Titanocene methylidene, Tebbe methylenation

A few years later, Tebbe and co-workers found that the methylene-bridged metallacycle 3, which has become known as the Tebbe reagent, is useful for the methylenation of ketones and aldehydes [5]. Titanocene-methylidene 4, the active species of this olefination, also transforms carboxylic acid derivatives into heteroatom-substituted olefins. Because the carbene complex 4 is much less basic than conventional olefination reagents such as phosphorus ylides, it can be employed for the olefination of carbonyl compounds possessing highly acidic a-protons or of highly hindered ketones, and has become an indispensable tool in organic synthesis. Various methods for the preparation of titaniumcarbonyl olefination. This chapter focuses on the use of metal-carbene complexes and some related species in carbonyl olefination (Scheme 4.2). 

Methylenation of carboxylic acid derivatives The Tebbe reagent 3 is extremely valuable as a reagent for the methylenation of carboxylic acid derivatives, which is generally unsuccessful using phosphorus ylides. Esters and lactones are readily transformed into enol ethers (Table 4.3), especially when a Lewis base such as THE is present in the reaction mixture. In the methylenation of a,j8-unsaturated esters, the internal olefin is not involved in the reaction, and the configuration of the double bond is maintained (entry 4). When carbonyl compounds bearing a terminal double bond are subjected to the methylenation, significantly lower yields are observed (entries 6 and 11), which may be attributable to competitive formation of a titanacycle from titanocene-methylidene 4 and the terminal olefin. 

Carbonyl Olefination with Titanocene-Methylidene and Related Reagents 157 Tab. 4.4. Methylenation of amides, imides, and thiol esters with the Tebbe reagent 3. 

A limitation of the methylenation of carboxylic acid derivatives with Tebbe-type reagents such as 3 and 11 is that highly electrophilic acid anhydrides and acid halides cannot be transformed to the corresponding enol esters or alkenyl halides. The reaction of titanocene-methylidene generated from 11 with add chlorides results in the formation of acylation products via titanium enolates 12 [44] rather than methylenation. Since the titanium enolates 12 are stable and do not isomerize to the more highly substituted enolates, they are useful for regioselective aldol reactions (Scheme 4.11) [44a]. Although similar titanium enolates are also produced... 

The readion of titanocene dichloride with the methylene di-Grignard reagent affords the organotitanium species 14, which behaves like the Tebbe reagent 14 reacts with olefins to produce various titanacydobutanes 11 [47]. The interesting spiro metallacycle 15, which is formed from two equivalents of 14, reacts with benzophenone to produce 1,1-diphenylethylene (80% yield) and forms the titanocene-methylidene complex 16 on treatment with trimethyl phosphine (Scheme 4.14) [48]. 

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. ... 

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). ... 

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