publication . Article . 2016

Protected diazonium salts: A continuous-flow preparation of triazenes including the anticancer compounds dacarbazine and mitozolomide

Christiane Schotten; Abdul Hadi Aldmairi; Yerbol Sagatov; Martyn Shepherd; Duncan L. Browne;
Open Access
  • Published: 01 Sep 2016 Journal: Journal of Flow Chemistry, volume 6, pages 218-225 (issn: 2062-249X, eissn: 2063-0212, Copyright policy)
  • Publisher: Springer Nature
  • Country: United Kingdom
Herein, we report a continuous-flow process for the preparation of triazenes, whereby diazonium salts are generated and converted into their masked or protected triazene derivatives. Key to realizing the process, which is applicable to a wide range of substrates, is the identification of solvent and reagent parameters that avoid fouling and clogging in the tubing used in these studies. The process has also been applied to prepare the antineoplastic agents mitozolomide and dacarbazine. We also report isolation and differential scanning calorimetry (DSC) analysis of an anthranilic acidderived triazene whose related diazonium salt is a contact explosive. The data h...
Persistent Identifiers
free text keywords: Organic Chemistry, Chemistry (miscellaneous), Fluid Flow and Transfer Processes, QD, Triazene, chemistry.chemical_compound, chemistry, Green chemistry, Differential scanning calorimetry, Solvent, High-performance liquid chromatography, Reagent, Fouling, Exothermic process
Related Organizations
24 references, page 1 of 2

1. (a) Mo, F.; Dong, G.; Zhang, Y.; Wang, J. Org. Biomol. Chem. 2013, 11, AQ11 1582; (b) Kölmel, D. K.; Jung, N.; Bräse, S. Aust. J. Chem. 2014, 67, 328; (c) Roglans, A.; Pla-Quintana, A.; Moreno-Mañas, M. Chem. Rev. 2006, 106, 4622; (d) Felpin, F.-X.; Nassar-Hardy, L.; Le Callonnec, F.; Fouquet, E. Tetrahedron 2011, 67, 2815; (e) Taylor, J. G.; Moro, A. V.; Correia, C. R. D. Eur. J. Org. Chem. 2011, 1403.

2. (a) Mich, T. F.; Nienhouse, E. J.; Farina, T. E.; Tufariello, J. J. J. Chem. Ed. 1968, 45, 272; (b) Sheng, M.; Frurip, D.; Gorman, D. J. Loss Prevent. Proc. 2015, 38, 114.

3. For reviews on continuous-flow processing of diazonium salts and diazo compounds, see: (a) Deadman, B. J.; Collins, S. G.; Maguire, A. R. Chem. Eur. J. 2015, 21, 2298; (b) Müller, S. T. R.; Smith, D.; Hellier, P.; Wirth, T. Synlett 2014, 25, 871; (c) Oger, N.; Le Grognec, E.; Felpin, F.-X. Org. Chem. Front. 2015, 2, 590-614.

5. (a) Lazny, R.; Sienkiewicz, M.; Bräse, S. Tetrahedron 2001, 57, 5825- 5832; (b) Kimball, D. B.; Haley, M. M. Angew. Chem., Int. Ed. 2002, 41, 3338- 3351; (c) May, C.; Moody, C. J. J. Chem. Soc. 1988, 2, 247-250; (d) Vaughan, K. Org. Prep. Proc. Int. 2001, 33, 59-74.

