Highly Asymmetric Addition Of Grignard Reagents To Aldehydes Catalyzed By BINOL-Ti Ate-complex

Grignard reagents are among the most important and traditional organometal reagents. Addition of Grignard reagents to double bonds is one of most reliable methods for forming Carbon-Carbon bonds. Catalytic asymmetric addition of Grignard reagents to aldehydes can produce numerous chiral sec-alcohols, many of them have different biologically activities. However, there are few success report on asymmetric alkylation by Grignard reagents to carbonyl compounds due to the intrinsic high reactivities of Grignard reagents.For very long time, many research groups focus on using more than a stoichiometric amount of a chiral auxiliaries to obtain high enantioselectivity. There were mainly two sorts of processes reported on highly catalytic asymmetric addition of Grignard reagents to aldehydes. The former case was to transform Grignard reagent RMgX into other organometal reagents such as R₂Zn and R-Ti derivatives via complicated procedures at extremely low temperature. The later case was to link a chiral ligand to Mg in the form of organomagnesium amides or use chiral amine ligand catalyzing the alkylation of aldehydes. As a result, realizing the highly asymmetric addition of real Grignard reagents to aldehydes at mild conditions is more fascinating and challenging.We transformed RMgBr into R-Ti derivatives with the production of byproduct MgBr(O^i-Pr) at the same time, but we didn't need romove the Mg salt by centrifugation or chelating reagents, for bis[2-(N,N-dimethylamino)ethyl] ether (BDMAEE) could chelate with Mg atom and thereby reduced the Louis acidity of Mg salt, so we used R-Ti derivatives produced in situ to alkylate the aldehydes induced by BINOL-Ti complexes.. At the same time BDMAEE could chelate with Mg atom of RMgBr so as to reduce the reactivity of RMgBr, so this reaction didn't need much excess of Ti(O^i-Pr)₄ to transform RMgBr into R-Ti derivatives. The amounts of (S)-BINOL, Ti(O^i-Pr)₄ and RMgBr have great effects on the enantioselection. Under the optimized reaction condition, moderate to good enantioselection in the alkylation of aldehydes using 10% BINOL were achieved.^i-BuMgBr was the best Grignard reagent and its enantioselection was up to 94%. Under 15% BINOL conditions, varieties of aryl aldehydes were used to test this reaction, and their enantioselections were all over 97% and the highest two samples were over 99%. High enantioselection with ee>90% were gained for alphatic aldehydes, heterocyclic aldehydes as well as a,Î’-unsatured aldehydes.