Mechanistic Investigation of Castagnoli–Cushman Multicomponent Reactions Leading to a Three-Component Synthesis of Dihydroisoquinolones

• DOI: 10.1021/acs.joc.1c01163
• Publication Date: 2021-08-05T14:47:57Z
• Authors: Sara Y. Howard; Michael J. Di Maso; Kristin Shimabukuro; Noah P. Burlow; Darlene Q. Tan; James C. Fettinger; Thomas C. Malig; Jason E. Hein; Jared T. Shaw
• Keywords: Maleic anhydride; Amide; Imine; Reactivity; Reactive intermediate

The mechanisms for the three- and four-component variants of Castagnoli–Cushman reaction (CCR) have been investigated. A series crossover experiments were conducted to probe structure reactivity known amide-acid intermediates CCR (3CR 4CR, respectively). Control paired with in situ monitoring infrared spectroscopy 4CR align a mechanism which amide-acids derived from maleic anhydride can reversibly form free amine cyclic anhydride. Although this equilibrium is unfavorable, aldehyde present trap primary through imine formation react enol Mannich-like mechanism. This detailed mechanistic investigation coupled additional supports an analogous 3CR has led elucidation new conditions homophthalic anhydride, amines, aldehydes dihydroisoquinolones good yields excellent diastereoselectivity. work represents culmination more than decade speculation 3- enabling design multicomponent reactions that exploit novel