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Iron-assisted nucleophilic aromatic substitution on solid phase.

Thomas Ruhland1, Kia S Bang, Kim Andersen

  • 1Department of Combinatorial Chemistry, Medicinal Chemistry Research, H. Lundbeck A/S, 9 Ottiliavej, DK-2500 Valby, Denmark. tr@lundbeck.com

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Summary

This study introduces a novel solid-phase synthesis for unsymmetrically substituted phenylpiperazines and phenyl-1,4-diazepanes using iron-assisted S(N)Ar reactions. This method simplifies the synthesis and overcomes challenges in removing iron catalysts, enabling efficient library generation.

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Area of Science:

  • Organic Chemistry
  • Medicinal Chemistry
  • Synthetic Chemistry

Background:

  • Nucleophilic aromatic substitution (S(N)Ar) reactions are fundamental in organic synthesis.
  • Iron catalysis offers a cost-effective and potentially greener alternative to traditional catalysts.
  • Solid-phase synthesis enables efficient library generation and purification.

Purpose of the Study:

  • To develop and investigate iron-assisted S(N)Ar reactions on solid phase for the first time.
  • To synthesize a library of unsymmetrically substituted phenylpiperazines and phenyl-1,4-diazepanes.
  • To explore the scope of this methodology with various nucleophiles and address catalyst removal challenges.

Main Methods:

  • Solid-phase synthesis utilizing iron-assisted S(N)Ar reactions.
  • Reaction optimization with diverse nucleophiles from Groups V and VI (N, P, O, S, Se).
  • Photochemical decomplexation of resin-bound iron using 1,10-phenanthroline.

Main Results:

  • Successful synthesis of 36 unsymmetrically substituted phenylpiperazines and phenyl-1,4-diazepanes.
  • Demonstration of the broad scope of iron-assisted S(N)Ar reactions on solid phase.
  • Efficient removal of iron catalyst under mild irradiation conditions, overcoming solution-phase limitations.

Conclusions:

  • A novel and efficient solid-phase strategy for synthesizing phenylpiperazine and phenyl-1,4-diazepane libraries has been established.
  • Iron-assisted S(N)Ar reactions on solid phase offer a versatile platform for drug discovery and chemical biology.
  • The developed photochemical decomplexation method provides a significant advantage over traditional solution-phase techniques.