Buchwald titanium catalysts

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. ... 

As a final example not strictly within the bounds of this section, the work of Buchwald s group can be cited [109]. This demonstrates that asyrmnetric hydrogenations can be achieved with metals other than Rh or Ru (albeit rarely ). In this case, the reduction of simple enamines with high enantioselectivity is demonstrated with titanium catalysts. The genesis of the ligand lies in the cyclopen-tadienyl complexes developed for stereospecific polymerization, but its application here results in a useful transformation (cyclic enamines provide a difficult problem for the conventional asymmetric hydrogenation catalyst) illustrated in Fig. 32. 

Titanium complexes that are similar to Duthaler s ( 2.5.2) can be generated from TiCl4, Ti(Or-Pr)4 and diacetoneglucose 1.48. These complexes catalyze asymmetric hetero-Diels-Alder reactions, and give high enantiomeric excesses [827], Corey and coworkers [828] also prepared a chiral titanium catalyst derived from cis-/V-sulfonyl-2-amino-1 -indanol and used this to catalyze asymmetric Diels-Alder reactions. Buchwald and coworkers [829, 830] have proposed the use of titanocene-binaphthol catalysts for asymmetric hydrogenation of imines or trisubsti-tuted olefins. 

Kablaoui NM, Buchwald SL (1996) Development of a method for the reductive cychzation of enones by a titanium catalyst. J Am Chem Soc 118 3182-3191... 

Given the importance of chiral amines to synthetic chemistry as well as other fields asymmetric hydrogenation of imines has attracted wide interest but limited success compared to C=C and C=0 bond reduction. The first asymmetric hydrogenation of imines was carried out in the seventies with mthenium- and rhodium-based catalysts, followed later by titanium and zirconium systems [82]. Buchwald found that... 

With regard to PK-type reactions, Buchwald studied titanium species as efficient catalysts in the PKR and in PK-like reactions with cyanides. Following preliminary results with [Cp2Ti(PMe3)2] and [Cp2TiCl2] [79-81], they reported a more practical procedure which improved the TON using commercial titanocene dicarbonyl (33) [82,83]. This complex is able to catalyze the... 

All effective catalysts for the asymmetric reduction of prochiral C=N groups are based on complexes of rhodium, iridium, ruthenium, and titanium. Whereas in early investigations (before 1984) emphasis was on Rh and Ru catalysts, most recent efforts were devoted to Ir and Ti catalysts. In contrast to the noble metal catalysts which are classical coordination complexes, Buchwald s a sa-titanocene catalyst for the enantioselective hydrogenation of ketimines represents a new type of hydrogenation catalyst [6]. In this chapter important results and characteristics of effective enantioselective catalysts and are summarized. 

In the case of the hydrosilylation of C=N bonds, extremely high levels of enantioselectivity were dramatically realized by use of the (tetrahydroinde-nyl)titanium(IV) fluoride T4 (Fig. 12) by Buchwald in 1996 [55]. The in situ catalyst uniquely derived by mixing the titanocene fluoride T4 (1.0-0.02 mol %) with phenylsilane PhSiHj (1.5 eq referred to ketone) as hydrogen atom donor reduces the imines 13-17 (Fig. 13) to the amines A3-A7 in 80-96% yields (Table 3). An alternative activation method for the titanocene by addition of methanol and pyrrolidine was also described. In this case, the imine from acetophenone and methylamine, 13, was converted at room temperature to 35 °C to give the corresponding secondary amine in 94-95% yield with 97-99% ees (S). Moreover, alkylimines were also reduced in 92-99% ees. 

Buchwald and coworkers developed a series of titanium complexes into highly efficient catalysts for hydrosilylation of ketones. Esters were catalytically converted to alcohols by catalysts formed through reaction of Cp2TiCl2 with n-Buli, followed by reaction with HSi(OEt)3 [66]. Subsequent studies with chiral Ti catalysts led to highly enantioselective hydrosilylation of ketones [67]. 

Buchwald and coworkers have used the titanium version of the Brintzinger catalyst (2.100) in the asymmetric reduction of trisubstituted alkenes. The catalyst is reduced in situ to a titanium(lll) hydride species (see Section 3.6). The reduction is achieved with "butyllithium and hydrogen, whilst the silane serves to stabihse... 

Group 4 metallocene complexes can also be used as catalysts in the reduction of C=N bonds. Willoughby and Buchwald employed the titanium-based Brintzinger catalyst (3.54) for the asymmetric reduction of imines. The catalyst is activated by reduction to what is assumed to be the titanium(III) hydride species (3.55). The best substrates for this catalyst are cyclic imines, which afford products with 95-98% ee. Various functional groups including alkenes, vinyl silanes, acetals and alcohols were not affected under the reaction conditions. For example, the imine (3.56) was reduced with excellent enantioselectivity, without reduction of the alkene moiety. 

As well as rhodium-catalysed hydrosilylation, asymmetric ruthenium and titanium-catalysed hydrosilylation have also been reported. Amongst these, Buchwald s report of the hydrosilylation of ketones using titanocene catalysts and inexpensive polymethyUiydrosiloxane (PMHS) appear to be the most general. 

Buchwald reported an important advance in enantioselective C=N reductions with the chiral titanocene catalyst 186 (X,X = l,l -binaphth-2,2 -diolate) [137]. The reduction of cyclic imines with 186 and silanes afforded products with high selectivity however, reductions of acyclic imines were considerably less selective. It was suggested that this arose from the fact that, unlike cyclic imines, acyclic imines are found as mixtures of equilibrating cis and trans isomers. An important breakthrough was achieved with the observation that in situ activation of the difluoride catalyst 187 (X = F) gave a catalytically active titanium hydride species that promotes the hydrosilylation of both cyclic and acyclic amines with excellent enantiomeric excess [138]. Subsequent investigations revealed that the addition of a primary amine had a beneficial effect on the scope of the reaction [138, 139]. A demonstration of the utility of this method was reported by Buchwald in the enantioselective synthesis of the alkaloid frans-solenopsin A (190), a constituent of fire-ant venom (Scheme 11.29) [140]. 

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