Catalytic Enantioselective Alkylation and Arylation of Aldehydes by Using Grignard Reagents

Abstract

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

Catalytic Enantioselective Synthesis of Diarylmethanols from Aryl Bromides and Aldehydes by Using Organolithium Reagents

“…A recent report from this laboratory showed that Grignard reagents can be used in the enantioselective arylation of aldehydes by using a titanium(IV) catalyst derived from DPP‐H 8 ‐BINOL 1 (2 mol‐%) in the presence of excess titanium tetraisopropoxide [Equation (1)] 8b,8c. The reaction protocol involves the slow addition of a ca.…”

Catalytic asymmetric alkylation of ketones using organometallic reagents

“…Indeed, catalytic non-asymmetric addition of Grignard reagents to ketones has become possible only recently using Zn(II) salts as catalyst [38]. In 2008 Harada et al reported that highly enantioselective catalytic addition of Grignard reagents to aldehydes is possible, albeit requiring the use of excess titanium tetraisopropoxide, most probably via formation of organotitanium reagents as nucleophiles [39,40].…”

Development of Highly Active Chiral Titanium Catalysts for the Enantioselective Addition of Various Organometallic Reagents to Aldehydes

“…The following optimization study led us to establish reaction conditions that enable high enantioselectivity at 2 mol % catalyst loading, as exemplified by the butylation of benzaldehyde using BuMgCl (2 M in Et 2 O) (Scheme ) 21. Thus, the Grignard reagent is first mixed with Ti(O i Pr) 4 in CH 2 Cl 2 and the resulting mixed reagent is added for 2 h to a CH 2 Cl 2 solution of the aldehyde, Ti(O i Pr) 4 , and 2 mol % of DPP‐BINOL 7 at 0 °C.…”

“…The approach based on the use of Grignard reagents as the mixed reagents with Ti(O i Pr) 4 is also successful in the enantioselective arylation of aldehydes 21b,24. The mixed reagents derived from aryl Grignard reagents are stable and do not need to be employed in excess.…”

“…The scope of the catalytic enantioselective arylation reaction was expanded further by the use of functionalized Grignard reagents 12 , which are prepared in situ by halogen/Mg exchange of aryl halides 11 (Scheme ) 21b,26. In method A, the functionalized Grignard reagents are generated by I/Mg exchange reaction of aryl iodides with i PrMgCl in THF according to a protocol developed by Knochel et al27 The resulting reagents are used in the subsequent enantioselective reaction after removing THF in vacuo, because otherwise the enantioselectivity of the reaction is decreased considerably.…”