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Article

Highly Regioselective 1,3-Dipolar Cycloaddition of Nitrilimines and Thioaurones Towards Spiro-2-Pyrazolines: Synthesis, Characterization, and Mechanistic Study

by
Mohamed Bakhouch
1,*,
Bouchra Es-Sounni
1,
Ayoub Ouaddi
1,
Khaoula Oudghiri
2,
Mohammed Chalkha
3,
Lahoucine Bahsis
4,*,
Taoufiq Benali
5,
Mohamed Bourass
6,
Rabiaa Fdil
1,
Mohamed Akhazzane
7 and
Mohamed El Yazidi
7
1
Bioorganic Chemistry Team, Department of Chemistry, Faculty of Sciences, Chouaïb Doukkali University, El Jadida 24000, Morocco
2
Laboratoire de Recherche en Développement Durable et Santé, Faculté des Sciences et Techniques de Marrakech, Université Cadi Ayyad, Marrakech 40000, Morocco
3
Laboratory of Materials Engineering for the Environment and Natural Resources, Faculty of Sciences and Techniques, University of Moulay Ismail of Meknes, B.P 509, Boutalamine, Errachidia 52000, Morocco
4
Laboratoire de Chimie Analytique et Moléculaire, LCAM, Faculté Poly disciplinaire de Safi, Université Cadi Ayyad, Safi 4162, Morocco
5
Environment and Health Team, Polydisciplinary Faculty of Safi, Cadi Ayyad University, Safi 46030, Morocco
6
Laboratoire de Physicochimie des Polymères et des Interfaces (LPPI), Cy Cergy Paris Université, 5 Mail Gay CEDEX, 95031 Cergy-Pontoise, France
7
Engineering Laboratory of Organometallic, Molecular Materials and Environment, Faculty of Sciences Dhar EL Mahraz, University Sidi Mohamed Ben Abdellah, P.O. Box 1796, Fez 30000, Morocco
*
Authors to whom correspondence should be addressed.
Reactions 2024, 5(4), 1066-1079; https://doi.org/10.3390/reactions5040056
Submission received: 8 November 2024 / Revised: 27 November 2024 / Accepted: 12 December 2024 / Published: 14 December 2024
(This article belongs to the Special Issue Cycloaddition Reactions at the Beginning of the Third Millennium)
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Versions Notes

Abstract

:
In this paper, we report a highly regioselective 1,3-dipolar cycloaddition (1,3-DC) reaction of nitrilimines with thioaurone derivatives that afforded the hitherto unreported spiropyrazolines. Spectroscopic and spectrometric data were utilized to confirm the structure of all products and elucidate the reaction’s regiochemistry. A mechanistic study was performed within the Molecular Electron Density Theory (MEDT) at the B3LYP/6-311G(d,p) computational level to explain the regioselectivity observed. The electron localization function (ELF) topological analysis confirms the carbenoid-type (cb-type) mechanism of the cycloaddition reactions between nitrilimines and thioaurones. The intermolecular interactions between reagents in this reaction account for the regioselectivity observed experimentally.

1. Introduction

Thioaurones, or 2-Arylidenebenzo[b]thiophen-3(2H)-ones, are the sulfur analogs of aurones [1]. This class of sulfur compounds has garnered significant attention in recent years [2,3,4,5]. They are widely used as starting materials to prepare a plethora of heterocyclic compounds with promising biological interest [6,7]. Furthermore, thioaurones are known for their use as photoswitchable materials [8,9] and thioindigo dyes [10,11], and they are also reported to be cytotoxic to cancer cells [12] as well as useful for measuring lipophilicity [13]. However, despite being known of for more than a century, their therapeutic properties have not yet been well explored [6,7]. The preparation of these derivatives could be carried out throughout several reported methods [5,14,15,16,17,18].
In addition, the chemistry of pyrazole derivatives has attracted much attention because of their synthetic and biological interest [19,20]. The pyrazole moiety is involved in a wide range of synthetic and natural heterocyclic compounds with biological interest [21,22,23]. Moreover, this azaheterocycle was found in commercially available herbicidal, fungicidal, and insecticidal agents, like pyazosulfuron-ethyl, sedaxane, and chlorantraniliprole (Figure 1) [24,25,26].
Otherwise, spiroheterocyclic systems offer extraordinary motifs that have captured the interest of researchers due to their multiple biological uses [27,28]. Furthermore, these spirocycles possess intriguing structural characteristics, including conformational rigidity and distinctive three-dimensional geometry, making them attractive targets in the field of organic synthesis [29]. Spiropyrazoline is one of the most significant spiroheterocycles, and it has numerous applications in various fields [30,31]. Many spiropyrazoline derivatives have been reported to exhibit a wide range of biological activities, including anticancer [21,22], fungicidal [30], antimicrobial [32], and anti-Alzheimer [19] activities. Therefore, discovering convenient and efficient synthetic strategies for spiropyrazolines represents a pertinent and timely topic in the field of organic synthesis [33]. Up to this point, 1,3-DC reactions remain the most versatile reactions in regard to preparing interesting spiroheterocycles encompassing pyrazole derivatives [34].
To pursue our ongoing research focused on the investigation of the regio- and stereoselectivity of 1,3-DC reactions [35,36,37,38], our aim in this paper is to describe the 1,3-DC of nitrilimines with thioaurone derivatives. The structure of the obtained cycloadducts and regiochemistry of the reaction will also be deeply discussed. Theoretical studies are also performed through the MEDT method and ELF topological analysis to gather more information on the possible mechanisms and all intermediates participated in this 1,3-DC reaction.

2. Materials and Methods

Reagents and solvent were obtained from commercial suppliers and were used as received. Ready-to-use silica gel-coated with aluminum plates (Merck 60 F254, thickness: 0.2 mm) TLC were used to control the advancement of reactions and spots were revealed with a UV lamp (254–365 nm). Purification of obtained products was carried through column chromatography using Merck 60 silica gel (230–400 Mesh) as the stationary phase (Darmstadt, Germany). Melting points were determined with a calibrated KOFLER apparatus. 1H and 13C NMR spectra were recorded using a BRUKER AVANCE IITM 300 MHz instrument at room temperature (Ettlingen, Germany). The frequency of the device and the solvents used are specified in the experimental part. Chemical shifts are given in ppm and coupling constants are given in Hz. The FT-IR IR spectrum was recorded using a Thermo ScientificTM Nicolet iS10 FT-IR spectrometer (Waltham, MA USA). Mass spectra were recorded using a Q-exactive mass spectrometer (Thermo) at CESAMO (Bordeaux, France). The instrument is equipped with an ESI source, and spectra were stored in positive mode.

2.1. Synthesis of Spiropyrazolines 3

To a solution of thioaurones (8 mmol) and α-chloroarylidene-phenylhydrazones (4 mmol) in anhydrous chloroform, 4 mmol of triethylamine were added. The reaction mixture was left under magnetic stirring at room temperature, and the evolution of the reaction was monitored by TLC. Once the reaction was over, the reaction mixture was distilled using rotary evaporator to remove the solvent. The residue was treated with diethyl ether and the triethylamine hydrochloride precipitate was filtered off. The obtained crude product was purified by silica gel column chromatography using hexane/ether 8/2 to obtain pure spiropyrazoline.

