RuCl2 -DAIPEN

Manufacture of ruthenium precatalysts for asymmetric hydrogenation. The technology in-licensed from the JST for the asymmetric reduction of ketones originally employed BINAP as the diphosphine and an expensive diamine, DAIPEN." Owing to the presence of several patents surrounding ruthenium complexes of BINAP and Xylyl-BINAP, [HexaPHEMP-RuCl2-diamine] and [PhanePHOS-RuCl2-diamine] were introduced as alternative catalyst systems in which a cheaper diamine is used. Compared to the BINAP-based systems both of these can offer superior performance in terms of activity and selectivity and have been used in commercial manufacture of chiral alcohols on multi-100 Kg scales. 

Racemic 2-phenylpropiophenone, which has an enantiomerically labile a-stereogenic center under basic conditions, was hydrogenated with RuCl2[(S)-XylBINAP] [(S)-DAIPEN] and (CH3)3COK to afford predominantly the 1R,2R al-... 

Substrate/catalyst molar ratio.b fra s-RuCl2[(S)-tolbinap] [(S)-daipen] + (CH3)3COK was used as a cat alyst. 

Hydrogenation of 2,2,2-trifluoroacetophenones catalyzed by fra s-RuCl2[(S)-XylBINAP][(S)-DAIPEN] with (CH3)3COK afforded the S trifluoro alcohols in 94-96% ee (Scheme 6) [6]. The presence of an electron-donating or electron-withdrawing group at the 4 position had little effect on the enantioselectivity. The sense of the enantioselection was the same as that observed in the reaction of simple acetophenone. 

Hydrogenation of 2,2,2-trifluoroacetophenone and its derivatives with a mixture of trans-RuCl2[(S)-xylbinap][(S)-daipen] and (CH3)3COK in 2-propanol gives the S alcohols quantitatively with a high optical purity (Scheme 1,64) [258]. Unlike with many chiral borane reagents [264], the sense of enantioface discrimination is the same as in hydrogenation of acetophenone. The electronic effects of 4 -substituents on the enantioselectivity are small. These chiral fluorinated alcohols are useful as components of new functionalized materials [265]. 

The vast majority of catalyst systems in Table 19.5 utilize ruthenium as a metal examples include trans-RuH -BHJfbinap l -diamine) (Ohkuma, 2002), trans-RuCl2[(R)-xylbinap][(R)-daipen] (Ohkuma, 2000b), and trans-RuCl2[P(C6H4-4-CH3)3]2(ethylenediamine) (Ohkuma, 2000a). 

Use of a BINAP/chiral diamine Ru complex trans- RuCl2[(R)-xylbinap][(R)-daipen] or the S,S complex efficiently catalyzes asymmetric hydrogenation of heteroaromatic ketones, with little influence of the ring properties on the enantioselectivity. Duloxetine, an inhibitor of serotonin and norepinephrine uptake carriers, has been synthesized in this way (Ohkuma, 2000b). 

Enantioface selection of prochiral diaryl ketones is generally difficult because electronically and sterically similar two aryl groups are attached to the carbonyl group. Overreduction of diaryl methanols to diaryl methanes is also another problem, but these problems are overcome by use of the Ru ternary catalyst system (Scheme 2.4b). Thus, by using (S,S)-20/KOC(CH3)3, 2-substituted benzophenones are quantitatively reduced to the diaryl methanols without any detectable diaryl methanes [102], With 3- or 4-substituted benzophenones, enantioselectivities are moderate. Benzoylferrocene is hydrogenated in the presence of trans-RuCl2 (S)-tol-binap (S)-daipen and a base to afford the S alcohol in 95% e.e. 

Highly enantioselective hydrogenation of simple dialkyl ketones is limited to a specific case. Cydopropyl methyl ketone or methyl 1-methylcyclopropyl ketone, for example, can be hydrogenated in 95-98% optical yield in the presence of trans-S)-xylbinap (S)-daipen ",4>RuCl2 (S)-xylbinap (S)-daipen /KOC(CH3)3 [67a, 81c[. 

BINAP-Ru complexes show an excellent enantioselectivity in the hydrogenation of a-, /3-, or y-amino, -hydroxy, and -alkoxy ketones. Thus, a-dialkylamino ketones are effectively converted by (S)-BINAP-RuCl2 complexes to the chiral /3-amino alcohols with up to 99% e.e. (Eq. 2.25) [119, 120]. A normally unreactive Ru diacetate complex may be used for the hydrogenation of a-dimethylaminoacetone [119]. With a trans-RuCl2 (R)-xylbinap (R)-daipen ((R,R)-20)/KOC(CH3)3 catalyst system, a variety of a- and /3-amino ketones are hydrogenated in high optical yields [114]. Thus, a-(dimethylamino)acetone is converted to the S amino alcohol in 92% e.e. with an S/C of 2000 under 8 atm H2, whereas a-(dimethylamino)acetophenone is converted to the R alcohol in 93% e.e. with the same catalyst. The reversed sense of... 

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