Tethered cyclotrimerization

Intermolecular cyclotrimerization of alkynes using Wilkinson s catalyst has also afforded substituted carbazole derivatives. This reaction was extended to an intramolecular version by offering the possibility for a six-membered ring annotation that cannot be achieved easily in the corresponding intermolecular version. Intramolecular cyclotrimerization is completely regioselective due to an additional tether. 

Intramolecular [2+2+2] cyclotrimerizations of diynes and triynes possessing heteroatom tethers furnish benzoheterocycles. The cyclization of triynes 88 using the Grubbs catalyst 76 proceeds via cascade metathesis as shown in Eq. (35) to yield a tricyclic product 89 [88]. This novel type of catalytic alkyne cyclotrimerization can be applied to the cycloaddition of 1,6-diynes with monoalkynes [89]. 

A common limitation of most classes of cyclotrimerizations is the difficulty associated with controlling the chemoselectivity of the process. In most instances involving inter-molecular couplings, multiple incorporation of the same aUcyne imit is imavoidable. However, with systems in which two aUcynes, or one alkene and one aUcyne are tethered, synthetically useful processes become possible. The first example of a selective addition of two equivalents of an allcyne and one alkene was reported by ChalkTsuda has applied this process to applications in polymer chemistry,and Ikeda has developed a similar method employing cyclic enones (Scheme 47).P l... 

Chemo- and regioselective ruthenium-catalyzed cyclotrimerization of alkynes was accomplished through a temporary boron tether. Crude aryl boronates were obtained in a one-pot procedure in which they were subjected to a Suzuki-Miyaura coupling with aryl halides (Scheme 9.50) [103]. 

Alkynylnitriles are notoriously difficult to react in [2 - - 2 - - 2] cyclotrimerization reactions, since in the catalytic cycle a reaction between the triple bond of the alkynylnitrile and the external alkyne occurs first, followed by the intramolecular insertion of the tethered cyano group. " " Thus, these substrates are prone to undesired side reactions with two external alkynes and with another alkynylnitrile. Immobilization on a solid support can alleviate these problems through spatial separation. The immobilized substrate 77 reacted smoothly to the fused pyridines 78 that are subsequently cleaved from the polymeric support to 79 (Scheme 6.18). Control reactions of alkynylnitriles in solution phase under otherwise identical conditions delivered the corresponding fused pyridines in only 8-23% yield. 

Regioselectivity can usually be reliably obtained when two of the alkyne partners are tethered. A Cp RuCl(cod)-catalyzed intermolecular cyclotrimerization of three different monoalkynes could be performed by an in situ-tethering approach with the formation of a temporal C-B-O linkage from alkynylboronates and propargyl alcohols [13-15] [Eq. (9)]. The resultant arylboronates could not be isolated and were further converted to substituted biaryls via the Suzuki-Miyaura coupling or into a sequential one-pot process [14], or to phtalides via a palladium-catalyzed carbonylation [15]. 

Stepwise sequential cross-cyclotrimerization was investigated for the synthesis of polyaromatic compounds (Scheme 3.32) [31]. For example, alkyne-tethered tris(thiophene) 156 was transformed into 157 in a good overall yield via two cycloaddition sequences using catalyst 32. Subsequent dehydroaromatization in the presence of 10 mol % of iodine under ultraviolet irradiation resulted in polyheteroaromatic... 

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... 

Yamamoto, Y., Ishii, J., Nishiyama, H. and Itoh, K. (2004) Ru(II)-catalyzed chemo-and regioselective cyclotrimerization of three unsymmetrical alkynes through boron temporary tether. One-pot four-component coupling via cyclotrimerization/Suzuki-Miyaura coupling. Journal of the American Chemical Society, 126(12), 3712-3713. 

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