Cyclotrimerization, intermolecular

Following these investigations, Das and Roy first reported a Grubbs -catalyzed version of these intermolecular cyclotrimerizations, using 2-propynyl derivatives and a ruthenium carbenoid catalyst, which thus afforded mixtures of regioisomeric aryl... 

An intermolecular cyclotrimerization of an acetylenic nitrile was reported to proceed via the same alkyne-tantalum complex. The resultant pyridine derivative was obtained in 73% yield (Scheme 56).210... 

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. 

The 1,3,5-unsymmetrically substituted benzene 224 was prepared in 64% yield by intermolecular cyclotrimerization of 1,3-decadiyne (223). The reaction was surprisingly regioselective to give 224 as a single product [68]. 

SCHEME 3.76 Proposed mechanism for the Ru(ll)-catalyzed intermolecular cyclotrimerization of alkynes. 

Use of (PCy3)2Cl2Ru=CHPh (1) in Other Synthetie Transformations. As well as finding widespread use in metathesis, (1) has found applications as a catalyst for other important reactions. These include hydrosilylation of alk3Ties dehydrogenative condensation of alcohols and hydrosilylation of carbonyls intermolecular cyclotrimerization of terminal alkynes conversion of triynes to benzene derivatives Kharasch additions (Z)-selective cross-dimerization of ary-lacetylenes with silylacetylenes and hydrogenation of natural rubber. ... 

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]. 

When the third triple bond of the intermolecular cyclotrimerization is a nitrile derivative, pyridines can be obtained [16, 17]. The reaction took place with electron-deficient monoalkynes and electron-poor nitriles [Eq. (10)]. 

The first report on rhodium-catalyzed [2 + 2 + 2] cycloaddifion of alkynes is the intermolecular cyclotrimerization of dimethyl acetylenedicarboxylate (DMAD) catalyzed by a neutral rhodacyclopentadiene/arsine complex in 1968 [6]. After this initial report, various neutral rhodium(I) complexes were developed for intermolecular [2 + 2 + 2] cycloaddition of internal alkynes (Scheme 4.1) [7-13], Among them, (T) -cyclopentadienyl)rhodium(I) complexes [7-9,13] are the best-investigated catalysts. Neutral rhodium(ni) complexes have also been employed as catalysts [14,15], A RhCls/amine system effectively catalyzes [2 + 2 + 2] cycloaddition of internal alkynes [15]. 

Tanaka, K., Toyoda, K., Wada, A., Shirasaka, K. and Hirano, M. (2005) Chemo- and regioselective intermolecular cyclotrimerization of terminal alkynes catalyzed by cationic rhodium (I)/modified BINAP complexes application to one-step synthesis of paracyclophanes. Chemistry—A European Journal, 11(4), 1145-1156. 

S. K. Das and R. Roy, Mild Ruthenium-catalyzed intermolecular alkyne cyclotrimerization, Tetrahedron Lett., 40 (1999) 4015 -018. 

Given the commercial availability of alkynes as two-carbon components, the intermolecular [5 + 2]-cycloaddition of alkynes and VCPs represents a potentially practical route to seven-membered rings. However, initial attempts at an intermolecular [5 + 2]-reaction of alkynes and VCPs with modified Wilkinson s catalysts led to cyclotrimerization of the alkynes and/or isomerization of the VCPs. The first intermolecular [5 + 2]-cycloaddition of alkynes was realized... 

Ir-complexes also demonstrate catalyhc achvity in the intermolecular [2+2+2] cycloaddition of three monoalkynes, when Takeuchi examined the mixed cyclotrimerization of two alkynes. In this situation the choice of ligand was shown to determine the excellent chemoselechvity for example, when the Ir-dppe complex was used, 2 1 cycloadducts of DM AD and mono- or disubstituted alkynes were obtained, but when Ir-F-dppe (l,2-bis[bis(pentafluorophenyl)phosphino]eth ane) one was used, a 1 2 cycloadduct of DMAD and l,4-dimethoxybut-2-yne was obtained (Schemes 11.7 and 11.8) [15]. A regioselective cyclotrimerizahon of three alkynes was achieved by [lrH(cod)(dppm)] (bis(diphenylphosphino)methane), and 1,2,4-triarylbenzenes were obtained exclusively (Scheme 11.9) [16]. 

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 regiochemical product distribution of the co-cyclization of two or three different alkynes occurs statistically. In some cases carefully controlled reaction conditions allow isolation of a main product from mixed cyclotrimerizations. For example, l,2,3,4-tetraphenyl-5,6-diethylbenzene can be obtained from cobalt-catalyzed reaction of tolane and 3-hexyne in good yield [62]. The first example of an intermolecular, regiospecific cross-benzannulation reaction catalyzed by Pd(PPh3)4 was reported by Yamamoto [63]. The reaction of 2-alky 1-but-l-ene-3-yne with disubstituted diynes leads exclusively in high yields to... 

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). ... 

Ru3(CO)i2 coordinated with 2-(diphenylphosphino)benzonitrile catalysed the regioselective 2 + 2 + 2-cyclotrimerization of trifluoromethyl-substituted aryl alkynes in high yields and with a high regio-selectivity4 The alkyne 2 + 2 + 2-cyclotrimerization reaction has been applied to the synthesis of the central 4,5,6-tricyclic core (94) of 4,5,6-trinems (Scheme 30)4 The NbC /DMI-catalysed intermolecular 2 + 2 + 2-cycloadditions of terminal alkynes, internal alkynes, and alkenes produced 1,3,4,5-tetrasubstituted 1,3-cyclohexadienes in excellent yields and with high chemo- and regio-selectivities. ... 

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... 

Intermolecular Alkyne Cyclotrimerization The cyclotrimerization of three different alkynes to give Unear products have been described mainly using Ni-based catalysts (see Section 3.3.1) [51, 52]. Nevertheless, Yamamoto... 

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. 

Figure 3.14 Gibbs free energy profile at 298.15 K of the triplet reaction pathway (PES-T1) for methylacetylene cyclotrimerization over the Cr ll)/Si02 cluster model. The reaction pathway via intermolecular [4 + 2] cycloaddition is depicted in black, while the stepwise pathway is in gray. The reaction to generate 1,3-dimethyle-cyclobutadiene 5Ea is in light black. Energies are in kcal/mol and relative to 1C plus the corresponding number of methylacetylenes.

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