Utilizing MEDT analysis of [3 + 2] cycloaddition reaction: x-ray crystallography of spirooxindole linked with thiophene/furan heterocycles and triazole framework

Abstract

Hybridization of spirooxindole with different pharmacophores such as triazole and heterocycle such as thiophene and furan moiety was achieved by the [3 + 2] cycloaddition (32CA) reaction approach. Structural investigations of the compounds 4a and 4b were performed using X-ray single crystal structure determinations and Hirshfeld analysis. Both compounds crystallized in monoclinic crystal system. The space group is P2₁/c for 4a and P2₁/n for 4b. The crystal parameters are a = 10.2619(3) Å, b = 13.6776(3) Å, c = 10.9318(3), β = 116.640(4)° for the former while a = 13.0012(1) Å, b = 14.9692(1) Å, c = 14.1178(1) Å, β = 97.101(1)° for the latter. In both compounds, the aryl group and the triazole moieties are twisted from one another. The twist angle is 84.75˚for 4a while 86.64˚ for 4b. Based on Hirshfeld calculations, the Cl…H, O…H, N…H and C…H non-covalent interactions in 4a while the O…H interactions in 4b are the most important. The molecular mechanism of the key 32CA reaction between the in situ generated azomethine ylides and the corresponding chalcones has been studied within the Molecular Electron Density Theory (MEDT). The MEDT study reveals that the low activation energies and high experimental selectivity are the result of the supernucleophilic character of the ylides and the strong electrophilicity of the chalcones, which favour the process through a high polar character. This high polar character accounts for the total endo selectivity experimentally found.

Introduction

The field of diversity-oriented and combination organic syntheses, which focuses on the construction of heterocyclic hybrids possessing various structural features and significant pharmacological relevance, has garnered considerable interest in recent decades. The chemical industry and scientific community face a significant challenge in applying readily available initial substances in a way that adheres to atom economics and environmental considerations [1].

The synthesis of spiro-hybrid heterocycles has attracted considerable attention from both chemists and medicinal/pharmaceutical researchers. This is due to the significant importance of these compounds in various fields, including but not limited to, drug discovery, material sciences, and organic synthesis. The spiro-hybrid heterocyclic framework offers unique structural features and diverse physicochemical properties, making them attractive targets for the design and development of novel compounds with potential applications in the pharmaceutical and chemical industries.

The multi-component reaction (MCR) approach is preferred for constructing spirohybrids. It enables researchers to create diverse heterocycles in a single process, with fewer workup steps, easy mechanization, and simple purification. This method is eco-friendly, reproducible and follows the principle of atom economy [2, 3]. Specifically, heterocycles of spiropyrrolidine are found in natural and synthetic compounds, exhibiting important pharmacological properties. They can be produced through a [3 + 2] cycloaddition mechanism involving multi-component reactions (MCRs) [4,5,6] Numerous naturally occurring alkaloids, such as horsfiline, contain the spiropyrrolidine structural motif and have been used in traditional medicine [7]. It has been reported that spirotryprostatine A and B [8], as well as mitraphylline, are highly effective anti-cancer agents [9]. A large number of synthetic spiropyrrolidines analogs have been synthesized and evaluated against various targets, including cancer activity, in addition to naturally occurring compounds [10, 11], local anesthetics [12], analgesic and anti-inflammation [13] and other activity, such as anti-mycobacterial [14] and anti-microbial agents [15], and others [16,17,18,19,20,21,22].

The 1,2,3-triazole unit has potential pharmacological application [23], like being a carbonic anhydrase inhibitor, and is widely studied in synthetic chemistry [24], treatment of tuberculosis [25,26,27] and agent of antimalarial [27] and others.

Organic chemists have extensively studied the electronic structure of three-atom components (TACs) that are generated in situ as intermediates in 32CA reactions. These studies have been aided by the Molecular Electron Density Theory (MEDT) [28]. Four different types of three-atom-components (TACs) have been characterized, namely zwitterionic (zw),carbenoid (cb),pseudo(mono)radical (pmr),and pseudodiradical (pdr) TACs, and an excellent structure/reactivity relationship was found towards ethylene [29]. It is worth mentioning that pseudo(mono)radical and pseudodiradical TACs exhibit high reactivity as a result of their inherent instability. The electronic configurations and associated reactivities can be altered through the process of substitution.

