Assembly of 1,2,3,4-Tetrahydropyrrolo[1,2-a]pyrazines via the Domino Reaction of 2-Imidazolines and Terminal Electron-Deficient Alkynes

Abstract

The transformation of 2-imidazolines into 1,2,3,4-tetrahydropyrrolo­[1,2-a]­pyrazines has been realized. A pseudo-three-component reaction of 2-imidazolines with terminal electron-deficient alkynes (2 equiv) first generates imidazolidines, containing an N-vinylpropargylamine fragment. The latter can then undergo a base-catalyzed domino aza-Claisen rearrangement/cyclization reaction sequence, simultaneously constructing pyrrole and pyrazine rings. The process works in a broad substrate scope, delivering pyrrolo­[1,2-a]­pyrazines in good to excellent yields (45–90%). This two-step approach can be carried out in a one-pot fashion without a noticeable decrease in yield. Remarkably, a three-component protocol for the introduction of two different alkynes has been also developed.

Domino Approach for the Synthesis of Pyridinium Salts and 1,2,3,8a-Tetrahydroimidazo[1,2-a]pyridines from 2-Imidazolines and Propiolic Acid Esters

“…Adducts 3a – y were obtained by the reaction of 2-imidazolines 1 with methyl, ethyl, and p -methoxybenzyl esters of propiolic acid ( 2a – c ), using a previously published procedure (Scheme ). In most cases, the yields were 78–96%, except for 1-isopropyl-2-phenyl-2-imidazoline and reactions with p -methoxybenzyl propiolate 2c .…”

“…Other reagents were purchased from commercial sources and were used as received. Compounds 1a – d , 1h – i , 1n , 1p–1q , 1t , 3a – d , 3h – i , 3n – o , and 3y were prepared by following the literature procedure. , For known compounds, the 1 H and 13 C NMR spectra are consistent with previously reported literature. , For compounds 7a– 7s , structural assignments were made with additional information from gCOSY, gHSQC, and gHMBC experiments.…”

“…The reactivity of 2-imidazolines presents an appealing strategy for the synthesis of diverse heterocycles . Previously, we proposed a new type of synthetic intermediates containing an N -propargyl-β-enaminoester fragment, which was used in the synthesis of pyrroles (“imidazoline-to-pyrrole” strategy) and tetrahydropyrrolopyrazines (“imidazoline-to-pyrazine” strategy). , These adducts of 2-imidazolines and 2 molecules of methyl propiolate can be easily obtained in high yields as a result of pseudo-3CR. In the present work, we report protic acid-promoted transformation of such adducts into pyridinium salts and imidazo­[1,2- a ]­pyridines“imidazoline-to-pyridine” approachwhich represents a domino route for the synthesis of these compounds starting from 2-imidazolines and propiolic acid esters (Scheme e).…”

Pseudo-multicomponent reactions

“…In 2022 N. E. Golantsov and L. V. Voskressensky 26 reported a base catalyzed one-pot synthesis of 1,2,3,4-tetrahydropyrrolo[1,2- a ]pyrazines via a pseudo three-component reaction between imidazolines 53a–n and two equivalents of electron-deficient terminal alkynes (methyl propiolate 54a or acetylacetylene 54b), obtaining the products 61a–v in moderate to excellent yields. To explain the transformation of imidazolines to pyrazines, the authors proposed a reaction mechanism ( Scheme 7 ).…”