Synthesis of Guanidines and Some of Their Biological Applications

  • Julian W. Shaw
  • David H. Grayson
  • Isabel Rozas
Part of the Topics in Heterocyclic Chemistry book series (TOPICS, volume 50)


Guanidine is one of the most versatile functional groups in chemistry; compounds containing this system have found application in a diversity of biological activities, and in this chapter, the advances in the field of the synthesis of guanidines are presented. First, the preparation of acyclic guanidines involving the reaction of an amine with an activated guanidine precursor followed by the deprotection to yield the corresponding free guanidine is discussed. Thiourea derivatives as guanidylating agents have been widely used as guanidine precursors using coupling reagents or metal-catalysed guanidylation. Alternatively, S-methylisothiourea has shown to be a very efficient guanidylating agent, and N,N′,N″-trisubstituted guanidines have also been used to install the guanidine functionality. Despite the similarity between urea and thiourea, the former has received much less attention; however, its application in guanidine synthesis has also been proved. Examples of the preparation of guanidines using cyanamides that react with derivatised amines as well as the use of copper-catalysed cross-coupling chemistry are also presented. Moreover, cyclic guanidines such as 2-aminoimidazolines (five-membered rings), 2-amino-1,4,5,6-tetrahydropyrimidines (six-membered rings) and 2-amino-4,5,6,7-tetrahydro-1H-1,3-diazepines (seven-membered rings) are present in many natural products and compounds of medicinal interest. Accordingly, an overview of the methods found in the literature for the preparation of these cyclic guanidines is presented. Finally, some biological applications of guanidines as DNA minor groove binders, kinase inhibitors and α2-noradrenaline receptors antagonists are discussed.


