In 2013, we reported the CuCl catalyzed and base-assisted solvent free mechanochemical coupling reaction between poorly nucleophilic sulfonamides and (thio)isocyanates to furnish various sulfonyl(thio)urea compounds[1]. Sulfonyl-ureas have been recognized as one of the most successful class of drugs used in combating Type II diabetes (estimated 450 million people afflicted worldwide in 2012[2]). Using our green and simple protocol, we have successfully synthesized several sulfonyl-(thio)urea compounds, including two first generation anti-diabetic sulfonyl-urea drugs, namely Tolbutamide� (or Orinase�), and Chlorpropamide� in high yields. A second generation drug, Glibenclamide�, was also obtained via a two-step mechanochemical process[3]. In addition, we also developed and successfully extended the mechanochemical CuCl catalysis to conduct the first direct coupling of arylsulfonamides with carbodiimides to afford arylsulfonyl-guanidines, a motif present in various biologically active compounds. This is a novel coupling reaction that works poorly in solution but we achieved high to excellent yields using mechanosynthesis. The presented results demonstrate how mechanochemical synthesis can address the explicit demands from pharmaceutical industries to develop cleaner, more efficient and low-solvent synthetic procedures [4] and we believe that the presented transition-metal catalysed and solvent-free strategy for sulfonyl-(thio)urea and sulfonyl-guanidine synthesis will be highly attractive for modern medicinal and pharmaceutical synthesis. Tan et al., Chem Commun., 2014 , Advance Article, DOI: 10.1039/c3cc47905fInternational Diabetes Federation  Diabetes Atlas 2012 update: http://www.idf.org/sites/default/files/5E_IDFAtlasPoster_2012_EN.pdf S?trukil et al., Chem. Commun., 2012 , 48, 12100.Shearouse et al., Curr. Opin. Drug Discovery Dev., 2009 , 12, 772.

Mechanochemical catalytic synthesis of pharmaceutically relevant sulfonyl-ureas, -thioureas and -guanidines

248th National Meeting (2014)

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