A theoretical investigation on the regioselectivity of the intramolecular hetero Diels-Alder and 1,3-dipolar cycloaddition of 2-vinyloxybenzaldehyde derivatives

Abstract

The present paper reports a systematic computational analysis study of the two possible pathways, fused and bridged, for an intramolecular hetero Diels-Alder (IMHDA) and an intramolecular 1,3-dipolar cycloaddition (IMDCA) of 2-(vinyloxy)benzaldehyde derivatives. The potential energy surface analyses for both reactions are in agreement with the experimental observations. The activation energies associated with the two regioisomeric channels in the IMHDA reaction showed that the bridged product is favored, although in the IMDCA, the most stable transition state results in the fused product. The global electronic properties of the fragments within each molecule were studied to discuss the reactivity patterns and charge transfer direction in the intramolecular processes. The asynchronicity of the bond formation and aromaticity of the optimized TSs in the Diels-Alder reaction as well as cycloaddition reaction were evaluated. Finally, the 1 H-NMR chemical shifts of the possible regioisomers were calculated using the GIAO method, the values of which for the most stable products were in agreement with the experimental data for both reactions.

Intramolecular [3 + 2] Cycloaddition Reactions of Unsaturated Nitrile Oxides. A Study from the Perspective of Bond Evolution Theory (BET)

“…31,32 The interest for synthetic and theoretical studies on intramolecular 32CA reactions has increased considerably owing to their potential applications. Mahshid et al 28 The goal of this paper is to elucidate the electron density reorganization along the reactive pathway of the intramolecular 32 CA studied by Hassner and Dehaen 35 and Kim et al 36 with the aid of bond evolution theory. Within this theory, the electron density rearrangement and the bonding changes along a reaction path are the key ingredients for characterizing the reaction mechanism.…”

“…27 Among these, intramolecular cycloadditions are suitable tools for the efficient assembly of complex molecular structures (fused and bridged). 28 The 32CA reactions of nitrile oxides are welldocumented in the literature. These reactions provide an efficient route to the synthesis of isoxazolines, which are versatile intermediates for the synthesis of natural products, as well as biologically and medically active compounds.…”

“…Moreover, they are among the most powerful methods for the construction of complex rings and, in particular, 32CA’s, which constitute an important class of these reactions, offer a convenient one-step route to the construction of various complex five-membered heterocycles . Among these, intramolecular cycloadditions are suitable tools for the efficient assembly of complex molecular structures (fused and bridged) . The 32CA reactions of nitrile oxides are well-documented in the literature.…”

“…These reactions provide an efficient route to the synthesis of isoxazolines, which are versatile intermediates for the synthesis of natural products, as well as biologically and medically active compounds. , They are also excellent substrates for the synthesis of β-amino acids, C-disaccharides, imino/amino polyols, amino sugars, and novel aza-heterocycles. , The interest for synthetic and theoretical studies on intramolecular 32CA reactions has increased considerably owing to their potential applications. Mahshid et al reported a theoretical investigation with the B3LYP exchange–correlation (XC) functional and the 6-31G­(d,p) basis set on the regioselectivity of the intramolecular hetero Diels–Alder and 32CA reactions of 2-(vinyloxy)­benzaldehyde derivatives through two reactive channels (fused and bridged) in which the most stable transition state (TS) results in the fused product. Very recently, Domingo et al also studied an intramolecular 32CA reaction of cyclic nitrones within molecular electron density theory at the MPWB1K/6-311G­(d) computational level.…”

Recent applications of the hetero Diels–Alder reaction in the total synthesis of natural products

“…16 Intramolecular hetero Diels-Alder (IMHDA) reactions seemed to be a versatile protocol for the construction of new polycyclic systems, which were fruitfully used in the design of framework for some naturally occurring products and biologically active compounds. [17][18][19] Due to these features, HDA reaction expectedly has been the subject of numerous reviews 20,21 and books 10,22 and have been extensively employed as key steps in the synthesis of several complex organic molecules. [23][24][25][26][27][28][29][30][31][32] Perhaps the most important feature of HDA is its asymmetric versions.…”