1,3-Diynes: A Versatile Precursor in Transition-Metal Catalyzed (Mediated) C−H Functionalizations

Transition metal-catalyzed C−H functionalization of diverse arenes with alkyne units has attracted enormous attention for decades since they provide straightforward access to various functionalization/annulations, which are commonly present in bioactive compounds and natural products. Recently, conjugated alkynes (1,3-diynes) have been utilized as key coupling partner in many C−H activation reactions due to their versatile characteristic properties. The presence of two C≡C bonds in conjugated 1,3-diyne brings the new diversity in synthetic transformations, such as chemo-, regioselective pathways, mono-bis functionalizations, cascade annulations, etc. Herein, we summarized the latest developments in the realm of transition-metal-catalyzed C−H functionalizations of diverse arenes with 1,3-diynes. Moreover, we highlighted the diverse transformations, conditions, mechanisms and applications of the corresponding reaction in detail.     

Rhodium(III)-Catalyzed Asymmetric [4+1] and [5+1] Annulation of Arenes and 1,3-Enynes: A Distinct Mechanism of Allyl Formation and Allyl Functionalization

We report chiral Rh^III cyclopentadienyl-catalyzed enantioselective synthesis of lactams and isochromenes through oxidative [4+1] and [5+1] annulation, respectively, between arenes and 1,3-enynes. The reaction proceeds through a C−H activation, alkenyl-to-allyl rearrangement, and a nucleophilic cyclization cascade. The mechanisms of the [4+1] annulations were elucidated by a combination of experimental and computational methods. DFT studies indicated that, following the C−H activation and alkyne insertion, a Rh^III alkenyl intermediate undergoes δ-hydrogen elimination of the allylic C−H via a six-membered ring transition state to produce a Rh^III enallene hydride intermediate. Subsequent hydride insertion and allyl rearrangement affords several rhodium(III) allyl intermediates, and a rare Rh^III η⁴ ene-allyl species with π-agostic interaction undergoes SN₂′-type external attack by the nitrogen nucleophile, instead of C−N reductive elimination, as the stereodetermining step.     

Palladium‐Catalyzed Regioselective Aromatic Extension of Internal Alkynes through a Norbornene‐Controlled Reaction Sequence

A regioselective aromatic π‐extension reaction of internal alkynes is reported. The proposed method employs three easily available components, namely aryl halides, 2‐haloarylcarboxylic acids, and disubstituted acetylenes. The transformation is driven by a controlled reaction sequence of C?H activation, decarboxylation, and annulation to give poly(hetero)aromatic compounds in a site‐selective fashion. Unlike in previously reported palladium‐catalyzed three‐component annulations, alkyne carbopalladation is the last step of this tandem reaction.     

Cobalt‐Catalyzed Oxidase C−H/N−H Alkyne Annulation: Mechanistic Insights and Access to Anticancer Agents

Cp*‐free cobalt‐catalyzed alkyne annulations by C?H/N?H functionalizations were accomplished with molecular O₂ as the sole oxidant. The user‐friendly oxidase strategy proved viable with various internal and terminal alkynes through kinetically relevant C?H cobaltation, providing among others step‐economical access to the anticancer topoisomerase‐I inhibitor 21,22‐dimethoxyrosettacin. DFT calculations suggest that electronic effects control the regioselectivity of the alkyne insertion step.     

Synthesis of Phenalenyl‐Fused Pyrylium Cations: Divergent C−H Activation/Annulation Reaction Sequence of Naphthalene Aldehydes with Alkynes

Described herein is the synthesis of stable oxonium‐doped polycyclic aromatic hydrocarbons (PAHs) by the rhodium‐catalyzed C−H activation/annulations of naphthalene‐type aldehydes with internal alkynes. This protocol provides four divergent reaction types, including two unexpected annulations with an oxygen transposition process, which lead to diverse types of phenalenyl‐fused pyrylium cations comprising a four‐, five‐, or six‐ring‐fused π‐conjugated core. The annulations exhibit an exquisite regioselectivity and a high tolerance of sensitive functional groups. These PAHs feature intriguing photophysical properties such as full‐color tunable fluorescence emission, high quantum yield, and positively charged core, and can be reduced easily to the phenalenyl radicals.     

