Ambident polyfluoroalkyl-substituted pyrazoles in the methylation reactions

Journal of Fluorine Chemistry 195 (2017) 47–56

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Journal of Fluorine Chemistry j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / fl u o r

Ambident polyfluoroalkyl-substituted pyrazoles in the methylation reactions Anna E. Ivanovaa,* , Yanina V. Burgarta , Viktor I. Saloutina , Pavel A. Slepukhina , Sophia S. Borisevichb , Sergey L. Khursanb a Postovsky Institute of Organic Synthesis, Russian Academy of Sciences (Ural Branch), 22/20 S. Kovalevskoy/Akademicheskaya St., Ekaterinburg, 620990 Russia b Ufa Institute of Chemistry, Russian Academy of Sciences, 71 October Ave., Ufa, 450054 Russia

A R T I C L E I N F O

Article history: Received 15 November 2016 Received in revised form 10 January 2017 Accepted 10 January 2017 Available online 19 January 2017 Keywords: Polyfluoroalkylpyrazoles Ambident nucleophiles Methylation Regioselectivity DFT-study

A B S T R A C T

The reactivity of polyfluoroalkyl-containing pyrazoles has been estimated using the quantum chemical calculations. A good regioselectivity in the methylation of polyfluoroalkylpyrazoles was reached while varying the reaction conditions. Under basic conditions, methylation of such pyrazoles led to the preferred formation of 3-RF-pyrazoles, whereas the use of dimethyl sulfate in the absence of a base resulted in the predominant formation of 5-RF-pyrazoles. A proposed mechanism of methylation was discussed. © 2017 Elsevier B.V. All rights reserved.

1. Introduction Trifluoromethyl-containing pyrazoles are of significant practical interest because of the use of their derivatives as pharmaceutical agents and agrochemicals [1,2]. Among them there are one of the best selling drugs – Celebrex (celecoxib, anti-inflammatory drug, a selective inhibitor of COX-2), veterinary anti-arthritic Mavacoxib (trocoxil), as well as such drugs being under clinical studies as SC-560 (anticancer activity), AS-136A (antiviral action), and Razaxaban (anticoagulant activity) (Fig. 1) [3]. Fungicide Penthiopyrad [4], herbicide Fluazolate [5] and insecticide DP-23 have been used as agrochemicals (Fig. 2) [3]. The high importance of the pyrazole skeleton was shown in recent reviews [6–9]. The vast majority of bioactive pyrazoles represent N-substituted derivatives containing the methyl or aryl substituent at the nitrogen atom. The synthesis of such pyrazoles, including polyfluoroalkylated analogues, is based mainly on the cyclization of 1,3-bielectrophiles with substituted hydrazines, hydrazides, semicarbazide, etc. One of the most popular 1,3bielectrophilic blocks are the polyfluoroalkyl-containing 1,3dicarbonyl compounds and their derivatives. So, a large number of pyrazoles was produced by cyclization of various

* Corresponding author. E-mail address: [email protected] (A.E. Ivanova). http://dx.doi.org/10.1016/j.jfluchem.2017.01.009 0022-1139/© 2017 Elsevier B.V. All rights reserved.

polyfluoroalkyl-1,3-diketones with substituted hydrazines (Scheme 1) [10–19]. However the formation of two regioisomers with trifluoromethyl group in the position C-3 (isomer I) or C-5 (isomer II) often takes place in these reactions. In the most cases, the 3-RF-isomer is the major [10,12,15–20], and 5-RF-pyrazole isomer is mostly isolated in a hydrated form [4,20–26]. A convenient method for the synthesis of N-substituted pyrazoles is the alkylation of pyrazole core. It should be noted that the alkylation is one of the basic methods for construction of the carbon skeleton of the molecule; this reaction is of great importance in organic synthesis, including preparation of medicinal agents. According to the recent estimates, the proportion of alkylation reactions in the design of new medicines is 17% [27]. Alkylation of polyfluoroalkylcontaining pyrazoles as ambident nucleophiles can proceed at two nonequivalent N1 and N2 reaction centers (conventional numeration) to form the corresponding 3RF- and 5-RF-regioisomers (Scheme 2). The examples of nonselective alkylation of 5-methyl-3-polyfluoroalkylpyrazoles with various alkyl halides were described [28–31]. At the same time, benzylation of 4-substituted 5-methyl-3-trifluoromethylpyrazoles occurs regiospecifically to form 3-EF3-isomer [32]. The data on methylation of 3-polyfluoroalkylpyrazoles are limited. It is known that the methylation of 5-methyl-3-trifluoromethylpyrazole and 4-bromo-3-trifluoromethylpyrazoles with methyl iodide leads to regiospecific formation of 3-CF3-pyrazoles [33,34].

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A.E. Ivanova et al. / Journal of Fluorine Chemistry 195 (2017) 47–56

Fig. 1. Trifluoromethylpyrazole-based pharmaceutical agents.

Fig. 2. Trifluoromethylpyrazole-based agrochemicals.

Scheme 1. Synthesis of N-substituted pyrazoles by cyclization of 1,3-diketones with hydrazines.

Scheme 2. Alkylation of polyfluoroalkylpyrazoles.

A.E. Ivanova et al. / Journal of Fluorine Chemistry 195 (2017) 47–56

It should be also noted that so far there is no convenient method for the 5-RF-pyrazoles synthesis. These compounds were prepared via recyclisation of hard-to-reach trifluoromethylsydnone [5] or dehydration of 5-hydroxy-5-RF-pyrazolines isolated from a mixture with 3-RF-pyrazoles that was obtained by cyclization of 1,3diketone with methylhydrazine [23]. In this work the reactivity of polyfluoroalkylpyrazoles 1a-g and their 4-substituted derivatives 1h-j has been studied using the quantum-chemical methods and methylation reactions. To explain the mechanism, the theoretical modeling of the methylation reaction has been carried out using the density functional theory (DFT).

