Solvent-free Knoevenagel condensations and Michael additions in the solid state and in the melt with quantitative yield

Organic synthesis by Twin Screw Extrusion (TSE): continuous, scalable and solvent-free

“…Kaupp et al first investigated the Knoevenagel condensation between vanillin and barbituric acid in the solid state, 10 and Stolle et al successfully highlighted the potential of this system to be carried out on a larger scale mechanochemically, via planetary ball milling. 8,9 We therefore chose this as the first organic reaction to be studied by twin screw extrusion, and subsequently extended it to include the reaction of barbituric acid with two other aldehydes, veratraldehyde and 5-bromovanillin (Scheme 1).…”

“…(Scheme 2) by ball milling. 10 Unfortunately we could not reproduce this reaction in the ball mill, obtaining instead a mixture of unidentified products together with the starting materials. However, in our hands the reaction was successful by TSE as discussed below.…”

“…[1][2][3][4][5] Avoiding toxic solvents not only decreases potential hazards, but can also reduce the overall cost of a process. 5 A variety of materials and compounds have been prepared mechanochemically including metal alloys, 6 metal organic frameworks (MOFs), 7 and organic compounds from reactions such as the Knoevenagel condensation [8][9][10] and Wittig reaction, 11 amongst others. 12 However, two main drawbacks of mechanochemical synthesis are the general lack of both temperature control and scalability.…”

“…12 In particular, several successful mechanochemical condensation reactions have been reported, including the Knoevenagel condensation and Aldol reaction. 8,9 , 17 , 10 Other examples of organic reactions performed mechanochemically include the Wittig reaction, Diels-Alder, click and Suzuki reactions, some of which usually require quite stringent conditions in their conventional solution-based synthesis such as the use of dry solvents and inert atmospheres. However, there are several examples where ball milling has been done successfully without such rigorous conditions.…”

Organocatalytic clean synthesis of densely functionalized 4H-pyrans by bifunctional tetraethylammonium 2-(carbamoyl)benzoate using ball milling technique under mild conditions

“…Subsequently, some specific books and review papers have been published on the topic. Some typical examples include the carbon-carbon or carbon-heteroatom bond formation, oxidation by solid oxidants, asymmetric organocatalytic reactions, dehydrogenative coupling, and peptide or polymeric material synthesis (9,(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31). Furthermore, organocatalysis, namely the use of small organic molecules to catalyze organic transformations, is a relatively new and popular field within the domain of organic synthesis.…”