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Article

Fluorinated and Non-Fluorinated 1,4-Diarylpyrazoles via MnO2-Mediated Mechanochemical Deacylative Oxidation of 5-Acylpyrazolines †

by
Greta Utecht-Jarzyńska
1,
Anna Kowalczyk
1,2 and
Marcin Jasiński
1,*
1
Department of Organic and Applied Chemistry, Faculty of Chemistry, University of Lodz, Tamka 12, 91403 Lodz, Poland
2
Doctoral School of Exact and Natural Sciences, University of Lodz, Banacha 12/16, 90237 Lodz, Poland
*
Author to whom correspondence should be addressed.
†
Dedicated to Professor Stanisław Leśniak (University of Lodz) on the occasion of his 70th birthday.
Molecules 2022, 27(23), 8446; https://doi.org/10.3390/molecules27238446
Submission received: 4 November 2022 / Revised: 25 November 2022 / Accepted: 29 November 2022 / Published: 2 December 2022
(This article belongs to the Special Issue Recent Advances in the Synthesis, Functionalization and Applications of Pyrazole-Type Compounds II)
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Versions Notes

Abstract

:
A solvent-free two-step synthesis of polyfunctionalized pyrazoles under ball-milling mechanochemical conditions was developed. The protocol comprises (3 + 2)-cycloaddition of in situ generated nitrile imines and chalcones, followed by oxidation of the initially formed 5-acylpyrazolines with activated MnO2. The second step proceeds via an exclusive deacylative pathway, to give a series of 1,4-diarylpyrazoles functionalized with a fluorinated (CF3) or non-fluorinated (Ph, COOEt, Ac) substituent at C(3) of the heterocyclic ring. In contrast, MnO2-mediated oxidation of a model isomeric 4-acylpyrazoline proceeded with low chemoselectivity, leading to fully substituted pyrazole as a major product formed via dehydrogenative aromatization. The presented approach extends the scope of the known methods carried out in organic solvents and enables the preparation of polyfunctionalized pyrazoles, which are of general interest in medicine and material sciences.

Graphical Abstract

1. Introduction

Due to the discovery of a number of practical applications, there is increasing interest in the chemistry of pyrazole-based compounds, and fluorinated analogues are of special significance in medicine, crop protection, as well as material sciences [1,2,3,4]. The title heterocycle constitutes a key structural element of pharmaceuticals and agrochemicals; they exhibit a variety of biological activities such as being anti-inflammatory (e.g., Celecoxib, Lonazolac), antibacterial, anticancer (e.g., Crizotinib), anti-obesity (e.g., Rimonabant), antidepressant (e.g., Fezolamine), antiviral (e.g., Lenacapavir), and antifungal (e.g., Penthiopyrad), and have been widely applied as pesticides (Figure 1) [5,6,7,8,9,10,11,12,13]. In addition, some pyrazoles have been successfully applied in polymer chemistry, as well as for the preparation of advanced liquid crystalline materials [14,15]. Furthermore, polyfunctionalized pyrazoles can efficiently act as ligands in transition metal-catalyzed reactions [1,2,16]. Taking into account the general significance of this class of N-heterocycles, the development of new synthetic protocols to access pyrazoles with the desired substitution patterns is of great interest.
Out of the various synthetic methodologies for the preparation of pyrazole derivatives available thus far, condensation of 1,3-dielectrophilic agents (typically 1,3-diketones or their synthetic equivalents) with hydrazines is considered the most versatile and commonly applied strategy [1,2,4,5]. However, this classical method often suffers from regioselectivity issues and leads to isomeric pyrazoles, along with other by-products, which require tedious separation, e.g., using chromatography techniques. Hence, (3 + 2)-cycloaddition processes are an attractive alternative and enable straightforward access to the pyrazole skeleton through simultaneous formation of new carbon–carbon and carbon–nitrogen bonds. In this context, diazoalkanes, and particularly nitrile imines, have been recognized as readily available and powerful 1,3-dipoles for the construction of the pyrazole ring [1,2,17].
On the other hand, the negative impacts on the environment and public health caused by the large amount of waste solvents produced during classical organic synthesis have to be taken into account. Recently, there has been a rapid development of green and sustainable synthetic protocols based on mechanochemical approaches, in which the reaction is activated by the absorption of mechanical energy originating from collisions of milling balls [18,19,20,21]. More importantly, these reactions can be performed either without any solvent or require only small amounts of so-called “liquid assisted grinding solvent” (LAGs), and in many instances the chemo- and regio-selectivity switch, leading to rather unexpected products being observed upon mechanochemical activation. Several interesting applications of mechanochemistry in the synthesis of pharmaceutically-relevant N-containing compounds, such as Dantrolene (muscle relaxant), Tolbutamide (antidiabetic), and Axitinib (anticancer), have been reported [22,23,24]. Furthermore, the presented technique has been successfully applied for preparation of pyrazoles, mainly via condensation reactions starting with 1,3-dicarbonyls [25,26,27,28,29,30], chalcones [31], or enaminones [32], and appropriate hydrazine derivatives. Notably, to the best of our knowledge, no mechanochemical nitrile imine (3 + 2)-cycloadditions leading to pyrazoles have been reported.
In a series of recent works, we and other groups have demonstrated fluorinated nitrile imines of type 1 and C=C or C≡C dipolarophiles as superior reaction partners for the efficient preparation of fluoroalkylated pyrazole and pyrazoline derivatives. For example, electron-rich enamines [33], vinyl ethers [34], alkoxyallenes [35], and benzynes [36], as well as electron-deficient nitro- [37] and cyanoalkenes [38], isoxazolidinediones [39], quinones [40], and ynone derivatives [41] have served as dipolarophilic agents. Exemplary reactions leading to polysubstituted pyrazoles 2–4 and bicyclic analogues 5 (indazoles) are depicted in Scheme 1a. More recently, we disclosed a general two-step protocol for two types of multi-substituted 3-trifluoromethylpyrazoles comprising (3 + 2)-cycloaddition of in situ generated nitrile imines 1 with chalcones, followed by MnO2-mediated aromatization of the first 5-acylpyrazolines 6 formed [42]. Remarkably, depending on the solvent used, the oxidation step preferentially afforded fully substituted pyrazoles 7 (in polar solvents such as DMF or DMSO) or proceeded via a deacylative pathway (in non-polar solvents, e.g., in hexane), leading to 1,3,4-trisubstituted pyrazoles 8 as major products (Scheme 1b). Taking into account the well-documented significance of both fluorinated and non-fluorinated pyrazoles in medicine and material sciences, the solvent-free mechanochemical protocols of the above (3 + 2)-cycloaddition reaction and subsequent oxidation step should be examined. Furthermore, the scope of the studied processes, towards non-fluorinated analogues, should also be checked. Here, we report our recent results on a two-step synthesis of 1,4-diarylpyrazoles functionalized with CF3, COOEt, Ac, or Ph groups at C(3) of the heterocyclic ring, under solvent-free ball-milling mechanochemical conditions.