49

R RF 1.5 MeI

R RF

R1

N N

MeCN, K2CO3 reflux

3a-j

N NH 1a-j

R1 + Me

2a,c,e,f,h-j (minor)

R 5 Me2SO 4 80 oC

RF

R1

+

3c,e,f,h-j (minor)

N N Me 2a,c,e,f,h-j Scheme 4. Methylation of pyrazoles 1a–j.

2. Results and discussion To the best of our knowledge, up to now, the nucleophilicity of polyfluoroalkylpyrazoles 1 has not been studied using quantumchemical methods. To pre-evaluate reactivity of polyfluoroalkylpyrazoles 1 we performed the quantum-chemical calculations for compounds 1a,b which can exist in different N1H- (I) and N2H- (II) tautomeric forms due to reversible transfer of hydrogen atom between two nitrogen atoms N1 and N2 (Scheme 3). According to quantum-chemical calculations, tautomeric forms I of pyrazoles 1a,b are the most thermodynamically stable. The difference in the values of the Gibbs free energies for the possible tautomeric forms I and II was evaluated under experimental conditions of the methylation taking into account acetonitrile as a solvent, see Scheme 3 (the calculations performed in the approximation of an ideal gas are given in parentheses). It should be noted that a more thermodynamically stable form I was previously recorded for pyrazole 1a using X-ray diffraction [35]. The N2 reaction centers of more stable tautomers 1a,b,I are characterized by the positive values of dual descriptor of the Fukui function Df that indicates their greater nucleophilicity [36]. However, the Fukui indexes for both atoms N1 and N2 are differed slightly (Scheme 3), which indicates their close nucleophilicity. More detailed results of the global and local reactivity assessment of pyrazoles are presented in Supporting information. So, a priori estimates of the pyrazoles 1a,b reactivity confirm their ambident nucleophilicity. This suggests that regioselectivity of their transformations can influence other factors, in particular, the thermodynamic stability of intermediates and the reaction products. Then the reactivity of pyrazoles 1 as ambident nucleophiles was studied using the methylation reactions. It has been found that the pyrazoles 1a-j react with methyl iodide under refluxing in acetonitrile in the presence of potassium carbonate to form a mixture of regioisomers 2a,c,e,f,h-j and 3a-j with a predominance of isomers 3a-j in all cases (Scheme 4, Table 1). The formation of the only isomers 3b,d,g was observed in the reaction of methylsubstituted pyrazoles 1b,d,g. The major isomers 3c,e,f,h-j were

Scheme 3. Data of quantum-chemical calculations for tautomeric forms of pyrazoles 1a,b.

isolated from their mixture with the second minor isomers 3c,e,f, h-j by column chromatography. Next, dimethyl sulfate was used as a methylating reagent. It has been found that heating of pyrazoles 1a-j at 80
C with the 5-fold excess of dimethyl sulfate for 8 h without catalyst (Scheme 3, Table 1) leads to the formation of compounds 2c,e,f,h-j as major products and isomers 3c,e,f,h-j in small quantities only. The reaction of pyrazole 1a occurred regiospecifically to give product 2a. Unfortunately, the interaction of methyl-substituted pyrazoles 1b,d,g with Me2SO4 led to the formation of a mixture of unidentified products. The predominant isomers 2c,f,h-j were isolated by column chromatography using the corresponding eluent. The 1H and 19F NMR spectroscopy data were used to determine the 3-RF- or 5-RF-isomeric structure of the obtained pyrazoles 2 and 3. Previously it has been found that 3-CF3-group of 4-(het) arylazo-3,5-bis(trifluoromethyl)-1-methylpyrazole in the 19F NMR spectrum is observed as a singlet in a higher field at d 63.8 (62.7) ppm compared to unresolved quartet signal of 5-EF3groups at 60.8 (58.8) ppm [37]. It allowed us to attribute the signals of the fluorine nuclei in 19F NMR spectra of products 3a,b,h, i at d 61.7 (63.1) ppm to 3-EF3-pyrazoles and the signals of products 2a,b,h,i at d 58.3 (61.6) ppm to 5-EF3-pyrazoles. It should be noted that the shifts of the EF3-group signals of pyrazoles 3a,b,h,i are observed at the same region as the starting N-unsubstituted pyrazoles 1a,b,h,i (Table 2). In addition, the EF3-group of the 4-substitued pyrazoles 2i,j in the 19F NMR spectra in CDCl3 was observed as a multiplet due to the spin–spin coupling with the neighboring protons of the Nmethyl group (see Experimental). A similar splitting was observed for the proton signals of N-methyl groups of pyrazoles 2i,j in the 1H NMR spectra. However, in the case of the 4-unsubstituted pyrazole 2a such splitting was absent. The isomeric structure of the N-methyl-substituted pyrazoles 2c,e,f,j and 3c,e,f,j with polyfluoroalkyl substituents was determined using the 19F chemical shifts of the a-EF2-groups. Thus, the a-EF2-group signals of 3-RF-pyrazoles 3c,e,f,j resonate at a higher field compared to the a-EF2-group signals of 5-RF-pyrazoles 2c,e,f, j (Table 2). It should be noted that the routine 19F NMR experiment-based approach proposed by us to the assignment of regioisomeric pyrazoles 2 and 3 is easier as compared to the NOESY NMR experiments used in [23]. Additionally the regioisomeric structure of pyrazoles 2 h and 3i was confirmed by the single-crystal X-ray diffraction (Fig. 3). According to the X-ray diffraction data, compounds 2 h and 3i have a trans-configuration of the aza-group. Both aryl and hetaryl substituents at the aza-group are located approximately in the azagroup plane. Both compounds have the same orientation of the aza-group relative to CF3-substituent in the heterocycle. For compound 3i, N-Me group is located in adjacent position to C-Me substituent and for compound 2 h, N-Me group is located at

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Table 1 The ratio of isomers and overall yield of N-methylpyrazoles. RF

Pyrazoles

R1

R

Methylation with MeI a

EF3 EF3

a b c d e f g h i j

C2F5 C2F5 H(CF2)2 C3F7 C3F7 EF3 EF3 C3F7

H H H H H H H 4-MeC6H4NN 4-MeC6H4NN 4-MeOC6H4NN

a The ratio of isomers was determined according to the removal of the solvent). b The yields of the isolated products. c mixture of unidentified products.