2.2. Spectroscopic Data of the Synthetized Spiropyrazolines 3

2.2.1. 2′,4′,5′-Triphenyl-2′,4′-dihydro-3H-spiro[benzo[b]thiophene-2,3′-pyrazol]-3-one (3aa)

Yellow solid. Yield: 80%. m.p.: 170 °C. ATR-IR (ν in cm−1): 3061 (=C-H), 1701 (C=O), 1591 (C=N), 1492 (C=C). 1H NMR (300 MHz, CDCl3, δ in ppm): 5.42 (s, 1H, H5′), 6.95 (dt, 1H, HAr, 3Jo = 8.34 Hz, 4Jm = 1.38 Hz), 7.02 (dd, 2H, HAr, 3Jo = 8.06 Hz, 4Jm = 1.74 Hz), 7.06 (d, 1H, HAr, 3Jo = 7.96 Hz), 7.13–7.29 (m, 11H, HAr), 7.49 (dt, 1H, HAr, 3Jo = 8.00 Hz, 4Jm = 1.33 Hz), 7.56 (dd, 1H, HAr, 3Jo = 7.69 Hz, 4Jm = 2.08 Hz), 7.89 (dd, 1H, HAr, 3Jo = 7.76 Hz, 4Jm = 0.74 Hz). 13C NMR (75 MHz, CDCl3, δ in ppm): 65.28 (C5′), 92.02 (C1′), 116.18, 122.03, 124.40, 125.15, 127.07, 127.38, 128.13, 128.22, 128.29, 128.79 (Cq-CO), 128.88, 130.10, 131.27 (Cq-C4′), 134.52 (Cq-C5′), 136.99, 142.42 (Cq-N), 149.69 (Cq-S), 150.90 (C4′), 200.52 (C=O). HRMS: Mass calculated for [C28H21ON2S]+: 433.13691, found: 433.13706, Δmass peak = 0.34 ppm.

2.2.2. 4′-[4-Chlorophenyl]-2′,5′-diphenyl-2′,4′-dihydro-3H-spiro[benzo[b]thiophene-2,3′-pyrazol]-3-one (3ab)

Yellow solid. Yield: 60%. m.p.: 184 °C. ATR-IR (ν in cm−1): 3028 (=C-H), 1704 (C=O), 1591 (C=N), 1485 (C=C). 1H NMR (300 MHz, CDCl3, δ in ppm): 5.36 (s, 1H, H5′), 6.94 (dt, 1H, HAr, 3Jo = 8.35 Hz, 4Jm = 1.24 Hz), 7.00 (dd, 2H, HAr, 3Jo = 7.89 Hz, 4Jm = 1.50 Hz), 7.07 (d, 1H, HAr, 3Jo = 7.95 Hz), 7.12 (dd, 2H, HAr, 3Jo = 8.78 Hz, 4Jm = 1.28 Hz), 7.18 (dt, 3H, HAr, 3Jo = 8.95 Hz, 4Jm = 2.15 Hz), 7.24 (dt, 5H, HAr, 3Jo = 7.84 Hz, 4Jm = 1.21 Hz), 7.48 (dd, 3H, HAr, 3Jo = 8.70 Hz, 4Jm = 2.13 Hz), 7.88 (dd, 3H, HAr, 3Jo = 7.76 Hz, 4Jm = 0.75 Hz). 13C NMR (75 MHz, CDCl3, δ in ppm): 65.07 (C5′), 91.98 (C1′), 116.30, 122.24, 124.36, 125.20, 127.40, 128.21, 128.28, 128.33, 128.54, 128.68 (Cq-CO), 128.87, 129.82 (Cq-C4′), 130.03, 134.27 (Cq-Cl), 134.66 (Cq-C5′), 137.02, 142.23 (Cq-N), 148.52 (Cq-S), 150.81 (C4′), 200.32 (C=O). HRMS: Mass calculated for [C28H19ON2ClS+Na]+: 489.07988, found: 489.08007, Δmass peak = 0.38 ppm.

2.2.3. 5′-[4-Methylphenyl]-2′,4′-diphenyl-2′,4′-dihydro-3H-spiro[benzo[b]thiophene-2,3′-pyrazol]-3-one (3ba)

Yellow solid. Yield: 75%. m.p.: 180 °C. ATR-IR (ν in cm−1): 3024 (=C-H), 1704 (C=O), 1591 (C=N), 1494 (C=C). 1H NMR (300 MHz, CDCl3, δ in ppm): 2.29 (s, 3H, CH3), 5.43 (s, 1H, H5′), 6.94 (dd, 3H, HAr, 3Jo = 8.16 Hz, 4Jm = 2.35 Hz), 7.01 (dd, 2H, HAr, 3Jo = 7.98 Hz), 7.08 (d, 1H, HAr, 3Jo = 7.95 Hz), 7.21 (dd, 5H, HAr, 3Jo = 6.41 Hz, 4Jm = 2.15 Hz), 7.29 (dd, 3H, HAr, 3Jo = 5.78 Hz, 4Jm = 2.47 Hz), 7.48 (dt, 1H, HAr, 3Jo = 8.07 Hz, 4Jm = 1.37 Hz), 7.60 (dd, 2H, HAr, 3Jo = 7.46 Hz, 4Jm = 2.28 Hz), 7.91 (dd, 1H, HAr, 3Jo = 7.74 Hz, 4Jm = 0.73 Hz). 13C NMR (75 MHz, CDCl3, δ in ppm): 21.27 (CH3), 64.97 (C5′), 92.11 (C1′), 116.26, 122.00, 124.44, 125.15, 127.11, 127.37, 128.30, 128.80 (Cq-CO), 128.84, 128.89, 129.04, 129.93, 131.43 (Cq-C4′), 131.67 (Cq- C5′), 136.98, 137.89 (Cq-CH3), 142.55 (Cq-N), 149.97 (Cq-S), 151.01 (C4′), 200.64 (C=O). HRMS: Mass calculated for [C29H22ON2S+H]+: 447.15256, found: 447.15258, Δmass peak = 0.05 ppm.

2.2.4. 5′-[4-Chlorophenyl]-2′,4′-diphenyl-2′,4′-dihydro-3H-spiro[benzo[b]thiophene-2,3′-pyrazol]-3-one (3ca)

Yellow solid. Yield: 70%. m.p.: 153 °C. ATR-IR (ν in cm−1): 3056 (=C-H), 1705 (C=O), 1596 (C=N), 1497 (C=C). 1H NMR (300 MHz, CDCl3, δ in ppm): 5.41 (s, 1H, H5′), 6.95 (d, 3H, HAr, 3Jo = 8.36 Hz), 7.08–7.31 (m, 11H, HAr), 7.49–7.54 (m, 3H, HAr), 7.89 (dd, 1H, HAr, 3Jo = 7.76 Hz, 4Jm = 0.75 Hz). 13C NMR (75 MHz, CDCl3, δ in ppm): 64.61 (C5′), 91.88 (C1′), 116.21, 122.22, 124.53, 125.33, 127.04, 127.44, 128.40, 128.48, 128.71 (Cq-CO), 128.91, 129.03, 130.97 (Cq- C4′), 131.42, 132.89 (Cq- C5′), 134.10 (Cq-Cl), 137.21, 142.28 (Cq-N), 149.19 (Cq-S), 150.57 (C4′), 200.23 (C=O). HRMS: Mass calculated for [C28H21ON2S]+: 433.13691, found: 433.13706, Δmass peak = 0.34 ppm.

2.3. Computational Details

All optimizations were performed with Gaussian 09 [39] using the B3LYP method [40,41] and the 6-311G(d,p) basis set. The solvent effect was performed using dichloromethane (DCM). The electronic chemical potential (µ) and chemical hardness (η) were calculated using the energy of the frontier molecular orbitals HOMO and LUMO. µ = (EH + EL)/2 The global electrophilicity and nucleophilicity indexes were calculated using the following formulas: ω = µ2/2η and N = EH − EH (TCE) [42,43]. The local reactivity index is obtained from the analysis of the Mulliken atomic spin density of the reagents [44]. The local electrophilicity and nucleophilicity indices can be redefined as follows: ωk = ω·Pk+ and Nk = N·Pk-. The electron localization function (ELF) analysis was also performed through Multiwfn software (version 2.1.2) [45].