Guanidine Synthesis 









Camphor sulfonic acid


















Dess–Martin periodinane


Dimethyl sulfoxide


Deoxyribonucleic acid










Hydrogen bond


Lithium diisopropylamine


Lithium hexamethyldisilazide




Minor groove binder












Positron emission tomography














Pyridinium tribromide


Ribonucleic acid


Recovered starting material


tetra-Butylammonium bromide








Trifluoroacetic acid


Trifluoroacetic anhydride










Turnover number








4-Toluenesulfonyl chloride




  1. 1.
    Menor-Salvan C, Marin-Yaseli MR (2012) Chem Soc Rev 41:5404–5415CrossRefGoogle Scholar
  2. 2.
    Haas DJ, Harris DR, Mills HH (1965) Acta Crystallogr 19:676–679CrossRefGoogle Scholar
  3. 3.
    Yamada T, Liu X, Englert U, Yamane H, Dronskowski R (2009) Chem Eur J 15:5651–5655CrossRefGoogle Scholar
  4. 4.
    Parker EJ, Pratt AJ (2010) In: Hughes AB (ed) Amino acids, peptides, proteins in organic chemistry. Wiley-VCH, Weinheim, pp 1–82Google Scholar
  5. 5.
    Sokalingam S, Raghunathan G, Soundrarajan N, Lee SG (2012) PLoS One 7:e40410CrossRefGoogle Scholar
  6. 6.
    Dougherty DA (2013) Acc Chem Res 46:885–893CrossRefGoogle Scholar
  7. 7.
    Crowley PB, Golovin A (2005) Proteins 59:231–239CrossRefGoogle Scholar
  8. 8.
    Blanco F, Kelly B, Sanchez-Sanz G, Trujillo C, Alkorta I, Elguero J, Rozas I (2013) J Phys Chem B 11:11608–11616CrossRefGoogle Scholar
  9. 9.
    Kelly B, Sanchez-Sanz G, Blanco F, Rozas I (2012) Comput Theor Chem 998:64–73CrossRefGoogle Scholar
  10. 10.
    Gund P (1972) J Chem Ed 49:100–103CrossRefGoogle Scholar
  11. 11.
    Blanco F, Kelly B, Alkorta I, Rozas I, Elguero J (2011) Chem Phys Lett 511:129–134CrossRefGoogle Scholar
  12. 12.
    Rozas I, Sanchez-Sanz G, Alkorta I, Elguero J (2013) J Phys Org Chem 26:378–385CrossRefGoogle Scholar
  13. 13.
    Sączewski F, Balewski Ł (2013) Expert Opin Ther Pat 23:965–995CrossRefGoogle Scholar
  14. 14.
    Berlinck RG, Trindade-Silva AE, Santos MF (2012) Nat Prod Rep 29:1382–1406CrossRefGoogle Scholar
  15. 15.
    Kishi Y, Aratani M, Fukuyama T, Nakatsubo F, Goto T, Inoue S, Tanino H, Sugiura S, Kakoi H (1972) J Am Chem Soc 94:9217–9219CrossRefGoogle Scholar
  16. 16.
    Suhs T, Konig B (2006) Mini Rev Org Chem 3:315–331CrossRefGoogle Scholar
  17. 17.
    Kim KS, Qian LG (1993) Tetrahedron Lett 34:7677–7680CrossRefGoogle Scholar
  18. 18.
    Chen H-M, Li G, Cao L-H (2008) J Chin Chem Soc 55:474–478CrossRefGoogle Scholar
  19. 19.
    Diez-Cecilia E, Kelly B, Perez C, Zisterer DM, Nevin DK, Lloyd DG, Rozas I (2014) Eur J Med Chem 81:427–441CrossRefGoogle Scholar
  20. 20.
    Kelly B, McMullan M, Muguruza C, Ortega JE, Meana JJ, Callado LF, Rozas I (2015) J Med Chem 58:963–977CrossRefGoogle Scholar
  21. 21.
    Cunha S, Rodrigues MT, da Silva CC, Napolitano HB, Vencato I, Lariucci C (2005) Tetrahedron 61:10536–10540CrossRefGoogle Scholar
  22. 22.
    O’Donovan DH, Rozas I (2011) Tetrahedron Lett 52:4117–4119CrossRefGoogle Scholar
  23. 23.
    Cunha S, Rodrigues MT (2006) Tetrahedron Lett 47:6955–6956CrossRefGoogle Scholar
  24. 24.
    Kelly B, Rozas I (2013) Tetrahedron Lett 54:3982–3984CrossRefGoogle Scholar
  25. 25.
