Synthesis of Unexpected Dimethyl 2-(4-Chlorophenyl)-2,3-dihydropyrrolo[2,1-a]isoquinoline-1,3-dicarboxylate via Hydrolysis/Cycloaddition/Elimination Cascades: Single Crystal X-ray and Chemical Structure Insights

Mezna Altowyan,Assem Barakat,Aminah Alkharboush,Matti Haukka,Saied Soliman,Nora Al-Shaalan

doi:10.3390/cryst12010006

Abstract

Hydrolysis/[3 + 2] cycloaddition/elimination cascades employed for the synthesis of unexpected tricyclic compound derived from isoquinoline. Reaction of ethylene derivative 1 with the isoquinoline ester iminium ion 2 in alkaline medium (MeOH/NEt3) under reflux for 1 h resulted in the formation of the fused pyrrolo[2,1-a]isoquinoline derivative 3. Its structure was elucidated by X-ray single crystal and other spectrophotometric tools. Hirshfeld calculations for 3 and its crystal structure analysis revealed the importance of the short O…H (19.1%) contacts and the relatively long H…C (17.1%), Cl…H (10.6%) and C…C (6.1%) interactions in the molecular packing. DFT calculations were used to compute the electronic and spectroscopic properties of the studied system. The studied compound has polar nature (3.5953 Debye). TD-DFT calculations assigned the shortest wavelength band (220 nm) to the HOMO−1→LUMO+2 (57%), HOMO−1→LUMO+4 (14%) mixed excitations. The calculated NMR chemical shifts correlated very well with the experimental data (R2 = 0.93–0.94).

Highlights

Quinoline and isoquinoline analogues are privileged structures which exploited for the synthesis of polyheterocycles for the applications in the therapeutic area [1,2,3]
[3 + 2] Cycloaddition reaction via azomethine ylide is one of the most straightforward, powerful, and efficient reactions that offered the construction of fused tricyclic compound based on pyrrolo[2,1-a]isoquinoline [12]
Many examples described in the literature for the synthesis of pyrrolo[2,1-a]isoquinolines using metal mediated syntheses such as silver-catalyzed cycloisomerization/dipolar cycloaddition reported by Porco Jr. et al [13]

Summary

Introduction

Quinoline and isoquinoline analogues are privileged structures which exploited for the synthesis of polyheterocycles for the applications in the therapeutic area [1,2,3]. Pyrrolo[2,1-a]isoquinoline is a core structure in many natural products with pharmaceutical targets including human topoisomerase I inhibitors and anti-HIV-1 activities as lamellarins [9,10,11], and others such as trollines, crispines, and oleraceins [1]. This framework remarks as a skeleton for many synthesized molecules as important, interesting and attractive goal in organic synthesis. Many examples described in the literature for the synthesis of pyrrolo[2,1-a]isoquinolines using metal mediated syntheses such as silver-catalyzed cycloisomerization/dipolar cycloaddition reported by Porco Jr. et al [13].

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Results

Conclusion