Neutral Nazarov reaction using protic solvents as activators

Herein, we report a neutral Nazarov reaction using protic solvents instead of strong acids as activators. The key to the success of this reaction lies in the rational design of the divinyl ketone substrates. In particular, the introduction of electron-donating groups (EDGs) at the beta- and beta '-positions of the carbonyl group in the divinyl ketone increases the Lewis basicity dramatically, an EDG at alpha-position promotes the cyclization, and the presence of a phenoxy group at beta-position enables the irreversible elimination of phenol from the cyclized intermediate, thus shifting the reversible cyclization to the product side. This phenol-releasing reaction can be applied to clip chemistry to target acidic biological environments. Herein, we report a neutral Nazarov reaction using protic solvents as activators. The key to success is that the presence of a phenoxy group at beta-position enables the irreversible elimination of phenol from the cyclized intermediate, thus shifting the reversible cyclization to the product side. This phenol-releasing reaction can be applied to clip chemistry to target acidic biological environments.