Asymmetric Catalysis DOI: 10.1002/anie.200600741 From Aryl Bromides to Enantioenriched Benzylic Alcohols in a Single Flask: Catalytic Asymmetric Arylation of Aldehydes** JeungGonKimandPatrickJ.Walsh* Dedicated to Professor Madeleine JoulliØ The catalytic asymmetric addition of aryl groups to aldehydes has generated an enormous amount of attention. [1] The resulting diarylmethanols are important constituents of biologically active compounds, such as clemastine, [2] orphena- drine, [3,4] neobenodine, [3,4] chloropheniramine, [5,6] cizolir- tine, [7] and carbinoxamine. [8] Although the majority of enan- tioselective aldehyde arylation reactions rely on the use of costly diphenylzinc ($55–75 g À1 ), important advances in the use of other aryl transfer reagents, such as arylboronic acids [9,10] and Ph 2 Si(OMe) 2 , [11] have been reported. Although a limited number of aryl boronic acids are commercially available, they are quite expensive as well (e.g., PhB(OH) 2 $225.00 mol À1 from Aldrich). A more practical and versatile method would begin with aryl bromides, many of which are commercially available and inexpensive (compare PhBr $2.50 mol À1 from Aldrich). There are no reports, however, of successful catalytic asymmetric aryl additions to aldehydes that begin with aryl bromides. [12,13] Herein, we disclose a one- pot method that begins with aryl bromides for the in situ generation of aryl zinc intermediates and their catalytic asymmetric addition to aldehydes to afford highly enantioen- riched diarylmethanols and benzylic alcohols. We chose to examine the amino alcohol ligand MIB developed by Nugent [14,15] in the asymmetric addition of commercial ZnPh 2 to 2-naphthylaldehyde [Eq. (1)]. We were pleased to find that phenylation proceeded in toluene with 94% enantioselectivity (Table 1, entry 1). Unfortunately, transmetalation of phenyllithium with ZnCl 2 in toluene was unsuccessful because of the insolubility of ZnCl 2 in this medium. In contrast, ethereal solvents are known to promote transmetalation reactions. The asymmetric addition in diethyl ether, however, gave a low enantioselectivity (60%; Table 1, entry 2). In an attempt to balance both the solvating proper- ties of diethyl ether, needed for the transmetalation, and the low polarity of toluene, we examined tert-butyl methyl ether (tBuOMe). A reaction mixture of commercial ZnPh 2 ,(À)- MIB, and 2-naphthylaldehyde in tBuOMe furnished the product in 88% ee (Table 1, entry 3). A solvent system of tBuOMe and hexanes (1:3) exhibited about the same Table 1: Commercially available ZnPh 2 versus ZnPh 2 formed in situ. Entry ZnPh 2 Solvent ee [%] 1 commercial toluene 94 2 commercial Et 2 O 60 3 commercial tBuOMe 88 4 commercial tBuOMe/Hex (1:3) 89 5 in situ tBuOMe/Hex (1:3) 2 [*] Dr. J. G. Kim, Prof. P. J. Walsh P. Roy and Diana T. Vagelos Laboratories University of Pennsylvania Department of Chemistry 231 South 34th Street, Philadelphia, PA 19104-6323 (USA) Fax: (+ 1)215-573-6743 E-mail: pwalsh@sas.upenn.edu [**] We thank the National Institutes of Health (National Institute of General Medical Sciences) and the National Science Foundation for support of this research. Supporting information for this article is available on the WWW under http://www.angewandte.org or from the author. Angewandte Chemie 4175 Angew. Chem. Int. Ed. 2006, 45, 4175–4178 # 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim