Palladium-Catalyzed Synthesis of Isoquinolinones via Sequential Cyclization and N-O Bond Cleavage of N-Methoxy-o-alkynylbenzamides

Abstract

A palladium-catalyzed controlled 6-endo-dig cyclization process has been developed for the chemoselective synthesis of isoquinolin-1-ones from N-alkoxy-o-alkynylbenzamides. The mechanism and scope of the reaction have also been investigated. Deuterium-labeling studies were used to confirm the intramolecular 1,5-hydrogen shift as a key step in the transformation.Isoquinolinones, which are also known as 1-oxo-1,2-dihydroisoquinolines, are one of the key structural units found in plant alkaloid derivatives. 1 These structures can also be found in synthetic molecules that possess a range of biological activities. 2 Isoquinolinone itself has been used as a basic building block for the synthesis of more complex isoquinolinone ring systems. 3 The development of practical synthetic strategies for the construction of isoquinolinone systems has been extensively explored by a number of material, organic, and pharmaceutical chemists because of the widespread occurrence and utility of this structural motif. Of these methods, the use of an intramolecular reaction is one of the most convenient tools for the preparation of substituted isoquinolinone derivatives. 4 To date, several methods have been developed for the construction of the isoquinolinone framework involving the cyclization reaction of benzamide derivatives. 5 The cyclization of o-alkynylbenzamides in particular represents a straightforward and powerful strategy for the direct synthesis of isoquinolinones. Although a variety of different methods has been reported for the intramolecular annulation of o-alkynylbenzamide using either a base, 6 electrophile, 7 or transition-metal catalyst, 6,8 these methods often suffers from a lack of regioselectivity because of competitive cyclization processes that can occur through either the 5-exo or 6-endo cyclization modes. Moreover, the oxygen and nitrogen atoms of the amide moieties involved in these methods can both behave as nucleophiles, leading to a lack of chemoselectivity in the cyclized products. The development of a method providing exclusive control over chemo-and regioselective outcomes of the reaction is therefore both desirable and challenging.During the course of our ongoing investigations based on the reactivity of the nitrogen-oxygen bond, 9 we recently found that the intramolecular cyclization of Weinreb amides bearing an alkyne moiety proceeded predominantly via the O-nucleophilic attack of the carbonyl group in the presence of CuCl 2 /NCS to form isobenzofuran-1-ones. 10 Interestingly, however, much less is known about influencing the chemoselective nucleophilic attack of the amide nitrogen over the carbonyl oxygen in Weinreb amides. 11 It was envisaged that the coordination of a palladium catalyst to both the N-alkoxyamide and alkyne would lead to the formation of a product resulting from the opposing chemo-and regioselectivities. Herein, we report the development of a method for the palladium-catalyzed cyclization of N-alkoxy-o-alkynylbenzamides to afford isoquinolin-1-ones exclusively.

Radical Addition-Initiated Domino Reactions of Conjugated Oxime Ethers

“…As part of our ongoing research on the development of novel domino reactions, [3][4][5][6][7][8][9] we have recently focused our attention on the radical reactions of conjugated imines. Conjugated imines can be used as versatile building blocks for the efficient construction of nitrogen-containing heterocycles, as well as amino acids and amines, because they contain several reactive sites.…”