DOI: 10.1002/adsc.200900787 Novel Cinchona-Aminobenzimidazole Bifunctional Organocatalysts Lei Zhang, a Myoung-Mo Lee, b Soo-Mi Lee, b Jihye Lee, b Maosheng Cheng, a Byeong-Seon Jeong, c Hyeung-geun Park, b, * and Sang-sup Jew b, * a Shenyang Pharmaceutical University, Shenyang Wenhua Road 103, Shenyang, Liaoning 110016, Peoples Republic of China b Research Institute of Pharmaceutical Sciences and College of Pharmacy, Seoul National University, Seoul 151-742, Republic of Korea fax: (+ 82)-2-872-9129, (+ 82)-2-888-7621; phone: (+ 82)-2-880-7871, (+ 82)-2-880-7872 E-mail: hgpk@snu.ac.kr or ssjew@snu.ac.kr c College of Pharmacy, Yeungnam University, Gyeongsan 712-749, Republic of Korea Received: October 18, 2009; Revised: November 11, 2009; Published online: December 8, 2009 Supporting information for this article is available on the WWW under http ://dx.doi.org/10.1002/adsc.200900787. Abstract: Efficient Cinchona-derived chiral 2-ami- nobenzimidazole catalysts were prepared by the coupling of 5,7-bis(trifluoromethyl)-2-chlorobenzi- midazole with C(9S)-aminodihydroquinine or C(9R)-aminodihydroquinidine and successively ap- plied to the Michael addition of dimethyl malonate to nitroolefins as very efficient chiral Lewis acid bi- functional organocatalysts (up to > 99% ee). Keywords: 2-aminobenzimidazoles; bifunctional catalysts ; Cinchona alkaloids; enantioselectivity; or- ganocatalysts Since Jacobsens group first disclosed thiourea-based chiral ligands for the metal-free Strecker reaction in 1998, thioureas have been extensively studied as Lewis acid organocatalysts given their functionality as hydrogen bond donors, and successfully applied to various useful organic reactions. [1] Especially, thiour- eas conjugated with chiral amines have been devel- oped as chiral bifunctional catalysts capable of simul- taneously activating both nucleophiles and electro- philes in a reaction by their Brønsted/Lewis acidic (thiourea moiety) and basic (chiral amine moiety) functionalities. As such, they have successfully been applied to various asymmetric syntheses (Figure 1). [2] The cumulative results reveal that the electron- withdrawing moiety, for instance, trifluoromethyl group not only increases N À H acidity, but also con- tributes to the conformational rigidity of the catalyst by polarizing the adjacent H atoms, which in turn fa- cilitates a hydrogen bonding interaction with the sulfur atom in the thioureas. [3] The N-3,5-bis(trifluoro- methyl)phenyl group, introduced by Schreiners group in 2002, has been popularly employed in the design of thiourea-based organocatalysts thus far. [4] In 2005, Gçbels group introduced metal-free cata- lysts derived from 2-aminobenzimidazoles for the cleavage of RNA (Scheme 1). [5] The guanidine moiety in tris[2-(benzimidazol-2-ylamino)ethyl]amine (1) effi- ciently activated phosphates by hydrogen bonding, which could facilitate the cleavage of phosphate esters to cyclic phosphate 3 under neutral conditions (pH 7.0). Since the 2-aminobenzimidazole group is conformationally more rigid and bears a more acidic N À H compared to the corresponding thiourea group as in Figure 1, N-substituted-2-aminobenzimidazoles could serve as new Lewis acid organocatalysts. [6] In this paper, we report new Cinchona alkaloid-derived 2-aminobenzimidazole catalysts and their application in enantioselective Michael additions. [7] First, the catalytic activity of a 2-aminobenzimida- zole-containing compound in a Brønsted acid-cata- lyzed reaction was examined. Model compound 5 was prepared according to a known synthetic method [8] Figure 1. Thiourea-based bifunctional organocatalysts. Adv. Synth. Catal. 2009, 351, 3063 – 3066  2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 3063 COMMUNICATIONS