First practical synthesis of novel 1‐phosphonylated pyrrolo[1,2‐a]pyrazine derivatives

Abstract

We present a convenient synthetic approach to novel 1‐phosphonylated pyrrolo[1,2‐a]pyrazine derivatives based in efficient three‐component reactions. According to this method, N‐functionalized 2‐formylpyrrole derivatives are used as bifunctional coupling reagents in the reaction with dialkyl phosphites and amines to access to the target compounds.

Synthetic Methods for Azaheterocyclic Phosphonates and Their Biological Activity: An Update 2004–2024

“…381 To improve it, they prepared the substituted imine 737 (R 1 ≠ H) and performed the hydrophosphonylation with bulky dialkyl phosphites, giving good yields but moderate diastereomeric ratios. By changing the phosphorus nucleophile for tris(trimethylsilyl)phosphite (739) in the presence of bromotrimethylsilane (BrTMS), the authors obtained the chiral 383 To synthesize 1,2-dihydropyrrolo[1,2-a]pyrazine-1-phosphonates 758, Kim and co-workers reported a Sc(OTf) 3catalyzed three-component coupling between pyrrole derivatives 755, amines 756, and trialkylphosphites 757 (Scheme 135). This one-pot procedure tolerates different pyrroles and amines, and the functionalized pyrazines are obtained in moderate and very good yields via a Kabachnik−Fields reaction followed by a intramolecular dehydrative cyclization.…”

“…The tetrahydro pyrazines 754 were obtained in moderate yields by performing a three-component reaction between N-(2chloroethyl) pyrrole (751), ammonium acetate (752), and dialkylphosphite 753 in the presence of anhydrous Na 2 SO 4 in acetonitrile at 60 °C. 383 To synthesize 1,2-dihydropyrrolo[1,2-a]pyrazine-1-phosphonates 758, Kim and co-workers reported a Sc(OTf) 3catalyzed three-component coupling between pyrrole derivatives 755, amines 756, and trialkylphosphites 757 (Scheme 135). This one-pot procedure tolerates different pyrroles and amines, and the functionalized pyrazines are obtained in moderate and very good yields via a Kabachnik−Fields reaction followed by a intramolecular dehydrative cyclization.…”

“…With the aim to develop a mild and environmentally friendly protocol, ethyl-2-(2-formyl-1 H -pyrrol-1-yl)­acetate 748 was used in the three-component reaction to access directly the phosphonylated pyrazine 750 . The tetrahydro pyrazines 754 were obtained in moderate yields by performing a three-component reaction between N -(2-chloroethyl) pyrrole ( 751 ), ammonium acetate ( 752 ), and dialkylphosphite 753 in the presence of anhydrous Na 2 SO 4 in acetonitrile at 60 °C …”

One-Pot Phosphonylation of Heteroaromatic Lithium Reagents: The Scope and Limitations of Its Use for the Synthesis of Heteroaromatic Phosphonates

“…Finally, the formation of lithium derivatives or Grignard reagents using aryl halides as substrates may be also employed [ 2 , 6 , 7 ]. In the past decade, interesting methods of nontypical specific procedures for the synthesis of heteroaromatic phosphonates have been studied and elaborated [ 12 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ].…”