Titanocene(III) mediated radical cyclizations of epoxides for the synthesis of medium-sized cyclic ethers

Titanocene(III) chloride (Cp₂TiCl) mediated 7-exo and 8-endo radical cyclizations of epoxides towards the synthesis of 7- and 8-membered cyclic ethers have been described. Titanocene(III) chloride was prepared in situ from commercially available titanocene dichloride (Cp₂TiCl₂) and activated zinc dust in THF.     

Titanocene (III) chloride mediated radical induced synthesis of (−)-methylenolactocin and (−)-protolichesterinic acid

Enantioselective synthesis of two anti-tumor antibiotics, (−)-methylenolactocin and (−)-protolichesterinic acid, has been achieved through titanocene(III) chloride mediated radical cyclization reaction starting from commercially available d-mannitol. Titanocene(III) chloride (Cp₂TiCl) was prepared in situ from commercially available titanocene dichloride (Cp₂TiCl₂) and zinc dust in THF.     

Titanocene(III) chloride mediated radical induced asymmetric synthesis of α-methylene bis-γ-butyrolactone

Asymmetric synthesis of α-methylene bis-γ-butyrolactone has been synthesized using titanocene(III) chloride as a radical source. Titanocene(III) chloride (Cp₂TiCl) was prepared in situ from commercially available titanocene dichloride (Cp₂TiCl₂) and zinc dust in THF.     

Proliferative and anti-proliferative effects of titanium- and iron-based metallocene anti-cancer drugs

In previous work we have found that Cp₂TiCl₂ and its corresponding derivative of tamoxifen, Titanocene tamoxifen, show an unexpected proliferative effect on hormone dependent breast cancer cells MCF-7. In order to check if this behavior is a general trend for titanocene derivatives we have tested two other titanocene derivatives, Titanocene Y and Titanocene K, on this cell line. Interestingly, these two titanocene complexes behave in a totally different manner. Titanocene K is highly proliferative on MCF-7 cells even at low concentrations (0.5 μM), thus behave almost similarly to Cp₂TiCl₂. This proliferative effect is also observed in the presence of bovine serum albumin (BSA). In contrast, Titanocene Y alone has almost no effect on MCF-7 at a concentration of 10 μM, but exhibits a significant dose dependent cytotoxic effect of up to 50% when incubated with BSA (20-50 μg/mL). This confirms the crucial role played by the binding to serum proteins in the expression of the in vivo, cytotoxicity of the titanocene complexes. From the hydridolithiation reaction of 6-p-anisylfulvene with LiBEt₃H followed by transmetallation with iron dichloride [bis-[(p-methoxy-benzyl)cyclopentadienyl]iron(II)] (Ferrocene Y) was synthesised. This complex, which was characterised by single crystal X-ray diffraction, contains the robust ferrocenyl unit instead of Ti associated with easily leaving groups such as chlorine and shows only a modest cytotoxicity against MCF-7 or MDA-MB-231 cells.     

Formation of conjugated dienes by the reaction of titanocene alkenylidene complexes with alkynes

Titanocene alkenylidene complexes, generated by the reductive metallation of 1,1-dichloro-1-alkenes with the titanocene(II) species Cp₂Ti[P(OEt)₃]₂, reacted with alkynes to produce conjugated dienes.     

Free radical-promoted conjugate addition of activated bromo compounds using titanocene(III) chloride as the radical initiator

Free radical-promoted conjugate addition of activated bromo compounds to α,β-unsaturated ketones and reactive α,β-unsaturated esters has been described using titanocene(III) chloride (Cp₂TiCl) as the radical initiator. Cp₂TiCl was prepared in situ from commercially available Cp₂TiCl₂ and activated zinc dust in THF.     

Radical-mediated synthesis of 3,4-dihydroisocoumarins: total synthesis of hydrangenol

A radically promoted synthesis of 3,4-dihydroisocoumarins has been achieved in moderate to good yields using titanocene(III) chloride (Cp₂TiCl) as the radical initiator. The total synthesis of (±)-hydrangenol has been completed using this radical technology. Cp₂TiCl was prepared in situ from commercially available titanocene dichloride (Cp₂TiCl₂) and Zn-dust in THF under argon.     

