602 Letters in Organic Chemistry, 2008, 5, 602-606 1570-1786/08 $55.00+.00 © 2008 Bentham Science Publishers Ltd. Enantioselective Michael Addition of Dimethyl Malonate to (E)- - Nitrostyrenes Catalyzed by Cinchona Alkaloids Under Solvent-Free Con- dition Francesco Fringuelli*, Luca Castrica, Ferdinando Pizzo* and Luigi Vaccaro Laboratory of Green Synthetic Organic Chemistry, Dipartimento di Chimica, Università di Perugia, Via Elce di Sotto, 8 06123 – Perugia Italia Received June 10, 2008: Revised September 11, 2008: Accepted September 12, 2008 Abstract: Under solvent-free condition the addition of dimethyl malonate (1) to (E)- -nitrostyrenes 2a-j proceeds smoothly in the presence of 2.5 mol% of 6’-hydroxy cinchonine (QD-OH) and equimolar amounts of reagents at 30 °C. The corresponding products 3a-j are obtained with satisfactory enantiomeric excesses (68-88%) and high yields (70- 92%). Keywords: Nitroalkenes, organocatalysts, solvent-free condition, Michael addition. INTRODUCTION Catalytic asymmetric 1,4-addition of malonates to conju- gate nitroolefins provides a rapid access route to chiral - nitro carboxylatyes from readily accessible starting materials [1]. These nitrocompounds are attractive and versatile build- ing blocks that can be easily transformed into a wide range of pharmaceuticals and biologically active compounds [1]. Several procedures have been reported for this transfor- mation by using metal-based catalysts in organic solvents [2]. To eliminate the use of metal catalysts, more recently or- ganocatalytic versions have been proposed [3], where the catalyst is able to activate both reactants through a Lewis/Brønsted base and Brønsted acid moieties that steer the addition of the nucleophile to nitroalkene [4]. Efficient results have been achieved by using thiourea- [3a,c,d] or guanidine-based catalysts [3h]. Cinchona alkaloids have found applications as chiral re- solving agents and chiral additives in enantioselective trans- formations because they are inexpensive, readily available and easy to be modified [5]. The asymmetric 1,4-addition of malonates to (E)- - nitroalkenes catalyzed by Cinchona alkaloids has been car- ried out in organic solvent and in the presence of excess of nucleophile (2-3 equivs) with a significant amount of chiral base (up to 10 mol%) and generally at low temperatures (- 20/-60 °C). No attention has been paid to the development of this transformation under solvent-free condition [3b, e-g]. In the last fifteen years we have been studying the use of water in organic synthesis [6] and we have showed that by controlling the pH of the aqueous medium the efficiency of a *Address correspondence to this author at the Laboratory of Green Synthe- tic Organic Chemistry, Dipartimento di Chimica, Università di Perugia, Via Elce di Sotto, 8 06123 – Perugia Italia; Tel: +39 075 5855541; Fax: +39 075 5855560; E-mail: frifra@unipg.it; pizzo@unipg.it catalyst and the regio- ad stereoselectivity of a process can be strongly influenced. More recently we have been paying attention to the use of solvent-free condition (SolFC) [7] and we have been de- veloping one-pot multistep protocols for the synthesis of target molecules under SolFC, or by using a combination of the use of water and SolFC [8]. Examples of enantioselective processes performed in SolFC are rare in literature [9], perhaps due to the difficulty of obtaining satisfactory ee under highly concentrated condi- tion. Currently, we have decided to investigate the asymmetric 1,4-addition of dimethyl malonate (1) to (E)- -nitrostyrenes 2 catalyzed by Cinchona alkaloids under SolFC with the aim of using equimolar amounts of reagents, room temperature, and a low catalyst loading. We have started our study by investigating the addition of dimethyl malonate (1) to (E)- -nitrostyrene (2a) in the presence of a set of commercial and synthetic Cinchona alka- loids (Fig. 1) under SolFC at 30 °C. The results are illus- trated in Table 1. Conversion of 2a to 3a was always complete but only synthetic 6’-hydroxy cinchonine (QD-OH) [3b, 10] provided a satisfactory enantioselectivity. By using 0.1 equivalents of catalyst, 3a was isolated in a 92% yield and 74 ee% (Table 1, entry 7). Enantioselectivity performances of QD-OH were found identical by reducing the loading up to 0.025 equivalents (Table 1, entry 9). A further reduction in the catalyst’s amount resulted in a long reaction time (Table 1, entry 10). By lowering the temperature to –20 °C it resulted only in a moderate increase of the selectivity (82% ee) (Table 1, foot- note e). The best compromise is represented by the use of 2.5 mol% of QD-OH at 30 °C. The efficiency of QD-OH can be understood by consid- ering the better ability of this molecule to establish an