A general and efficient synthesis of pyrazoles catalyzed by Sc(OTf)3 under solvent-free conditions

Abstracts

Pyrazoles were prepared in excellent yields via solventless condensation of various 1,3-diketones (R¹COCHXCOCH3, R¹ = Me, Ph; X = H, Me, Cl) and hydrazines, acylhydrazines or sulfonyl hydrazines in the presence of a catalytic amount of Sc(OTf)3 at room temperature. Additionally, the catalyst could be recovered easily after the reactions and reused without evident loss in activity.

scandium(III) triflate; pyrazoles; 1,3-diketones; hydrazines; hydrazides; solvent-free

Pirazóis foram preparados em excelentes rendimentos via reação de condensação entre várias 1,3-dicetonas (R¹COCHXCOCH3, R¹ = Me, Ph; X = H, Me, Cl) e hidrazinas, acilhidrazinas ou sulfonil hidrazinas, na presença de quantidades catalíticas de Sc(OTf)3, a temperatura ambiente, na ausência de solventes. Adicionalmente, o catalisador foi facilmente recuperado após as reações e reutilizado sem perda evidente na atividade.

ARTICLE

A general and efficient synthesis of pyrazoles catalyzed by Sc(OTf)₃ under solvent-free conditions

Wei Xiong^I; Jiu-Xi Chen^I; Miao-Chang Liu^I; Jin-Chang Ding^I; Hua-Yue Wu^I,*; Wei-Ke Su^{I, II,*}

^ICollege of Chemistry and Materials Engineering, Wenzhou University, 325027 Wenzhou, China

^IIZhejiang Key Laboratory of Pharmaceutical Engineering, College of Pharmaceutical Sciences, Zhejiang University of Technology, 310014 Hangzhou, P. R., China

ABSTRACT

Pyrazoles were prepared in excellent yields via solventless condensation of various 1,3-diketones (R¹COCHXCOCH₃, R¹ = Me, Ph; X = H, Me, Cl) and hydrazines, acylhydrazines or sulfonyl hydrazines in the presence of a catalytic amount of Sc(OTf)₃ at room temperature. Additionally, the catalyst could be recovered easily after the reactions and reused without evident loss in activity.

Keywords: scandium(III) triflate, pyrazoles, 1,3-diketones, hydrazines, hydrazides, solvent-free

RESUMO

Pirazóis foram preparados em excelentes rendimentos via reação de condensação entre várias 1,3-dicetonas (R¹COCHXCOCH₃, R¹ = Me, Ph; X = H, Me, Cl) e hidrazinas, acilhidrazinas ou sulfonil hidrazinas, na presença de quantidades catalíticas de Sc(OTf)₃, a temperatura ambiente, na ausência de solventes. Adicionalmente, o catalisador foi facilmente recuperado após as reações e reutilizado sem perda evidente na atividade.

Introduction

Pyrazole and its derivatives constitute an important class of compounds, which exhibit various biological and pharmaceutical activities¹ ranging from antitumor² to antiinflammatory,³ antipsychotic,⁴ antimicrobial,⁵ antiviral⁶ and antifungal⁷ activities. They are also useful intermediates for many industrial products.⁸ It is therefore not surprising that many synthetic methods have been developed for the preparation of the heterocycles. The heterocycles can be synthesized via 1,3-dipolar cycloadditions of diazo compounds,⁹ reaction of acetylenic ketones¹⁰ or chalcones¹¹ and hydrazines, a four-component coupling of terminal alkynes, hydrazine, carbon monoxide, and aryl iodides.¹² Recently, a few efficient methods have been reported, too.¹³ Moreover, pyrazoles can also be successfully obtained from the direct condensation of 1,3-diketones and hydrazines.¹⁴ This is the most simple and straightforward procedure for their synthesis, a variety of catalysts such as H₂SO₄,¹⁵ polystyrene supported sulfonic acid,¹⁶ layered zirconium sulfophenyl phosphonate [a-Zr(CH₃PO₃)_1.2(O₃PC₆H₄SO₃H)_0.8],¹⁷ have been employed to effect this transformation. Although these methods are suitable for certain synthetic conditions, sometimes, however, many of these procedures are associated with one or more disadvantages such as long reaction time, low yield, use of volatile organic solvents, requirement of excess of reagents or catalysts, special apparatus and harsh reaction conditions. And some of them need stoichiometric amount of acids which can be trapped by hydrazines in this condensation. Due to the importance of these compounds, the development of convenient, environmentally benign, high-yielding and clean approaches is highly desirable. To our knowledge, less attention has been paid to the synthesis of pyrazoles from 1,3-diketones and acylhydrazines/sulfonyl hydrazines in the presence of Lewis acid.

