Synthesis of N-phenyl-N-(3-(piperidin-1-yl)propyl)benzofuran-2-carboxamides as new selective ligands for sigma receptors.

Novel benzofuran-2-carboxamide ligands, which are selective for sigma receptors, have been synthesized via a microwave-assisted Perkin rearrangement reaction and a modified Finkelstein halogen-exchange used to facilitate N-alkylation. The ligands synthesized are the 3-methyl-N-phenyl-N-(3-(piperidin-1-yl)propyl)benzofuran-2-carboxamides (KSCM-1, KSCM-5 and KSCM-11). The benzofuran-2-carboxamide structure was N-arylated and N-alkylated to include both N-phenyl and N-(3-(piperidin-1-yl)propyl substituents, respectively. These new carboxamides exhibit high affinity at the sigma-1 receptor with K(i) values ranging from 7.8 to 34nM. Ligand KSCM-1 with two methoxy substituents at C-5 and C-6 of the benzofuran ring, and K(i)=27.5nM at sigma-1 was found to be more selective for sigma-1 over sigma-2.

Expedited Synthesis of Benzofuran-2-Carboxylic Acids via Microwave-Assisted Perkin Rearrangement Reaction.

3-Halocoumarins are readily converted into benzofuran-2-carboxylic acids via a Perkin (coumarin-benzofuran ring contraction) rearrangement reaction. This rearrangement entails initial base catalyzed ring fission. The resulting phenoxide anion then attacks a vinyl halide to produce the final benzofuran moiety. We explored this reaction under microwave reaction conditions and were able to significantly reduce reaction times as well as obtain very high yields of a series of benzofuran-2-carboxylic acid derivatives.