Copper‐Catalyzed Recyclable Synthesis of (Z)‐3‐Alkylideneisoindolinones by Cycloisomerization of 2‐Alkynylbenzamides in Ionic Liquids

Abstract

The cycloisomerization of readily available 2‐alkynylbenzamides has been conveniently carried out with CuCl2 as catalyst under basic conditions in 1‐ethyl‐3‐methylimidazolium ethyl sulfate (EmimEtSO4) as an unconventional solvent. The process leads to (Z)‐3‐alkylideneisoindolin‐1‐ones in a chemo‐, regio‐, and stereoselective manner. The catalyst/solvent/base system could be recycled several times without appreciable loss of activity. The structures of representative products, that are, (Z)‐3‐benzylidene‐2‐phenylisoindolin‐1‐one and (Z)‐3‐pentylidene‐2‐phenylisoindolin‐1‐one, have been confirmed by X‐ray diffraction analysis, and DFT (density functional theory) calculations have been carried out to clarify the roles exerted by the base and CuCl2 in favoring the reaction course leading to (Z)‐3‐alkylideneisoindolinones.

Alkali‐Metal Promoted Chemo‐ and Regioselective Cycloisomerization Reactions to (Z)‐3‐Alkylideneisoindolin‐1‐ones: Unusual Positive Role of H2O

“…Based on the above mentioned results and the previous alkali metal ions‐promoted intramolecular cyclization of 2‐ethynylarenes,, we proposed a possible mechanism for this Na 2 CO 3 /H 2 O‐mediated anionic heterocyclization reaction (Scheme ). While strong bases such as NaH or t BuOK have been used to induce a similar cycloisomerization,, reports on the usage of a mild base to promote deprotonation of enamides to form cyclic azaheterocycles have been proven to be effective .…”

“…Serviceable yields of 2 a were obtained when more than 3.0 equivalents of H 2 O was added (entries 9, 12–16, Table ), yet only a slow and sluggish conversion was observed when the reaction was carried out under anhydrous conditions, or when the solvent was pure water (entries 13 and 17, Table ). This unusual result was a sharp contrast to the previous copper‐catalyzed heterocyclization of 2‐alkynylbenzamides in an ionic liquid solvent to deliver isochromenones as the product, in which the O‐endo‐dig cyclization process with elimination of aniline as the leaving group was favored, . The presence of water in DMF can improve the solubility of sodium carbonate in an organic solvent, thus should dynamically help to accelerate the reaction.…”

“…An improved reaction was disclosed by Liu et al , who developed t BuOK‐catalyzed selective cycloisomerization of alkynols or alkynylamines, to selectively produce exo ‐alkenyl heterocyclic products . Most recently, Gabriele and co‐workers reported a selective synthesis of ( Z )‐3‐alkylideneisoindolinone diastereoisomers through CuCl 2 ‐catalyzed cyclization reaction of 2‐alkynylbenzamides in ionic liquids (1‐ethyl‐3‐methylimidazolium ethyl sulfate, EmimEtSO 4 ) …”

Definition of green synthetic tools based on safer reaction media, heterogeneous catalysis, and flow technology

“…Several promising directions have been undertaken by the green chemistry community and excellent results have been achieved using non-conventional solvents as water [10][11][12][13][14][15], supercritical CO 2 [16][17][18][19], ionic liquids [20][21][22] as well as biomass-derived solvents that feature the obvious advantage of deriving from renewable resources [23][24][25]. In the latter case, additional considerations should be made by evaluating the synthetic route used for their preparation but can be certainly considered as "greener" and promising alternatives to fossil based solvents.…”

Regio- and Stereoselective Synthesis of Isoindolin-1-ones through BuLi-Mediated Iodoaminocyclization of 2-(1-Alkynyl)benzamides

“…Several research groups have developed various interesting approaches (>200 research articles in the recent literature) for the synthesis of the isoindolin-1-ones. , More particularly, alkyne annulation reactions have been used for the synthesis of isoindolinones, e.g. through metal catalyzed reactions (including Pd-catalyzed, − Cu-catalyzed/mediated, − and Ru-catalyzed), base-mediated annulations, − etc. , …”