Ph Me Ph Me Et Ph Me Ph Me Me 19

Methylation with Me2SO4 b

Ratio of isomers , 3: 2

Overall yield , 3 + 2, %

Ratio of isomersa , 3: 2

Overall yieldb , 3 + 2, %

54: 46 100: 0 57: 42 100: 0 93: 7 55: 45 100: 0 72: 28 88: 12 82: 18

79 60 71 45 49 62 55 80 75 84

0: 100 mixc 2: 98 mixc 10: 90 3: 97 mixc 6: 94 20: 87 12: 88

68 mixc 54 mixc 25 63 mixc 76 73 78

F NMR spectra of the reaction mass (in the reactions with Me2SO4 after treatment with 5%-aq. NaHCO3 and

Table 2 The 19F chemical shifts of EF3 (a-CF2)-groups in pyrazoles 1, 2, 3a . Pyrazoles

RF

R

R1

EF3 (a-CF2)-group of pyrazoles 1, ppm 3-EF3 (a-CF2)-group of pyrazoles 3, ppm 5-EF3 (a-CF2)-group of pyrazoles 2, ppm

a b c d e

EF3 EF3

H H H H H

Ph Me Ph Me Et

63.3 61.6 114.3 114.2 136.8

H H 4-MeC6H4NN

Ph 112.9 Me 112.0 Ph 63.7 63b 92: 8 Me 62.5 100: 0

f g h

C2F5 C2F5 H (CF2)2 C3F7 C3F7 EF3

i

EF3

4-MeC6H4NN

j

C3F7

4MeOC6H4NN

a b

Me 110.6 111.3b 95: 5

63.2 61.7 114.0 114.2 137.4

61.6 – 111.5 – 134.6

111.8 112.0 63.1 62.4b 94: 6 62.6 62.55b 95: 5 110.3 110.8b 97: 3

109.1 – 58.5 100: 0 58.3 59.7b 94: 6 108.1 108.7b 95: 5

19 F NMR spectra were recorded in CDCl3. The chemical shifts of minor geometric isomer.

Fig. 3. X-Ray structures of 1,5-dimethyl-4-[(4-methylphenyl)diazenyl]-3-trifluoromethyl-1H-pyrazole 3i and 1-methyl-4-[(4-methylphenyl)diazenyl]-5-trifluoromethyl-3phenyl-1H-pyrazole 2 h.

A.E. Ivanova et al. / Journal of Fluorine Chemistry 195 (2017) 47–56

C CF3-substituent. Compound 2 h with aryl substituent in the heterocycle is characterized by a stronger conjugation with the aza-group (the lengths of the  N¼N  bonds are 1.225 Å and 1.246 Å for 3i and 2 h, respectively; lengths of the Csp2–N = bonds in heteroarene are 1.420 Å and 1.401 Å for 3i and 2 h, respectively). Any specific shortened intermolecular contacts were not observed in the crystal. The Z,E-isomerism is known to be characteristic of 4arylazopyrazoles 2h-j and 3h-j as the result of the different position of the substituents relative to the N¼N bond. Besides, each pair of Z- and E-isomers can exist as two s-cis- or s-transconformers due to the different position of N¼N bond and pyrazolic C¼C bond. The presence of two isomeric cis- and trans-Eforms was noted earlier for bis(trifluoromethyl)substituted 4arylazopyrazoles in CDCl3. However, according to X-ray, 1,5dimethyl-4-phenylazo-3-trifluoromethylpyrazol existed in crystals as a mixture of s-trans-E- and s-cis-E-forms in 81: 19 ratio [37]. The presence of two geometric isomers was observed for the obtained 4-arylazopyrazoles 2i,j, 3h-j and starting pyrazoles 1 h,j, which was manifested by two signals of CF3-groups in the 19F NMR spectra (the ratio of geometric isomers and the chemical shifts of their CF3 (a-CF2)-groups are listed in Table 2). In addition, the doubling of the N-methyl or phenyl group signals was observed in the 1H NMR spectra of compounds 2i,j and 3h-j. 4-Arylazopyrazoles 1i, 2 h exist in the only form. One can assume that the more stable s-cis- or s-trans-E-isomers are the dominant forms. According to X-ray diffraction, the obtained 5-CF3-pyrazole 2 h exists as s-cis-E-form in crystals, and 3-CF3-pyrazole 3i exists as strans-E-conformer in crystals (Fig. 3). These forms are likely to be preferred for 5-RF- and 3-RF-pyrazoles 2 and 3 in the solutions. Determination of regioisomeric structure of the methylated pyrazoles allowed us to conclude that methylation with methyl iodide in the presence of K2CO3 proceeds preferably at the N1 center to form 3-RF-pyrazoles 3 as the main products, whereas the reactions with an excess of dimethyl sulfate occur preferably at the N2 center to form 5-RF-pyrazoles 2 (Scheme 4). It should be noted that when methyl iodide was used, 3-RFisomers 3b,d,g were formed as the only products in the reactions of 4-unsubstituted C-methyl-containing pyrazoles 1b,d,g, whereas the predominance of regioisomers 3a,c,f was insignificant for Cphenyl-substituted analogues 1a,c,f (Table 1). For C-ethyl-containing pyrazole 1e, there was only minor formation of 5-RFisomer 2e, which is consistent with the general tendency of the regioselectivity dependence on the non-fluorinated substituent structure. The same dependence was observed for 4-aryldiazenylpyrazoles 1h-j. The reason for such a pronounced regioselectivity in the methylation of pyrazoles 1 is worth discussing. However, a slight difference in the nucleophilicity indices of the N1 and N2 reaction centers (Scheme 3) cannot explain (within the Pearson’s hard soft acid base theory) a change in the methylation direction when different methylating agents were used. To understand the mechanism of the studied reactions, we performed the additional experiments on the methylation of

