Chiral titanocenes

A quite different type of titanium catalyst has been used in an inverse electron-demand 1,3-dipolar cycloaddition. Bosnich et al. applied the chiral titanocene-(OTf)2 complex 32 for the 1,3-dipolar cycloaddition between the cyclic nitrone 14a and the ketene acetal 2c (Scheme 6.25). The reaction only proceeded in the presence of the catalyst and a good cis/trans ratio of 8 92 was obtained using catalyst 32, however, only 14% ee was observed for the major isomer [70]. 

Catalytic enantioselective synthesis of vzc-diols is a challenging issue. Chiral induction using chiral ligands is difficult to achieve. The moderately enantioselective pinacolization of benzaldehyde is demonstrated to be performed by the chiral titanocene catalysts 15 and 16 [42,43]. 

Asymmetric hydrogenation of 3,4-hydroisoquinolines with Ir-chiral phosphorus ligand complexes has been studied. Although the highest enantioselectivity to date is obtained with a chiral titanocene catalyst,308,308a 308c chiral BCPM-Ir or BINAP-Ir complexes with additive phthalimide or F4-phthalimide have shown some good selectivity. Some examples are listed in Table 24. 

Racemic 2,5-disubstituted 1-pyrrolines were kinetically resolved effectively by hydrogenation with a chiral titanocene catalyst 26 at 50% conversion, which indicates a large difference in the reaction rate of the enantiomers (Table 21.19, entries 4 and 5), while 2,3- or 2,4-disubstituted 1-pyrrolines showed moderate selectivity in the kinetic resolution (entries 6 and 7) [118]. The enantioselectivity of the major product with cis-configuration was very high for all disubstituted pyrrolidines. The high selectivity obtained with 2,5-disubstituted pyrrolines can be explained by the interaction of the substituent at C5 with the tetrahydroinde-nyl moieties of the catalyst [Eq. (17)]. 

Broene and Buchwald37 synthesized chiral titanocene compound 22 for the asymmetric hydrogenation of trisubstituted olefins. 

TABLE 6-3. Chiral Titanocene-Catalyzed Asymmetric Hydrogenation of Unfunctionalized Trisubstituted Olefins... 

Similar success was also achieved by Willoughby and Buchwald100a with a chiral titanocene catalyst. The high ee obtained by Burk and Feaster101a in the asymmetric hydrogenation of 98 was also consistent with the preferred coordination of one isomer forced by the bidentate chelation of the hydrazones. 

Hydrogenation of imines, e.g. 45-48, with a chiral titanocene catalyst at 2000 psig gave the corresponding optically active secondary amines in high enantiomeric excess74. Imines are reduced to amines by trichlorosilane/boron trifluoride etherate in benzene75. 

Hydrogenation of enamines in the presence of a chiral titanocene catalyst yields optically active amines in more than 90% enantiomeric excess, e.g. equation 80220. 

The Brintzinger-type C2-chiral titanocene catalysts efficiently promote asymmetric hydrogenation of imines (Figure 1.30). A variety of cyclic and acyclic imines are reduced with excellent enantioselectivity by using these catalysts. The active hydrogenation species 30B is produced by treatment of the titanocene binaphtholate derivative 30A with n-butyllithium followed by phenylsilane. 

Figure 1.30. Asymmetric hydrogenation of imines with a chiral titanocene catalyst.

It was 1996 when Buchwald and Hicks reported the first example of an asymmetric PKR involving a catalytic amount of a chiral titanocene complex. The titanium catalyst (6 ,6 )-(EBTHI)Ti(GO)2 (EBTHI = ethylene-1,2-bis( 7 -4,5,6,7-tetrahydro-l-indenyl)) obtained in situ by treatment of (6 ,6 )-(EBTHI)TiMe2 under CO pressure was efficient for the formation of enantiomerically enriched carbocyclization adducts. ... 

A chiral titanocene complex catalyzes enantioselective hydrogenation of imines in a moderate to high optical yield (Scheme 78) (117). 

Highly enantioselective hydrogenation of geometry-fixed cyclic imines has been achieved by the use of certain chiral Ti and Ir catalysts [14,17]. In particular, a chiral titanocene catalyst developed by Buchwald possess excellent enanti-odifferentiating ability for a variety of cyclic substrates [18]. 

Keywords Asymmetric hydrosilylation, optically active alcohols, amines, Chiral Titanocene Catalysts, Acyclic Imines, Cyclic Imines, Chiral Rhodium Catalysts, aromatic ketones... 

