Molecular Diversity

, Volume 15, Issue 3, pp 631–638 | Cite as

Stepwise aromatic nucleophilic substitution in continuous flow. Synthesis of an unsymmetrically substituted 3,5-diamino-benzonitrile library

  • László Lengyel
  • Viktor Gyóllai
  • Tamás Nagy
  • György Dormán
  • Péter Terleczky
  • Viktor Háda
  • Katalin Nógrádi
  • Ferenc Sebők
  • László Ürge
  • Ferenc Darvas
Full-Length Paper

Abstract

Aromatic or heteroaromatic ring precursors with 2–3 identical functionalities are often used in sequential derivatization depending on the reactivity difference or the selective execution of the reaction such as nucleophilic aromatic substitution. Continuous flow chemistry offers an enhanced parameter space (pressure and temperature) with rapid parameter optimization that ensures selectivity in many cases. We developed a flow chemistry procedure to carry out a stepwise aromatic nucleophilic substitution of difluoro-benzenes having an activating group in meta position to the fluorines. The mono-aminated products were obtained in high yield and selectivity in an extremely short reaction time, while applying higher temperature, longer reaction zone (or time), and employing higher excess of another amine reactant, the subsequent introduction of the second amino group was also successfully achieved leading to an unsymmetrically substituted 3,5-diamino-benzonitrile library.

Keywords

Continuous flow chemistry Nucleophilic substitution Enhanced parameter space Fluorine–amine exchange 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Supplementary material

11030_2010_9300_MOESM1_ESM.doc (170 kb)
ESM 1 (DOC 170 kb)