3. Results and Discussion

3.1. Synthesis

Thioaurones used as starting materials in this work were prepared by adopting our previously published procedure [36,37,46]. Thioaurones were allowed to react with nitrilimines, which were generated in situ by treating hydrazonoyl chlorides with triethylamine with a view to generate the desired spiropyrazolines. Indeed, the reaction between thioaurone and nitrilimines in refluxed toluene was previously described by our team [36]. It was shown that the undertaken reaction led to the formation of 1,3,4,5-tetrasubstituted pyrazoles in the absence of any traces of the spirocycloadduct. In fact, this later underwent a ring-opening in the benzothiophenone moiety and a subsequent nucleophilic addition of the thiolate group on a second hydrazonoyl chloride molecule (Scheme 1).
Given the biological interest of spiropyrazolines, we decided to further investigate the behavior of nitrilimines towards thioaurones under mild conditions. For this purpose, we carried out the reaction between thioaurones and N-phenyl-C-arylnitrilimines (generated in situ from α-chloroarylidene-phenylhydrazones by action of triethylamine) in chloroform under magnetic stirring at room temperature. Indeed, when we initially used an equimolar amount of the two reagents, the formation of two products was revealed by TLC. Upon isolating and analyzing these products, we found that the reaction produced both the spiropyrazoline (Scheme 2) and 1,3,4,5-tetra-substituted pyrazoles obtained in our previous study (Scheme 1). After the optimization of the reaction condition to obtain only the spirocycloadduct, we found that, in the use of two moles of thioaurones against one mole of nitrilimines precursor, the reaction resulted in the formation of spirocycloadduct as a single product only, with satisfactory yields (Scheme 2). We have also shown that the cycloaddition reaction is highly regioselective, leading exclusively to a single spiropyrazoline 3, and no trace of the second regiosiomer 3′ was detected (Scheme 2).
The reaction yielded a series of novel spiropyrazolines via a highly regioselective 1,3-DC of nitrilimines onto the exocyclic double bond of thioaurones. The structure of the obtained spirocycloadducts 3 and the regiochemistry of the cycloaddition reactions were established based on their IR, NMR and HRMS data. The FT-IR spectra (Figures S1, S5, S9 and S13) of the resulting cycloadducts showed the presence of an absorption band of around 1700 cm−1 that was attributed to the stretching vibration of the carbonyl group (C=O), showing an increase of approximately 20 cm−1 over the starting materials and indicating the loss of conjugation of the carbonyl group [46]. The 1H NMR spectra (Figures S2, S6, S10 and S14) show, in addition to signals attributed to aromatic protons, a singlet signal at a range of 5.36–5.43 ppm assigned to the proton H5′ at position 5′ of the pyrazoline ring which is revealed in favor of the proposed regioisomer 3. For the other regioisomer 3′, a high value of chemical shift should be expected for the pyrazoline proton (around 6 ppm) [47]. The 13C NMR spectra (Figures S3, S7, S11 and S15) reveal the presence of a signal of around 65 ppm corresponding to the carbon C5′ and a signal around 92 ppm assigned to the spiranic carbon C1′ for the observed regioisomer 3. It seems that the chemical shift value obtained for C1′ is more compatible with the regioisomeric structure 3 rather than 3′, as it closely resembles the reported quaternary carbon atom bonding with a sulfur and a nitrogen atom [48]. The 13C NMR spectra also reveal the presence of a signal at 200 ppm that corresponds to the carbon of the carbonyl group. This signal is deshielded by approximately 12 ppm compared to the carbonyl group signal (around 188 ppm) of starting materials (thioaurones) [36,37,46], suggesting a loss of the conjugation of the carbonyl group.
Overall, the chemical shift values of the proton H5′ of the pyrazoline ring, tertiary carbon C4, and the spiro-quaternary carbon C1′ are fully consistent with the proposed regiochemistry for the spirocycloadducts 3 and further confirm the regioselective action of ntrilimines on thioaurones used as dipolarophiles. These chemical shift values are also perfectly coherent with those found in the literature, in which the nitrogenous termination of the 1,3-dipole (N-phenyl-C-arylnitrilimine) is attached to the spiro-quaternary carbon atom [29,49,50]. In addition, similar results were obtained with the nitrogen aza-aurone analogs of thioaurones during cycloaddition with nitrilimines [51]. Furthermore, the mass spectra of all the newly synthesized spiropyrazolines consistently (Figures S4, S8 and S12) exhibit a molecular ion peak [M + H]+ or [M + Na]+, aligning precisely to the molecular weights of the proposed structures, thereby confirming the structures of the final spirocycloadducts.

3.2. Mechanistic Study of 1,3-DC Reaction

The 1,3-DC reactions present a significant challenge for the synthesis of organic compounds with a wide range of excellent applications, as outlined in reference [52]. The feasibility of these reactions is contingent upon the electronic structures of the three-atom components (TACs) involved, which are dependent upon the TACs’ structures, including pseudo diradical (pdr), pseudo(mono)radical (pmr), carbenoid (cb), or zwitterionic (zw) (Figure 2) [53,54,55]. In our investigation, the 1,3-DC reaction of nitrilimines and thioaurones was found to conduct to spiropyrazolines via two potential pathways with regard to the regioselective attacks, as illustrated in Scheme 2 [56,57]. Recently, theoretical investigations have indicated that the Molecular Electron Density Theory (MEDT) [58] can establish a significant correlation between the electronic structure of TACs and their reactivity toward ethylene structures in 1,3-DC reactions [59]. To gain insight into the observed regioselectivity during the cycloaddition reaction between nitrilimines and thioaurone, as well as the corresponding mechanistic pathway, theoretical investigations were conducted within the framework of the Molecular Electron Density Theory (MEDT) method. These investigations were presented in four sections: (i) an ELF topological analysis of reagents; (ii) the reactivity indexes being calculated using an analysis of the Conceptual Density Functional Theory (CDFT) indices; (iii) an investigation of the potential 1,3-DC reaction profiles; (iv) an ELF topological analysis of all 1,3-DC reaction intermediates.

3.2.1. ELF Topological Analysis of Reagents

The ELF (Electronic Localization Function) topology analysis, initially proposed by Becke and Edgecombe [60] and subsequently developed by Silvi and Savin [61], enables a quantitative correlation between chemical structure and electron density distribution through a precise mathematical representation of the Lewis valence theory. A recent study has demonstrated a notable correlation between the molecular reactivity and the electronic structure of the TACs involved in 1,3-DC reactions, as revealed by the ELF analysis [62]. To gain further insight into the electronic structure, an ELF analysis was conducted on the two reagents involved in the cycloaddition between nitrilimine (1a) and thioaurone (2a) (Figure 3). The topological analysis of the electron localization function (ELF) of 1a reveals the presence of two disynaptic basins, designated as V(C1, N2) and V′(C1, N2), with a total electron population of 4.9 electrons (e). Additionally, two monosynaptic basins, V(N3) and V(C1), are observed, integrating 3.94 and 1.21 e, respectively. Additionally, a V(N2, N3) disynaptic basin is observed, integrating 2.12 e. The Lewis structure of 1a is distinguished by a C1≡N2 delocalized triple bond and a N2-N3 single bond along with a lone pair at the N3 which integrates 3.39 e. This evidence corroborates the hypothesis that 1a participates as a carbenoid TAC in the 1,3-DC reactions (Figure 3) [63]. The ELF analysis of 2a indicates the absence of a monosynaptic basin in the C4-C5 double bond and the presence of two V(C4, C5) and V′(C4, C5) disynaptic basins, with a total population of 3.38 e. This finding corroborates the double bond nature of C4–C5 (Figure 3).
These results confirm that the nitrilimines were classified as a carbenoid TAC (Figure 4), and it has been confirmed that the cb-type 1,3-DC reaction needs suitable nucleophilic/electrophilic activations [62].

