Transition metal catalyzed cyclotrimerizations

Through the years, the development of transition metal-catalyzed methodologies, notably involving cyclotrimerization and Sonogashira or Heck cross coupling, has paved the way for rapid and efficient access to aryl glycoclusters with desired and controlled valency. 

Transition metal-catalyzed intermolecular [2 + 2 + 2] cyclotrimerization of alkynes to benzene derivatives has been extensively studied. In this section, the focus is on the cyclo-trimerizations of the substrates bearing three independent unsaturated bond components. The key issue with this type of process usually involves the challenge of controlling regioselectivity [1—1]. However, 1,3,5-trisubstituted benzene 44 can be obtained as the sole product in good yield when 3-butyn-2-one 43 is used as the substrate for the cyclotrimerization catalyzed by Rh2(pfb)4 (pfb=perfluorobutyrate) in the presence of EtsSiH under a CO atmosphere (Eq. 11) [30]. 

The transition metal-catalyzed [2 -i- 2 -i- 2] cyclocotrimerization of two molecules of an alkyne with an alkene has studied to a lesser degree compared to the parent alkyne cyclotrimerization [9], although the resultant cyclohexadiene is a valuable synthetic intermediate (e.g., a diene component for the Diels-Alder reaction). This is because a 2 1 coupling of an alkyne and an alkene is generally difficult to compete with the more facile alkyne cyclotrimerization. The success of the selective coupling depends on the electronic balance between the employed alkyne and alkene components the combinations of an electron-deficient alkene with a neutral alkyne [35] or an electron-deficient alkyne with a neutral alkene [36] were successful in the previous... 

The transition metal-catalyzed cyclotrimerization of acetylene (eq. (1)) was discovered by Berthelot [1] back in the mid-19th century using heterogeneous systems. 

Whereas the transition metal catalyzed cyclotrimerization and cyclotetramerization of alkynes leading to benzene or cyclooctatetraene and their derivatives is a rather common reaction, there exist only a few examples of cooligomerizations between alkynes and alkenes or 1,3-butadienes leading to 1,3- or 1,4-cyclohexadiene derivatives20S). It is therefore surprising that the [3+2]-cycloaddition between methylenecyclopropanes and alkynes, catalyzed by triarylphosphite modified Ni(0) compound, is a rather convenient method to synthesize 4-methylenecyclopentenes 206). A wide range of methylenecyclopropanes and alkynes, in the latter case mainly 1,2-disubstituted ones, can be used for these reactions (Eqs. 98-100, see p. 127-128). 

Transition-metal-catalyzed [2 + 2 + 2]-cycloaddition of alkynes, so-called cyclotrimerization, has been widely investigated as a powerful tool to construct benzene rings.117 Cyclotrimerization of the amino-dialkynes and dialkynyl ethers 109 with alkynes provides various kinds of benzene-fused aza- and oxa-heterocyclic compounds 111 (Scheme 39, route a).118 The key intermediate for the [2 + 2 + 2]-cycloaddition is the metallacyclopentadienes 110, as men-... 

Similar to cyclodimerizations, transition metal catalyzed cyclooligomerizations and cocyclooligomerizations involve dicarborative addition steps. The most important examples of this type are represented by cyclotrimerization and cyclotetramerization of alkenes. dienes, alkynes and systems with hetero multiple bonds, leading to carbocyclic and heterocyclic six-, eight- or twelve-membered rings1 ... 

Applications of transition metal catalyzed cyclooligomerizations and cocyclooligomerizations to stereoselective synthesis are restricted to some special methods, such as cyclotrimerizations and cocyclotrimerizations of alkenes and alkynes ([2 + 2 + 2] cyclooligomerizations), as well as homo-Diels-Alder reactions of norbornadiene (formal [2 -b 2 + 2] cyclooligomerizations). 

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... 

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. 

The first example of a transition metal-catalyzed cycUzation of arynes was reported in 1998 [112], when benzyne generated from o-(trimethylsilyl)phenyl triflate was shown to undergo cyclotrimerization in the presence of a catalytic amount of Pd(PPh3)4 to afford triphenylene (208) (Scheme 12.60). 