Re-Catalyzed Annulations of Weakly Coordinating N-Carbamoyl Indoles/Indolines with Alkynes via C−H/C−N Bond Cleavage

Described herein are rhenium-catalyzed [3+2] annulations of N-carbamoyl indoles with alkynes via C−H/C−N bond cleavage, which provide rapid access to fused-ring pyrroloindolone derivatives. For the first time, the weakly coordinating O-directing group was successfully employed in rhenium-catalyzed C−H activation reactions, enabled by the unique catalytic trio of Re₂(CO)₁₀, Me₂Zn and ZnCl₂. Mechanistic studies revealed that aminozinc species plays an important role in the reaction. Based on the mechanistic understanding, a more powerful catalytic trio of Re₂(CO)₁₀, [MeZnNPh₂]₂ and Zn(OTf)₂ was devised and applied successfully in the [4+2] annulations of indolines and alkynes affording pyrroloquinolinone derivatives.     

Electrooxidative Ruthenium‐Catalyzed C−H/O−H Annulation by Weak O‐Coordination

Electrocatalysis has been identified as a powerful strategy for organometallic catalysis, and yet electrocatalytic C?H activation is restricted to strongly N‐coordinating directing groups. The first example of electrocatalytic C?H activation by weak O‐coordination is presented, in which a versatile ruthenium(II) carboxylate catalyst enables electrooxidative C?H/O?H functionalization for alkyne annulations in the absence of metal oxidants; thereby exploiting sustainable electricity as the sole oxidant. Mechanistic insights provide strong support for a facile organometallic C?H ruthenation and an effective electrochemical reoxidation of the key ruthenium(0) intermediate.     

α‐MsO/TsO/Cl Ketones as Oxidized Alkyne Equivalents: Redox‐Neutral Rhodium(III)‐Catalyzed CH Activation for the Synthesis of N‐Heterocycles

α‐Halo and pseudohalo ketones are used for the first time as C(sp³)‐based electrophiles in transition‐metal‐catalyzed C? H activation and as oxidized alkyne equivalents in Rh^III‐catalyzed redox‐neutral annulations to generate diverse N‐heterocycles. This transformation is efficient and scalable. Due to the mild reaction conditions, a variety of functional groups could be tolerated.     

Catalytic 1,4‐Rhodium(III) Migration Enables 1,3‐Enynes to Function as One‐Carbon Oxidative Annulation Partners in C?H Functionalizations

1,3‐Enynes containing allylic hydrogens cis to the alkyne are shown to act as one‐carbon partners, rather than two‐carbon partners, in various rhodium‐catalyzed oxidative annulations. The mechanism of these unexpected transformations is proposed to occur through double C H activation, involving a hitherto rare example of the 1,4‐migration of a Rh^III species. This phenomenon is general across a variety of substrates, and provides a diverse range of heterocyclic products.     

Catalytic 1,4‐Rhodium(III) Migration Enables 1,3‐Enynes to Function as One‐Carbon Oxidative Annulation Partners in CH Functionalizations

1,3‐Enynes containing allylic hydrogens cis to the alkyne are shown to act as one‐carbon partners, rather than two‐carbon partners, in various rhodium‐catalyzed oxidative annulations. The mechanism of these unexpected transformations is proposed to occur through double C? H activation, involving a hitherto rare example of the 1,4‐migration of a Rh^III species. This phenomenon is general across a variety of substrates, and provides a diverse range of heterocyclic products.     

