Synlett 2009(17): 2882-2883  
DOI: 10.1055/s-0029-1217993
SPOTLIGHT
© Georg Thieme Verlag Stuttgart ˙ New York

1,3-Disubstituted Thioureas: Versatile Building Blocks for the Construction of Heterocycles

Harisadhan Ghosh*
Department of Chemistry, Indian Institute of Technology Guwa­hati, Guwahati 781 039, India.
e-Mail: h.ghosh@iitg.ernet.in;

Dedicated to my mentor, Professor Bhisma K. Patel for his constant encouragement.


Further Information

Publication History

Publication Date:
02 October 2009 (online)

Biographical Sketches

Harisadhan Ghosh was born in Burdwan, West Bengal, India, in 1983. He received his B.Sc. (2004) and M. Sc. (2006) degrees in ­Organic Chemistry from Visva-Bharati University, Santiniketan, India. Currently he is carrying out his Ph.D thesis under the supervision of Prof. Bhisma K. Patel as a CSIR junior research fellow. His research interests focus on hypervalent iodine mediated organic synthesis.

Introduction

Derivatives of thioureas, also known as thiocarbanilides, are versatile intermediates for the synthesis of flame retardants, vulcanization accelerators, plant protection agents, pesticides, fungicides, peptizing agents, corrosion inhibitors, and thiazole drugs. 1,3-Disubstituted thioureas are the main precursors for the synthesis of disubstituted carbodiimides [¹a] and trisubstituted guanidines. [¹b] The use of substituted thiourea as organocatalyst is common. [¹c]

Preparation:

Symmetrical 1,3-disubstituted thioureas can be easily prepared from amines and carbon disulfide in ethanol under reflux. [²] Whereas the unsymmetrical thioureas can be obtained by reacting an amine with an isothiocyanate of another amine (Scheme 1). [³]

Scheme 1 Synthesis of symmetrical and unsymmetrical thioureas

Most of the 1,3-disubstituted thioureas are stable solids, which makes them convenient for storage and transportation. The presence of both nitrogen and sulfur in thioureas, which are common heteroatoms in bioactive heterocycles, makes them important precursors for the construction of heterocycles.

Abstracts

(A) Synthesis of Thiazolidene-2-imines: 1,3-Disubstituted thioureas react with an enolizable ketone and 1,1′-(ethane-1,2-diyl)dipyridinium bistribromide (EDPBT) in the presence of triethylamine to give thiazolidene-2-imine derivatives. [4] The unsymmetrical thiourea gives a regioisomeric mixture of products and the regioselectivity is dependent on the pKa values of the corresponding amines attached to the thiourea moiety. [5]

(B) Synthesis of 2-Imino-4-thiazolidinones: A facile, general and high-yielding protocol for the synthesis of novel 2-imino-4-thiazolidinone has been described utilizing 1,3-disubstituted thiourea and chloroacetylchloride in solvent-free conditions at room temperature. [6]

(C) Synthesis of 1,3-Thiazolidin-2-imines: The reaction of 1,3-di­substituted thiourea with epichlorohydrin in DMF gives 2-arylim­ino-3-aryl-1,3-thiazolidine. [7] In this reaction, Yb(OTf)3 has been used as the catalyst and inversion of configuration was observed at the chiral center of the epoxide.

(D) Synthesis of N-Substituted 2-Amino Benzimidazoles and Benzoxazoles: N-substituted 2-amino benzimidazoles and benzoxazoles have been prepared using suitable desulfurizing agent, such as CuCl or diacetoxyiodobenzene (DIB), starting from in situ generated N-(2-amino/hydroxy aryl)thioureas. [8] [9]

(E) Synthesis of Substituted 2-Mercapto Benzimidazoles and 2-Amino Benzothiazoles by Catalytic Approaches: Substituted 2-mercapto benzimidazoles have been synthesized from their corresponding 1,3-disubstituted thioureas through S-alkylation followed by copper-catalyzed intramolecular N-arylation. [¹0] In a similar strategy Castillon and co-workers have reported the synthesis of 2-amino benzothiazoles by a palladium-catalyzed cyclization of o-bromo­phenylthioureas. [¹¹] These types of heterocycles have immense importance in medicinal chemistry.

(F) Synthesis of N,N′-Disubstituted Thiobarbituric Acids: 1,3-Di­substituted 2-thiobarbituric acids have been prepared in excellent yield from 1,3-disubstituted thioureas, via an acylation-cyclization strategy. [¹²] These heterocycles have pharmaceutical importance as anticonvulsants, immunotropic, anti-inflammatory, and antineoplastic agents as well as in the synthesis of other biologically active compounds.

