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Bis(cyclopentadienyl)titanium(III) chloride

Bis(cyclopentadienyl)titanium(III) chloride, also known as the Nugent–RajanBabu reagent, is the organotitanium compound which exists as a dimer with the formula [(C5H5)2TiCl]2. It is an air sensitive green solid. The complex finds specialized use in synthetic organic chemistry as a single electron reductant.

In the presence of a suitable solvent that can act as a two-electron donor ("solv"), such as an ether like tetrahydrofuran, the dimer separates and forms a chemical equilibrium between the forms [(C5H5)2TiCl] and [(C5H5)2Ti(solv)Cl]. It is these forms that are responsible for much of the chemical properties of this reagent, which is also the reason that the substance is sometimes written as [(C5H5)2TiCl] or [Cp2TiCl], where Cp− represents the cyclopentadienyl anion.

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.

Synthesis and structure

It was first reported in 1955 by Geoffrey Wilkinson[1] It is commonly prepared by reducing titanocene dichloride with zinc,[2] manganese, or magnesium.[3] For use in organic synthesis, the reagent is often prepared and used directly in situ.[4]

The molecule adopts a dimeric structure with bridging chlorides,[5] though in an appropriate solvent such as THF,[4] exists in a chemical equilibrium with monomeric structures:[5]

Nugent–RajanBabu reagent synthesis and equilibrium in solution
The calculated spin density of the ground state singlet biradical (broken symmetry density functional theory, TPSSh/def2-TZVP).

The molecule has been measured to be an open shell singlet with a J-coupling constant of -138 cm−1.[5]

The compound is also known as the Nugent–RajanBabu reagent, after scientists William A. Nugent and T. V. (Babu) RajanBabu, and has found applications in free radical and organometallic chemistry.[6]


Use in organic synthesis

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.[7] As can be seen in the above illustration, subsequent reaction proceeds along a pathway determined by added reagents and reaction conditions:[8]

The reagent has been used in the synthesis of over 20 natural products.[6][7][14] Ceratopicanol is a naturally-occurring sesquiterpene and its carbon skeleton is incorporated with the structures of both anislactone A and merrilactone A.[8][14] A regioselective epoxide opening and 5-exo dig radical cyclization to forge the core of ceratopicanol.[14][18] Addition of a hydrochloride salt to the reaction facilitates release of the oxygen-bound titanium(IV) intermediate, allowing the reagent to be recycled.[19]

The Madagascan periwinkle Catharanthus roseus L. is the source for a number of important natural products, including catharanthine and vindoline[20] 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.[8][21][22][23] The newer semi-synthetic chemotherapeutic agent vinorelbine is used in the treatment of non-small-cell lung cancer[22][24] and is not known to occur naturally. However, it can be prepared either from vindoline and catharanthine[22][25] or from leurosine,[26] in both cases by synthesis of anhydrovinblastine, which "can be considered as the key intermediate for the synthesis of vinorelbine."[22] The leurosine pathway uses the Nugent–RajanBabu reagent in a highly chemoselective de-oxygenation of leurosine.[14][26] Anhydrovinblastine is then reacted sequentially with N-bromosuccinimide and trifluoroacetic acid followed by silver tetrafluoroborate to yield vinorelbine.[25]

Additional reactivity

Cyclic and benzylic ketones are reduced to their respective alcohols.[27]

Example of Barbier-type reaction catalysed by Cp2TiCl

Bis(cyclopentadienyl)titanium(III) chloride also effects both Pinacol[28][29] and McMurry[30] couplings of aldehydes and ketones. Barbier-type reactivity is observed between aldehydes or ketones and allyl electrophiles under catalytic conditions.[31] 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.[32] 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.[30]

Catalytic modification: addition of a mildly acidic HCl salt promotes cleavage of the TiIV–O bond and allows regeneration of Cp2TiIIICl using a stoichiometric reductant

Mechanism

The dimeric titanium(III) complex reversibly dissociates to the monomer Cp2TiCl. This 15 electron species is Lewis acidic and thus binds epoxides and carbonyl compounds.[33] 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.[34]

References

  1. ^ Birmingham, J. M.; Fischer, A. K.; Wilkinson, G. (1955). "The reduction of bis-cyclopentadienyl compounds". Naturwissenschaften. 42 (4): 96. Bibcode:1955NW.....42Q..96B. doi:10.1007/BF00617242. S2CID 44523847.
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    This review article was corrected to refer to the "Nugent–RajanBabu Reagent" rather than the "Nugent Reagent" by:
    Rosales, Antonio; Rodríguez-Garcia, Ignacio; Muñoz-Bascón, Juan; Roldan-Molina, Esther; Padial, Natalia M.; Morales, Laura P.; García-Ocaña, Marta; Oltra, J. Enrique (2015). "The Nugent–RajanBabu Reagent: A Formidable Tool in Contemporary Radical and Organometallic Chemistry". European Journal of Organic Chemistry. 2015 (21): 4592. doi:10.1002/ejoc.201500761.
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