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This is the Experimental
Procedure page. (30): T a solution of 28 (9 mg, 0.03 mol) in toluene, was added a stoichiometric amount of MgBr2, and the mixture was stirred at room temperature for 15 hours. Water was then added to quench the reaction. The aqueous layer was extracted 3 times with diethyl ether (3 x 10mL). The organic layer was dried over MgSO4 and filtered, and the solvent was evaporated. The crude product was purified by flash silica chromatography (10% EtOAc/hexane) to afford 11 mg of 30 (99% yield) as a colorless oil. IV. Related Papers to Step 27 Titanium-Mediated Carbonyl Olefinations. I. Methylenations of Carbonyl Compounds with Dimethyltitanocene Petasis, N.A.; Bzowej, E.I. J. Am. Chem. Soc.1990, 112, 6392. The Petasis Reagent is a more practical reagent to use in the methylatio of an aldehyde, ketone, lactone, or ester, as it is free from synthetic difficulties. For instance, it is not possible to convert an ester or lactone using Tebbe or Wittig-type reagents. Also, the Petasis Reagent, Cp2Ti(CH3)2, is readily prepared from titanocene dichloride, as shown below. IMAGE I Olefinations required at least two equivalents of Tebbe's reagent drives the reaction to completion. Teh icnreased reaction rate in THF suggests polare intermediates. Research shows that readily enolizable aldehydes and ketone were efficiently olefinated. Also, a disubstituted alpha carbon in an aldehyde reacts faster than a mono-substituted alpha carbon. IMAGE 2 Esters and lactone reacted at a slower rate, due to different conformational geometry of the titanium intermediate complexes. IMAGE 4 Additionally, in esters,a different intermediate may be formed that allows observed H/D scrambling to take place between the ester and Cp2Ti(CD3)2 Other Papers Related to Step 27: 1. Berget,P.E.; Schore, N.E. Organometallics. 2005, 25, 552-553. a. Shows how to recylce Titanochene Dichloride using the Petasis Olfefination. IMAGE 5 2. Cook, M.J.; Fleming, E.I. Tetrahedron Lett. 2005, 46, 297-300. a. Use of microwaves increases reaction rate with petasis Olefination. 3. Mesaros, E.F.; Meyer, E.A.; Smith III, A.B. J. Am. Chem. Soc. 2005, 127, 6948-6949. a. Used in Petasis Olefination in order to accomplish a rearrangement and ring closure in synthesis ---------------------------------------------------- V. Leading Question Provide a brief lesson to your peers about the Tebbe and Petasis Olefination reactions. What is olefination? Here is the general Theme: Olefination: Invovles a carbonyl group that is transformed into a carbon-carbon double bond (an olefin, or alkene) via a four membered ring intermediate. Many organometallic* reagents can be used, but here is some focus on the Petasis and Tebbe olefinations. *Organometallic compound: characterized by the presence of one or more metal-carbon bonds, in which the carbon involved would, apart form the metal-carbon bond, would be considered an organic compound. Tebbe Reagent A red solid that is pyrophoric (ignites spontaneously in air) and typically used under nitrogen or argon. The Ti and Al bonds are bridged by both CH2 and chloride ligands (an atom, ion, or function that donates its electrons through a coordinate covalent bond, in which only of of the atoms involved in the bond is contributing electrons to the bond) to one or more central atoms or iions, usually metals; an array of such ligands around a center is termed a complex. Tebbe reagent: Cp2TiCh2ClAl(CH3)2 IMAGE 6 note: Cp aromatic five-membered ring IMAGE 7 pi electrons shared by entire structure Petasis Reagent Preparation of Petasis Reagent: IMAGE 8 Cp2TiCh2 is what actually does the olefination, and it is known as the Schrock carbene. The preparation of the Hrock carbene gives of methane gas. Here is how an olefination with the Petasis Reagent works: IMAGE 9 Application: Microwave-assisted, regioselective, petasis Olefination of unsymmetrical oxalates. Formation of pyruvate-based enol ethers and enamines The petasis reagent olefinates ketones, aldehydes, and amides into an alkene via the Schrock carbene efficiently. It does not work well with esters and thioesters. Cook and Fleming prove that even when an excess of the Petasis reagent is use, the non acid sensitive group is chemoselectively favored. IMAGE 10 The reaction proceede slwoly when R was used. After 24 hours at 65�C, only there was only a 43% yield of the product. The reaction was driven to completion after the temperature was elevated. However, under microwave conditions, the reaction was driven to completion in only thrity minutes. When the Petasis reagent was subjected to less reactive substrates (R1, R2, R3), reactivity and reaction rate increased when under microwave conditions. In order to drive the reaction all the way to completion, 3 equivalents of the Petasis reagent were used. Even with the excess reagent, only one carbonyl was olefinated (the lessa cid sensitive group, as shown above). Another benefit of the microwave assisted reaction is that a cleaner reaction mixture was obtained. References: 1. Cook, M.J.; Fleming, E.I. Tetrahedron Lett. 2005, 46, 297-300. 2. Morency, L.; Barriaul, L. J. Org. Chem. 2005, 70, 8841-8853. ---------------------------------------- I. MECHANISM Studies Toward the Total Synthesis of Vinigrol. Synthesis of the Octalin Ring. Steps 27-30 (via 28) Formation of titanium alkylidene complex (Schrock carbene) from petasis reagent IMAGE 11 (over 2 pages) ** Note: this mechanism is completed under the assumption that stoichiometric amounts of reagents are used.
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