Triynes intramolecular reactions

Two precedent examples had been reported of the enantioselective [2+2+2] cycloaddition of alkynes. In one case, an enantioposition-selective intermolecular reaction of a triyne with acetylene generated an asymmetric carbon at the benzylic position of a formed benzene ring [19]. In the other case, an intramolecular reaction of a triyne induced helical chirality [20]. Both reactions were developed by chiral Ni catalysts. 

The Ir-MeDUPHOS catalyst also functioned efficiently in an intramolecular reaction, where triynes, which possessed ortho-substituted aryl groups on their termini, were transformed into ortho-diarylbenzene derivatives, which have adjacent two axial chiralities (Scheme 11.14) [22]. 

Patterns of [2 - - 2 - - 2] cycloaddition for the synthesis of cyclophane are depicted in Scheme 8.1. Intermolecular reaction of diyne and monoyne can provide ortho, meta, and para isomers as dipodal cyclophanes (pattern A). Linear triyne can be transformed into ortho-ortho and ortho-meta isomers by an intramolecular reaction (pattern B). In the reaction of branched triyne, symmetrical 1,3,5- and unsymmetrical 1,2,4-isomers can be obtained as tripodal cyclophanes (pattern C). The choice of catalyst and tether is very important for induction of the aforementioned regioselectivities. 

Pattern C was reported in 1966 Hubert used a Ziegler catalyst in the intramolecular reaction of carbon-branched triynes, and a mixture of regioisomers was obtained, albeit in low yield (Scheme 8.2) [3]. 

Enantioselective reaction was achieved by cationic rhodium/chiral diphosphine complexes. The intramolecular reaction of linear triynes gave planar-chiral meta-cyclophanes in excellent ee. The intermolecular reaction of diynes with alkyne afforded planar-chiral para-cyclophanes with strained benzene ring in moderate to excellent ee. The intramolecular reaction of branched triynes gave planar-chiral tripodal-cyclophanes in excellent ee. 

In the presence of an excess of small alkynes the typical [3+2+1 jbenzannulation has to compete with a [2+2+1+lj (two-alkyne) annulation resulting from two consecutive alkyne insertion steps. The selectivity for this variant is increased for an intramolecular reaction. Diynyl-arylcarbene complexes 31 and 32, in which the carbene moiety is tethered by an appropriate spacer to two alkyne functionalities, are formed in a chemoselective Diels-Alder reaction of the more electron-deficient bond in the triyne carbene precursor complexes 35 and 36 with Danishefsky s diene a final thermal two-alkyne annulation affords the steroid skeleton 33. The sequence can be performed as a one-pot procedure in yields of 30%... 

The cyclization of the enediynes 110 in AcOH gives the cyclohexadiene derivative 114. The reaction starts by the insertion of the triple bond into Pd—H to give 111, followed by tandem insertion of the triple bond and two double bonds to yield the triene system 113, which is cyclized to give the cyclohexadiene system 114. Another possibility is the direct formation of 114 from 112 by endo-rype. insertion of an exo-methylene double bond[53]. The appropriately structured triyne 115 undergoes Pd-catalyzed cyclization to form an aromatic ring 116 in boiling MeCN, by repeating the intramolecular insertion three times. In this cyclization too, addition of AcOH (5 mol%) is essential to start the reaction[54]. 

Cycloaddition of aUcynes catalysed by transition metals is one of the most efficient and valuable ways to prepare benzene and pyridine systems [12], Among the possible catalytic systems able to catalyse this reaction, cobalt and iron complexes containing NHCs as ligands have shown high catalytic activity in the intramolecular cyclotrimerisation of triynes 36 (Scheme 5.10) [13]. The reaction was catalysed with low loading of a combination of zinc powder and CoC or FeClj with two or three equivalents of IPr carbene, respectively. 

The reaction of triallylborane with silicon triyne 123 is interesting. A113B attacks both internal and external triple bonds giving rise to silole 124 and two heterocycles with bridgehead boron 125 and 126 in a 1 3 3 ratio as a result of competitive sequential reactions (Scheme 52). When 1,1-allylboration of the internal C C bond followed by intramolecular 1,1-vinyIboration takes place, the silole 124 is formed, while in another case 1,1-allylboration followed by a series of intramolecular 1,2-allylboration reactions leads to boron derivatives 125 and 126 <2002JOM(657)146>. 

