Cycloaddition of triynes

SCHEME 21.24 Rh-catalyzed atroposelective intramolecular double [2+2+2] cycloaddition. 

The intramoleeular [2+2+2] cycloaddition of triynes is particularly effective for the synthesis of helicenes and helicene-like molecules. For example, the novel direct synthesis of fully 

SCHEME 21.25 Enantioselective synthesis of planar chiral tripodal cyclophanes. 

SCHEME 21.27 Enantioselective synthesis of [7]heUcene-like molecules. 

TRANSITION METAL-MEDIATED AROMATIC RING CONSTRUCTION 

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Cyclization of triynes to benzenes,4 Wilkinson s catalyst catalyzes [2 + 2+2]cycloaddition of 1,6-heptadiynes with monoynes to form substituted benzenes. Intramolecular [2+2 + 2]cycloaddition of triynes is also possible with this catalyst. 

Substituted tetraphenylenes are known as interesting biaryl-based chiral cyclic scaffolds. The cationic rhodium(l)/Cy-BINAP or QuinoxP complex-catalyzed enantioselective double homo-[2+2+2] cycloaddition of triynes afforded chiral tetraphenylenes with high enantioselec-tivity (Scheme 21.20) [24]. 

The intramolecular [2+2+2] cycloaddition of triynes affords tricyclic compounds, which are not readily accessible by other methods. The double [2+2+2] cycloaddition of a diphenylphosphinoyl-substituted hexayne proceeded in the presence of the cationic rhodium(I)/tol-BINAP catalyst to give the corresponding Cj-symmetric axially chiral biaryl bisphosphine oxide with high enantioselectivity (Scheme 21.24) [28]. 

The highly enantioselective synthesis of [7]helicene-hke molecules has been achieved in the cationic rhodium(I)/Me-Duphos complex-catalyzed [2+2+2] cycloaddition of triynes (Scheme 21-27) [31]. 

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). 

In 2010, Stara, Stary, and co-workers developed the synthesis of fully aromatic [5]helicenes via the cobalt-mediated intramolecular [2- -2-1-2] cycloaddition of triynes followed by the double silica gel-assisted acetic acid elimination (Scheme 10.4) [7]. A diazapentahelicene (X = N, R = H) was also synthesized in good yield by this method (Scheme 10.4) [7]. 

Complete intramolecular [2 + 2 + 2] cycloaddition of triynes is mediated by the cobalt(I), nickel(O), and rhodium(I) complexes. This method constructs three rings in one step, and double [2 + 2 + 2] cycloaddition of hexaynes enabled the long helicene synthesis through the formation of six rings. 

Intermolecular [2+2+2] Cycloaddition of Triynes Incorporating Heteroatoms Cyclotrimerization of aminodialkynes or dialkynyl esters 2.40 with alkynes affords a variety of benzene-fused aza- and oxa-heterocyclic compounds 2.42 (Scheme 2.15). The key intermediate in this [2+2+2] cycloaddition reaction is metallocyclopentadiene 2.41 [4]. 

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]. 

Shibata, T., Tsuchikama, K. and Otsuka, M. (2006) Enantioselective intramolecular [24-24-2] cycloaddition of triynes for the synthesis of atropisomeric chiral ortho-diarylbenzene derivatives. Tetrahedron Asymmetry, 17(4), 614-619. 

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. 

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. 

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]. 

In a study of rhodium-catalyzed [2 + 2 + 2] cycloadditions of alkynes <88JCS(P1)1357>, the intramolecular [2 + 2 + 2] cycloaddition of4,9-dioxadodeca-l,6,12-triyne catalyzed by Wilkinson s catalyst [(PPh3)3RhCl] over a prolonged period of time gave the dihydropyrano- and tetrahydrofuro-fused 6-6-5 tricyclic benzene derivative (67) in moderate yield (Equation (38)). It should be noted that an analogous bis-tetrahydrofuro-fused 5-6-5 tricyclic compound could be prepared (74%) under similar conditions, but after only 3 h at room temperature. 

The bismuthonium ylide 519 is converted into the annelated furans 522 on treatment with terminal alkynes in the presence of copper(I) chloride. It is suggested that the process involves the carbene 520 and the diradical 521. Intramolecular [2 + 2 + 2] cycloaddition of the triyne 523 mediated by tris(triphenylphosphine)rhodium(I) chloride gives the tetrahydrofuranobenzofuran 524. ... 

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. 

Regarding the construction of helical chirality through intramolecular cycloaddition of designed triynes, the Ni(cod)2/(7 )-Quinap catalytic system has shown nice efficiency and allows the straightforward preparation of dibenzo[6]helicenes (Scheme 7.3) [7]. 

A rhodium-catalyzed cycloisomerization reaction of triyne 137 to 141 involves cleavage of the C=C triple bond (Scheme 7.49) [68]. The following reaction pathway is proposed initially, oxidative cyclization produces the rhodacycle 138, which then undergoes reductive elimination. The rhodium cyclobutadiene complex 139 is thus generated, and then undergoes oxidative addition to produce the rhodacycle 140. This isomerization from 138 to 140 would reduce the steric congestion of the heUcal structure. Subsequently, a cycloaddition reaction between the rhodacycle and the pendant alkyne moiety takes place to afford 141. 

In many cases, standard catalysts such as CpCo(CO)2 or CpCo(COD) necessitate heat and visible light irradiation to be active. Conversely, CpCo(C2H4)2 turns over at room or lower temperatures [8]. However, these catalysts are sensitive to oxygen and usually require thoroughly degassed solvents. Complex III is a new air- and moisture-stable catalyst for [2- -2-1-2] cycloadditions [9], Heat is still necessary, but not irradiation. The reaction can be carried out in hot toluene or in microwaved dimethylformamide (DMF). Crude solvents can be used as found in the laboratory without purification. The catalyst is still active after months of storage in simple vials. Whereas the first report focused on simple cycloadditions of alkynes 10 or triynes 14 (Scheme 1.4), complex HI proved useful as well with more sophisticated systems (see Section 1.2.2). 

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. 

The central six-membered ring unit in the illudalane or pterosin class of sesquiterpenes makes them a suitable target for a proof of the synthetic power of the transition-metal-catalyzed [2 + 2 + 2] alkyne cycloaddition in natural product synthesis. A first example in this field was provided by the intramolecular version of the [2 + 2 + 2] alkyne cyclotrimerization in the synthesis of calomelanolactone (15) [8] and pterosin Z (16), both of which have been isolated Ifom the silver fern Pityrogramma calome-lanos (Scheme 7.4) [9]. Wilkinson s complex served here as the catalyst, and the cyclotrimerization of triyne 13 proceeded at room temperature to give the tricycle 14. The latter was used as a common synthetic intermediate for completion of the synthesis of calomelanolactone (15) and pterosin Z (16) within four and three synthetic steps, respectively. 

Cyclization of triyne 63 was mediated by the CpCo(C2H4)2 complex and resulted in formation of the tetrahydrobenz[a]anthracene 64 (80% yield) after acidic workup. However, a stoichiometric amount of the more reactive but quite sensitive CpCo(C2H4)2 complex was necessary to execute this intramolecular [2 - - 2 - - 2] cycloaddition within reasonable chemical yields. Other cobalt reagents, such as the CpCo(CO)2 or the CpCo(cod) complexes, were less effective. Anthracene 64 was then oxidized to give the tetrahydrobenz[a]anthraquinone 65, which after deprotection and a regioselective photooxidation provided (-)-8-0-methyltetrangomycin (59). 

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