6. (a) Liu, C.-Y.; Knochel, P. J. Org. Chem. 2007, 72, 7106-7115; (b) Goeminne, A.; Scammells, P. J.; Devine, S. M.; Flynn, B. L. Tetrahedron Lett. 2010, 51, 6882-6885; (c) Saeki, T.; Matsunaga, T.; Son, E.-C.; Tamao, K. Adv. Synth. Catal. 2004, 346, 1689-1692; (d) Saeki, T.; Son, E.-C.; Tamao, K. Org. Let. 2004, 6, 617- 619; (e) Bräse, S.; Schroen, M. Angew. Chem., Int. Ed. 1999, 38, 1071-1073; (f) Barbero, M.; Degani, I.; Diulgheroff, N.; Dughera, S.; Fochi, R. Synthesis 2001, 14, 2180-2190; (g) Döbele, M.; Vanderheiden, S.; Jung, N.; Bräse, S. Angew. Chem., Int. Ed. 2010, 49, 5986-5988; (h) Wang, C.; Chen, H.; Wang, Zh.; Chen, J.; Huang, Y. Angew. Chem., Int. Ed. 2012, 51, 7242-7245; (i) Sun, H.; Wang, C.; Yang, Y.-F.; Chen, P.; Wu, Y.-D.; Zhang, X. J. Org. Chem. 2014, 79, 11863-11872; (j) Lazny, R.; Poplawski, J.; Kobberling, J.; Enders, D.; Bräse, S. Synlett 1999, 8, 1304-1306; (k) Liu, C.-Y.; Knochel, P. Org. Let. 2005, 7, 2543-2546; (l) Lormann, M.; Dahmen, S.; Bräse, S. Tetrahedron Lett. 2000, 41, 3813-3816; (m) Satyamurthy, N.; Barrio, J. R.; Bida, G. T.; Phelps, M. E. Tetrahedron Lett. 1990, 31, 4409-4412; (n) Hudson, J. L.; Jian, H.; Leonard, A. D.; Stephenson, J. J.; Tour, J. M. Chem. Mater. 2006, 18, 2766-2770; (o) Gross, M. L.; Blank, D. H.; Welch, W. M. J. Org. Chem. 1993, 58, 2104-2109; (p) Patrick, T. B.; Juehne, T.; Reeb, E.; Hennessy, D. Tetrahedron Lett. 2001, 42, 3553-3354.

7. (a) Reisman, S. E.; Ready, J. M.; Weiss, M. M.; Hasuoka, A.; Hirata, M.; Tamaki, K.; Smith, C. J.; Wood, J. L. J. Am. Chem. Soc. 2008, 130, 2087-2100; (b) Hafner, A.; Bräse, S. Angew. Chem., Int. Ed. 2012, 51, 3713-3715; (c) Wang, C.; Chen, H.; Wang, Zh.; Chen, J.; Huang, Y. Angew. Chem., Int. Ed. 2012, 51, 7242-7245; (d) Hafner, A.; Feuerstein, T. J.; Bräse, S. Org. Let. 2013, 15, 3468- 3471; (e) Hafner, A.; Bihlmeier, A.; Nieger, M.; Klopper, W.; Bräse, S. J. Org. Chem. 2013, 78, 7938-7948.

8. (a) Zhang, F.; Spring, D. R. Chem. Soc. Rev. 2014, 43, 6906-6919; (b) Wang, C.; Huang, Y. Synlett 2013, 24, 145-149.

9. For some reviews on hazardous flow, see: (a) Gutmann, B.; Cantillo, D.; Kappe, C. O. Angew. Chem., Int. Ed. 2015, 54, 6688-6728; (b) Kulkarni, A. A. Beilstein J. Org. Chem. 2014, 10, 405-424; (c) Yoshida, J.-I.; Takahashi, Y.; Nagaki, A. Chem. Commun. 2013, 49, 9896; (d) Gutmann, B.; Kappe, C. O. Chim. Oggi Chem. Today 2015, 33, 3.

