Titanocene-mediated radical reactions

Barrero, Oltra and coworkers reported on the use of epoxygeranyl acetate in titanocene-mediated cyclizations and found that the termination of the reaction took place via a /i-hydride elimination after trapping of the radical by the second equivalent of Cp2TiCr [94,95]. This finding together with Takahashi s tandem cyclization [96] (see below) marks the first example of extremely interesting developments in epoxypolyene cyclizations via radicals that are discussed separately in the following section. 

It is also essential that competing radical pathways are excluded. The radical intermediates should therefore be relatively persistent. This is the case here, because tertiary radicals are relatively slowly trapped by hydrogen atom donors, e.g., THF, which is usually applied as solvent in titanocene-mediated or -catalyzed reactions, or a second equivalent of Cp2TiCl. Flowever, in the absence of other pathways this reduction, which was followed by a -hydride elimination, was observed [75,76]. Our results with 10 are summarized in Table 5. 

The mechanism of titanocene (TiCp2Cl2)-mediated 3-exo cyclization of vinyl epoxides containing carbonyl, phenyl, and vinyl groups has been determined by DFT calculations and experimental studies (Scheme 52).86 The reaction is exothermic and reversible, in contradiction to an earlier mechanistic proposal. The energies of activation for ring closure are among the lowest known for radical reactions. The crucial step for a successful completion of the reaction is rapid trapping of the cyclopropylcarbinyl... 

Borane, methanol, and water, which have B-H and O-H bonds too strong to allow participation in radical reactions, are activated towards HAT by complexa-tion with NHCs, boranes, or titanocene(III) complexes. This novel concept has resulted in exciting applications in both radical chain reactions and transition metal mediated and catalyzed transformations. 

GansSuer et al. studied the tandem titanocene-mediated cyclization/inter-molecular addition to Michael acceptors [132]. After treatment with t-butyl acrylate in the presence of Zn, collidine hydrochloride and catalytic amounts of titanocene [133], epoxide 143 yielded the desired bicycUc product 144 in reasonable yield and high diastereoselectivity (Scheme 46). Remarkably, alkyne 145 led to the first example of an intermolecular addition involving a vinylic radical. The success of this reaction was attributed by the authors... 

A brilliant synthetic methodology leading to a-methylene/arylidene-8-lac-tones in a one-pot manner has been delivered by Roy and co-workers, using titanocene(iii)-mediated radical-induced addition of epoxides to MBH adducts. " As shown in Scheme 4.101, lactones 315 were obtained in 48-72% yields on treatment of epoxide 314 and MBH acetates with Cp2TiCl in THF the reaction proceeded by Michael addition followed by in situ lactonization. However, using 3-acetoxy-2-methylenenitrile instead of MBH acetates did not give the lactone 315, but afforded a 5N2 -type product as an inseparable mixture of ( )- and (Z)-isomers in a ratio of 84 16 in 61% yield. 

To study the effects of water and other solvents on titanocene(III)-mediated processes we used the transannular cychzation of epoxygerma-crolides as a model reaction [47]. Thus, we found that in anhydrous, non-halogenated solvents such as THF the reaction led selectively to decalins with an exocyclic double bond (Scheme 5). In an aqueous medium (THF/H2O), however, the characteristic lime green color of Cp2TiCl turned deep blue and the main product was a reduced decalin (Scheme 5). Under these conditions, water (either H2O or D2O) proved to be more effective than the toxic and expensive hydrogen-atom donor 1,4-cyclohexadiene for the reduction of tertiary radicals [47]. This is an unusual phenomenon in free-radical chemistry [48-50], subsequently exploited by us for the selective reduction of aromatic ketones as we shall see later [51,52]. 

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