Ruthenium catalysis cycloaddition

Related co-cyclotrimerizations of two alkyne molecules with limited isocyanates have also been achieved using cobalt and nickel catalysts. With respect to intramolecular versions, two examples of the cobalt(I)-catalyzed cycloaddition of a,m-diynes with isocyanates have been reported to afford bicyclic pyri-dones only in low yields, although 2,3-dihydro-5(lff)-indolizinones were successfully obtained from isocyanatoalkynes and several silylalkynes with the same cobalt catalysis [19]. On the other hand, the ruthenium catalysis using Cp RuCl(cod) as a precatalyst effectively catalyzed the cycloaddition of 1,6-diynes 21 with 4 equiv. of isocyanates in refluxing 1,2-dichloroethane to afford bicyclic pyridones 25 in 58-93% yield (Eq. 12) [20]. In this case,both aryl and aliphatic isocyanates can be widely employed. 

A highly electron-deficient carbon-oxygen double bond can also participate in the co-cyclotrimerization with alkynes under the ruthenium catalysis. The cycloaddition of commercially available diethyl ketomalonate with the diynes 21 proceeded at 90 °C in the presence of 5-10 mol % Cp RuCl(cod). The expected fused 2ff-pyrans 27, however, underwent thermal electrocyclic ringopening to produce cyclopentene derivatives 28 (Eq. 14) [23]. 

In addition to these intramolecular [2+2+2] cycloadditions, intramolecular [4+2] cycloaddition of yne-enones 29 leading to fused pyrans 30 has been achieved by means of the ruthenium catalysis with a cationic complex, CpRu(MeCN)3PF6 (Eq. 15) [24], Such hetero Diels-Alder cycloaddition was considered to proceed via an oxaruthenacycle 31. 

Ruthenium catalysis has been extensively explored during the past decade [114]. Newly developed carbon-carbon bond forming cyclizations such as [2+2+2] cycloaddition, RCMs, and cycloisomerizations have dramatically expanded the scope of heterocycle synthesis. Relatively unexplored catalytic carbon-heteroatom bond formations have also made significant contributions to this area. Further progress in ruthenium catalysis will not only improve the conventional synthetic methodologies, but will also open the way to an unprecedented class of heterocyclic compounds, which might have a significant potential as pharmaceuticals or functional materials. 

It is now usual to promote these cycloadditions by catalysts for example, reaction with A -tosyl-ynamides, using ruthenium or copper catalysts, giving 1-substituted 5- and 4-amino triazoles, respectively the formation of the 1,4-substitution pattern with copper catalysis and 1,5-pattem with ruthenium catalysis seems to be general. The latter metal will also promote addition to internal alkynes. ... 

In this chapter we outline advances in the ruthenium-mediated alkyne [2 + 2 + 2] cycloaddition reactions. These can be classified into two major categories in terms of the types of products (1) syntheses of benzene derivatives via alkyne [2 + 2 + 2] cycloadditions and (2) syntheses of heteroaromatics via [2 + 2 + 2] cocycloadditions of alkynes with nitriles or heterocumulenes. Benzene ring-forming reactions are essentially prototypes of the corresponding heteroaromatic annulations. Therefore, the first class of reactions is reviewed in the next section and followed by a discussion of the second class of reactions. The mechanistic aspects and synthetic applications of ruthenium-catalyzed [2 + 2 + 2] cycloadditions are also described to exemplify the scientific and practical significance of ruthenium catalysis. 

The reactions that yield benzene rings can be categorized further into the following types according to the substrates involved (1) intermolecular cycloaddition of three alkynes (cyclotrimerization), (2) partially intramolecular cycloaddition ofdiynes with alkynes, and (3) fully intramolecular cyclotrimerization of triynes. In the next section, the synthetic routes to benzene derivatives using ruthenium-catalyzed cycloaddition are surveyed according to these classifications. Classic examples of [2 + 2 + 2] alkyne cycloadditions using stoichiometric ruthenium mediators are included since they provide useful information on the further development of ruthenium catalysis. 

Originally, the pyridine construction reaction was based on cobalt catalysis and restricted to the use of acetonitrile or alkyl nitriles as one of the cycloaddition partners. However, recent advancements in this area have led to the development of certain ruthenium or rhodium catalysts, allowing the use of methylcyanoformate as an electron-deficient nitrile component in crossed [2 - - 2 - - 2]-cycloaddition reactions [39]. From the point of view of applications, the use of methylcyanoformate in transition-metal-catalyzed pyridine formation reaction is quite beneficial because the ester moiety might serve as a functional group for further manipulations. It might also serve as a protective group of the cyanide moiety, because cyanide itself cannot be used in this reaction. These considerations led to the design of a quite flexible approach to substituted 3-(130)- and y-carbolines (131) based on transition-metal-catalyzed [2 -f 2 -I- 2] cycloaddition reactions between functionalized yne-ynamides (129) and methylcyanoformate (Scheme 7.28) [40]. 

Although in principle the thermal [2-I-2-I-2] cycloaddition process is allowed by orbital symmetry rules, there are problems with the entropy component, which may be overcome by using transition metal catalysis. This approach (Scheme 2.35) is one of the most convenient for the synthesis of pyridines 2.100. Metal-induced cycloaddition of two alkyne and one nitrile molecules has been described in general reviews of cycloaddition reactions [3,4]. However in some reviews on heterocycles the nitriles are considered as equivalent to alkyne in the [2+2+2] cyclotrimerization reaction [76], in particular, for the synthesis of pyridines and pyridinones in the reactions catalyzed by cobalt, ruthenium, titanium, and zirconium. 

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