Added benefits: Grignard reagents can be employed in the asymmetric alkylation of aldehydes by using a titanium(IV) catalyst derived from binol in the presence of excess titanium tetraisopropoxide (see scheme). The reaction proceeds with a low catalyst loading (2 mol %) and exhibits high enantioselectivity for both aromatic and unsaturated aldehydes and for both alkyl and aryl Grignard reagents.
We have developed an efficient and practical method for the catalytic enantioselective alkylation and arylation of aldehydes by using Grignard reagents in combination with titanium tetraisopropoxide. Grignard reagents and titanium tetraisopropoxide are mixed in a molar ratio of ca. 1:2. In the presence of catalyst (24 mol %), which is formed in situ from a BINOL ligand 4a and 4b and titanium tetraisopropoxide, the resulting mixed titanium reagents undergo addition to aldehydes with high enantioselectivities (typically >90% ee) and high yields. The method is applicable to various combination of aldehydes (R 1 CHO; R 1 = aryl, heteroaryl, 1-alkenyl, and alkyl) and Grignard reagents (R 2 MgX; R 2 = primary alkyl and aryl). Thus, a variety of enantiomerically enriched secondary alcohols (R 1 CH*(OH)R 2 ) can be prepared. It has also been demonstrated that functionalized aryl Grignard reagents can be employed to generate highly functionalized diarylmethanols. The preparative utility of the method has been shown by the fact that the reaction is operationally simple, can be carried out on a 10-mmol scale without any difficulty, and the ligands can be readily recovered.The catalytic enantioselective addition of organometallic reagents to aldehydes and ketones leading to enantiomerically enriched secondary and tertiary alcohols is a reaction of fundamental importance in modern synthetic organic chemistry. The development of efficient catalytic systems has received widespread attention for a long time.1 In the early days, attempts were made to employ Grignard reagents and organolithium reagents in the presence of more than stoichiometric amounts of chiral diamines or other chiral modifiers.2,3
A general method has been developed for preparing enantioenriched secondary alcohols by starting from aryl bromides and aldehydes. Aryl bromides were first treated with BuLi, and the resulting aryllithium reagents were mixed with titanium tetraisopropoxide and magnesium bromide. The reac-
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