Metal triflates are unique Lewis acids that are currently of great research interest.¹⁸ Firstly, metal triflates are air- and water- stable, thermal stable, less toxic, easily recovered and reused. In addition, metal triflates are still active in the coexistence of many substrates containing nitrogen, oxygen, phosphorous, and sulfur atoms. Due to these advantages, they are widely used in organic synthesis.¹⁹ Recently, we have successfully applied metal triflates into several reactions.²⁰ In continuation of our interest in green chemistry and Lewis acid-catalyzed organic reactions,²¹ we herein develop a green, simple and practical method for the synthesis of pyrazoles from 1,3-diketones with hydrazines, acylhydrazines and sulfonyl hydrazines catalyzed by Sc(OTf)₃ under solvent-free conditions.

Results and Discussion

To optimize the reaction conditions, we studied the condensation of pentane-2,4-dione with benzohydrazide in various reaction conditions and the results were summarized in Table 1.

Among the various catalyst such as Sc(OTf)₃, Cu(OTf)₂, Zn(OTf)₂, Yb(OTf)₃, InCl₃, ZrSO₄·4H₂O (Table 1, entries 1-6), Sc(OTf)₃ was found to be the most effective catalyst in terms of reaction yields and rate. Then, the reaction was performed in different amounts of Sc(OTf)₃. It was found that the yield was not significantly affected by adding amount of Sc(OTf)₃, and 2 mol % of Sc(OTf)₃ was sufficient, and excessive amount of catalyst did not increase the yield remarkably (Table 1, entries 1, 7 and 8). The use of 2 mol % Sc(OTf)₃ was optimal to ensure high reaction efficiency at room temperature in the absence of solvent. It was found that only the intermediate (5-hydroxy-3,5-dimethyl-4,5-dihydro-1H-pyrazol-1-yl)(phenyl)methanone (4) was observed when the mixture was stirred under similar conditions in the absence of Sc(OTf)₃, even after 1 h (Table 1, entry 9). It was proved that the catalyst did play an important role in this reaction.

The general efficiency of this protocol was then studied for the synthesis of a variety of pyrazoles and the results were summarized in Table 2.

As can be seen from Table 2, various hydrazines and acylhydrazines reacted efficiently with 1,3-diketones to afford the desired pyrazoles in good yields. A series of aromatic hydrazides bearing either electron-donating (Table 2, entries 1, 2, 9, 10, 13 and 14) or electron-withdrawing (Table 2, entries 4, 12, 16) groups on aromatic ring were investigated. The substitution group on the phenyl ring did not seem to affect the reaction significantly either in the yield of product or the rate of the reaction. Moreover, we also examined the condensation of aliphatic hydrazide with 1,3-diketone (Table 2, entry 5). Similarly, the corresponding product was obtained with good yields. Apart from the spectroscopic evidence, meanwhile, the structure of 3i (Table 2, entry 9) was confirmed by a single crystal X-ray diffraction analysis (Figure 1).²²