Pyrrolidines are a group of heterocyclic compounds characterized by five-membered rings. These compounds play a crucial role in drug design due to their significant pharmacological relevance [30,31,32]. Pyrrolidines can be readily synthesized through the 32CA reaction of azomethine ylides (AYs) with olefins. The process of drug design often involves adding a spiro-ring to heterocyclic compounds to restrict their conformation. Spirooxindoles are formed when exocyclic AY, which is derived from a dicarbonyl molecule called isatin, interacts with other compounds. These spirooxindoles have significant pharmacological effects [10, 21, 33, 34].

As part of our ongoing research program [35, 36], we are exploring multi-component reactions for synthesizing functionalized molecules with distinct pharmacophores, including spiropyrrolidine, 1,2,3-triazole unit, and heterocycles scaffold within a single compound. Our previous results have shown promising outcomes in this field. Such compounds could be crucial in the field of drug discovery and may have significant importance. In this study, we present a novel series of spiropyrrolidine analogs, synthesized, characterized, and analyzed via X-ray structure. Additionally, we provide mechanistic insights into the 32CA reaction method based on the MEDT [28].

Results and discussion

The synthesis of spirooxindole hybrids incorporating heterocycle such as thiophene and furan moiety conjugated with triazole scaffold was achieved using the 32CA reaction approach, as illustrated in Scheme 1 and following a previously described method [22]. The requested ethylene derivatives 1a,b for this 32CA reaction was synthezied according to our described method [22]. To achieve the 32CA method, the process involves generating in situ azomethine ylides (AYs) by reacting isatin derivatives (2a,b) with L-proline (3). Subsequently, the AYs were reacted with ethylene derivatives 1a,b, leading to the formation of the novel spirooxindole compounds 4a,b. This synthetic process resulted in the creation of asymmetric molecules with four chiral centers in a regio- and diastereoselective manner and high chemical yield.

The complexity of the molecular structure of the synthesized spirooxindoles was confirmed through NMR spectroscopic analyses (see Supplementary Materials), which matched the proposed structures. As an example the ¹H-NMR of the spirooxindole 4a has shown the expected protons as follow: δ 10.28 (s, 1H) assigned for the secondary amine proton; the aromatic region 7.99–6.48 ppm were assigned for the aromatic protons including the heterocyles protons; then fused rings protons and the methyl group of the triazole ring was assigned in the aliphatic region. The ¹³C-NMR sectrum data shown the expected carbons. Additionally, two crystalline compounds were successfully obtained, and their structures were definitively determined through single-crystal X-ray diffraction analysis. The mechanism underlying this synthesis process adhered to a regiospecific and diastereospecific pathway, consistent with previously reported literature. In this pathway, the 32CA reaction proceeded through an ortho/endo mechanism in a two-stage one-step process.

Scheme 1

Synthesis of the spirooxindoles 4a,b

Crystal structure description

Further characterization for the structure of the studied compounds was performed by obtaining single crystals from the target compounds then determining their single crystal X-ray structures. For 4a, the X-ray structure is presented in Fig. 1. The crystal system for 4a is monoclinic while space group is P2(1) (No. 4). The unit cell parameters are a = 10.2619(3) Å, b = 13.6776(3) Å, c = 10.9318(3), β = 116.640(4)°. There is one molecule of 4a in the asymmetric unit while z = 2. Other crystal data details are depicted in Table 1. For example, the crystal density is 1.534 mg/m³ and the unit cell volume is 1371.48(8) ų. The X-ray structure confirmed with no doubt the engagement of the different bioactive moieties in on organic hybrid. The phenyl group attached to the triazole ring is almost located perpendicular to it. The angle between their mean planes is 84.75˚. Some selected bond distances and angles are given in Table S1 (Supplementary data).

Fig. 1

X-ray structure of 4a. The displacement ellipsoids are drawn at 50% probability level

Table 1 Crystal data

The molecular packing of 4a is dominated by strong N(4)-H(4)…O(1) hydrogen bonds in addition to the weak C(4)-H(4a)…O(2), C(21)-H(21B)…Cl(4) and C(23)-H(23)…Cl(3) interactions. The H(4)…O(1) distance is 2.13(4) Å while the H(4a)…O(2), H(21B)…Cl(4) and H(23)…Cl(3) distances are 2.38, 2.87 and 2.81 Å, respectively. Details about the geometric parameters of these non-covalent interactions are listed in Table 2. While presentation of the different contacts and hyydrogen bond packing scheme is shown in Fig. 2.