Titanocene(III) chloride mediated radical-induced synthesis of 3,4-dihydroisocoumarins: synthesis of (±)-hydrangenol, (±)-phyllodulcin, (±)-macrophyllol and (±)-thunberginol G

A radical-promoted synthesis of 3,4-dihydroisocoumarins has been achieved in moderate to good yields using titanocene(III) chloride (Cp₂TiCl) as the radical initiator. The total synthesis of four naturally occurring dihydrocoumarins hydrangenol, phyllodulcin, macrophyllol and thunberginol G has been accomplished using the radical technology. Cp₂TiCl was prepared in situ from commercially available titanocene dichloride (Cp₂TiCl₂) and Zn-dust in THF under argon.     

Radical promoted cyclizations of aromatic carbonyl compounds to benzopyrans using titanocene(III) chloride

Aromatic carbonyl compounds undergo smooth intramolecular radical cyclization with alkenes or alkynes using titanocene(III) chloride to furnish the corresponding benzopyrans. The radical initiator, Cp₂TiCl, was prepared in situ from commercially available titanocene dichloride (Cp₂TiCl₂) and zinc dust in THF under argon.     

Titanocene(III) chloride mediated radical-induced one-pot synthesis of α-methylene-γ-butyrolactones

A simple and efficient methodology has been developed for the one-pot preparation of α-methylene-γ-butyrolactones by free-radical induced Barbier-type reaction of methyl 2-(bromomethyl)acrylate and aldehydes followed by in situ lactonization. The radical initiator titanocene(III) chloride (Cp₂TiCl) was easily generated in situ from commercially available Cp₂TiCl₂ and activated zinc dust in THF. Ketones remained unaffected under the reaction conditions.     

Polymerization of 1,3-butadiene, 4-methyl-1,3-pentadiene and styrene with catalyst systems based on biscyclopentadienyl derivatives of titanium

1,3-Butadiene, 4-methyl-1,3-pentadiene and styrene were polymerized with dicyclopentadienyltitanium dichloride/methylaluminoxane (Cp₂TiCl₂/MAO) and dicyclopentadienyltitanium chloride/MAO (Cp₂TiCl/MAO). These systems are less active than cyclopentadienyltitanium trichloride/MAO (CpTiCl₃/MAO), but show the same stereospecificity as the latter; they give predominantly cis-1,4-polybutadiene, 1,2-syndiotactic poly(4-methyl-1,3-pentadiene) and syndiotactic polystyrene. Cp₂TiCl/MAO is much more active than Cp₂TiCl₂/MAO; this is probably due to the fact that in the reaction of Cp₂TiCl₂ with MAO, only a small amount of Ti(IV) is reduced to Ti(III), which is the active species in the polymerization of styrene and 1,3-dienes. An interpretation of the structure of the active species in Cp₂TiCl/MAO is reported.     

The importance of steric factors in the formation and structures of heterobinuclear wedge-like sandwich derivatives. The crystal and molecular structure of niobocenehydrido-(σ,π-cyclopentadienylidene)iron(dicarbonyl)(Nb—fe)

CpFe(CO)₂CH₃ reacts with Cp₂NbH made from Cp₂NbBH₄ and Et₃N to give Cp₂$\text{NbH(μ-C}{}_5\text{H}{}_4\text{)F}$e (III). As shown by X-ray diffraction, III contains the Cp₂NbH sandwich fragment with a 46.8° angle between the rings linked with the dicarbonyliron moiety by the NbFe bond (2.968 Å), observed for the first time, and a cyclopentadienyl bridge C₅H₄, involving the NbC. σ-bond (2.189 Å) and C₅H₄Fe π-bond (2.085 Å). A probable reaction scheme leading to III and general patterns of formation of other heterobinuclear derivatives of sandwich complexes Cp₂MLM′(L′)n are discussed. The importance of steric effects due to nonbonded interligand interactions between the M′(L′)n fragment and the sandwich system is emphasized. Increase of steric strain in the binuclear system facilitates its unusual transformations.     