    Ramadas K, Srinivasan N (1995) Tetrahedron Lett 36:2841–2844CrossRefGoogle Scholar
  26. 26.
    Shibanuma T, Shiono M, Mukaiyama T (1977) Chem Lett 575–576Google Scholar
  27. 27.
    Ohara K, Vasseur JJ, Smietana M (2009) Tetrahedron Lett 50:1463–1465CrossRefGoogle Scholar
  28. 28.
    Porcheddu A, De Luca L, Giacomelli G (2009) Synlett 3368–3372Google Scholar
  29. 29.
    Maryanoff CA, Stanzione RC, Plampin JN, Mills JE (1986) J Org Chem 51:1882–1884CrossRefGoogle Scholar
  30. 30.
    Isidro-Llobet A, Alvarez M, Albericio F (2009) Chem Rev 109:2455–2504CrossRefGoogle Scholar
  31. 31.
    Manimala JC, Anslyn EV (2002) Tetrahedron Lett 43:565–567CrossRefGoogle Scholar
  32. 32.
    Madalengoitia J, Flemer S (2007) Synthesis 1848–1860Google Scholar
  33. 33.
    Alonso-Moreno C, Antinolo A, Carrillo-Hermosilla F, Otero A (2014) Chem Soc Rev 43:3406–3425CrossRefGoogle Scholar
  34. 34.
    Kantam ML, Priyadarshini S, Joseph PJA, Srinivas P, Vinu A, Klabunde KJ, Nishina Y (2012) Tetrahedron 68:5730–5737CrossRefGoogle Scholar
  35. 35.
    Pottabathula S, Royo B (2012) Tetrahedron Lett 53:5156–5158CrossRefGoogle Scholar
  36. 36.
    Toy PH, Lam Y (eds) (2012) Solid-phase organic synthesis: concepts, strategies, applications. Wiley, HobokenGoogle Scholar
  37. 37.
    Drewry DH, Gerritz SW, Linn JA (1997) Tetrahedron Lett 38:3377–3380CrossRefGoogle Scholar
  38. 38.
    Josey JA, Tarlton CA, Payne CE (1998) Tetrahedron Lett 39:5899–5902CrossRefGoogle Scholar
  39. 39.
    Ube H, Uraguchi D, Terada M (2007) J Organomet Chem 692:545–549CrossRefGoogle Scholar
  40. 40.
    Powell DA, Ramsden PD, Batey RA (2003) J Org Chem 68:2300–2309CrossRefGoogle Scholar
  41. 41.
    Ma D, Xia C, Jiang J, Zhang J, Tang W (2003) J Org Chem 68:442–451CrossRefGoogle Scholar
  42. 42.
    Kim M, Mulcahy JV, Espino CG, Bois JD (2006) Org Lett 8:1073–1076CrossRefGoogle Scholar
  43. 43.
    Roizen JL, Zalatan DN, Bois JD (2013) Angew Chem Int Ed Engl 52:11343–11346CrossRefGoogle Scholar
  44. 44.
    Wang S, Romo D (2008) Angew Chem Int Ed Engl 47:1284–1286CrossRefGoogle Scholar
  45. 45.
    Feichtinger K, Zapf C, Sings HL, Goodman M (1998) J Org Chem 63:3804–3805CrossRefGoogle Scholar
  46. 46.
    Baker TJ, Rew Y, Goodman M (2000) Pure Appl Chem 72:347–354CrossRefGoogle Scholar
  47. 47.
    Wu YQ, Hamilton SK, Wilkinson DE, Hamilton GS (2002) J Org Chem 67:7553–7556CrossRefGoogle Scholar
  48. 48.
    Bernatowicz MS, Wu YL, Matsueda GR (1992) J Org Chem 57:2497–2502CrossRefGoogle Scholar
  49. 49.
    Yong YF, Kowalski JA, Thoen JC, Lipton MA (1999) Tetrahedron Lett 40:53–56CrossRefGoogle Scholar
  50. 50.
    Musiol HJ, Moroder L (2001) Org Lett 3:3859–3861CrossRefGoogle Scholar
  51. 51.
    Gagnon PE, Boivin JL, Dickson JH (1959) Can J Chem 37:520–524CrossRefGoogle Scholar
  52. 52.
    Rachlin S, Bramm E, Ahnfelt-Ronne I, Arrigoni-Martelli E (1980) J Med Chem 23:13–20CrossRefGoogle Scholar
  53. 53.
    Wang Z (2010) Comprehensive organic name reactions, reagents. Wiley, HobokenCrossRefGoogle Scholar
  54. 54.
    Elliott AJ, Morris PE Jr, Petty SL, Williams CH (1997) J Org Chem 62:8071–8075CrossRefGoogle Scholar
  55. 55.
