Titanocene methylidene

Although the molybdenum and ruthenium complexes 1-3 have gained widespread popularity as initiators of RCM, the cydopentadienyl titanium derivative 93 (Tebbe reagent) [28,29] can also be used to promote olefin metathesis processes (Scheme 13) [28]. In a stoichiometric sense, 93 can be also used to promote the conversion of carbonyls into olefins [28b, 29]. Both transformations are thought to proceed via the reactive titanocene methylidene 94, which is released from the Tebbe reagent 93 on treatment with base. Subsequent reaction of 94 with olefins produces metallacyclobutanes 95 and 97. Isolation of these adducts, and extensive kinetic and labeling studies, have aided in the eluddation of the mechanism of metathesis processes [28]. 

Formation of Titanocene-Methylidene and its Reaction with Olefins... 

In 1978, Tebbe and co-workers reported the formation of the metallacyde 4, commonly referred to as the Tebbe reagent, by the reaction of two equivalents of trimethylaluminum with titanocene dichloride. The expulsion of dimethylaluminum chloride by the action of a Lewis base affords the titanocene-methylidene 5 (Scheme 14.4) [8]. 

Scheme 14.4. Formation of titanocene-methylidene from the Tebbe reagent.

Aluminum-free titanocene-methylidene can be generated by thermolysis of titana-cyclobutanes 6, which are prepared by reaction of the Tebbe reagent with appropriate olefins in the presence of pyridine bases [9]. Alternatively, the titanacyclobutanes are accessible from titanocene dichloride and bis-Grignard reagents [10] or from 71-allyl titanocene precursors [11]. The a-elimination of methane from dimethyltitanocene 7 provides a convenient means of preparing titanocene-methylidene under almost neutral conditions [12] (Scheme 14.5). 

Tebbe and co-workers reported the first olefin metatheses between titanocene-methyli-dene and simple terminal olefins [13]. They showed cross-metathesis between isotopically labeled isobutene and methylenecyclohexane to be catalyzed by titanocene-methylidene. This process is referred to as degenerate olefm metathesis as it does not yield any new olefin (Scheme 14.6). The intermediate titanacyclobutane has been isolated and characterized [14], and its stability [15] and mechanism of rearrangement [16] have been investigated. 

One of the synthetically useful titanium-based olefin metatheses is the reaction of titanocene-methylidene with terminal allenes 8. Productive olefin metathesis occurs when titanacyclobutanes are treated with 8 (Scheme 14.7) [17] and the resulting a-alkyli-... 

Scheme 14.7. Olefin metathesis of titanocene-methylidene with substituted allenes.

Tandem carbonyl olefmation—olefm metathesis utilizing the Tebbe reagent or dimethyl-titanocene is employed for the direct conversion of olefmic esters to six- and seven-mem-bered cyclic enol ethers. Titanocene-methylidene initially reacts with the ester carbonyl of 11 to form the vinyl ether 12. The ensuing productive olefm metathesis between titano-cene methylidene and the cis-1,2 -disubstituted double bond in the same molecule produces the alkylidene-titanocene 13. Ring-closing olefin metathesis (RCM) of the latter affords the cyclic vinyl ether 14 (Scheme 14.8) [18]. This sequence of reactions is useful for the construction of the complex cyclic polyether frameworks of maitotoxin [19]. 

Despite the successful reactions mentioned above, olefin metathesis utilizing titanocene-methylidene is not necessarily regarded as a useful synthetic tool. Indeed, the steric interaction between the substituent at the carbon a to titanium and the bulky cyclopentadienyl ligand disfavors the formation of the titanocene-alkylidene 15. Hence, cleavage of the titanacycle affords only titanocene-methylidene and the starting olefin (Scheme 14.9). 

Scheme 14.9. Reaction of titanocene-methylidene with internal olefins.

The major obstacle to this approach is that there are few reagents capable of generating higher homologues of titanocene-methylidene. Although the procedure is not straightforward, the titanacycle 21 formed by the addition of diisobutylaluminum hydride to the double bond of (l-propenyl)titanocene chloride 22 serves as a titanocene-propylidene 23 equivalent in carbonyl olefmation (Scheme 14.12) [22]. 