51

pyrazole 1a under different conditions (Table 3). In addition, the DFT modeling of key intermediates and final products for reactions of pyrazoles 1a,b were carried out. It has been found that regioisomers 3a and 2a are formed in approximately equal amounts in the presence of a base regardless of the methylating agent (entries 1–3 in Table 3). From this it follows that the reactions with MeI and Me2SO4 in the presence of a base take place by the same mechanism. We can assume that at first the action of a base on pyrazole 1a leads to the formation of an intermediate anion Aa that then reacts with the methylating reagent to give isomers 3a and 2a (Scheme 5). The reaction requires N-H bond breaking in the starting pyrazoles 1a,b to form metastable anionic species, and the loss of H+ in both tautomeric forms I and II leads to the same anions Aa, b (Scheme 5), in which the negative charge is delocalized between N1 and N2 nitrogen atoms. The shape of anion Ab HOMO orbital is seemed to support this a priori conclusion (Fig. 4). In this regard, an attack of any methylating agent to both of these centers is equally probable, and therefore, the regioselectivity of these reactions may be due to the thermodynamic stability of the end products. Indeed, the relative values of Gibbs free energies of isomers 2b and 3b determined both under the experimental conditions (DG
= 16.2 kJ/mol (MeCN)) and in terms of the ideal gas (DG
= 8.3 kJ/mol) indicate low probability of the formation of 5-CF3isomer 2b (Scheme 5), (Scheme 5), which corresponds to 100% occupancy of isomer 3b and is consistent with the experimental data (Table 1). More complex combination of stabilization/ destabilization factors of 5-CF3-isomers 2a and 3a is implemented for the methylation products of pyrazole 1a. In terms of the ideal gas isomer 2a is thermodynamically more stable (DG
= -3.5 kJ/ mol) than 3-CF3-analog 3a due to the steric repulsion of vicinal methyl and phenyl substituents in pyrazole 3a. Pyrazolyl and phenyl rings in isomer 2a are coplanar making the p-conjugation between them to be the most effective. In contrast, the methyl substituent in pyrazole 3a causes a reversal of planes of these fragments relative to each other by 45
; in this case, a part of the conjugation energy stabilizing molecule is lost. Modeling of the isomers in acetonitrile shows that 3-CF3isomer 3a becomes slightly thermodynamically more stable (DG
= 2.4 kJ/mol) compared to 5-CF3-isomer 2a, which corresponds to 70: 30 equilibrium occupancies of isomers 3a: 2a. It is reasonably consistent with the close yields of these isomers under the experimental conditions (Table 3, entries 1–3). A similar extra stabilization effect of isomer 3b in polar solvent, acetonitrile (Scheme 5) suggests that the methylated isomeric products of pyrazoles 1a and 1b differ substantially depending on the character of the electron density distribution in the molecule, the measure of which is its dipole moment. The results of our calculations in terms of the ideal gas demonstrate that the magnitudes of the dipole moments of 3-CF3pyrazoles 3a,b (m3a = 6.08 and m3b = 6.05 D) are much more than these of regioisomers 2a,b (m2a = 1.03 and m2b = 1.12 D), therefore compounds 3a,b are more efficiently stabilized by the polar solvent. Acetonitrile as a polar solvent further increases the

Table 3 Methylation of pyrazole 1a under different conditions. Entry

Conditions of pyrazole 1a methylation

Ratio of isomers, 3a: 2a

Conversion of the starting pyrazole 1aa ,%

1 2 3 4 5 6

1.5 MeI, MeCN, reflux, 8 h, K2CO3 1.5 MeI, Me2CO, reflux, 8 h, Cs2CO3 1.5 Me2SO4, MeCN, reflux, 8 h, K2CO3 5 MeI, MeCN, reflux, 8 h 1.5 Me2SO4, MeCN, reflux, 8 h 5 Me2SO4, 80
C, 8 h

54: 46 44: 56 46: 54 – 2: 98 0: 100

100 70 100 0 88 100

a

The conversion of the starting pyrazole 1a was determined by

19

F NMR spectra of the reaction mixture.

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A.E. Ivanova et al. / Journal of Fluorine Chemistry 195 (2017) 47–56

Scheme 5. Possible mechanism of methylation in the presence of a base (compound 2b is not formed in the experiment).

Fig. 4. A shape of HOMO orbital of anion Ab: e = 5.00 eV.

difference in dipole moments of the isomers: m3a = 7.62 and m3b = 7.72 D vs m2a = 0.89 and m2b = 1.08 D, respectively. The explanation of the observed regularities by the example of isomers 2b and 3b in the framework of a simple vector scheme for addition of dipole moments of polar fragments, namely the dipole moments of the pyrazole skeleton (Fig. 5, 3.5-dimethylpyrazole is used as a model compound) and polar trifluoromethyl group. According to our calculations, the CF3-group dipole moment is mCF3  3.6 D. It is obvious that the orientation of this dipole is determined by the spatial orientation of the C-CF3 bond in the pyrazole. The relative position of the polar fragments in compound 2b is such that two vector dipoles are almost anti-collinear, and the resulting dipole moment is small in absolute value; the opposite pattern is