2. Results and Discussion

The required CF3-nitrile imines of type 1 are readily available propargyl-type 1,3-dipoles, which can be generated in situ via base-induced dehydrohalogenation of the respective hydrazonoyl halides (or pseudohalides) [17,43]. A series of key precursors, namely hydrazonoyl bromides 9, were prepared according to the general literature protocols, starting with commercially available substrates, i.e., fluoral hydrate and arylhydrazines [43,44,45,46]. According to our previous observations, the reversible generation of trifluoroacetonitrile imines 1 from the corresponding bromide 9 proceeds smoothly upon treatment with excess Et3N, at room temperature, in anhydrous THF as the solvent of choice. For this reason, initial mechanochemical experiments (steel balls, ø 7 mm; 25 Hz) were carried out using the known C-trifluoromethyl-N-phenyl nitrile imine (1a) and chalcone (10a) selected as model substrates, in the presence of Et3N (Scheme 2). As evidenced by TLC monitoring, a rapid (3 + 2)-cycloaddition reaction was observed, and after 1 h the expected 3-trifluoromethylpyrazoline 6a was identified as a major component of the crude reaction mixture, along with small amounts of regioisomeric derivative 6′a (in ca. 7:1 ratio, respectively), however, in moderate yield (56% conversion estimated based on 1H NMR spectrum of crude mixture), as unconsumed chalcone 10a accompanied by unidentified decomposition products of bromide 9a were also detected. Then, the influence of a series of inorganic bases on the reaction course was briefly checked (Table 1). Whereas application of K2CO3 as a base enhanced the conversion significantly (82%), further optimization with respect to the amount of nitrile imine precursor 9a (1.2 equiv.) and with the volume of the vessel used (5 mL) provided the (3 + 2)-cycloadducts in an excellent 93% yield. Subsequent separation by column chromatography provided spectroscopically pure samples of two pyrazolines, 6a (75%) and 6′a (13%). The relative orientation of substituents along the C(4)-C(5) bond in 6a and 6′a was established based on the 1H NMR spectra and by comparison with the literature data on other trans-configured 5-acylpyrazolines [42,47]. For example, in the case of compound 6a, the diagnostic protons appeared as doublet of quartets (JH-H = 5.6 Hz, 4JH-F ≈ 0.9 Hz) at δ 4.37 (4-H) and as doublet (JH-H = 5.6 Hz) at δ 5.76 (5-H), thereby confirming the fully diastereoselective addition of 1,3-dipole 1a onto the C=C bond of the conjugated system of 10a. The structure of minor isomer 6′a was elucidated on the basis of 1H and 13C NMR supplemented with 2D NMR measurements (HMQC, HMBC). For example, in the 1H NMR spectrum of 6′a, along with the characteristic set of signals attributed to phenyl groups, two additional absorptions, i.e., broadened doublet (J = 7.3 Hz) located at δ 5.04 (4-H) and doublet (JH-H = 7.3 Hz) at δ 5.65 (5-H) nicely matched the proposed structure of 6′a. Furthermore, in the 13C NMR spectrum of 6′a, two diagnostic quartets found at δ 120.9 (1JC-F = 269.8 Hz) and δ 133.5 (2JC-F = 38.0 Hz), attributed to the CF3 group and C-3 atom, respectively, as well as a low intensity absorption (s) at δ 194.5 attributed to the C=O group, were found.
It should be noted that the reaction of 9a with 10a carried out under classical conditions, i.e., in THF solution at room temperature, leads to pyrazoline 6a (79%) exclusively, although after a rather long reaction time (4 days) [42]. In contrast, the mechanochemical activation of the studied (3 + 2)-cycloaddition provided the desired material 6a in a comparable yield (75%) after a remarkably shorter reaction time of 3 h, but the competitive formation of small amounts of isomeric product 6′a was observed.
With the optimized conditions in hand, we next turned our attention to the scope and limitations of the developed mechanochemical 1,3-dipolar cycloaddition. A series of nitrile imine precursors of type 9, bearing either electron-donating (9b–9d) or electron-withdrawing (9e, 9g, and 9h) groups X located at para position of the phenyl ring, as well as disubstituted derivative 9f (2,4-Cl2), were examined in (3 + 2)-cycloadditions with a model chalcone (10a) (Scheme 3). As shown in Table 2, higher chemical yields were observed for reactions carried out with nitrile imine precursors 9b–9d, i.e., bearing groups increasing the electron density at the negatively charged N-termini of the in situ generated dipole 1, and the expected products 6b–6d (58–71%) were obtained after 3 h of only ball-milling. In contrast, in experiments performed with bromides functionalized with a strong EWG group (NO2, 9g), and also with a PhCOO moiety (9h), complete consumption of the starting materials was observed after remarkably longer time (up to 24 h). In the latter cases, the formation of complex reaction mixtures also made the chromatographic isolation of the desired 5-benzoylpyrazolines 6 more difficult. Interestingly, despite the above differences, no remarkable impact of the electronic character of groups X on the regioselectivity of the studied (3 + 2)-cycloaddition could be observed. In all the cases, a mixture of isomeric products 6a–6h and 6′a–6′h in comparable ratios of ca. 4:1, respectively, were formed.
Next, to check the scope of chalcones and to test the functional group tolerance of mechanochemical (3 + 2)-cycloaddition, a series of aryl- and ferrocenyl-functionalized enones 10b–10o were also added to the study and examined in reaction with N-(p-tolyl) nitrile imine 1b, selected as a handful 1H NMR-diagnostic representative (Scheme 4). In general, the expected 5-acylpyrazolines 6i–6v were obtained in moderate to high yields, although longer reaction times were required to lead the reaction to completion in most cases (Table 3). Thus, apart from halogens (Cl, Br) and haloalkyl units (additional CF3 group at phenyl ring), alkylamino and alkoxy substituents, as well as a ferrocenyl moiety, could be introduced.
Similarly to the results collected for series 6/6′a–6/6′h (Scheme 2 and Scheme 3, Table 2), (3 + 2)-cycloadditions of 1b with selected chalcones 10b–10o proceeded in a comparable regioselectivity of ca. 4:1 in favor of 5-acylpyrazolines 6. Again, only trans-configured products could be detected in the mother liquors. Interestingly, in the case of 3,4-methylenedioxy-functionalized chalcone (10f) and 3,4-dimethoxy analogue (10e), exceptionally high selectivity (ca. 9:1) or exclusive formation of target 5-acylpyrazolines 6m and 6l, respectively, was observed. On the other hand, the reaction of 1b with another electron-rich chalcone, namely 4-(dimethylamino)chalcone (10g), provided only the expected (3 + 2)-cycloadducts 6n and 6′n as a ca. 2:1 mixture. Possibly, the observed decrease of selectivity resulted from the presence of the basic Me2N group in 10g, which can compete with K2CO3 in dehydrohalogenation of 9b, thereby changing the electronic properties of chalcone 10g, due to protonation. The observed moderate yield in cycloadditions of 1b with chalcones 10c and 10m, leading to pyrazolines 6j (38%) and 6t (39%), also deserves a brief comment. Seemingly, the presence of the redox-active Fc group alters the reaction outcome and leads to complex mixtures, irrespective of the substitution pattern in chalcone.
Prompted by the results disclosed in our recent work on the solvent-dependent oxidation of 5-benzoylpyrazolines [42], a series of 3-trifluoromethylated cycloadducts of type 6 were oxidized with an excess of activated MnO2 under mechanochemical conditions. In a typical experiment, pyrazoline 6a (1.0 mmol) was reacted with oxidant (activated MnO2, ca. 85%, <10 μm, 40 equiv.) using zirconium oxide ball-milling equipment (ball, ø 10 mm; jar, 10 mL), at 25 Hz. After the reaction was complete (1.5 h), the resulting material was washed with AcOEt and filtered through a short silica gel pad, to give 1,5-diphenyl-3-trifluoromethylpyrazole (8a), isolated as a sole product in excellent purity and a yield of 97% (Scheme 5). The observed result for MnO2-mediated mechanochemical deacylative oxidation nicely correspond to the recently reported aromatizative debenzoylation of 6a carried out in non-polar solvents (i.e., hexane solutions). However, the latter protocol provided the final product 8a after 2 days, by heating the reactants in organic medium at 60 °C [42].
Unfortunately, an attempted one-pot two-step synthesis of pyrazole 8a was in vain. In the mentioned experiment, hydrazonoyl bromide 9a and chalcone 10a were mechanochemically reacted under the developed conditions (in the presence of K2CO3), followed by treatment of the resulting crude reaction mixture with excess activated MnO2. To our surprise, none of the expected pyrazole 8a was detected in the mixture, thus indicating the necessity of (at least partial) pre-purification of the intermediate 5-benzoylpyrazoline 6a. Indeed, simple filtration of crude 6a through a short silica gel pad enabled fast synthesis of desired material 8a, which was isolated in a high 66% overall yield (for two steps).
In continuation, a series of pyrazolines 6b–6s was examined in reaction with MnO2 under mechanochemical activation to afford the expected 1,4-diaryl-3-trifluoromethylpyrazoles 8b–8s identified as the exclusive aromatization products, which were generally isolated in excellent yields. Only in the case of 4-benzoyloxy derivative (6h) and ferrocenyl-functionalized analogue (6j), either partial decomposition of the starting material or competitive dehydrogenative oxidation, leading to a fully substituted analogue (7j), respectively, was observed, and moderate amounts of the final pyrazoles 8h (53%) and 8j (50%) were isolated. Surprisingly, the attempted oxidation of pyrazoline 6n bearing Me2N group resulted in complete decomposition of the starting material under the applied conditions. In order to check the reaction outcome in mechanochemical oxidation of isomeric 4-acyl-pyrazolines of type 6′, available as minor products in (3 + 2)-cycloaddition of nitrile imines 1 and chalcones 10, a model trans-4-benzoyl-5-phenyl-1-p-tolyl-3-trifluoromethylpyrazoline (6′b) was also examined under analogous reaction conditions. As shown in Scheme 6, treatment of the starting material 6′b with excess MnO2 provided, after 1.5 h of milling, a mixture of two pyrazole-based products in ca. 2:3 ratio, and they were identified as 5-phenyl-1-p-tolyl-3-trfiluoromethylpyrazole (11b, 38%) and its 4-benzoylated analogue 12b (56%). This result indicates that, in contrast to 5-acylpyrazoline 6b, ball-milling oxidation of its structural isomer 4-acylpyrazoline 6′b proceeds in low chemoselectivity and leads to dehydrogenative oxidation of product 12b as a major component of the mixture.
Finally, to further check the scope, a series of non-fluorinated pyrazolines 13a–13g were prepared and examined in a mechanochemical oxidation reaction with activated MnO2. Following the general protocol, five nitrile imine precursors 14a–14e bearing either phenyl group or selected electron-withdrawing substituents (COOEt, Ac) located at the C-termini were reacted with a set of representative chalcones: 10a (X = H), 10d (OMe), 10h (Cl), and 10k (X = NO2) (Scheme 7). The first formed 5-acylpyrazoline derivatives 13 were pre-purified by filtration through a short silica gel pad and subsequently reacted with MnO2 to provide the expected 1,3,4-trisubstituted pyrazoles 15a–15g in an acceptable overall yield of 32–56% (for two steps). However, in the case of the highly electron-deficient nitrile imine 1e functionalized with O2NC6H4- and Ac groups, the (3 + 2)-cycloaddition step with chalcone 10a afforded a complex mixture in which trace amounts of the expected pyrazoline 13h (<5%) were detected. The presented results indicate that, along with trifluoromethylated nitrile imines, analogues bearing aryl, ester or acyl groups can also be applied in the developed two-step synthesis of 1,3,4-trisubstituted pyrazoles.
It should be pointed out that all the presented deacylative oxidations of benzoyl-pyrazolines were performed using activated MnO2 (≈85% purity, <10 μm, Sigma Aldrich, St. Louis, MO, USA), which was used as received. In order to gain a greater insight about the studied transformation, non-activated manganese dioxide (Reagent Plus ®, >99%, Sigma Aldrich) was also tested, but in this case no deacylative aromatization could be observed when using 5-benzoylpyrazoline 6b as a model compound. To test if hydroxyl radicals were involved in deacylative aromatization of 6b, the latter experiment was repeated in the presence of trace amounts of water, but the reaction was not triggered. Finally, treatment of the resulting insoluble material formed in deacylative oxidation of 6b with aqueous methanol released a colorless byproduct identified as benzoic acid. Based on these observations, the mechanism of the studied reaction is tentatively proposed. As depicted in Scheme 8, oxidation of 6b proceeds preferentially at C(4), leading to fairly stable benzyl-type radical A. Then, the acyl group is transferred [48] from A onto the activated surface of the heterogeneous oxidant to give the aromatized product 8b [49]. On the other hand, the presence of the benzoyl group at C(4) in isomeric pyrazoline 6′b enhances the acidity of this position; and thus, the oxidation may possibly be initiated either at C(4) or at C(5), leading to a mixture of products formed via competitive dehydrogenation vs. deacylative aromatization processes.