Furthermore, the advantage of the present protocol was also evidenced when less reactive hydrazines were used in the following reactions. Wang and Qin ¹⁵ reported that the solventless condensation of 2,4-dinitrophenylhydrazine with 2,4-pentanedione only afforded hydrazone derivative 2,2'-(pentane-2,4-diylidene)bis(1-(2,4-dinitrophenyl) hydrazine) (5) in the presence of sulfuric acid. However, 2,4-dinitrophenyl hydrazine smoothly reacted with 2,4-pentanedione to afford the desired pyrazole derivative (3h) in excellent yield (99%) using the present protocol (Table 2, entry 8). And other less reactive hydrazines such as 4-nitro-phenyl hydrazinecan also smoothly reacted with 1,3-diketones to afford the desired product in high yields (Table 2, entry 7). It is noteworthy that we also examined the activity of recycled Sc(OTf)₃ catalyst. The reaction mixture was washed with water, extracted with ethyl acetate, and the aqueous phase was dried at 140 ºC for 4 h. The residue could be reused for the next batch reaction. It was found that Sc(OTf)₃ could be reused three times without evident loss of activity (with the yields of the corresponding product being 95%, 94%, and 92%, respectively); Table 2, entry 1.

Next, we examined the condensation reactions of 1,3-diketones with p-toluenesulfonylhydrazide (Scheme 1). 3,5-Dimethyl-1-tosyl-1H-pyrazole (3q) and 4-chloro-3,5-dimethyl-1-tosyl-1H-pyrazole (3r) were obtained in 99%, and 82% yields respectively when the reaction was performed at 60 ºC in the presence of Sc(OTf)₃. Nevertheless, trace product was obtained in the absence of catalysts, which also further proved that Sc(OTf)₃ did play an important role in this reaction.

Finally, to extend the scope of triflate-catalyzed method of pyrazoles formation, an unsymmetrical diketone such as 1-phenylbutane-1,3-dione was employed. As shown in Scheme 2, the reaction was also performed smoothly and a very good regioselectivity was also observed (3s : 3s' = 13 : 1, ratio based on its ¹H NMR spectrum).

In summary, a new catalytic protocol to synthesize pyrazoles has been developed. Compared to previous reported methodologies, the present protocol features simple work-up, short reaction time, environmentally benign, easy recovery and reuse of metal triflate and mild reaction conditions with excellent yield. Currently, studies on the extension of this protocol are ongoing in our laboratory.

Experimental

All reagents were commercial available and used without any purification. Melting points were recorded on Digital Melting Point Apparatus WRS-1B and are uncorrected. IR spectra were recorded on a Bruker-EQUINOX55 spectrometer. Mass spectra (EI, 70 eV) were measured with SHIMADZU GCMS-QP2010 Plus. ¹H NMR and ¹³C NMR spectra were recorded on a Brucker AC 300 instrument using CDCl₃ as the solvent with tetramethylsilane (TMS) as an internal standard at room temperature. Chemical shifts were given in d relative to TMS, the coupling constants J are given in Hz. Elemental analysis was determined on a Carlo-Erba 1108 instrument. X-ray diffraction data were collected on a Bruker Smart Apex diffractometer with graphite-monochromated (Mo Ka, λ 0.70173Å) radiation using SMART. All reactions were conducted using standard Schlenk techniques. Column chromatography was performed using EM Silica gel 60 (300-400 mesh).

General procedure for the preparation of pyrazoles

The hydazines/hydrazides (1.0 mmol) and Sc(OTf)₃ (2 mol %) were placed in a Schlenk reaction tube with efficient stirring or mixing, then 1,3-diketone (1.0 mmol) was added. The mixture was stirred for 20 min at room temperature. After completion of the reaction, as indicated by TLC, the reaction mixture was washed with water, extracted with ethyl acetate, the organic phase was separated and dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum. Then, the residue was purified by flash column chromatography on a silica gel to give the corresponding product.

The spectral and analytical data of some representative compounds are given below.

