Novel guanidinyl pyrrolidine salt-based bifunctional organocatalysts: application in asymmetric conjugate addition of malonates to enones Emmanuel Riguet * Université de Reims Champagne-Ardenne, Institut de Chimie Moléculaire de Reims, CNRS UMR 6229, UFR Sciences Exactes et Naturelles, BP 1039, 51687, REIMS Cedex 2, France article info Article history: Received 8 April 2009 Revised 5 May 2009 Accepted 6 May 2009 Available online 10 May 2009 Keywords: Asymmetric organocatalysis Chiral guanidine Conjugate addition abstract Novel guanidinyl pyrrolidine salts are useful bifunctional organocatalysts for the asymmetric addition of malonates to enones. These organocatalysts are effective under a wide range of reaction conditions and afford products in high yield and enantioselectivity. Ó 2009 Elsevier Ltd. All rights reserved. Nowadays, asymmetric organocatalysis is recognised as a valu- able addition and/or as an alternative methodology to more estab- lished metal-based procedures. 1 Since the two seminal reports by List, Lerner and Barbas 2 and MacMillan and co-workers, 3 two modes of aminocatalysis, namely enamine activation 4 and imini- um activation, 5 have been extensively exploited in asymmetric organocatalysis. The iminium activation strategy has been used in a wide range of organocatalytic processes including cycloaddi- tion, 5 transfer hydrogenation 6 and 1,4-addition. 7 In the latter case, the conjugate addition of malonates to enones has attracted spe- cific attention in synthetic organic chemistry. Pioneering work, introduced proline rubidium salts to catalyse the addition of di- iso-propyl and di-tert-butyl malonates to both acyclic and cyclic enones. Products were obtained with low to good enantioselectiv- ities (35–88% ee). 8,9 Ten years later, a highly efficient methodology was reported using an imidazolidine catalyst. High yields (up to 99%) and good to excellent enantioselectivities (84–99% ee) were obtained. 10 However, when the more synthetically useful dimeth- ylmalonate was used ee’s were moderate. Long reaction times as well as a large excess of malonate were required. Recently Ley and co-workers introduced a new methodology based on the use of proline tetrazole catalyst and a stoichiometric amount of base. In this case only 1.5 equiv of malonate was used and the reaction time was reduced to 3 days. Moreover, good to high enantioselec- tivities were obtained when both dimethylmalonate and diethyl- malonate were used. 11,12 Only very recently, Zhao and Yang reported a highly efficient strategy using primary–secondary dia- mine catalysts. 13 Indeed the use of 20 mol % of catalyst gave the de- sired products in a relatively short reaction time (24 h) in excellent yields (up to 99%) and enantioselectivities (up to 99% ee) for a wide range of acyclic enones. When cyclohexenone was used, reaction times increased considerably (150 h) and products were obtained in moderate yield but still with good enantioselectivity (90% ee). It is noteworthy, that strategies based on other activation modes have recently led to efficient organocatalytic enantioselective mal- onate addition to enones, 14,15 albeit sometimes less efficient with cyclic enones. 14 The results reported herein concern the application of new organocatalysts I containing a pyrrolidine ring and an acyclic gua- nidine moiety (Fig. 1). The initial hypothesis was that the pK a of guanidine would be well suited for deprotonation of the malonate. Moreover, the pre- sumed ability of guanidinium ion to efficiently complex a malonate by both electrostatic interaction and two-directional hydrogen bonds would be suitable for the efficient orientation of nucleo- philic attack of malonate. Consequently, the attack of the nucleo- phile could occur syn with respect to the pyrrolidine substituent, 0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2009.05.011 * Tel.: +33 (0) 26 9131 96; fax: +33 (0) 26 9131 66. E-mail address: emmanuel.riguet@univ-reims.fr N H H N N H N H Ar Ia Ib Ic Ar = I Figure 1. Organocatalysts with pyrrolidine guanidine scaffold. Tetrahedron Letters 50 (2009) 4283–4285 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet