Theoretical study of the regio- and stereoselectivity of the intramolecular Povarov reactions yielding 5H-chromeno[2,3-c] acridine derivatives

The intramolecular Povarov (IMP) reactions involved in the synthesis of 5H-chromeno[2,3-c] acridine derivatives [Tetrahedron Lett., 2010, 51, 3071–3074] have been studied using density functional theory (DFT) methods. The studied IMP reaction is a domino process that comprises two consecutive reactions: (i) a BF3 Lewis acid catalysed intramolecular aza-Diels–Alder (IMADA) reaction of an alkene tethered chromene imine (ATCI) giving a formal [4 + 2] cycloadduct, and (ii) a 1,3-hydrogen shift yielding the final chromeno product. The possible regio-(fused/bridged) and stereo-(cis/trans) isomeric channels associated with the IMADA reaction were thoroughly investigated and analysed. The activation Gibbs free energies in acetonitrile, calculated at the MPW1B95/6-311G(d,p) level of theory, show that the formation of the trans-fused chromeno acridine is favoured both kinetically and thermodynamically as found experimentally. Thermochemical calculations show that the intramolecular nature of the IMADA reaction, which does not present appreciable activation entropy, makes it possible for the IMP reaction to take place. Intrinsic reaction coordinate (IRC) calculations and the topological analysis of the electron localization function (ELF) of some relevant points on the IRC curve show that the formation of the favoured trans-fused cycloadduct takes place via a non-concerted two-stage one-step mechanism. At the most favourable transition state, TS-tf-B, the formation of the first C1–C6 single bond has already started, while the formation of the second C4–C5 has not started yet. The global electron density transfer (GEDT) calculated at the transition states in combination with the analysis of DFT-based reactivity indices of the ATCI reveal the remarkable polar characteristic of the studied reactions. Analysis of the substituent effects on the cis/trans selectivity show that the trans stereoisomer is favoured independently on the electronic nature of substituents in clear agreement with experimental findings.