BCSJ : Vol. 83 (2010) , No. 1 pp.19-32

Catalytic Enantioselective Alkylation and Arylation of Aldehydes by Using Grignard Reagents

Yusuke Muramatsu¹⁾, Shinichi Kanehira¹⁾, Masato Tanigawa¹⁾, Yuta Miyawaki¹⁾ and Toshiro Harada¹⁾

1) Department of Chemistry and Materials Technology, Kyoto Institute of Technology

(Received September 2, 2009)

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 (2–4 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 (R¹CHO; R¹ = aryl, heteroaryl, 1-alkenyl, and alkyl) and Grignard reagents (R²MgX; R² = primary alkyl and aryl). Thus, a variety of enantiomerically enriched secondary alcohols (R¹CH*(OH)R²) 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.

Grignard reagents can be used in enantioselective alkylation and arylation of aldehydes by using chiral titanium(IV) catalysts in the presence of titanium tetraisopropoxide. The reaction proceeds with a low catalyst loading, exhibiting high enantioselectivity for various Grignard reagents and aldehydes.