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Cross Metathesis
Olefin Metathesis
Ring Closing Metathesis
Synthesis of 1,3-dienes

Enyne Metathesis

The Enyne Metathesis is a ruthenium-catalyzed bond reorganization reaction between alkynes and alkenes to produce 1,3-dienes. The intermolecular process is called Cross-Enyne Metathesis, whereas intramolecular reactions are referred as Ring-Closing Enyne Metathesis (RCEYM).

Mechanism of the Enyne Metathesis

Enyne metathesis, or the so-called cycloisomerization reactions, were first reported using palladium(II) and platinum(II) salts and are mechanistically distinct from metal carbene-mediated pathways. As ruthenium carbenes are nowadays catalyst of choice in alkene metathesis and currently also in enyne bond reorganizations, we will focus on this family of catalysts. Ruthenium carbenes are commercially available, tolerate many functional groups and new catalysts are constantly being developed.

In the initiation step, the stable catalyst undergoes cycloaddition to the substrate forming a ruthenacylcobutane. Subsequent cycloelimination releases a stable styrene derivative, which generally does not interfere in cross metathesis reactions. The catalyst is then bound to the substrate in form of a metal carbene, which reacts intramolecularly with the triple bond to yield a vinyl carbene. More details are shown in the scheme for the catalytic cycle.

In the catalytic cycle (top), this vinyl carbene first adds to the double bond of the substrate forming a ruthenacyclobutane. Cycloelimination at this stage gives a ruthenium carbene under release of the product (lower right). Subsequent intramolecular cycloaddition with the alkyne gives a vinylcarbene intermediate via a ruthenacyclobutene transition state. The vinyl carbene reacts with another substrate molecule to give the product via methylene transfer, and the catalytic cycle continous.

The driving force of the reaction is the formation of a thermodynamically stable, conjugated 1,3-diene.

As such reactions are conducted under conditions of dilution that favor the RCEYM over competing cross-alkene metathesis or cross-enyne metathesis, the availability of the methylene is the rate-limiting step. In addition, the vinyl carbene is quite stable. Using less reactive catalysts, Mori has developed a system under an atmosphere of ethylene. In the presence of excess ethylene, there is a much better opportunity for catalyst regeneration to occur:

M. Mori, N. Sakakibara, A. Kinoshita, J. Org. Chem., 1998, 63, 6082-6083.

Ethylene thus maintains a higher concentration of active catalyst and reduces the amount of catalyst that is in resting states.

Another striking feature is that self-metathesis of ethylene is a neutral process in terms of the progress of the reaction. In addition, ethylene suppresses alkyne polymerization, as shown by Fogg (J. Am. Chem. Soc. 2011, 133, 15918).

We have discussed the mechanism in which catalyst attack occurs first at the alkene followed by attack at the alkyne. This mechanistic variant is also known as the "ene-first" mechanism or the “ene-then-yne” mechanism. An "alkyne first" pathway would lead to a mixture of regioisomers, which can only be observed for a few substrates:

NMR evidence favors the "ene-first" pathway, as new carbene proton resonances can be observed. However, due to absence of carbene protons in the "alkyne pathway", NMR cannot rule out the yne-first mechanism as a competitive pathway.

Using an alkyne and only 2-3 fold of excess of an alkene, the enyne metathesis allows the synthesis of cross-coupled products. Higher alkene concentration is beneficial to the reaction rate and helps keep the reactive intermediates in the enyne metathesis catalytic cycle. The drawback is the low E:Z selectivity, which is also a point that must be addressed in the cross alkene metathesis.

Using the second generation Grubbs' catalyst, the reaction is believed to involve an initial reaction with the alkene followed by the alkyne (for a kinetic study see: J. Am. Chem. Soc. 2005, 127, 5762. DOI).

However, very useful yields of cross-enyne metathesis products can be obtained, for example, by using an excess of ethylene:

K. Tonogakia, M. Mori, Tetrahedron Lett., 2002, 43, 2235-2238.

For a detailed mechanistic discussion and a plethora of further examples, please refer to the recent review by Steven T. Diver and Anthony J. Giessert (Chem. Rev. 2004, 104, 1317. DOI). Additional recent catalyst developments can also be found in the subsequent literature section and in newer reviews by Steven T. Diver: "Ene-yne metathesis" Diver, S. T., Griffiths, J. R., In: Olefin Metathesis: Theory and Practice. Vol.; Grela, K., Ed.; Wiley: Hoboken, New Jersey, 2014.