Host-Guest Interactions between Calixarenes and Cp(2)NbCl(2)

The possible inclusion complexes of Cp₂NbCl₂ into calixarenes hosts have been investigated. The existence of a true inclusion complex in the solid state was confirmed by a combination of NMR, ab-initio calculations, thermogravimetric analysis, FTIR, Raman and PXRD. Ab-initio calculations, ¹H NMR solution and solid state ¹³C CP-MAS NMR results demonstrated that p-sulfonic calix[6]arene does form an inclusion complex with Cp₂NbCl₂. Raman spectroscopy showed, for the inclusion compound of p-sulfonic calix[6]arene-Cp₂NbCl₂, a band between 500 and 850 cm⁻¹ characteristic of Nb-O vibration. This result suggests that Nb(V) may engage in coordination with the oxygen of the sulfonate group, as part of the host-guest interaction. However, it is important to mention that the niobocene dichloride (Cp₂NbCl₂) dissolves in water and undergoes oxidation and hydrolysis processes to yield Cp₂NbCl₂(OH) species. For that reason this band does not exclude that the Nb-O band belongs to Cp₂NbCl₂(OH). Solid State ¹³C CP-MAS NMR and solution ¹H NMR spectroscopies together with ab-initio results showed that Cp₂NbCl₂ is included in the p-sulfonic calix[6]arene cavity, with both Cp rings inside the cavity. In contrast, the solution ¹H NMR results demonstrated that calix[6]arene does not form inclusion complex with Cp₂NbCl₂ in CDCl₃ solution. Cp₂NbCl₂ is not included in the calix[6]arene cavity, possibly due to the lack of sulfonate heads which promote Nb-O interactions and assist the inclusion of Cp₂NbCl₂ into the cavity.     

Reactions of Ru(Cp) complexes with P(o-tolyl)3

Reaction of [Ru(Cp^∗)(CH₃CN)₃](PF₆) with P(o-tolyl)₃ affords [Ru(Cp^∗){(η⁶-o-tolyl)P(o-tolyl)₂}](PF₆) (4) in which the P-atom is not coordinated to the metal. The solid-state structure of 4 has been determined. A related reaction with P(p-tolyl)₃ reveals a small quantity [Ru(Cp^∗){(η⁶-p-tolyl)P(o-tolyl)₂}](PF₆), in solution, but mostly the expected bis-phosphine complex. Reaction of the Ru(IV) dication, [Ru(Cp^∗)(η³-PhCHCHCH₂)(DMF)₂](PF₆)₂, with P(o-tolyl)₃ gives a mixture of the phosphonium salt, C₆H₅CHCHCH₂P(o-tolyl)₃ (9) and the dication [Ru(Cp^∗) (η⁶-C₆H₅CHCHCH₂P(o-tolyl)₃)](PF₆)₂ (10). Salt 9 forms via attack of the P-atom on the allyl ligand. The latter product results from complexation of 9 via the phenyl group of the former allyl ligand. It would seem that the sterically demanding P(o-tolyl)₃ ligand is not readily compatible with the Ru(Cp^∗) fragment, in either the +2 or +4 oxidation state. Detailed NMR studies are reported.     

New effective reagent [Cp2ZrH2 · ClAlEt2]2 for alkene hydrometallation

New bimetallic complex [Cp₂ZrH₂ · ClAlEt₂]₂ (1) was synthesized, and its reactivity in hydrometallation reaction with the following alkenes was studied: hept-1-ene, okt-1-ene, α-methylstyrene, (1S)-β-pinene, (+)-camphene. Complex 1 shows the highest reactivity among the other known Al,Zr-bimetallic complexes: [Cp₂ZrH₂ · ClAlBuⁱ₂]₂ (2), [Cp₂ZrH₂ · AlEt₃]₂ (3), [Cp₂ZrH₂ · AlBuⁱ₃]₂ (4) and [Cp₂ZrH₂ · HAlBuⁱ₂] (5) as well as organoaluminium compounds (OAC): ⁱBu₂AlH, ⁱBu₃Al and ⁱBu₂AlCl in presence of Zr catalysts. Chlorine containing complexes 1 and 2 appear to be more effective in alkene hydrometallation, and relative hydrometallation rates are (1S)-β-pinene ? (+)-camphene < α-methylstyrene < oct-1-ene < hept-1-ene. Hydrometallation of (1S)-β-pinene and its subsequent oxidation with I₂ run with high diastereoselectivity and yield trans-myrtanol. However, the diastereoselectivity of (+)-camphene hydrometallation is less than that for (1S)-β-pinene, and the reaction gives predominately endo-camphanol.     

