Cross-cyclotrimerization

Cross-cyclotrimerization or cyclocotrimerization involving different alkyne components is a daunting challenge because of the increased difficulty in controlling both 

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In a study of catalytic asymmetric cross-cyclotrimerization leading to axially chiral biaryls, one example was reported for 3-(l-naphthyl)pyri-dine derivative 269, without mentioning the chirality of the obtained compound (07CEJ1117). 

Another type of benzannulation, which might be related to the benzannulation of conjugated enynes, is the Pd-catalyzed cyclotrimerization of 1,3-diynes (Scheme 1,3-Diynes cyclotrimerize in the presence of a Pd catalyst to give 1,3.5-trisubstituted benzene derivatives. In this reaction, too, the regioselectivity is perfectly controlled as shown in Scheme 4, and other products were never isolated. The reaction of various diynes is summarized in Table 7. Some functional groups such as olefins and ether linkages may be present in the side chain. An example for the cross-cyclotrimerization of a diyne and an aUcyne has also been reported (Scheme... 

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. 

In 1996, Garcia et al. reported cyclotrimerization of (trifluoromethyl)acetylene 390a using a bimetallic rhodium complex at room temperature to afford l,3,5-/ra (trifluoromethyl) benzene 391 in high yield (Scheme 2-33). Recently, Tanaka et al. reported a chemoselective and regioselective intermolecular cross-cyclotrimerization of two different alkynes using a cationic Rh complex as catalyst (Scheme 2-34). ° ... 

Typical procedure for the intermolecular cross-cyclotrimerization of dialkyl acetylene-dicarboxylates and terminal monoynei ... 

Axially chiral biaryls are an important class of molecules primarily because of their biological activity, as well as their use as chiral ligands. Although enantioselective cyclotrimerization of 1,6-diynes with alkynes or nitriles catalyzed by transition metals has been developed, it was difficult to realize the intermolecular cross-cyclotrimerization process with three alkynes. However, a cationic Rh-complex with (5)-H8-BINAP was found to catalyze effectively the regioselective and enantioselective intermolecular cross-cyclotrimerization of two alkynes 392 and 394 to give chiral biaryls 395 with 89-96% ee in good yields (Scheme 2-35). ... 

Recently, Tanaka and co-workers reported a chemo- and regioselective intermolecular cross-cyclotrimerization of alkynes 67 and 68 using cationic Rh complexes (Scheme 38) (77). 

Axially chiral biaryls are an important class of molecules for both biologically active compounds and chiral ligands (78-80). The most common approach to obtain biaryls is by aryl coupling followed by resolution of the racemic product to afford enantiopure biaryls. Even though enantioselective partial intramolecular cyclotrimerization of diyne with alkynes (81,82) or nitriles (83) were developed with various transitional metals, it was difficult to carry out complete intermolecular reaction. Using a cationic chiral rhodium complex as catalyst, a regioselective intermolecular cross-cyclotrimerization of alkynes 72 and 73 for... 

Heller, B., Gutnov, A., Fischer, C., Drexler, H. -J., Spannenberg, A., Redkin, D., Sunder-mann, C., Sundermaim, B. (2007). Phosphorous-bearing axiaUy chiral biaryls by catalytic asymmetric cross-cyclotrimerization and a first application in asymmetric hydrosilylation. Chemistry - A European Journal, 13, 1117-1128. 

Hara, J., Ishida, M., Kobayashi, M., Noguchi, K., Tanaka, K. (2014). Highly chemo-, regio-, and enantioselective rhodium-catalyzed cross-cyclotrimerization of two different alkynes with alkenes. Angewandte Chemie International Edition, 53, 2956-2959. 

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... 

A fast entry toward (5)-(-)-3-n-butylphtalide (74), a constituent of celery that is used in Chinese folk medicine, was found in the rhodium-catalyzed crossed [2 + 2 + 2] cycloaddition of chiral diyne ester 73, which can be assembled enan-tioselectively within a few steps, and acetylene as the monoyne component (Scheme 7.15) [25]. Notably, the reaction provided the crossed cyclotrimerization product 74 (72% yield) at room temperature under an acetylene atmosphere (1 atm) without the need for pressurization. 

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. 

Sugar templates also served in the cyclotrimerization strategy regarding analogs of amaryllidaceae constituents (i.e. derivatives of pancratistatin 181). Here, a cobalt-mediated crossed cyclotrimerization between the sugar-templated diyne 179 and bis-trimethylsilylacetylene (huge excess) delivered the tetracycle of interest (180) (Scheme 7.39) [54]. However, optimum conditions for the formation of 180 (83% yield) were found by syringe pump addition of a mixture of 179, CpCo(CO)2 and bis-trimethylsilylacetylene to a heated solution of bis-trimethylsilylacetylene in xylene. 

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