Document Type: Original Article


1 Medicinal Organic Chemistry Laboratory (MOCL), School of Pharmacy, Faculté des Sciences de la Santé, Universitéd'Abomey-Calavi, Campus du Champ de Foire, 01 BP 188, Cotonou, Bénin.

2 Medicinal Chemistry (CMFA), Louvain Drug Research Institute, UCLouvain. 73, B1.73.10Av. E. Mounier B-1200 Brussels, Belgium, E.U.

3 Pharmacognosy Recherch Group (GNOS), Louvain Drug Research Institute, UCLouvain. 72, Bte B1.72.03, Av. E. Mounier B-1200 Brussels, Belgium, E.U.

4 Medicinal Chemistry, College of Pharmacy. Medical Science Building, P6-33, PO. Box 100485, University of Florida, Gainesville, FL 32610, USA.


In a medicinal chemistry-driven drug discovery program aimed at synthesizing new topically-acting trypanocidal chemotherapeutic agents to treat the African trypanosomiasis, our research group became interested recently in new chemical entities bearing in their center a thiohydrazide (C=S) NHNH or thiosemicarbazide NH(C=S) NHNH central template flanked on both sides by lipophilic aryl moieties. In this context, benzopinacolone was found to react as a rather unusual acylating agent via a mechanism (addition/elimination) involving addition of the nucleophile (a thiosemicarbazide derivative), formation of a resulting tetrahedral adduct, and expulsion of a trityl anion moiety as leaving group, presumably through an anchimeric assistance effect by intramolecular participation of the thioureido side-chain via hydrogen bond formation. The present incidental discovery should be considered at this level as a first inception and further work is now being directed at closely examining the detailed mechanism of this exceptional chemical pathway, in a reaction involving the unusual breaking of a carbon-carbon bond (carbon acid as leaving group) in the rate-determining step and involving the decomposition of the intermediate tetrahedral adduct to get the final unexpected N-thiobenzoyl-thiosemicarbazide.

