Asymmetric Organocatalysis under Ball Milling Conditions

Sonochemical activation can strongly improve a wide range of chemical transformations however, the influence of ultrasound on asymmetric organocatalytic reactions is stiU a very weakly explored area. Based on reported examples it could be a very attractive and useful technique for accelerating organocatalytic reactions in heterogeneous systems (e.g., phase-transfer catalysis or reaction with solid substrates on water). Evaluation of the usefulness of ultrasound in homogenous systems (e.g., in enamine activation) is still difficult and this topic requires more systematic studies in the future. 

Asymmetric Organocatalysis under Ball Milling Conditions 

The use of ball nulls to assist solvent-free asymmetric organocatalytic processes is stih very rare. In 2006 Bohn and coworkers [59] reported the first examples of such apphcations. This technique was used in a prohne catalyzed aldol reaction between ketones and aromatic aldehydes. The asymmetric organocatalytic aldol reaction was very intensively studied since the pioneering work by list and Barbas in 2000/2001 [21]. In the vast majority of cases it was performed in different organic solvents (e.g., DMSO, DMF), but in recent years several eco-friendly solvent-free, or using water, protocols have been reported. Such reactions, avoiding the use of organic solvents, are especiaUy preferred in industrial-scale processes and the synthesis of pharmaceuticals. 

The reactions of solid ketones with solid aldehyde proceed much more slowly (1-1.6 days) than the reactions of liquid ketones, even though the use of solid reactants in many cases resulted in formation of a liquid phase. The reaction was also possible in ball mill when no phase change was observed (e.g., for l-Boc-4-piperidone withp-nitrobenzaldehyde). In such cases the mechanochemical method was faster (1-1.6 days) compared with conventional stirring (5-7 days). 

The application of ball mills in a proUne-catalyzed solvent-free organocatalytic aldol reaction has several advantages reactions proceed faster than under magnetic stirring, often with a high yield of anti-aldol products and very high diastereo-selectivities and enantioselectivities. Reactions proceed efficiently and cleanly with almost equimolar amounts of reactants and with a catalytic amount of inexpensive proline and, in addition, isolation of the product from the reaction mixture is easier. 

Catalyst (mol%) Additive (mol%) Time (h) Temperature (°q Yield (%) Anti/syn ee (%) 

---

Asymmetric Organocatalysis under Ball Milling Conditions... 

---