DFT studies on the diastereoselectivity and regioselectivity of multicomponent domino Knoevenagel/Diels–Alder reaction

Abstract

In this study, mechanism and stereochemistry of multicomponent domino Knoevenagel/Diels–Alder reaction were investigated theoretically. Structures of reagents, transition states, intermediates, and products were optimized at M062X/6-31[Formula: see text]G(d,p) level of theory. Although the mechanism of this reaction involved several processes, including bond rotation, isomerization, asymmetric cycloaddition, acid-base, and nucleophile–electrophile competitions, critical processes were studied to provide a clearer picture of the mechanism of this valuable reaction in terms of stereochemistry considerations. According to the results, the ring closure step of reaction performed via a polar Dield-Alder mechanism, having enthalpy at approximately 40[Formula: see text]kcal/mol. The diastereoselectivity of the reaction was controlled by the interaction of dienophile with the less hindered face of diene through a more stable endo transition state ([Formula: see text] and 27.31 in methanol and gas phase, respectively). HSAB criteria could explain the regioselectivity of this reaction by considering the least softness difference ([Formula: see text]) for interacting C-atoms based on Hirshfeld populations. The result was the creation of cis-spiro cyclohexanone under kinetic and thermodynamic controls as a predominant diastereoselective and regioselective product.

The evaluation of chemoselectivity in multicomponent domino Knoevenagel/Diels-Alder reaction: A DFT study

“…The chemoselectivity could happen through two possible steps. 35,42 Diels-Alder reaction step: In this step, cis-spiro 5-RS and 6-RS were produced through cyclization of diene 7 and dienophile 8. Based on the obtained results, Endo-Y orientation in 9-SR-TS was a transition state, which passed through to produce 9-RS, and finally 5-RS and/or 6-RS.…”

Revealing the Origin of Π‐facial and Regioselectivity in the Diels‐Alder Reaction of Unsymmetrical, Cage‐annulated 1,3‐Cyclohexadiene with Ethyl Propiolate Dienophile: a DFT Study

“…Diels-Alder (DA) reactions are one of the most widely studied reactions in organic chemistry due to their range of utility for the formation of six-membered rings with considerable diastereo-and regioselectivity. [1][2][3][4][5][6][7] The Diels-Alder reaction has been utilized for the formation of various agrochemicals, natural products, biomaterials, and other hetero-aromatic compounds. [8][9][10][11][12][13][14][15][16] The Diels-Alder reactions of π-facially differentiated cage-annulated 1,3-dienes are well-studied and have received attention from organic chemists.…”

“…[8][9][10][11][12][13][14][15][16] The Diels-Alder reactions of π-facially differentiated cage-annulated 1,3-dienes are well-studied and have received attention from organic chemists. [17][18][19][20][21][22][23][24][25] The cycloaddition reaction of hexacyclo [7.5.1.0 1,6 .0 6,13 .0 8,12 .0 10,14 ] pentadeca-2,4-diene-7,15-dione (HPDD) with ethyl propiolate (EP) was reported to give a mixture of two isomeric cycloadducts with a high degree of π-facial selectivity and the cycloadduct formed by syn-π-facial attack of EP to HPDD is obtained as a major product. (product ratio, syn:anti = 80 : 20) [Scheme 1].…”

“…(product ratio, syn:anti = 80 : 20) [Scheme 1]. The corresponding reaction of hexacyclo [7.5.2.0 1,6 .0 6,13 .0 8,12 .0 10,14 ] hexadeca-2,4-diene-7,16-dione (HHDD) with EP afforded only two of the four possible isomeric cycloadducts with higher degree of syn-π-facial selectivity, however, with modest distal/ proximal regioselectivity (product ratio, distal: proximal = 60 : 40) [Scheme 1]. The cycloaddition of EP with HPDD and HHDD proceeds via the syn-π-face approach.…”

“…Diels‐Alder (DA) reactions are one of the most widely studied reactions in organic chemistry due to their range of utility for the formation of six‐membered rings with considerable diastereo‐ and regioselectivity [1–7] . The Diels‐Alder reaction has been utilized for the formation of various agrochemicals, natural products, biomaterials, and other hetero‐aromatic compounds [8‐16] .…”