Abstract
In this review, the recent progress in the synthesis of ureas, thioureas and guanidines by solid-state mechanochemical ball milling is highlighted. While the literature is abundant on their preparation in conventional solution environment, it was not until the advent of solvent-free manual grinding using a mortar and pestle and automated ball milling that new synthetic opportunities have opened. The mechanochemical approach not only has enabled the quantitative synthesis of (thio)ureas and guanidines without using bulk solvents and the generation of byproducts, but it has also been established as a means to develop "click-type" chemistry for these classes of compounds and the concept of small molecule desymmetrization. Moreover, mechanochemistry has been demonstrated as an effective tool in reaction discovery, with emphasis on the reactivity differences in solution and in the solid state. These three classes of organic compounds share some structural features which are reflected in their physical and chemical properties, important for application as organocatalysts and sensors. On the other hand, the specific and unique nature of each of these functionalities render (thio)ureas and guanidines as the key constituents of pharmaceuticals and other biologically active compounds.
Highlights
The mechanochemical approach has enabled the quantitative synthesis ofureas and guanidines without using bulk solvents and the generation of byproducts, but it has been established as a means to develop "click-type" chemistry for these classes of compounds and the concept of small molecule desymmetrization
The urea molecule played the central role in the development of organic chemistry since its first documented synthesis in 1828 when the German chemist Friedrich Wöhler prepared it starting from ammonium cyanate (Scheme 1) [1]
In the course of our studies on mechanochemical desymmetrization, we investigated the reaction of o-pda and mono-urea 36 with phenyl isocyanate under the milling conditions used for the synthesis of bis-thioureas [35]
Summary
The urea molecule played the central role in the development of organic chemistry since its first documented synthesis in 1828 when the German chemist Friedrich Wöhler prepared it starting from ammonium cyanate (Scheme 1) [1]. This study demonstrated that solid-state ball milling can efficiently be employed for desymmetrization of ortho- and para-phenylenediamines, enabling selective functionalization of small symmetrical molecules through the extension of molecular structure in a one-pot twostep mechanochemical sequence Another typical synthetic method for the preparation of thioureas, if the desired isothiocyanate is not available, is the condensation of an amine with carbon disulfide [36]. The attempted addition of p-toluenesulfonamide to N,N'-dicyclohexylcarbodiimdie (DCC) failed in solution, and under solvent-free and LAG mechanochemical conditions (Scheme 20a) When this mixture was milled for 2 hours neat in the presence of 5 mol % of CuCl, the product 45a was obtained in 81%, while LAG (nitromethane, η = 0.25 μL mg−1) resulted in almost quantitative yield. With less reactive dialkyl carbodiimides the yields were poor, the introduction of an aromatic substituent (phenyl or 4-methoxyphenyl) in the carbodiimide component significantly increased the reactivity resulting in >90% conversion and >80% isolated yields of biguanides 49f and 49g (Table 1)
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