    Atwal KS, Ferrara FN, Ahmed SZ (1994) Tetrahedron Lett 35:8085–8088CrossRefGoogle Scholar
  56. 56.
    Mitsunobu O, Yamada Y (1967) Bull Chem Soc (Japan) 40:2380–2382CrossRefGoogle Scholar
  57. 57.
    Dembinski R (2004) Eur J Org Chem 2004:2763–2772CrossRefGoogle Scholar
  58. 58.
    Feichtinger K, Sings HL, Baker TJ, Matthews K, Goodman M (1998) J Org Chem 63:8432–8439CrossRefGoogle Scholar
  59. 59.
    Fishlock D, Guillemette JG, Lajoie GA (2002) J Org Chem 67:2352–2354CrossRefGoogle Scholar
  60. 60.
    Olivier KS, Van Nieuwenhze MS (2010) Org Lett 12:1680–1683CrossRefGoogle Scholar
  61. 61.
    Jacobson GB, Westerberg G, Markides KE, Långström B (1996) J Am Chem Soc 118:6868–6872CrossRefGoogle Scholar
  62. 62.
    Ha HH, Kim JS, Kim BM (2008) Bioorg Med Chem Lett 18:653–656CrossRefGoogle Scholar
  63. 63.
    Looper RE, Haussener TJ, Mack JB (2011) J Org Chem 76:6967–6971CrossRefGoogle Scholar
  64. 64.
    Beletskaya IP, Cheprakov AV (2004) Coord Chem Rev 248:2337–2364CrossRefGoogle Scholar
  65. 65.
    Sambiagio C, Marsden SP, Blacker AJ, McGowan PC (2014) Chem Soc Rev 43:3525–3550CrossRefGoogle Scholar
  66. 66.
    Zhang H, Cai Q, Ma D (2005) J Org Chem 70:5164–5173CrossRefGoogle Scholar
  67. 67.
    Cohen T, Wood J, Dietz AG (1974) Tetrahedron Lett 15:3555–3558CrossRefGoogle Scholar
  68. 68.
    Paine AJ (1987) J Am Chem Soc 109:1496–1502CrossRefGoogle Scholar
  69. 69.
    Deng X, McAllister H, Mani NS (2009) J Org Chem 74:5742–5745CrossRefGoogle Scholar
  70. 70.
    Cortes-Salva M, Nguyen BL, Cuevas J, Pennypacker KR, Antilla JC (2010) Org Lett 12:1316–1319CrossRefGoogle Scholar
  71. 71.
    Hammoud H, Schmitt M, Bihel F, Antheaume C, Bourguignon JJ (2012) J Org Chem 77:417–423CrossRefGoogle Scholar
  72. 72.
    Beletskaya IP, Cheprakov AV (2012) Organometallics 31:7753–7808CrossRefGoogle Scholar
  73. 73.
    Xing H, Zhang Y, Lai Y, Jiang Y, Ma D (2012) J Org Chem 77:5449–5453CrossRefGoogle Scholar
  74. 74.
    Li J, Neuville L (2013) Org Lett 15:6124–6127CrossRefGoogle Scholar
  75. 75.
    Miyabe H, Yoshida K, Reddy VK, Takemoto Y (2009) J Org Chem 74:305–311CrossRefGoogle Scholar
  76. 76.
    Dardonville C, Goya P, Rozas I, Alsasua A, Martin I, Borrego J (2000) Bioorg Med Chem 8:1567–1577CrossRefGoogle Scholar
  77. 77.
    Rodriguez F, Rozas I, Ortega JE, Meana JJ, Callado LF (2007) J Med Chem 50:4516–4527CrossRefGoogle Scholar
  78. 78.
    Kan WM, Lin SH, Chern CY (2005) Synth Commun 35:2633–2639CrossRefGoogle Scholar
  79. 79.
    Hensler ME, Bernstein G, Nizet V, Nefzi A (2006) Bioorg Med Chem Lett 16:5073–5079CrossRefGoogle Scholar
  80. 80.
    McKay AF, Kreling ME (1957) Can J Chem 35:1438–1445CrossRefGoogle Scholar
  81. 81.
    European Patent, EP01986801990Google Scholar
  82. 82.
    Ye WP, Leow DS, Goh SLM, Tan CT, Chian CH, Tan CH (2006) Tetrahedron Lett 47:1007–1010CrossRefGoogle Scholar
  83. 83.
    Corey EJ, Grogan MJ (1999) Org Lett 1:157–160CrossRefGoogle Scholar
  84. 84.
    Yamamoto Y, Mizuno H, Tsuritani T, Mase T (2009) Tetrahedron Lett 50:5813–5815CrossRefGoogle Scholar
  85. 85.
    Li J (2009) Name reactions. Springer, Berlin, pp 332–333CrossRefGoogle Scholar
  86. 86.
