Ruthenium-Mediated Cycloaddition

Aromatic ring systems are ubiquitous in natural products, drugs, and functional and 

Transition-Metal-Mediated Aromatic Ring Construction, First Edition. Edited by Ken Tanaka, 2013 John Wiley Sons, Inc. Published 2013 by John Wiley Sons, Inc. 

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. 

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CEJ1358> and the ruthenium mediated isomerization of double bonds (cf. Scheme 89, Section 8.11.7) <2007TL137> are recent examples of transition metal catalyzed manipulations at the side chain carbon atoms of 1,3-heterocycles. A novel side-chain addition reaction of aldehydes to 6-alkylidene-l,3-dioxin-4-ones was used for the construction of intermediates of lophotoxin <2006CJC1226>. An acid-catalyzed intramolecular cycloaddition of a hydroxy group to an alkene has been effected by the presence of an adjacent 1,3-dithiane moiety <2006TL4549>. 

Strategies to pyridines include a ruthenium-mediated [2+2+2] cycloaddition to produce annulated products <20010L2117>. Reaction of 1,6-heptadiynes with electron-deficient nitriles yields the pyridine (Equation 175), whereas the same strategy using isocyanates leads to the 2-pyridone (Equation 176). 

The cobalt-mediated cycloaddition of an alkyne, an alkene, and CO leading to a cyclopentenone has been known as the Pauson-Khand (PK) reaction [78], Due to its synthetic importance, numerous variants - especially catalytic reactions - have been developed to date [79]. The first ruthenium-catalyzed PK reaction of enynes has been achieved using Ru3(CO)i2 by two research groups independently (Scheme... 

A mechanism has been proposed by Blechert for this metathesis cascade, which involved the formation of a number of carbon-carbon bonds (in principle, a ruthenium-mediated [2-I-2+2] cycloaddition is also plausible for this transformation [49]). This postulated mechanism, as shown for the conversion of triyne 141 into the substituted aromatic system 142, is depicted in Scheme 17.27 [50]. Initially, complex 1-Ru adds to the less hindered acetylene of 141 to afford the vinyl carbene complex 143, which then undergoes an intramolecular metathesis reaction to afford 144 via 145. The conjugated complex 144 can then undergo a further RCM reaction to yield the product 142. 

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. 

The asymmetric synthesis of allenes via enantioselective hydrogenation of ketones with ruthenium(II) catalyst was reported by Malacria and co-workers (Scheme 4.11) [15, 16]. The ketone 46 was hydrogenated in the presence of iPrOH, KOH and 5 mol% of a chiral ruthenium catalyst, prepared from [(p-cymene) RuC12]2 and (S,S)-TsDPEN (2 equiv./Ru), to afford 47 in 75% yield with 95% ee. The alcohol 47 was converted into the corresponding chiral allene 48 (>95% ee) by the reaction of the corresponding mesylate with MeCu(CN)MgBr. A phosphine oxide derivative of the allenediyne 48 was proved to be a substrate for a cobalt-mediated [2 + 2+ 2] cycloaddition. 

Another focus of this chapter is the alkynol cycloisomerization mediated by Group 6 metal complexes. Experimental and theoretical studies showed that both exo- and endo- cycloisomerization are feasible. The cycloisomerization involves not only alkyne-to-vinylidene tautomerization but alo proton transfer steps. Therefore, the theoretical studies demonstrated that the solvent effect played a crucial role in determining the regioselectivity of cycloisomerization products. [2 + 2] cycloaddition of the metal vinylidene C=C bond in a ruthenium complex with the C=C bond of a vinyl group, together with the implication in metathesis reactions, was discussed. In addition, [2 + 2] cycloaddition of titanocene vinylidene with different unsaturated molecules was also briefly discussed. 

A ruthenium-promoted carbonylation of allenyl alcohols 884 is a powerful method for the synthesis of 5,6-dihydropyran-2-ones 885 (Equation 356) <20000L441, 2003JOC8571>. Co2(CO)6-mediated tandem [5+1]/ [2+2+1] cycloaddition reactions of the epoxide 886 with carbon monoxide provide a one-pot synthesis of tricyclic 5,6-dihydropyran-2-ones 887 in good yield (Equation 357) <2003JA9610>. 

Abstract This review gives an insight into the growing field of transition metal-catalyzed cascades. More particularly, we have focused on the construction of complex molecules from acyclic precursors. Several approaches have been devised. We have not covered palladium-mediated cyclizations, multiple Heck reactions, or ruthenium-catalyzed metathesis reactions because they are discussed in others chapters of this book. This manuscript is composed of two main parts. In the first part, we emphasize cascade sequences involving cycloaddition, cycloisomerization, or ene-type reactions. Most of these reaction sequences involve a transition metal-catalyzed step that is either followed by another reaction promoted by the same catalyst or by a purely thermal reaction. A simple change in the temperature of the reaction mixture is often the only technical requirement to go from one step to another. The second part covers the cascades relying on transition metalo carbenoid intermediates, which have recently undergone tremendous... 

Other metal-mediated reactions of azide reagents to terminal alkynes have also been reported. Indium(ll) triflate catalyzed tandem azidation/l,3-dipolar cycloaddition of various (o,(o-dialkoxyalkynes 134 with trimethylsilyl azide yielded fused 1,2,3-triazoles 135 <05TL8639>. A new ruthenium-catalyzed process for the regioselective synthesis of 1,5-disubstituted-1,2,3-triazoles has been developed <05JA15998>. 

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