Selective Monoarylation of Benzenediols via Dianion Intermediates

Abstract

Application of the S_NAr reaction on benzenediols with arylfluorides revealed an enhancement in monosubstitution selectivity over bis substitution when excess base was used. This trend was studied using symmetrical and nonsymmetrical benzenediols with various levels of steric hindrance. The effect of various bases was examined. A 100% monoselectivity was achieved in the presence of 2.5 equiv. of Cs₂CO₃. The methodology was employed in the synthesis of an important pharmaceutical product, 1, an arylether.

Keywords:

• S_NAr
• benzenediol
• selective monoarylation
• resorcinal

Acknowledgments

The authors thank Lisa Zollars for NMR NOE work in identifying the asymmetric monoarylated products. We also thank Richard Hoying for the scale‐up of 2 and the Lilly Analytical Technologies department for structural characterization.