Syntheses and properties of NCN-bridged tri- and tetranuclear complexes of cobalt and rhodium

The reaction of [Cp¹CoI₂]₂ (1b) with 2 equiv of NaNCNH affords the 16-membered macrocyclic NCNH-bridged tetracobalt(III) complex [Cp¹CoI(μ₂-NCNH-N,N′)]₄ (2b), while that with 2 equiv of Na₂NCN yields the C₃-elongated cubane-like NCN-bridged tetracobalt(III) complex [Cp¹Co(μ₃-NCN-N,N,N′)₃(CoCp¹)₃(μ₃-NCN-N,N,N)] (4b). Treatment of [Cp¹RhCl₂]₂ (1c) with 2 equiv of NaNCNH gives the C₃-elongated cubane-like tetrarhodium(III) complex [Cp¹Rh(μ₃-NCN-N,N,N′)₃(RhCp¹)₃(μ₃-NCN-N,N,N)] (4c) via the macrocyclic complex [Cp¹RhCl(μ₂-NCNH-N,N′)]₄ (2c). On the other hand, the reaction of [Cp¹CoCl]₂ (7) with Na₂NCN affords the anionic bis(NCN)-capped tricobalt(II) complex Na[(Cp¹Co)₃(μ₃-NCN-N,N,N)₂] (6). The molecular structures of complexes 2b · CH₂Cl₂ and 4c · 2C₆H₆ have been confirmed by X-ray analyses. The electrochemical properties of these types of NCN-bridged group 9 metal complexes have also been examined.     

Nichtklassische organolanthanoid(II)komplexe: Darstellung und reaktivität der ersten organoneodym(II)verbindung

NdCl₂(THF)₂ reacts with KCp to give [K(THF)_n]₂[Cp₂NdCl₂] (1) which represents the first divalent organoneodymium complex. Treatment of 1 with ^tBuCl, [Me₂NC(S)S]₂ or MesSeSeMes affords the organoneodymium(III) complexes Cp₂NdCl(THF) (2), Cp₂Nd(S₂CNMe₂) (3) and Cp₂NdSeMes(THF) (4) (Cp = η⁵- pentamethylcyclopentadienyl).     

The structure and formation of niobocene carbonyl heteronuclear derivatives. The molecular structures of Cp2Nb(CO)(μ-CO)Mn(CO)4, Cp2Nb(CO)(μ-H)Ni(CO)3 and [Cp2Nb(CO)(μ-H)]2Mo(CO)4

The heteronuclear Cp₂Nb(CO)(μ-CO)Mn(CO)₄ (I), Cp₂Nb(CO)(μ-H)Ni(CO)₃ (II) and [Cp₂Nb(CO)(μ-H)]₂M(CO)₄ (III, M = Mo;IV, M = W) complexes were prepared by reaction of Cp₂NbBH₄/Et₃N with Mn₂(CO)₁₀ in refluxing toluene, direct reaction of Cp₂NbBH₄ with Ni(CO)₄ in ether, and reaction of Cp₂NbBH₄/Et₃N with M(CO)₅. THF complexes (M = Mo or W) in THF/benzene mixture. An X-ray investigation of compounds I–III was performed. It is established that in I the bonding between Mn(CO)₅ and Cp₂Nb(CO) (with the angle (α) between the ring planes being 44.2(5)°) fragments takes place via a direct NbMn bond (3.176(1) Å) and a highly asymmetric carbonyl bridge (MnC_co 1.837(5) Å, NbC_co 2.781(5) Å). On the other hand, in complex II the sandwich Cp₂Nb(CO)H molecule (angle α = 37.8°) is combined with the Ni(CO)₃ group generally via a hydride bridge (NbH 1.83 Å, NiH 1.68 Å, NbHNi angle 132.7°) whereas the large Nb?Ni distance, 3.218(1) Å, shows the weakening or even absence of the direct NbNi bond. Similarly, in complex III two Cp₂Nb(CO)H molecules (with α angles equal to 41.4 and 43.0°, respectively) are joined to the Mo(CO)₄ group via the hydride bridges (NbH 1.83 and 1.75 Å and MoH 2.04 and 2.06 Å) producing a cis-form. The direct NbMo bonds are probably absent, since the Nb?Mo distances are rather long (3.579 and 3.565 Å). The effect of electronic and steric factors on the structure of heteronuclear niobocene carbonyl derivatives is discussed.     