3.2.2. Analysis of the CDFT Indexes

The global reactivity indexes were employed as a robust analytical instrument for elucidating the regioselectivity and chemoselectivity of reactions based on the measurement of the global electron density transfer (GEDT) value [64,65]. In order to achieve this, the global properties, namely the electronic chemical potential (µ), chemical hardness (η), global electrophilicity (ω), and global nucleophilicity (N) for both reagents, were calculated and are presented in Table 1. The results indicate that the electronic chemical potential of the nitrilimine, μ = −3.53 eV, is higher than that of thioaurone, μ = −4.29 eV. This suggests that, at the transition states (TSs), the global electron density transfer (GEDT) will occur from the nitrilimine to the thioaurone. The global electrophilicity and nucleophilicity indexes of the reactants were calculated (Table 1) [66]. The results demonstrate that the nitrilimine functions as a marginal electrophile (ω = 1.70 eV) and a robust nucleophile (N = 3.76 eV), whereas the thioaurone exhibits characteristics of a strong electrophile (ω = 2.73 eV) and a potent nucleophile (N = 3.14 eV) within the context of the electrophilicity and nucleophilicity scales [67]. These findings corroborate the hypothesis that, in addition to the cycloaddition reaction, the thioaurone functions as an electrophile and the nitrilimine functions as a nucleophile with a polar character.
In a recent study, the bond-forming process, along a polar reaction, was performed with the aim of providing an explanation for the regio- or chemoselectivity issues observed in organic reactions. This was achieved through the analysis of local reactivity indexes derived from Parr functions [68]. By analyzing the local electrophilicity ωk at the electrophilic reagent and the local nucleophilicity Nk at the nucleophilic reagent, we can gain insight into the regioselectivity observed experimentally [69,70]. In order to better understand this phenomenon, we have calculated and summarized the values of the local nucleophilicity at the nitrilimine (1a) and the local electrophilicity at the thioaurone (2a) in Figure 5.
The analysis of local nucleophilicity at nitrilimine 1a indicates that the carbon atom C1 is the most nucleophilic activated center at 1a, with Nk (C1) = 0.25 eV. The analysis of the local electrophilicity at thioaurone 2a indicates that the carbon atom (C5) is the most electrophilic center, with ωk (C5) = 0.67 eV. The 1,3-DC reaction between nitrilimine and thioaurone will be achieved through the interaction of the carbon atom in the β position (C5) of 2a with the carbon atom (C1) of the –N=N=C– fragment. These results confirm the selective synthesis of spirocycloadduct 3aa, which aligns with the experimental observations.

3.2.3. Reaction Profiles

The mechanistic study of the title reaction began with an investigation into the potential reaction pathways for the cycloaddition between nitrilimine 1 and thioaurone 2a. The findings suggest that the analysis of the reaction profile associated with this 1,3-DC reaction indicates that it may occur through a one-step mechanism. The relative energies, in DCM, are presented in Scheme 3.
Path A has an activation energy of 11.87 kcal/mol, which is 3.75 kcal/mol more than path B. These transition states lead to the formation of products 3aa and 3′aa by −43.22 and −44.58 kcal/mol. Figure 6 shows the TS geometries for both paths of the 1,3-DC reaction. In the TSA, the distances C1-C5 and N3-C4 are 1.873 and 2.841 Å. The corresponding bond lengths at the TSB are 2.295 and 2.002 Å.
We calculated the GEDT at the TSs to see if this 1,3-DC reaction is polar. A GEDT value below 0.05 e indicates a non-polar reaction. A value above 0.20 e indicates a polar reaction. The GEDT values at the TSs are 0.202 e at TSA and 0.155 e at TSB. The higher GEDT at TSA accounts for the higher regioselectivity. These results confirm that the more favorable product is 3aa.

3.2.4. ELF Topological Analysis of Intermediates

To better understand this 1,3-DC reaction, the reaction profile of the cycloaddition between nitrilimine 1a and thioaurone 2a was investigated using the ELF (Scheme 4 and Figure S16). Table 2 shows the results, and Scheme 4 illustrates the Lewis representations. At intermediate I, 1a changes. A new basin was created at C1, integrating V(C1) = 0.99 e, which can be attributed to a pseudo radical center C1. The electron density at the V(C1, N2) disynaptic basin is slightly reduced by 0.17 e, as well as that of the V(N3) monosynaptic basin, which is also reduced by 0.2 e. A similar reduction is seen at the V(N2, N3) disynaptic basin, with a slight reduction of 0.06 e. The V(C4, C5) and V′(C4, C5) basins are regrouped in the V(C4, C5) disynaptic basin by a reduction in electron density of 0.2 e. The ELF analysis shows a strong electron depopulation of the C1-N2 bond by 1.54 and 0.26 e. The monosynaptic basin at C1 is increased by 0.27 e and decreased by 0.16 e at N3. A new monosynaptic basin is located at N2, integrating 1.80 e. At TSA, the two V(C1, N2) disynaptic basins merged into one, with a population change of −0.18 e. The V(N2) monosynaptic basin increased by 0.25 e, and the monosynaptic basin of C1 was not observed. A strong depopulation of 0.48 e towards the V(C4, C5) disynaptic basin occurred. A new disynaptic basin, V(C1, C5), was observed, integrating 1.72 e. At III, the electron population was found to have increased by 0.15 e for the V(C1, N2) disynaptic basin and decreased by 0.40 e for the V(C4, C5) disynaptic basin. The electron density of V(N2) increased by 0.23 e, while that of V(N3) exhibited a slight decrease of 0.06 e. Additionally, a new monosynaptic basin was identified at C4, integrating V(C4) = 0.89 e. The disynaptic basin of the C1-C5 bond demonstrated an increase of 0.07 e. Finally, a new disynaptic basin, V(N3, C4), was observed in 3aa, integrating 1.69 e, indicative of the formation of a new N3-C4 single bond. The C1-C5 bond exhibits an increase of 0.07 e in its synaptic basin. Ultimately, a new disynaptic basin, designated V(N3, C4), was identified in 3aa, integrating 1.69 e, indicative of the formation of a novel N3-C4 single bond. This bond formation was accompanied by a notable depopulation of the V(N2, N3) and V(C4, C5) disynaptic basins, indicating that the majority of this bond was created by the displacement of part of the electron population of the V(N3) and V(C4) monosynaptic basins. Furthermore, the two V(C1, N2) and V(N2, N3) disynaptic basins in the 1a framework have decreased to less than 0.7 e and the V(C4, C5) disynaptic basins have decreased by 0.4 e. The ELF basin attractor positions at all reported intermediates are provided in the Supporting Information File. These findings indicate that the formation of the two single bonds did not occur at the TSA. Furthermore, the formation of the C1-C5 single bonds is more advanced than that of the N3-C4 bond, which supports the hypothesis that the C1-C5 bond formation requires a C1 non-bonding electron density. This evidence also confirms the CB-type mechanism of the 1,3-DC reaction between 1a and 2a, as demonstrated by the ELF topological analysis.

