III)-catalyzed atroposelective macrocyclization, which involves the C-H activation of aniline, and a subsequent oxidation [3 + 2] annulation reaction with an intramolecular alkyne. This protocol achieves the construction of indoles, macrocyclization, and planar chirality control in a single step. Importantly, this strategy produces macrocyclic atropisomers bearing full-carbon ansa chains, which represent challenging targets in organic synthesis. Thermodynamic experiments revealed that the rotational barrier of the full-carbon ansa chain-linked macrocyclic atropisomer was lower than that of the atropisomer bearing an oxa-ansa chain. The reaction mechanism was elucidated by computational studies, which revealed that the C-H activation and intramolecular alkyne insertion steps collectively determined the enantioselectivity.

Unconventional Insertions of Internal Alkynes into a Mixed-Valent Silaiminyl-Silylene.

The reactivity of a mixed-valent silaiminyl-silylene [LSi-Si(NDipp)L] (L = PhC(NtBu)2, Dipp = 2,6-iPr-C6H3) toward various substituted internal alkynes was investigated. In contrast to previous reports that primarily yield [Si(μ-C2)Si]-modified rings via 1,2-addition of two silylenes in the center of the molecule, our study reveals a novel reaction pathway. The introduction of [R1-C≡C-R2] (R1 = Ph or SiMe3, R2 = Ph or C≡CSiMe3) gave unconventional insertion into one of the amidinate ligands, followed by migration of the {NtBu} group to bridge two Si atoms. This results in the formation of diverse expanded silacycles.

Pd/Cu Dual Metal-Catalyzed Regioselective [2 + 2 + 2] Cycloaddition of Malononitriles with Alkynes to Densely Substituted Pyridines.

Transition metal-catalyzed [2 + 2 + 2] cycloaddition of nitriles and two alkynes is an efficient method for assembling pyridines. However, examples employing palladium catalysis have rarely been disclosed, and the processes of reactivity and selectivity remain unclear. We report here a palladium/copper dual metal-catalyzed [2 + 2 + 2] cycloaddition of diynyl-tethered malononitriles and terminal alkynes to synthesize densely substituted pyridines. This method features a good substrate scope, synthetically useful yields, and perfect regioselectivity. The derivatization of the pyridine products demonstrates the potential application of this method in synthesizing heterocycles and as ligands in photocatalysis. Preliminary mechanistic studies suggest that the reaction undergoes aza-oxidative cycloaddition of Pd(0) with nitrile and alkyne, followed by alkyne insertion and reductive elimination. The presence of copper is crucial to its reactivity and regioselectivity.

Rh(III)-Catalyzed Regioselective Alkyne Insertion in the Context of C-H Activation and Lactonization Reactions: Synthesis of Fused 1,2-Oxaphospholenes.

Herein, we report an expedient synthesis of fused phosphorus-containing heterocycles via Rh-catalyzed cascade C-H activation, alkyne insertion, and lactonization reactions. The substrate scope and the group tolerance are good, as various substituted benzoic acids, N-methoxybenzamides, and 2-phenylindoles could go through the reactions smoothly to afford the corresponding products in moderate to high yields. Additionally, excellent regioselectivities are shown in the alkyne insertion with the assistance of an electron-withdrawing phosphonate group.

Post-Synthetic Modification of Calix[4]arene Framework by Iridium-Mediated Alkyne Insertion into an Inert C-C Bond: A Novel Strategy for Unsymmetrical Macrocycles.

As a novel synthetic method for unsymmetrical macrocycles, we herein developed a post-synthetic modification of calix[4]arenes by insertion of a terminal alkyne into an inert C(methylene)-C(aryl) bond of the macrocyclic framework. In this transformation, C-iridated calix[4]arenes, readily synthesized through C-H bond activation of the parent calix[4]arene, undergoes C(methylene)-C(aryl) bond cleavage followed by insertion of an alkyne to provide a ring-expanded calix[4]arene complex. Removal of the iridium metal from the resulting complex was readily accomplished by a simple treatment with an acid. The developed sequential method affords novel unsymmetrical, monofunctionalized macrocyclic compounds via 3 steps from the parent calix[4]arene in good yield. The unique unsymmetrical structures of the alkyne-inserted macrocycles were evaluated by X-ray single crystal analyses. On the basis of theoretical calculations, we propose a reaction mechanism involving an uncommon C-C bond cleavage step through δ-carbon elimination for the ring enlargement process.