3. Materials and Methods

3.1. Chemical Synthesis General Methods

Experimental procedures: The ball-milling apparatus used was a Retsch MM 400 mixer mill (Retsch GmbH, Haan, Germany). Mechanochemical (3 + 2)-cycloadditions were performed in 5 mL stainless steel jars, with three stainless steel balls (7 mm diameter); oxidation reactions were conducted in 10 mL zirconium oxide jars, with one zirconium oxide ball (10 mm diameter). Solvents (hexane, CH2Cl2, AcOEt) were purchased and used as received. Products were purified by filtration through a short silica gel plug or by standard column chromatography (CC) on silica gel (230–400 mesh; Merck, Kenilworth, NJ, USA). The NMR spectra were taken on a Bruker AVIII instrument (1H at 600 MHz, 13C at 151 MHz, and 19F at 565 MHz) (Bruker BioSpin AG, Fällanden, Switzerland). Chemical shifts are reported relative to solvent residual peaks; for CDCl3: 1H NMR: δ = 7.26, 13C NMR: δ = 77.16, or to CFCl3 (19F NMR: δ = 0.00) used as an external standard. Multiplicity of the signals in 13C NMR spectra were deduced based on supplementary 2D measurements (HMQC, HMBC). The IR spectra were measured with an Agilent Cary 630 FTIR spectrometer (Agilent Technologies, Santa Clara, CA, USA), in neat. MS (ESI) were performed with a Varian 500-MS LC Ion Trap (Varian, Inc., Walnut Creek, CA, USA), while high resolution MS (ESI-TOF) measurements were taken with a Waters Synapt G2-Si mass spectrometer (Waters Corporation, Milford, MA, USA). Elemental analyses were performed with a Vario EL III (Elementar Analysensysteme GmbH, Langenselbold, Germany) instrument. Melting points were determined in capillaries with a MEL-TEMP apparatus (Laboratory Devices, Holliston, MA, USA) and are uncorrected. 1H, 13C, and 19F NMR spectra of all new compounds can be found at Supplementary Materials file.
Starting materials: The CF3-nitrile imine precursors of type 9 were prepared by bromination of the corresponding trifluoroacetaldehyde arylhydrazones with NBS, according to the general protocol [43]. The required fluoral hydrazones were synthesized following the general literature procedure by condensation of aqueous fluoral hydrate (~75% in H2O) with commercial arylhydrazines [46]. Non-fluorinated hydrazonoyl chlorides 14a–14e were prepared as previously reported [44,45]. Chalcones 10 were purchased or prepared via classical Claisen–Schmidt condensation, starting with appropriate aldehydes and methyl ketones, in ethanol. Activated MnO2 (ca. 85%, <10 μm, Sigma-Aldrich, product no. 217646-100G), as well as the other commercially available solvents and starting materials, were purchased and used as received.

