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

The three component condensation reactions involving isoquinoline, dimethyl acetylenedicarboxylate and carbonyl dipolarophiles such as oand p-benzoquinones and Nsubstituted isatins constitute a one-pot synthesis of a variety of [1,3]oxazino isoquinoline derivatives via 1,4-dipolar cycloaddition.


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. 2Noteworthy developments in this area have been the introduction of heteroaromatic betaines as 1,4-dipoles 3 and the utilization of 1,4-dipole equivalents in formal 1,4-dipolar cycloaddition reactions. 4part from a few isolated reports in the literature, 5 the potential of "Huisgen 1,4-dipoles" for the construction of various six membered heterocycles remains underexploited.An interesting example of this type is the dipole 1 generated from isoquinoline and dimethyl acetylenedicarboxylate (DMAD), whose existence was confirmed by Huisgen 6 (Figure 1).

Figure 1
In view of our recent interest in developing novel multicomponent reactions for heterocyclic synthesis via dipolar intermediates 7 we were intrigued by the possibility of trapping the dipole 1 with various dipolarophiles.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
Reaction of isoquinoline and DMAD with 1,2-and 1,4-benzoquinones Against the background presented above and in the context of our general interest in the dipolarophilic profile of quinonoid compounds, 9 we examined the possibility of trapping the 1,4dipole 1 with o-and p-benzoquinones.

Scheme 1
The products 5 and 6 were characterized by spectroscopic techniques.The IR spectrum showed strong absorptions at 1742, 1708 and 1667 cm -1 indicating the presence of ester and enone carbonyls.In the 1 H NMR spectrum of 5, signals due to the three methoxy groups were visible at δ 3.94, 3.54 and 3.40; the corresponding signals for 6 were observed at δ 3.90, 3,64 and 3.47.The ring junction proton of 5 was discernible as a singlet at δ 6.50; the corresponding signal for 6 was seen as singlet at δ 6.68.In 13 C NMR spectrum of 5, the characteristic signal for the spirocarbon was observed at δ 78.2, whereas in the spectrum of 6, it was discernible at δ 80.9.The signals corresponding to ester and enone carbonyls of 5 were seen at δ 163.4,163.5 and 194.9 and those for 6 were visible at δ 163.4,164.2 and 193.1.Finally the structure and stereochemistry of the product 6 was unambiguously established by single crystal X-ray analysis.

Scheme 2
Analogous results were obtained with a number of other quinones and the results are summarised in Table 1.Mechanistically the reaction can be considered to proceed via the initial formation of the 1,4-dipolar intermediate 1 from isoquinoline and DMAD, followed by its trapping with quinone carbonyl in a cycloaddition mode to give the corresponding spiro [1,3]oxazino isoquinolines (Scheme 3).Reaction conditions = DME, Ar,rt, 6 h, a ratio of isomers.b isolated yield.

Reaction of Isoquinoline and DMAD with N-substituted Isatins
Impressed by the reactivity of the dipole 1 towards quinones, it was interesting to explore its reactivity towards 1,2-diones such as N-substituted isatins.Thus the reaction of N-substituted isatins with DMAD and isoquinoline afforded the spiro [1,3] he products were purified by chromatography and characterized by spectroscopic analysis.The IR spectrum of 33 showed the characteristic ester carbonyl absorptions at 1741 and 1711 cm -1 .The amide carbonyl absorption was seen at 1620 cm -1 .In the 1 H NMR spectrum, signals due to the methoxy groups were observed as singlets at δ 3.98 and 3.53 whereas the olefinic protons were visible as doublets at δ 6.42 (J = 7.73 Hz) and 5.83 (J = 7.74 Hz).In the 13 C NMR spectrum, the three resonance signals corresponding to the ester and amide carbonyls were seen at δ 162.9, 163.1 and 173.3.The signal due to the spirocarbon was discernible at δ 79.1.All the other signals were also in agreement with the assigned structure.

Conclusions
In conclusion, we have developed some novel and interesting three component condensation reactions via 1,4-dipolar cycloaddition, affording a facile entry into a variety of isoquinoline fused heterocycles.In this context, it is noteworthy that these isoquinoline derivatives are known to possess interesting biological activities. 10

Experimental Section
General Procedures.Melting points were recorded on a Buchi melting point apparatus and are uncorrected.NMR spectra were recorded at 300 ( 1 H) and 75 ( 13 C) MHz on a Bruker DPX-300 MHz NMR spectrometer.The spectra were run in CDCl 3 -CCl 4 , v/v 3:1 and chemical shifts are reported (δ) relative to TMS ( 1 H) and CDCl 3 ( 13 C) as the internal standards.Mass spectra were recorded under EI/HRMS (at 5000) resolution using an Auto Spec.M mass spectrometer.IR spectra were recorded on a Nicolet Impact 400D FT-IR spectrophotometer.Elemental analyses

Table 1 .
Reaction of isoquinoline and DMAD with quinines