Bis(cyclopentadienyl)titanium(III) chloride, also known as theNugent–RajanBabu reagent, is theorganotitanium compound which exists as adimer with the formula [(C5H5)2TiCl]2. It is an air sensitive green solid. The complex finds some use insynthetic organic chemistry as a single electronreductant.[1]
In the presence of a suitable solvent that can serve as atwo-electron donor ("solv"), such as anether liketetrahydrofuran, the dimer separates and forms achemical equilibrium between the forms [(C5H5)2TiCl]2 and [(C5H5)2Ti(solv)Cl]. It is these forms that are responsible for much of the chemical properties of thisreagent, which is also the reason that the substance is sometimes written as [(C5H5)2TiCl] or [Cp2TiCl], where Cp− represents thecyclopentadienyl anion.
Nugent–RajanBabu reagent synthesis and equilibrium in solutionThe calculated spin density of the ground state singlet biradical (broken symmetry density functional theory, TPSSh/def2-TZVP).
The molecule has been measured to be anopen shell singlet with a J-coupling constant of -138 cm−1.[6]
Bis(cyclopentadienyl)titanium(III) chloride effects theanti-Markovnikov opening ofepoxides to afree radical intermediate and is tolerant of alcohols and some basic nitrogen functional groups, however it is sensitive to oxidizing functional groups such asnitro groups.[8] As can be seen in the above illustration, subsequent reaction proceeds along a pathway determined by added reagents and reaction conditions:[9]
In the presence of hydrogen atom donors, such as1,4-cyclohexadiene,[10]tBuSH,[11] water,[12] the intermediate is protonated to analcohol product. This transformation provides the complementary regioisomer to that of an epoxide opening using a metal hydride;[8] in particular, the use oflithium aluminium hydride to form the Markovnikov alcohol and particularly axial cyclohexanols fromepoxycyclohexanes is well known.[13][14]
Reaction of the intermediate with a second equivalent of Cp2TiCl traps the radical as an alkyl-titanium(IV) species which can either undergoβ-hydride elimination (favoured for 3° species) or dehydration via β-alkoxy elimination; in both cases anolefin product is generated.[8][9][15]
The radical intermediate can also be trappedintramolecularly when an appropriate acceptormoiety (such as an alkene, alkyne, carbonyl, etc.) is present in the epoxide. Synthesis of natural products with multiple ring systems have taken advantage of this pathway.[15] Intermolecular trapping ofacrylates andacrylonitriles with radicals derived fromepoxides is possible,[16] as well as conjunctive intra-intermolecular variants.[17]
The reagent has been used in the synthesis of over 20 natural products.[7][8][15]Ceratopicanol is a naturally occurringsesquiterpene and its carbon skeleton is incorporated with the structures of bothanislactone A andmerrilactone A.[9][15] A regioselective epoxide opening and 5-exo dig radical cyclization to forge the core of ceratopicanol.[15][19] Addition of a hydrochloride salt to the reaction facilitates release of the oxygen-bound titanium(IV) intermediate, allowing the reagent to be recycled.[20]
Example ofBarbier-type reaction catalysed by Cp2TiCl
Bis(cyclopentadienyl)titanium(III) chloride also effects bothPinacol[29][30] andMcMurry[31] couplings of aldehydes and ketones.Barbier-type reactivity is observed between aldehydes or ketones and allyl electrophiles under catalytic conditions.[32] 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 affordMichael type adducts.[33] 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.[31]
Catalytic modification: addition of a mildly acidic HCl salt promotes cleavage of theTiIV–O bond and allows regeneration ofCp2TiIIICl using a stoichiometric reductant
The dimeric titanium(III) complex reversibly dissociates to the monomer Cp2TiCl. This 15 electron species isLewis acidic and thus binds epoxides and carbonyl compounds.[34] The complex transfers a single electron to the coordinated substrate generating an alkyl centeredradical 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.[35]
^Martínez, Antonio Rosales; Morales, Laura Pozo; Ojeda, Emilio Díaz; Rodríguez, María Castro; Rodríguez-García, Ignacio (2021). "The Proven Versatility of Cp2TiCl".The Journal of Organic Chemistry.86 (2):1311–1329.doi:10.1021/acs.joc.0c01233.hdl:10835/18354.PMID33147037.
