DOI: 10.1002/adsc.200800430 Prolinamides versus Prolinethioamides as Recyclable Catalysts in the Enantioselective Solvent-Free Inter- and Intramolecular Aldol Reactions Diana Almas ¸i, a Diego A. Alonso, a, * and Carmen Nµjera a, * a Departamento de Química Orgµnica and Instituto de Síntesis Orgµnica (ISO), Facultad de Ciencias, Universidad de Alicante, Apartado 99, 03080, Alicante, Spain Fax: (+ 34)-96-590-3549; e-mail: diego.alonso@ua.escnajera@ua.es Received: June 11, 2008; Published online: November 4, 2008 Supporting information for this article is available on the WWW under http ://dx.doi.org/10.1002/adsc.200800430. Abstract: A solvent-free asymmetric and direct anti-aldol reaction of aliphatic ketones with aromat- ic aldehydes catalyzed by recyclable l-proline- ACHTUNGTRENNUNGamides and l-prolinethioamides 3 is studied. The l- prolinethioamide 3d (5 mol%), derived from l-Pro and (R)-1-aminoindane, is the most efficient cata- lyst for this process affording the anti-aldol adducts in high yields with excellent diastereo- and enantio- selectivities (up to > 98/2 dr, up to 98% ee) at 0 8C or room temperature. Prolinethioamide 3d is an ef- fective organocatalyst for the first asymmetric, sol- vent-free, intramolecular Hajos–Parrish–Eder– Sauer–Wiechert reaction with comparable or higher levels of enantioselectivity (up to 88% ee) to re- ported catalysts in organic solvents. Moreover, or- ganocatalyst 3d can be easily recovered and reused by a simple acid/base extraction. Keywords: aldol reaction; asymmetric catalysis; or- ganocatalysis; prolinethioamides; solvent-free reac- tions Asymmetric organocatalysis has definitively matured to become a recognized third discipline together with biocatalysis and metal complex catalysis, providing operationally simple, economic and environmentally friendly strategies to prepare enantioenriched com- pounds. [1] On the other hand, the necessity to further reduce any source of pollution has led to a growing interest in the development of organic reactions in aqueous media [2] and under solvent-free conditions. [3] Reactions under solvent-free conditions usually need shorter reaction times, simpler reactors and result in simple and efficient work-up procedures. For these reasons, organocatalyzed processes under solvent-free conditions have become a highly pursued goal in green chemistry. [4] The aldol reaction is one of the most important carbon-carbon bond-forming processes [5] since gener- ates b-hydroxy carbonyl compounds, derivatives which are found in many natural products and drugs. Very recently, great emphasis has been given to the design of new chiral organocatalysts for the aldol re- action. [6] Most of these studies have been performed in organic or aqueous solvents or using a large excess of nucleophile (5–138 equivalents) which allows it to act as reaction media as well. With respect to the sol- vent-free protocols, only a few catalytic systems have been shown to work satisfactorily when 3 or less equivalents of nucleophile donor are used (Figure 1). [7] l-Proline (10 mol%) has been used as or- ganocatalyst for a fast aldol reaction (5–36 h) of sym- metrical alkyl ketones (1.2 equiv.) with aromatic alde- hydes using a ball-milling technique. [7a,b] The use of conventional magnetic stirring in the same solvent- free reactions afforded similar results but longer reac- tion times were required (1 to 4 days). Hayashi has Figure 1. Organocatalysts for the direct solvent-free aldol re- action. Adv. Synth. Catal. 2008, 350, 2467 – 2472  2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 2467 COMMUNICATIONS