Titanocene dichloride/KI: an efficient catalytic system for synthesis of cyclic carbonates from epoxides and CO2

Titanocene dichloride (Cp₂TiCl₂)/KI was developed to be an efficient catalytic system for the cycloaddition of CO₂ to epoxides to synthesize relevant cyclic carbonates from epoxides and CO₂. Various influencing factors on the coupling reaction, such as co‐catalyst, temperature, CO₂ pressure and reaction time, were investigated. The optimal reaction conditions were KI as co‐catalyst, 150 °C reaction temperature, 12 atm CO₂ pressure and 4 h reaction time using THF as solvent for the synthesis of propylene carbonate in 98% yield. Copyright © 2013 John Wiley & Sons, Ltd.     

Reactivity of the 30-electron dimolybdenum anion [Mo2(η-C5H5)2(μ-PCy2)(μ-CO)2] towards β,γ-unsaturated organic halides: Alkenyl, allenyl and alkoxycarbyne derivatives

The 30-electron dimolybdenum anion [Mo₂Cp₂(μ-PCy₂)(μ-CO)₂]⁻ reacts at room temperature with allyl chloride to give the unsaturated σ:π-bonded alkenyl derivative trans-[Mo₂Cp₂(μ-η¹:η²-CMeCH₂)(μ-PCy₂)(CO)₂], this requiring a 2,1-hydrogen shift in the allyl moiety probably induced by the unsaturated nature of the dimetal center. In a similar way, the dimolybdenum anion reacts with trans-1-chloro-2-butene (crotyl chloride) to give a mixture of the alkenyl complexes trans-[Mo₂Cp₂(μ-η¹:η²-CEtCH₂)(μ-PCy₂)(CO)₂] and trans-[Mo₂Cp₂(μ-η¹:η²-CMeCHMe)(μ-PCy₂)(CO)₂] in a 3:2 ratio, which could not be separated by column chromatography. All these alkenyl species exhibit a dynamic behavior in solution (fast on the NMR timescale even at low temperatures) involving alternative π-bonding of the alkenyl ligand to each metal center. In contrast, the title anion reacts with propargyl chloride (ClCH₂-CCH) without further rearrangement of the propargyl moiety, to afford the allenyl derivative trans-[Mo₂Cp₂{μ-η²:η³-CH₂CCH)}(μ-PCy₂)(CO)₂] as the major species. Acryloyl chloride (ClC(O)-CHCH₂) also reacts with the title anion to give a mixture of two products, the carbyne complex [Mo₂Cp₂{μ-COC(O)CHCH₂}(μ-PCy₂)(μ-CO)] and the vinyl trans-[Mo₂Cp₂(μ-η¹:η²-CHCH₂)(μ-PCy₂)(CO)₂], in a 1:1 ratio. This reaction is a unique case in which a single electrophile can attack both nucleophilic positions in the dimolybdenum anion, these being located at the O(carbonyl) and metal sites, respectively. The formation of the vinyl derivative requires the decarbonylation of a metal-bound acryloyl group, which proved to be an irreversible reaction, since the addition of CO to the above alkenyl complex gave instead the tricarbonyl vinyl derivative cis-[Mo₂Cp₂(μ-η¹:η²-CHCH₂)(μ-PCy₂)(CO)₃]. The structure of this electron-precise complex was confirmed through a single-crystal X-ray diffraction analysis (Mo−Mo = 3.0858(7) Å).