^Barrero, Alejandro F.; Oltra, J. Enrique; Cuerva, Juan M.; Rosales, Antonio (2002). "Effects of solvents and water in Ti(III)-mediated radical cyclizations of epoxygermacrolides. Straightforward synthesis and absolute stereochemistry of (+)-3α-hydroxyreynosin and related eudesmanolides".Journal of Organic Chemistry.67 (8):2566–2571.doi:10.1021/jo016277e.PMID11950302.
^Rickborn, Bruce; Quartucci, Joe (1964). "Stereochemistry and mechanism of lithium aluminum hydride and mixed hydride reduction of 4-t-butylcyclohexene oxide".Journal of Organic Chemistry.29 (11):3185–3188.doi:10.1021/jo01034a015.
^Rickborn, Bruce; Lamke, Wallace E. (1967). "Reduction of epoxides. II. The lithium aluminum hydride and mixed hydride reduction of 3-methylcyclohexene oxide".Journal of Organic Chemistry.32 (3):537–539.doi:10.1021/jo01278a005.
^Clive, D. L. J.; Magnuson, Steven R.; Manning, Hartford W.; Mayhew, Darrin L. (1996). "Cyclopentannulation by an iterative process of sequential Claisen rearrangement and enyne radical closure: Routes to triquinane and propellane systems and use in the synthesis of (±)-ceratopicanol".Journal of Organic Chemistry.61 (6):2095–2108.doi:10.1021/jo951930h.
^abNgo, Quoc Anh; Roussi, Fanny; Cormier, Anthony; Thoret, Sylviane; Knossow, Marcel; Guénard, Daniel; Guéritte, Françoise (2009). "Synthesis and biological evaluation ofVinca alkaloids and phomopsin hybrids".Journal of Medicinal Chemistry.52 (1):134–142.doi:10.1021/jm801064y.PMID19072542.
^abHardouin, Christophe; Doris, Eric; Rousseau, Bernard; Mioskowski, Charles (2002). "Concise synthesis of anhydrovinblastine from leurosine".Organic Letters.4 (7):1151–1153.doi:10.1021/ol025560c.PMID11922805.
^Barrero, Alejandro F.; Rosales, Antonio; Cuerva, Juan M.; Gansäuer, Andreas; Oltra, J. Enrique (2003). "Titanocene-catalysed, selective reduction of ketones in aqueous media. A safe, mild, inexpensive procedure for the synthesis of secondary alcohols via radical chemistry".Tetrahedron Letters.44 (5):1079–1082.doi:10.1016/S0040-4039(02)02703-X.
^Gansäuer, Andreas (1997). "Pinacol coupling of aromatic aldehydes catalysed by a titanocene complex: A transition metal catalysed radical reaction".Chemical Communications.1997 (5):457–458.doi:10.1039/A608438I.
^Paradas, Miguel; Campaña, Araceli G.; Estévez, Rosa E.; Cienfuegos, Luis Álvarez de; Jiménez, Tania; Robles, Rafael; Cuerva, Juan M.; Oltra, J. Enrique (2009). "Unexpected TiIII/Mn-promoted pinacol coupling of ketones".Journal of Organic Chemistry.74 (9):3616–3619.doi:10.1021/jo9005238.PMID19334701.
^abDiéguez, Horacio R.; López, Armando; Domingo, Victoriano; Arteaga, Jesús F.; Dobado, José A.; Herrador, M. Mar; Moral, José F. Quílez del; Barrero, Alejandro F. (2010). "Weakening C—O bonds: Ti(III), a new reagent for alcohol deoxygenation and carbonyl coupling olefination".Journal of the American Chemical Society.132 (1):254–259.doi:10.1021/ja906083c.PMID20000601.
^Rosales, Antonio; Oller-López, Juan L.; Justicia, José; Gansäuer, Andreas; Oltra, J. Enrique; Cuerva, Juan M. (2004). "Unprecedented Barbier-type reactions catalysed by titanocene(III)".Chemical Communications.2004 (22):2628–2629.doi:10.1039/B411173G.PMID15543313.