observed for isomer 3b (Fig. 5). The difference of the dipole moments of isomers 2a and 3a can be explained in the same way. Thus, the results of our experimental and theoretical investigations allow us to conclude that methylation in the presence of a base for all pyrazoles 1 proceeds through the formation of anionic intermediate; the main determinant of the ratio of regioisomers is the thermodynamic stability of the methylation products. The presence of bulky substituents in the pyrazole cycle and the polarity of the solvent are additional factors influencing regioselectivity of the reaction products formation. Further, we have found that pyrazole 1a does not react with methyl iodide in the absence of a base (Table 3, entry 4). However, its reaction with Me2SO4 without a base resulted in the formation of almost one 5-RF-isomer in the solvent or in an excess of the methylating reagent (Table 3, entries 5 and 6) that suggests the realization of another mechanism in this case. Apparently, dimethyl sulfate as the stronger methylating reagent [38] can react with pyrazoles 1 in the absence of a base to form intermediate salts KI and KII (Scheme 6), their decomposition with an aqueous sodium bicarbonate resulted in pyrazoles 2 and 3. Under these conditions, less reactive methyl iodide does not react with pyrazoles 1 (Table 3, entry 4). Using DFT simulation of the reactions of pyrazoles 1a,b, we considered the possibility of the formation of cation salts that can be formally produced as a result of the attack of methylating reagent at the nitrogen atoms of both tautomeric forms I and II. The

Fig. 5. The orientation of the dipole moment vectors of 3,5-dimethylpyrazole and isomers 2b and 3b.

A.E. Ivanova et al. / Journal of Fluorine Chemistry 195 (2017) 47–56

53

Scheme 6. Possible mechanism of methylation without a base.

addition of methyl cation to more thermodynamically stable tautomer I can proceed at nucleophilic centers N2 and N1 to give cations KI and KI’, respectively. It has been found that cation KI’ is extremely unstable compared to cation KI (DG
(KI’) > > DG
(KI)) (Scheme 6), therefore the methylation occurs exclusively at the pyridine-like N2 atom of pyrazoles 1a,b. The same ratio of Gibbs free energies is in the pair of cations KII and KII’. Although the thermodynamic stability of cations KI and KII is close, the formation of cation KII is unlikely due to the low equilibrium concentration of the less thermodynamically stable tautomeric form II (Scheme 3). The subsequent deprotonation of the most stable cation KI leads to the formation of isomers 2a,b as the major reaction products (Scheme 6). Thus, methylation of pyrazoles 1 with dimethyl sulfate proceeds via cationic mechanism as a result of the methylating reagent attack at the pyridine-like nitrogen. The selective formation of 5-RF-isomers 2 is caused by the thermodynamic preference of the tautomeric form I of the starting pyrazoles 1. The formation of hardly separable mixtures in the reactions of Cmethyl-substituted pyrazoles 1b,d,g is likely to be due to further transformations of cation KI. 3. Conclusion In summary, we can conclude that methylation of polyfluoroalkyl-containing pyrazoles with methyl iodide under basic conditions leads to the predominant formation of 3-RF-pyrazoles while the use of dimethyl sulfate in the absence of a base results in the predominant formation of 5-RF-pyrazoles. A proposed mechanism of methylation was discussed. The developed method for the selective methylation can be applied for the purposeful preparation of 3-RF – or 5-RF-pyrazoles. 4. Experimental Melting points were obtained on a Stuart SMP30 apparatus in open capillaries. The IR spectra were recorded at 4000–400 cm1 on a Perkin Elmer Spectrum One Fourier-transformed IR spectrometer equipped with a diffuse reflectance attachment (DRA) or a frustrated total internal reflection (FTIR) technique. The NMR spectra were recorded on a Bruker AVANCE-500 spectrometer (1H: 500 MHz, relative to SiMe4, 19F: 470 MHz relative to E6F6) and on a Bruker DRX-400 spectrometer (1=: 400 MHz, relative to SiMe4; 19 F: 376 MHz, relative to E6F6). The 19F chemical shifts have been

reported relative to CFCl3 as an external standard. The microanalyses were carried out on a Perkin Elmer PE 2400 series II elemental analyzer. The column chromatography was performed on Merck silica gel 60 (0.063–0.2 mm). GC–MS analysis was carried out using a Trace GC Ultra DSQ II gas chromatograph–mass spectrometer (USA) with a Thermo TR–5 ms capillary column 30-m long, 0.25 mm in diameter, 0.25 mm thick film. Total ion current scanning was performed in the mass range 20–1000 Da in electron impact mode (70 eV). 5. Computation details Theoretical calculations were performed using the GAUSSIAN 09 program [39]. The TPSS [40] method with the basic sets 6– 311 + G(d,p) [41,42] was used throughout the work for geometry optimization, frequency calculation and NBO analysis [43,44]. The type of stationary points of the potential energy surface (PES) was characterized by the Hessian matrix. If the Hessian matrix was positive definite at the total energy, then the stationary point attained a local minimum of the PES (reagent or product of reaction). Thermodynamic parameters were calculated by simulating the experimental conditions: acetonitrile as solvent (polarized continuum model [45]), a temperature of 354.6 K and pressure of 1 atm. NBO analysis was performed in the gas phase approximation. Definition of Fukui function [36] for an atom A (in our case – atom N), can be shown as: þ f N ¼ qAN  qANþ1 for nucleophilic attack 

f N ¼ qAN1  qAN for electrophilic attack, when qA is the atomic charge. Summarily, dual descriptors of Fukui function can be written as:     Df A ¼ f þA  f A ¼ qAN  qANþ1  qAN1  qAN ¼ 2qAN  qANþ1  qAN1 All calculation were carried out on a cluster computer in the region center for share computer equipment at the Ufa Institute of Chemistry (RAS). The starting pyrazoles 1 were obtained by the previously reported method [46]. 5.1. General method for methylation of pyrazoles 1 Method 1. A mixture of pyrazole 1a-j (0.7 mmol), MeI (0.141 g, 1 mmol), K2CO3 (0.138 g, 1 mmol) in MeCN (15 mL) was refluxed for

