Titanocene reagents

The Wittig reaction efficiently olefinates aldehydes and ketones, but not esters or amides. Several early-transition-metal approaches have been taken to this problem. Recently, Takeshi Takeda of the Tokyo University of Agriculture and Technology reported (Tetrahedron Lett. 44 5571,2003) that the titanocene reagent can effect the condensation of an amide 10 with a thioacetal 11 to give the enamine 12. On hydrolysis, 12 is converted into the ketone 13. When the reaction is intramolecular, reduction proceeds all the way, to give the pyrrolidine IS. 

Asymmetric Alkene Isomerization. The chiral titanocene reagent (1) serves as precatalyst for the isomerization of alkene (4) (eq 3). Active isomerization catalyst is obtained by in situ reduction of (1) with Lithium Aluminum Hydride (164 °C, 30 min). Treatment of the achiral substrate (4) with 2 mol % catalyst produced axially dissymmetric product (5)-(5) in 44-76% ee (100% yield). The reaction is slow at room temperature (120 h required for complete reaction) faster rates are obtained at higher temperatures, but at the expense of lower product enantiomeric purity. 

Cyclopentenones." As an alternative method to the Pauson-Khand reaction the cyclocarbonylation of enynes is achievable with the titanocene reagent derived from CpjTiClj, Mg, and (EtO)jP, followed by treatement with triphosgene. 

The y9-titanoxy radicals formed after epoxide opening can also add to a.,P-unsaturated esters. The resulting enol radicals are reduced by a second equivalent of the titanocene reagent to yield titanium enolates. After aqueous workup the corresponding hydroxy esters or lactones are obtained. This method allows easy access to (5-lactones in a one-step procedure from epoxides (Scheme 21) [33bj. 

Cyclisations initiated by zirconocene 1-butene are incompatible with ester functionality, a limitation which has been overcome by the use of a diethyl titanocene reagent which gives titanocycles exemplified by 23 (Scheme 5.8). 

The reagent titanocene dichloride reduces carboxylic esters in a different manner from that of 10-86, 19-36, or 19-38. The products are the alkane RCH3 and the alcohol R OH. The mechanism probably involves an alkene intermediate. Aromatic acids can be reduced to methylbenzenes by a procedure involving refluxing first with trichlorosilane in MeCN, then with tripropylamine added, and finally with KOH and MeOH (after removal of the MeCN). The following sequence has been suggested ... 

To improve the utility of Nugent s and RajanBabu s conditions even further, catalytic conditions for cyclizations have been developed. They address the issue of reagent control of the cyclization and the mode of its termination. The formation of an alkyl titanocene species after reductive trapping allows two distinctive pathways for the regeneration of the catalyst. 

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]. 

Novel Titanocene and Zirconocene Reagents with Bis(trimethylsilyl)acetylene... 

Figure 10.1. Novel titanocene and zirconocene reagents incorporating bis(trimethylsilyl)acetylene.

The (3-metaloxy radical was first exploited for synthetic purposes in C—H and C—C bond-forming reactions by Nugent and RajanBabu through the use of titanocene(III) chloride as an electron-transfer reagent [5]. They established that the (3-titaniumoxy radicals formed after electron transfer can be reduced by hydrogen atom donors, e. g. 1,4-cy-clohexadiene or tert-butyl thiol, that they add to a,(3-unsaturated carbonyl compounds, and that they can react intramolecularly with olefins in 5-exo cyclizations. 

It should not be forgotten, however, that titanocene(III) complexes are also excellent reagents for the deoxygenation of epoxides, as demonstrated independently by Schobert [13] and by Nugent and RajanBabu [5d[. An example of a reaction yielding a highly acid-sensitive product in reasonable yield is shown in Scheme 12.5. 

More recently, Doris et al. have described the reductive ring-opening of a-keto epoxides [16]. In this manner, p-hydroxy ketones can be obtained in high yields. The synthesis of enantiomerically pure compounds can easily be realized. The titanocene] 111) reagents are distinctly superior to samarium diiodide, which is also known to induce this transformation. 

We are currently employing substituted titanocene complexes to achieve reagent-con-trolled cyclizations. 

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). 

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]. 

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]. 

An unusual reductive elimination can ensue from titanacyclobutanes possessing an alkenyl group at the carbon a to the titanium atom. Thus, alkenylcarbene complexes 48, prepared by the desulfurization of (fy-unsaturated thioacetals 49 or l,3-bis(phe-nylthio)propene derivatives 50 with a titanocene(II) reagent, react with terminal olefins to produce alkenylcyclopropanes 51 (Scheme 14.22, Table 14.4) [37]. This facile reductive... 

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. 

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