Asymmetric, Catalytic Phenyl Transfer to Imines: Highly Enantioselective Synthesis of Diarylmethylamines** Nina Hermanns, Stefan Dahmen, Carsten Bolm, and Stefan Br‰se* Enantiomerically pure diarylmethylamines are important intermediates in the synthesis of biologically active com- pounds. [1] Cetirizine hydrochloride (1) stands out from several drug candidates as a commercially important nonsedating antihistamine agent. Binding studies indicate that the R enantiomer displays a better pharmacological profile than the racemate. [2] Despite the impor- tance of enantiopure diarylme- thylamines, synthetic accesses and especially asymmetric (cata- lytic) processes for their synthesis are rather limited. [3] While there are several synthetic routes to, for example, enantiopure cetirizine that utilize resolution techniques, [4] stoichiometric amounts of chromium complexes, [5] or diastereoselective approaches with chiral auxiliaries, [6] to the best of our knowledge there is only a single report on an asymmetric catalytic addition of an organometallic arylation agent to an imine derivative. Hay- ashi and Ishigedani described a highly enantioselective rhodium-catalyzed process for the arylation of N-sulfonyl- imines with aryl stannanes (up to 96 % ee). [7] For quite some time we have been engaged in the asymmetric transfer of a phenyl group from organozinc reagents and have developed a protocol for the highly enantioselective transfer of a phenyl group to aldehydes using ferrocene (R p ,S)-2 and cyrhetrene (R p ,S)-3. [8] However, a major difficulty in the development of asymmetric processes for the transfer of a phenyl group remains the much higher reactivity of diphenylzinc relative to dialkylzinc and the concomitant rapid uncatalyzed background reaction. Recently, we developed a catalytic procedure for the enantioselective addition of diethylzinc to masked N-formyl- imines by employing catalytic amounts of [2.2]paracyclo- phane-based ketimines. [9, 10] We now report on the combina- tion of both methods, which leads to the first highly enantioselective addition of phenylzinc to imines and gives rise to optically active diarylmethylamines in very high enantiomeric excesses. At the outset of our study we examined the use of different N,O-ligands (Scheme 1) in the phenylation of N-[p-tolylmeth- yl-(toluene-4-sulfonyl)]formamide (7a, Table 1). This class of N-acylimine precursors is readily available in a one-pot synthesis from benzaldehyde, amide, and p-tolylsulfinic acid. [11] The addition to the imine then proceeds by deproto- nation of amide 7a, followed by elimination of the sulfinate to form N-formylimine 8a. Addition of the zinc reagent gives rise to the N-formylamine 9a. We started out by employing the reaction conditions developed for the enantioselective transfer of a phenyl group to aldehydes using a mixed zinc reagent formed in situ from diphenylzinc and diethylzinc. This reagent selectively transfers only the phenyl moiety to the substrate to afford N-formylamine 9a in very high yield without formation of the corresponding ethylation product. [12] The ligand screening (Table 1) showed that ferrocene (R p ,S)-2 and cyrhetrene 3, which represent the best ligands for the enantioselective transfer of a phenyl group to aldehydes (up to 99 % ee) so far, gave only moderate enantioselectivities in the addition to imine 8a (entries 1 and 3). The catalysis with diastereomeric ferrocene (S p ,S)-2 did not lead to any improvement (entry 2). In contrast, the use of [2.2]paracyclophane-based ketimines 4±6 [13] gave rise to N- formyldiarylmethylamines in good to excellent enantioselec- tivities (up to 97 % ee, entry 11). Ketimine (R p ,S)-6 showed the best results in the ligand screening and was chosen for further optimization studies. Interestingly, (S p )-5 bearing only the element of planar chirality, also gave rise to the product amine in very high enantioselectivity (entry 6). Within our ongoing study of [2.2]paracyclophane-based N,O-ligands, this ZUSCHRIFTEN 3844 ¹ 2002 WILEY-VCH Verlag GmbH&Co. KGaA, Weinheim 0044-8249/02/11419-3844 $ 20.00+.50/0 Angew. Chem. 2002, 114, Nr. 19 [*] Prof. Dr. S. Br‰se Kekulÿ-Institut f¸r Organische Chemie und Biochemie der Rheini- schen Friedrich-Wilhelms-Universit‰t Bonn Gerhard-Domagk-Strasse 1, 53121 Bonn (Germany) Fax: (þ 49) 228-739608 E-mail: braese@uni-bonn.de Dipl.-Chem. N. Hermanns, Dipl.-Chem. S. Dahmen, Prof. Dr. C. Bolm Institut f¸r Organische Chemie der Rheinisch-Westf‰lischen Techni- schen Hochschule Aachen Professor-Pirlet-Strasse 1, 52074 Aachen (Germany) [**] We are grateful to the Fonds der Chemischen Industrie and to the Deutsche Forschungsgemeinschaft (DFG) within the SFB 380 ™Asym- metric Synthesis by Chemical and Biological Methods∫ for financial support. Supporting information for this article is available on the WWW under http://www.angewandte.org or from the author. Cl N N O OH O • 2 HCl 1 Scheme 1. N,O-Ligands employed in the asymmetric transfer of a phenyl group to imines.