10. (a) Hartwig, J.; Ceylan, S.; Kupracz, L.; Coutable, L.; Kirschning, A. Angew. Chem., Int. Ed. 2013, 52, 9813; (b) Ghislieri, D.; Gilmore, K.; Seeberger, P. H. Angew. Chem., Int. Ed. 2015, 54, 678; (c) Newton, S.; Carter, C. F.; Pearson, C. M.; Alves, L. de C.; Lange, H.; Thansandote, P.; Ley, S. V. Angew. Chem., Int. Ed. 2014, 53, 4915; (d) Kupracz, L.; A. Kirschning Adv. Synth. Catal. 2013, 355, 3375; (e) Pastre, J. C.; Browne, D. L.; O'Brien, M.; Ley, S. V. Org. Process Res. Dev. 2013, 17, 1183; (f) Murray, P. R. D.; Browne, D. L.; Pastre, J. C.; Butters, C.; Guthri, D.; Ley, S. V. Org. Process Res. Dev. 2013, 17, 1192; (g) Battilocchio, C.; Baxendale, I. R.; Biava, M.; Kitching, M. O.; Ley, S. V. Org. Process Res. Dev. 2012, 16, 798; (h) Kabeshov, M. A.; Musio, B.; Murray, P. R. D.; Browne, D. L.; Ley, S. V. Org. Lett. 2014, 16, 4618; (i) Lau, S.-H.; Galván, A.; Merchant, R. R.; Battilocchio, C.; Souto, J. A.; Berry, M. B.; Ley, S. V. Org. Lett. 2015, 17, 3218; (j) Correia, C. A.; Gilmore, K.; McQuade, D. T.; Seeberger, P. H. Angew. Chem., Int. Ed. 2015, 54, 4945; (k) Tsubogo, T.; Oyamada, H.; Kobayash, S. Nature 2015, 520, 329; (l) Adamo, A.; Beingessner, R. L.; Behnam, M.; Chen, J.; Jamison, T. F.; Jensen, K. F.; Monbaliu, J.-C. M.; Myerson, A. S.; Revalor, E. M.; Snead, D. R.; Stelzer, T.; Weeranoppanant, N.; Wong, S. Y.; Zhang, P. Science 2016, 352, 61-67.

11. For handling solids in flow, see: (a) Deadman, B. J.; Browne, D. L.; Baxendale, I. R.; Ley, S. V. Chem. Eng. Technol. 2015, 38, 259-264; (b) Browne, D. L.; Deadman, B. J.; Ashe, R.; Baxendale, I. R.; Ley, S. V. Org. Proc. Res. Dev. 2011, 15, 693-697; (c) Hartman, R. L. Org. Process Res. Dev. 2012, 16, 870- 887; (d) Sedelmeier, J.; Ley, S. V.; Baxendale, I. R.; Baumann, M. Org. Lett. 2010, 12, 3618-3621; (e) Kelly, C. B.; Lee, C. X.; Leadbeater, N. E. Tetrahedron Lett. 2011, 52, 263-265; (f) Noel, T.; Naber, J. R.; Hartman, R. L.; McMullen, J. P.; Jensen, K. F.; Buchwald, S. L. Chem. Sci. 2011, 2, 287-290.

12. 19th WHO Model List of Essential Medicines (April 2015). http://www. (accessed May 19, 2016).

13. Xicoy, B.; Ribera, J-M.; Miralles, P.; Berenguer, J.; Rubio, R.; Mahillo, B.; Valencia. M-E.; Abella, E.; López-Guillermo, A.; Sureda, A.; Morgades, M.; Navarro, J-T.; Esteban, H. Haematologica 2007, 92, 191-198.

14. (a) Zarei, A.; Khazdooz, L.; Aghaei, H.; Azizi, G.; Chermahini, A. N.; Hajipour, A. R. Dyes Pig. 2014, 101, 295-302; (b) Lunazzi, L.; Cerioni, G.; Foresti, E.; Macciantelli, D. J. Chem. Soc. Perkin Trans. 2 1978, 7, 686-691.

15. Chen, M.; Buchwald, S. L. Angew. Chem., Int. Ed. 2013, 52, 4247.

16. Clark, A. S.; Deans, B.; Stevens, M. F. G.; Tisdale, M. J.; Wheelhouse, R. T.; Denny, B. J.; Hartley, J. A. J. Med. Chem. 1995, 38, 1493-1504.

24 references, page 1 of 2
Any information missing or wrong?Report an Issue