(3,5-Dimethyl-1H-pyrazol-1-yl)(2-ethoxyphenyl)methanone (3a)

White solid, mp 70 ºC; ¹H NMR (300 MHz, CDCl₃): δ (ppm) 1.19 (t, 3H, J 7.0 Hz, CH₃), 2.16 (s, 3H, CH₃), 2.62 (s, 3H, CH₃), 4.02 (q, 2H, J 7.0 Hz, CH₂), 6.00 (s, 1H, CH), 6.93-7.03 (m, 2H, ArH), 7.40-7.46 (m, 2H, ArH); ¹³C NMR (75 MHz, CDCl₃): δ (ppm) 13.9, 14.2, 14.6 (3CH₃), 64.2 (CH₂), 110.9 (C4), 112.7, 120.2, 125.2, 129.7, 132.1 (5C, Ph), 144.0 (C5), 151.9 (C3), 156.9 (C-OEt, Ph), 168.6 (C=O); IR (KBr) ν_max/cm^-1: 3068, 2974, 2928, 2890, 1709, 1587, 1485, 1401, 1336, 1250, 1038, 900, 664; MS (EI, 70 eV): m/z (%) = 244 (M⁺, 1), 199 (67), 149 (28), 121 (100), 93 (21), 65 (19). Anal. Calc. for C₁₄H₁₆N₂O₂: C, 68.83; H, 6.60; N, 11.47. Found: C, 68.75; H, 6.64; N, 11.52.

(3,5-Dimethyl-1H-pyrazol-1-yl)(4-methoxyphenyl)methanone (3b)

White solid, mp 48 ºC; ¹H NMR (300 MHz, CDCl₃): δ (ppm) 2.22 (s, 3H, CH₃), 2.57 (s, 3H, CH₃), 3.80 (s, 3H, CH₃), 5.99 (s, 1H, CH), 6.91 (d, 2H, J 8.3 Hz, ArH), 8.03 (m, 2H, J 8.3 Hz, ArH); ¹³C NMR (75 MHz, CDCl₃): δ (ppm) 13.8, 14.2 (2CH₃), 55.4 (OCH₃), 110.7 (C4), 113.3, 125.3, 134.0 (3C, Ph), 144.9 (C5), 151.6 (C3), 163.2 (C-OMe, Ph), 167.4 (C=O); IR (KBr) ν_max/cm^-1: 3033, 2928, 1689, 1602, 1342, 1262, 669; MS (EI, 70 eV): m/z (%) = 230 (M⁺, 7), 135 (100), 107 (10), 92 (10), 77 (15). Anal. Calc. for C₁₃H₁₄N₂O₂: C, 67.81; H, 6.13; N, 12.17. Found: C, 67.88; H, 6.26; N, 12.19.

(3,5-Dimethyl-1H-pyrazol-1-yl)(phenyl)methanone (3c)¹⁵

Colorless oil; ¹H NMR (300 MHz, CDCl₃): δ (ppm) 2.24 (s, 3H, CH₃), 2.63 (s, 3H, CH₃), 6.05 (s, 3H, CH), 7.42-7.54 (m, 3H, ArH), 7.98 (d, 2H, J 7.2 Hz, ArH); ¹³C NMR (75 MHz, CDCl₃): δ (ppm) 13.9, 14.4 (2CH₃), 111.1 (C4), 127.9, 131.4, 132.4, 133.4 (6C, Ph), 145.1 (C5), 152.1 (C3), 168.4 (C=O); IR (KBr) ν_max/cm^-1: 3063, 2976, 2928, 1698, 1586, 1340, 918, 705.

(2-Chlorophenyl)(3,5-dimethyl-1H-pyrazol-1-yl)methanone (3d)²³

Colorless oil; ¹H NMR (300MHz, CDCl₃): δ (ppm) 2.13 (s, 3H, CH₃), 2.65 (s, 3H, CH₃), 6.03 (s, 1H, CH), 7.29-7.47 (m, 4H, ArH); ¹³C NMR (75 MHz, CDCl₃): δ (ppm) 13.9, 14.2 (2CH₃), 111.9 (C4), 126.4, 129.3, 129.6, 131.2, 131.5, 135.2 (6C, Ph), 144.4 (C5), 153.2 (C3), 167.4 (C=O); IR (KBr) ν_max/cm^-1: 3066, 2978, 2929, 1712, 1587, 1346, 967, 918, 746, 652.

