Synthesis of Isocoumarins with Different Substituted Patterns via Passerini–Aldol Sequence

Abstract

An efficient combination between the Passerini three-component reaction and aldol condensation has been developed for the synthesis of bicyclic isocoumarins with different substituted patterns via solvent-dependent domino pathways. These two operationally friendly methods simultaneously install C–O and C–C bonds in a one-pot manner, allowing the utilization of low-cost and readily accessible 2-formylbenzoic acid, isocyanides, and arylglyoxals. Mechanisms of formation of different substituted isocoumarin derivatives are also proposed.

A Photocatalytic Meerwein Approach to the Synthesis of Isochromanones and Isochromenones

“…The interest in these molecules is clearly witnessed by the recent isolation of icumazole A and by the total synthesis of noricumazole A (Scheme ), two molecules characterised by a marked activity against various fungi and yeasts. [2a] Moreover, ( S )‐4‐(1 H ‐imidazol‐1‐yl)‐3,3‐dimethylisochroman‐1‐one has been discovered to be a significant aldosterone inhibitor . Noteworthy, amicoumacins (Scheme ) belong to an interesting family of antibiotics bearing the isochromanone core that are currently under study for their antibacterial, anti‐inflammatory, anti‐ulcer and antineoplastic action .…”

“…The large number of applications has triggered the development of various synthetic routes towards compounds A – C . The synthesis of dihydroisocoumarins comprises the ortho ‐lithiation of aromatic compounds,[9a] the oxidation of the isochromane moiety,[9b], [9c] NHC‐,[9d] rhodium‐ or palladium‐catalysed[9h] reactions or procedures based either on rearrangements of isobenzofurans[9i] or the Passerini aldol sequence . In addition, isochromenone tricycles have been synthesised by metal‐catalysed and metal‐free classic oxidative lactonisation .…”

Aldo‐X Bifunctional Building Blocks for the Synthesis of Heterocycles

“…Recently, a Passerini‐aldol sequential reaction was also reported, with which two types of isocoumarin derivatives could be synthesized from 112 a , tert ‐butyl isocyanide, and 1‐(4‐bromophenyl)‐2,2‐dihydroxyethanone. If the reaction was carried out with methanol, an isomeric product of 128 could be formed, whereas in 1,4‐dioxane product 129 would be generated (Scheme ).…”

An Unprecedented Synthesis of 3,3‐Disubstituted Isochroman‐1,4‐diones Using Nitrones as Oxygen Atom Donors

“…The isochroman‐1‐one (isocoumarin) moiety is a widely known structural motif in a variety of natural products possessing significant biological and pharmacological activities and therefore have gained immense synthetic interest (Fig. ). Similarly, isochroman‐1,3‐diones and isochroman‐1,4‐diones are also known to have enhanced biological properties.…”