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4–8 h. Then the inorganic residue formed was filtered off and the filtrate was concentrated. Compounds 3a-j and 2a,c,e,f,h-j were obtained by column chromatography using chloroform as an eluent. Pyrazoles 3b,d,g were isolated as individual substances. Pyrazoles 3c,e,h-j were isolated as individual substances by column chromatography using chloroform–hexane 2: 1 as an eluent. Method 2 (for pyrazole 1a). A mixture of pyrazole 1a (0.065 g, 0.3 mmol), MeI (0.085 g, 0.6 mmol), Cs2CO3 (0.196 g, 0.6 mmol) in Me2CO (15 mL) was refluxed for 8 h. Then the inorganic residue was filtered off and the filtrate was concentrated. Compounds 3a and 2a were obtained by column chromatography using chloroform as an eluent. Method 3 (for pyrazole 1a). A mixture of pyrazole 1a (0.15 g, 0.71 mmol), Me2SO4 (0.189 g, 1.5 mmol), K2CO3 (0.21 g, 1.5 mmol) in MeCN (15 mL) was refluxed for 8 h. Then the inorganic residue was filtered off and the filtrate was concentrated. Method 4 (for pyrazole 1a). A mixture of pyrazole 1a (0.15 g, 0.71 mmol), MeI (0.5 g, 3.55 mmol) in MeCN (15 mL) was refluxed for 8 h. The solvent was removed under reduced pressure. Method 5 (for pyrazole 1a). A mixture of pyrazole 1a (0.1 g, 0.53 mmol), Me2SO4 (0.189 g, 1.5 mmol) in MeCN (15 mL) was refluxed for 8 h. The solvent was removed under reduced pressure. Chloroform (20 mL) was added and the reaction mixture was washed twice with 5% solution of NaHCO3. The solvent was removed under reduced pressure. Method 6. A mixture of pyrazoles 1a-j (1 mmol) and Me2SO4 (0.63 g, 5 mmol) was stirred at 80
E for 8 h. Chloroform (20 mL) was added and the reaction mixture was washed twice with 5% solution of NaHCO3. The solvent was removed. Compounds 2a,c,e,f, h-j and 3c,e,f,h-j were obtained by column chromatography using chloroform as an eluent. Compound 2a was isolated as individual substance. Compounds 2c,f,h-j were isolated as individual substances from the mixture by column chromatography using chloroform–hexane 2: 1 as an eluent. The yields of compounds 2, 3 and their ratio are given in Tables 1 and 3. 1-Methyl-3-phenyl-5(-trifluoromethyl)-1H-pyrazole (2a). The 1H and 19F NMR spectral data were in accordance with the literature [5,23]. 1-Methyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazole (3a). The 1H and 19F NMR spectral data were in accordance with the literature [47]. 1,5-Dimethyl-3-(trifluoromethyl)-1H-pyrazole (3b). Yield 60%; spectral data and physicochemical properties were in accordance with the literature [23,34]. 1-Methyl-5-(pentafluoroethyl)-3-phenyl-1H-pyrazole (2c). Colorless oil; yield 46%; 1H NMR (500 MHz, CDCl3): d = 4.05 (s, 3H, Me), 6.89 (s, 1H, H-4), 7.34-7.43 (m, 3=, Hm,p, Ph), 7.76-7.78 (m, 2=, Ho, Ph). 19F NMR (470 MHz, CDCl3): d = 111.5 (br. s, 2F, CF2), 85.0 (t, CF3, 3F, 3JF-F = 2.9 Hz). IR (FTIR): 3069 (CH), 1439 (C¼N, C¼C), 1213 (C-F) cm1. Analysis: Calc. for C12H9F5N2: C, 52.18; H, 3.28; F, 34.39; N, 10.14%. Found: C, 51.99; H, 3.25; N, 10.28%. MS, m/z (%): 276 [M]+ (99), 207 [M-CF3]+ (100), 77 [C6H5]+ (19). 1-Methyl-3-(pentafluoroethyl)-5-phenyl-1H-pyrazole (3c). Colorless oil; yield 37% 1H NMR (400 MHz, CDCl3): d = 3.94 (s, 3H, Me), 6.58 (s, 1H, H-4), 7.41-7.51 (m, 5H, Ph). 19F NMR (3760 MHz, CDCl3): d = 114.0 (br. s, 2F, CF2), 85.6 (t, CF3, 3F, 3JF-F = 2.3 Hz). MS, m/z (%): 276 [M]+ (43), 207 [M-CF3]+ (100), 77 [C6H5]+ (11). IR (FTIR): 3066 (C H), 1469 (C¼N, C¼C), 1189–1215 (C-F) cm1. Analysis: Calc. for C12H9F5N2: C, 52.18; H, 3.28; F, 34.39; N, 10.14%. Found: C, 52.03; H, 3.25; N, 10.05%. MS, m/z (%): 276 [M]+ (43), 207 [M-CF3]+ (100), 77 [C6H5]+ (11). 1,5-Dimethyl-3-(pentafluoroethyl)-1H-pyrazole (3d). Colorless oil; yield 45%; 1H NMR (400 MHz, CDCl3): d = 2.31 (s, 3H, Me-5), 3.84 (s, 3H, Me-1), 6.30 (s, 1H, H-4). 19F NMR (376 MHz, CDCl3):

d = 114.2 (m, 2F, CF2), 85.8 (t, 3F, CF3, 3JF-F = 2.4 Hz). IR (FTIR):