Nickel-catalyzed defluorinative asymmetric cyclization of Trifluoromethyl-substituted 1,6-Enynes: Insights from DFT calculations on the reaction mechanism and selectivity

Density functional theory (DFT) calculations were employed to elucidate the mechanism and selectivity of nickel-catalyzed defluorinative asymmetric cyclization reactions of trifluoromethyl-substituted 1,6-enynes. The results indicate that the product is formed via a stepwise addition cyclization mechanism, including sequential steps of ligand coordination, transmetalation, ligand exchange, alkyne insertion, olefin insertion, β-F elimination, another transmetalation, and a final ligand exchange. The regioselectivity is primarily governed by the alkyne insertion step, where electrostatic interactions strongly favor 1,2-insertion of the carbon-carbon triple bond over 2,1-insertion. The enantioselectivity is largely determined during the insertion step of the olefin insertion step, with the (S)-product forming preferentially over the (R)-product due to stronger non-covalent interactions between the ligand and the substrate, minimal catalyst conformational distortion, and enhanced electronic interactions between the catalyst and the substrate.

Biphenylene and 1‐Azabiphenylene as a Platform for Synthesis of Azapolyaromatic Compounds

AbstractAttempts to carry out intramolecular annulation of 9,10‐diarylbenzo[h]quinolines and 9,10‐di(hetero)arylphenanthrenes to aromatics with expanded π‐conjugated systems by using different methods are described. The starting compounds (9,10‐diarylbenzo[h]quinolines and 9,10‐di(hetero)arylphenanthrenes) were prepared by C−C bond activation in 1‐azabiphenylene or biphenylene followed by insertion of internal alkynes. Interestingly, unlike in purely carbon‐based aromatics, the course of the annulation turned out to be highly dependent on the structure of maternal compounds. In a handful of cases were obtained the expected or desired products. In others, unexpected rearrangements of the basic molecular frameworks were observed.

Temperature-Dependent Divergent Cyclopentadiene Synthesis through Cobalt-Catalyzed C-C Activation of Cyclopropenes.

We report a temperature-dependent divergent approach to synthesize multisubstituted cyclopentadienes through cobalt-catalyzed carbon-carbon (C-C) bond activation of cyclopropenes and ring expansion with internal alkynes. By employing different heating procedures, two cyclopentadiene substitution isomers were efficiently and selectively constructed. This reaction does not require preactivation of the metal catalyst or additional reducing reagents. Preliminary mechanistic investigations suggest that the key steps are oxidative addition of the cyclopropene to cobalt catalyst, followed by alkyne insertion and 1,5-ester shift.

Pd-Catalyzed Chelation-Assisted Regioselective and Site Selective Cyclative C-H Annulation of Alkynyl Oximes with Activated Alkynes.

Electrophilic cyclization and concomitant C-H annulation constitute an expedient cascade strategy for the construction of multicyclic scaffolds with precise substitutional patterns. We report here a novel Pd-catalyzed cyclative annulation of ynone oxime with activated alkynes. The cascade features a dual regioselectivity including site selective C-H activation and chelation-assisted selective insertion of alkynes. Control experiments together with kinetic experiments give insights into the mechanism.

In Silico Analysis of the Aromaticity of Some Carbo-Metallabenzenes and Carbo-Dimetallabenzenes (Carbo-mers Proposed from Metallabenzenes).

In the current work, we introduce a novel class of molecules termed carbo-metallabenzenes, and their aromaticity has been comprehensively analyzed. The molecules were strategically designed with the insertion of acetylene (C≡C or C2) units in some selected metallabenzenes. Furthermore, if a second metallic unit is inserted (replacing a sp2 carbon) in the carbo-metallabenzenes rings, a new family of carbo-mers is generated, and this second group has been named as carbo-dimetallabenzenes. The primary objective of this work is to ascertain, through various methodologies, whether these newly proposed molecules retain the aromatic characteristics observed in carbo-benzene. The methodologies employed for bond analysis and aromaticity exploration include the analysis of the molecular orbitals, energy decomposition analysis, electron density of delocalized bonds, magnetically induced current density, and the induced magnetic field (Bind). This study sheds light on that the insertion of the metallic centers reduces the electronic delocalization and their aromaticity is, in some cases, comparable with the electronic delocalization of the inorganic iminobora-borazine and also provides valuable insights into their electronic structure through a multifaceted analysis.

Expanding Olefin-Linked Covalent Organic Frameworks toward Selective Photocatalytic Oxidation of Organic Sulfides.