    González-Rosende ME, Castillo E, Asíns B, Mamouni R, Sepúlveda-Arques J (2007) Tetrahedron 63:8709–8714CrossRefGoogle Scholar
  87. 87.
    Schroif-Gregoire C, Travert N, Zaparucha A, Al-Mourabit A (2006) Org Lett 8:2961–2964CrossRefGoogle Scholar
  88. 88.
    Zhou L, Chen J, Zhou J, Yeung YY (2011) Org Lett 13:5804–5807CrossRefGoogle Scholar
  89. 89.
    Bera S, Wallimann T, Ray S, Ray M (2008) FEBS J 275:5899–5909CrossRefGoogle Scholar
  90. 90.
    Guiheneuf S, Paquin L, Carreaux F, Durieu E, Meijer L, Bazureau JP (2012) Org Biomol Chem 10:978–987CrossRefGoogle Scholar
  91. 91.
    Li CM, Danishefsky SJ (2006) Tetrahedron Lett 47:385–387CrossRefGoogle Scholar
  92. 92.
    Olson DE, Roberts DA, Du Bois J (2012) Org Lett 14:6174–6177CrossRefGoogle Scholar
  93. 93.
    Hinman A, Du Bois J (2003) J Am Chem Soc 125:11510–11511CrossRefGoogle Scholar
  94. 94.
    Mulcahy JV, Du Bois J (2008) J Am Chem Soc 130:12630–12631CrossRefGoogle Scholar
  95. 95.
    Zhao B, Du H, Shi Y (2008) Org Lett 10:1087–1090CrossRefGoogle Scholar
  96. 96.
    Butler DCD, Inman GA, Alper H (2000) J Org Chem 65:5887–5890CrossRefGoogle Scholar
  97. 97.
    Godleski SA (1991) In: Trost BM, Fleming I, Semmelhack MF (eds) Comprehensive organic synthesis, vol 4. Pergamon, Oxford, pp 585–662, Chapter 3.3CrossRefGoogle Scholar
  98. 98.
    Craig RA 2nd, O’Connor NR, Goldberg AF, Stoltz BM (2014) Chem Eur J 20:4806–4813CrossRefGoogle Scholar
  99. 99.
    Hovelmann CH, Streuff J, Brelot L, Muniz K (2008) Chem Commun 2334–2336Google Scholar
  100. 100.
    Gainer MJ, Bennett NR, Takahashi Y, Looper RE (2011) Angew Chem Int Ed Engl 50:684–687CrossRefGoogle Scholar
  101. 101.
    Ritter S, Horino Y, Lex J, Schmalz HG (2006) Synlett 3309–3313Google Scholar
  102. 102.
    Bhonde VR, Looper RE (2011) J Am Chem Soc 133:20172–20174CrossRefGoogle Scholar
  103. 103.
    Pereshivko OP, Peshkov VA, Ermolatev DS, van Hove S, Van Hecke K, Van Meervelt L, van der Eycken EV (2011) Synthesis 1587–1594Google Scholar
  104. 104.
    Ishikawa M, Tsushima M, Kubota D, Yanagisawa Y, Hiraiwa Y, Kojima Y, Ajito K, Anzai N (2008) Org Proc Res Dev 12:596–602CrossRefGoogle Scholar
  105. 105.
    Baskaran S, Hanan E, Byun D, Shen W (2004) Tetrahedron Lett 45:2107–2111CrossRefGoogle Scholar
  106. 106.
    Looper RE, Runnegar MTC, Williams RM (2006) Tetrahedron 62:4549–4562CrossRefGoogle Scholar
  107. 107.
    Larraufie MH, Ollivier C, Fensterbank L, Malacria M, Lacote E (2010) Angew Chem Int Ed Engl 49:2178–2181CrossRefGoogle Scholar
  108. 108.
    Nilsson BL, Overman LE (2006) J Org Chem 71:7706–7714CrossRefGoogle Scholar
  109. 109.
    Nagasawa K, Georgieva A, Takahashi H, Nakata T (2001) Tetrahedron 57:8959–8964CrossRefGoogle Scholar
  110. 110.
    Perl NR, Ide ND, Prajapati S, Perfect HH, Duron SG, Gin DY (2010) J Am Chem Soc 132:1802–1803CrossRefGoogle Scholar
  111. 111.
    Nishikawa T, Asai M, Isobe M (2002) J Am Chem Soc 124:7847–7852CrossRefGoogle Scholar
  112. 112.
    Aranha Potter R, Bowser AM, Yang Y, Madalengoitia JS, Ziller JW (2013) J Org Chem 78:11772–11782CrossRefGoogle Scholar
  113. 113.
    Ding H, Roberts AG, Harran PG (2012) Angew Chem Int Ed Engl 51:4340–4343CrossRefGoogle Scholar