3.1.1. General Procedure for Mechanochemical Synthesis of Pyrazolines 6, 6′, and 13

Hydrazonoyl halide 9 or 14 (1.2 mmol), chalcone 10 (1.0 mmol), and solid K2CO3 (1.3 mmol, 179 mg) were placed in a 5 mL stainless steel grinding jar with three stainless steel balls (7 mm diameter). The jar was closed and ball-milled at 25 Hz until the starting chalcone was fully consumed. Then, CH2Cl2 (10 mL) was added, the precipitate was filtered off, washed with CH2Cl2 (2 × 10 mL), and the solvent was removed under vacuum. The crude product of type 6 or 13 was purified by standard column chromatography (CC) or pre-purified by flash column chromatography (FCC) on silica. The structures of known pyrazolines 6c–6k, 6o, 6q, 6r, 6t–6v were confirmed based on 1H NMR spectra supplemented by ESI-MS measurements and by comparison with original samples [42]; the byproducts 6′c–6′v were not isolated. In the case of non-fluorinated analogues, crude pyrazolines 13a,13d–13g were pre-purified by FCC and used for the next step, without further purification.
trans-5-Benzoyl-1,4-diphenyl-3-trifluoromethyl-4,5-dihydro-1H-pyrazole (6a) [50]: light yellow solid, 296 mg (75%), mp 159–161 °C. 1H NMR (600 MHz, CDCl3) δ 4.37 (dq, 4JH-F ≈ 0.9 Hz, JH-H = 5.6 Hz, 1H, 4-H), 5.76 (d, JH-H = 5.6 Hz, 1H, 5-H), 6.94–7.06, 7.19–7.29, 7.39–7.44, 7.48–7.52, 7.65–7.68, 7.87–7.89 (6m, 3H, 4H, 3H, 2H, 1H, 2H). 13C NMR (151 MHz, CDCl3) δ 55.6, 74.3, 113.8, 120.9 (q, 1JC-F = 270.6 Hz, CF3), 121.6, 127.7, 128.9, 129.2, 129.3, 129.5, 129.7, 133.1, 134.7, 137.5, 138.1 (q, 2JC-F = 37.0 Hz, C-3), 142.7, 192.1. 19F NMR (565 MHz, CDCl3) δ −63.0 (sbr, CF3). ESI-MS (m/z) 417.2 (100, [M + Na]+).
trans-4-Benzoyl-1,5-diphenyl-3-trifluoromethyl-4,5-dihydro-1H-pyrazole (6′a): obtained as a minor product in the reaction of 9a with 10a; yellow solid, 51 mg (13%), mp 125–126 °C.
1H NMR (600 MHz, CDCl3) δ 5.04 (dbr, JH-H ≈ 7.3 Hz, 1H, 4-H), 5.65 (d, JH-H = 7.3 Hz, 1H, 5-H), 6.88–6.91, 7.03–7.06, 7.17–7.20, 7.23–7.25, 7.33–7.40, 7.48–7.51, 7.63–7.66, 7.88–7.90 (8m, 1H, 2H, 2H, 2H, 3H, 2H, 1H, 2H). 13C NMR (151 MHz, CDCl3) δ 61.2, 71.0, 114.8, 120.9 (q, 1JC-F = 269.8 Hz, CF3), 121.7, 126.0, 128.9, 129.14, 129.15, 129.16, 129.8, 133.5 (q, 2JC-F = 38.0 Hz, C-3), 134.5, 135.5, 139.6, 142.6, 194.5. 19F NMR (565 MHz, CDCl3) δ −63.1 (s, CF3). IR (neat) v 1677, 1595, 1577, 1301, 1264, 1208, 1148, 1118, 1066 cm−1. ESI-MS (m/z) 417.1 (31, [M + Na]+), 395.2 (100, [M + H]+).
trans-5-Benzoyl-1-(p-tolyl)-4-phenyl-3-trifluoromethyl-4,5-dihydro-1H-pyrazole (6b) [51]: light yellow solid, 286 mg (70%), mp 145–147 °C. 1H NMR (600 MHz, CDCl3) δ 2.30 (s, 3H, Me), 4.38 (dq, 4JH-F ≈ 1.0 Hz, JH-H ≈ 5.7 Hz, 1H, 4-H), 5.78 (dbr, J ≈ 5.7 Hz, 1H, 5-H), 6.97, 7.09 (2d, J = 8.6 Hz, 2H each), 7.21–7.25, 7.40–7.52, 7.66–7.69, 7.88–7.91 (4m, 2H, 5H, 1H, 2H). 13C NMR (151 MHz, CDCl3) δ 20.7, 55.6, 74.6, 113.9, 121.0 (q, 1JC-F = 270.3 Hz, CF3), 127.5, 129.0, 129.1, 129.3, 129.7, 130.0, 130.9, 133.2, 134.6, 137.4 (q, 2JC-F = 36.8 Hz, C-3), 137.6, 140.5, 192.3. 19F NMR (565 MHz, CDCl3) δ −63.1 (s, CF3). ESI-MS (m/z) 431.2 (100, [M + Na]+).
trans-4-Benzoyl-1-(p-tolyl)-5-phenyl-3-trifluoromethyl-4,5-dihydro-1H-pyrazole (6′b): obtained as a minor product in the reaction of 9b with 10a; thick yellow oil, 53 mg (13%). 1 H NMR (600 MHz, CDCl3) δ 2.23 (s, 3H, Me), 5.04 (dqbr, 4JH-F ≈ 1.6 Hz, JH-H ≈ 7.5 Hz, 1H, 4-H), 5.64 (d, JH-H ≈ 7.5 Hz, 1H, 5-H), 6.93–7.00, 7.22–7.25, 7.32–7.39, 7.47–7.50, 7.63–7.66, 7.87–7.90 (6m, 4H, 2H, 3H, 2H, 1H, 2H). 13C NMR (151 MHz, CDCl3) δ 20.7, 61.1, 71.2, 114.8, 121.0 (q, 1JC-F = 269.5 Hz, CF3), 126.1, 128.8, 129.12, 129.14, 129.7, 129.8, 131.2, 132.8 (q, 2JC-F = 37.9 Hz, C-3), 134.5, 135.4, 139.7, 140.3, 194.6. 19F NMR (565 MHz, CDCl3) δ −63.0 (s, CF3). IR (neat) v 1752, 1662, 1495, 1446, 1260, 1219, 1163, 1133 cm−1. ESI-MS (m/z) 431.4 (100, [M + Na]+), 409.5 (39, [M + H]+). Anal. Calcd for C24H19F3N2O (408.1): C 70.58, H 4.69, N 6.86; found: C 70.49, H 4.69, N 6.89.
trans-5-Benzoyl-4-(3′,4′-dimethoxyphenyl)-1-(p-tolyl)-3-trifluoromethyl-4,5-dihydro-1H-pyrazole (6l): light yellow solid, 347 mg (74%), mp 122–123 °C. 1H NMR (600 MHz, CDCl3) δ 2.27 (s, 3H, Me), 3.81, 3.91 (2s, 3H each, 2OMe), 4.33 (dbr, J ≈ 5.9 Hz, 1H, 4-H), 5.73 (d, J = 5.9 Hz, 1H, 5-H), 6.65 (d, J = 2.1 Hz, 1H), 6.76 (dd, J = 2.1, 8.2 Hz, 1H), 6.88 (d, J = 8.2 Hz, 1 H), 6.91–6.93, 7.05–7.08, 7.48–7.51, 7.64–7.68, 7.87–7.90 (5m, 2H, 2H, 2H, 1H, 2H). 13C NMR (151 MHz, CDCl3) δ 20.7, 55.4, 56.1, 56.2, 74.5, 110.4, 111.8, 113.9, 120.2, 121.0 (q, 1JC-F = 270.4 Hz, CF3), 129.3 *, 129.8, 130.0, 131.0, 133.2, 134.6, 137.4 (q, 2JC-F = 36.6 Hz, C-3), 140.5, 149.5, 149.8, 192.4; * higher intensity. 19F NMR (565 MHz, CDCl3) δ −62.2 (s, CF3). IR (neat) v 1695, 1595, 1513, 1450, 1293, 1230, 1118 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C26H24F3N2O3 469.1739, found 469.1743.
