SHORT COMMUNICATION DOI: 10.1002/ejoc.201101283 Catalytic Enantioselective Addition of MeMgBr and Other Grignard Reagents to Aldehydes Emilio Fernández-Mateos, [a] Beatriz Maciá,* [a] Diego J. Ramón, [a] and Miguel Yus* [a] Dedicated to Professor Dr. Carmen Nájera on the occasion of her 60th birthday Keywords: Asymmetric catalysis / Grignard reaction / Aldehydes / Alcohols / Titanium Herein, we report an efficient catalyst for the challenging enantioselective addition of MeMgBr to aldehydes. Unprece- dented yields and enantioselectivities are achieved in the re- action with a broad range of aldehydes. Moreover, a variety Introduction The chiral methyl carbinol moiety is present in a large number of natural products and biologically active com- pounds, [1] and its synthesis is of great importance to both academia and industry. One of the most efficient ap- proaches to this structural fragment is the catalytic asym- metric addition of a methyl group to an aldehyde, which involves the formation of both a new C–C bond and the corresponding stereogenic center. [2] Enantioselective cata- lyzed versions of this key transformation have been studied extensively with dimethylzinc [3,4] and trimethylaluminum. [5] However, for the highly reactive methyllithium and methyl Grignard reagents, the progress has been limited [6] and more than stoichiometric amounts of a chiral modifier are usually required to obtain good enantioselectivity. [7] As an alternative, methyl Grignard reagents can be transmetalated into dimethylzinc [8] or methyltitanium triisopropoxide [9] and, after tedious removal of the generated magnesium salts, used in asymmetric additions to aldehydes. Recently, two notable examples of the highly enantioselective cata- lytic addition of Grignard reagents to aldehydes have been reported by Harada [10] and later by Da. [11] Both approaches comprise the use of an excess amount of titanium(IV) isop- ropoxide and no salt exclusion is needed to achieve high enantioselectivities. Nevertheless, none of these systems seems to be effective for the addition of methyl Grignard reagents, and very low enantioselectivities are obtained with [a] Organic Chemistry Department, Alicante University, Aptdo. 99 03080 Alicante, Spain Fax: +34-965-903-549 E-mail: beatriz.macia@ua.es yus@ua.es Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/ejoc.201101283. Eur. J. Org. Chem. 2011, 6851–6855 © 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 6851 of Grignard reagents can be also added to aromatic and ali- phatic aldehydes in good yields and enantioselectivities in a simple one-pot procedure under mild conditions. the use of a high catalyst loading (40 mol-%). [11] Here, we report a facile one-pot methodology for the addition of MeMgBr to different aldehydes by using an excess amount of titanium tetraisopropoxide in the presence of a catalytic amount of the readily available chiral ligand (S a ,R)-L1 (Fig- ure 1). [12] This methodology provides the highest enantio- selectivities and yields reported so far for this process. Moreover, enantioselective alkylation of a wide variety of aldehydes by using other longer-chain Grignard reagents proved to be also effective with this catalytic system. Figure 1. Chiral ligands used in this study. Results and Discussion The recently published straightforward synthesis of 1,1'- binaphthalene-2-α-arylmethan-2'-ols (Ar-BINMOLs) by Lai and Xu [12] encouraged us to analyze these kinds of bi- naphthyl-based chiral diols as ligands in the enantioselec- tive addition of Grignard reagents to carbonyl compounds. As a model reaction for this study, we chose the addition of MeMgBr to o-methylbenzaldehyde (1a) or benzaldehyde (1b). The first promising results were achieved with 10 mol- % of ligand (S a ,R)-L1, which provided 20 and 35% ee and full conversion in the addition of MeMgBr to 1a at 0 °C with the use of toluene or diethyl ether, respectively, as sol- vent (Table 1, Entries 1 & 2). Other solvents like DCM, THF, and tBuOMe were evaluated, but the enantio-