Cyclotrimerization of triynes

The [2+2+2] cyclotrimerization of triynes has been reported using rhodium catalysts <2003JA12143> under biphasic conditions. Thus, the cyclization of triyne 174 proceeds rapidly in a biphasic system to produce the tricyclic compound in good yield using an in t/r -generated water-soluble rhodium catalyst (Equation 108) <2003JA7784>. 

The [2+2+2] cyclotrimerization of triynes has also been reported to proceed in high yields using palladium catalysts in refluxing toluene (Equation (109) Table 12) <2003CEJ2469>. 

Cyclotrimerization of triynes has been reported using cobalt or iron complexes of NHCs without CO and Cp ligands.31 Benzannulated compounds have been isolated with up to quantitative yields. 

CyclOtrimerization of Triynes. Transitional metal-catalyzed intermolecu-lar [2+2+2] cyclotrimerization of alkynes to benzenes has been extensively studied with several catalyst systems including palladium, cobalt, nickel, rhodium, and other transition metals (73-75). Owing to its high atom-economical nature in comparison to conventional methods, this process has received a significant... 

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. 

Scheme 4-310. Cyclotrimerization of triynes catalyzed by iron salts.

Most of the general synthetic strategies overcome this limitation by using two components in the synthesis of alkynes (Scheme 2.2) [9]. Although the formation of metallocycles is limited by geometry and entropic component, this intermolecular concept works well for the construction of larger polycyclic systems from simple unsaturated precursors. The development of the intermolecular version of cyclotrimerization of triynes led to the use of a,w-diynes 2.7 as one... 

Saino, N., Kogure, D. and Okamoto, S. (2005) Intramolecular cyclotrimerization of triynes catalyzed by N-heterocyclic carbene-CoCli/Zn or -FeCb/Zn. Organic Letters, 7(14), 3065-3067. 

Table 32 Co-catalyzed cyclotrimerization of triynes into helicenes...

The intramolecular thermal cyclotrimerization of dodeca-1,6,11-triyne (110) at 450-600 °C afforded l,2,3,6,7,8-hexahydro[a5]indacene (112) and dehydro derivatives. An exothermic cycloaromatization mechanism has been proposed. An initial formation of a single bond gives diradical (111) which is then trapped by an alkyne. °... 

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]. 

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]. 

Aromatic compounds can be prepared by cyclotrimerization of alkynes or triynes. Cyclotrimerization is possible by heating to 450-600°C with no catalyst. The spontaneous (no catalyst) trimeiization of t-BuC=CF gave 1,2,3-tri-tert-butyl, 5,6-trifluorobenzene (220), the first time three adjacent tert-butyl groups had been put onto a benzene ring. The fact that this is a head-to-head joining allows formation of 220 from two alkynes. The fact that 219 (a Dewar benzene) was also isolated lends support to this scheme. Three equivalents of 3-hexyne trimerized to hexaethylbenzene at 200°C in the presence of Si2Cl6. ... 

Diederich and co-workers have synthesized a triscluster complex 47 of the unusual Cjg molecule via oxidative cyclotrimerization of the hexatriyne complex 48 (Scheme 4-17) [72]. The cyclocoupling efficiency benefits from the bent geometry of the coordinated triyne (a = 138°). Other noteworthy features include (1) the regioselective complexation of the silylated triyne (2) efficient desilylation of the complexed triyne. 

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). ... 

Scheme 9.5 Intramolecular Rh-catalyzed [2+2+2] cyclotrimerization of a triyne substrate leading to 6-oxa-allocolchicinoids, as described by Schmalz and coworkers [10].

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. ... 

Fully intramolecular [2 + 2 + 2] cyclization of triynes affords tricyclic products with complete chemo- and regioselectivity. Despite this advantage, this method is underdeveloped, which is probably due to the diminished accessibility of the triyne substrates. Peters and Blechert reported the first ruthenium-catalyzed fully intramolecular cyclotrimerization using the metathesis cascade strategy with Grubbs catalyst [23]. Later, Yamamoto et al. demonstrated that complex 6 efficiently catalyzes the cyclization of various triynes [14]. Examples of 1,6,11-triyne cyclization are summarized in Table 3.11. As an example, diether 58 (X = = O, R = H) underwent [2 + 2 + 2]... 

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... 

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]. 

Sakurai, H., Nakadaira, Y., Hosomi, A., Eriyama, Y., Hirama, K. and Kabuto, C. (1984) Intramolecular cyclotrimerization of macrocyclic and acyclic triynes with Group 6 metal carbonyls. The formation of fulvene and benzene. Journal of the American Chemical Society, 106(26), 8315-8316. 

Intramolecular cyclization of triynes is the underlying strategy for the preparation of helicenes. Cyclotrimerization of a suitable starting material resulted in the formation of various [5], [6], and [7]-helicenes with 5-7 rings. Some representative examples are given in Table 32 [90]. 

The problem of regioisomerism was avoided by utilizing intramolecular triynes such as 46 as substrates for the cyclotrimerization process. However, many diimines and pyridinimines seem to give very reactive complexes so that further developments can be envisaged. 

Triynes 261 in which the alkyne linkages are properly spaced can undergo intramolecular cyclotrimerization to aromatics 262 and 263 in the presence of Ziegler-type catalysts-"h... 

An intramolecular cyclotrimerization has been reported by condensation of a diyne with an alkyne in the presence of a palladium, molybdenum, nickel, rhodium, iridium, or ruthenium catalyst. Triynes have been... 

Nitrogen-containing 15-membered trialkyne macrocycles, such as l,6,ll-frw(aiylsulfonyl)-l,6,ll-triazacyclopentadeca-3,8,13-triynes and enediynes as 1,6,11-frw(arylsulfonyl)-1,6,11-triazacyclopentadeca-3-ene-8,13-diynes have been prepared and subjected to a [2+2+2]-cyclotrimerization process catalyzed by transition metal complexes, e.g., RhCl(CO)(PPh3)2 <05JOC2033>. The reaction of pemosylated diethylenetriamine and 2-substituted propan-1,3-... 

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. 

The cyclotrimerization can also be used to form unusual and challenging aromatic systems, including biaryls and helicenes (Scheme 11.22)." ° The triyne substrate 11.63 was constructed by a Sonogashira reaction of... 

The alcyopterosins represent an interesting set of illudalanes that were isolated from deep-sea soft corals and whose members represent the first nitrate esters to be found in any natural product [10]. The rhodium-catalyzed intramolecular cyclotrimerization method has been utilized here to gain access to the 5-6-5 and 6-6-5, as well as the bicyclic ring systems of this set of marine illudalanes (Schemes 7.5 to 7.7). The synthesis of enantiopure triyne 21, as needed for alcyopterosin E (22), was straightforward, starting from readily available L-ascorbic acid (17) and isophorone (20), to provide the alkyne building blocks 18 and 19 in seven and six steps, respectively (Scheme 7.5) [11]. 

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. ... 

---