Alkyne trimerisation

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An alkyne trimerisation reaction is a 2+2+2 cyclization reaction where three alkyne molecules react to form a benzene compound. The reaction is 'pseudo' pericyclic since it has not been observed to occur without the assistance of metal catalysis; and the metal catalyst assembles the ring stepwise via intermediates which are not directly in between (in a geometric sense) the starting material and products.

In the example of phenylacetylene a simple catalyst system of cobalt(II) bromide / zinc / zinc iodide suffices to obtain 99% chemical yield and 97% regioselectivity in favor of the ortho substituted reaction product 1 [1].

Scheme 1. Alkyne trimerization

[edit] Mechanism

The reaction mechanism for trimerization is fairly well understood. A 2007 mechanism consistent with in silico and experimental data is depicted below for a cobaltocene catalyst [2]

Alkyne trimerization mechanism Agenet 2007

The ligand L in the 18-electron compound CpCoL2 (A) can be triphenylphosphine or carbon monoxide. These ligands are replaced by the alkyne in two steps forming first B and then C which enters the catalytic cycle by oxidative coupling to the 16 VE cobaltacyclopentadiene metallacycle D. This compound forms in its singlet state and therefore first relaxes to the triplet state. This intermediate coordinates to another equivalent of ligand to form E and then forms cobaltanorbornene F (see: norbornadiene) on accepting an alkyne unit in one [4+2]cycloaddition step. In the final step benzene is liberated in a reductive elimination with formation of CpCoL which can re-enter the cycle by accepting two units of alkyne. When the ligand is less of a sigma donor such as ethylene or THF (as a solvent) or when the alkyne is electron-poor as in butynedioic acid a different cycle takes over where another alkyne unit and not a ligand adds to intermediate D. In the remainder of this cycle (not depicted) the new intermediate forms an CpCo(η4arene) complex and then a CpCo(η6arene) sandwich compound before eliminating benzene and CpCo.

[edit] Scope

The trimerisation can be extended to inclusion of benzyne.[3] Benzyne is generated in situ from a benzene compound with a triflate and a trimethylsilyl substituent in the ortho- positions and reacts with a di-yne such as 1,7-octadiyne and with a nickel(II) bromide / zinc catalyst system (NiBr2 bis(diphenylphosphino) ethane / Zn) to the corresponding naphthalene derivative.

Alkyne trimerization involving an aryne

In the catalytic cycle elementary zinc serves to reduce nickel(II) to nickel(0) to which can then coordinate two alkyne bonds. A cyclometalation step follows to the nickelcyclopentadiene intermediate and then coordination of the benzyne which gives a C-H insertion reaction to the nickelcycloheptatriene compound. Reductive elimination liberates the tetrahydroanthracene compound.

In one study, a combination of a [2+2+2] trimerization and a [4+2] cycloaddition gives access to a Taxol analogue[4] (Scheme 2 [5] ). In this reaction sequence the trimerization takes place in xylene with catalyst the cobaltocene CpCo(CO)2 (one Cp unit replaced by two carbonmonoxide ligands) and with irradiation. The two main components are held together by a temporary silicon tether.

Scheme 2. Taxol framework Ref. Chouraqui 2006

Dicobalt octacarbonyl catalyzes the trimerization towards a hexakis(4-ferrocenylphenyl)benzene [6][7]:

Scheme 3. Hexakis(4-ferrocenylphenyl)benzene

[edit] References

  1. ^ Gerhard Hilt , Thomas Vogler, Wilfried Hess, Fabrizio Galbiati (2005). "A simple cobalt catalyst system for the efficient and regioselective cyclotrimerisation of alkynes". Chemical Communications 2005 (11): 1474 - 1475. doi:10.1039/b417832g. 
  2. ^ Cobalt-Catalyzed Cyclotrimerization of Alkynes: The Answer to the Puzzle of Parallel Reaction Pathways Nicolas Agenet, Vincent Gandon, K. Peter C. Vollhardt, Max Malacria, and Corinne Aubert J. Am. Chem. Soc.; 2007; 129(28) pp 8860 - 8871; (Article) doi:10.1021/ja072208r
  3. ^ Jen-Chieh Hsieh and Chien-Hong Cheng (2005). "Nickel-catalyzed cocyclotrimerization of arynes with diynes; a novel method for synthesis of naphthalene derivatives". Chemical Communications 2005 (19): 2459 - 2461. doi:10.1039/b415691a. 
  4. ^ G. Chouraqui, M. Petit, P. Phansavath, C. Aubert and M. Malacria (2006). "From an Acyclic, Polyunsaturated Precursor to the Polycyclic Taxane Ring System: The [4+2]/[2+2+2] and [2+2+2]/[4+2] Cyclization Strategies". European Journal of Organic Chemistry 2006 (6): 1413-1421. doi:10.1002/ejoc.200500762. 
  5. ^ Reaction sequence: a] CpCo(CO)2, xylene, irradiation b] desilylation by Tetra-n-butylammonium fluoride c] intramolecular ring closure by butyllithium (oxygen nucleophile) and tosyl chloride (tosyl leaving group) e] desilylation by Tetra-n-butylammonium fluoride e] oxidation IBX acid to ketone f] enolate formation with NaHMDS followed by selenation with phenylseleniumchloride g] selenium oxidation and elimination with sodium periodate h] Diels-Alder reaction with boron trifluoride
  6. ^ V. J. Chebny, D. Dhar, S. V. Lindeman and R. Rathore (2006). "Simultaneous Ejection of Six Electrons at a Constant Potential by Hexakis(4-ferrocenylphenyl)benzene". Org. Lett. 8 (22): 5041-5044. doi:10.1021/ol061904d. 
  7. ^ In a redox reaction the six ferrocene substituents lose an electron each at one and the same potential.