Calix[n]arene-Catalyzed Three-Component Povarov Reaction: Microwave-Assisted Synthesis of Julolidines and Mechanistic Insights

Abstract

A new one-pot cascade reaction-based application of Povarov reactions with a p-sulfonic acid calix[4]arene catalyst for the synthesis of a series of 34 julolidine derivatives with substituents at C8 or C9 in good to excellent yields is reported. These microwave-assisted reactions proceeded efficiently, had short reaction times, were metal-free, were low cost, and used an inexpensive, easily available and nontoxic catalyst. These advantages, along with a simple workup procedure, make this protocol a very efficient and green alternative to the traditional methods for constructing these types of N-heterocyclic skeletons. In addition, this protocol allows the formation of julolidine structures, which requires the construction of four new C-C bonds and two C-N bonds. A mechanism for the Povarov reaction involving a stepwise sequence via ionic intermediates was proposed and validated.

Synthesis and Derivatization of Julolidine: A Powerful Heterocyclic Structure

“…In this same work, Abranches et al (2018) also elucidated the mechanism of the Povarov reaction under the reaction conditions used . After Mannich‐type reactions between in situ generated imines and 2,3‐dihydrofuran, the oxonium ions 80 and 81 were formed.…”

“…Despite the large reaction time (48 h), compounds 74a and 74d were obtained good yields (98 and 70 %, respectively). More recently, Abranches and co‐workers (2018) reported a new synthetic strategy for obtaining furojulolidines utilizing just 1 mol‐% CX4SO 3 H as catalyst under microwave irradiation, obtaining furojulolidines 75a – q with good to excellent yields in only 20 minutes of reaction (Scheme ).…”

“…After Mannich‐type reactions between in situ generated imines and 2,3‐dihydrofuran, the oxonium ions 80 and 81 were formed. The ring closure and subsequent formation of furojulolidines occurred after a Friedel‐Crafts reaction …”

The Povarov Reaction: A Versatile Method to Synthesize Tetrahydroquinolines, Quinolines and Julolidines

“…The methodology exhibited a long reaction time (48 h) and the four furojuloli-dines were obtained in 38-98% yields. Abranches et al 29 also reported the synthesis of furojulolidines 109 and 110 by utilizing just 1 mol% of CX4SO 3 H as a recoverable and reusable organocatalyst under microwave irradiation in 20 minutes, obtaining 34 furojulolidines in yields of 45-96% (Scheme 26, B). In 2019, de Paiva et al 30 synthesized the furojulolidines 109 and 110 by applying silica-supported psulfonic acid calix [4]arene (CX4SO 3 HSi(n)), as a recoverable and reusable heterogeneous catalyst, under solvent-free conditions and microwave irradiation for 10 minutes, obtaining furojulolidines in yields of 58-97% (Scheme 26, C).…”

Synthesis of julolidines via one‐pot cascade three component Povarov reaction in the presence of silica sulfuric acid

“…In the Povarov reaction, the imine is produced via acid‐catalyzed reaction between anilines and aldehyde and reacts with a nucleophilic alkene through an aza‐Diels‐Alder or Mannich type reaction (Scheme 2) [10,11]. The Povarov reaction with simple alkenes such as styrene gave low yields of corresponding julolidine derivatives in the presence of TFA as an acid catalyst [12]. Recently, a new one‐pot cascade reaction‐based application of Povarov reaction with a p ‐sulfonic acid calix[4]arene catalyst under microwave irradiation has been reported by S. A. Fernendez and co‐workers for the synthesis of a series of julolidine derivatives [13,14].…”