trans-5-Benzoyl-4-(3′,4′-methylenedioxyphenyl)-1-(p-tolyl)-3-trifluoromethyl-4,5-dihydro-1H-pyrazole (6m): pale yellow solid, 307 mg (68%), mp 125–126 °C. 1H NMR (600 MHz, CDCl3) δ 2.28 (s, 3H, Me), 4.31 (dbr, J ≈ 5.5 Hz, 1H, 4-H), 5.73 (d, J = 5.5 Hz, 1H, 5-H), 6.01 (AB system, J = 4.8 Hz, 2H, OCH2O), 6.66–6.69 (m, 2H), 6.82 (d, J = 7.8 Hz, 1H), 6.92–6.94, 7.07–7.09, 7.50–7.54, 7.66–7.69, 7.90–7.92 (5m, 2H, 2H, 2H, 1H, 2H). 13C NMR (151 MHz, CDCl3) δ 20.7, 55.3, 74.4, 101.7, 107.6, 109.0, 113.8, 121.0 (q, 1JC-F = 270.3 Hz, CF3), 121.9, 129.2, 129.3, 130.0, 131.0, 131.2, 133.1, 134.6, 137.5 (q, 2JC-F = 36.7 Hz, C-3), 140.4, 148.2, 148.9, 192.2. 19F NMR (565 MHz, CDCl3) δ −62.3 (s, CF3). IR (neat) v 1685, 1595, 1517, 1446, 1245, 1118 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C25H20F3N2O3 453.1426, found 453.1427.
trans-5-Benzoyl-4-(4′-dimethylaminophenyl)-1-(p-tolyl)-3-trifluoromethyl-4,5-dihydro-1H-pyrazole (6n): orange solid, 208 mg (46%), mp 163–165 °C. 1H NMR (600 MHz, CDCl3) δ 2.27 (s, 3H, Me), 2.99 (s, 6H, 2Me), 4.30 (dbr, J ≈ 5.5 Hz, 1H, 4-H), 5.69 (d, J = 5.5 Hz, 1H, 5-H), 6.69–6.72, 6.90–6.92, 7.03–7.07, 7.47–7.51, 7.64–7.66, 7.89–7.91 (6m, 2H, 2H, 4H, 2H, 1H, 2H). 13C NMR (151 MHz, CDCl3) δ 20.7, 40.5, 55.1, 74.7, 112.9, 113.7, 121.1 (q, 1JC-F = 270.5 Hz, CF3), 124.6, 128.5, 129.22, 129.25, 130.0, 130.6, 133.3, 134.4, 138.1 (q, 2JC-F = 36.2 Hz, C-3), 140.7, 150.7, 192.5. 19F NMR (565 MHz, CDCl3) δ −62.3 (s, CF3). IR (neat) v 1696, 1595, 1517, 1297, 1230, 1185, 1118, 1066 cm−1. ESI-MS (m/z) 474.4 (100, [M + Na]+), 452.4 (97, [M + H]+). Anal. Calcd for C26H24F3N3O (451.2): C 69.17, H 5.36, N 9.31; found: C 69.11, H 5.26, N 9.30.
trans-5-Benzoyl-4-(2′-chlorophenyl)-1-(p-tolyl)-3-trifluoromethyl-4,5-dihydro-1H-pyrazole (6p): thick light orange oil, 252 mg (57%). 1H NMR (600 MHz, CDCl3) δ 2.28 (s, 3H, Me), 5.10 (sbr, 1H, 4-H), 5.76 (sbr, 1H, 5-H), 6.93–6.95, 7.06–7.09, 7.25–7.36, 7.43–7.50, 7.64–7.67, 7.84–7.88 (6m, 2H, 2H, 3H, 3H, 1H, 2H). 13C NMR (151 MHz, CDCl3) δ 20.7, 50.9(br), 74.0(br), 113.9, 120.8 (q, 1JC-F = 270.3 Hz, CF3), 128.4(br), 129.1, 129.2 *, 130.0, 130.2, 130.4(br), 131.2, 133.2(br), 136.6, 135.3(br), 136.8 (qbr, 2JC-F ≈ 37.0 Hz, C-3), 140.4, 192.6; *higher intensity. 19F NMR (565 MHz, CDCl3) δ −62.6 (s, CF3). IR (neat) v 1692, 1599, 1517, 1297, 1230, 1118, 1066 cm−1. ESI-MS (m/z) 465.4 (100, [M + Na]+), 443.5 (83, [M + H]+). Anal. Calcd for C24H18F3N2O (442.1): C 65.09, H 4.10, N 6.33; found: C 65.00, H 4.02, N 6.14.
trans-5-Benzoyl-4-(3′-nitrophenyl)-1-(p-tolyl)-3-trifluoromethyl-4,5-dihydro-1H-pyrazole (6s): light yellow solid, 295 mg (65%), mp 170–172 °C. 1H NMR (600 MHz, CDCl3) δ 2.28 (s, 3H, Me), 4.50 (dbr, J ≈ 5.6 Hz, 1H, 4-H), 5.75 (d, J = 5.6 Hz, 1H, 5-H), 6.93–6.95, 7.07–7.09, 7.50–7.54 (3m, 2H, 2H, 2H), 7.55 (dt, J = 1.4, 7.8 Hz, 1H), 7.62–7.65, 7.68–7.71, 7.85–7.87 (3m, 1H, 1H, 2H), 8.07 (pseudo-t, J ≈ 2.0 Hz, 1H), 8.28 (ddd, J = 1.1, 2.2, 8.2 Hz, 1 H). 13C NMR (151 MHz, CDCl3) δ 20.7, 54.8, 74.1, 114.1, 120.8 (q, 1JC-F = 270.2 Hz, CF3), 122.7, 124.1, 129.1, 129.6, 130.1, 131.0, 131.7, 132.9, 133.6, 135.0, 136.1 (q, 2JC-F = 37.3 Hz, C-3), 139.5, 140.0, 149.0, 191.6. 19F NMR (565 MHz, CDCl3) δ −62.2 (s, CF3). IR (neat) v 1689, 1595, 1536, 1353, 1297, 1230, 1152, 1122, 1070 cm−1. ESI-MS (m/z) 476.4 (100, [M + Na]+), 454.4 (50, [M + H]+). Anal. Calcd for C24H18F3N3O3 (453.1): C 63.58, H 4.00, N 9.27; found: C 63.49, H 4.04, N 9.29.
Ethyl trans-5-benzoyl-4-phenyl-1-(p-tolyl)-4,5-dihydro-1H-pyrazole-3-carboxylate (13b): light yellow solid, 234 mg (57%), mp 133–134 °C. 1H NMR (600 MHz, CDCl3) δ 1.20 (t, J = 7.1 Hz, 3H, Et), 2.28 (s, 3H, Me), 4.13 (dq, J = 7.1, 10.9 Hz, 1H, Et), 4.20 (dq, J = 7.1, 10.9 Hz, 1H, Et), 4.46 (d, J = 4.9 Hz, 1H, 4-H), 5.79 (d, J = 4.9 Hz, 1H, 5-H), 7.02–7.09, 7.21–7.23, 7.34–7.40, 7.49–7.52, 7.65–7.67, 7.90–7.92 (6m, 4H, 2H, 3H, 2H, 1H, 2H). 13C NMR (151 MHz, CDCl3) δ 14.2, 20.7, 55.4, 61.2, 74.3, 114.4, 127.5, 128.4, 129.2, 129.3, 129.5, 130.0, 131.4, 133.1, 134.5, 139.4, 139.98, 139.99, 161.8, 192.1. IR (neat) v 1696, 1513, 1279, 1219, 1152, 1100, 1014 cm−1. ESI-MS (m/z) 435.4 (100, [M + Na]+), 413.4 (31, [M + H]+). Anal. Calcd for C26H24N2O3 (412.2): C 75.71, H 5.86, N 6.79; found: C 75.71, H 6.04, N 6.80.
Ethyl trans-5-benzoyl-4-(4′-chlorophenyl)-1-(p-tolyl)-4,5-dihydro-1H-pyrazole-3-carboxylate (13c): yellow solid, 245 mg (55%), mp 157–159 °C. 1H NMR (600 MHz, CDCl3) δ 1.22 (t, J = 7.1 Hz, 3H, Et), 2.27 (s, 3H, Me), 4.14 (dq, J = 7.1, 10.9 Hz, 1H, Et), 4.21 (dq, J = 7.1, 10.9 Hz, 1H, Et), 4.42 (d, J = 5.0 Hz, 1H, 4-H), 5.74 (d, J = 5.0 Hz, 1H, 5-H), 7.00–7.03, 7.07–7.09, 7.14–7.16, 7.34–7.36, 7.49–7.53, 7.66–7.69, 7.87–7.89 (7m, 2H, 2H 2H, 2H, 2H, 1H, 2H). 13C NMR (151 MHz, CDCl3) δ 14.3, 20.8, 54.8, 61.3, 74.1, 114.4, 128.9, 129.1, 129.4, 129.7, 130.0, 131.7, 133.0, 134.4, 134.7, 138.0, 139.5, 139.8, 161.7, 191.8. ESI-MS (m/z) 469.4 (100, [M + Na]+), 447.4 (63, [M + H]+). Anal. Calcd for C26H23ClN2O3 (446.1): C 69.87, H 5.19, N 6.27; found: C 69.72, H 5.04, N 6.01.