Fig. 2

The important contacts (A) and H-bond scheme (B) for 4a

Table 2 Hydrogen bonds for 4a and 4b [Å and °]

For 4b, the structure is confirmed using single crystal X-ray crystallography as shown in Fig. 3. Similar to 4a, the compound 4b crystallized in the same crystal system and P2₁/n space group. The lattice parameters are a = 13.0012(1) Å, b = 14.9692(1) Å, c = 14.1178(1) Å, β = 97.101(1)°. The asymmetric unit contains one molecule of 4b while z = 4 (Table 1). The crystal density is 1.454 Mg/m³ and the unit cell volume is 2726.50(3) ų. In this case, the aryl group and the triazole moieties make an angle of 86.64˚ which also indicated the perpendicularity of the two ring on each other.

Fig. 3

X-ray structure of 4b. The displacement ellipsoids are drawn at 50% probability level

The molecules of 4b are packed in the three dimensional via N(6)-H(6)…N(2) hydrogen bonds and the non-classical C(2)-H(2)…O(1) interaction. The H(6)…N(2) and H(2)…O(1) distances are 2.52(2) and 2.24 Å, respectively while the N(6)…N(2) and C(2)…O(1) distances are 3.267(2) and 3.152(1) Å. Presentation of these contacts and their geometric details are presented in Fig. 4a; Table 2.

Fig. 4

The important contacts (A) and H-bond scheme (B) for 4b

Hirshfeld surface analysis

In order to shed the light on the detailed supramolecular structure aspects of the studied compounds, Hirshfeld topology analysis was performed. The resulting mapped surfaces for 4a are presented in Fig. 5. Different red spots were observed at the d_norm map are found related to the Cl…H, O…H, N…H and C…H non-covalent interactions. These contacts appeared as short interactions with distances shorter than the vdWs radii sum of the interacting atoms. In this crystal structure, no evidences from the curvedness and shape index about the presence of π-π stacking interactions.

Fig. 5

Hirshfeld d_norm, shape index and curvedness maps for 4a showing the most important interactions; A) Cl…H, B) O…H, C) N…H and D) C…H

On the other hand, the analysis of the fingerprint plots gave indication on the percentages of all possible contacts in the crystals structure. These interactions and their percentages are presented in Fig. 6. The major contacts are the H…H and Cl…H interactions which represent more than half the amount of all other contacts. The percentages of the most important contacts are 25.4%, 10.3%, 7.1% and 13.9% the Cl…H, O…H, N…H and C…H non-covalent interactions, respectively. There are many other contacts were detected in this crystal structure, but all have small percentages and appeared as blue regions in the d_norm map. Hence are considered less important and weak compared to the Cl…H, O…H, N…H and C…H non-covalent interactions.

Fig. 6

Intermolecular contacts and their percentages in 4a

In addition, careful inspection for the decomposed fingerprint plots of the Cl…H, O…H, N…H and C…H non-covalent interactions further revealed the importance of these contacts in the molecular packing. All these contacts appeared either as sharp spikes or wing which is the characteristic features of short interactions which have great significance in the supramolecular structure of 4a (Fig. 7). Summary of the short contacts and the respective interaction distances are presented in Table 3. The Cl3…H23, O1…H4, N2…H28 and C6…H21A are the shortest non-covalent interactions detected in this crystal structure. Their interaction distances are 2.738, 1.912, 2.59 and 2.691 Å, respectively where all have shorter distances than the vdWs radii sum of the interacting atoms.

Fig. 7

Decomposed fingerprint plots for the short contacts in 4a

Table 3 Interaction distances for the short contacts in 4a

For the compound 4b, the Hirshfeld mapped surfaces are shown in Fig. 8. It is clear that the most important non-covalent interaction is the O…H contacts. No other contacts appeared as red spot in the d_norm which exclude the importance of these interactions in the molecular packing. The shortest O…H interactions are O2…H8B and O1…H2 contacts. Their interaction distances are 2.546 and 2.118 Å, respectively. Also, no evidences from the curvedness and shape index about the presence of π-π stacking interactions.

Fig. 8

Hirshfeld d_norm, shape index and curvedness maps for 4b showing the most important interactions as intense red spots

Presentation of all possible intermolecular interactions and their contributions in the molecular packing is shown in Fig. 9. The most dominant contacts are the H…H, Cl…H, O…H and C…H non-covalent interactions where their percentages are calculated to be 36.5, 19.5, 13.7 and 12.5%, respectively. In the same figure the fingerprint of the O…H interactions is presented. It clearly seen as sharp spikes occurred at short distances which further revealed the importance of the O…H non-covalent interactions in the molecular packing of 4b.