1-(3,5-Dimethyl-1H-pyrazol-1-yl)ethanone (3e)¹⁵

Colorless oil; ¹H NMR (300 MHz, CDCl₃): δ (ppm) 2.21 (s, 3H, CH₃), 2.51 (s, 3H, CH₃), 2.63 (s, 3H, CH₃), 5.92 (s, 1H, CH); ¹³C NMR (75 MHz, CDCl₃): δ (ppm) 13.8, 14.6 (2CH₃), 23.5 (CH₃CO) , 111.1 (C4), 144.0 (C5), 152.0 (C3), 171.5 (C=O); IR (KBr) ν_max/cm^-1: 2924, 2859, 1730, 1666, 1457, 1142, 647.

3,5-Dimethyl-1-phenyl-1H-pyrazole (3f)¹⁵

Yellow oil; ¹H NMR (300MHz, CDCl₃): δ (ppm) 2.25 (s, 3H, CH₃), 2.29 (s, 3H, CH₃), 5.96 (s, 1H, CH), 7.28-7.40 (m, 5H, ArH); ¹³C NMR (75 MHz, CDCl₃): δ (ppm) 12.3, 13.5 (2CH₃), 107.0 (C4), 124.6, 127.2, 128.9, 139.3 (6C, Ph), 139.9 (C5), 148.9 (C3); IR (KBr) ν_max/cm^-1: 3059, 2923, 1598, 1555, 1501, 1421, 1376, 778, 693.

3,5-Dimethyl-1-(4-nitrophenyl)-1H-pyrazole (3g)²⁴

Yellow solid, mp 100-101 ºC; ¹H NMR (300 MHz, CDCl₃): δ (ppm) 2.29 (s, 3H, CH₃), 2.41 (s, 3H, CH₃), 6.06 (s, 1H, CH), 7.66 (d, 2H, J 7.3 Hz, ArH), 8.30 (d, 2H, J 7.3 Hz, ArH); ¹³C NMR (75 MHz, CDCl₃): δ (ppm) 13.2, 13.5 (2CH₃), 109.4 (C4), 123.5, 124.8 (4C, Ph), 139.9 (C5), 145.0 (C-NO₂, Ph), 145.5 (C-N, Ph), 150.9 (C3); IR (KBr) ν_max/cm^-1: 3102, 2977, 2923, 1660, 1598, 1513, 1331, 1103, 852.

1-(2,4-Dinitrophenyl)-3,5-dimethyl-1H-pyrazole (3h)²⁴

Yellow solid, mp 122-123 ºC; ¹H NMR (300 MHz, CDCl₃): δ (ppm) 2.24 (s, 3H, CH₃), 2.26 (s, 3H, CH₃), 6.09 (s, 1H, CH), 7.69 (d, 1H, J 8.7 Hz, ArH), 8.52 (dd, 1H, J₁ 8.7 Hz, J₂ 2.0 Hz, ArH), 8.78 (s, 1H, ArH); ¹³C NMR (75 MHz, CDCl₃): δ (ppm) 11.6, 13.5 (2CH₃), 108.9 (C4), 121.0, 127.3, 129.3, 137.9 (4C, Ph), 140.9 (C5), 145.6 , 146.2 (2C-NO₂, Ph), 152.4 (C3); IR (KBr) ν_max/cm^-1: 3120, 3077, 2928, 2865, 1612, 1532, 1432, 1344, 1124, 1025, 973, 903, 671.