3.1.2. General Procedure for Oxidation Reactions with Activated Manganese Dioxide

5-Acylpyrazoline of type 6 or 13 (1.0 mmol) and activated MnO2 (40 mmol, 4.09 g) were placed in a 10 mL zirconium oxide grinding jar with one zirconium oxide ball (10 mm diameter). The jar was closed and subjected to grinding for 1.5 h in a vibratory ball-mill operated at 25Hz. After AcOEt (20 mL) was added, the resulting mixture was filtered through a thin pad of silica gel and the solvent was evaporated to give pyrazole 8 or 15. In the case of 4-benzoylpyrazoline 6′b, the resulting products 11b and 12b were purified using standard column chromatography (SiO2). The structure of known fluorinated pyrazoles, i.e., 8a–8k, 8n, 8q, and 8r were confirmed based on 1H NMR spectra and by comparison with the original samples [42].
4-(3′,4′-Dimethoxyphenyl)-1-(p-tolyl)-3-trifluoromethylpyrazole (8l): colorless solid, 326 mg (90%), mp 129–130 °C. 1H NMR (600 MHz, CDCl3) δ 2.38 (s, 3H, Me), 3.898, 3.901 (2s, 3H each, 2OMe), 6.88–6.91, 6.99–7.03, 7.25–7.27, 7.58–7.60 (4m, 1H, 2H, 2H, 2H), 7.93 (s, 1H, 5-H). 13C NMR (151 MHz, CDCl3) δ 21.0, 55.90, 55.91, 111.3, 112.0, 119.6, 120.9, 121.8 (q, 1JC-F = 269.7 Hz, CF3), 122.9, 123.5(br), 127.3, 130.2, 137.0, 137.8, 139.9 (q, 2JC-F = 36.4 Hz, C-3), 148.9*; *higher intensity. 19F NMR (565 MHz, CDCl3) δ −59.3 (s, CF3). IR (neat) v 1491, 1241, 1163, 1118 cm−1. (–)-ESI-MS (m/z) 361.4 (100, [M–H]–). Anal. Calcd for C19H17F3N2O2 (362.1): C 62.98, H 4.73, N 7.73; found: C 63.00, H 4.69, N 7.44.
4-(3′,4′-Methylenedioxyphenyl)-1-(p-tolyl)-3-trifluoromethylpyrazole (8m): colorless solid, 294 mg (85%), mp 99–100 °C. 1H NMR (600 MHz, CDCl3) δ 2.40 (s, 3H, Me), 6.00 (s, 2H, OCH2O), 6.85–6.87, 6.93–6.95, 7.27–7.29, 7.59–7.61 (4m, 1H, 2H, 2H, 2H), 7.90 (sbr, 1H, 5-H). 13C NMR (151 MHz, CDCl3) δ 21.1, 101.4, 108.5, 109.3, 119.7, 121.7 (q, 1JC-F = 269.8 Hz, CF3), 122.4(br), 123.4(br), 127.5, 130.2, 137.1, 137.9, 140.0 (q, 2JC-F = 36.5 Hz, C-3), 147.6, 147.9. 19F NMR (565 MHz, CDCl3) δ −59.4 (s, CF3). IR (neat) v 1480, 1223, 1167, 1118, 1036 cm−1. ESI-MS (m/z) 369.4 (100, [M + Na]+), 347.4 (76, [M + H]+). Anal. Calcd for C18H13F3N2O2 (346.1): C 62.43, H 3.78, N 8.09; found: C 62.60, H 3.92, N 8.08.
4-(2′-Chlorophenyl)-1-(p-tolyl)-3-trifluoromethylpyrazole (8p): thick light yellow oil, 299 mg (89%). 1H NMR (600 MHz, CDCl3) δ 2.42 (s, 3H, Me), 7.29–7.36, 7.40–7.42, 7.48–7.51, 7.62–7.65 (4m, 4H, 1H, 1H, 2H), 7.99 (s, 1H, 5-H). 13C NMR (151 MHz, CDCl3) δ 21.1, 119.7(br), 119.8, 121.4 (q, 1JC-F = 270.1 Hz, CF3), 126.7, 128.8, 129.5, 129.7, 129.8, 130.3, 132.2(br), 134.1, 137.1, 138.0, 141.3 (q, 2JC-F = 36.6 Hz, C-3). 19F NMR (565 MHz, CDCl3) δ −60.0 (s, CF3). IR (neat) v 1521, 1495, 1290, 1223, 1170, 1116, 1062 cm−1. ESI-MS (m/z) 359.3 (23, [M + Na]+), 337.3 (100, [M + H]+). Anal. Calcd for C17H12ClF3N2 (336.1): C 60.64, H 3.59, N 8.32; found: C 60.51, H 3.39, N 8.47.
4-(3′-Nitrophenyl)-1-(p-tolyl)-3-trifluoromethylpyrazole (8s): colorless solid, 257 mg (74%), mp 147–148 °C. 1H NMR (600 MHz, CDCl3) δ 2.43 (s, 3H, Me), 7.31–7.33, 7.61–7.64, 7.82–7.84 (3m, 2H, 3H, 1H), 8.08 (s, 1H, 5-H), 8.24 (ddd, J = 1.0, 2.3, 8.2 Hz, 1H), 8.34 (pseudo-t, J ≈ 2.0 Hz, 1H). 13C NMR (151 MHz, CDCl3) δ 21.2, 119.9, 121.3(br), 121.5 (q, 1JC-F = 269.8 Hz, CF3), 122.9, 123.6, 128.0, 129.8, 130.4, 132.2, 134.8(br), 136.8, 138.5, 140.2 (q, 2JC-F = 37.1 Hz, C-3), 148.5. 19F NMR (565 MHz, CDCl3) δ −59.4 (s, CF3). IR (neat) v 1521, 1349, 1282, 1226, 1170, 1118, 1074 cm−1. ESI-MS (m/z) 370.3 (100, [M + Na]+), 348.3 (70, [M + H]+). Anal. Calcd for C17H12F3N3O2 (347.1): C 58.79, H 3.48, N 12.10; found: C 58.85, H 3.51, N 12.08.
5-Phenyl-1-(p-tolyl)-3-trifluoromethylpyrazole (11b) [34]: obtained as a minor product in oxidation of 6′b; light yellow solid, 114 mg (38%), mp 74–76 °C. 1H NMR (600 MHz, CDCl3) δ 2.37 (s, 3H, Me), 6.74 (sbr, 1H, 4-H), 7.14–7.24, 7.30–7.36 (2m, 6H, 3H). 13C NMR (151 MHz, CDCl3) δ 21.3, 105.5, 121.5 (q, 1JC-F = 268.8 Hz, CF3), 125.5, 128.8, 128.95, 129.02, 129.5(br), 129.8, 137.0, 138.6, 143.2 (q, 2JC-F = 38.3 Hz, C-3), 144.7. 19F NMR (565 MHz, CDCl3) δ −62.2 (s, CF3). IR (neat) v 1454, 1230, 1129, 1073 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H14F3N2 303.1109, found 303.1104.
4-Benzoyl-5-phenyl-1-(p-tolyl)-3-trifluoromethylpyrazole (12b): colorless solid, 228 mg (56%), mp 139–140 °C. 1H NMR (600 MHz, CDCl3) δ 2.35 (s, 3H, Me), 7.07–7.10, 7.13–7.21, 7.28–7.32, 7.43–7.46, 7.72–7.74 (5m, 2H, 7H, 2H, 1H, 2H). 13C NMR (151 MHz, CDCl3) δ 21.3, 119.8(br), 121.0 (q, 1JC-F = 270.4 Hz, CF3), 125.4, 127.9, 128.4, 128.7, 129.5, 129.8, 129.9, 130.1, 133.5, 136.3, 137.5, 139.0, 141.5 (q, 2JC-F = 37.9 Hz, C-3), 144.4. 19F NMR (565 MHz, CDCl3) δ −60.3 (s, CF3). IR (neat) v 1659, 1484, 1443, 1223, 1156, 1129, 1059 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C24H18F3N2O 407.1371, found 407.1369.
1,3,4-Triphenylpyrazole (15a) [52]: light yellow solid, 97 mg (33%; for two steps, starting with 1.0 mmol of chalcone 10a and chloride 14a), mp 96–98 °C. 1H NMR (600 MHz, CDCl3) δ 7.29–7.37, 7.47–7.50, 7.60–7.62, 7.80–7.82 (4m, 9H, 2H, 2H, 2H), 8.03 (s, 1H, 5-H). 13C NMR (151 MHz, CDCl3) δ 119.1, 123.1, 126.6, 126.8, 127.1, 128.1, 128.5, 128.6, 128.7, 128.9, 129.6, 133.0, 133.3, 140.1, 150.6. IR (neat) v 1722, 1599, 1502, 1401, 1215, 1059 cm−1. ESI-MS (m/z) 297.3 (100, [M + H]+).
Ethyl 4-phenyl-1-(p-tolyl)-pyrazole-3-carboxylate (15b): colorless solid, 205 mg (67%), mp 99–102 °C. 1H NMR (600 MHz, CDCl3) δ 1.32 (t, J = 7.1 Hz, 3H, Et), 2.41 (s, 3H, Me), 4.37 (q, J = 7.1 Hz, 2H, Et), 7.27–7.29, 7.33–7.37, 7.39–7.42, 7.51–7.53, 7.64–7.66 (5m, 2H, 1H, 2H, 2H, 2H), 7.93 (s, 1H, 5-H). 13C NMR (151 MHz, CDCl3) δ 14.3, 21.2, 61.2, 120.1, 127.5, 127.7, 127.8, 128.2, 129.5, 130.2, 131.7, 137.4, 137.8, 141.2, 162.7. IR (neat) v 1722, 1610, 1517, 1465, 1279, 1226, 1141 cm−1. ESI-MS (m/z) 329.2 (25, [M + Na]+), 307.2 (100, [M + H]+). Anal. Calcd for C19H18N2O2 (306.1): C 74.49, H 5.92, N 9.14; found: C 74.47, H 6.00, N 9.21.
Ethyl 4-(4′-chlorophenyl)-1-(p-tolyl)-pyrazole-3-carboxylate (15c): colorless solid, 218 mg (64%), mp 136–137 °C. 1H NMR (600 MHz, CDCl3) δ 1.34 (t, J = 7.1 Hz, 3H, Et), 2.41 (s, 3H, Me), 4.38 (q, J = 7.1 Hz, 2H, Et), 7.27–7.29, 7.36–7.38, 7.45–7.47, 7.63–7.66 (4m, 2H, 2H, 2H, 2H), 7.92 (s, 1H, 5-H). 13C NMR (151 MHz, CDCl3) δ 14.4, 21.2, 61.3, 120.1, 126.4, 127.8, 128.4, 130.18, 130.20, 133.7, 137.2, 138.0, 141.1, 162.5. IR (neat) v 1707, 1476, 1442, 1349, 1282, 1226, 1156, 1107, 1077, 1033 cm−1. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H18ClN2O2 341.1057, found 341.1063.
3-Acetyl-4-phenyl-1-(p-tolyl)-pyrazole (15d): colorless solid, 102 mg (37%; for two steps, starting with 1.0 mmol of chalcone 10a and chloride 14c), mp 137–139 °C. 1H NMR (600 MHz, CDCl3) δ 2.42 (s, 3H, Me), 2.69 (s, 3H, Ac), 7.29–7.35, 7.38–7.41, 7.55–7.57, 7.65–7.67 (4m, 3H, 2H, 2H, 2H), 7.94 (s, 1H, 5-H). 13C NMR (151 MHz, CDCl3) δ 21.2, 28.1, 119.6, 126.4, 127.7, 127.9, 128.3, 129.4, 130.3, 131.7, 137.4, 137.8, 137.6, 194.8. IR (neat) v 1681, 1517, 1349, 1219, 1111 cm−1. ESI-MS (m/z) 299.3 (100, [M + Na]+), 277.3 (87, [M + H]+). Anal. Calcd for C18H16N2O (276.1): C 78.24, H 5.84, N 10.14; found: C 78.01, H 5.82, N 10.00.
3-Acetyl-4-(4′-methoxyphenyl)-1-(p-tolyl)-pyrazole (15e): light brown solid, 98 mg (32%; for two steps, starting with 1.0 mmol of chalcone 10d and chloride 14c), mp 108–109 °C. 1H NMR (600 MHz, CDCl3) δ 2.42 (s, 3H, Me), 2.68 (s, 3H, Ac), 3.84 (s, 3H, OMe), 6.92–6.95, 7.29–7.32, 7.49–7.52, 7.64–7.67 (4m, 2H each), 7.89 (s, 1H, 5-H). 13C NMR (151 MHz, CDCl3) δ 21.2, 28.1, 55.5, 113.8, 119.6, 124.1, 126.1, 127.5, 130.3, 130.6, 137.5, 137.7, 147.6, 159.3, 194.8. IR (neat) v 1692, 1551, 1498, 1450, 1387, 1346, 1249, 1182, 1107, 1029 cm−1. ESI-MS (m/z) 329.1 (100, [M + Na]+), 307.2 (71, [M + H]+). HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H19N2O2 307.1447, found 307.1445.
3-Acetyl-4-(4′-nitrophenyl)-1-(p-tolyl)-pyrazole (15f): light yellow solid, 144 mg (45%; for two steps, starting with 1.0 mmol of chalcone 10h and chloride 14c), mp 191–192 °C. 1H NMR (600 MHz, CDCl3) δ 2.44 (s, 3H, Me), 2.72 (s, 3H, Ac), 7.32–7.34, 7.65–7.67, 7.73–7.75 (3m, 2H each), 8.02 (s, 1H, 5-H), 8.23–8.25 (m, 2H). 13C NMR (151 MHz, CDCl3) δ 21.2, 27.9, 119.8, 123.5, 124.2, 128.4, 130.1, 130.4, 137.1, 138.4, 138.7, 147.2, 147.6, 194.7. IR (neat) v 1692, 1603, 1502, 1334, 1215, 1103, 1073 cm−1. ESI-MS (m/z) 344.9 (100, [M + Na]+). Anal. Calcd for C18H15N3O3 (321.1): C 67.28, H 4.71, N 13.08; found: C 67.35, H 4.93, N 12.95.
3-Acetyl-1-(4′-methoxyphenyl)-4-phenylpyrazole (15g): orange solid, 163 mg (56%; for two steps, starting with 1.0 mmol of chalcone 10a and chloride 14d), mp 109–111 °C. 1H NMR (600 MHz, CDCl3) δ 2.69 (s, 3H, Ac), 3.87 (s, 3H, OMe), 7.00–7.03, 7.32–7.35, 7.38–7.41, 7.55–7.57, 7.67–7.70 (5m, 2H, 1H, 2H, 2H, 2H), 7.88 (s, 1H, 5-H). 13C NMR (151 MHz, CDCl3) δ 28.0, 55.7, 114.8, 121.3, 126.3, 127.6, 128.0, 128.2, 129.3, 131.7, 133.3, 147.5, 159.2, 194.6. IR (neat) v 1685, 1513, 1466, 1353, 1260, 1221, 1174, 1118, 1029 cm−1. ESI-MS (m/z) 315.1 (92, [M + Na]+), 293.2 (100, [M + H]+). Anal. Calcd for C18H16N2O2 (292.1): C 73.95, H 5.52, N 9.58; found: C 73.99, H 5.74, N 9.49.