1178–1198 (C-F) cm1. Analysis: Calc. for C7H7F5N2: C, 39.26; H, 3.30; N, 13.08; F, 44.36%. Found: C, 39.17; H, 3.23; N, 12.99%. 3-Ethyl-1-methyl-5-(1,1,2,2-tetrafluoroethyl)-1H-pyrazole (2e). 1H NMR (500 MHz, CDCl3): d = 1.26 (t, 3H, Me, 3J = 7.6 Hz), 2.67 (q, 2H, CH2, 3J = 7.6 Hz), 3.97 (s, 3H, Me), 6.00 (tt, 1H, H(CF2)2, 2JH3 19 F NMR (470 MHz, CDCl3): F = 53.7, JH-F = 2.6 Hz), 6.39 (s, 1H, H-4). d = 134.6 (td, 2F, H(CF2)2, 2JF-H = 53,7 3JF-F = 5.4 Hz), 110.4 (m, 2F, H(CF2)2). MS, m/z (%): 210 [M]+ (67), 195 [M-CH3]+ (100), 159 [MHCF2]+ (36), 51 [HCF2]+ (15). 5-Ethyl-1-methyl-3-(1,1,2,2-tetrafluoroethyl)-1H-pyrazole (3e). Yellow oil; yield 20%; 1H NMR (500 MHz, CDCl3): d = 1.26 (t, 3H, Me, 3J = 7.6 Hz), 2.67 (q, 2H, CH2, 3J = 7.6 Hz), 3.97 (s, 3H, Me), 6.00 (tt, 1H, H(CF2)2, 2JH-F = 53.7, 3JH-F = 2.6 Hz), 6.39 (s, 1H, H-4). 19F NMR (470 MHz, CDCl3): d = 137.4 (td, 2F, H(CF2)2, 3JF-F = 7.4, 2JF2 JF-H = 53.6, 3JF-F = 7.4 Hz). IR H = 4.4 Hz), 114.1 (dt, 2F, H(CF2)2, (FTIR): 1476 (C¼N, C¼C), 1110 (C-F) cm1. Analysis: Calc. for C8H10F4N2: C, 45.72; H, 4.80; F, 36.16; N, 13.33%. Found: C, 45.65; H, 4.79; N, 13.28%. MS, m/z (%): 210 [M]+ (23), 195 [M-CH3]+ (16), 159 [M-HCF2]+ (100). 5-(Heptafluoropropyl)-1-methyl-3-phenyl-1H-pyrazole (2f). Colorless oil; yield 60%; 1H NMR (500 MHz, CDCl3): d = 4.04 (s, 3H, Me), 6.9 (s, 1H, H-4), 7.32-7.43 (m, 3=, Hm,p, Ph), 7.77-7.79 (m, 2=, Ho, Ph). 19F NMR (470 MHz, CDCl3): d = 126.8 (m, 2F, CF2), 109.1 (m, 2F, CF2), 81.1 (t, CF3, 3F, 3JF-F = 9.9 Hz). IR (FTIR): 3030, 3066 (CH), 1439 (C¼N, C¼C), 1184–1233 (C-F) cm1. Analysis: Calc. for C13H9F7N2: C, 47.86; H, 2.78; F, 40.77; N, 8.59%. Found: C, 47.74; H, 2.79; N, 8.36%. 3-(Heptafluoropropyl)-1-methyl-5-phenyl-1H-pyrazole (3f). Colorless oil; yield 32%; 1H NMR (500 MHz, CDCl3): d = 3.95 (s, 3H, Me), 6.58 (s, 1H, H-4), 7.42-7.51 (m, 5H, Ph). 19F NMR (470 MHz, CDCl3): d = 128.0 (m, 2F, CF2), 111.8 (m, 2F, CF2), 81.3 (t, CF3, 3F, 3 JF-F = 9.6 Hz). Analysis: Calc. for C13H9F7N2: C, 47.86; H, 2.78; F, 40.77; N, 8.59%. Found: C, 47.73; H, 2.56; N, 8.49%. 1,5-Dimethyl-3-(heptafluoropropyl)-1H-pyrazole (3 g). Yellow oil; yield 55%; spectral data and physicochemical properties were in accordance with the literature [19]. 1-Methyl-4-[(4-methylphenyl)diazenyl]-5-trifluoromethyl-3-phenyl-1H-pyrazole (2 h). Orange crystals, 69%, mp, 76–78
C; 1H NMR (500 MHz, CDCl3): d = 2.42 (s, 3=, E6=4Me), 4.14 (m, 3H, *, J = 1.6 MHz, Me-1), 7.28–7.29 (m, 2=, Hm, E6=4); 7.36-7.43 (m, 3H, Hm,p, Ph); 7.71–7.73 (m, 2=, Ho, E6=4), 7.82-7.84 (m, 2=, Ho, Ph). 19F NMR (470 MHz, CDCl3): d = 58.5 (m, J = 1.6 MHz, CF3). IR (DRA): 3058 (E-H), 1485, 1442 (C¼N, C¼C), 1145 (C-F) cm1. Analysis: Calc. for E18=15N4F3: 62.79, = 4.39, N 16.27, F, 16.55%. Found: C, 62.60; H, 4.36; N, 16.18%. MS, m/z (%): 344 [M]+ (8), 91 [C7H7]+ (100), 89 [C7H5]+ (15), 77 [C6H5]+ (13), 51 [C4H3]+ (11), 43 [CH3N2]+ (12). 1-Methyl-4-[(4-methylphenyl)diazenyl]-3-trifluoromethyl-5-phenyl-1H-pyrazole (3 h). Yield 55%; spectral data and physicochemical properties were in accordance with the literature [48]. 1,3-Dimethyl-4-[(4-methylphenyl)diazenyl]-5-trifluoromethyl1H-pyrazole (2i). Orange crystals, 48%, mp, 58–60
C; 1H NMR (500 MHz, CDCl3): d = 2.42 (s, 3=, E6=4Me); 2.48 (s, 3=, c, Me-3); 4.01 (3.90) (m, 3H, J = 1.1, Me-1); 7.27–7.29 (m, 2=, Hm, E6=4); 7.73–7.75 (m, 2=, Ho, E6=4). 19F NMR (470 MHz, CDCl3): d = 58.3 (-59.7) (m, J = 1.1, CF3). IR (DRA): 3036 (C H), 1129 (C-F) cm1. Analysis: Calc. for E13=13N4F3: E 55.32; = 4.64; N 19.85; F, 20.19%. Found: C, 55.51; H, 4.71; N, 20.09%. MS, m/z (%): 282 [M]+ (8), 163 [M-C7H7N2]+ (19), 91 [C7H7]+ (100), 51 [C4H3]+ (24), 43 [CH3N2]+ (75) 1,5-Dimethyl-4-[(4-methylphenyl)diazenyl]-3-trifluoromethyl1H-pyrazole (3i). Orange crystals, 63%, mp, 119–120
C; 1H NMR (500 MHz, CDCl3): d = 2.42 (2.33) (s, 3=, E6=4Me); 2.62 (s, 3=, Me3); 3.88 (3.68) (s, 3H, Me-1); 7.27–7.29 (m, 2=, Hm, E6=4); 7.73– 7.75 (m, 2=, Ho, E6=4). 19F NMR (470 MHz, CDCl3): d = 62.6 (-62.55) (s, CF3). IR (DRA): 3032 (C H), 1425, 1448 (C¼N, C¼C),

