Solvent-free ball-milling conditions

One of the most studied processes is the direct intermolecular asymmetric aldol condensation catalysed by proline and primary amines, which generally uses DMSO as solvent. The same reaction has been demonstrated to also occur using mechanochemical techniques, under solvent-free ball-milling conditions. This chemistry is generally referred to as enamine catalysis , since the electrophilic substitution reactions in the a-position of carbonyl compounds occur via enamine intermediates, as outlined in the catalytic cycle shown in Scheme 1.1. A ketone or an a-branched aldehyde, the donor carbonyl compound, is the enamine precursor and an aromatic aldehyde, the acceptor carbonyl compound, acts as the electrophile. Scheme 1.1 shows the TS for the ratedetermining enamine addition step, which is critical for the achievement of enantiocontrol, as calculated by Houk. ... 

Naimi-Jamal et al. reported that anhydrous piperazine is an efficient organocata-lyst for the preparation of 2-amino-4ff-pyrans 158 and tetrahydro //-chromenes 159 via a three-component condensation under solvent-free ball-milling conditions at ambient temperature [47]. Without the presence of the catalyst, the reaction of p-chlorobenzaldehyde, malononitrile, and ethyl acetoacetate did not take place, even by heating at 80°C. However, an excellent yield of products was obtained by ball milling... 

Required Schiff base substrates were also prepared in solvent-free ball-mill conditions by mechanochemical transimination reaction. Grinding of an equimolar amount of the methyl ester of glycine hydrochloride and benzophenone imine for 3 h exclusively produced Schiff base (Scheme 2.60). Aqueous washing eliminated ammonium chloride, and the pure product was obtained without recrystallization in nearly quantitative yield. The reaction time was reduced to 3h compared with one night for the synthesis in solution. 

Recently, Lamaty and coworkers [70] demonstrated asymmetric phase-transfer catalyzed alkylation of fert-butyl glycinate-benzophenone Schiff base under solvent-free ball milling conditions (Scheme 21.33). The reaction proceeds with different alkylating agents in the presence of the cinchonidine-derived ammonium salt (10mol%) with very high yields (91-97%). This protocol reduces the reaction time however, the enantioselectivity (36-75% ee) is lower compared to conventional method with solvents (>90% ee) [71]. 

The enantioselective Michael addition of aldehydes R CH2CHO to nitroalkenes R CH=CHN02 in aqueous solution was compared with the reaction performed under solvent-free ball-milling conditions. From the range of pyrrolidine-derived organocatalysts (325), O-lauroyl-trans-4-hydroxyproline worked best in the aqueous media, whereas (325) proved to be most efficient in the ball-milling technique. ... 

Szuppa T, Stolle A, Ondruschka B, Hopfe W. An alternative solvent-free synthesis of nopinone under ball-milling conditions investigation of reaction parameters. ChemSusChem 2010 3 1181-91. 

Fteproduced Irom Tullberg Schacher F, Peters D. Frejd T. Solvent-free Heck-Jeffery reactions under ball-milling conditions applied to the synthesis of unnatural amino acids precwsors and indoles. Synthesis 2006 1183-9. With permission from Thieme PubHshers. 

Fteproduced Horn Jorres M. Mersmann S, Raabe G, Bokn C. Organocatalytic solvent-free hydrogen bonding mediated asymmetric Michael additions under ball milling conditions. Green Chem 2013 15 612-6. With permission from the Ftoyal Society of Chemistry. 

Reproduced from Herndndez JG, Garcfa-Ldpez V, Juaristi Solvent-free asymmetric aldol reaction organocatalyzed by (S)-prollne-contalnlng thiodipeptides under ball-milling conditions. Tetrahedron 2012 68 92-7. Copyright (2012), with permission from Elsevier. 

Reproduced with permission from Machuca E, Rojas Y, Juarlsti E Synthesis and evaluation of (S)-prolhe-contalnlng a. p-dipeptides as organocatalysts In solvent-free asymmetric aldol reactions under ball-milling conditions. Asian J Org Chem 2015 4 46-53. Copyright (2015), Wiley. 

Reproduced from Dong Y-W, Wang G-W, Wang L. Solvent-free synthesis of naphthopyrans under ball-milling conditions. Tetrahedron 2008 64 10148-54. Copyright (2008), with permission from Elsevier. 

Su W, Yu J, Li Z, Jiang Z. Solvent-free cross-dehydrogenative coupling reactions under high speed ball-milling conditions applied to the synthesis of functionahzed tetrahy-droisoquinolines. J Org Chem 2011 76 9144-50. 

Lamaty and collaborators have carried out solvent-free synthesis of nitrones in a ball mill [43]. Equimolar amounts of various aldehydes and A -substituted-hydrox-ylamines were used in conjunction with sodium bicarbonate (Scheme 3.64). For stoichiometric reaction between benzaldehyde and AT-methylhydroxylamine hydrochloride, small amount of dichloromethane was used. This reaction proceeded as a one-step condensation to give the corresponding nitrones in nearly quantitative yields, without the need to exclude air and moisture, in a shorter reaction time than by classical methods, but with comparable yields, where excess of reagents under inert atmosphere are reacted at room temperature or under heating for 1 or 2days (selected results. Table 3.32). Furthermore, the F,Z-isomeric ratio of the products obtained in ball-milling conditions were identical to those already reported in literature all the nitrones were in the more stable Z-form, with the exception of A -(naphth-2-ylmethylidene) methylamine A -oxide, known to be in the F-form. Microwave-assisted reactions gave lower yields than ball mill. 

Reproduced Hvm Zhu X, Zhang Q. Su W. Solvent-free N-arylatlon of amines with arylboronic acids under ball milling conditions. RSC Adv 2014 4 22775-8, with permission Horn the Royal Society of Chemistry. 

Michael additions of aldehydes to nitroalkene with catalyst Cl can also be performed under solvent-free conditions in a ball-mill. The reaction was considerably more efficient under ball-milling conditions than with conventional stirring. Ball-milling reactions proceeded faster and afforded the... 

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