Titanocene enolates

As in the reductive ring-opening, titanocene—oxygen bonds have to be protonated. Here, a titanium enolate, which is generated after reductive trapping of an enol radical, has to be protonated, in addition to a simple titanocene alkoxide. As before, 2,4,6-collidine hydrochloride constitutes a suitable acid to achieve catalytic turnover, but here zinc dust turned out to be the reductant of choice [31c], The features of the stoichiometric reaction are preserved under our conditions. Acrylates and acrylonitriles are excellent radical acceptors in these reactions. Methyl vinyl ketone did not yield the desired addition product. Under the standard reaction conditions, a-substituted acceptors are readily tolerated, but (3-substitution gives the products only in low yields. 

The key features of the catalytic cycle are trapping of the radical generated after cycliza-tion by an a,P-unsaturated carbonyl compound, reduction of the enol radical to give an enolate, and subsequent protonation of the titanocene alkoxide and enolate. The diaster-eoselectivity observed is essentially the same as that achieved in the simple cyclization reaction. An important point is that the tandem reactions can be carried out with alkynes as radical acceptors. The trapping of the formed vinyl radical with unsaturated carbonyl compounds occurs with very high stereoselectivity, as shown in Scheme 12.21. 

Silyltitanation of 1,3-dienes with Cp2Ti(SiMe2Ph) selectively affords 4-silylated r 3-allyl-titanocenes, which can further react with carbonyl compounds, C02, or a proton source [26]. Hydrotitanation of acyclic and cyclic 1,3-dienes functionalized at C-2 with a silyloxy group has been achieved [27]. The complexes formed undergo highly stereoselective addition with aldehydes to produce, after basic work-up, anti diastereomeric (3-hydroxy enol silanes. These compounds have proved to be versatile building blocks for stereocontrolled polypropionate synthesis. Thus, the combination of allyltitanation and Mukayiama aldol or tandem aldol-Tishchenko reactions provides a short access to five- or six-carbon polypropionate stereosequences (Scheme 13.15) [28],... 

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]. 

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]. 

The Diels-Alder reaction outlined above is a typical example of the utilization of axially chiral allenes, accessible through 1,6-addition or other methods, to generate selectively new stereogenic centers. This transfer of chirality is also possible via in-termolecular Diels-Alder reactions of vinylallenes [57], aldol reactions of allenyl eno-lates [19f] and Ireland-Claisen rearrangements of silyl allenylketene acetals [58]. Furthermore, it has been utilized recently in the diastereoselective oxidation of titanium allenyl enolates (formed by deprotonation of /3-allenecarboxylates of type 65 and transmetalation with titanocene dichloride) with dimethyl dioxirane (DMDO) [25, 59] and in subsequent acid- or gold-catalyzed cycloisomerization reactions of a-hydroxyallenes into 2,5-dihydrofurans (cf. Chapter 15) [25, 59, 60],... 

The Petasis reagent, dimethyl titanocene (4.93) can also be used for the methylenation of carbonyl compounds. The Petasis reagent (4.93) is prepared by the reaction of methyl magnesium chloride or methyllithium with titanocene dichloride (Cp2TiCl2). Carbonyl compounds on heating with 4.93 at 60-65° C in a toluene solution give the corresponding alkenes or enol ethers. 

Stille, J. R., Grubbs, R. H. Synthetic applications of titanocene methylene complexes selective formation of ketone enolates and their reactions. J. Am. Chem. Soc. 1983, 105, 1664-1665. 

Alkenes. Titanocene bis(triethyl phosphite), which is prepared in situ from titanocene dichloride, triethylphosphite, and Mg, promotes carbonyl olefmation with gem-dichlorides and dithioacetals [e.g., l,l-bis(phenylthio)cyclobutane ] including those derived from enals (to give 1,3-dienes). Enol ethers-and alkenyl sulfides are obtained in the analogous reaction with dithioorthoformates and trithioorthoformates. Cross-coupling of dithioacetal and thiolesters furnishes predominantly (Z)-alkenyl sulfides. ... 

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. 

Zirconocene-derived allenyl enolate (6) was used for the synthesis of allenyl alcohol (7) (Equation 3) [4], Compared with the corresponding titanocene or lithium enolates derived from allenyl esters (5), zirconium enolates (6) gave alcohol (7) in better yields after oxidation with dimethyldioxolane. 

Enol Ether Synthesis. A 2-(trimethylsilyl)ethyl-based dithioorthoformate was prepared via copper(II) bromide-promoted oxidative coupling of bis(phenylthio)-methyltributylstannane. The dithioorthoformate thus prepared is treated with a titanocene(II) reagent followed by the addition of ketones or esters to promote alkoxymethylidenation as exemplified in eq 32. ... 

---