Reactions of 3-Arylisocoumarins with N-Nucleophiles – A Route to Novel Azaheterocycles

Abstract

This review highlights the promising science that has arisen from the synthesis of novel azaheterocycles from isocoumarins. Specific topics include their synthesis and biological activity. Isocoumarins (1H-isochromen-1-ones) are promising synthons, in particular due to the presence of a deoxybenzoin fragment which opens up wide possibilities for synthetic transformations. The deoxybenzoin cycle is highly susceptible to the action of various nucleophilic agents; its oxygen atom participates in recyclization reactions under the action of N-nucleophiles where it is replaced by a nitrogen atom, making it possible to obtain isoquinolones via a reaction with ammonia, primary amines, hydroxylamine and benzodiazepinones via a reaction with hydrazine. We systematize literature data, including patents (about 60 publications in all), demonstrate the routes of 3- arylisocoumarins modification under the action of N-nucleophiles - ammonia and primary amines, diamines, secondary amines, (het)arylamines, hydroxylamine, and hydrazines, and discuss the practical importance of these studies for medicinal chemistry.

Distinctive Features of 3‐Acetyl‐ and 3‐Benzoyl‐Isocoumarins’ Interaction with Active Primary Amines

“…A significant result was that one-pot synthesis could be carried out without isolating the intermediate products Only a few examples of the detection of 3-hydroxytetrahydroisoquinolones caused by the recyclization of isocoumarins under the action of primary amines are described in the literature. [1,10] This is likely due to the harsh conditions of the recyclization of isocoumarins to isoquinolones. Therefore, the side carbonyl group is expected to participate in the reaction during the recyclization of isocoumarins 1a,b under the action of an excess of methylamine.…”

“…This strategy may be more advantageous than direct cyclization into isoquinoline, especially when the substrates for recyclization, such as 1 H ‐isochromen‐1‐ones, can be readily synthesized from available reagents. We analyzed variations in the applications of this approach for the synthesis of practically significant 3‐(het)arylisoquinolin‐1‐ones in a previous review [1] . Notably, many isoquinolines with active functional groups and useful properties can be obtained via the recyclization of isocoumarins using ammonia, primary amines, and other nucleophiles with an NH 2 group (e. g., hydrazine, hydroxylamine).…”

Amino acid sulfonamides based on 4-(1-oxo-1H-isochromen-3-yl)benzenesulfonyl chloride

“…Synthetic [1][2] and natural [2][3] сompounds that contain the isocoumarin (1H-isochromen-1-one) fragment are well known group of oxygen containing heterocycle. These substances have a tremendous potential as starting materials in synthetic organic chemistry (synthesis of isoquinolines [4]) or as bioactive compounds [5][6]. However, isocoumarins can be found in the scientific literature not as often as isomeric chromones and coumarins.…”

1H-isochromene-1-ones and isoquinoline-1(2H)-ones with carbonyl group in position 3: Features of synthetic approaches and transformation

“…It is worth noting that the chemistry of these classes of heterocyclic compounds developed in parallel from the very beginning because one of the approaches to the formation of the isoquinolin-1(2H)-one 5 is the recyclization of the 1H-isochromen-1-ones system 6 under the action of compounds with a primary amino group (scheme 1; the results for 3-arylsubstituted derivatives are summarized and analyzed in reviews). 9,10 Scheme 1. Recyclization of 1H-isochromen-1-one system into isoquinolin-1(2H)-one.…”

“…We describe the application of various methods for implementing the transformation shown in Scheme 1. Thus, the reaction was carried out by heating with primary amines in ethanol at elevated pressure; boiling in ethanol under normal pressure but with an excess of amine; boiling in pyridine; boiling in toluene in an inert atmosphere; and when heated without solvent (for example, heat at 100-120 °С in a sealed tube or an autoclave; you can read more about variations of this technique in reviews 9,10 ). Synthetic equivalents of ammonia were also used: AcONH4, (NH4)2CO3, HCONH2, etc.…”