Cyclotrimerization 4 + 2 cycloaddition

Scheme 6. Vollhardt s tandem alkyne cyclotrimerization/o-quinodimethane cycloaddition strategy for polycycle synthesis.

Ruthenium(ll)-catalyzed cycloadditions of diynes with bicycloalkenes illustrate the synthetic importance of ruthena-cyclopentatrienes as biscarbenoid intermediates.380 Reaction of 1,6-diyne 448 and biscyclic alkene 449 with ruthenium catalyst afforded a mixture of biscyclopropanation product 450 and cyclotrimerization product 451 (Scheme 113). 

Based on this work, Itoh and co-workers developed ruthenium(n)-catalyzed [2 + 2 + 2]-cyclotrimerizations of 1,6-diynes 174 and electron-deficient nitriles (Equation (34)),368>368a These partially intramolecular cycloadditions proceed through ruthenacycle intermediates as well. The importance of using electronically activated nitriles is underlined by the fact that acetonitrile and benzonitrile gave only very low yields. 

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]. 

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... 

A combination of the alkyne cyclotrimerization catalyzed by RhCl(PPh3)3 with a 1,3-dipolar cycloaddition provides rapid access to 3-dihydroindenylmethyl-3,7-diaza[3.3.0]-octane 61 in excellent yield thus five new bonds, four stereocenters, and three rings are created in a one-pot operation (Scheme 7.18) [41]. 

With 9-diazofluorene, [3 + 2]cycloaddition products of type 111 were obtained in pentane or hexane, while N2 loss and subsequent cyclotrimerization occurred in CH2CI2, CCLt, and benzene (178). With acceptor-substituted diazo compounds of the type RCH=N2 [R = C02Et (179), COMe (180,181), and PO(OEt)2 (182)], the initially formed A -phosphapyrazolines rapidly tautomerized and bicyclic A -phosphapyrazolines such as 112 and 113 were formed. 

Transformations to the cyclotrimeric boiazines and cyclotetrameric tetraza-2,4,6,8,l,3,5,7-tetraboracanes also occur. The rate of dimerization for amino iminoboranes has been shown to be stabilized by bulky substituents (76,79,83). This stabilization through dimerization is essentially a [2 + 2] cycloaddition. There are a number of examples of these compounds forming cycloadducts with other unsaturated polar molecules (78). Iminoboranes can add to electron-deficient carbene complexes of titanium such as (C5H5)2Ti(CH2) [84601-70-7] by [2 + 2] cyclo addition, yielding the metallacycle shown in equation 26 (84). 

The phyllocladane skeleton 131 was constructed efficiently by stereoselective formations of six carbon-carbon bonds and four rings via a one-pot sequence of cyclizations the ene type, [2+2+2], and [4+2] cycloadditions. In this synthesis, the Conia ene reaction of 127 takes place under mild conditions to generate 128, and the cyclotrimerization of its diyne with 118 gives 129. These two reactions are catalysed by CpCo(CO)2. Finally, ring-opening to give 130 and intramolecular Diels-Alder reaction in the presence of DPPE produced the phyllocladane skeleton 131 in a total yield of 42% [55]. 

An analogous cleavage of a nickeladisilacyclopentene with alkyne is shown in entry 116. It has been pointed out (297) that these reactions show certain similarities to metal-catalyzed cyclotrimerization of alkynes or to cycloaddition of alkynes and substituted disilanes, postulated to involve Si-metal intermediates. 

Related co-cyclotrimerizations of two alkyne molecules with limited isocyanates have also been achieved using cobalt and nickel catalysts. With respect to intramolecular versions, two examples of the cobalt(I)-catalyzed cycloaddition of a,m-diynes with isocyanates have been reported to afford bicyclic pyri-dones only in low yields, although 2,3-dihydro-5(lff)-indolizinones were successfully obtained from isocyanatoalkynes and several silylalkynes with the same cobalt catalysis [19]. On the other hand, the ruthenium catalysis using Cp RuCl(cod) as a precatalyst effectively catalyzed the cycloaddition of 1,6-diynes 21 with 4 equiv. of isocyanates in refluxing 1,2-dichloroethane to afford bicyclic pyridones 25 in 58-93% yield (Eq. 12) [20]. In this case,both aryl and aliphatic isocyanates can be widely employed. 

A highly electron-deficient carbon-oxygen double bond can also participate in the co-cyclotrimerization with alkynes under the ruthenium catalysis. The cycloaddition of commercially available diethyl ketomalonate with the diynes 21 proceeded at 90 °C in the presence of 5-10 mol % Cp RuCl(cod). The expected fused 2ff-pyrans 27, however, underwent thermal electrocyclic ringopening to produce cyclopentene derivatives 28 (Eq. 14) [23]. 

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]. 

Complex 224 is also obtained by cyclotrimerization of acetylene promoted by complex 223, with displacement of the bicyclotriene ligand. It is noteworthy that complex 223 is obtained from 200 by simple cycloaddition of alkyne to the cyclooctatriene ligand (139) [Eq. (24)]. 

Numerous transition metal-mediated [2 + 2+2] cycloadditions have been utilized in the synthesis of pyridines . Selective cyclotrimerization of alkynes with nitriles leads to pentasubstituted pyridines 310 with minimal formation of benzenoid byproducts (Scheme 157) <20000L3131>. Different alkynes can be utilized in the same strategy if a sequential approach is used (Scheme 158) <2000JA4994>. 

The Pauson-Khand reaction (PKR) is among the most powerful transformations in terms of molecular complexity increment [1]. Only a few of other reactions like the Diels-Alder, or the cyclotrimerization of alkynes can compete with the PKR, which consists formally of a [2 + 2 + 1] cycloaddition in which a triple bond, a double bond and carbon monoxide form a cy-clopentenone [2-12], This constitutes one of the best ways to construct cyclopentenones, which upon further transformations can be converted into structures present in numerous natural products (Scheme 1). 

Rh(l)-catalyzed [2-I-2-I-2] cyclotrimerization of 1,6-diynes (e.g., 1391 and 1394) with monoynes (e.g., 1392) in combination with stereospecific Ag(i)-catalyzed aldimine (metallo)azomethine ylide — cycloaddition cascades affords rapid access to complex heterocyclic benzene derivatives 1393 and 1395 in one-pot processes with the generation of five new bonds, four stereocenters and three rings (Schemes 266 and 267) <2000T8967>. 

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