Ruthenium-Induced Cyclization of Heteroatom-Functionalized Alkynes: Progress,Challenges and Perspectives

Metal-induced cyclization of functionalized alkynes represents one of the most general approaches to prepare organic heterocycles. Although Ru^II centers are well-established to promote alkyne to vinylidene rearrangements and many Ru^II-mediated alkyne cyclizations have been rationalized to be the results of post-vinylidene transformations, recent discoveries indicate that Ru^II centers can serve as electrophiles and induce alkyne cyclizations without vinylidene intermediacy. In this Minireview, an overview of the Ru^II-induced cyclization of heteroatom-functionalized alkynes in the last decade is provided, with an emphasis on the discoveries and validations of the unconventional “non-vinylidene-involving” pathways.     

Hydroxy‐Directed Ruthenium‐Catalyzed Alkene/Alkyne Coupling: Increased Scope,Stereochemical Implications,and Mechanistic Rationale

The recognition of the dual binding mode of propargyl and allyl alcohols to [Cp*Ru] fragments fostered the development of a highly regioselective intermolecular Alder‐ene‐type reaction of alkynes with 1,2‐disubstituted alkenes. The increased substrate scope opens new perspectives in stereochemical terms. As the loaded catalyst is chiral‐at‐metal, stereochemical information is efficiently relayed from the propargylic site to the emerging C−C bond. This interpretation is based on the X‐ray structure of the first Cp*Ru complex carrying an intact enyne ligand, and provides valuable insights into bonding and activation of the substrates. Computational data draw a clear picture of the principles governing regio‐ and stereocontrol.     

A Combined Experimental and Computational Study on the Cycloisomerization of 2‐Ethynylbiaryls Catalyzed by Dicationic Arene Ruthenium Complexes

Ruthenium‐catalyzed cycloisomerization of 2‐ethynylbiaryls was investigated to identify an optimal ruthenium catalyst system. A combination of [η⁶‐(p‐cymene)RuCl₂(PR₃)] and two equivalents of AgPF₆ effectively converted 2‐ethynylbiphenyls into phenanthrenes in chlorobenzene at 120 °C over 20 h. Moreover, 2‐ethynylheterobiaryls were found to be favorable substrates for this ruthenium catalysis, thus achieving the cycloisomerization of previously unused heterocyclic substrates. Moreover, several control experiments and DFT calculations of model complexes were performed to propose a plausible reaction mechanism.     

Catalytic [2+2+1] Synthesis of Fused Thiophenes Using Thiocarbonyls as Sulfur Donors

The use of N‐(p‐chlorophenyl)methylbenzoxazole‐2‐thione as a sulfur‐atom donor enables the catalytic [2+2+1] cycloaddition of diynes in wet DMF at 80 °C when open to air, thus affording diverse fused thiophenes with good yields and wide functional‐group compatibility. A plausible mechanism, involving a cationic ruthenacycle intermediate, was also proposed on the basis of several control experiments.     

Ruthenium‐Catalyzed Cycloisomerization of 2,2′‐Diethynyl‐ biphenyls Involving Cleavage of a Carbon–Carbon Triple Bond

A ruthenium complex catalyzes a new cycloisomerization reaction of 2,2′‐diethynylbiphenyls to form 9‐ethynylphenanthrenes, thereby cleaving the carbon–carbon triple bond of the original ethynyl group. A metal–vinylidene complex is generated from one of the two ethynyl groups, and its carbon–carbon double bond undergoes a [2+2] cycloaddition with the other ethynyl group to form a cyclobutene. The phenanthrene skeleton is constructed by the subsequent electrocyclic ring opening of the cyclobutene moiety.     