4. Conclusions

In summary, we describe in the current study the synthesis of novel spiropyrazolines derived from thioaurones through a highly regioselective 1,3-DC reaction with nitrilimines. The structure and the regioselectivity of the spirocycloadducts were carefully established using well-known spectroscopic methods (i.e., IR, 1H NMR, and 13C NMR) and corroborated by mass spectrometry. Additionally, the mechanistic study of the 1,3-DC reaction between nitrilimines and thioaurones was conducted using the MEDT method at the B3LYP/6-311G(d,p) computational level. The analysis of the local reactivity indexes obtained from the Parr functions is in good agreement with experimental observations, following the more favorable interactions that take place for a regioselective synthesis of the corresponding product. Importantly, this cycloaddition reaction follows a two-step mechanism, involving the formation of a C-C bond followed by a C-N bond. The analysis of the ionic nature of reagents confirms the cb-type pathway of the 1,3-DC reaction between nitrilimines and thioaurones, as supported by the ELF topological analysis.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/reactions5040056/s1. Copies of the spectra (IR, NMR, and HRMS) of the newly synthesized spiropyrazolines and all additional data analyzed during this study can be found in the electronic Supplementary Material.

Author Contributions

Investigation, M.B. (Mohamed Bakhouch); writing—original draft, B.E.-S.; wonceptualization, A.O.; methodology, M.C.; software, K.O., resources, L.B., software, T.B., visualization, M.B. (Mohamed Bourass); project administration, R.F.; formal analysis, M.A., supervision, M.E.Y. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Data Availability Statement

There are no data associated to this work. Data sharing is not applicable to this article.

Acknowledgments

The authors kindly acknowledge the City of Innovation of the Sidi Mohamed Ben Abdellah University for spectroscopic measurement. This work has benefited from the facilities of the CESAMO platform (Bordeaux University).

Conflicts of Interest

The authors declare that they have no conflicts of interest.