DFT mechanistic study on nickel/IPr-catalyzed aldehyde–alkyne reductive couplings with trialkylsilane/dialkylsilane

Density functional theory calculations were carried out to reveal the mechanistic details of aldehyde–alkyne reductive couplings with trialkylsilane/dialkylsilane. The reaction with trialkylsilane is found to proceed through oxidative cyclization, Si-H/Ni-O σ-bond metathesis, and C(sp²)-H reductive elimination, leading to silylated allylic alcohols. The steric hindrance between the n-pent group of alkyne and iPr group of the NHC ligand determines the regioselectivity. While for the reaction with dialkylsilane, the present calculations propose a new mechanism, which consists of oxidative cyclization, Si−H/Ni−O σ-bond metathesis, Ni−C/Si−H σ-bond metathesis, and dehydrogenation, resulting in oxasilacyclopentenes. The calculated energy profiles rationalize the experimentally observed chemodivergence.     

Frontispiece: Photocatalytic Terminal C−C Coupling Reaction Inside Water Soluble Nanocages

Developing methods that activate C−H bonds directly with high selectivity for C−C bond formation in complex organic synthesis has been a major chemistry challenge. Recently it has been shown that photoactivation of weakly polarized C−H bonds can be carried out inside a cationic water-soluble nanocage with visible light-mediated host-guest charge transfer (CT) chemistry. Using this novel photoredox activation paradigm, here we demonstrate C−C bond formation to photo-generate 1,3-diynes at room temperature in water from terminal aromatic alkynes for the first time. The formation of cavity-confined alkyne radical cation and the proton-removed neutral radical species highlight the unique C−C coupling step driven by supramolecular preorganization.     

Ruthenium‐Catalyzed Oxidative Coupling/Cyclization of Isoquinolones with Alkynes through C?H/N?H Activation: Mechanism Study and Synthesis of Dibenzo[a,g]quinolizin‐8‐one Derivatives

The mechanism of [{RuCl₂(p‐cymene)}₂]‐catalyzed oxidative annulations of isoquinolones with alkynes was investigated in detail. The first step is an acetate‐assisted C? H bond activation process to form cyclometalated compounds. Subsequent mono‐alkyne insertion of the Ru? C bonds of the cyclometalated compounds then takes place. Finally, oxidative coupling of the C? N bond of the insertion compounds occurs to afford Ru⁰ sandwich complexes that undergo oxidation to regenerate the catalytically active Ru^II complex with the copper oxidant and release the desired dibenzo[a,g]quinolizin‐8‐one derivatives. All of the relevant intermediates were fully characterized and determined by single crystal X‐ray diffraction analysis. The [{RuCl₂(p‐cymene)}₂]‐catalyzed C? H bond functionalization of isoquinolones with alkynes to synthesize dibenzo[a,g]quinolizin‐8‐one derivatives through C? H/N? H activation was also demonstrated.     

Catalyst-Controlled Regiodivergent Alkyne Insertion in the Context of C−H Activation and Diels–Alder Reactions: Synthesis of Fused and Bridged Cycles

Rhodium(III)- and cobalt(III)-catalyzed C−H activation of indoles and coupling with 1,6-enynes is discussed. Under rhodium(III) catalysis, the alkyne insertion follows 2,1-regioselectivity with a subsequent type-I intramolecular Diels–Alder reaction (IMDA) to afford [6,5]-fused cycles. When catalyzed by the cobalt(III) congener, 1,2-insertion of the alkyne is preferred, and followed by a rare type-II IMDA, thus leading to bridged [3,3,1]-cycles. This selectivity of the alkyne insertion was mainly tuned by the steric sensitivity of the catalyst.     

