1,4-Dipolar cycloaddition in organic synthesis: A facile route to isoquinoline fused heterocycles

Vijay Nair,Luxmi Varma,Sreemathi Viji,Anakkalil Ramachandran Sreekanth,Saumini Mathew,Akkattu Thankappan Nair Biju,Narayana Pillai Abhilash,Viktor V Zhdankin

doi:10.3998/ark.5550190.0006.b15

Abstract

The three component condensation reactions involving isoquinoline, dimethyl acetylenedicarboxylate and carbonyl dipolarophiles such as o- and p-benzoquinones and N- substituted isatins constitute a one-pot synthesis of a variety of (1,3)oxazino isoquinoline derivatives via 1,4-dipolar cycloaddition.

Highlights

In addition to the well known hetero-Diels-Alder reactions,1 1,4-dipolar cycloaddition constitutes a potentially versatile process for the construction of six membered heterocycles
An interesting example of this type is the dipole 1 generated from isoquinoline and dimethyl acetylenedicarboxylate (DMAD), whose existence was confirmed by Huisgen6 (Figure 1)
Investigations carried out in this context have demonstrated that the dipole 1 can be effectively trapped by N- tosylimines resulting in the diastereoselective synthesis of 2H-pyrimido[2,1-a]isoquinolines.8a Our preliminary results from studies using quinones as dipolarophiles have shown that the reaction leads to a one-pot synthesis of spiro[1,3]oxazino[2,3a]isoquinolines.8b In this paper we disclose the results of our extended investigations on the reactivity of dipole 1 towards various carbonyl dipolarophiles; the reactions constitute a facile route to isoquinoline fused heterocycles, which are interesting from the standpoint of their potential biological activity

Summary

Introduction

In addition to the well known hetero-Diels-Alder reactions,1 1,4-dipolar cycloaddition constitutes a potentially versatile process for the construction of six membered heterocycles. The basic principles of 1,4-dipolar cycloaddition were provided by the pioneering work of Huisgen and coworkers.. The basic principles of 1,4-dipolar cycloaddition were provided by the pioneering work of Huisgen and coworkers.2 Noteworthy developments in this area have been the introduction of heteroaromatic betaines as 1,4-dipoles and the utilization of 1,4-dipole equivalents in formal 1,4-dipolar cycloaddition reactions.. Apart from a few isolated reports in the literature, the potential of "Huisgen 1,4-dipoles" for the construction of various six membered heterocycles remains underexploited. Investigations carried out in this context have demonstrated that the dipole 1 can be effectively trapped by N- tosylimines resulting in the diastereoselective synthesis of 2H-pyrimido[2,1-a]isoquinolines.8a Our preliminary results from studies using quinones as dipolarophiles have shown that the reaction leads to a one-pot synthesis of spiro[1,3]oxazino[2,3a]isoquinolines.8b In this paper we disclose the results of our extended investigations on the reactivity of dipole 1 towards various carbonyl dipolarophiles; the reactions constitute a facile route to isoquinoline fused heterocycles, which are interesting from the standpoint of their potential biological activity

Results and Discussion

H N CO2Me

Conclusions