References

  1. La Monica, G.; Alamia, F.; Bono, A.; Lauria, A.; Martorana, A. Scaffold-Hopping Strategies in Aurone Optimization: A Comprehensive Review of Synthetic Procedures and Biological Activities of Nitrogen and Sulfur Analogues. Molecules 2024, 29, 2813. [Google Scholar] [CrossRef]
  2. Zhang, Y.; Yu, A.; Jia, J.; Ma, S.; Li, K.; Wei, Y.; Meng, X. NaH Promoted [4+3] Annulation of Crotonate-Derived Sulfur Ylides with Thioaurones: Synthesis of 2,5-Dihydrobenzo[4,5]Thieno[3,2-b]Oxepines. Chem. Commun. 2017, 53, 10672–10675. [Google Scholar] [CrossRef] [PubMed]
  3. Ma, S.; Yu, A.; Zhang, L.; Meng, X. Phosphine-Catalyzed Domino Reaction of Thioaurones and Allenoate: Synthesis of Benzothiophene-Fused Dioxabicyclo[3.3.1]Nonane Derivatives. J. Org. Chem. 2018, 83, 5410–5419. [Google Scholar] [CrossRef]
  4. Ding, W.; Yu, A.; Zhang, L.; Meng, X. Construction of Eight-Membered Cyclic Diaryl Sulfides via Domino Reaction of Arynes with Thioaurone Analogues and DFT Study on the Reaction Mechanism. Org. Lett. 2019, 21, 9014–9018. [Google Scholar] [CrossRef]
  5. Bakhouch, M.; Es-Sounni, B.; Nakkabi, A.; Yazidi, M.E. Thioaurones: Recent Advances in Synthesis, Reactivity, and Biological Activity. Mini-Rev. Org. Chem. 2021, 18, 313–327. [Google Scholar] [CrossRef]
  6. Zaher, A.F.; Abuel-Maaty, S.M.; El-Nassan, H.B.; Amer, S.A.S.; Abdelghany, T.M. Synthesis, Antitumor Screening and Cell Cycle Analysis of Novel Benzothieno[3,2-b]Pyran Derivatives. J. Enzym. Inhib. Med. Chem. 2016, 31, 145–153. [Google Scholar] [CrossRef]
  7. Mouineer, A.; Zaher, A.; El-Malah, A.; Sobh, E.A.-F. Design, Synthesis, Antitumor Activity, Cell Cycle Analysis and ELISA Assay for Cyclin Dependant Kinase-2 of a New (4-Aryl-6-Flouro-4H-Benzo[4,5]Thieno[3,2-b]Pyran) Derivatives. Mediterr. J. Chem. 2017, 6, 165–179. [Google Scholar] [CrossRef]
  8. Zweig, J.E.; Newhouse, T.R. Isomer-Specific Hydrogen Bonding as a Design Principle for Bidirectionally Quantitative and Redshifted Hemithioindigo Photoswitches. J. Am. Chem. Soc. 2017, 139, 10956–10959. [Google Scholar] [CrossRef] [PubMed]
  9. Erdélyi, M.; Karlén, A.; Gogoll, A. A New Tool in Peptide Engineering: A Photoswitchable Stilbene-Type β-Hairpin Mimetic. Chem. A Eur. J. 2006, 12, 403–412. [Google Scholar] [CrossRef]
  10. Costa, A.L.; Gomes, A.C.; Pereira, R.C.; Pillinger, M.; Gonçalves, I.S.; Pineiro, M.; Seixas de Melo, J.S. Interactions and Supramolecular Organization of Sulfonated Indigo and Thioindigo Dyes in Layered Hydroxide Hosts. Langmuir 2018, 34, 453–464. [Google Scholar] [CrossRef] [PubMed]
  11. Koeppe, B.; Römpp, F. Reversible Spatial Control in Aqueous Media by Visible Light: A Thioindigo Photoswitch That Is Soluble and Operates Efficiently in Water. Chem. A Eur. J. 2018, 24, 14382–14386. [Google Scholar] [CrossRef] [PubMed]
  12. Konieczny, M.T.; Konieczny, W.; Okabe, S.; Tsujimoto, H.; Suda, Y.; Wierzba, K. Synthesis and Cytostatic Activity of 4,7-Dihydroxythioaurone Derivatives. Effect of B Ring Substitution on the Activity. Chem. Pharm. Bull. 2006, 54, 350–353. [Google Scholar] [CrossRef]
  13. Hallgas, B.; Patonay, T.; Kiss-Szikszai, A.; Dobos, Z.; Hollósy, F.; Erős, D.; Őrfi, L.; Kéri, G.; Idei, M. Comparison of Measured and Calculated Lipophilicity of Substituted Aurones and Related Compounds. J. Chromatogr. B 2004, 801, 229–235. [Google Scholar] [CrossRef]
  14. Lee, J.I. Novel Synthesis of Thioaurones by the Regioselective Cyclization of 1-(2-Benzylthio)Phenyl-3-Phenyl-2-Propyn-1-Ones Derived from Thiosalicylic Acid. Bull. Korean Chem. Soc. 2019, 40, 70–73. [Google Scholar] [CrossRef]
  15. Nguyen, T.B.; Retailleau, P. Cooperative Activating Effect of Tertiary Amine/DMSO on Elemental Sulfur: Direct Access to Thioaurones from 2′-Nitrochalcones under Mild Conditions. Org. Lett. 2018, 20, 186–189. [Google Scholar] [CrossRef] [PubMed]
  16. Konieczny, M.T.; Konieczny, W. Synthesis and Reactivity of Thioaurones over the Past One Hundered Years. ChemInform 2005, 36, 451–464. [Google Scholar] [CrossRef]
  17. Lee, J.I. Synthetic Approaches to (Z)-Thioaurones. Bull. Korean Chem. Soc. 2021, 42, 1210–1219. [Google Scholar] [CrossRef]
  18. In Lee, J. A Review of the Syntheses of (Thio)Flavones, 4-Quinolones, (Thio)Aurones, and Azaaurones from 2′-Substituted Alkynones. Bull. Korean Chem. Soc. 2021, 42, 1610–1623. [Google Scholar] [CrossRef]
  19. Gutti, G.; Kumar, D.; Paliwal, P.; Ganeshpurkar, A.; Lahre, K.; Kumar, A.; Krishnamurthy, S.; Singh, S.K. Development of Pyrazole and Spiropyrazoline Analogs as Multifunctional Agents for Treatment of Alzheimer’s Disease. Bioorganic Chem. 2019, 90, 103080. [Google Scholar] [CrossRef]
  20. Nunes, R.C.; Ribeiro, C.J.A.; Monteiro, Â.; Rodrigues, C.M.P.; Amaral, J.D.; Santos, M.M.M. In Vitro Targeting of Colon Cancer Cells Using Spiropyrazoline Oxindoles. Eur. J. Med. Chem. 2017, 139, 168–179. [Google Scholar] [CrossRef]
  21. Monteiro, Â.; Gonçalves, L.M.; Santos, M.M.M. Synthesis of Novel Spiropyrazoline Oxindoles and Evaluation of Cytotoxicity in Cancer Cell Lines. Eur. J. Med. Chem. 2014, 79, 266–272. [Google Scholar] [CrossRef]
  22. Ansari, A.; Ali, A.; Asif, M. Shamsuzzaman Review: Biologically Active Pyrazole Derivatives. New J. Chem. 2017, 41, 16–41. [Google Scholar] [CrossRef]
  23. Kumar, V.; Kaur, K.; Gupta, G.K.; Sharma, A.K. Pyrazole Containing Natural Products: Synthetic Preview and Biological Significance. Eur. J. Med. Chem. 2013, 69, 735–753. [Google Scholar] [CrossRef]
  24. Zeun, R.; Scalliet, G.; Oostendorp, M. Biological Activity of Sedaxane—A Novel Broad-Spectrum Fungicide for Seed Treatment. Pest Manag. Sci. 2013, 69, 527–534. [Google Scholar] [CrossRef] [PubMed]
  25. Britton, J.; Jamison, T.F. Synthesis of Celecoxib, Mavacoxib, SC-560, Fluxapyroxad, and Bixafen Enabled by Continuous Flow Reaction Modules. Eur. J. Org. Chem. 2017, 2017, 6566–6574. [Google Scholar] [CrossRef]
  26. Kang, S.; Song, B.; Wu, J.; He, M.; Hu, D.; Jin, L.; Zeng, S.; Xue, W.; Yang, S. Design, Synthesis and Insecticidal Activities of Novel Acetamido Derivatives Containing N-Pyridylpyrazole Carboxamides. Eur. J. Med. Chem. 2013, 67, 14–18. [Google Scholar] [CrossRef] [PubMed]
  27. Boddy, A.J.; Bull, J.A. Stereoselective Synthesis and Applications of Spirocyclic Oxindoles. Org. Chem. Front. 2021, 8, 1026–1084. [Google Scholar] [CrossRef]
  28. Altowyan, M.S.; Barakat, A.; Al-Majid, A.M.; Al-Ghulikah, H.A. Spiroindolone Analogues as Potential Hypoglycemic with Dual Inhibitory Activity on α-Amylase and α-Glucosidase. Molecules 2019, 24, 2342. [Google Scholar] [CrossRef]
  29. Farghaly, T.A.; Abbas, I.M.; Hassan, W.M.I.; Lotfy, M.S.; Al-Qurashi, N.T.; Hadda, T.B. Structure Determination and Quantum Chemical Analysis of 1,3-Dipolar Cycloaddition of Nitrile Imines and New Dipolarophiles and POM Analyses of the Products as Potential Breast Cancer Inhibitors. Russ. J. Org. Chem. 2020, 56, 1258–1271. [Google Scholar] [CrossRef]
  30. Yang, C.; Li, J.; Zhou, R.; Chen, X.; Gao, Y.; He, Z. Facile Synthesis of Spirooxindole-Pyrazolines and Spirobenzofuranone-Pyrazolines and Their Fungicidal Activity. Org. Biomol. Chem. 2015, 13, 4869–4878. [Google Scholar] [CrossRef]
  31. Raposo, L.R.; Silva, A.; Silva, D.; Roma-Rodrigues, C.; Espadinha, M.; Baptista, P.V.; Santos, M.M.M.; Fernandes, A.R. Exploiting the Antiproliferative Potential of Spiropyrazoline Oxindoles in a Human Ovarian Cancer Cell Line. Bioorganic Med. Chem. 2021, 30, 115880. [Google Scholar] [CrossRef]
  32. Dawood, K.M. Synthesis of Spiro-Pyrazole-3,3′-Thiopyrano[2,3-b]Pyridines and Azolo[a]Pyrido[2′,3′:5,6]Thiopyrano[3,4-d]Pyrimidines as New Ring Systems with Antifungal and Antibacterial Activities. J. Heterocycl. Chem. 2005, 42, 221–225. [Google Scholar] [CrossRef]
  33. Sadiq, Z.; Naz, S.; Hussain, E.A.; Aslam, U. Spiropyrazolines: A Worthy Insight into the Recent Strategies and Synthetic Applications. Lett. Org. Chem. 2019, 16, 357–391. [Google Scholar] [CrossRef]
  34. Shawali, A.S.; Abdelhamid, A.O. Synthesis of Spiro-Heterocycles via 1,3-Dipolar Cycloadditions of Nitrilimines to Exoheterocyclic Enones. Site-, Regio- and Stereo-Selectivities Overview. Curr. Org. Chem. 2012, 16, 2673–2689. [Google Scholar] [CrossRef]
  35. Boughaleb, A.; Al Houari, G.; Bennani, B.; Daoudi, M.; Garrigues, B.; Kerbal, A.; El Yazidi, M. Cycloaddition des N-Phényl-C-Arylnitrilimines sur des Dérivés de la 2-Benzylidènebenzo[b]tiophèn-3(2H)-One (Thioaurones). J. Soc. Chim. Tunisie 2010, 12, 109–115. [Google Scholar]
  36. Boughaleb, A.; Akhazzane, M.; Alhouari, G.; Bennani, B.; Daoudi, M.; Garrigues, B.; Kerbal, A. Cycloaddition Des Arylnitriloxydes Sur Des Dérivés de La 2-Benzylidènebenzo[b]Tiophen-3(2H)-One (Thioaurones). J. Soc. Chim. Tunisie 2011, 13, 117–122. [Google Scholar]
  37. Rhazi, Y.; Chalkha, M.; Nakkabi, A.; Hammoudan, I.; Akhazzane, M.; Bakhouch, M.; Chtita, S.; El Yazidi, M. Novel Quinazolinone–Isoxazoline Hybrids: Synthesis, Spectroscopic Characterization, and DFT Mechanistic Study. Chemistry 2022, 4, 969–982. [Google Scholar] [CrossRef]
  38. Chalkha, M.; Nour, H.; Chebbac, K.; Nakkabi, A.; Bahsis, L.; Bakhouch, M.; Akhazzane, M.; Bourass, M.; Chtita, S.; Bin Jardan, Y.A.; et al. Synthesis, Characterization, DFT Mechanistic Study, Antimicrobial Activity, Molecular Modeling, and ADMET Properties of Novel Pyrazole-Isoxazoline Hybrids. ACS Omega 2022, 7, 46731–46744. [Google Scholar] [CrossRef] [PubMed]
  39. Frisch, M.J.; Trucks, G.W.; Schlegel, H.B.; Scuseria, G.E.; Robb, M.A.; Cheeseman, J.R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G.A.; et al. Gaussian 09; Gaussian Inc: Wallingford, CT, USA, 2009. [Google Scholar]
  40. Becke, A.D. Density-functional Thermochemistry. III. The Role of Exact Exchange. J. Chem. Phys. 1993, 98, 5648–5652. [Google Scholar] [CrossRef]
  41. Lee, C.; Yang, W.; Parr, R.G. Development of the Colle-Salvetti Correlation-Energy Formula into a Functional of the Electron Density. Phys. Rev. B 1988, 37, 785–789. [Google Scholar] [CrossRef] [PubMed]
  42. Parr, R.G.; Szentpály, L.v.; Liu, S. Electrophilicity Index. J. Am. Chem. Soc. 1999, 121, 1922–1924. [Google Scholar] [CrossRef]
  43. Domingo, L.R.; Pérez, P. The Nucleophilicity N Index in Organic Chemistry. Org. Biomol. Chem. 2011, 9, 7168–7175. [Google Scholar] [CrossRef] [PubMed]
