Document Type: Original Article

Authors

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

Abstract

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.

Graphical Abstract

Keywords

Main Subjects

 

  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.