Ball milling has been applied in numerous solvent-free carbon-carbon bond formations. In many cases, these transformations proved superior to the analogous reactions performed in solution. The reaction scope involves purely organic addition and coupling reactions, transformations involving metals (in stoichiometric and catalytic amounts) as well as asymmetric organocatalyses.

Anti-aldol products with up to >99 % enantiomeric excess (ee) have been obtained by proline catalysis in excellent yields under experimentally simple solvent-free conditions. Efficient mixing of all the components is accomplished by applying a mechanochemical technique (ball milling). The catalysis is air and moisture tolerant and can be performed with non-purified starting materials. Even mixtures of solely solid compounds react, giving (mostly solid) products through a partially homogeneous (honey-like) intermediate melt. Since the reactant ratio is almost 1:1 (avoiding the common excess of ketone), the product isolation is easy leading to high aldol product yields.

Ball milling is a mechanochemical technique, which is widely applied to the grinding of minerals into fine particles and the preparation and modification of inorganic solids.[1] Its use in synthetic organic chemistry is relatively scarce, and the few reported examples include the functionalization of fullerenes, [2a] the reductive benzylation of malonitrile, [2b] the preparation of phosphorus ylides, [3] the protection of amines, [4] and Heck-type cross-coupling reactions.[5] The latter transformation caught our attention as it represents a scalable metal catalysis under solvent-free reaction conditions.[6] Utilizing otherwise cheap and simple starting materials, it allows a significant decrease in the amount of harmful organic reagents, thus leading to an improved and benign chemical synthesis.As impressive advances have recently been achieved in asymmetric organocatalysis [7] and with the vision that such metal-free reactions could benefit from the inherent solventfree conditions of the ball-milling technology, we initiated a program that studies a combination of both approaches.The alkaloid-mediated asymmetric opening of a cyclic meso anhydride was studied as the initial organocatalytic test reaction in the ball mill (Scheme 1).[8] Usually this reaction is performed at low temperatures (e.g., À60 8C) in an organic solvent, such as toluene or toluene/carbon tetrachloride mixtures, with methanol or benzyl alcohol as the nucleophile; products with high enantiomeric excess (up to 99 % ee) are formed after 24-48 hours in almost quantitative yields. The solvent-free variant was performed in a commercially available planetary micromill with two 45-mL grinding bowls containing 5-mm diameter balls, both composed of chemically inert and nonabrasive zirconium oxide. To allow comparison with previous results obtained in solution, structurally related, yet solid, starting materials (anhydride 1 and p-methylbenzyl alcohol (2) in combination with quinidine) were chosen. To prevent "overheating" of the reaction mixture, a milling cycle with a rotational speed of 250 rpm for 25 min followed by a 5-min cooling pause (to be repeated for 24-36 h until full consumption of the educts) was selected. [9] Under those conditions, the following observations were made: 1) The solvent-free asymmetric anhydride opening proceeded well and afforded hemiester 3 in high yield (91 %). 2) An enantioselective excess of 61 % ee was achieved, which compares well with reactions performed in solution at comparable temperatures (ambient and higher). 3) Whereas the reaction in solution generally requires three equivalents of the nucleophile to achieve high conversion after a reasonable reaction time, the ball-milling conditions allow the amount of this starting material to be lowered to one equivalent without significantly affecting the yield. As a consequence, a tedious extractive workup can be avoided and a simple acid wash to remove the alkaloid yields the hemiester in high purity.[10] Scheme 1. Alkaloid-mediated asymmetric opening of a cyclic me...