  44. Domingo, L.R.; Pérez, P.; Sáez, J.A. Understanding the Local Reactivity in Polar Organic Reactions through Electrophilic and Nucleophilic Parr Functions. RSC Adv. 2013, 3, 1486–1494. [Google Scholar] [CrossRef]
  45. Lu, T.; Chen, F. Multiwfn: A Multifunctional Wavefunction Analyzer. J. Comput. Chem. 2012, 33, 580–592. [Google Scholar] [CrossRef]
  46. Bakhouch, M.; Houari, G.A.; Daoudi, M.; Kerbal, A.; Yazidi, M.E. Michael Addition of Active Methylene Compounds to (Z)-2-Arylidenebenzo[b]Thiophen-3(2H)-Ones. Mediterr. J. Chem. 2015, 4, 9–17. [Google Scholar] [CrossRef]
  47. Hassaneen, H.M.; Daboun, H.A.; Abdelhadi, H.A.; Abdel-reheim, N.A. Site Selectivity and Regiochemistry of Nitrilimines. Cycloadditions to 1,3-Diphenyl-2-Thiono-4-Imidazolidinone and Its 5-Phenylmethylene Derivatives. Phosphorus Sulfur Silicon Relat. Elem. 1995, 107, 269–273. [Google Scholar] [CrossRef]
  48. Kerbal, A.; Vebrel, J.; Roche, M.; Laude, B. Reaction of Diarylnitrilimines with 3-Arylidene-4-Isothiochromanones. A General Approach to the First Thiadiazaphenanthrene. Tetrahedron Lett. 1990, 31, 4145–4146. [Google Scholar] [CrossRef]
  49. Akkurt, M.; Yıldırım, S.Ö.; Badri, R.; Kerbal, A.; Hadda, T.B.; Büyükgüngör, O. 4-p-Anisyl-1,2′-Diphenyl-3-p-Tolyl-2′,3′-Dihydrospiro [2-Pyrazoline-5,3′-Isoquinolin]-4′(1′H)-One. Acta Crystallogr. Sect. E 2006, 62, o5022–o5023. [Google Scholar] [CrossRef]
  50. Dawood, K.M. Regio- and Stereoselective Synthesis of Bis-Spiropyrazoline-5,3′-Chroman(Thiochroman)-4-One Derivatives via Bis-Nitrilimines. Tetrahedron 2005, 61, 5229–5233. [Google Scholar] [CrossRef]
  51. Chalkha, M.; Bakhouch, M.; Akhazzane, M.; Bourass, M.; Nicolas, Y.; Al Houari, G.; El Yazidi, M. Design, Synthesis and Characterization of Functionalized Pyrazole Derivatives Bearing Amide and Sulfonamide Moieties from Aza-Aurones. J. Chem. Sci. 2020, 132, 86. [Google Scholar] [CrossRef]
  52. Ukaji, Y.; Soeta, T. Development of New Methods for The Construction of Heterocycles Based on Cycloaddition Reaction of 1,3-Dipoles. In Methods and Applications of Cycloaddition Reactions in Organic Syntheses; John Wiley & Sons, Ltd.: Hoboken, NJ, USA, 2014; pp. 263–282. ISBN 978-1-118-77817-3. [Google Scholar]
  53. Campeau, D.; Pommainville, A.; Gagosz, F. Ynamides as Three-Atom Components in Cycloadditions: An Unexplored Chemical Reaction Space. J. Am. Chem. Soc. 2021, 143, 9601–9611. [Google Scholar] [CrossRef]
  54. Ríos-Gutiérrez, M.; Domingo, L.R.; Ghodsi, F. Unveiling the Different Reactivity of Bent and Linear Three-Atom-Components Participating in [3 + 2] Cycloaddition Reactions. Organics 2021, 2, 274–286. [Google Scholar] [CrossRef]
  55. Deepthi, A.; Acharjee, N.; Sruthi, S.L.; Meenakshy, C.B. An Overview of Nitrile Imine Based [3+2] Cycloadditions over Half a Decade. Tetrahedron 2022, 116, 132812. [Google Scholar] [CrossRef]
  56. Tu, L.; Gao, L.; Wang, Q.; Cao, Z.; Huang, R.; Zheng, Y.; Liu, J. Substrate-Switched Chemodivergent Pyrazole and Pyrazoline Synthesis: [3 + 2] Cycloaddition/Ring-Opening Rearrangement Reaction of Azadienes with Nitrile Imines. J. Org. Chem. 2022, 87, 3389–3401. [Google Scholar] [CrossRef]
  57. Deng, Q.; Meng, X. Recent Advances in the Cycloaddition Reactions of 2-Benzylidene-1-Benzofuran-3-Ones, and Their Sulfur, Nitrogen and Methylene Analogues. Chem. Asian J. 2020, 15, 2838–2853. [Google Scholar] [CrossRef]
  58. Domingo, L.R. Molecular Electron Density Theory: A Modern View of Reactivity in Organic Chemistry. Molecules 2016, 21, 1319. [Google Scholar] [CrossRef] [PubMed]
  59. Ríos-Gutiérrez, M.; Domingo, L.R. Unravelling the Mysteries of the [3+2] Cycloaddition Reactions. Eur. J. Org. Chem. 2019, 2019, 267–282. [Google Scholar] [CrossRef]
  60. Becke, A.D.; Edgecombe, K.E. A Simple Measure of Electron Localization in Atomic and Molecular Systems. J. Chem. Phys. 1990, 92, 5397–5403. [Google Scholar] [CrossRef]
  61. Silvi, B.; Savin, A. Classification of Chemical Bonds Based on Topological Analysis of Electron Localization Functions. Nature 1994, 371, 683–686. [Google Scholar] [CrossRef]
  62. Ríos-Gutiérrez, M.; Domingo, L.R. The Carbenoid-Type Reactivity of Simplest Nitrile Imine from a Molecular Electron Density Theory Perspective. Tetrahedron 2019, 75, 1961–1967. [Google Scholar] [CrossRef]
  63. Domingo, L.R.; Ríos-Gutiérrez, M. A Molecular Electron Density Theory Study of the Reactivity of Azomethine Imine in [3+2] Cycloaddition Reactions. Molecules 2017, 22, 750. [Google Scholar] [CrossRef]
  64. Domingo, L.R.; Kula, K.; Ríos-Gutiérrez, M.; Jasiński, R. Understanding the Participation of Fluorinated Azomethine Ylides in Carbenoid-Type [3 + 2] Cycloaddition Reactions with Ynal Systems: A Molecular Electron Density Theory Study. J. Org. Chem. 2021, 86, 12644–12653. [Google Scholar] [CrossRef] [PubMed]
  65. Domingo, L.R.; Ríos-Gutiérrez, M.; Acharjee, N. A Molecular Electron Density Theory Study of the Lewis Acid Catalyzed [3+2] Cycloaddition Reactions of Nitrones with Nucleophilic Ethylenes. Eur. J. Org. Chem. 2022, 2022, e202101417. [Google Scholar] [CrossRef]
  66. Domingo, L.R.; Aurell, M.J.; Pérez, P.; Contreras, R. Quantitative Characterization of the Global Electrophilicity Power of Common Diene/Dienophile Pairs in Diels–Alder Reactions. Tetrahedron 2002, 58, 4417–4423. [Google Scholar] [CrossRef]
  67. Jaramillo, P.; Domingo, L.R.; Chamorro, E.; Pérez, P. A Further Exploration of a Nucleophilicity Index Based on the Gas-Phase Ionization Potentials. J. Mol. Struct. THEOCHEM 2008, 865, 68–72. [Google Scholar] [CrossRef]
  68. Domingo, L.R. A New C–C Bond Formation Model Based on the Quantum Chemical Topology of Electron Density. RSC Adv. 2014, 4, 32415–32428. [Google Scholar] [CrossRef]
  69. Bahsis, L.; Hrimla, M.; Ben El Ayouchia, H.; Anane, H.; Julve, M.; Stiriba, S.-E. 2-Aminobenzothiazole-Containing Copper(II) Complex as Catalyst in Click Chemistry: An Experimental and Theoretical Study. Catalysts 2020, 10, 776. [Google Scholar] [CrossRef]
  70. Domingo, L.R.; Ríos-Gutiérrez, M.; Aurell, M.J. Unveiling the Regioselectivity in Electrophilic Aromatic Substitution Reactions of Deactivated Benzenes through Molecular Electron Density Theory. New J. Chem. 2021, 45, 13626–13638. [Google Scholar] [CrossRef]
Reactions 05 00056 g001
Figure 1. Bioactive compounds bearing pyrazole nucleus.
Figure 1. Bioactive compounds bearing pyrazole nucleus.
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Scheme 1. Synthesis of tetrasubstituted pyrazoles.
Scheme 1. Synthesis of tetrasubstituted pyrazoles.
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Scheme 2. A 1,3-dipolar cycloaddition of nitrilimines with thioaurones.
Scheme 2. A 1,3-dipolar cycloaddition of nitrilimines with thioaurones.
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Figure 2. The four possible models for different TAC structures.
Figure 2. The four possible models for different TAC structures.
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Figure 3. ELF basin isosurface and attractor positions of nitrilimine (1a) and thioaurone (2a) at B3LYP/6-311G(d,p) level (values in average number of electrons, e).
Figure 3. ELF basin isosurface and attractor positions of nitrilimine (1a) and thioaurone (2a) at B3LYP/6-311G(d,p) level (values in average number of electrons, e).
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Figure 4. ELF-based Lewis-like structures of nitrilimine (1a) and thioaurone (2a).
Figure 4. ELF-based Lewis-like structures of nitrilimine (1a) and thioaurone (2a).
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Figure 5. The local nucleophilicity Nk (in blue color) and local electrophilicity ωk (in red color) of both reagents were calculated using the Parr function (values are in eV).
Figure 5. The local nucleophilicity Nk (in blue color) and local electrophilicity ωk (in red color) of both reagents were calculated using the Parr function (values are in eV).
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Scheme 3. Energy profiles for the cycloaddition reaction between nitrilimine 1a and thioaurone 2a (all values are reported in Kcal/mol).
Scheme 3. Energy profiles for the cycloaddition reaction between nitrilimine 1a and thioaurone 2a (all values are reported in Kcal/mol).
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Figure 6. Three-dimensional geometries of the TSs structures involved in the cycloaddition reaction between 1a and 2a.
Figure 6. Three-dimensional geometries of the TSs structures involved in the cycloaddition reaction between 1a and 2a.
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Scheme 4. ELF-based Lewis structures of the intermediates involved in the 1,3-DC reaction between 1a and 2a.
Scheme 4. ELF-based Lewis structures of the intermediates involved in the 1,3-DC reaction between 1a and 2a.
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Table 1. Global electronic proprieties and reactivity indexes, values were reported in eV.
Table 1. Global electronic proprieties and reactivity indexes, values were reported in eV.
HOMO LUMOµηωN
Nitrilimine (1a)−5.35−1.69−3.533.661.703.76
Thioaurone (2a)−5.97−2.60−4.293.372.733.14
Table 2. ELF valence basin populations of the intermediates involved in the 1,3-DC reaction of 1a with 2a [values in the average number of electrons (e)].
Table 2. ELF valence basin populations of the intermediates involved in the 1,3-DC reaction of 1a with 2a [values in the average number of electrons (e)].
StructuresIIITSAIII3aa
V(C1, N2)2.541.003.053.203.03
V′(C1, N2)2.492.23---
V(C1)0.991.26---
V(N2)-1.802.052.282.28
V(N3)3.193.032.932.872.82
V(C4) 0.89
V(N2, N3)2.062.032.031.971.44
V(C4, C5)3.273.172.692.291.89
V′(C4, C5)-----
V(C1, C5)--1.721.792.04
V(N3, C4)----1.69
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Bakhouch, M.; Es-Sounni, B.; Ouaddi, A.; Oudghiri, K.; Chalkha, M.; Bahsis, L.; Benali, T.; Bourass, M.; Fdil, R.; Akhazzane, M.; et al. Highly Regioselective 1,3-Dipolar Cycloaddition of Nitrilimines and Thioaurones Towards Spiro-2-Pyrazolines: Synthesis, Characterization, and Mechanistic Study. Reactions 2024, 5, 1066-1079. https://doi.org/10.3390/reactions5040056

