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