Fig. 9

Intermolecular contacts and their percentages (A) and the fingerprint plot for the short O…H contacts (B) in 4b

MEDT study of the 32CA reaction between AYs 5a, b and chalcones 1a, b

Analysis of the reactivity indices of the reagents

Analysis of quantum chemical reactivity indices [37,38,39] is a powerful tool to predict and understand the reactivity in cycloaddition reactions. The global reactivity indices, namely, the electronic chemical potential µ, chemical hardness η, electrophilicity ω, and nucleophilicity N, at the ground state of chalcones 1a,b and the in situ generated AYs 5a,b are gathered in Table 4.

Table 4 ωB97X-D/6-311G(d, p) gas-phase electronic chemical potential µ, chemical hardness η, electrophilicity ω, and nucleophilicity N, at the ground state of chalcones 1a,b and AYs 5a,b. data for the unsubstituted AY 9 is also included

The electronic chemical potentials [40] µ of AYs 5a, −3.17 eV, and 5b, −2.94 eV, are higher than those of chalcones 1a,b, ca. −4.3 eV, indicating that along a polar 32CA reaction, the electron density will flux from the AYs to the chalcones. This behavior allows classifying these 32CA reactions as forward electron density flux (FEDF) processes [41, 42] in which the AYs are identified as the nucleophilic species and the chalcones as the electrophilic component.

The chemical hardness [40] η values of chalcones 1a,b, ca. 7.6 eV, are higher than those of the AYs, ca. 6.9 eV, showing a higher tendency of the latter species to electron density deformation.

The electrophilicity [43] ω and nucleophilicity [44] N indices chalcones 1a,b are ca. 1.2 and 3.3 eV, respectively, being classified as strong electrophiles and strong nucleophiles within the corresponding electrophilicity and nucleophilicity scales defined at the ωB97X-D/6-311G(d, p) computational level [45]. Consequently, these compounds can be categorized as ambiphilic species [46]. Substitution of the furan ring by the thiophene ring causes no significant changes in the reactivity of these α,β-unsaturated carbonyl compounds. Only the electrophilicity ω index increases very slightly, by 0.1 eV.

On the other hand, the electrophilicity ω indices of AYs 5a and 5b are 0.73 and 0.63 eV, respectively, which allow classifying these TACs as moderate electrophiles [45]. The nucleophilicity N indices, 4.79 (5a) and 5.01 (5b) eV, permit their classification as supernucleophilic species for being higher than 3.96 e [39, 45]. This behavior is typical of AYs [47], which are usually very reactive and unstable nucleophilic reagents that need to be generated in situ. Substitution of one H atom at AY 9 by the electron-withdrawing chlorine –Cl atom decreases the nucleophilicity N index of AY 5a by 0.18 eV, while substitution by electron-donating –Me group scarcely enhances the nucleophilicity of AY 5b by only 0.04 eV. Thus, substitution at AY 9 neither causes significant changes in the reactivity of these TACs.

The supernucleophilic character of AY 5a,b together with the strong electrophilic character of chalcones 1a,b suggest that the corresponding 32CA reactions of FEDF will have a high polar character. The high polar character facilitates the reaction through more favorable nucleophilic/electrophilic interactions that will lead to lower activation energies.

Along a polar reaction involving non-symmetric species, the most favorable reaction path is that involving the two-center interaction between the most nucleophilic and the most electrophilic centers of the two reagents [48]. The analysis of the nucleophilic $\:{P}_{k}^{-}$ and electrophilic $\:{P}_{k}^{+}$ Parr functions [49] has shown to be an accurate tool for the study of the local reactivity in polar processes. Hence, according to the global reactivity of the reagents, the nucleophilic $\:{P}_{k}^{-}$ Parr functions of AY 5a and the electrophilic $\:{P}_{k}^{+}$ Parr functions of the more electrophilic chalcone 1a were analyzed (see Fig. 10).

