Click Mechanochemistry: Quantitative Synthesis of “Ready to Use” Chiral Organocatalysts by Efficient Two‐Fold Thiourea Coupling to Vicinal Diamines

Abstract

Mechanochemical methods of neat grinding and liquid-assisted grinding have been applied to the synthesis of mono- and bis(thiourea)s by using the click coupling of aromatic and aliphatic diamines with aromatic isothiocyanates. The ability to modify the reaction conditions allowed the optimization of each reaction, leading to the quantitative formation of chiral bis(thiourea)s with known uses as organocatalysts or anion sensors. Quantitative reaction yields, combined with the fact that mechanochemical reaction conditions avoid the use of bulk solvents, enabled solution-based purification methods (such as chromatography or recrystallization) to be completely avoided. Importantly, by using selected model reactions, we also show that the described mechanochemical reaction procedures can be readily scaled up to at least the one-gram scale. In that way, mechanochemical synthesis provides a facile method to fully transform valuable enantiomerically pure reagents into useful products that can immediately be applied in their designed purpose. This was demonstrated by using some of the mechanochemically prepared reagents as organocatalysts in a model Morita-Baylis-Hillman reaction and as cyanide ion sensors in organic solvents. The use of electronically and sterically hindered ortho-phenylenediamine revealed that mechanochemical reaction conditions can be readily optimized to form either the 1:1 or the 1:2 click-coupling product, demonstrating that reaction stoichiometry can be more efficiently controlled under these conditions than in solution-based syntheses. In this way, it was shown that excellent stoichiometric control by mechanochemistry, previously established for mechanochemical syntheses of cocrystals and coordination polymers, can also be achieved in the context of covalent-bond formation.

Organic Synthesis without Conventional Solvents

“…[27] Another example for a reaction enabled by mechanochemistry is the synthesis of an adamantoid cyclophosphazene. [34,35] Both products where isolated in more than 95 % yield. However, milling the starting material in the presence of LiCl (20 %) for 90 min resulted in the formation of the product in 53 % isolated yield (Scheme 3).…”

“…All attempts to prepare this compound in solution failed; a variety of solvents was tested at high temperature. [34,35] One of the newest discoveries of mechanochemistry are reactions that are catalyzed by enzymes. [28] Scheme 3.…”

Mechanochemistry assisted asymmetric organocatalysis: A sustainable approach

“…Mechanochemical methods of neat grinding and liquid-assisted grinding (LAG) have been applied to the synthesis of mono- and bis(thiourea)s in quantitative yield by using the click coupling of aromatic or aliphatic diamines with aromatic isothiocyanates (Scheme 9) [54]. The mechanochemically prepared chiral molecules were applied as organocatalysts in an enantioselective MBH reaction and as cyanide ion sensors in organic solvents.…”

CHAPTER 4. Asymmetric Organocatalytic Reactions under Ball Milling

“…Scheme 4.9 Asymmetric Morita-Baylis-Hillman addition reaction organocatalyzed by bis(thiourea) 12, synthesized in situ in a ball-mill 42. …”