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

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.