An Azomethine Ylide Approach to Complex Alkaloid-like Heterocycles

Link: http://pubs.acs.org/cgi-bin/abstract.cgi/joceah/asap/abs/jo062579a.html

From William V. Murray at Johnson and Johnson Pharmaceutical Research and Development LLC, Cranbury, New Jersey

The report in JOC Note ASAP detailed the reaction sequence leading to the formation of alkaloid-like tricyclic pyrrole via an intermolecular [3+2] dipolar cycloaddition between nitrone and alkyne.

In their early studies of the intramolecular Diels-Alder reaction of 1, it was found that instead of obtaining enamine 2, they obtained nitrone 3. According to their calculation, 3 is 11 kcal more stable than 2.

When nitrone 3 was subjected to dipolar cycloaddition to alkyne as a dipolarophile in toluene at 60-80 C, isoxazole 4 was obtained. However, in subsequent studies when nitrone 3a was subjected to DMAD and the reaction was heated in toluene at reflux, instead of obtaining isoxazole 4a as expected, a different product was obtained. After careful spectral analysis and x-ray crystallography, the new product was found to be the pyrrole 5a.

The product 5a was later found to the thermal rearrangement product of 4a when the reaction mixture was heated at higher temperature (refluxing toluene).

The scope of this cycloaddition-thermal rearrangement sequence was studied with different nitrones and dipolarophiles and the results are summarized in the table below.

Along with the scope of the reaction, a reaction mechanism of the transformation from 4 to 5 was also proposed as illustrated below.

This is believed to be the working mechanism as it fits well with the result of the reaction between nitrone 3b and the dipolarophile where X is a phenyl group. In this case, the reaction took longer (110 C/5 h) than other entries because of the inherent stability of phenyl ketone which made it less prone to cyclization by enamine addition (vide supra). The featured transformation (4 to 5) is an interesting reaction and can make a good reaction mechanism question.