Synthesis of 5-substituted pyrrole-2-carboxaldehydes. Part I. Generation of formal 5-lithiopyrrole-2-carboxaldehyde equivalents by bromine-lithium exchange of 2-bromo-6-(diisopropylamino)-1-azafulvene derivatives

The first known lithiated 1-azafulvene derivatives, e.g., 8 and 13 a, were generated by a low-temperature bromine-lithium exchange procedure with tert-butyllithium. These lithio species show substantial stability at ≤ −90 °C because, at these temperatures, the sterically demanding 6-diisopropylamino moiety, unlike the dimethylamino group, completely inhibits nucleophilic addition to C-6. At higher temperatures, the addition of tert-butyllithium to C-6 is significant and it can become the dominant process. The lithio species 8 is a useful formal equivalent of 5-lithiopyrrole-2-carboxaldehyde since, on reaction with electrophilic reagents and subsequent hydrolysis, a wide variety of regiochemically pure 5-substituted pyrrole-2-carboxaldehydes is formed. The 6-dialkylamino-1-azafulvenes described herein exist predominantly or exclusively as the syn conformer in solution at room temperature. This conformational preference is confirmed by a significance NOE effect between H-4 and H-6 in the parent diisopropylamino compound 3 f. The origin of the syn conformational preference stems from a substantial contribution of the charge-separated form 16 to the ground state structure of these compounds, a phenomenon that is strongly supported by variable temperature NMR measurements on 2-bromo-6-diisopropylamino-1-azafulvene ( 3 c). Keywords: 2-bromo-6-diisopropylamino-1-azafulvenes, stereochemistry, lithiation, pyrrole-2-carboxaldehydes.