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  1. Kasséhin U. C., Gbaguidi F. A., Kapanda C.N., McCurdy C., Poupaert J.H. Solvent effect and catalysis in the synthesis of thiosemicarbazone derivatives from ketones and 4’-phenylthiosemicarbazide. Afr. J. Pure Appl. Chem2014; 8:110.
  2. Kasséhin U.C., Gbaguidi F. A., McCurdy C., Poupaert J.H. Trypanocidalactivity of a thioacyl-thiosemicarbazidederivativeassociatingbothimmunostimulating thalidomide and anti-parasiticthiosemicarbazide pharmacophores. J. Chem. Pharm. Res2015 ;7 :48.
  3. Herschlag D., Jencks W.P. Nucleophiles of high reactivity in phosphoryl transfer reactions: alpha-effect compounds and fluoride ion. J. Am. Chem. Soc.1990; 112:1951.
  4. Bunce E., Um I.H. The α-effect and its modulation by solvent. Tetrahedron 2004; 60:7801.
  5. Kalia J, Raines RT. Hydrolytic stability of hydrazones and oximes. Angew. Chem. 2008, 120:7633.
  6. Umamatheswari S, Kabilan S. Synthesis and antimicrobial studies of novel 2,4-diaryl-3-azabicyclo [3.3.1] nonan-9-one 4'-phenylthiosemicarbazones. J. Enzyme. Inhib. Med. Chem. 2011; 26:9.
  7. Pandeya S. N., Yogeeswari P., Sriram D., de Clercq E., Pannecouque C., Witvrouw M. Synthesis and screening for anti-HIV activity of some N-Mannich bases of isatin derivatives. Chemotherapy1999; 4:6.
  8. Houngue H.D., Aguida B.S., Kasséhin U.C., Poupaert J.H., Gbaguidi F. A. Biological evaluation of a series of thiosemicarbazones. Targeting the large subunit ribosomal protein El42 from human 80S ribosomes. MOJ. Biorg. Org. Chem. 2017; 1:1.
  9. Mallari J. P., Guiguemde W. A., Guy R. K. Antimalarial activity of thiosemicarbazones and purine derived nitriles Bioorg. Med. Chem. Lett.2009; 19:3546.
  10. Kasséhin U. C., Gbaguidi F. A., McCurdy C., Poupaert J.H., Synthesis of antitrypanosomalthiosemicarbazones using anthranilic acid as an innovative green nucleophilic catalyst. J. Chem. Pharm. Res.2014; 6:607.
  11. Sayer J. M., Jencks W. P. General base catalysis of thiosemicarbazone formation. J. Am. Chem. Soc.1969; 91:6353.
  12. Dunn P. J. The importance of green chemistry in process research and development. Chem. Soc. Rev. 2012; 41:1452.
  13. P. T. Anastas and J. C. Warner, Green Chemistry: Theory and Practice. Ed. New-york, Oxford University Press, 1998.135 pages.
  14. Anastas P.T, Eghbali N. Green chemistry: principles and practice. Chem. Soc. Rev.2010; 39:301.
  15. Anastas P.T., Kirchhoff MM. Origins, current status, and future challenges of green chemistry Acc. Chem. Res.2002;35:686.
  16. Anastas P.T. Green Chemistry Next: Moving from Evolutionary to Revolutionary. Aldrichimica. 2015; 48:3.
  17. Anastas P. T., Lankey R. L. Life cycle assessment and green chemistry: the yin and yang of industrial ecology. Green Chem. 2000; 2:289.
  18. Sheldon R.A. Fundamentals of green chemistry: efficiency in reaction design. Chem. Soc. Rev. 2012; 41:1437.
  19. Wubbels G.G. Catalysis of photochemical reactions. Acc. Chem. Res.1983; 16:285.
  20. Cohen E. La reduction des cétonesaromatiques. Rec. trav. Chim. 1920; 39:243.
  21. Ciamician G., Silber P. Chemischelichtwirkungen. Ber. 1900; 33: 2911.
  22. Potey L.C., Kosalge S.B., Sarode R.S. Synthesis and analysis of benzopinacol from benzophenone by photoreduction in green chemistry. Int. j. pharm. drug. anal. 2014; 2: 55.
  23. Dormán G., Nakamura H., Pulsipher A., Prestwich G.D. The Life of Pi Star: Exploring the exciting and forbidden worlds of the benzophenone photophore. Chem. Rev. 2016;116: 1528.
  24. Migita M. Studies on molecular-rearrangements of α–glycols IV: Influence of substituents on a pinacone in its reactivity. Reduction of di-p-methoxy-benzophenone. Bcsj1932 ;7 :334.
  25. Zhao G., Jiang T., Gao H., Han B., Huanga J., Suna D. Mannich reaction using acidic ionic liquids as catalysts and solvents. Green Chem.2004 ;6 :75.
  26. Gómez-Martínez M., Baeza A., Alonso D.A. Pinacol Rearrangement and direct nucleophilic substitution of allylic alcohols promoted by graphene oxide and graphene oxide CO2H. Chem.Cat. Chem.2017;9: 1032.
  27. Drosos N., Ozkal E., Cacherat B., Thiel W., Morandi B. Catalytic reductive pinacol-type rearrangement of unactivated 1,2-diols through a concerted, stereoinvertive mechanism. Angew. Chem.2017; 56:13377.
  28. Beadle J.R., Korzeniowski S.H., Rosenberg D.E., Garcia-Slanga B.J., Gokel G.W. Phase-transfer-catalyzed Gomberg-Bachmann synthesis of unsymmetrical biarenes: a survey of catalysts and substrates. J. Org. Chem.1984; 49:1594.
  29. Kasséhin U.C., Gbaguidi F.A., Kapanda C.N., McCurdy C., Bigot A. K., Poupaert J.H. Electronic and steric effects in the control of the Anilinium chloride catalyzed condensation reaction between aldones and 4-phenylthiosemicarbazide. Afr. J. Pure Appl. Chem. 2013; 7:325.