(G) Synthesis of Triazoles: Chorev and co-workers have reported a thiophile-promoted synthesis of disubstituted 4H-[1,2,4]-triazol-3-ylamines. [¹³] When 1,3-disubstituted thiourea was reacted with formic hydrazide and mercury(II) acetate as thiophile, the reaction mixture produced acyl hydrazide adduct, which was cyclized to the corresponding [1,2,4]triazole under acidic conditions.

    References:

  • 1a Williams A. Ibrahim IT. Chem. Rev.  1981,  81:  589 
  • 1b Ramadas K. Janarthanan N. Pritha R. Synlett  1997,  1053 
  • 1c Zhang Z. Schreiner PR. Chem. Soc. Rev.  2009,  38:  1187 
  • 2 Vogel AI. Tatchell AR. Furnis BS. Hannaford AJ. Smith PWG. Vogel’s Textbook of Practical Organic Chemistry   Pearson; Prentice Hall: 2005. 5th Ed., p.966 
  • 3 Nath J. Ghosh H. Yella R. Patel BK. Eur. J. Org. Chem.  2009,  1849 
  • 4 Singh CB. Murru S. Kavala V. Patel BK. Org. Lett.  2006,  8:  5397 
  • 5 Murru S. Singh CB. Kavala V. Patel BK. Tetrahedron  2008,  64:  1931 
  • 6 Yella R. Ghosh H. Patel BK. Green Chem.  2008,  10:  1307 
  • 7 Su W. Liu C. Shan W. Synlett  2008,  725 
  • 8 Wang X.-J. Zhang L. Xu Y. Krishnamurthy D. Senanayake CH. Tetrahedron Lett.  2004,  45:  7167 
  • 9 Ghosh H. Yella R. Nath J. Patel BK. Eur. J. Org. Chem.  2008,  6189 
  • 10 Murru S. Patel BK. Bras JL. Muzart J. J. Org. Chem.  2009,  74:  2217 
  • 11 Bened C. Bravo F. Uriz P. Fernandez E. Claver C. Castillon S. Tetrahedron Lett.  2003,  44:  6073 
  • 12 Heath PC. Huang CQ. Lowe RF. McCarthy JR. Weigel LO. Whitten JP. Tetrahedron Lett.  2001,  42:  1607 
  • 13 Natarajan A. Guo Y. Arthanari H. Wagner G. Halperin JA. Chorev M. J. Org. Chem.  2005,  70:  6362 

    References:

  • 1a Williams A. Ibrahim IT. Chem. Rev.  1981,  81:  589 
  • 1b Ramadas K. Janarthanan N. Pritha R. Synlett  1997,  1053 
  • 1c Zhang Z. Schreiner PR. Chem. Soc. Rev.  2009,  38:  1187 
  • 2 Vogel AI. Tatchell AR. Furnis BS. Hannaford AJ. Smith PWG. Vogel’s Textbook of Practical Organic Chemistry   Pearson; Prentice Hall: 2005. 5th Ed., p.966 
  • 3 Nath J. Ghosh H. Yella R. Patel BK. Eur. J. Org. Chem.  2009,  1849 
  • 4 Singh CB. Murru S. Kavala V. Patel BK. Org. Lett.  2006,  8:  5397 
  • 5 Murru S. Singh CB. Kavala V. Patel BK. Tetrahedron  2008,  64:  1931 
  • 6 Yella R. Ghosh H. Patel BK. Green Chem.  2008,  10:  1307 
  • 7 Su W. Liu C. Shan W. Synlett  2008,  725 
  • 8 Wang X.-J. Zhang L. Xu Y. Krishnamurthy D. Senanayake CH. Tetrahedron Lett.  2004,  45:  7167 
  • 9 Ghosh H. Yella R. Nath J. Patel BK. Eur. J. Org. Chem.  2008,  6189 
  • 10 Murru S. Patel BK. Bras JL. Muzart J. J. Org. Chem.  2009,  74:  2217 
  • 11 Bened C. Bravo F. Uriz P. Fernandez E. Claver C. Castillon S. Tetrahedron Lett.  2003,  44:  6073 
  • 12 Heath PC. Huang CQ. Lowe RF. McCarthy JR. Weigel LO. Whitten JP. Tetrahedron Lett.  2001,  42:  1607 
  • 13 Natarajan A. Guo Y. Arthanari H. Wagner G. Halperin JA. Chorev M. J. Org. Chem.  2005,  70:  6362 

Scheme 1 Synthesis of symmetrical and unsymmetrical thioureas