Fig. 10

ωB97X-D/6-311G(d, p) gas-phase nucleophilic $\:{P}_{k}^{-}$ Parr functions of AY 5a and most relevant electrophilic $\:{P}_{k}^{+}$ Parr functions of the more electrophilic chalcone 1a

Analysis of the nucleophilic $\:{P}_{k}^{-}$ Parr functions of AY 5b indicates that the C1 carbon, $\:{P}_{C1}^{-}$ = 0.44, is slightly more nucleophilically activated than the C3 carbon, $\:{P}_{C3}^{-}$ = 0.30 (see Scheme 2 for atom labels). Note that similar AYs have been previously characterized [50, 51] to present a reactive pseudoradical center [52] at the more nucleophilic C1 carbon, classifying these species as pseudo(mono)radical TACs [29]. On the other hand, analysis of the electrophilic $\:{P}_{k}^{+}$ Parr functions of chalcone 1a shows that the β-conjugated C4 carbon, $\:{P}_{C4}^{+}$ = 0.30, is considerably more electrophilic than the carbonyl C6 carbon, $\:{P}_{C6}^{+}$ = 0.19. Consequently, according to the local nucleophilic and electrophilic properties, the most favorable two-center interaction along the 32CA reaction of AYs 5a,b with chalcones 1a,b should take place between the C1 and C4 carbon atoms, leading to the meta regioisomeric cycloadducts (see later, Scheme 2).

Study of the competitive reaction paths

Due to the non-symmetry of the reagents, the 32CA reaction between AYs 5a,b and chalcones 1a,b can take place along two ortho/meta regioisomeric reaction paths and two endo/exo stereoisomeric approach modes, leading to a total of four competitive pathways (see Scheme 2). Considering that the β-conjugated C4 carbon of chalcones 1a,b is the most electrophilic center, only the chemoisomeric reaction path involving the C4−C5 double bond has been computationally studied herein. Note, indeed, that the corresponding chemoisomeric reaction paths on the C6−O7 carbonyl bond of similar chalcones have been ruled out in analogous 32CA reactions [36]. Furthermore, the potential energy surface is explored only for the 32CA reaction involving the most electrophilic reagent, i.e. chalcone 1a with AY 5a. A conformational analysis of the reagents and products was performed whenever different conformers were possible in order to consider only the most stable structures. The enthalpy profiles associated with the four competitive reaction paths are represented in Fig. 11, while full thermodynamic data are given in Table S2 in the Supplementary Material.

Scheme 2

Studied competitive reaction paths associated with the 32CA reaction of AY 5a with chalcone 1a. ωB97X-D/6-311G(d, p) relative enthalpies, in methanol, are given in kcal·mol^− 1

Analysis of the stationary points found along the four considered reaction paths indicates that the 32CA reaction between AY 5a and chalcone 1a takes place through a one-step mechanism. Each reaction path starts with the formation of a stable molecular complex (MC) by weak intermolecular interactions between the reagents. However, due to the thermodynamic equilibrium between the several MCs, only the most stable complex, MC-on, was selected as the energy reference. Formation of MC-on is strongly exothermic by 16.9 kcal·mol⁻¹ (see Scheme 2 and Fig. 11). Considering the formation of MC-on, the activation enthalpies for the four isomeric paths range from 12.0 kcal·mol⁻¹ (TS-on) to 16.3 kcal·mol⁻¹ (TS-mx). On the other hand, the reaction enthalpies are found between −36.0 (6a) and −39.6 (4a) kcal·mol⁻¹. The highly exothermic character of this reaction suggests that the 32CA reactions is irreversible under the experimental conditions. Together with the relatively short reaction time (5 h), a kinetic control of the product mixture is expected. As the meta TS-mn and exoTS-ox are 1.0 and 3.2 kcal·mol⁻¹ higher in energy than the more favourable TS-on, a high ortho regioselectivity and a total endo stereoselectivity is computationally obtained, which accounts for the exclusive experimental formation of 4a via TS-on.

Both the experimental and computational regioselectivity differ from the meta regioselectivity predicted by analysis of the Parr functions. This is because there can be other factors that overcome the weight of the local nucleophilic/electrophilic interactions, such as non-covalent interactions. Indeed, a previous theoretical study of a similar 32CA reaction [50] revealed that the formation of two intermolecular hydrogen bonds between the two interacting frameworks at the most favorable TS-on accounted for the unexpected ortho regioselectivity experimentally observed.