Although the reaction of a titanium carbene complex with an olefin generally affords the olefin metathesis product, in certain cases the intermediate titanacyclobutane may decompose through reductive elimination to give a cyclopropane. A small amount of the cyclopropane derivative is produced by the reaction of titanocene-methylidene with isobutene or ethene in the presence of triethylamine or THF [8], In order to accelerate the reductive elimination from titanacyclobutane to form the cyclopropane, oxidation with iodine is required (Scheme 14.21) [36], The stereochemistry obtained indicates that this reaction proceeds through the formation of y-iodoalkyltitanium species 46 and 47. A subsequent intramolecular SN2 reaction produces the cyclopropane. 

Reactions of titanocene-methylidene generated from titanacyclobutanes with acyl chlorides 55 [46] or acid anhydrides 56 [47] lead initially to the titanium enolates 57 (Scheme 14.24), which then afford aldols upon treatment with the carbonyl compounds. On the other hand, five-membered cyclic anhydrides are methylenated with dimethyltitanocene (Table 14.5, entry 7) [45]. 

Another titanium-based reagent for the methylenation of carbonyl compounds is that prepared from dibromomethane/zinc/titanium tetrachloride and related systems (Scheme 14.25) [48]. These systems transform a wide variety of carboxylic acid derivatives to terminal olefins in the same way as titanocene-methylidene does. 

Table 14.5. Carbonyl methylenation utilizing titanocene-methylidene...

As noted above, titanocene-alkylidenes can be prepared using various methods and starting materials. Like the methylidene complex, higher alkylidene complexes are useful for the transformation of carbonyl compounds to highly substituted olefins. Ketones and aldehydes are converted into substituted allenes by treatment with titanocene-alkenylidenes prepared by olefin metathesis between titanocene-methylidene and substituted allenes (see Scheme 14.7) [17]. Titanocene-alkenylidene complexes can also be prepared from... 

Since the hybridization and structure of the nitrile group resemble those of alkynes, titanium carbene complexes react with nitriles in a similar fashion. Titanocene-methylidene generated from titanacyclobutane or dimethyltitanocene reacts with two equivalents of a nitrile to form a 1,3-diazatitanacyclohexadiene 81. Hydrolysis of 81 affords p-ketoena-mines 82 or 4-amino-l-azadienes 83 (Scheme 14.35) [65,78]. The formation of the azati-tanacyclobutene by the reaction of methylidene/zinc halide complex with benzonitrile has also been studied [44]. 

Scheme 14.35. The reaction of titanocene-methylidene with nitriles.

The reaction of titanocene-alkylidenes generated from thioacetals with nitriles followed by hydrolysis affords ketones. Like the reaction of titanocene-methylidene, this reaction may proceed via the azatitanacydobutene 87 and/or the vinylimido complex 88, which reacts with an organic halide to form an a-substituted ketone [80] (Scheme 14.37). 

In the Tebbe reaction with pyridine iV-oxides and their benzo derivatives, regioselective attack at the cr-position occurs along with the expected deoxygenation (Equations 47 and 48) <2000AGE2529>. The presumed organome-tallic intermediate is the titanocene methylidene complex [Cp2Ti=CH2]. 

Titanocene methylidene phosphine complexes Cp2Ti= CH2L (L = PMes, PMe2Ph, PEts) have been generated by the thermolysis of titanocene metallacyclobutanes in the presence of excess phosphine (equation 9). These titanocene methylidene phosphine complexes have been found to react with alkenes, alkynes, and CO to form metallacyclobutanes, metallacyclobutenes, and a ketene complex, respectively. The phosphine ligand is labile, and an equilibrium mixture is rapidly established if a second phosphine is added. ... 

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. 

Formation of Titanocene-Methylidene and its Reaction with Olefins 476 Formation of Trtanocene-Alkylidenes and their Application to Olefin Metathesis 479... 

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