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DOI: 10.1055/sos-SD-210-00168

Arévalo, M. J.; Lavilla, R.Science of Synthesis: Multicomponent Reactions, (20141324.

Anilines are the reactants of choice for classical Povarov reactions, and most reports deal with these substrates. A wide variety of substitution patterns allows productive condensations. As seen above, extremely activated anilines (e.g., 4-methoxyaniline) preclude the reaction, as they trap the in situ formed imines. Also 2,6-disubstituted anilines or very deactivated derivatives (e.g., 3-nitroaniline) are unable to complete the multicomponent reaction through the usual Pictet–Spengler step.[‌12‌] As also seen in previous examples, some heteroaromatic amines can proceed through the expected Povarov pathway. On the other hand, primary aliphatic amines containing no aromatic ring cannot undergo standard Povarov transformations. The reaction of these substrates with 1,4-dihydropyridines 63 and ethyl glyoxylate in the presence of scandium(III) trifluoromethanesulfonate in acetonitrile gives rise to a mixture of adducts 64 and 65 (Scheme 34).[‌62‌] Following a mechanistic analysis, it was found that the selectivity can be increased by modification of the stoichiometry of the reactants and the reaction conditions. Thus, treating 2.2 equivalents of the amine and 2 equivalents of ethyl glyoxylate with 1 equivalent of the dihydropyridine 63 at room temperature in the presence of 4-Å molecular sieves gives around 40% yield of the bicyclic aminals 64 in a stereoselective manner. However, when using 1 equivalent of ethyl glyoxylate and warming to 60 °C for extended reaction times (72 h), the rearranged tetrahydropyridines 65 are obtained. Both processes favor trans stereochemistries.

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