Fig. 11

ωB97X-D/6-311G(d, p) enthalpy profile, in methanol, for the 32CA reaction of AY 5a with chalcone 1a. Enthalpies are given in kcal·mol^− 1

The optimized geometries of the four isomeric transition states (TSs) in methanol are represented in Fig. 12. The C−C distances between the interacting carbons provide insights into the new single-bond formation processes. Except for the most unfavorable TS-mx, the other three TSs exhibit an asynchronous behavior, with the shorter C−C distance involving the most electrophilic β-conjugated C4 carbon of chalcone 1a. The most favorable TS-on, characterized by C3−C4 and C1−C5 distances of 2.085 and 2.703 Å, respectively, has the highest degree of asynchronicity. Examining the intrinsic reaction coordinate (IRC) path [53] from the highly asynchronous TS-on to 4a reveals that the 32CA reaction follows a non-concerted two-stage,one-step mechanism [46]. In this mechanism, the formation of the second C1−C5 single bond begins only after the first C3−C4 single bond is fully formed.

Fig. 12

ωB97X-D/6-311G (d, p) optimized geometries in methanol of the TSs involved in the 32CA reaction of AY 5a with chalcone 1a. Distances are expressed in angstroms, Å, while GEDT values, in red, are given in average number of electrons, e

Finally, analysis of the global electron density transfer (GEDT) [54] at the most favorable TS-on allows quantifying the polar behavior of this 32CA reaction. GEDT values lower than 0.05 e correspond to non-polar processes, while values higher than 0.20 e characterize polar processes. The GEDT values at the four TSs are given in Fig. 12. The GEDT at TS-on is 0.29 e. This high value, which is the result of the supernucleophilic character of AY 5a and the strong electrophilic characteristic of chalcone 1a (see Table 4), confirms the high polar nature of this 32CA reaction, which accounts for its low activation enthalpy of 12.0 kcal·mol⁻¹ via TS-on and the complete endo stereoselectivity. Note that polar cycloaddition reactions normally exhibit endo stereoselectivity. The direction of the flux of the electron density, from AY 5a to chalcone 1a, allows classifying this 32CA reaction as FEDF [41, 42], in agreement with the analysis of the reactivity indicators.

Materials and methods

Synthesis of 1-(5-methyl-1-(2,4,6-trichlorophenyl)-1 H-1,2,3-triazol-4-yl)ethan-1-one 1

To a stirring solution of 2,4,6-trichloroaniline (6.05 g, 0.0308 mol) in dil. HCl (40 mL, 3 M). A solution of sodium nitrite (2.34 g, 0.0339 mol, 25 mL, 1 M) is treated at temperature < 10 ^oC. The progress of the reaction is confirmed by liberation of brown gases (1 h). When the brown gases crases a solution of sodium azide (4.006 g, 0.0616 mol) is added to the stirring cold reaction mass. The formation of product is confirmed by TLC (1 h). The reaction mixture was extracted using diethylether. A brown viscous liquid confirmed the product 1.

A solution of the appropriate azide (10.0 mmol, 2.22 gm) and acetylacetone (2.0 g, 20.0 mmol) in CHCl₃ (20 ml) was treated by adding Et₃N (2.02 g, 20.0 mmol) and DBU (0.76 g, 5.00 mmol). The reaction mixture was stirred at room temperature for 1–2 h. The solvent was removed and water is added then extracted with Et₂O, dried with Na₂SO₄, evaporated and the solid product was washed with the n-hexane to provide pure compound.

¹H NMR (500 MHz, DMSO-d₆) δ 8.14 (s, 2 H), 2.66 (s, 3 H), 2.68–2.62 (m, 1H), 2.37 (s, 3 H); ¹³C NMR (126 MHz, DMSO-d₆) δ 193.55, 142.99, 140.00, 138.09, 134.38, 130.07, 129.66, 28.15, 8.99. m.p: 131 °C; powder.

Synthesis of the chalcones 2a, b

(E)-1-(5-Methyl-1-(2,4,6-trichlorophenyl)-1 H-1,2,3-triazol-4-yl)-3-(thiophen-2-yl)prop-2-en-1-one 2a

A mixture of thiophene-2-carbaldehyde (2 mmol, 224 mg) and 1-(5-methyl-1-(2,4,6-trichlorophenyl)-1H-1,2,3-triazol-4-yl)ethan-1-one 1 (0.609 g, 2.0 mmol) dissolved in ethanol (20 mL) was added slowly to an aqueous solution of potassium hydroxide (2.0 mmol, 112 mg) in water (10 mL). The mixture was stirred in crushed-ice bath for 2 h, stirred at 20 ~ 25 ℃ for 4 h. The mixture was filtrated and the residue was washed with cold water and cold alcohol dried to give the titled compound without further purification.

