Titanocene dichloride,

The titanocene dichloride complexes derived from the camphor- and pinene-annulated ligands 126 and 127 were tested as enantioselective hydrogenation catalyst and using 2-phenylbutene as substrate 2-phenylbutane was obtained with ee up to 34% [148, 149]. 

Mit Titanocen-dichlorid/Natrium werden dagegen Alkane und als Nebenprodukte A1 kohole erhalten1 (Vorsicht Der bei der Aufarbeitungentstehende graue Niederschlag aus Titan-Polymeren ist an der Luft selbstentziindlich). 

Das Reduktionspaar Titanocen-dichlorid/Natrium in Benzol ist zur Reduktion von Carbonsaure-estern zu Alkanen hervorragend geeignet4 ... 

Oxirane werden ebenfalls durch Titanocen-dichlorid/Natrium in Benzol zu Alkanen und Alkoholen (Nebenprodukt) reduziert (vgl. a.S.547) ... 

The reagent titanocene dichloride reduces carboxylic esters in a different manner from that of 10-86, 19-36, or 19-38. The products are the alkane RCH3 and the alcohol R OH. The mechanism probably involves an alkene intermediate. Aromatic acids can be reduced to methylbenzenes by a procedure involving refluxing first with trichlorosilane in MeCN, then with tripropylamine added, and finally with KOH and MeOH (after removal of the MeCN). The following sequence has been suggested ... 

Though the usual product of epoxide reductions is the alcohol (10-85), epoxides are reduced all the way to the alkane by titanocene dichloride and Et3SiH-BH3. ... 

Reduction of carboxylic esters with titanocene dichloride... 

In 1985, Eisch et al. isolated a cationic alkenyltitanium complex (55) by the insertion of an alkyne into the cationic Ti-C bond generated from titanocene dichloride and methylaluminum dichloride (Eq. 2) [77], Similarly, a mixture of Cp2TiCl(CH2SiMe3) and A1C13 afforded the solvent-separated ion pairs,... 

Therefore, we derided to initiate a program directed towards the development of a tita-nocene-catalyzed epoxide opening [3c]. Since titanocene dichloride is formed in the stoichiometric reaction after the protic quench, the challenge to be met is the regeneration of the redox-active species in situ, the fundamental requirement for a catalytic reaction. This underlying problem is depicted in Scheme 12.12. 

The opening of a, (3-epoxy ketones, as recently reported by Doris et al., can also be carried out with catalytic amounts of titanocene dichloride [16]. Thus, the relatively sensitive (3-hydroxy ketones are also readily tolerated under the catalytic conditions. 

The problem of diastereoselectivity in additions to cyclic radicals arising from the opening of bi- or tricyclic epoxides, e. g. cycloheptene oxide or norbornene oxide, has been addressed only recently [32], In the former case, reasonable selectivities can be obtained with titanocene dichloride (trans cis = 76 24), but excellent selectivities are observed with bis(tert-butyl)titanocene dichloride (transxis = 94 6), as shown in Scheme 12.17. 

In 1978, Tebbe and co-workers reported the formation of the metallacyde 4, commonly referred to as the Tebbe reagent, by the reaction of two equivalents of trimethylaluminum with titanocene dichloride. The expulsion of dimethylaluminum chloride by the action of a Lewis base affords the titanocene-methylidene 5 (Scheme 14.4) [8]. 

Aluminum-free titanocene-methylidene can be generated by thermolysis of titana-cyclobutanes 6, which are prepared by reaction of the Tebbe reagent with appropriate olefins in the presence of pyridine bases [9]. Alternatively, the titanacyclobutanes are accessible from titanocene dichloride and bis-Grignard reagents [10] or from 71-allyl titanocene precursors [11]. The a-elimination of methane from dimethyltitanocene 7 provides a convenient means of preparing titanocene-methylidene under almost neutral conditions [12] (Scheme 14.5). 

Methylenative dimerization takes place when terminal alkynes are treated with the tita-nocene/methylidene/zinc halide complex generated from titanocene dichloride and CH2(ZnI)2. The process is believed to involve the formation of a titanacyclobutene intermediate [75],... 