It is possible to carry out the [2+2+2] cyclotrimerization reaction in a regioselective manner by using a partially or completely intramolecular approach. Rhodium-catalyzed intramolecular cyclotrimerization of 1,6,11-triynes, which construct fused 5-6-5 ring-systems, has been studied extensively [33-36]. Cyclization of 1,6,11-triyne 47 catalyzed by RhCl(PPh3)3, gives the tricyclic benzene 48 in good yield (Eq. 14) [33a]. 

In previous works this group had observed a competition between the PKR and a [2 + 2 + 2] cyclization in the second reaction step of three triple bonds. Thus, when reacting linear triynes 174 under catalytic, high CO pressure, cobalt mediated PKR conditions, they obtained mixtures of products 175 coming from two [2 + 2 + 1] cycloadditions, and 176 from a [2 + 2 + 1]/ [2 + 2 + 2] tandem reaction. When the triple bonds were ether linked, the latter was the favored reaction, while with substrates lacking oxygen atoms, the iterative PKRs was the major pathway (Scheme 51) [166]. When the reaction was performed intramolecularly between a diyne and an alkyne, the only reaction products were the result of a [2 + 2 + 1 ]/[2 + 2 + 2] tandem cycloaddition [167,168]. 

The ifaodium-catalyzed intramolecular cyclotrimerization of 1,6,11-triyne 419, forming 5-6-5 fiised-ring system 420, has been extensively studied (Scheme 2-41, eq. i).[220b,276] reaction has also been used as the key step in the synthesis of a marine illudalane sesquiterpenoid, alcyopterosin E (423) (Scheme 2-41, eq. 2)P as well as in die asymmetric synthesis of chiral diphosphine ligands 425 (Scheme 2-41, eq. 3). ... 

A mechanism has been proposed by Blechert for this metathesis cascade, which involved the formation of a number of carbon-carbon bonds (in principle, a ruthenium-mediated [2-I-2+2] cycloaddition is also plausible for this transformation [49]). This postulated mechanism, as shown for the conversion of triyne 141 into the substituted aromatic system 142, is depicted in Scheme 17.27 [50]. Initially, complex 1-Ru adds to the less hindered acetylene of 141 to afford the vinyl carbene complex 143, which then undergoes an intramolecular metathesis reaction to afford 144 via 145. The conjugated complex 144 can then undergo a further RCM reaction to yield the product 142. 

All three alkynes can be incorporated into a single molecule, making the reaction entirely intramolecular. This has been used in a synthesis of Cryptoacetalide 11.60 (Scheme 11.21). The triyne 11.58 was constructed by coupling a diyne 11.56 containing a carboxylic acid with an alkynol 11.57. A ruthenium catalyst was found to be most effective for the cyclotrimerization, combined with microwave heating. The synthesis was completed by deprotection and free-radical spiroketal formation. 

Complexation of triynes to Pd(0) has been reported to give homoleptic palladium alkyne complexes that show a trigonal-planar arrangement with all of the alkyne carbons and Pd in the same plane. Complex 73 is a macrocyclic complex synthesized by reaction of the triyne with Pd(PPh3)4- Due to coordination to the metal, the alkyne carbons are shifted to the center of the cycle and their substituents deviate from linearity by about 22°. Complex 74 undergoes clean intramolecular cyclization at room temperature upon addition of PPh3 (Equation (24)). No intermediate complexes were detected in the course of this reaction, which is an example of the important cycloisomerization of alkynes and enynes catalyzed, among other transition metal complexes, by Pd(0) derivatives. 

Utilizing the same achiral building block 5, Haley and coworkers have also synthesized the less-symmetrical [22]annulene (Scheme 6.2) [11]. Triyne 5 was converted to oligomer 11 via a one-pot desilylation/alkynylation reaction with bis(2-iodophenyl)ethyne. Compound 11 was subsequently desilylated and subjected to intramolecular oxidative homocoupling conditions to provide the chiral annulene 12 in 59% yield. X-ray crystallographic analysis of 12 showed that the helical macrocycle adopts a distorted saddle-shaped conformation in the solid-state that is relatively free from strain. 

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. 

