Title : Palladium-catalyzed benzylic like nucleophilic substitution of benzofuran 2 ylmethyl acetate with N, S, O and C soft nucleophiles

Abstract:

The benzo[b]furan core is a motif present in several natural and unnatural pharmacologically active compounds exhibiting various biological properties including anti-infiammatory, anti-oxidant, anti-arrhythmic, hemostatic, antimicrobial, anti-viral, antifungal, and anti-tumor activities and are antagonists for the H3 receptor and angiotensin II.¹ Particularly, 1-(benzofuran-2-ylmethyl)-4-benzylpiperazine (Figure 1) has been selected as lead compound for s1 receptor affinity and selectivity over the s2 receptor.

Figure 1. 1-(benzofuran-2-ylmethyl)-4-benzylpiperazine

Due to the remarkable properties of compounds this compound, we decided to develop a new protocol for the preparation of variously substituted 2-(aminomethyl)benzo [b]furans evaluating the possibility that benzofuran-2-ylmethyl acetate 1 could undergo a palladium-catalyzed benzylic-like nucleophilic substitution in the presence of various nucleophiles (Scheme 1) to afford the 2-(aminomethyl)benzo[b]furan structure 

Scheme 1. Work Hypothesis

Results of our investigation, summarized in the scheme 2, showed that the catalytic system dramatically influence the reaction outcome: with nitrogen based nucleophiles the reaction works well with Pd₂(dba)₃/dppf, while with sulfur, oxygen and carbo-nucleophiles [Pd(η³-C₃H₅)Cl]₂/XPhos is more efficient. Furthermore, the reaction revealed to be regioselective since the nucleophilic substitution occurs only on the benzylic position of the η³-(benzofuryl)methyl complex.

Scheme 2 Palladium-catalyzed benzylic-like nucleophilic substitution of benzofuran-2-ylmethyl acetate with N, S, O and C soft nucleophiles. ³

The usually high to excellent yields and the simplicity of the experimental procedure make this method particularly convenient for the preparation of this class of compounds. The main detail of our investigation will be discussed during the presentation.

Biography:

Antonia Iazzetti is professor assistant at Catholic University of the Sacred Heart of Rome. Since her PhD in Pharmaceutical Science at Sapienza University of Rome in 2013, she worked in the field of organometallic chemistry focusing on the transition metal-mediated synthesis of heterocycles. Recently, working in the frame of a relevant European research project (Horizon 2020), she has aimed to the valorization of industrial by-products developing innovative and sustainable extraction/purification/concentration technology to be applied to the recovery of valuable compound from production side-streams. She is author of more than 30 scientific publications in international journals indexed by Scopus and WOS.