References

  1. 1.
    Dallinger D, Kappe CO (2005) Creating chemical diversity space by scaffold decoration of dihydropyrimidines. Pure Appl Chem 77: 155–161. doi:10.1351/pac200577010155 CrossRefGoogle Scholar
  2. 2.
    Beeler AB, Schaus SE, Porco JA Jr. (2005) Chemical library synthesis using convergent apporaches. Curr Opin Chem Biol 9: 77–284. doi:10.1016/j.cbpa.2005.04.005 CrossRefGoogle Scholar
  3. 3.
    Stanková M, Lebl M (1996) Library generation through successive substitution of trichlorotriazine. Mol Divers 2: 75–80. doi:10.1007/BF01718703 PubMedCrossRefGoogle Scholar
  4. 4.
    Belfield AJ, Brown GR, Foubister AJ (1999) Recent synthetic advances in the nucleophilic amination of benzenes. Tetrahedron 55: 11399–11428. doi:10.1016/S0040-4020(99)00818-2 CrossRefGoogle Scholar
  5. 5.
    Miller J, Parker AJ (1961) Dipolar aprotic solvents in bimolecular aromatic nucleophilic substitution reactions. J Am Chem Soc 83: 117–123. doi:10.1021/ja01462a023 CrossRefGoogle Scholar
  6. 6.
    Kappe CO, Dallinger D. (2009) Controlled microwave heating in modern organic synthesis: highlights from the 2004–2008 literature. Mol Divers 13: 71–193. doi:10.1007/s11030-009-9138-8 PubMedCrossRefGoogle Scholar
  7. 7.
    Brown GR, Foubister AJ, Roberts CA, Wells SL, Wood R (2001) Improved yields of meta-amination and symmetrical and unsymmetrical diamination of benzenes. Tet Lett 42(23): 3917–3919. doi:10.1016/S0040-4039(01)00582-2 CrossRefGoogle Scholar
  8. 8.
    Darvas F, Dormán G, Lengyel L, Kovács I, Jones R, Ürge L (2009) High pressure, high temperature reactions in continuous flow. Merging discovery and process chemistry. Chim Oggi 27: 40–43Google Scholar
  9. 9.
    Razzaq T, Glasnov TN, Kappe CO (2009) Continuous flow microreactor chemistry under high temperature/pressure conditions. Eur J Org Chem 1321–1325. doi:10.1002/ejoc.200900077
  10. 10.
    Roppe J, Smith ND, Huang D, Tehrani L, Wang B, Anderson J, Brodkin J, Chung J, Jiang X (2004) Discovery of novel heteroarylazoles that are metabotropic glutamate subtype 5 receptor antagonists with anxiolytic activity. J Med Chem 47: 4645–4648. doi:10.1021/jm049828c PubMedCrossRefGoogle Scholar
  11. 11.
    Nelder JA, Mead R (1965) A simplex method for function minimization. Comput J 7: 308–313. doi:10.1093/comjnl/7.4.308 Google Scholar
  12. 12.
    Simplex Pro is a product of Compudrug Ltd., Sedona, AZ, USA. http://www.compudrug.com
  13. 13.
    Hiroyuki N, Satoru O, Atsumi Minami R, Mochizuki M, Hirotani M, Kumazawa K, Eiji E (2005) Synthesis and antitumor activity of novel pyrimidinyl pyrazole derivatives. III. synthesis and antitumor activity of 3-phenylpiperazinyl-1-trans-propenes. Chem Pharm Bull 53: 153–163. doi:10.1248/cpb.53.153 CrossRefGoogle Scholar
  14. 14.
    Tehrani LR, Smith ND, Huang D, Poon SF, Roppe JR, Seiders TJ, Chapman DF, Chung J, Cramer M, Cosford NDP (2005) 3-[Substituted]-5-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitriles: identification of highly potent and selective metabotropic glutamate subtype 5 receptor antagonists. Bioorg Med Chem Lett 15: 5061–5064. doi:10.1016/j.bmcl.2005.07.062 PubMedCrossRefGoogle Scholar
  15. 15.
    Poon SF, Eastman BW, Chapman DF, Chung J, Cramer M, Holtz G, Cosford NDP, Smith ND (2004) 3-[3-Fluoro-5-(5-pyridin-2-yl-2H-tetrazol-2-yl)phenyl]-4-methylpyridine: a highly potent and orally bioavailable metabotropic glutamate subtype 5 (mGlu5) receptor antagonist. Bioorg Med Chem Lett 14: 5477–5480. doi:10.1016/j.bmcl.2004.09.011 PubMedCrossRefGoogle Scholar
  16. 16.
    Meade EA, Sznaidman M, Pollard GT, Beauchamp LM, Howard JL (1998) Anxiolytic activity of analogues of 4-benzylamino-2-methyl-7H-pyrrolo[2,3-d]pyrimidines. Eur J Med Chem 33: 363–374. doi:10.1016/S0223-5234(98)80003-2 CrossRefGoogle Scholar
  17. 17.
    Shojiro M, Makiko O, Toshimichi M, Takashi H, Haruki N (2003) Pd black deposited on polypropylene sheet as a highly selective catalyst for hydrogenation of alkenes. Tetrahedron Lett 44: 3717–3722. doi:10.1016/S0040-4039(03)00551-3 CrossRefGoogle Scholar
  18. 18.
    Jones R, Godorhazy L, Varga N, Szalay D, Urge L, Darvas F (2006) Continuous-flow high pressure hydrogenation reactor for optimization and high-throughput synthesis. J Comb Chem 8: 110–116. doi:10.1021/cc050107o PubMedCrossRefGoogle Scholar
  19. 19.
    X-Cube FlashTM is a product of ThalesNano Inc, Budapest, Hungary, www.thalesnano.com

Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  • László Lengyel
    • 1
  • Viktor Gyóllai
    • 1
  • Tamás Nagy
    • 1
    • 3
  • György Dormán
    • 1
  • Péter Terleczky
    • 2
  • Viktor Háda
    • 2
  • Katalin Nógrádi
    • 2
  • Ferenc Sebők
    • 2
  • László Ürge
    • 1
  • Ferenc Darvas
    • 1
  1. 1.ThalesNano Inc.BudapestHungary
  2. 2.Gedeon Richter plc.BudapestHungary
  3. 3.EGIS plc.BudapestHungary

Personalised recommendations