Intramolecular [3+2] Cycloaddition Approach to Nicotine Analogues

Significance

A key intramolecular [3+2] cyclo­addition reaction as part of the construction of a new series of tricyclic nicotine analogues is reported. First, a metal-halogen exchange reaction leads to the formation of the pyridine aldehyde. Treatment with N-methylglycine leads to the requisite ylide which undergoes intramolecular [3+2] cycloaddition. Following decarboxylation and reduction, the cis-tricyclics are produced in good overall yields. Cycloaddition precursors are generated by standard metal-halogen exchange and nucleophilic aromatic substitution sequences. In an alternate route, nucleophilic 4-chloro displacement leads to substituted systems which undergo cycloaddition to afford analogous heteroatom products.