Dimethyltitanocene reagent

An inseparable mixture of 51 and 54 (3 2 ratio) was methylenated with dimethyltitanocene reagent to furnish enol ethers 52 and 55 in 90% yield (Scheme 3.1.4). Thermal rearrangement of the mixture in a sealed tube produced the desired cyclooctenone 53 and the isomeric 6-5 system 58. The Claisen rearrangement of 52 proceeded with high stereoselectivity. The formation of 58 is a result of the partial isomerization of 52 to 57 followed by an alternative Claisen rearrangement Another product obtained was the enol ether 56, formed by the isomerization of 55. It was too hindered to perform the Claisen rearrangement of 55 and 56. Molecular models indicated that the chairtransition state R should be more favored over the chair-boat transition state [50]. 

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). 

Similarly to alkenes, alkynes react with various titanium-methylidene precursors, such as the Tebbe reagent [13,63], titanacydobutanes [9b, 64], and dimethyltitanocene [65] to form the titanium-containing unsaturated cyclic compounds, titanacydobutenes 67 (Scheme 14.29). Alternatively, 2,3-diphenyltitanacydobutene can be prepared by the reaction of the complex titanocene(II) bis(trimethylphosphine) with 1,2-diphenylcyclopropene [66]. Substituent effects in titanacydobutenes [67], the preparation of titanocene-vinylke-tene complexes by carbonylation of titanacydobutenes [68], and titanacyclobutene-vinylcar-bene complex interconversion [69] have been investigated. 

Petasis, et al. have discovered that dimethyltitanocene is an excellent substitute for the Tebbe reagent" for the methylenation of heteroatom-substituted carbonyl compounds. ... 

The advantages of this reagent are its straightfonvard synthesis and relative air stability. The previous procedure for the synthesis of dimethyltitanocene used methyllithium in diethyl ether, which is unsuitable for large scale operations because of its extreme pyrophoricity. In addition, the method isolated the compound as a crystalline solid, which the submitters have found to be very unstable. The method described here addresses both of these concerns, and can be used to prepare multiple kilograms of the reagent. 

Dimethyltitanocene (213), called the Petasis reagent, can be used for alkenation of carbonyls (aldehydes, ketones, esters, thioesters and lactones). This reagent is prepared more easily than the Tebbe reagent by the reaction of titanocene dichloride with MeLi. However, this reagent may not be a carbene complex and its reaction may be explained as a nucleophilic attack of the methyl group at the carbonyl [67], Alkenylsilanes are prepared from carbonyl compounds. Tri(trimethylsilyl)titanacyclobutene (216), as a... 

Dimethyltitanocene, Cp2Ti(CH3)2, (1) m.p. 97°. This reagent is prepared by reaction of titanocene dichloride, Cp2TiCl2, with CH3Li (95% yield). It is stable for several months when stored in the dark in toluene or THF, but decomposes rapidly in the solid state.1... 

In this reaction, acetals are used as dication equivalent of one-carbon unit 72, whereas 71 provides a dianion 73 <95TL5581>. A new stereocontrolled synthesis of substituted tetrahydrofiirans starts with dioxalones 74. A titanium-mediated methylenation using dimethyltitanocene (THF, 60 C) with subsequent treatment of 75 with trialkylaluminium reagents results in the formation of tetrahydrofiirans 76 <95JA6394>. 

A useful alternative to phosphorus ylids are the titanium reagents, such as, 71, prepared from dicyclopentadienyltitanium dichloride and trimethylaluminum. Treatment of a carbonyl compound with the titanium cyclopentadienide complex 71 Tebbe s reagent) in toluene-THF containing a small amount of pyridine " leads to the alkene. Dimethyltitanocene (Me2TiCp2), called the Petasis reagent, is a convenient and highly useful alternative to The mechanism of Petasis... 

Siebeneicher, H., Doye, S. Dimethyltitanocene Cp2TiMe2 a useful reagent for C-C and C-N bond formation. J. Prakt. Chem. 2000, 342, 102-106. 

The original medicinal chemistry route used a dimethyltitanocene-mediated olefmation of resulting ester 2. Although examples of this reagent in the conversion of esters to vinyl ethers had been reported, this reagent had never been produced on a multi-kilogram scale. Therefore, a significant amount of fundamental research was performed that resulted in an improved preparation, mechanistic elucidation, titration method for... 

The Petasis reagent (Me2TiCp2, dimethyltitanocene) undergoes similar olefi-nation reactions with ketones and aldehydes. The originally proposed mechanism [3] was very different from that of Tebbe olefmation. However, later experimental data seem to suggest that both Petasis and Tebbe olefmation share the same mechanism, i.e. the carbene mechanism involving a four-membered titanium oxide ring intermediate [6]. 

The Petasis reagent (Me2TiCp2, dimethyltitanocene) undergoes similar olefination reactions with ketones and aldehydes [5]. However, the mechanism is very different. 

As noted in the previous section, one drawback of the Tebbe reagent 3 is that an acidic aluminum compound is produced when it is converted into titanocene-methylidene 4. The instabUity of 3 toward air and water necessitates special techniques for its preparation and is also an obstacle to its use in organic synthesis. In this sense, dimethyltitanocene 30 is a convenient precursor for the preparation of titanocene-methylidene 4 (Scheme 4.22). 

Methylenation of ketones and aldehydes Similarly to the Tebbe reagent, dimethyltitanocene 30 is compatible with hydroxyl groups, and its low basicity also ex-... 

The following examples illustrate the chemoselectivity of the dimethyltitanocene-mediated methylenation (Scheme 4.26). As for the Tebbe reagent 3, the rate of... 

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