Mechanism of Alkyne Alkoxycarbonylation at a Pd Catalyst with P,N Hemilabile Ligands: A Density Functional Study

A detailed mechanism for alkyne alkoxycarbonylation mediated by a palladium catalyst has been characterised at the B3PW91‐D3/PCM level of density functional theory (including bulk solvation and dispersion corrections). This transformation, investigated via the methoxycarbonylation of propyne, involves a uniquely dual role for the P,N hemilabile ligand acting co‐catalytically as both an in situ base and proton relay coupled with a Pd⁰ centre, allowing for surmountable barriers (highest ΔG^≠ of 22.9 kcal mol^?1 for alcoholysis). This proton‐shuffle between methanol and coordinated propyne accounts for experimental requirements (high acid concentration) and reproduces observed regioselectivities as a function of ligand structure. A simple ligand modification is proposed, which is predicted to improve catalytic turnover by three orders of magnitude.     

Highly Diastereoselective Hydrosilane-Assisted Rhodium-Catalyzed Spiro-Type Cycloisomerization of Succinimide and Pyrazolone-Based Functional 1,6-Dienes

Organosilicon compounds are important reagents and synthetic intermediates that play a key role in the construction of new materials and complex products. Here we show a highly diastereoselective rhodium-catalyzed cycloisomerization of 1,6-dienes, in which the use of (EtO)₃SiH accelerates the intramolecular cyclization reaction to afford a novel spiro-fused succinimide and pyrazolone derivatives in moderate to excellent yields as a single diastereoisomer. The proposed mechanism involves an active Rh−H species from the hydrosilane that is the H-donor in this spiro-type cycloisomerization reaction.     

Anionic Access to Silylated and Germylated Binuclear Heterocycles

A simple access to silylated and germylated binuclear heterocycles, based on an original anionic rearrangement, is described. A set of electron‐rich and electron‐poor silylated aromatic and heteroaromatic substrates were tested to understand the mechanism and the factors controlling this rearrangement, in particular its regioselectivity. This parameter was shown to follow the rules proposed before from a few examples. Then, the effect of the substituents borne by the silicon itself, in particular the selectivity of the ligand transfer, was studied. Additionally, this chemistry was extended to germylated substrates. A hypervalent germanium species, comparable to the putative intermediate proposed with silicon, seems to be involved. However, a pathway implicating the elimination of LiCH₂Cl was observed for the first time with this element, leading to unexpected products of the benzo‐oxa (or benzo‐aza) germol‐type.     

Gold‐ and Platinum‐Catalyzed Cycloisomerization of Enynyl Esters versus Allenenyl Esters: An Experimental and Theoretical Study

Ester‐way to heaven : Unexpected formation of bicyclo[3.1.0]hexene 4 was the main focus of combined experimental and theoretical studies on the Au‐catalyzed cycloisomerization of branched dienyne 1 (see scheme), which provided better understanding of the mechanistic details governing the cyclization of enynes bearing a propargylic ester group.

     

Gold‐Catalyzed Cycloisomerization and Diels–Alder Reaction of 1,4,9‐Dienyne Esters to 3 a,6‐Methanoisoindole Esters with Pro‐Inflammatory Cytokine Antagonist Activity

A synthetic method to prepare 3a,6‐methanoisoindole esters efficiently by gold(I)‐catalyzed tandem 1,2‐acyloxy migration/Nazarov cyclization followed by Diels–Alder reaction of 1,4,9‐dienyne esters is described. We also report the ability of one example to inhibit binding of tumor necrosis factor‐α (TNF‐α) to the tumor necrosis factor receptor 1 (TNFR1) site and TNF‐α‐induced nuclear factor κ‐light‐chain‐enhancer of activated B cells (NF‐κB) activation in cell at a half‐maximal inhibitory concentration (IC₅₀) value of 6.6 μM . Along with this is a study showing the isoindolyl derivative to exhibit low toxicity toward human hepatocellular liver carcinoma (HepG2) cells and its possible mode of activity based on molecular modeling analysis.     

Efficient One-Pot Synthesis of Naphthoquinone-Fused Phosphorous Heterocycles via Mannich-Type Reaction

A series of naphthoquinone-fused phosphorus heterocycles was synthesized via a three-component Mannich-type reaction. 2-Chloroethoxylphosphorodichloridite was used as a phosphorus substrate to explore the structure–activity relationships of the 2-position of the heterocycles. One spiral heterocycle compound was structurally characterized by a single-crystal X-ray diffraction analysis.     

