Synthesis of benzoquinone compounds by a microdroplet-accelerated retro-Diels–Alder reaction

Abstract

The unique environment of water microdroplets has enabled several novel organic transformations to be reported in recent years. Given the significance of the retro-Diels–Alder (rDA) reaction in organic and natural product synthesis, we demonstrate a highly accelerated rDA reaction using water microdroplets. The rDA reaction is a reversible process of the classical Diels–Alder cycloaddition, triggered by the dissociation of a six-membered ring, typically under thermal conditions. In this study, Diels–Alder adducts dissolved in water/methanol were electro-sprayed using nitrogen gas at a pressure of 120 psi, leading to efficient rDA product formation of benzoquinones. The products were characterized by mass spectrometry (MS) and tandem mass spectrometry (MS²). Additionally, crude samples were collected after passage through a 40 mm heated channel (150 °C) for ≈1.2 ms in xylene solvents sprayed under 50 psi for 30 minutes, the distance between sprayer and collection chamber kept at 240 mm. The structures were further confirmed using MS, IR, ¹H-NMR, and ¹³C-NMR analyses. Notably, 2.6 mg of the blue scorpion venom compound, 5-methoxy-2,3-bis(methylthio)cyclohexa-2,5-diene-1,4-dione, was obtained in 60% isolated yield. This compound, originally isolated from scorpion venom, exhibits remarkable antimicrobial activity against Mycobacterium tuberculosis and the priority pathogen Acinetobacter baumannii. The products were formed within milliseconds, representing a significant rate enhancement compared to traditional bulk-phase rDA reactions.