Asymmetric hydrosilylation of several AT-alkyl ketimines with PMHS was effectively promoted by the chiral titanocene catalyst (S)-ll (Scheme 8) [24,25], The... 

Several cyclic imines were reduced with phenylsilane as a reducing agent in the presence of the chiral titanocene catalyst 11 followed by a workup process to give the corresponding cyclic amines in excellent ee [26]. The hydrosilylation of 2-propyl-3,4,5,6-tetrahydropyridine with (R)-ll (substrate Ti=100 l) in THF at room temperature was completed in about 6 h (Scheme 14) [29]. The reaction mixture was treated with an acid and then with an aqueous base to afford (S)-coniine, the poisonous hemlock alkaloid, in 99% ee. 

As shown in Scheme 1.30, the chiral titanocene catalyst 34 hydrogenates unfunctionalized, disubstituted styrenes under 136 atm of hydrogen at 65°C to give the saturation products with 83 to >99% ee [156]. A high enantioselectivity is now realized only with aryl-substituted olefins. The enantioselectivity of 41% ee attained 2-ethyl-1-hexene and 34 as catalyst is the highest for hydrogenation of non-aromatic olefins. 

As in asymmetric hydrogenation of olefins and ketones, chiral diphosphine-Rh or -Ir complexes have frequently been used as catalysts [ 1,162,335]. Recently, a chiral titanocene catalyst... 

As shown in Scheme 1.95, the chiral titanocene catalyst 34 (see Scheme 1.10) prepared from 33, n-C4HgLi, andC6H5SiH3 shows a moderate-to-good enantioselectivity in the hydrogenation of /V-benzyl i mines of aryl methyl ketones, whereas the catalytic activity is rather low even at 137 atm [346]. The ketimine with R1 = 4-CH3OC6H4 is hydrogenated with (/ )-34 to give the R amine with 86% ee. The E Z of the imine substrate affects the enantioselection. The optical... 

The chiral titanocene catalyst 34 is very effective for the kinetic resolution of racemic 2,5-disubstituted 1-pyrrolines. When hydrogenation of racemic 5-methyl-2-phenyl-1-pyrroline with (Y)-34 is interrupted at ca. 50% conversion, unreacted R substrate with 99% ee is obtainable with a (2S,5S)-cA-pyrrolidine derivative with 99% ee (Scheme 1.98) [353], As summarized in the table, some other racemic substrates can be resolved in >95% optical yield. 

Asymmetric hydrogenation of Scheme 1.101 provides a general route to isoquinoline alkaloids (see Section 1.3.1.1). An imine substrate is hydrogenated with the chiral titanocene (/ )-34 to give the S product with 98% ee [346a,b,352], A neutral BCPM-Ir complex with phthalimide in toluene also shows high enantioselection [358]. The choice of a weakly polar... 

Another important development is chiral titanocene catalyst using 203 as the catalyst precursor225. The (R, R)-(EBTK)Ti(OR)2 (203) is proposed to generate the active catalyst species, (R, R)-(EBTHI)TiH , upon reaction with n-BuLi (2 equivalents) and polymethyl-hydrosiloxane (PMHS). This chiral Ti-catalyst system is highly efficient for the reactions of aromatic alkyl ketones achieving >90% ee in many cases. In sharp contrast to this, only 24% ee is obtained for the reaction of cyclohexyl methyl ketones. However, the reaction of cyclohexen-l-yl methyl ketone achieved 85-90% ee. Thus, it is extremely important for this chiral Ti-catalyst to have a 7r-system to be effective. 

Asymmetric hydrogenation has been reported to occur in excellent yield and ee when a trisubstituted alkene is hydrogenated with a chiral titanocene catalyst (equation 84)334. A similar reaction, but with variable enantioselectivity, may also be obtained with chiral Rh, Ru and Co catalysts335-338. Disubstituted alkenes (mainly 1,1-disubstituted) may also be... 

The chiral titanocene complex 61 is an excellent catalyst for the enantioselective hydrosilyation of the ketone 131 with PMHS (133) to afford the alcohol 132 with 91 % ee [80]. Efficient asymmetric hydrosilylation of symmerical diketones is catalysed by the Rh complex coordinated by EtTRAP. Biacetyl (134) was converted to (2S,3S)-2,3-butanediol (135) with 95% ee in 69% yield [81]. 

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