The Pipecolic linker (Pip) was designed on a basis of side reaction observed on BAL linkers while synthetizing a focused library of long-chain arylpiperazines [1]. It represents new strategy for immobilization and structural modifications on solid support of primary, secondary and aromatic amines as well as alcohols, phenols, thiols and hydrazides [2,3].

Herein we present new application for Pipecolic linker for the synthesis of N₁-arylsulfonyl-(1,2,3,6-tetra-hydropyridin-4-yl)-1H-indole (I) and 5-arylsulfonyl-(1,2,3,6-tetra-hydropyridin-4-yl)-1H-indole (II) derivatives.

The synthesis of sets I and II was performed on polystyrene and ChemMatrix resins, respectively. The strategy employed attachment of the 4-piperidone to the Pip resin, followed by condensation with respective indole derivatives. Then, the key stage in the synthesis of set I analogs was sulfonylation of the resin-bound indole derivative in basic conditions of BTPP (phosphazene base P₁-t-Bu-tris(tetramethylene)). The critical for synthesis of set II compounds was reduction of 5-nitro function. This was accomplished using ChemMatrix resin and sodium dithionite treatment in basic conditions.

Presented solid-phase synthetic routes opens possibility for generation of combinatorial variations extending the variety of substituted sulfonamides available in the development of CNS acting agents.

References

[1] Zajdel, P.; Subra, G.; Bojarski, A. J.; Duszyńska, B.; Pawłowski, M.; Martinez, J. A  new class of arylpiperazine derivatives: the library synthesis on SynPhase lanterns and biological evaluation on serotonin 5-HT1A and 5-HT2A receptors. J. Comb. Chem. 2004, 6, 761–767.

[2] Zajdel, P.; Nomezine, G.; Masurier, N.; Amblard, M.; Pawłowski, M.; Martinez, J.; Subra, G. A new highly versatile handle for chemistry on a solid support: the pipecolic linker. Chem. Eur. J. 2010, 16, 7547–7553.

[3] Zajdel, P.; Masurier, N.; Sanchez, P.; Pawłowski, M.; Kreiter, A.; Nomezine, G.; Enjalbal, C.; Amblard, M.; Martinez, J.; Subra, G. Recycling the versatile pipecolic linker. J. Comb. Chem. 2010, 12, 747–753.

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