Cobalt metal-catalyzed cyclotrimerization

Novel transition metal-mediated strategies were also well represented this past year. Takahashi and co-workers reported a s nickel-catalyzed reaction between azaziconacyclopentadienes (9) and alkynes to form pyridines (10) of varying substitution patterns <00JA4994>. This methodology, a formal cyclotrimerization, is also noteworthy since two different alkynes can be used. In similar fashion, Eaton reported an aqueous, cobalt(II) catalyzed cyclotrimerization between two identical acetylenes and one nitrile to afford substituted pyridines . 

When a monosubstituted acetylene RCsCH is heated with nickel or cobalt carbonyls, it gives the 1,2,4-trisubstituted benzene as major product, the 1,3,5-benzene as minor product, and little if any of the 1,2,3-isomer. Coordination of the metal with the triple bond has been considered to be involved [52]. Thus, in the transition-metal-catalyzed cyclotrimerization, the... 

Compared with the Diels-Alder reaction, the [2+2+2]-cycloaddition is potentially more powerful since the number of new bonds as well as chirality centers that are formed is higher. Unfortunately, the reaction seems to be entropically or kinetically unfavorable. This disadvantage can, however, be overcome by the use of transition metal catalysts (templates). Among the most successful examples of this reaction type, the nickel(II) catalyzed Reppe reactions 96), the cobalt(I) catalyzed cocyclizations of a,to-diynes with alkynes 97), the cobalt(I) catalyzed pyridine synthesis 985 and last but not least the palladium(0) catalyzed cyclotrimerizations of 3,3-dialkylcyclopropenes to frans-cr-tris-homobenzenes must be mentioned. The latter has been known for ten years 99>. 

Transition-metal-catalyzed intermolecular [2+2+2] cyclotrimerization of alkynes to benzenes has been extensively studied with several catalyst systems involving palladium, cobalt, nickel, rhodium, and other transition metals. This methodology can be applied to the preparation of polysubstituted benzenes. The major challenge of this transformation is control of regioselectivity of unsymmetrical alkynes, particularly in the cross-cyclotrimerization of two or three alkynes. 

Volhardt s tZZ-estrone synthesis was the first application of a transition-metal-catalyzed [2 -1- 2 -I- 2] alkyne cyclotrimerization in natural product synthesis, and the overall beauty of the synthetic sequence is still appealing [4,5]. Undoubtedly, this brilliant synthesis is a classic in its field. Following a D ABCD ring formation approach, the tetracyclic core of estrone was produced in a single reaction step by profiting from a reaction cascade that started with a cobalt-mediated crossed [2 + 2 + 2] alkyne cycloaddifion, which was followed by a benzocyclobutane to o-quinodimethane rearrangement, and was finalized by an intramolecular Diels-Alder reaction (Scheme 7.2). 

An early contribution to use of the transition-metal-catalyzed pyridine formation reaction was the synthesis of vitamin Be (124) via the crossed-cyclotrimerization reaction of the bis-stannylated diyne 122 with acetonitrile under cobalt catalysis (Scheme 7.26) [36a andb]. The underlying crossed [2 - - 2 - - 2] cycloaddition reaction here provided the fused pyridine 123 in 76% yield after a regioselective destannylation effected by treatment of the cycloaddition product with aluminum oxide. 

The cobalt catalyzed cocyclization of alkynes with heterofunctional substrates is not limited to nitriles. cpCo-core complexes are capable of co-oligomerizing alkynes with a number of C,C, C,N or C,0 double bonds in a Diels-Alder-type reaction. Chen, in our laboratories, has observed that these cycloadditions are best performed with the help of stabilizers such as ketones or acetic esters that are weakly coordinated to the cobalt and prevent the alkynes from being cyclotrimerized at the metal center... 

Alkyne cyclotrimerization occurs at various homogeneous and heterogeneous transition metal and Ziegler-type catalysts [7], Substituted benzenes have been prepared in the presence of iron, cobalt, and nickel carbonyls [8] as well as trialkyl- and triarylchromium compounds [9]. Bis(acrylonitrile)nickel [10] and bis(benzonitrile)palladium chloride [11] catalyze the cyclotrimerization of tolane to hexaphenylbenzene. NiCl2 reduced by NaBH4 has been utilized for the trimer-ization of 3-hexyne to hexaethylbenzene [12]. Ta2Cl6(tetrahydrothiophene)3 and Nb2Cl6(tetrahydrothiophene)3 as well as 7 -Ind-, and 77 -Ru-rhodium... 

Likewise when two alkyne molecules coordinate to a transition metal such as Co(I) with subsequent coupling of the C-C bond, oxidative cyclization takes place to give a metallacyclopentadiene. Further reaction of another alkyne molecule with the metallacyclopentadiene followed by reductive elimination liberates benzene derivatives. Thus cyclotrimerization of three alkyne molecules catalyzed by a cobalt complex [40,41] can be performed. If a nitrile is used as the second component, pyridine derivatives are obtained catalytically as shown in Scheme 1.13 [42]. The catalytic cyclotrimerization and cyclodimerization of alkynes and conjugated enynes have found extensive applications in synthesis of complex cyclic compounds such as steroid derivatives [43]. 

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. 

Among transition-metal complex catalyzed reactions of alkynes with carbon-heteroatom unsaturated compounds the most studied is co-cyclotrimer-ization of alkynes with nitriles to pyridines. For this process the same complexes can be used as for the cyclotrimerization of alkynes. The first report of a cyclopentadienylcobalt complex catalyzed co-cyclotrimerization of alkynes with nitriles appeared in 1973 [92] and was soon followed by other papers [93]. Co-cyclotrimerization of alkynes and nitriles with all its aspects has been recently reviewed [94] and because of that we will focus only on recent developments in this area. In this regard, advances have been made in simple co-cy-clotrimerization of ethyne with various nitriles [95], combinatorial synthesis of substituted pyridines [96], and co-cyclotrimerization of hydroxyalkynes with nitriles in aqueous media catalyzed by cobalt complex with hydrophobic chain attached to the cyclopentadienyl ring [97]. 

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