The AlCl3–L Reagent and its Application to the Regioselective Carbon–Carbon Bond Formation

Abstract

Use of the AlCl₃–L reagent in the regioselective acylation of benzodioxinic de- rivatives. Spectroscopic studies show the presence of coordination compounds as reaction intermediates, being the responsible of the observed regioselectivity.

Introduction

Carbon–carbon bond forming reactions are one of the most important processes in organic synthe- sis. Many of these transformations are promoted by ordinary Lewis acids, which activates a wide vari- ety of functional groups. The reactions usually proceed efficiently but with low chemo– and regiose- lectivities. For this reason, it is of great interest the development of new methodologies to perform these organic transformations in a selective form.

We have demonstrated that the combination of AlCl3 with an organic donor ligand is an excellent reagent for the acylation reaction of benzodioxin derivatives, which is carried out in the absence of added solvent [1,2]. Derivatives of this nucleus bearing an acyl group in position 6 or 7 are key inter- mediates in the preparation of therapeutically valuable benzodioxin compounds [3].

Results and Discusion

The use of AlCl3 in conjunction with DMF, DMSO or DMA and acyl halides or anhydrides pro- duce the regioselective functionalization of benzodioxin derivatives in excellent yields.

Both the 6– and 7– position of the aromatic ring are activated towards the electrophilic attack. However, acylation of 2–substituted–1,4–benzodioxin derivative 1 provides the 6–acyl compound as the major or unique product, and the same reaction with the saturated analogs 2 affords the 7–acyl compound as the main product, whatever the nature of the R1 group.

The experimental results demonstrate that the nature of the reacting electrophile and the donor li- gand employed have almost no influence on the isomeric distribution which is function exclusively on the substrate structure.

Spectroscopic studies reveal the presence of coordination compounds as reaction intermediates. The NMR ¹H and ¹³C spectra of reaction mixtures show a complexed entity between the AlCl₃–L reagent and the polar functionality of the aromatic substrate. The formation of this complex seems to be re- sponsible for the inversion of the regioselectivity between the saturated and unsaturated benzodioxinic compounds.

Acknowledgements

Financial support from Consejo Nacional de Investigaciones Científicas y Técni- cas (CONICET), Universidad Nacional de Rosario and Agencia Nacional de Promoción Científica y Tecnológica is gratefully acknowledged.