AMA Style

Bakhouch M, Es-Sounni B, Ouaddi A, Oudghiri K, Chalkha M, Bahsis L, Benali T, Bourass M, Fdil R, Akhazzane M, et al. Highly Regioselective 1,3-Dipolar Cycloaddition of Nitrilimines and Thioaurones Towards Spiro-2-Pyrazolines: Synthesis, Characterization, and Mechanistic Study. Reactions. 2024; 5(4):1066-1079. https://doi.org/10.3390/reactions5040056

Chicago/Turabian Style

Bakhouch, Mohamed, Bouchra Es-Sounni, Ayoub Ouaddi, Khaoula Oudghiri, Mohammed Chalkha, Lahoucine Bahsis, Taoufiq Benali, Mohamed Bourass, Rabiaa Fdil, Mohamed Akhazzane, and et al. 2024. "Highly Regioselective 1,3-Dipolar Cycloaddition of Nitrilimines and Thioaurones Towards Spiro-2-Pyrazolines: Synthesis, Characterization, and Mechanistic Study" Reactions 5, no. 4: 1066-1079. https://doi.org/10.3390/reactions5040056

APA Style

Bakhouch, M., Es-Sounni, B., Ouaddi, A., Oudghiri, K., Chalkha, M., Bahsis, L., Benali, T., Bourass, M., Fdil, R., Akhazzane, M., & El Yazidi, M. (2024). Highly Regioselective 1,3-Dipolar Cycloaddition of Nitrilimines and Thioaurones Towards Spiro-2-Pyrazolines: Synthesis, Characterization, and Mechanistic Study. Reactions, 5(4), 1066-1079. https://doi.org/10.3390/reactions5040056

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