Finally, transition metal-catalyzed reactions of arynes have been explored as a useful method for the construction of a wide variety of carbo- and heteocycles. These reactions include cyclotrimerization of arynes, cocyclization of arynes with alkynes or alkenes, and carbopaUadation of arynes with Pd-complexes. Moreover, some insertion reactions of arynes into a-bonds are also catalyzed by metal complexes. 

Transition-metal-catalyzed cyclotrimerizations are powerful tools for the construction of polyaromatic compounds, which are potential building blocks for functional materials [1]. Specifically, ruthenium-catalyzed cyclotrimerizations have been applied to the synthesis of polyaromatic functional molecules, as summarized in this section. 

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). 

The central six-membered ring unit in the illudalane or pterosin class of sesquiterpenes makes them a suitable target for a proof of the synthetic power of the transition-metal-catalyzed [2 + 2 + 2] alkyne cycloaddition in natural product synthesis. A first example in this field was provided by the intramolecular version of the [2 + 2 + 2] alkyne cyclotrimerization in the synthesis of calomelanolactone (15) [8] and pterosin Z (16), both of which have been isolated Ifom the silver fern Pityrogramma calome-lanos (Scheme 7.4) [9]. Wilkinson s complex served here as the catalyst, and the cyclotrimerization of triyne 13 proceeded at room temperature to give the tricycle 14. The latter was used as a common synthetic intermediate for completion of the synthesis of calomelanolactone (15) and pterosin Z (16) within four and three synthetic steps, respectively. 

The transition-metal-catalyzed crossed [2 + 2 + 2] alkyne cyclotrimerization for the construction of a benzene unit also found uses in the synthesis of carbocyclic and heterocyclic natural products. Although this version has its challenges in the chemo-and regioselective outcome, its advantages are evident and lie in less labor-intensive syntheses of the alkyne building blocks. 

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 use of [RhCl(CO)2]2 in intermolecular [5+2] cycloadditions often require heating, which in turn promotes competing cyclotrimerization of alkyne starting materials, decomposition of the VCP, or formation of undesired secondary isomerization products. Such transition metal-catalyzed intermolecular cycloadditions pose particular chemo-and regioselectivity challenges as well as entropic penalties not encountered in intramolecular processes, as the latter benefit from tether-derived alignment and proximity of reactive functionalities not possible in the former. In this context, Wender et al. have recently demonstrated that the cationic rhodium(I) complex, [RhCCioHsKcod)]" SbFe, promoted the remarkably efficient intermolecular [5+2] cycloaddition of 1-alkoxy-VCP 37, and 1-alkyi-VCP 42... 

Grothahn, D.B. (1995) Transition metal alkyne complexes transition metal catalyzed cyclotrimerization, in Comprehensive Organometallic Chemistry II, vol. 12 (eds. E.W. Abel, F.G.A. Stone, G. Wilkinson, and L.S. Hegedus), Pergamon, Oxford, pp. 741-770. 

Pd-cataly2ed reactions of butadiene are different from those catalyzed by other transition metal complexes. Unlike Ni(0) catalysts, neither the well known cyclodimerization nor cyclotrimerization to form COD or CDT[1,2] takes place with Pd(0) catalysts. Pd(0) complexes catalyze two important reactions of conjugated dienes[3,4]. The first type is linear dimerization. The most characteristic and useful reaction of butadiene catalyzed by Pd(0) is dimerization with incorporation of nucleophiles. The bis-rr-allylpalladium complex 3 is believed to be an intermediate of 1,3,7-octatriene (7j and telomers 5 and 6[5,6]. The complex 3 is the resonance form of 2,5-divinylpalladacyclopentane (1) and pallada-3,7-cyclononadiene (2) formed by the oxidative cyclization of butadiene. The second reaction characteristic of Pd is the co-cyclization of butadiene with C = 0 bonds of aldehydes[7-9] and CO jlO] and C = N bonds of Schiff bases[ll] and isocyanate[12] to form the six-membered heterocyclic compounds 9 with two vinyl groups. The cyclization is explained by the insertion of these unsaturated bonds into the complex 1 to generate 8 and its reductive elimination to give 9. 

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 . 

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