(2-Ethoxyphenyl)(3,4,5-trimethyl-1H-pyrazol-1-yl)methanone (3i)

White solid, mp 60 ºC; ¹H NMR (300 MHz, CDCl₃): δ (ppm) 1.17 (t, 3H, J 7.0 Hz, CH₃), 1.91 (s, 3H, CH₃), 2.09 (s, 3H, CH₃), 2.54 (s, 3H, CH₃), 3.99 (q, 2H, J 7.0 Hz, CH₂), 6.90-6.99 (m, 2H, ArH), 7.35-7.41 (m, 2H, ArH); ¹³C NMR (75 MHz, CDCl₃): δ (ppm) 7.7, 12.4, 12.5, 14.6 (4CH₃), 64.2 (CH₂), 112.7 (C4), 117.3, 120.1, 125.6, 129.6, 131.8 (5C, Ph), 139.5 (C5), 152.3 (C3), 156.7 (C-OEt, Ph), 168.4 (C=O); IR (KBr) ν_max/cm^-1: 3047, 2981, 2927, 2881, 1717, 1593, 1488, 1442, 1386, 1343, 901,753, 655; MS (EI, 70 eV): m/z (%) = 258 (M⁺, 1), 213 (75), 149 (28), 121 (100), 93 (22), 65 (18). Anal. Calc. for C₁₅H₁₈N₂O₂: C, 69.74; H, 7.02; N, 10.84. Found: C, 69.78; H, 6.97; N, 10.89.

(4-Methoxyphenyl)(3,4,5-trimethyl-1H-pyrazol-1-yl)methanone (3j)

Yellow solid, mp 80-81 ºC; ¹H NMR (300 MHz, CDCl₃): δ (ppm) 1.93 (s, 3H, CH₃), 2.18 (s, 3H, CH₃), 2.51 (s, 3H, CH₃), 3.83 (s, 3H, CH₃), 6.92 (d, 2H, J 8.9 Hz, ArH), 8.00 (d, 2H, J 8.9 Hz, ArH); ¹³C NMR (75 MHz, CDCl₃): δ (ppm) 7.7, 12.4, 12.5 (3CH₃), 55.4 (OCH₃), 113.2 (C4), 117.1, 125.7, 133.9 (5C, Ph), 140.4 (C5), 152.0 (C3), 163.0 (C-OMe, Ph), 167.5 (C=O); IR (KBr) ν_max/cm^-1: 3031, 2924, 2846, 1677, 1601, 1501, 1340, 1256, 906, 617; MS (EI, 70 eV): m/z (%) = 244 (M⁺, 8), 135 (100), 107 (10), 92 (10), 77 (15). Anal. Calc. for C₁₄H₁₆N₂O₂: C, 68.83; H, 6.60; N, 11.47. Found: C, 68.90; H, 6.53; N, 11.52.

Phenyl(3,4,5-trimethyl-1H-pyrazol-1-yl)methanone (3k)²⁵

Colorless oil; ¹H NMR (300 MHz, CDCl₃): δ (ppm) 1.95 (s, 3H, CH₃), 2.18 (s, 3H, CH₃), 2.54 (s, 3H, CH₃), 7.41-7.53 (m, 3H, ArH), 7.95 (d, 2H, J 8.5 Hz, ArH); ¹³C NMR (75 MHz, CDCl₃): δ (ppm) 7.7, 12.4, 12.6 (3CH₃), 117.5 (C4), 127.8, 131.3, 132.2, 133.7 (6C, Ph), 140.5 (C5), 152.5 (C3), 168.4 (C=O); IR (KBr) ν_max/cm^-1: 3063, 2925, 2863, 1692, 1601, 1343, 910, 708.

(2-Chlorophenyl)(3,4,5-trimethyl-1H-pyrazol-1-yl)methanone (3l)

White solid, mp 96-97 ºC; ¹H NMR (300 MHz, CDCl₃): δ (ppm) 1.97 (s, 3H, CH₃), 2.14 (s, 3H, CH₃), 2.62 (s, 3H, CH₃), 7.35-7.47 (m, 4H, ArH); ¹³C NMR (75 MHz, CDCl₃): δ (ppm) 7.7, 12.5, 14.2 (3CH₃), 118.3 (C4), 126.4, 129.2, 129.7, 131.0, 131.6, 135.5 (6C, Ph), 139.8 (C5), 153.7 (C3), 167.3 (C=O); IR (KBr) ν_max/cm^-1: 3042, 2926, 1699, 1604, 1348, 1050, 907, 756, 637; MS (EI, 70 eV): m/z (%) = 248 (M⁺, 1), 213 (100), 139 (84), 111 (39), 75 (17). Anal. Calc. for C₁₃H₁₃ClN₂O: C, 62.78; H, 5.27; N, 11.26. Found: C, 62.81; H, 5.22; N, 11.33.