  114. 114.
    Buchi G, Rodriguez AD, Yakushijin K (1989) J Org Chem 54:4494–4496CrossRefGoogle Scholar
  115. 115.
    Yu M, Pochapsky SS, Snider BB (2008) J Org Chem 73:9065–9074CrossRefGoogle Scholar
  116. 116.
    Sawayama Y, Nishikawa T (2011) Angew Chem Int Ed Engl 50:7176–7178CrossRefGoogle Scholar
  117. 117.
    Shaw JW, Grayson DH, Rozas I (2014) Eur J Org Chem 161–174Google Scholar
  118. 118.
    Shaw JW, Grayson DH, Rozas I (2014) Arkivoc 3565–3569Google Scholar
  119. 119.
    Zaed AM, Sutherland A (2010) Org Biomol Chem 8:4394–4399CrossRefGoogle Scholar
  120. 120.
    Zhou HB, Alper H (2004) Tetrahedron 60:73–79CrossRefGoogle Scholar
  121. 121.
    Sączewski F, Balewski Ł (2009) Expert Opin Ther Pat 19:1417–1448CrossRefGoogle Scholar
  122. 122.
    Dardonville C, Barrett MP, Brun R, Kaiser M, Tanious F, Wilson WD (2006) J Med Chem 49:3748–3752CrossRefGoogle Scholar
  123. 123.
    Nagle PS, Rodriguez F, Kahvedzic A, Quinn SJ, Rozas I (2009) J Med Chem 52:7113–7121CrossRefGoogle Scholar
  124. 124.
    McKeever C, Kaiser M, Rozas I (2013) J Med Chem 56:700–711CrossRefGoogle Scholar
  125. 125.
    O’Sullivan P, Rozas I (2014) ChemMedChem 9:2063–2073Google Scholar
  126. 126.
    Goonan Á, Kahvedzic A, Rodriguez F, Nagle PS, McCabe T, Rozas I, Erdozain AM, Meana JJ, Callado LF (2008) Bioorg Med Chem 16:8210–8217CrossRefGoogle Scholar
  127. 127.
    Kahvedzic A, Nathwani S-M, Zisterer D, Rozas I (2013) J Med Chem 56:451–459CrossRefGoogle Scholar
  128. 128.
    Nagle PS, Rodriguez F, Quinn SJ, O’Donovan DH, Kelly JM, Nguyen B, Wilson WD, Rozas I (2010) Org Biomol Chem 8:5558–5567CrossRefGoogle Scholar
  129. 129.
    Nagle PS, Rodriguez F, Nguyen B, Wilson WD, Rozas I (2012) J Med Chem 55:4397–4406CrossRefGoogle Scholar
  130. 130.
    Kahvedzic A, Nathwani S-M, Zisterer D, Rozas I (2015)Google Scholar
  131. 131.
    Diez-Cecilia E, Carson R, Kelly B, van Schaybroeck S, Murray JT, Rozas I (2015)Google Scholar
  132. 132.
    Rodriguez F, Rozas I, Ortega JE, Erdozain AM, Meana JJ, Callado LF (2008) J Med Chem 51:3304–3312CrossRefGoogle Scholar
  133. 133.
    Rodriguez F, Rozas I, Erdozain AM, Meana JJ, Callado LF (2009) J Med Chem 52:601–609CrossRefGoogle Scholar
  134. 134.
    Nakamura S (2012) Antidepressants and morphological plasticity of monoamine neurons. In: Lu R-B (ed) Effects of antidepressants. InTech, Rijeka. ISBN 978-953-51-0663-0Google Scholar
  135. 135.
    Muguruza C, Rodriguez F, Rozas I, Meana JJ, Uriguen L, Callado LF (2013) Neuropharmacology 65:13–19CrossRefGoogle Scholar
  136. 136.
    O’Donovan DH, Muguruza C, Callado LF, Rozas I (2014) Eur J Med Chem 82:242–254CrossRefGoogle Scholar
  137. 137.
    McMullan M, Kelly B, Erdozain AM, Callado LF, Rozas I (2015)Google Scholar
  138. 138.
    Nagle PS, McKeever C, Rodriguez F, Nguyen B, Wilson WD, Rozas I (2014) J Med Chem 57:4397–4406CrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Julian W. Shaw
    • 1
  • David H. Grayson
    • 1
  • Isabel Rozas
    • 1
  1. 1.School of Chemistry, Trinity Biomedical Sciences InstituteTrinity College DublinDublin 2Ireland

Personalised recommendations