Tebbe olefination

The Tebbe s reagent, i-chlorobis(cyclopentadienyl)(dimethylaluminiijni)- i-methylenetitanium, transforms a carbonyl compound to the corresponding exo-olefin. 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 253, Springer-Verlag Berlin Heidelberg 2009 

Straus, D. A. Encyclopedia of Reagents for Organic Synthesis John Wiley Sons, 2000. (Review). 

Tebbe reagent, hi Name Reactions for Homolotions-Part 1 Li, J. J., Corey, 

The common element between Tebbe and Petasis methylenation is that both share the same reactive intermediate, titanocene methylidene 5, in the reaction pathway. Hughes has provided a strong evidence that the Petasis reaction proceeds by the rate-determining generation of titanocene methylidene 5 via an a-elimination to remove of methane, followed by a rapid reaction with the carbonyl compound.  

P-unsaturated esters 12 and 14, spirobislactone 16, and vinylogous lactone 18 are smoothly methylenated by Petasis reagent. Silyl esters 22 and 24 are converted to silyl enol ethers 23 and 25. Carbonate 20 can be methylenated to give ketene acetal 21. Amide 26 and lactams can be methylenated, however the reaction is generally sluggish and the complete separation of Ti species is usually difficult. In a similar manner, thioester 28 and selenoester 30 are converted to alkenyl sulphide 29 and alkenyl selenide 31, respectively. Additionally it has been demonstrated that acyl silanes can be converted to the corresponding alkenyl silanes. 

An elegant example of the preparation, storage, and use of the Petasis reagent for methylenation in multikilogram scale (250 kg, 474 mole) was provided by Payack and co-workers at Merck Process Chemistry Department in 2004. The Petasis reagent should be stored refrigerated as a solution (in 

Grubbs reagents, titanacycles 50 and 51 were prepared by the reaction of Tebbe reagent with a terminal alkene in the presence of a Lewis base. When these complexes are heated, reactive titanocene methylidene 5 is regenerated and will methylenate carbonyl group (49 to 53).  

Takeda and co-workers discovered that the easily accessible thioacetals 54 and 56 can be reduced by a low-valent titanium reagent to give Schrock carbenes that are competent to alkylidenate aldehydes, ketones, esters. 

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The initial synthesis of aprepitant (1), which relies on a Tebbe olefination and reduction to install a methyl group on the benzyl ether side chain, is shown in Scheme 3.8,19 The initial steps are from a literature-precedented synthesis of p-fluorophenyl glycine based on conversion of chiral oxazolidinone 33 to azide 34. Formation of morpholinone intermediate 36 proceeds via benzylation and reaction with 1,2-dibromoethane. 

While the original synthesis of 1 features a clever use of the Tebbe olefination reaction, the process routes use elegant methods to set the ring stereochemistry through displacement reactions (and equilibration), followed by reduction, reactions that are much more scalable. This difference reflects the contrasting need for SAR development in the medicinal chemistry work vs. the need for scalability in the process work. 

Other temporary connections, such as ketal tethers were also tested. Tebbe olefination of acetate 266 and ketal formation with sugar alcohol 255 lead to tethered intermediate 267, which is cyclized to a C-analog derivative 268 of the a-D-Man(l— 4)-D-Glc disaccharide after ketal cleavage [118] (O Scheme 56). 

The active species in the Tebbe olefination is believed to be the nucleophilic (Schrock-type) titanocene methylidene, which is formed from the Tebbe reagent upon coordination of the aluminum with a Lewis base (e.g., pyridine). This methylidene in its uncomplexed form, however, has never been isolated or observed spectroscopically owing to its extreme reactivity. The same intermediate can also be generated by other means." The titanocene methylidene reacts with the carbonyl group to form an oxatitanacyclobutane intermediate that breaks down to titanocene oxide and the desired methenylated compound (alkene). The driving force is the formation of the very strong titanium-oxygen bond. 

Tebbe olefination One-carbon homologation of carbonyl compounds to afford the corresponding 1,1-disubstituted alkenes. 454... 

Peterson olefination, Takai-Utimoto olefination, Tebbe olefination, Wittig reaction, Wittig reaction - Schlosser modification ... 

Walters, M. A. Chameleon catches in combinatorial chemistry Tebbe olefination of polymer supported esters and the synthesis of amines, cyclohexanones, enones, methyl ketones and thiazoles. Chemtracts 1999,12, 679-683. 

Our next objective was to methylenate the hemiacetal 40a,so as to obtain diene 39 (Scheme 14). Standard Wittig olefination procedures on 40 with methyl triphenylphosphoranylidene, generated in situ from methyl triphenylphosphonium bromide and w-BuLi, or with KOBu-t in THF (Entries 1 and 2, Scheme 14) simply furnished unreacted starting material. Tebbe olefinations were also unsuccessful a complex mixture of products arising under the conditions investigated in Entry 3 (Scheme... 

Tebbe olefination, 441 Tebbe olefinations, 368 Tebbe s reagent, 457 Tedania ignis, 246 Tedanolide, 246 tedanolide, 256 TEMPO, 250, 301 temporary silicon tether, 103 Tennant quinoline synthesis, 7 tetra-n-butylammonium fluoride (TBAF), 214 2-(7-aza-1 H-benzotriazole-1 -yl)-1,1,3, 3-tetramethyluronium hexafluorophosphate (HATU), 25... 

Hydroxytetrahydrofurans. Triisobutylaluminum acts both as a Lewis acid to catalyze the isomerization of 4-methylene-1,3-dioxolanes to 2-oxotetrahydrofurans (via C-O bond cleavage and C-C bond formation) and as a reducing agent for the ketone group of the intermediate. The 4-methyIene-1,3-dioxolanes are available by a Tebbe olefination. 

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