Cascade Synthesis in Water: Michael Addition/Hemiketalization/Retro-Claisen Fragmentation Catalyzed by CatAnionic...

N,N-didodecylammonium N,N-didodecyldithiocarbamate (AmDTC-C₁₂C₁₂) underwent self-assembly to form a CatAnionic vesicular nanoreactor in water. AmDTC-C₁₂C₁₂ can be readily prepared by condensation between N,N-didodecylamine and carbon disulfide. Previously, the cascade Michael addition/hemiketalization/retro-Claisen fragmentation was reported, but it required petroleum-based organic solvents as reaction media. Herein, the application of AmDTC-C₁₂C₁₂ in aqueous cascade synthesis is investigated. Initially, we explored the catalytic activity of AmDTC-C₁₂C₁₂ (10 mol %) in the synthesis of 4H-chromene through a double-cascade Michael addition/hemiketalization. The reaction occurred in water at room temperature using 2-hydroxy-trans-β-nitrostyrene as Michael acceptor and acetylacetone as Michael donor, yielding 2-chromanol intermediates. Subsequent acidic dehydration of 2-chromanols produced 4H-chromenes with moderate yields (34-60 %) and phenyl acetates of γ-nitro ketone as co-products (13-31 %), deriving from retro-Claisen fragmentation. Surprisingly, using Michael donors with aromatic moieties on the 1,3-dicarbonyls resulted in spontaneous triple-cascade Michael addition/hemiketalization/retro-Claisen fragmentation in water without the need for acidic dehydration. The γ-nitro ketones were obtained as sole products, with no detection of 4H-chromenes, in moderate to high yields (24-84 %) for symmetrical 1,3-dicarbonyl containing two aromatic groups. Unsymmetrical 1,3-dicarbonyl bearing aromatic/aliphatic or aromatic/aromatic groups afforded γ-nitro ketones in favorable yields (73-97 %).