Recent Literature

An improved 1,3-diene synthesis from alkyne and ethylene using cross-enyne metathesis
K. Tonogakia, M. Mori, Tetrahedron Lett., 2002, 43, 2235-2238.

Inhibitory Effect of Ethylene in Ene-Yne Metathesis: The Case for Ruthenacyclobutane Resting States
T. M. Gregg, J. B. Keister, S. T. Diver, J. Am. Chem. Soc., 2013, 135, 16777-16780.

The Grubbs 1,3-dimesityl-4,5-dihydroimidazol-2-ylidene-substituted ruthenium complex also catalyzes ethylene-alkyne cross-metathesis of alkynes having free hydroxyl groups and coordinating functionality at the propargylic and homopropargylic positions. Hindered alkynes also react efficiently under the reported conditions.
J. R. Clark, J. M. French, E. Jecs, S. T. Diver, Org. Lett., 2012, 14, 4178-4181.

Expanded Scope in Ethylene-Alkyne Cross-Metathesis:  Coordinating Heteroatom Functionality at the Propargylic Position
A. Smulik, S. T. Diver, Org. Lett., 2000, 2, 2271-2274.

A Rapid and Simple Cleanup Procedure for Metathesis Reactions
B. R. Galan, K. P. Kalbarczyk, S. Szczepankiewicz, J. B. Keister, S. T. Diver, Org. Lett., 2007, 9, 1203-1206.

Phosphabicyclononane-Containing Ru Complexes: Efficient Pre-Catalysts for Olefin Metathesis Reactions
F. Boeda, H. Clavier, M. Jordaan, W. H. Meyer, S. P. Nolan, J. Org. Chem., 2008, 73, 259-263.

Remarkable Effect of Ethylene Gas in the Intramolecular Enyne Metathesis of Terminal Alkynes
M. Mori, N. Sakakibara, A. Kinoshita, J. Org. Chem., 1998, 63, 6082-6083.

Convenient Access to Functionalized Vinylcyclopentenols from Alkynyloxiranes
L. Wang, M. L. Maddess, M. Lautens, J. Org. Chem., 2007, 72, 1822-1825.

Enyne Cross-Metathesis with Strained, Geminally-Substituted Alkenes: Direct Access to Highly Substituted 1,3-Dienes
D. A. Clark, B. S. Basile, W. S. Karnofel, S. T. Diver, Org. Lett., 2008, 10, 4927-4929.

Aminocarbonyl Group Containing Hoveyda-Grubbs-Type Complexes: Synthesis and Activity in Olefin Metathesis Transformations
D. Rix, F. Caijo, I. Laurent, F. Boeda, H. Clavier, S. P. Nolan, M. Mauduit, J. Org. Chem., 2008, 73, 4225-4228.

Advanced Fine-Tuning of Grubbs/Hoveyda Olefin Metathesis Catalysts: A Further Step toward an Optimum Balance between Antinomic Properties
M. Bieniek, R. Bujok, M. Cabaj, N. Lugan, G. Lavigne, D. Arlt, K. Grela, J. Am. Chem. Soc., 2006, 128, 13652-13653.

Synthesis of 1,2,3-Substituted Pyrroles from Propargylamines via a One-Pot Tandem Enyne Cross Metathesis-Cyclization Reaction
H. Chachignon, N. Scalacci, E. Petricci, D. Castagnolo J. Org. Chem., 2015, 80, 5287-5295.

Synthesis of Styrenes Using Ruthenium-Catalyzed Ring-Closing Enyne Metathesis
K. Yoshida, Y. Shishikura, H. Takahashi, T. Imamoto, Org. Lett., 2008, 10, 2777-2780.

Allenylidene-to-Indenylidene Rearrangement in Arene-Ruthenium Complexes: A Key Step to Highly Active Catalysts for Olefin Metathesis Reactions
R. Castarlenas, C. Vovard, C. Fischmeister, P. H. Dixneuf, J. Am. Chem. Soc., 2006, 128, 4079-4089.

Efficient Method for the Synthesis of Chiral Pyrrolidine Derivatives via Ring-Closing Enyne Metathesis Reaction
Q. Yang, H. Alper, W.-J Xiao, Org. Lett., 2007, 9, 769-771.

Synthesis of Eight-Membered Ring Compounds Using Enyne Metathesis
M. Mori, T. Kitamura, N. Sakakibara, Y. Sato, Org. Lett., 2000, 2, 543-545.