4. Conclusions

In summary, a solvent-free two-step mechanochemical synthesis of trifluoromethylated and non-fluorinated polysubstituted pyrazoles was developed, starting with simple substrates, i.e., chalcones and hydrazonoyl halides. The latter served as precursors for the K2CO3-induced in situ generation of nitrile imines, which were efficiently trapped with chalcones, to give the respective (3 + 2)-cycloadducts in moderate to high regioselectivity and fair yields. The first formed trans-configured 5-acylpyrazolines were oxidized with activated manganese dioxide under ball-milling to afford pyrazoles, formed through exclusive deacylative aromatization of the ring. Based on additional experiments, a mechanistic scenario comprising acyl-transfer onto the surface of heterogeneous oxidant was proposed. The presented results extend the scope of the previously reported method for the synthesis of the title compounds in organic solvents [42] and supplements recent developments, both in the synthesis of pyrazoles [2,53,54,55] and the application of nitrile imines as building blocks for organic synthesis [17,34,35,36,37,38,39,40,41,42,43,44,45,56,57,58,59].

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules27238446/s1: Copies of 1H, 13C, and 19F NMR spectra of all new compounds.

Author Contributions

Conceptualization and methodology, M.J. and G.U.-J.; investigation, G.U.-J. and A.K.; writing—original draft preparation, G.U.-J.; writing—review and editing, M.J.; supervision, M.J.; project administration, M.J.; funding acquisition, M.J. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the University of Lodz within the framework of IDUB grant (M.J.; Grant No. 3/IDUB/DOS/2021).

Data Availability Statement

All the electronic experimental data and samples of new materials are available from the authors.