m.p: 327 °C; powder. ¹H NMR (400 MHz, CDCl₃) δ 8.07 (d, J = 15.8 Hz, 1H), 7.86 (d, J = 15.4 Hz, 1H), 7.57 (s, 2 H), 7.43 (dd, J = 11.8, 4.4 Hz, 2 H), 7.13–7.05 (m, 1H), 2.49 (s, 2 H), 2.51–2.39 (m, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 183.80, 143.45, 140.61, 140.54, 138.16, 136.61, 135.13, 132.37, 130.06, 129.45, 129.25, 129.16, 128.36, 121.82, 9.29.

(E)-3-(Furan-2-yl)-1-(5-methyl-1-(2,4,6-trichlorophenyl)-1 H-1,2,3-triazol-4-yl)prop-2-en-1-one 2b

A mixture of furan-2-carbaldehyde (2 mmol, 192 mg) and 1-(5-methyl-1-(2,4,6-trichlorophenyl)-1H-1,2,3-triazol-4-yl)ethan-1-one 1 (0.609 g, 2.0 mmol) dissolved in ethanol (20 mL) was added slowly to an aqueous solution of potassium hydroxide (2.0 mmol, 112 mg) in water (10 mL). The mixture was stirred in crushed-ice bath for 2 h, stirred at 20 ~ 25 ℃ for 4 h. The mixture was filtrated and the residue was washed with cold water and cold alcohol dried to give the titled compound without further purification.

m.p: 80 °C; powder. ¹H NMR (400 MHz, CDCl₃) δ 7.92 (d, J = 15.5 Hz, 1H), 7.71 (d, J = 15.9 Hz, 1H), 7.55 (d, J = 11.8 Hz, 3 H), 6.77 (d, J = 3.5 Hz, 1H), 6.50 (d, J = 2.9 Hz, 1H), 2.49 (s, 3 H); ¹³C NMR (101 MHz, CDCl₃) δ 184.02, 151.90, 145.23, 143.51, 140.46, 138.13, 135.13, 130.48, 130.08, 129.12, 121.29, 116.75, 112.52, 9.40.

Synthesis of spirooxindoles derviatives 4a, b

(1’S,2’S,3R)-6-Chloro-2’-(5-methyl-1-(2,4,6-trichlorophenyl)-1 H-1,2,3-triazole-4-carbonyl)-1’-(thiophen-2-yl)-1’,2’,5’,6’,7’,7a’-hexahydrospiro[indoline-3,3’-pyrrolizin]-2-one 4a

A mixture of 2a (198.5 mg, 0.5mmol), 6-Cl- isatin (90.5 mg, 0.5 mmol) and L-proline (57.5 mg, 0.5 mmol) in methanol (10 mL) was refluxed on oil bath for appropriate time 5–8 h. After completion of the reaction as evident from TLC, the reaction was kept at room temperature overnight and the solid precipitated was filtered off without any further purification as faint yellow crystalline compound. As an example, the reaction has been scaled up to a 1-mole scale, and it remains producible without affecting the chemical structure or the chemical yield.

m.p: 161 °C; crystal. ¹H NMR (500 MHz, DMSO-d₆) δ 10.28 (s, 1H), 7.99 (s, 1H), 8.04–7.94 (m, 1H), 7.32 (dd, J = 5.1, 1.2 Hz, 1H), 6.98 (dt, J = 3.2, 1.1 Hz, 1H), 6.95–6.80 (m, 2 H), 6.48 (dd, J = 8.4, 4.5 Hz, 1H), 4.86 (d, J = 10.8 Hz, 1H), 4.15–3.99 (m, 2 H), 3.25 (d, J = 7.6 Hz, 2 H), 3.22 (s, 1H), 2.75 (td, J = 8.8, 6.4 Hz, 1H), 2.36 (s, 1H), 2.43–2.28 (m, 1H), 1.97–1.83 (m, 2 H), 1.79–1.61 (m, 1H), 1.71 (s, 1H); ¹³C NMR (126 MHz, DMSO-d₆) δ 191.45, 178.74, 157.69, 155.81, 142.84, 141.77, 139.40, 138.61, 137.26, 133.68, 133.28, 129.11, 129.08, 128.50, 126.85, 124.47, 124.07, 115.46, 115.28, 114.17, 113.97, 109.88, 71.48, 70.40, 65.62, 47.64, 45.27, 27.77, 25.37, 7.46.

