Titanocene(III) mediated 8-endo radical cyclizations for the synthesis of eight-membered cyclic ethers

Titanocene(III) chloride (Cp₂TiCl) mediated 8-endo radical cyclizations towards the synthesis of eight-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.     

Synthesis and reactivity of rhodium(III) pentamethylcyclopentadienyl complexes of N-B-PTA(BH3): X-ray crystal structures of [CpRhCl2{N-B}-PTA(BH3)] and [CpRh{N-B-PTA(BH3)}(η-CH2 = CHPh)]

The reaction between 1-boranyl-1,3,5-triaza-7-phosphaadamantane ligand N-B-PTA(BH₃) and [Cp^∗RhCl(μ-Cl)]₂ affords [Cp^∗Rh{N-B-PTA(BH₃)}Cl₂] (3) or [Cp_∗Rh{N-B-PTA(BH₃)}₂Cl]Cl (5) containing one or two P-bonded boronated PTA ligands. The hydride [Cp_∗Rh{N-B-PTA(BH₃)}H₂] (8) was also obtained by reaction of 3 with NaBH₄ and alternatively by direct hydroboration of [Cp^∗Rh(PTA)Cl₂] with excess NaBH₄. Moderately slow hydrolysis of the N-boranyl rhodium complexes affords dihydrogen, H₃BO₃ and the corresponding PTA derivatives, including the water-soluble dihydride [Cp^∗Rh(PTA)H₂] (9). Finally, the reaction of 8 with electron poor alkynes gives the alkene complexes [Cp^∗Rh{N-B-PTA(BH₃)}(η²-CH₂ = CHR)] (R = Ph, 10; C(O)OEt, 11) as a mixture of rotamers η²-coordinated to rhodium without affecting the N-BH₃ moiety. The X-ray crystal structures of 3 and 10 were also obtained and are here discussed.     

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.     

Synthesis and characterization of binuclear μ-oxo and μ-telluro molybdenum(V) complexes, [CpMo(O)(μ-Te)]2

Pyrolysis of an in-situ generated intermediate, produced in the reaction of [Cp^∗MoCl₄], 1, (Cp^∗ = η⁵-C₅Me₅) with [LiBH₄·THF], with an excess of difuryl ditelluride in toluene at 90 °C yielded syn and anti isomers of [Cp^∗Mo(O)(μ-Te)]₂ (2, 3) and [Cp^∗₂Mo₂O₂(μ-O)(μ-Te)] (4, 5). In a similar fashion, dibenzyl diselenide yielded syn and anti isomers of [Cp^∗Mo(O)(μ-Se)]₂ (6, 7), along with the known nido-[(Cp^∗Mo)₂B₄H₈Se₂]. Note that in parallel with 2-7, [(Cp^∗Mo)₂B₅H₉] was isolated as the major product in both cases. Compounds 2-7 have been isolated in modest yield as orange to brown crystalline solids. All the new compounds have been characterized in solution by mass, IR, ¹H, ¹³C, ⁷⁷Se and ¹²⁵Te NMR spectroscopy, and the structural types were unequivocally established by crystallographic analysis of 2-4 and 7.     

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.     

Synthesis and reactivity against Cp2TiCl of 4-isoprenyl-β-lactams. Trapping of N-titanoimidoyl radicals from cyanoformyl-2-azetidinones

A Staudinger reaction between methoxyketene and two different imines formed from citral afforded, after chemical transformation, the (E/Z)-4-alkenylepoxy-2-azetidinones 2, 3 and 4. These compounds, by reaction with Cp₂TiCl, did not cyclize to afford the expected polycyclic β-lactams, but the corresponding allylic alcohols 12, 13 and 15 were obtained instead. Unexpectedly, the treatment of cyanoepoxide (E)-3 with Cp₂TiCl also gave the hydroxyl aldehyde (E)-14 whose formation suggests to us that a possible radical reduction of the cyano group might have occurred, and we lastly succeeded in the capture of the N-titanoimidoyl radicals. The behaviour observed for the isoprenoid side chain in the Staudinger reaction, the reactions with Cp₂TiCl, as well as the trapping of N-titanoimidoyl radicals generated from benzocyanoformyl-2-azetidinones with the Ti(III) reagent, are discussed.     

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.     

Coloured liquid anion-exchangers

Of the several stable and coloured uninegative ions examined, trans-bis(dimethylglyoximato) dinitritocobaltate(III) ([Co(C₄H₇O₂)₂(NO₂)₂]^-, termed goldenate ion, G^-) can advantageously replace the erdmannate ion in the formation of a more photochemically stable coloured anion-exchanger derived from Aliquat-336 chloride. Quantitative spectrophotometric measurements of its displacement by chloride, bromide and perchlorate ions were made and are discussed together with literature data to examine the effect of parameters such as the nature of the cation and of the anion and change in the organic solvent on the relative and absolute values of extraction constants.     

