Bis(cyclopentadienyl)titanium(III) chloride effects the
anti-Markovnikov opening of
epoxides to a
free radical intermediate and is tolerant of alcohols and some basic nitrogen functional groups, however it is sensitive to oxidizing functional groups such as
nitro groups. As can be seen in the above illustration, subsequent reaction proceeds along a pathway determined by added reagents and reaction conditions:
tBuSH, water, the intermediate is protonated to an
alcohol product. This transformation provides the complementary regioisomer to that of an epoxide opening using a metal hydride; • Reaction of the intermediate with a second equivalent of Cp2TiCl traps the radical as an alkyl-titanium(IV) species which can either undergo
β-hydride elimination (favoured for 3° species) or dehydration via β-alkoxy elimination; in both cases an
olefin product is generated. Intermolecular trapping of
acrylates and
acrylonitriles with radicals derived from
epoxides is possible, as well as conjunctive intra-intermolecular variants. • Another pathway intercepts the radical intermediate with nickel catalysis and facilitates
enantioselective cross-coupling of opened epoxides with
halide and
pseudohalide electrophiles. An example of an application of this reagent is in the preparation of
vinorelbine, a
chemotherapeutic agent which can be prepared in three steps from the
naturally-occurring alkaloid leurosine. The reagent has been used in the synthesis of over 20 natural products. Addition of a hydrochloride salt to the reaction facilitates release of the oxygen-bound titanium(IV) intermediate, allowing the reagent to be recycled. The Madagascan periwinkle
Catharanthus roseus L. is the source for a number of important natural products, including
catharanthine and
vindoline and the
vinca alkaloids it produces from them:
leurosine and the
chemotherapy agents
vinblastine and
vincristine, all of which can be obtained from the plant. The newer
semi-synthetic chemotherapeutic agent
vinorelbine is used in the treatment of
non-small-cell lung cancer and is not known to occur naturally. However, it can be prepared either from vindoline and catharanthine or from leurosine, Anhydrovinblastine is then reacted sequentially with
N-bromosuccinimide and
trifluoroacetic acid followed by
silver tetrafluoroborate to yield vinorelbine. -type reaction catalysed by Cp2TiCl Bis(cyclopentadienyl)titanium(III) chloride also effects both
Pinacol and
McMurry couplings of aldehydes and ketones.
Barbier-type reactivity is observed between aldehydes or ketones and allyl electrophiles under catalytic conditions. The proposed mechanism involves titanium(III)-mediated generation of an allyl radical species which intercepts a titanium(III)-coordinated carbonyl. Another application involves the single electron reduction of enones to generate allylic radicals which can undergo intermolecular trapping with acrylonitriles to afford
Michael type adducts. Benzylic and allylic alcohols can be de-oxygenated under mild conditions using super-stoichiometric Cp2TiCl, however the reported scope for aliphatic alcohols is currently limited. The complex transfers a single electron to the coordinated substrate generating an alkyl centered
radical and an oxygen bound titanium(IV) species. This process is driven by the strength of the titanium-oxygen bond, as well as strain release in the case of epoxides. == References ==