Stereo‐ and Regioselective Alkyne Hydrometallation with Gold(III) Hydrides

The hydroauration of internal and terminal alkynes by gold(III) hydride complexes [(C^N^C)AuH] was found to be mediated by radicals and proceeds by an unexpected binuclear outer‐sphere mechanism to cleanly form trans‐insertion products. Radical precursors such as azobisisobutyronitrile lead to a drastic rate enhancement. DFT calculations support the proposed radical mechanism, with very low activation barriers, and rule out mononuclear mechanistic alternatives. These alkyne hydroaurations are highly regio‐ and stereospecific for the formation of Z‐vinyl isomers, with Z/E ratios of >99:1 in most cases.     

Cationic Heterocycles as Ligands: Synthesis and Reactivity with Anionic Nucleophiles of Cationic Triruthenium Clusters Containing C‐Metalated N‐Methylquinoxalinium or N‐Methylpyrazinium Ligands

The cationic cluster complexes [Ru₃(CO)₁₀(μ‐H)(μ‐κ²N,C‐L¹Me)]⁺ ( 3 ⁺; HL¹=quinoxaline) and [Ru₃(CO)₁₀(μ‐H)(μ‐κ²N,C‐L²Me)]⁺ ( 5 ⁺; HL²=pyrazine) have been prepared as triflate salts by treatment of their neutral precursors [Ru₃(CO)₁₀(μ‐H)(μ‐κ²N,C‐Lⁿ)] with methyl triflate. The cationic character of their heterocyclic ligands is responsible for their enhanced tendency to react with anionic nucleophiles relative to that of hydrido triruthenium carbonyl clusters that have neutral N‐heterocyclic ligands. These clusters react instantaneously with methyl lithium and potassium tris‐sec‐butylborohydride (K‐selectride) to give neutral products that contain novel nonaromatic N‐heterocyclic ligands. The following are the products that have been isolated: [Ru₃(CO)₉(μ‐H)(μ₃‐κ²N,C‐L¹Me₂)] ( 6 ; from 3 ⁺ and methyl lithium), [Ru₃(CO)₉(μ‐H)(μ₃‐κ²N,C‐L¹HMe)] ( 7 ; from 3 ⁺ and K‐selectride), [Ru₃(CO)₉(μ‐H)(μ₃‐κ²N,C‐L²Me₂)] ( 8 ; from 5 ⁺ and methyl lithium), and [Ru₃(CO)₉(μ‐H)(μ₃‐κ²N,C‐L²HMe)] ( 11 ; from 5 ⁺ and K‐selectride). Whereas the reactions of 3 ⁺ lead to products that arise from the attack of the corresponding nucleophile at the C atom of the only CH group adjacent to the N‐methyl group, the reactions of 5 ⁺ give mixtures of two products that arise from the attack of the nucleophile at one of the C atoms located on either side of the N‐methyl group. The LUMOs and the atomic charges of 3 ⁺ and 5 ⁺ confirm that the reactions of these clusters with anionic nucleophiles are orbital‐controlled rather than charge‐controlled processes. The N‐heterocyclic ligands of all of these neutral products are attached to the metal atoms in nonconventional face‐capping modes. Those of compounds 6 – 8 have the atoms of a ligand C?N fragment σ‐bonded to two Ru atoms and π‐bonded to the other Ru atom, whereas the ligand of compound 11 has a C? N fragment attached to a Ru atom through the N atom and to the remaining two Ru atoms through the C atom. A variable‐temperature ¹H NMR spectroscopic study showed that the ligand of compound 7 is involved in a fluxional process at temperatures above ?93 °C, the mechanism of which has been satisfactorily modeled with the help of DFT calculations and involves the interconversion of the two enantiomers of this cluster through a conformational change of the ligand CH₂ group, which moves from one side of the plane of the heterocyclic ligand to the other, and a 180° rotation of the entire organic ligand over a face of the metal triangle.     