Conflicts of Interest

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

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Molecules 27 08446 g001 550
Figure 1. Structures of selected fluorinated and non-fluorinated pyrazole-based pharmaceuticals and agrochemicals.
Figure 1. Structures of selected fluorinated and non-fluorinated pyrazole-based pharmaceuticals and agrochemicals.
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Molecules 27 08446 sch001 550
Scheme 1. Synthesis of fluoroalkylated pyrazoles through: (a) (3 + 2)-cycloadditions of nitrile imines 1 with selected C=C or C≡C dipolarophiles, leading to monocyclic (2–4) [34,39,41] and bicyclic (5) [36] derivatives and (b) trapping of 1 with enones, followed by MnO2-mediated oxidation of the first 5-acylpyrazolines 6 formed, leading to polysubstituted 3-trifluoromethylpyrazoles 7 and/or 8.
Scheme 1. Synthesis of fluoroalkylated pyrazoles through: (a) (3 + 2)-cycloadditions of nitrile imines 1 with selected C=C or C≡C dipolarophiles, leading to monocyclic (2–4) [34,39,41] and bicyclic (5) [36] derivatives and (b) trapping of 1 with enones, followed by MnO2-mediated oxidation of the first 5-acylpyrazolines 6 formed, leading to polysubstituted 3-trifluoromethylpyrazoles 7 and/or 8.
Molecules 27 08446 sch001
Molecules 27 08446 sch002 550
Scheme 2. Base-catalyzed mechanochemical (3 + 2)-cycloaddition of trifluoromethylated nitrile imine 1a derived from hydrazonoyl bromide 9a and chalcone (10a), leading to the isomeric benzoyl-pyrazolines 6a (major) and 6′a (minor).
Scheme 2. Base-catalyzed mechanochemical (3 + 2)-cycloaddition of trifluoromethylated nitrile imine 1a derived from hydrazonoyl bromide 9a and chalcone (10a), leading to the isomeric benzoyl-pyrazolines 6a (major) and 6′a (minor).
Molecules 27 08446 sch002
Molecules 27 08446 sch003 550
Scheme 3. Mechanochemical synthesis of 5-benzoyl-4-phenyl-3-trifluoromethylpyrazolines 6b–6h derived from chalcone (10a); scope of hydrazonoyl bromides 9.
Scheme 3. Mechanochemical synthesis of 5-benzoyl-4-phenyl-3-trifluoromethylpyrazolines 6b–6h derived from chalcone (10a); scope of hydrazonoyl bromides 9.
Molecules 27 08446 sch003
Molecules 27 08446 sch004 550
Scheme 4. Synthesis of 5-acyl-3-trifluoromethylpyrazolines 6i–6v using N-(p-tolyl) nitrile imine 1b generated in situ from hydrazonoyl bromide 9b; scope of chalcones 10.
Scheme 4. Synthesis of 5-acyl-3-trifluoromethylpyrazolines 6i–6v using N-(p-tolyl) nitrile imine 1b generated in situ from hydrazonoyl bromide 9b; scope of chalcones 10.
Molecules 27 08446 sch004
Molecules 27 08446 sch005 550
Scheme 5. Mechanochemical MnO2-mediated deacylative oxidation of 5-acylpyrazolines 6a–6s, leading to 1,4-diaryl-3-trifluoromethylpyrazoles 8a–8s.
Scheme 5. Mechanochemical MnO2-mediated deacylative oxidation of 5-acylpyrazolines 6a–6s, leading to 1,4-diaryl-3-trifluoromethylpyrazoles 8a–8s.
Molecules 27 08446 sch005
Molecules 27 08446 sch006 550
Scheme 6. Synthesis of pyrazoles 11b and 12b formed via competitive deacylative vs. dehydrogenative aromatization of 4-benzoylpyrazoline 6′b.
Scheme 6. Synthesis of pyrazoles 11b and 12b formed via competitive deacylative vs. dehydrogenative aromatization of 4-benzoylpyrazoline 6′b.
Molecules 27 08446 sch006
Molecules 27 08446 sch007 550
Scheme 7. Two-step synthesis of pyrazoles 15a–15g using non-fluorinated nitrile imine precursors of type 14.
Scheme 7. Two-step synthesis of pyrazoles 15a–15g using non-fluorinated nitrile imine precursors of type 14.
Molecules 27 08446 sch007
Molecules 27 08446 sch008 550
Scheme 8. Proposed mechanism of deacylative oxidation of 5-acylpyrazolines.
Scheme 8. Proposed mechanism of deacylative oxidation of 5-acylpyrazolines.
Molecules 27 08446 sch008
Table
Table 1. Optimization of (3 + 2)-cycloaddition reaction of 9a and 10a.
Table 1. Optimization of (3 + 2)-cycloaddition reaction of 9a and 10a.
EntryBase9a:10a:Base
(Ratio)		Time
(min)		Vjar
(mL)		Conversion 1 (%)Ratio (%) 1 (Isolated Yield)
6a6′a
1Et3N1.1:1.0:1.2601.5 56 28713
2CsF1.1:1.0:1.2601.5 27 27228
3KF1.1:1.0:1.2601.5 60 28416
4Cs2CO31.1:1.0:1.2601.5 45 27921
5K2CO31.1:1.0:1.2601.5828119
6K2CO31.1:1.0:1.2901.5848218
7K2CO31.2:1.0:1.39059380 (73)20 (13)
8K2CO31.2:1.0:1.318059382 (75)18 (13)
1 Estimated based on 1H NMR spectra of crude reaction mixtures; 2 Partial decomposition of starting bromide 9a.
Table
Table 2. Ball-milling (3 + 2)-cycloadditions of 9b–9h with model chalcone (10a).
Table 2. Ball-milling (3 + 2)-cycloadditions of 9b–9h with model chalcone (10a).
EntrySubstrateX6:6′ Ratio 1Yield of 6 (%) 2
19b4-Me81:196b (70)
29c4-i-Pr81:196c (71)
39d4-OBn83:176d (58)
49e4-Cl81:196e (53)
59f2,4-Cl277:236f (54)
69g4-NO274:266g (10)
7 39g4-NO279:216g (22)
8 39h4-PhCOO79:216h (17)
1 Estimated on the basis of 1H NMR spectra of crude reaction mixtures; 2 Isolated yield; 3 Grinding time 24 h.
Table
Table 3. Mechanochemical (3 + 2)-cycloadditions of 10b–10o with model nitrile imine 1b.
Table 3. Mechanochemical (3 + 2)-cycloadditions of 10b–10o with model nitrile imine 1b.
EntrySubstrateRR’Milling
Time (h)		6:6′ Ratio (%) 1Yield of 6 (%) 2
110b2-Nph 3Ph9 77:236i (74)
210cFc 3Ph24 85:156j (38)
310d4-MeOC6H4Ph20 76:246k (59)
410e3,4-(MeO)2C6H3Ph18100:06l (74)
510f3,4-methylenedioxyphenylPh1288:126m (68)
610g4-(Me2N)C6H4Ph3665:356n (46)
710h4-ClC6H4Ph979:216o (70)
810i2-ClC6H4Ph1077:236p (57)
910j4-CF3C6H4Ph971:296q (28)
1010k4-NO2C6H4Ph2873:276r (26)
1110l3-NO2C6H4Ph7279:216s (65)
1210mPhFc 32471:296t (39)
1310nPh4-BrC6H41685:156u (68)
1410oPh3,4-methylenedioxyphenyl2082:186v (81)
1 Estimated based on 1H NMR spectra of crude reaction mixtures; 2 Isolated yield; 3 2-Nph = naphth-2-yl; Fc = ferrocenyl.
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Utecht-Jarzyńska, G.; Kowalczyk, A.; Jasiński, M. Fluorinated and Non-Fluorinated 1,4-Diarylpyrazoles via MnO2-Mediated Mechanochemical Deacylative Oxidation of 5-Acylpyrazolines. Molecules 2022, 27, 8446. https://doi.org/10.3390/molecules27238446

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Utecht-Jarzyńska G, Kowalczyk A, Jasiński M. Fluorinated and Non-Fluorinated 1,4-Diarylpyrazoles via MnO2-Mediated Mechanochemical Deacylative Oxidation of 5-Acylpyrazolines. Molecules. 2022; 27(23):8446. https://doi.org/10.3390/molecules27238446

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Utecht-Jarzyńska, Greta, Anna Kowalczyk, and Marcin Jasiński. 2022. "Fluorinated and Non-Fluorinated 1,4-Diarylpyrazoles via MnO2-Mediated Mechanochemical Deacylative Oxidation of 5-Acylpyrazolines" Molecules 27, no. 23: 8446. https://doi.org/10.3390/molecules27238446

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