Synlett 2012; 23(12): 1779-1782
DOI: 10.1055/s-0031-1290698
letter
© Georg Thieme Verlag Stuttgart · New York

An Optimised Synthesis of 2-[2,3-Bis(tert-butoxycarbonyl)guanidino]ethylamine

Shane M. Hickey
Centre for Biotechnology, Chemistry and Systems Biology, School of Life and Environmental Sciences, Deakin University, Waurn Ponds, Victoria, 3216, Australia, Fax: +61(3)52271040   Email: fred.pfeffer@deakin.edu.au
,
Trent D. Ashton
Centre for Biotechnology, Chemistry and Systems Biology, School of Life and Environmental Sciences, Deakin University, Waurn Ponds, Victoria, 3216, Australia, Fax: +61(3)52271040   Email: fred.pfeffer@deakin.edu.au
,
Simren K. Khosa
Centre for Biotechnology, Chemistry and Systems Biology, School of Life and Environmental Sciences, Deakin University, Waurn Ponds, Victoria, 3216, Australia, Fax: +61(3)52271040   Email: fred.pfeffer@deakin.edu.au
,
Frederick M. Pfeffer*
Centre for Biotechnology, Chemistry and Systems Biology, School of Life and Environmental Sciences, Deakin University, Waurn Ponds, Victoria, 3216, Australia, Fax: +61(3)52271040   Email: fred.pfeffer@deakin.edu.au
› Author Affiliations
Further Information

Publication History

Received: 13 April 2012

Accepted after revision: 14 May 2012

Publication Date:
04 July 2012 (online)


Abstract

This short report describes an improved, reliable, and high-yielding (>90%) synthesis of 2-[2,3-bis(tert-butoxycarbonyl)guanidino]ethylamine. The method is scalable (>5 g), and the product obtained directly from the reaction mixture requires no further purification. In addition, this methodology can be successfully applied to other diamine substrates (1,3-propyl and 1,4-butyl; 70% and 61% yield, respectively).

Supporting Information

 
  • References and Notes

  • 1 Novoa A, Pellegrini-Moïse N, Bechet D, Barberi-Heyob M, Chapleur Y. Bioorg. Med. Chem. 2010; 18: 3285
  • 2 Nicolaou KC, Trujillo JI, Jandeleit B, Chibale K, Rosenfeld M, Diefenbach B, Cheresh DA, Goodman SL. Bioorg. Med. Chem. 1998; 6: 1185
  • 3 Späth A, König B. Tetrahedron Lett. 2010; 66: 1859
  • 4 Weiss S, Keller M, Bernhardt G, Buschauer A, König B. Bioorg. Med. Chem. 2010; 18: 6292
  • 5 Henderson LC, Li J, Nation RL, Velkov T, Pfeffer FM. Chem. Commun. 2010; 46: 3197
  • 6 Carmignani M, Volpe AR, Botta B, Espinal R, De Bonnevaux SC, De Luca C, Botta M, Corelli F, Tafi A, Sacco R, Delle Monache G. J. Med. Chem. 2001; 44: 2950
  • 7 Sigma-Aldrich online catalogue; Product code: 84190; US$338.81/g
  • 8 Expósito A, Fernández-Suárez M, Iglesias T, Muñoz L, Riguera R. J. Org. Chem. 2001; 66: 4206
  • 9 Hernandez MI. R, Royo FR, Meana J, Callado L. WO 2009080818, 2009
  • 10 Ohara K, Vasseur J.-J, Smietana M. Tetrahedron Lett. 2009; 50: 1463
  • 11 Feichtinger K, Sings HL, Baker TJ, Matthews K, Goodman M. J. Org. Chem. 1998; 63: 8432
  • 12 Feichtinger K, Zapf C, Sings HL, Goodman M. ChemInform 1998; 29: 3804
  • 13 Castagnolo D, Raffi F, Giorgi G, Botta M. Eur. J. Org. Chem. 2009; 334
  • 14 Sigma-Aldrich online catalogue; Product code: 15033; US$209.69/g
  • 15 Lim HA, Joy J, Hill J, San Brian Chia C. Eur. J. Med. Chem. 2011; 3130
  • 16 Wakimoto T, Nitta M, Kasahara K, Chiba T, Yiping Y, Tsuji K, Kan T, Nukaya H, Ishiguro M, Koike M, Yokoo Y, Suwa Y. Bioorg. Med. Chem. Lett. 2009; 19: 5905
  • 17 Radau G, Schermuly S, Fritsche A. Arch. Pharm. 2003; 336: 300
  • 18 Yuan JH, Yang XX, Lin H, Wang DX. Chin. Chem. Lett. 2011; 22: 1399
  • 19 Holland JP, Fisher V, Hickin JA, Peach JM. Eur. J. Inorg. Chem. 2010; 48
  • 20 2-[2,3-Bis( tert-butoxycarbonyl)guanidino]ethylamine (1) Boc-protected methylisothiourea 10 (5.81 g, 20.0 mmol) in CH2Cl2 (30 mL) was added in one portion to a stirred solution of 1,2-ethylenediamine (3.3 mL, 50.0 mmol) in CH2Cl2 (44 mL). The reaction was allowed to stir at 21 °C for 70 min. The reaction mixture was washed with H2O (3 × 25 mL), brine (30 mL), then dried (MgSO4) and filtered. Solvent was removed in vacuo at ambient temperature to afford 1 (5.37 g, 90%) as a white powder; mp 96.2–100.1 °C. 1H NMR (270 MHz, CDCl3): δ = 1.50 (9 H, br s, t-Bu), 1.51 (9 H, br s, t-Bu), 2.90 (2 H, t, J = 6.2 Hz, CH2), 3.49 (2 H, app q, Japp = 5.5 Hz, CH2), 8.67 (1 H, br s, NH), 11.51 (1 H, br s, NH). 13C NMR (67.5 MHz, CDCl3): δ = 28.2, 28.4, 41.1, 43.5, 79.4, 83.2, 153.3, 156.5, 163.7. ESI-HRMS: m/z calcd for C13H26N4O4 [M + H]+: 303.2027; found: 303.2032
  • 21 Nnanabu E, Burgess K. Org. Lett. 2006; 8: 1259
  • 22 Li G, Regunathan S, Barrow C, Eshraghi J, Cooper R, Reis D. Science 1994; 263: 966