Synthesis of 3-alkylideneisoindolin-1-ones through cyclocarbonylative Sonogashira reactions

The isoindolin-1-one moiety has been found in a growing number of naturally occurring compounds, such as fumaridine and fumaramine from Fumaria parviflora and Fumaria vaillantii.1 Many isoindolin-1-ones -based compounds revealed biological and pharmacological activities,2 while others have found application as moisture- and temperature-resistant pigments. Furthermore, 3-alkylideneisoindolin-1-ones are building blocks for the synthesis of more complex heterocycles: benzodiazepines, piperidines, subporphyrins and spiro-compounds.3 Due to their versatility, several cyclization protocol have been developed for their preparation.4 Recently, we reported that 1-alkylidenephthalans and 1-alkylideneisochromans can be easily obtained, respectively, from suitable o-alkynylbenzyl and o-alkynylhomobenzyl alcohols by means of palladium-catalysed cyclocarbonylative Sonogashira reactions with functionalized aryl iodides.5 The same protocol was then extended to N-Boc and N-tosyl o-ethynylbenzylamine as substrates, giving 1-alkylideneisoindolines as main products.6 Starting from these results, here we describe the application of Pd-catalyzed cyclocarbonylative Sonogashira coupling to the synthesis of 3-alkylideneisoindolin-1-ones. The reactions were performed using 2-ethynylbenzamide and functionalized iodoarenes under CO pressure (20 atm) with an excess of Et3N, catalytic PdCl2(PPh3)2 (0.4 mol%), at 100 °C for 4 h (optimized conditions), yielding the corresponding (Z)-3-alkylideneisoindolin-1-ones as main products (Figure 1). Unexpectedly, depending on the solvent used, different interesting by-products were obtained (3-amino-1H-inden-1-ones with CH2Cl2, benzonitrile derivatives with THF), and their formation will be tentatively explained.