A.E. Ivanova et al. / Journal of Fluorine Chemistry 195 (2017) 47–56

1134–1151 (C-F) cm1. Analysis: Calc. for E13=13N4F3: E 55.32; = 4.64; N 19.85; F, 20.19%. Found: C, 55.15; H, 4.64; N, 19.67%. MS, m/z (%): 282 [M]+ (16), 91 [C7H7]+ (100), 51 [C4H3]+ (25), 43 [CH3N2]+ (39). 5-(Heptafluoropropyl)-1,3-dimethyl-4-[(4-methoxyphenyl)diazenyl]-1H-pyrazole (2j). Orange crystals, 65%, mp, 83–85
C; 1H NMR (400 MHz, CDCl3): d = 2.49 (s, 3=, Me-3); 3.88 (s, 3=, s, OMe); 4.01 (3.95) (m, 3H, Me-1); 6.97–6.99 (m, 2=, Hm, E6=4); 7.79–7.81 (m, 2=, Ho, E6=4). 19F NMR (376 MHz, CDCl3): d = 127.0 (-126.7) (m, 2F, CF2), 108.1 (-108.7) (m, 2F, CF2), 81.2 (t, 3F, CF3, 3JFH), 2848 (Me-O), 1500 (C¼N, F = 9.4 Hz). IR (DRA): 3070, 3044 (C C¼C), 1212–1260 (C-F) cm1. Analysis: Calc. for E15=13N4F7O: E 45.24; = 3.29; N 14.07; F, 33.39%. Found: C, 45.12; H, 3.55; N, 13.94%. MS, m/z (%): 398 [M]+ (48), 291 [M- C7H7O]+ (30), 135 [C7H7N2O]+ (23), 107 [C7H7O]+ (100), 77 [C5H5]+ (39). 3-(Heptafluoropropyl)-1,5-dimethyl-4-[(4-methoxyphenyl)diazenyl]-1H-pyrazole (3j). Orange crystals, 61%, mp, 83–85
C; 1H NMR (400 MHz, CDCl3): d = 2.60 (s, 3=, Me-5); 3.88 (s, 3=, c, OMe); 3.90 (s, 3H, Me-1); 6.97–6.99 (m, 2=, Hm, E6=4); 7.79–7.81 (m, 2=, Ho, E6=4). 19F NMR (376 MHz, CDCl3): d = 127.1 (-127.2) (m, 2F, CF2), 110.3 (-110.8) (m, 2F, CF2), 81.3 (t, 3F, CF3, 3JF-F = 9.5 Hz). IR (DRA): 2819 (Me-O), 1498 (C¼N, C¼C), 1182–1231 (C-F) cm1. Analysis: Calc. for E15=13N4F7O: E 45.24; = 3.29; N 14.07; F, 33.39%. Found: C, 45.43; H, 3.42; N, 13.89%. MS, m/z (%): 398 [M]+ (71), 291 [M- C7H7O]+ (56), 135 [C7H7N2O]+ (28), 107 [C7H7O]+ (100), 77 [C5H5]+ (40). The XRD analyses were performed on a Xcalibur 3 diffractometer on standard procedure (MoK-irradiation, graphite monochromator, v-scans with 1o step at T = 295(2) K). Using Olex2 [49], the structure 2 h was solved by Direct Methods with the ShelXS [50] and structure 3i was solved by Charge Flipping with Superflip [51] structure solution programs. The structures were refined with the ShelXL [49] refinement package using Least Squares minimization. All non-hydrogen atoms were refined in anisotropic approximation, H-atoms were refined in isotropic approximation in the “rider” model. Crystal Data for 3i. C13H13F3N4, M = 282.27, triclinic, a = 7.4365 (5) Å, b = 8.7485(7) Å, c = 11.2011(10) Å, a = 98.428(7)
, b = 101.062 (6)
, g = 95.612(6)
, V = 701.48(10) Å3, space group P-1, Z = 2, m(MoKa) = 0.111 mm1, 6584 reflections measured, 3810 unique (Rint = 0.0203) which were used in all calculations. The final wR2 = 0.2098 (all data) and R1 = 0.0615 (I > 2s(I)). Crystal Data for 2 h. C18H15F3N4, M = 344.34, triclinic, a = 6.6610 (11) Å, b = 7.1621(10) Å, c = 19.0337(18) Å, a = 83.959(9)
, b = 83.578 (10)
, g = 66.328(15)
, V = 824.59(19) Å3, space group P-1, Z = 2, m(MoKa) = 0.109 mm1, 7373 reflections measured, 4090 unique (Rint = 0.0192) which were used in all calculations. The final wR2 = 0.2041 (all data) and R1 = 0.0643 (I >2s(I)). CCDC 1513398 (compound 2 h) and 1513399 (compound 3i) contain the supplementary crystallographic data for this paper. The data can be obtained free of charge from the Cambridge Crystallographic Data Centre via http://www.ccdc.cam.ac.uk Acknowledgement This work was financially supported by the Russian Science Foundation (grant 16-13-10255). Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j. jfluchem.2017.01.009.

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