Total Synthesis of Six 3,4-Unsubstituted Coumarins

In this article we describe a new methodology for the total synthesis of 3,4-unsubstituted coumarins from commercially available starting materials. Six examples were prepared, including five naturally occurring coumarins—7-hydroxy-6,8-dimethoxy-coumarin (isofraxidin), 7-hydroxy-6-methoxycoumarin (scopoletin), 6,7,8-trimethoxy-coumarin, 6,7-dimethoxycoumarin (scoparone), and 7,8-dihydroxycoumarin (daphnetin) and one synthetic coumarin, 7-hydroxy-6-ethoxycoumarin. Moreover, five important o-hydroxybenzaldehyde intermediates were also obtained, namely 2,4-dihydroxy-3,5-dimethoxybenzaldehyde, 2,4-dihydroxy-5-methoxybenzaldehyde, 5-ethoxy-2,4-dihydroxy-benzaldehyde, 2-hydroxy-3,4,5-trimethoxybenzaldehyde, and 2-hydroxy-4,5-dimethoxy-benzaldehyde. The method developed herein involves just three or four steps and allows for the rapid synthesis of these important molecules in excellent yields. This is the first synthesis of 6,7,8-trimethoxycoumarin and 7-hydroxy-6-ethoxycoumarin.