Ion-exchange-resin-catalyzed adamantylation of phenol derivatives with adamantanols: Developing a clean process for synthesis of 2-(1-adamantyl)-4-bromophenol, a key intermediate of adapalene.

Nan Wang,Xia Shi,Ronghua Wang,Gang Zou

doi:10.3762/bjoc.8.23

Abstract

A clean process has been developed for the synthesis of 2-adamantylphenol derivatives through adamantylation of substituted phenols with adamantanols catalyzed by commercially available and recyclable ion-exchange sulfonic acid resin in acetic acid. The sole byproduct of the adamantylation reaction, namely water, could be converted into the solvent acetic acid by addition of a slight excess of acetic anhydride during the work-up procedure, making the process waste-free except for regeneration of the ion-exchange resin, and facilitating the recycling of the resin catalyst. The ion-exchange sulfonic acid resin catalyst could be readily recycled by filtration and directly reused at least ten times without a significant loss of activity. The key intermediate of adapalene, 2-(1-adamantyl)-4-bromophenol, could be produced by means of this waste-free process.

Highlights

Introduction oAdamantylphenols and their derivatives are the key skeletons of synthetic retinoid analogues [1,2,3,4,5,6,7,8,9] and supporting ligands of many homogeneous transition-metal catalysts [10,11,12,13,14]
The water byproduct had to be thoroughly removed from the recovered resin by drying the resin under vacuum (
Acetic acid appeared to be the best choice of solvent for the resin-catalyzed adamantylation with 1-adamantanol (2a), as it gave the desired 2-(1-adamantyl)-4-bromophenol (3aa) in high yields within a shorter reaction time, but it made it possible to directly reuse the recovered resin catalyst since the byproduct, water, which is detrimental to the catalytic activity of such resins, could be converted into acetic acid by the addition of an equivalent amount of acetic anhydride during the work-up procedure

Summary

Introduction

Introduction oAdamantylphenols and their derivatives are the key skeletons of synthetic retinoid analogues [1,2,3,4,5,6,7,8,9] and supporting ligands of many homogeneous transition-metal catalysts [10,11,12,13,14]. Treatment of 4-bromophenol (1a) with 1.05 equiv of 1-adamantanol (2a) in the presence of a macroporous sulfonic acid cation-exchange resin (Amberlite 200, H+ form) in ethyl acetate or diethyl carbonate under reflux for 10–12 h gave the desired product 2-(1-adamantyl)-4-bromophenol (3aa) in good yields; no reaction occurred in acetonitrile under similar conditions (Table 1, entries 1–3).

Results

Conclusion