In addition to intermolecular reactions, intramolecular variants have been developed. In 1992, Negishi et al. reported the Pd(PPh3)4/AcOH-catalyzed intramolecular [2 -I- 2 -I- 2] cycloaddition of triyne 12 (Scheme 6.4) [9]. In this reaction, cascade-type cycloaddition via generation of Pd—H species from palladium and acetic acid proceeded to afford fused benzene 13 in good yield. The reaction of endiyne 14 bearing an alkenyl bromide moiety in the presence of EtsN also afforded the same product, 13, presumably through a similar mechanism (Scheme 6.4). 

As little as 3 to 5 mol % of RhCl(PPh3) induced the intramolecular cyclotrimerization reaction of triyne 43 to provide the tricyclic benzocylobutane 44. After attachment... 

Tanaka et al. examined chiral Rh-catalyzed intramolecular cycloaddition using triynes with substituents at both ends and obtained [7] to [lOJmeto-cyclophanes with high enantioselectivity. This is the first example of catalytic and enantioselective synthesis of planar-chiral cyclophanes using the [2+ 2+ 2]-cycloaddition approach (Scheme 8.14) [11a]. The tether structure of the 1,6-diyene moiety of the triynes affected the stereoselectivity, and the reaction of ester-tethered triynes realized almost perfect enantioselectivity (Scheme 8.15) [11a]. 

Shibata et al. disclosed the reaction of branched triynes in which a 1,6-diyne moiety and alkyne are connected by a rigid 2-aminophenyl tether. An intramolecular [2 + 2 + 2] cycloaddition gave tripodal cyclophanes in high yield with excellent ee (Scheme 8.18) [13a]. It is noteworthy that the [15]cyclophane skeleton (n = 10) can be constructed efficiently without racemization. This is the first example of the enantioselective synthesis of tripodal cyclophanes. 

Tanaka et al. overcame this limitation by designing the enantioselective completely intramolecular double [2- -2-1-2] cycloaddition. The reaction of diphenylphosphinoyl-substituted hexayne 94, prepared from triyne 93 in two steps, in the presence of the cationic rhodium(I)/tol-BINAP catalyst furnished C2-symmetric axially chiral biaryl bisphosphine oxide 95 in moderate yield with high enantioselectivity (Scheme 9.32) [25]. Subsequent recrystallization andreduction of bisphosphine oxide 95 furnished the corresponding enantiopure bisphosphine 96, which could be used as an effective chiral ligand for rhodium-catalyzed asymmetric hydrogenation and cycloaddition [25]. 

The asymmetric synthesis of [6]- and [7]helicene-like molecules was also accomplished by the cobalt-mediated diastereoselective intramolecular [2 - - 2 + 2] cycloaddition of phenol- or naphthol-linked chiral triynes possessing two stereogenic centers (Scheme 10.17) [16], Like the asymmetric synthesis of the helicene-like molecules shown in Schemes 10.13 and 10.16, (R) centrochirality perfectly induced (M) helical chirality in the reactions of the bulky p-tolyl-substituted triynes. 

An intramolecular version of this reaction is also feasible. Triynes can be cyclotrimerized to annulated benzenes in the presence of catalytic amounts of iron(III) or iron(II) chloride, an NHC or 2-iminomethylpyridine ligand, and Zn powder (Scheme 4-310). Good to excellent yields are achieved for this transformation. The iron salts can be applied as hydrates or in anhydrous form that accounts for the good practicability of the method. ... 

The reaction of [2+2+2] cycloaddition of acetylenes to form benzene has been known since the mid-nineteenth century. The first transition metal (nickel) complex used as an intermediate in the [2+2+2] cycloaddition reaction of alkynes was published by Reppe [1]. Pioneering work by Yamazaki considered the use of cobalt complexes to initiate the trimer-ization of diphenylacetylene to produce hexasubstituted benzenes [54]. Vollhardt used cobalt complexes to catalyze the reactions of [2+2+2] cycloaddition for obtaining natural products [55]. Since then, a variety of transition complexes of 8-10 elements like rhodium, nickel, and palladium have been found to be efficient catalysts for this reaction. However, enantioselective cycloaddition is restricted to a few examples. Mori has published data on the use of a chiral nickel catalyst for the intermolecular reaction of triynes with acetylene leading to the generation of an asymmetric carbon atom [56]. Star has published data on a chiral cobalt complex catalyzing the intramolecular cycloaddition of triynes to generate a product with helical chirality [57]. 

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