Abstract
The aza-vinylogous Povarov reaction between aromatic amines, α-ketoaldehydes or α-formylesters and α,β-unsaturated dimethylhydrazones was carried out in a sequential three-component fashion under mechanochemical conditions. Following extensive optimization work, the reaction was performed on a vibratory ball mill operating at 20 Hz and using zirconium oxide balls and milling jar, and afforded 1,2,3,4-tetrahydroquinolines and 1,2,3,4-tetrahydro- 1,5-naphthyridines functionalized at C-2, C-4 and also at C-6, in the latter case. This protocol generally afforded the target compounds in good to excellent yields and diastereoselectivities. A comparison of representative examples with the results obtained under conventional conditions revealed that the mechanochemical protocol affords faster Povarov reactions in comparable yields using a solvent-less environment.
Highlights
The aza-vinylogous Povarov reaction between aromatic amines, α-ketoaldehydes or α-formylesters and α,β-unsaturated dimethylhydrazones was carried out in a sequential threecomponent fashion under mechanochemical conditions
A more direct, relatively unexplored, approach to functionalized tetrahydroquinolines involves the use of dienes or dienophiles bearing functional groups
We have developed a Povarov reaction that furnishes tetrahydroquinolines bearing a quaternary stereocenter at C-4 attached to a dimethylhydrazone group and aryl substituents at C-2 by employing an α,β-unsaturated hydrazone as the dienophile (Scheme 1d) [11,12]
Summary
The aza-vinylogous Povarov reaction between aromatic amines, α-ketoaldehydes or α-formylesters and α,β-unsaturated dimethylhydrazones was carried out in a sequential threecomponent fashion under mechanochemical conditions. The reaction was performed on a vibratory ball mill operating at 20 Hz and using zirconium oxide balls and milling jar, and afforded 1,2,3,4-tetrahydroquinolines and 1,2,3,4-tetrahydro- 1,5-naphthyridines functionalized at C-2, C-4 and at C-6, in the latter case. A variety of post-condensation transformations may be performed on Povarov adducts, depending on the type of substituents and functional groups present in the structure In this connection, vinylogous Povarov reactions, i.e., those where an extended unsaturated moiety is present in the dienophile (Type I reactions) or in the imine (Type II reactions) [10], are interesting because they allow to obtain tetrahydroquinolines with an olefin substituent at C-4 or C-2, respectively (Scheme 1b,c). We have developed a Povarov reaction that furnishes tetrahydroquinolines bearing a quaternary stereocenter at C-4 attached to a dimethylhydrazone group and aryl substituents at C-2 by employing an α,β-unsaturated hydrazone as the dienophile (Scheme 1d) [11,12]
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