Capturing Elusive Cobaltacycle Intermediates: A Real‐Time Snapshot of the Cp*CoIII‐Catalyzed Oxidative Alkyne Annulation

Despite Cp*Co^III catalysts having emerged as a very attractive alternative to noble transition metals for the construction of heterocyclic scaffolds through C−H activation, the structure of the reactive species remains uncertain. Herein, we report the identification and unambiguous characterization of two long‐sought cyclometalated Cp*Co^III complexes that have been proposed as key intermediates in C−H functionalization reactions. The addition of MeCN as a stabilizing ligand plays a crucial role, allowing the access to otherwise highly reactive species. Mechanistic investigations demonstrate the intermediacy of these species in oxidative annulations with alkynes, including the direct observation, under catalytic conditions, of a previously elusive post‐migratory insertion seven‐membered cobaltacycle.     

Development of Gold‐catalyzed [4+1] and [2+2+1]/[4+2] Annulations between Propiolate Derivatives and Isoxazoles

Two new gold‐catalyzed annulations of isoxazoles with propiolates have been developed. Most isoxazoles follow an initial O attack on the alkyne to afford a [4+1] annulation product. This process results in a remarkable alkyne cleavage of initial propiolates. Unsubstituted isoxazoles proceed through an N attack step to yield formal [2+2+1]/[4+2] annulation products. These two annulation products arise initially from two seven‐membered heterocyclic intermediates, which then lead to products.     

Catalyst‐Controlled Regiodivergent Alkyne Insertion in the Context of C−H Activation and Diels–Alder Reactions: Synthesis of Fused and Bridged Cycles

Rhodium(III)‐ and cobalt(III)‐catalyzed C−H activation of indoles and coupling with 1,6‐enynes is discussed. Under rhodium(III) catalysis, the alkyne insertion follows 2,1‐regioselectivity with a subsequent type‐I intramolecular Diels–Alder reaction (IMDA) to afford [6,5]‐fused cycles. When catalyzed by the cobalt(III) congener, 1,2‐insertion of the alkyne is preferred, and followed by a rare type‐II IMDA, thus leading to bridged [3,3,1]‐cycles. This selectivity of the alkyne insertion was mainly tuned by the steric sensitivity of the catalyst.     

Rare-Earth Catalyzed C−H Bond Alumination of Terminal Alkynes

Organoaluminum reagents’ application in catalytic C−H bond functionalization is limited by competitive side reactions, such as carboalumination and hydroalumination. Herein, rare-earth tetramethylaluminate complexes are shown to catalyze the exclusive C−H bond metalation of terminal alkynes with the commodity reagents trimethyl-, triethyl-, and triisobutylaluminum. Kinetic experiments probing alkyl-group exchange between rare-earth aluminates and trialkylaluminum, C−H bond metalation of alkynes, and catalytic conversions reveal distinct pathways of catalytic aluminations with triethylaluminum versus trimethylaluminum. Most significantly, kinetic data point to reversible formation of a unique [Ln](AlR₄)₂⋅AlR₃ adduct, followed by turnover-limiting alkyne metalation. That is, C−H bond activation occurs from a more associated organometallic species, rather than the expected coordinatively unsaturated species. These mechanistic conclusions allude to a new general strategy for catalytic C−H bond alumination that make use of highly electrophilic metal catalysts.     

All‐Carbon [3+3] Oxidative Annulations of 1,3‐Enynes by Rhodium(III)‐Catalyzed CH Functionalization and 1,4‐Migration

1,3‐Enynes containing allylic hydrogens cis to the alkyne function as three‐carbon components in rhodium(III)‐catalyzed, all‐carbon [3+3] oxidative annulations to produce spirodialins. The proposed mechanism of these reactions involves the alkenyl‐to‐allyl 1,4‐rhodium(III) migration.     

All‐Carbon [3+3] Oxidative Annulations of 1,3‐Enynes by Rhodium(III)‐Catalyzed C?H Functionalization and 1,4‐Migration

1,3‐Enynes containing allylic hydrogens cis to the alkyne function as three‐carbon components in rhodium(III)‐catalyzed, all‐carbon [3+3] oxidative annulations to produce spirodialins. The proposed mechanism of these reactions involves the alkenyl‐to‐allyl 1,4‐rhodium(III) migration.