Catalyst structural effects in titanocene-catalyzed pinacol coupling: activity,stereoselectivity and mechanistic implications

The effects of catalyst structural variation on the activity and selectivity of titanocene-catalyzed pinacol coupling of cyclohexane carboxaldehyde by Mn/TMSCl have been evaluated. Complexes which have been tested include: Cp₂TiCl₂ (1), Cp₂TiBr₂ (2), (C₅Me₅)₂TiCl₂ (3), (1,3-t-Bu₂C₅H₃)₂TiCl₂ (4), (1,3-t-Bu₂C₅H₃)(Cp)TiCl₂ (5), ansa-[(η⁵-tetrahydroindenyl)CH₂CH₂(η⁵-tetrahydroindenyl)]TiCl₂ (6), and ansa-[(η⁵-Cp)CH₂CH₂(η⁵-fluorenyl)]TiCl₂ (7). Cp₂TiCl₂ (1) is the most active (pre)catalyst for pinacol silylether (8a) formation, but Brintzinger's complex 6 provides the best dl/meso diastereoselectivity (5:1). Complexes 2, 4 and 7 slowly catalyze the predominant formation of the corresponding pinacol acetal 9a as a secondary product. Comparative stoichiometric reactions of benzaldehyde/Me₃SiCl with [Cp₂TiCl·MnCl₂(THF)₂·Cp₂TiCl] (10) and [Cp₂TiCl]₂ (11) result in highly diastereoselective pinacol silylether formation with binuclear 11 (29:1), but primarily the production of pinacol acetal (9b) from trimetallic 10, suggesting a dominant role for the binuclear complex (or derived mononuclear species) in the catalytic systems employing Cp₂TiCl₂/M/TMSCl, contrary to previous suggestions.     

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.     

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.     

Synthesis and structural characterization of a coordinatively unsaturated ruthenium complex,CpRu(Ph2nacnac), and its CO adduct

Two new half sandwich ruthenium complexes with 2-N-phenylamino-4-N-phenylimino-2-pentene (Ph₂nacnac) ligands have been synthesized and characterized. Single crystal X-ray diffraction analysis reveals the monomeric, highly air sensitive complex Cp^∗Ru(Ph₂nacnac) (4) has a coordinatively unsaturated structure and the coordination environment around Ru(II) is effectively a triangle made up of Ct(Cp^∗)–N(1)–N(2). An air stable complex Cp^∗Ru(Ph₂nacnac)(CO) (5) is prepared by reaction of 4 with CO, and has a pseudo-tetrahedral geometry around the Ru(II) center, made up of Ct(Cp^∗)–N(1)–N(2)–C(28).     

π-Coordination de doubles liaisons azoteazote et carboneazote sur les fragments Cp2NbH et Cp2TaH

The trihydrides Cp₂MH₃ (M = Nb, Ta) react with diphenyl diazomethane giving Cp₂M(diazo)H complexes in which the diazo molecule is η²-N,N-bonded to the metal. When Cp₂TaH₃ is treated with the isonitrile CNCMe₂CH₂C(Me)₃, the complex Cp₂Ta[CH(CN)NR]H (R = CMe₂CH₂CMe₃) is obtained which contains an η²-coordinated CN bond.     

Synthesis and crystal structures of two (cyclopentadienyl)titanium(III) hydroborate complexes, [CpTiCl(BH4)]2 and Cp2Ti(B3H8)

Treatment of Cp^∗TiCl₃ and Cp₂TiCl₂ with NaB₃H₈ affords the titanium(III) hydroborate compounds [Cp^∗TiCl(BH₄)]₂ and Cp₂Ti(B₃H₈), respectively. The former compound arises by means of a new reaction, the metal-induced fragmentation of the B₃H₈ anion, and can also be made by treating Cp^∗TiCl₃ with LiBH₄. The latter compound has been previously described, but not characterized crystallographically. Both compounds have been studied by single crystal X-ray diffraction. Dimeric [Cp^∗TiCl(BH₄)]₂ has bridging chloride ligands and terminal Cp^∗ and BH₄ ligands. The Ti-Ti distance is 3.452(1) Å, which indicates that there is no metal-metal bonding interaction. The Ti-Cl distances are 2.440(2) Å and the Ti-Cl-Ti and Cl-Ti-Cl angles of 89.97(8) and 90.03(8)° so that the Ti₂Cl₂ unit is nearly a perfect square. The BH₄ groups are each tridentate, with a Ti-B distance of 2.220(9) Å and an average Ti-H distance of 1.98(5) Å. In Cp₂Ti(B₃H₈), the B₃H₈ ligand is bidentate, as is usually seen, and the Ti-B and Ti-H distances are 2.600(3) and 1.96(2) Å. The dihedral angle between the Ti-B(1)-B(2) plane and the B(1)-B(2)-B(3) plane is 123.4°. The Ti-B distances are 0.04 Å longer than those in niobium analog, Cp₂Nb(B₃H₈), despite the fact that the single bond metallic radius of Ti is 0.02 Å smaller than that of Nb. This lengthening of the bond is probably a consequence of the presence of one fewer skeletal bonding electron in Cp₂Ti(B₃H₈).