Organic Chemistry Portal
Organic Chemistry Highlights

Monday, June 19, 2006
Douglass Taber
University of Delaware

New Catalysts and Strategies for Alkene Metathesis

Alkene metathesis (“Grubbs Reaction”) is now well-developed as a synthetic method. Still, there is a continuing effort to develop more efficient catalysts, and to extend the range of substrates that will participate efficiently.

William V. Murray of Johnson & Johnson, Raritan, NJ (J. Org. Chem. 2005, 70, 9636. DOI: 10.1021/jo0514624) and Sally-Ann Poulsen of Griffith University, Brisbane (Tetrahedron Lett. 2005, 46, 7389. DOI: 10.1016/j.tetlet.2005.08.126) independently reported that intramolecular alkene metathesis can be conveniently carried out under microwave irradiation. The cross metathesis of 1 and 2 to give 4 using the Grubbs second generation catalyst 3 required 24 hours at room temperature, or two hours in refluxing CH2Cl2. On microwave irradiation in a sealed vial, the reaction was complete in 15 minutes. Rapid heating of the reaction vessel in a conventional heating bath gave the same result, so there does not appear to be any special rate enhancement from the microwave, but it may offer a convenience in process development.

Alkene migration in the starting material and/or the product can be a serious issue with the Grubbs reaction. Robert H. Grubbs of Caltech (J. Am. Chem. Soc. 2005, 127, 17160. DOI: 10.1021/ja052939w) reported that exposure of the diene 5 to G2 alone led mainly to 6. If 10 mol % of benzoquinone, or even better 2,6-dichloro or tetrafluorobenzoquinone, was included, the reaction delivered the simple metathesis product 7. Note that both 6 and 7 could potentially be useful. Joachim H. G. Steinke of Imperial College, London and Ramón Vilar of the Institute of Chemical Research of Catalonia (J. Org. Chem. 2005, 70, 8235. DOI: 10.1021/jo051120y) have found that monophenyl phosphoesters also suppress alkene migration.

Alkene metathesis is not limited to Ru catalysts. Fabien Gagosz of the Ecole Polytechnique, Palaiseau found (Org. Lett. 2005, 7, 4133. DOI: 10.1021/ol0515917) that an Au catalyst smoothly effected the metathesis cyclization of the ene yne substrate 8 to 9.

Esters can also participate in metathesis. In the course of establishing synthetic routes to the ladder polyether marine toxins, Jon D. Ranier of the University of Utah found (Tetrahedron Lett. 2005, 46, 7209. DOI: 10.1016/j.tetlet.2005.08.071) that the Takai-Utimoto stoichiometric Ti reagent effected direct conversion of alkenyl esters such as 10 into cyclic enol ethers such as 11.

Three interesting new families of Ru catalysts have been developed. Dennis P. Curran of the University of Pittsburgh has reported (J. Org. Chem. 2005, 70, 1636. DOI: 10.1021/jo048001n) light fluorous Grubbs-Hoveyda catalysts such as 12. Either alone or supported on fluorous silica gel, these catalysts are easily removed from the reaction mixture when the metathesis is complete. This minimizes Ru contamination of the product. The fluorous Ru catalyst can also be reused.

Deryn E. Fogg of the University of Ottawa has created (J. Am. Chem. Soc. 2005, 127, 11882. DOI: 10.1021/ja042736s) a new family of phenoxide-substituted Ru complexes, illustrated by 13. The pyridine ligand is labile, so these catalysts are fast. They also appear to be more robust than G2, allowing lower catalyst loadings. It is particularly important that these aryloxide catalysts have a high affinity for silica gel. A single chromatography led to organic products containing less than 100 ppm Ru.

Amir H. Hoveyda of Boston College has developed a series of chiral Ru catalysts. The most recent entry (J. Am. Chem. Soc. 2005, 127, 6877. DOI: 10.1021/ja050179j) is the easily prepared 16, that draws its chirality from the inexpensive diphenylethylenediamine. Exposure of prochiral 14 to an excess of styrene 15 in the presence of 5 mol % of the catalyst 16 for 30 min at room temperature delivered the cyclic ether 17 in 89% isolated yield and high ee.

D. F. Taber, Org. Chem. Highlights 2006, June 19.