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

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.


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 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 pharmaceuticallyrelevant 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 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 MnO 2 -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 CF 3 , COOEt, Ac, or Ph groups at C(3) of the heterocyclic ring, under solvent-free ball-milling mechanochemical conditions. protocol for two types of multi-substituted 3-trifluoromethylpyrazoles comprising (3 + 2)cycloaddition of in situ generated nitrile imines 1 with chalcones, followed by MnO2mediated 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. 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)(3)(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.

Results and Discussion
The required CF 3 -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 Et 3 N, 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 Et 3 N (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 1 H 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 K 2 CO 3 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 1 H 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 (J H-H = 5.6 Hz, 4 J H-F ≈ 0.9 Hz) at δ 4.37 (4-H) and as doublet (J H-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 1 H and 13 C NMR supplemented with 2D NMR measurements (HMQC, HMBC). For example, in the 1 H 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 (J H-H = 7.3 Hz) at δ 5.65 (5-H) nicely matched the proposed structure of 6 a. Furthermore, in the 13 C NMR spectrum of 6 a, two diagnostic quartets found at δ 120.9 ( 1 J C-F = 269.8 Hz) and δ 133.5 ( 2 J C-F = 38.0 Hz), attributed to the CF 3 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. 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 1 H NMR spectra and by comparison with the literature data on other transconfigured 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, 4 JH-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 1 H and 13 C NMR supplemented with 2D NMR measurements (HMQC, HMBC). For example, in the 1 H 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 13 C NMR spectrum of 6′a, two diagnostic quartets found at δ 120.9 ( 1 JC-F = 269.8 Hz) and δ 133.5 ( 2 JC-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. 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 benzoylpyrazolines 6a (major) and 6′a (minor).  (13) 1 Estimated based on 1 H NMR spectra of crude reaction mixtures; 2 Partial decomposition of starting bromide 9a.

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 benzoylpyrazolines 6a (major) and 6 a (minor). 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 electronwithdrawing (9e, 9g, and 9h) groups X located at para position of the phenyl ring, as well as disubstituted derivative 9f (2,4-Cl 2 ), 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 (NO 2 , 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.
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 ballmilling. 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. Scheme 3. Mechanochemical synthesis of 5-benzoyl-4-phenyl-3-trifluoromethylpyrazolines 6b-6h derived from chalcone (10a); scope of hydrazonoyl bromides 9.  (17) 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 1 H 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 (Schemes 2 and 3, Table 2), (3 + 2)-cycloadditions of 1b with selected chalcones 10b-10o proceeded in a comparable Scheme 3. Mechanochemical synthesis of 5-benzoyl-4-phenyl-3-trifluoromethylpyrazolines 6b-6h derived from chalcone (10a); scope of hydrazonoyl bromides 9. 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 1 H 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 CF 3 group at phenyl ring), alkylamino and alkoxy substituents, as well as a ferrocenyl moiety, could be introduced. Again, only trans-configur products could be detected in the mother liquors. Interestingly, in the case of 3 methylenedioxy-functionalized chalcone (10f) and 3,4-dimethoxy analogue (10 exceptionally high selectivity (ca. 9:1) or exclusive formation of target 5-acylpyrazolin 6m and 6l, respectively, was observed. On the other hand, the reaction of 1b with anoth electron-rich chalcone, namely 4-(dimethylamino)chalcone (10g), provided only t expected (3 + 2)-cycloadducts 6n and 6′n as a ca. 2:1 mixture. Possibly, the observ decrease of selectivity resulted from the presence of the basic Me2N group in 10g, whi can compete with K2CO3 in dehydrohalogenation of 9b, thereby changing the electron properties of chalcone 10g, due to protonation. The observed moderate yield cycloadditions of 1b with chalcones 10c and 10m, leading to pyrazolines 6j (38%) and (39%), also deserves a brief comment. Seemingly, the presence of the redox-active group alters the reaction outcome and leads to complex mixtures, irrespective of t 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 MnO 2 under mechanochemical conditions. In a typical experiment, pyrazoline 6a (1.0 mmol) was reacted with oxidant (activated MnO 2 , 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-3trifluoromethylpyrazole (8a), isolated as a sole product in excellent purity and a yield of 97% (Scheme 5). The observed result for MnO 2 -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 K 2 CO 3 ), followed by treatment of the resulting crude reaction mixture with excess activated MnO 2 . 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).
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 5benzoylpyrazoline 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 MnO 2 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 ferrocenylfunctionalized 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 Me 2 N 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-acylpyrazolines 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 MnO 2 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. 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-ptolyl-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 5acylpyrazoline 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 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 MnO 2 . 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 = NO 2 ) (Scheme 7). The first formed 5-acylpyrazoline derivatives 13 were pre-purified by filtration through a short silica gel pad and subsequently reacted with MnO 2 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 O 2 NC 6 H 4 -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 benzoylpyrazolines 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. Scheme 7. Two-step synthesis of pyrazoles 15a-15g using non-fluorinated nitrile imine precursors of type 14.
It should be pointed out that all the presented deacylative oxidations of benzoylpyrazolines were performed using activated MnO 2 (≈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. 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. Scheme 8. Proposed mechanism of deacylative oxidation of 5-acylpyrazolines.

Chemical Synthesis General Methods
Scheme 8. Proposed mechanism of deacylative oxidation of 5-acylpyrazolines.

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, CH 2 Cl 2 , 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 ( 1 H at 600 MHz, 13  Starting materials: The CF 3 -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 H 2 O) 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 MnO 2 (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 K 2 CO 3 (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, CH 2 Cl 2 (10 mL) was added, the precipitate was filtered off, washed with CH 2 Cl 2 (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 1 H 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.

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 K 2 CO 3 -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].