1,2,3,4,5-pentamethylcyclopentadiene (Cp*) is an organic molecule that serves as precursor to the well known Cp* ligand in organometallic chemistry. It possesses an acidic proton that is typically removed with organolithium reagents (i.e. nBuLi), affording the Cp*-Li salt which can be isolated and further transmetallated with main-group elements and transition metals. Cp* imparts more solubility, is more tightly-bound, renders the metal center more electron-rich, and provides more steric protection than cyclopentadiene (Cp). The downside is that Cp* is much more expensive than its unmethylated congener, meaning it will need to be synthesized in-house. Since its first synthesis in 1960,[1] the procedures employed have improved over the years.[2-4] By 1990, the group of Tobin Marks streamlined the synthesis into a more economical protocol amenable to hundred-gram scales.[5] They also published another protocol worthy of consideration.[6] These two Inorganic Syntheses protocols are the most viable to make pentamethylcyclopentadiene. Take your pick.
Reference 5 involves two reactions: 1) Reductive lithiation of 2-bromo-2-butene, followed by double nucleophilic addition onto ethyl acetate; and 2) Acid-catalyzed dehydration and cyclization of the resulting alcohol into pentamethylcyclopentadiene.
Reference 6 involves three reactions: 1) Double aldol condensation of 3-pentanone with 2eq. of acetaldehyde, followed by acid-induced cyclization into a tetrahydropyrone; 2) Acid-induced ring-opening and dehydration into an unsaturated dienone, followed by Nazarov cyclization into a cyclopent-2-enone; and 3) Nucleophilic addition of methyllithium to the cyclopent-2-enone, followed by acid-catalyzed dehydration to generate pentamethylcyclopentadiene.
Notes:
- Although some references say pentamethylcyclopentadiene is air and light sensitive it is stable enough to be handled in air. Its synthesis workup is done in air using aqueous washes after all. The references likely refer to long-term storage.
- Although the Inorganic syntheses procedure in reference 5 is fast and amenable to hundred-gram scales, it involves the use of 2-bromo-2-butene. Hundred-gram quantities of this reagent can be purchased from various vendors (i.e. Millipore-Sigma, Oakwood Chemical) for a moderate price, but should be purified by basic alumina to remove trace impurities which may interfere with the reaction. The lithiation step demands “rigorously anhydrous and anaerobic conditions” to ensure success.
- The procedure in reference 6 is also amenable to hundred-gram scales and is much less rigorous, but can take upwards of a week to finish.
- For a procedure to generate the Cp*-Li salt, refer to the appropriate Topic under the Group 1 category.
[1] deVries, L.; J. Org. Chem. 1960, 25, 10, 1838.
[2] Burger, U.; Delay, A.; Mazenod, F. Helv. Chim. Acta. 1974, 57, 2106-2111.
[3] Feitler, D.; Whitesides, G. M. Inorg. Chem. 1976, 15, 2, 466-469.
[4] Threlkel, R. S.; Bercaw, J. E.; Seidler, P. F.; Stryker, J. M.; Bergman, R. G. 1,2,3,4,5-pentamethylcyclopentadiene. Org. Synth. 1987, 65, 42. DOI: 10.15227/orgsyn.065.0042
[5] Manriquez, J. M.; Fagan, P. J.; Schertz, L. D.; Marks, T. J. 1,2,3,4,5-Pentamethylcyclopentadiene. Inorg. Synth. 1990, 28, 317-320.
[6] Fendrick, C. M.; Schertz, L. D.; Mintz, E. A.; Marks, T. J. Large-Scale Synthesis of 1,2,3,4,5-Pentamethylcyclopentadiene. Inorg. Synth. 1992, 29, 193-197.