To a solution of the titanocene(II) reagent 29 in THF (42 mL) in a 300-mL round-bottomed flask, prepared from titanocene dichloride (6.54 g, 26.3 mmol), magnesium turnings (0.766 g, 31.5 mmol), triethyl phosphite (8.96 mL, 52.5 mmol), and finely powdered 4 A molecular sieves (1.31 g) according to the procedure described above, was added a solution of l,l-bis(phenylthio)cyclobutane (63 2.29 g, 8.40 mmol) in THF (14 mL). The reaction mixture was stirred for 15 min. and then a solution of (S)-isopropyl 3-phenylpro-panethioate (91 1.46 g, 7.00 mmol) in THF (21 mL) was injected dropwise over a period of 10 min. The reaction mixture was refluxed for 1 h, then cooled, whereupon 1 m aq. NaOH solution (150 mL) was added. The insoluble materials produced were removed by filtration through Celite and washed with diethyl ether. The aqueous layer was separated and extracted with diethyl ether. The combined ethereal extracts were dried (Na2S04), filtered, and concentrated. The residual liquid was purified by column chromatography (silica gel, hexane) to afford 1.33 g (77%) of (l-isopropylthio-3-phenylpropan-1 -ylidene) cyclobutane (92). 

Titanium white pigments, commercial production of, 19 388 Titanium white rutile pigment, 19 391 Titanium zinc oxide, 5 603 Titanium-zirconium-molybdenum (TZM) alloy, 17 14-15 Titanocene, 25 118 Titanocene catalysts, 16 19 Titanocene dichloride, 25 105 Titanocene synthons, 25 116 Titanocycles, 25 116... 

Other metal complexes also have promising anticancer activity. Two Ti(IV) complexes are on clinical trial, an acetylacetonate derivative (budotitane) and titanocene dichloride, and the antimetastic activity of octahedral Ru(III) complexes is attracting attention, one of which is now on clinical trial. Ru(III), like several other metal ions, can be delivered to cells via the iron transport protein transferrin. 

The antitumor activity of titanocene dichloride 21 was first recognized in 1979 (150), and since then the activity of several other metallocenes (V, Nb, Mo, Fe, Ge, and Sn) has been reported (151). Most interest has centered on titanocene dichloride and on vanadocene dichloride 22, which are active against a diverse range of human carcinomas, including gastrointestinal and breast carcinomas, but not against head and neck cancers. There appears to be a lack of crossresistance between titanocene dichloride and cisplatin. 

Phase I dose-escalation trials of titanocene dichloride, formulated in maleic acid buffer, have shown that nephrotoxicity is cumulative... 

The Diels-Alder reaction outlined above is a typical example of the utilization of axially chiral allenes, accessible through 1,6-addition or other methods, to generate selectively new stereogenic centers. This transfer of chirality is also possible via in-termolecular Diels-Alder reactions of vinylallenes [57], aldol reactions of allenyl eno-lates [19f] and Ireland-Claisen rearrangements of silyl allenylketene acetals [58]. Furthermore, it has been utilized recently in the diastereoselective oxidation of titanium allenyl enolates (formed by deprotonation of /3-allenecarboxylates of type 65 and transmetalation with titanocene dichloride) with dimethyl dioxirane (DMDO) [25, 59] and in subsequent acid- or gold-catalyzed cycloisomerization reactions of a-hydroxyallenes into 2,5-dihydrofurans (cf. Chapter 15) [25, 59, 60],... 

An alternative, but related, route to allenic titanium reagents from propargylic esters has been reported recently. Reaction of titanocene dichloride with BuMgCl and Mg yields a reactive titanocene intermediate, formulated as Cp2Ti. This reduced Ti species reacts in situ by oxidative addition to propargylic acetates. The allenyltitanium reagents thus produced add to aldehydes and ketones, as expected, to afford homopropargylic alcohols (Table 9.27) [43]. 

Scheme 12.4 Grafting of titanocene dichloride onto siliceous supports and subsequent formation of active titanium centers.

A flask is charged with finely powdered molecular sieves (4 A, 50 mg), magnesium turnings (97 mg, 4.0 mmol), titanocene dichloride (249 mg, 1.0 mmol), THE (5 mL), triethyl phosphite (0.34 mL, 326 mg, 2.0 mmol) and 1-octene (224 mg, 2.0 mmol), in the order given. The resulting mixture is stirred for 2 h at room temperature and a solution of 2 [( )-2-phenylethenyl]-l,3-dithiane (111 mg, 0.5 mmol) in THF (2 mL) is added. The mixture is stirred for 4 h and then diluted with hexane (30 mL). Filtration through Celite, concentration of the filtrate, and purification of the product by preparative TLC gives 82 mg (72%) of the title compound as a mixture of cis and trans cyclopropanes (cis/trans 60 40). 

---