(1’S,2’S,3R)-1’-(Furan-2-yl)-5-methyl-2’-(5-methyl-1-(2,4,6-trichlorophenyl)-1 H-1,2,3-triazole-4-carbonyl)-1’,2’,5’,6’,7’,7a’-hexahydrospiro[indoline-3,3’-pyrrolizin]-2-one 4b

A mixture of 2b (190.5 mg, 0.5mmol), 5-Me- isatin (80.5 mg, 0.5 mmol) and L-proline (57 0.5 mg, 0.5 mmol) in methanol (10 mL) was refluxed on oil bath for appropriate time 5–8 h. After completion of the reaction as evident from TLC, the reaction was kept at room temperature overnight and the solid precipitated was filtered off without any further purification as faint yellow crystalline compound.

m.p: 193 °C; crystal. ¹H NMR (400 MHz, DMSO-d₆) δ 10.23 (s, 1H), 8.09–8.00 (m, 2 H), 7.59 (s, 1H), 6.82 (d, J = 7.3 Hz, 2 H), 6.48–6.37 (m, 2 H), 6.27 (d, J = 3.5 Hz, 1H), 4.99 (d, J = 10.7 Hz, 1H), 4.14 (ddd, J = 10.7, 7.0, 3.8 Hz, 1H), 3.97 (t, J = 10.4 Hz, 1H), 3.33 (d, J = 7.3 Hz, 1H), 2.85 (q, J = 8.4 Hz, 1H), 2.49–2.27 (m, 2 H), 2.14 (s, 3 H), 1.99 (s, 3 H), 2.12–1.63 (m, 4 H); ¹³C NMR (126 MHz, DMSO-d₆) δ 192.68, 179.58, 154.37, 142.67, 140.81, 140.08, 138.02, 134.69, 134.10, 129.43, 127.89, 125.56, 110.98, 109.71, 106.30, 71.77, 67.98, 62.36, 48.62, 44.28, 28.56, 25.73, 21.05, 8.29.

X-Ray structure determination

Crystals 4a and 4b were immersed in cryo-oil, mounted in a loop, and measured at a temperature of 120 K. “The X-ray diffraction data were collected on a Rigaku Oxford Diffraction Supernova diffractometer using Mo Kα radiation. The CrysAlisPro [55] software package was used for cell refinements and data reductions. A multi-scan (4a) or an analytical (4b) absorption correction (CrysAlisPro) [55] was applied to the intensities before the structure solution. The structures were solved by the intrinsic phasing (SHELXT) [56] method. Structural refinements were carried out using SHELXL [57] software with SHELXLE [58] graphical user interface. The NH hydrogen atoms, involved in hydrogen bonding, were located from the difference Fourier map and refined isotropically. All other hydrogen atoms were positioned geometrically and constrained to ride on their parent atoms, with C-H = 0.95-1.00 Å and U_iso = 1.2–1.5·U_eq(parent atom). The crystallographic details are summarized in Table 1. The topology analyses were performed using Crystal Explorer 17.5 program [59]”.

Conclusions

By Employing the 32CA approach two new spirooxindoles analoges successfully synthesized incorporated a triazole unit with thiophene and/or furan motif scaffold. Hirshfeld analysis based on the experimental X-ray structure, the molecular and supramolecular structures of both organic hybrids were described. The twist of the aryl and the triazole moieties is less (84.75˚) for 4a than that for 4b (86.64˚). The supramolecular structure of 4a is controlled by the Cl…H, O…H, N…H and C…H non-covalent interactions while in 4b the O…H interactions are the most important. By Employing the 32CA approach two new spirooxindoles analoges successfully synthesized incorporated a triazole unit with thiophene and/or furan motif scaffold. Hirshfeld analysis based on the experimental X-ray structure, the molecular and supramolecular structures of both organic hybrids were described. The twist of the aryl and the triazole moieties is less (84.75˚) for 4a than that for 4b (86.64˚). The supramolecular structure of 4a is controlled by the Cl…H, O…H, N…H and C…H non-covalent interactions while in 4b the O…H interactions are the most important.

The MEDT study of the key 32CA reaction step reveals that the low activation energies and high experimental selectivity are the result of the supernucleophilic character of the in situ generated azomethine ylides and the strong electrophilicity of the chalcones, which favour the process through a high polar character. This high polar character accounts for the total endo selectivity experimentally found.