Synthesis and Structure Elucidation of Novel Spirooxindole Linked to Ferrocene and Triazole Systems via [3 + 2] Cycloaddition Reaction

Abstract

In the present work, a novel heterocyclic hybrid of a spirooxindole system was synthesized via the attachment of ferrocene and triazole motifs into an azomethine ylide by [3 + 2] cycloaddition reaction protocol. The X-ray structure of the heterocyclic hybrid (1’’R,2’’S,3R)-2’’-(1-(3-chloro-4-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-carbonyl)-5-methyl-1’’-(ferrocin-2-yl)-1’’,2’’,5’’,6’’,7’’,7a’’-hexahydrospiro[indoline-3,3’’-pyrrolizin]-2-one revealed very well the expected structure, by using different analytical tools (FTIR and NMR spectroscopy). It crystallized in the triclinic-crystal system and the P-1-space group. The unit cell parameters are a = 9.1442(2) Å, b = 12.0872(3) Å, c = 14.1223(4) Å, α = 102.1700(10)°, β = 97.4190(10)°, γ = 99.1600(10)°, and V = 1484.81(7) Å3. There are two molecules per unit cell and one formula unit per asymmetric unit. Hirshfeld analysis was used to study the molecular packing of the heterocyclic hybrid. H···H (50.8%), H···C (14.2%), Cl···H (8.9%), O···H (7.3%), and N···H (5.1%) are the most dominant intermolecular contacts in the crystal structure. O···H, N···H, H···C, F···H, F···C, and O···O are the only contacts that have the characteristic features of short and significant interactions. AIM study indicated predominant covalent characters for the Fe–C interactions. Also, the electron density (ρ(r)) at the bond critical point correlated inversely with the Fe–C distances.

A Molecular Electron Density Theory Study of the [3+2] Cycloaddition Reaction of an Azomethine Ylide with an Electrophilic Ethylene Linked to Triazole and Ferrocene Units

“…It is interesting to highlight that while the activation enthalpies suggest that this 32CA reaction is completely ortho regioselective, in full agreement with the experimental outcomes [ 45 ], the activation Gibbs free energies markedly decrease the ortho regioselectivity as TS-mn is only 0.5 kcal·mol −1 above TS-on . This behavior is a consequence of the more unfavorable activation entropy associated with the ortho TSs (see later).…”

“…Finally, the IGM-δg inter at the regioisomeric TS-mn shows the presence of only one HB between the carbonyl O7 oxygen of ferrocene ethylene 22 and one of the dihydropyrrole hydrogens of AY 21 (see Figure S1 in Supplementary Material ). Consequently, the additional HB present at the most favorable TS-on can explain the fact that this TS is 5.4 kcal·mol −1 more stable than TS-mn , and, consequently, the origin of the unexpected ortho regioselectivity of this 32CA reaction [ 45 ].…”

“…Very recently, Barakat et al have experimentally reported the 32CA reaction of AY 18 with ethylene derivative 19 , in the synthesis of spirooxindoles 20 , with high ortho regio- and endo stereoselectivity (see Scheme 4 ) [ 45 ]. Interestingly, this 32CA shows an opposite regioselectivity to that shown in the reaction with vinyl sulphone 14 (see Scheme 3 ).…”

Synthesis and Characterization of New Spirooxindoles Including Triazole and Benzimidazole Pharmacophores via [3+2] Cycloaddition Reaction: An MEDT Study of the Mechanism and Selectivity

“…Recently, Barakat et al reported the synthesis of new spirooxindoles, IX, with the triazole moiety and a ferrocene scaffold using the 32CA reaction approach, and their mechanism was studied via molecular electron density theory (MEDT) [11,12]. Another representative example is the spirooxindole with a benzimidazole scaffold (see SP1 in Figure 1), which has been extensively studied and has shown to be a potent anti-cancer agent [13].…”