Vinylazaarenes as dienophiles in Lewis acid-promoted Diels–Alder reactions

Abstract

Vinyl-substituted azaarenes are rare and challenging substrates as dienophiles in Diels–Alder reactions; by employing Lewis acid activation, high yielding and highly selective cycloadditions with unactivated dienes are enabled.

Origin of Catalysis and Selectivity in Lewis Acid-Promoted Diels–Alder Reactions Involving Vinylazaarenes as Dienophiles

“…In particular, the reduction in the cycloaddition barrier (ΔΔ G ≠ = 2.9 kcal/mol and 3.4 kcal/mol, computed at 25 and 70 °C, respectively, for the endo -pathway) is consistent with the acceleration induced by the BF 3 catalyst observed experimentally. 7 In addition, the high activation barrier computed for the uncatalyzed reaction (Δ G ≠ ≈ 32 kcal/mol, at 70 °C) is also consistent with the low yield observed experimentally (ca. 3%, at 70 °C).…”

“…Once we have disclosed the factors controlling the catalysis in this cycloaddition, we then focus on those factors responsible for the remarkable endo/exo selectivity (>20:1) observed experimentally. 7 From the data in Figure 1 , the remarkable influence of the Lewis acid on the diastereoselectivity of the process becomes evident. Whereas almost no selectivity is found for the parent uncatalyzed reaction (ΔΔ G ≠ = 0.3 kcal/mol favoring the exo -cycloadduct), a clear endo -preference (ΔΔ G ≠ = 2.1 kcal/mol) is computed for the BF 3 -mediated cycloaddition.…”

“…Data in Figure 1 also indicate that the cycloaddition reaction involving 1-BF 3 and 2 is completely selective toward the formation of the 1,2-cycloadduct 2-BF 3 -endo at the expense of the corresponding 1,3-cycloadduct 2′-BF 3 -endo (ΔΔ G ≠ = 3.2 kcal/mol), which is again consistent with the experimental findings. 7 According to the ASM method, the higher barrier of the 1,3-pathway derives almost exclusively from a more destabilizing strain energy as compared to the favored 1,2-pathway, which in addition benefits from a stronger interaction at the transition state structure ( Figure 5 a). The partitioning of the key Δ E strain term into contributions coming from both reactants ( Figure 5 b) indicates that the higher (i.e., more destabilizing) total strain computed for the 1,3-pathway originates from the higher distortion required by both the dienophile and the diene (albeit to a lesser extent) reactants to adopt the geometry of the saddle point TS′-BF 3 -endo in comparison to the more stable TS-BF 3 -endo .…”

“… 8 In addition, this synthetic protocol seems general as it was successfully expanded to a good variety of dienes and different vinylazaarenes, including 2- or 4-vinylpyridines, quinolines, pyrazines, and pyrimidines. 7 …”

“…The observed great acceleration of the cycloaddition was rationalized by invoking the above-mentioned traditional LUMO-lowering concept 4 , 5 in view of the significant stabilization of the LUMO of the dienophile upon binding to BF 3 . 7 We have, however, recently demonstrated that this LUMO-lowering concept in slightly related LA-catalyzed Diels–Alder is rather incomplete as it does not consider the impact on the reverse HOMO (dienophile)–LUMO (diene) interaction, which indeed can offset the favorable HOMO (diene)–LUMO (dienophile) interaction. 9 As a result, we found that the reduction of the Pauli repulsion between the key occupied π-molecular orbitals and not the above orbital interactions constitutes the actual physical mechanism behind the acceleration promoted by LAs in Diels–Alder reactions.…”