Selectivities of Multicomponent [4 + 2]/[3 + 2] Cycloadditions of 3-Nitroindole with Substituted Alkenes: A DFT Analysis

Abstract

The chemo-, regio-, and stereoselectivities of multicomponent [4 + 2]/[3 + 2] domino cycloaddition reactions involving nitroindole derivatives with vinylethers and acrylates are studied computationnally and compared to experimental results. In this process, the nitroarene first reacts as an electron-deficient heterodiene with the electron-rich alkene following an inverse electron-demand [4 + 2] process, leading to a nitronate intermediate in a fully selective way. This intermediate exclusively interacts, in a second step, with the electron-deficient alkene and undergoes a chemo- and regioselective [3 + 2] cycloaddition. The density functional theory calculations reported in this Article fully account for the selectivities observed experimentally. Electronic displacements along the reaction path are examined using a topological analysis of the electron-localization function (ELF). The first [4 + 2] reaction follows a classical concerted, although asynchronous process, which is reliably described by the frontier molecular-orbital (FMO) model. In contrast, the electronic displacements observed during the second [3 + 2] step are unexpected, involving an electron donation by the electron-deficient reaction partner.

Transition‐Metal‐Free Tunable Chemoselective N Functionalization of Indoles with Ynamides

“…In our case, it is the stabilization of the resulting carbanion by the electron-withdrawing group which rationalizes the reaction between the two nucleophilic partners. [25] Having opened an access to hitherto unknown and novel compounds, we then investigated if further functionalizations were possible to obtain new polycyclic frameworks which might possess interesting biological activities. [26] To this purpose, 2-vinylindole (2 k) was reacted with N-tosyl-Nallylynamide (1 b) to give 4 kb, which could then be cyclized using Grubbs second-generation catalyst to afford 1,4diazocinoindole (10; Scheme 7).…”

Regioselectivity Switch Towards the Development of Innovative Diels‐Alder Cycloaddition and Productive Applications in Organic Synthesis

“…The latest technological era, along with a better understanding of mechanistic pathways allows for the speedy and clear identification of important products. In 2013, Isabelle and colleagues published one of the most notable selectivity in the Diels‐Alder domino/cascade approach [116] . They described a multicomponent process that included [4+2] and [3+2] cycloadditions.…”

Reactivity of 3-nitroindoles with electron-rich species

“…DFT calculations, reported on these multicomponent domino (4+2)/(3+2) cycloadditions of 3nitroindoles confirmed that, the endo approach with the regiochemistry observed experimentally was indeed the most favourable pathway for the primary (4+2) cycloaddition reaction. 59 The 3-nitroindole reacted through its LUMO as an electron-poor heterodiene in a concerted though asynchronous inverse demand hetero-Diels-Alder. The electronic rearrangements observed during this step were in line with the expected pathway and, for this first cycloaddition process, the FMO model provided perfectly reliable predictions (Scheme 40).…”