Synthesis of Aminopyridines and Aminopyridones by Cobalt‐Catalyzed [2+2+2] Cycloadditions Involving Yne‐Ynamides: Scope,Limitations, and Mechanistic Insights

An in‐depth study of the cobalt‐catalyzed [2+2+2] cycloaddition between yne‐ynamides and nitriles to afford aminopyridines has been carried out. About 30 nitriles exhibiting a broad range of steric demand and electronic properties have been evaluated, some of which open new perspectives in metal‐catalyzed arene formation. In particular, the use of [CpCo(CO)(dmfu)] (dmfu=dimethyl fumarate) as a precatalyst made possible the incorporation of electron‐deficient nitriles into the pyridine core. Modification of the substitution pattern at the yne‐ynamide allows the regioselectivity to be switched toward 3‐ or 4‐aminopyridines. Application of this synthetic methodology to the construction of the aminopyridone framework using a yne‐ynamide and an isocyanate was also briefly examined. DFT computations suggest that 3‐aminopyridines are formed by formal [4+2] cycloaddition between the nitrile and the intermediate cobaltacyclopentadiene, whereas 4‐aminopyridines arise from an insertion pathway.     

Cycloruthenated Complexes from Imine‐Based Heterocycles: Synthesis,Characterization, and Reactivity toward Alkynes

Novel cycloruthenated complexes 2 a – c , 4 a – c , and 6 a, b based on heteroaromatic cores have been synthesized by reaction of a series of heterocycle‐based imines with [{RuCl(η⁶‐p‐cymene)}₂(μ? Cl)₂] and Cu(OAc)₂. This approach has proved efficient for the cyclometalation of thiophene, benzothiophene, furan, benzofuran, pyrrole, and indole derivatives. In addition, even a double cyclometalation process over the same heterocyclic ring is possible, yielding unprecedented bimetallic complexes. These ruthenacycles react with 3‐hexyne through an unexpected pathway, which involves the coupling of the original imino heterocycle and acetylene followed by dearomatization to afford fused hetero‐hydropyridyl ligands bonded to the {Ru(p‐cymene)} organometallic moiety (i.e., 7 a – c and 8 a – c ). These complexes represent, as far as we know, the first examples of this type of compound within the context of cyclometalation, and an exhaustive analysis of their structure was carried out in solution and solid state. Furthermore, these unique species react with CuCl₂, which promotes the rearomatization and the release of highly valuable aromatic fused bis‐heterocycles (i.e., 9 a – c , 10 a – c, 11 a , and 12 a/12 a′ ), providing a novel and appealing synthetic route to this extraordinary family of molecules.     

Vinyl Dihydropyrans and Dihydrooxazines: Cyclizations of Catalytic Ruthenium Carbenes Derived from Alkynals and Alkynones

A novel synthesis of 2‐vinyldihydropyrans and dihydro‐1,4‐oxazines (morpholine derivatives) from alkynals and alkynones has been developed. The cyclizations require a mild generation of catalytic ruthenium carbenes from terminal alkynes and (trimethylsilyl)diazomethane followed by trapping with carbonyl nucleophiles. Mechanistic aspects of the new cyclizations are discussed.     

Functionalization of Alkynes by a (Salen)ruthenium(VI) Nitrido Complex

Exploring new reactivity of metal nitrides is of great interest because it can give insights to N₂ fixation chemistry and provide new methods for nitrogenation of organic substrates. In this work, reaction of a (salen)ruthenium(VI) nitrido complex with various alkynes results in the formation of novel (salen)ruthenium(III) imine complexes. Kinetic and computational studies suggest that the reactions go through an initial ruthenium(IV) aziro intermediate, followed by addition of nucleophiles to give the (salen)ruthenium(III) imine complexes. These unprecedented reactions provide a new pathway for nitrogenation of alkynes based on a metal nitride.