Olefin-linked covalent organic frameworks (COFs) have exhibited great potential in visible-light photocatalysis. In principle, expanding fully conjugated COFs can facilitate light absorption and charge transfer, leading to improved photocatalysis. Herein, three olefin-linked COFs with the same topology are synthesized by combining 2,4,6-trimethyl-1,3,5-triazine (TMT) with 1,3,5-triformylbenzene (TFB), 1,3,5-tris(4-formylphenyl)benzene (TFPB), and 1,3,5-tris(4-formylphenylethynyl)benzene (TFPEB), namely, TMT-TFB-COF, TMT-TFPB-COF, and TMT-TFPEB-COF, respectively. From TMT-TFB-COF to TMT-TFPB-COF, expanding phenyl rings provides only limited expansion for π-conjugation due to the steric effect of structural twisting. However, from TMT-TFPB-COF to TMT-TFPEB-COF, the insertion of acetylenes eliminates the steric effect and provides more delocalized π-electrons. As such, TMT-TFPEB-COF exhibits the best optoelectronic properties among these three olefin-linked COFs. Consequently, the photocatalytic performance of TMT-TFPEB-COF is much better than those of TMT-TFB-COF and TMT-TFPB-COF on the oxidation of organic sulfides into sulfoxides with oxygen. The desirable reusability and substrate compatibility of the TMT-TFPEB-COF photocatalyst are further confirmed. The selective formation of organic sulfoxides over TMT-TFPEB-COF under blue light irradiation proceeds via both electron- and energy-transfer pathways. This work highlights a rational design of expanding the π-conjugation of fully conjugated COFs toward selective visible-light photocatalysis.

Palladium-Catalyzed Regioselective B(3,5)-Dialkenylation and B(4)-Alkenylation of o-Carboranes.

Picolyl group directed B(3,5)-dialkenylation and B(4)-monoalkenylation of o-carboranes has been developed with a very low palladium catalyst loading. The degree of substitution is determined by the cage C(2)-substituents due to steric reasons. On the basis of experimental results, a plausible mechanism is proposed including electrophilic palladation and alkyne insertion followed by protonation.

Efficient Synthesis of Highly Fused Quinazolinone Derivatives via Multiple C−C Bond Formations and 1,4‐Palladium Migration

AbstractAn efficient palladium‐catalyzed annulation of 3‐arylquinazolinones with mono and double alkyne insertion was developed for the synthesis of fused quinazolinone derivatives in 43–80 % yields. A notable effect was observed in product yield, when bases/additives were modulated. The reaction mechanism is believed to proceed through C−X cleavage/alkyne insertion/1,4‐Pd migration and C−H annulation in a one‐pot manner.

Stereodivergent sila-germylenation vs. sila-stannylenation of an internal alkyne.

We report on the insertion of electron deficient alkyne, dimethyl acetylene dicarboxylate (DMAD), into the E-Si bond of hypersilyl tetrylenes, PhC(NtBu)2ESi(SiMe3)3 (E = Ge and Sn), at room temperature. Uniquely, the germylene leads to cis alkenes, while the stannylene gives access to trans alkenes, and the insight into divergent stereoselectivity has been obtained by DFT studies.

Palladium-catalyzed alkyne insertion and rearrangement reaction to synthesize oxindoles from o-iodonitroheteroarenes and alkynes

A novel tandem reaction involving Pd(ii)-catalyzed ortho-C–I bond functionalization, O-atom transfer, [1,2]-aryl shift and deoxygenation of o-iodonitroheteroarenes with alkynes for the synthesis of 3,3-disubstituted oxindoles is described.

Isatoic anhydride as a masked directing group and internal oxidant for Rh(III)-catalyzed decarbonylative annulation through C-H activation: insights from DFT calculations.

Density functional theory calculations uncovered a new mechanism for the rhodium-catalyzed decarbonylative annulation of isatoic anhydride with alkynes, in which the acyloxy group formed from the N-H deprotonation and C-O bond cleavage of isatoic anhydride acts as the directing group to assist the ortho C-H activation. From the generated five-membered rhodacycle intermediate, the final aminoisocoumarin product could be formed by subsequent steps of alkyne insertion, reductive elimination, decarbonylation, and protonation. The isocyanate moiety contained in the annulation intermediate was uncovered as a novel internal oxidant for the reaction, which oxidizes the Rh(I) to Rh(III) by decarbonylation.

Rh(iii)-catalyzed sp3/sp2-C-H heteroarylations via cascade C-H activation and cyclization.

The development of an efficient strategy for facile access to quinoline-based bis-heterocycles holds paramount importance in medicinal chemistry. Herein, we describe a unified approach for accessing 8-(indol-3-yl)methyl-quinolines by integrating Cp*Rh(iii)-catalyzed C(sp3)-H bond activation of 8-methylquinolines followed by nucleophilic cyclization with o-ethynylaniline derivatives. Remarkably, methoxybiaryl ynones under similar catalytic conditions delivered quinoline tethered spiro[5.5]enone scaffolds via a dearomative 6-endo-dig C-cyclization. Moreover, leveraging this method for C8(sp2)-H bond activation of quinoline-N-oxide furnished biologically relevant oxindolyl-quinolines. This reaction proceeds via C(sp2)-H bond activation, regioselective alkyne insertion, oxygen-atom-transfer (OAT) and intramolecular nucleophilic cyclization in a cascade manner. One C-C, one C-N and one C[double bond, length as m-dash]O bond were created with concomitant formation of a quaternary center.