(4-Chloro-3,5-dimethyl-1H-pyrazol-1-yl)(2-ethoxyphenyl)methanone (3m)

Yellow oil; ¹H NMR (300 MHz, CDCl₃): δ (ppm) 1.22 (t, 3H, J 7.0 Hz, CH₃), 2.21 (s, 3H, CH₃), 2.66 (s, 3H, CH₃), 4.05 (q, 2H, J 7.0 Hz, CH₂), 6.96-7.07 (m, 2H, ArH), 7.44-7.50 (m, 2H, ArH); ¹³C NMR (75 MHz, CDCl₃): δ (ppm) 11.8, 12.2, 14.6 (3CH₃), 64.2 (CH₂), 112.6 (C4), 114.4, 120.2, 124.2, 129.8, 132.5 (5C, Ph), 139.3 (C5), 149.3 (C3), 156.9 (C-OEt, Ph), 168.2 (C=O); IR (KBr) ν_max/cm^-1: 3069, 2981, 2929, 1717, 1595, 1488, 1449, 1340, 1254, 928, 755, 673; MS (EI, 70 eV): m/z (%) = 278 (M⁺, 2), 233 (35), 149 (54), 121 (100), 93 (19), 65 (17). Anal. Calc. for C₁₄H₁₅ClN₂O₂: C, 60.33; H, 5.42; N, 10.05. Found: C, 60.26; H, 5.39; N, 10.11.

(4-Chloro-3,5-dimethyl-1H-pyrazol-1-yl)(4-methoxyphenyl) methanone (3n)

White solid, mp 125-126 ºC; ¹H NMR (300 MHz, CDCl₃): δ (ppm) 2.29 (s, 3H, CH₃), 2.62 (s, 3H, CH₃), 3.89 (s, 3H, CH₃), 6.98 (d, 2H, J 8.4 Hz, ArH), 8.03 (d, 2H, J 8.5 Hz, ArH); ¹³C NMR (75 MHz, CDCl₃): δ (ppm) 11.8, 12.3 (2CH₃), 55.5 (OCH₃), 113.4 (C4), 114.1, 124.4, 134.0 (5C, Ph), 140.3 (C5), 149.0 (C3), 163.4 (C-OMe, Ph), 167.0 (C=O); IR (KBr) ν_max/cm^-1: 3079, 2928, 2843, 1689, 1602, 1504, 1454, 1344, 1266, 696; MS (EI, 70 eV): m/z (%) = 264 (M⁺, 5), 135 (100), 107 (9), 92 (10), 77 (14). Anal. Calc. for C₁₃H₁₃ClN₂O₂: C, 58.99; H, 4.95; N, 10.58. Found: C, 59.02; H, 4.89; N, 10.65.

(4-Chloro-3,5-dimethyl-1H-pyrazol-1-yl)(phenyl)methanone (3o)²⁶

White solid, mp 48-49 ºC; ¹H NMR (300 MHz, CDCl₃): δ (ppm) 2.29 (s, 3H, CH₃), 2.66 (s, 3H, CH₃), 7.47-7.61 (m, 3H, ArH), 7.97-8.00 (m, 2H, ArH); ¹³C NMR (75 MHz, CDCl₃): δ (ppm) 11.8, 12.4 (2CH₃), 114.9 (C4), 128.0, 131.4, 132.5, 132.7 (6C, Ph), 140.4 (C5), 149.6 (C3), 167.9 (C=O); IR (KBr) ν_max/cm^-1: 3066, 2926, 1700, 1588, 1487, 1447, 1343, 1272, 686.

(4-Chloro-3,5-dimethyl-1H-pyrazol-1-yl)(2-chlorophenyl)methanone (3p)

White solid, mp 81-82 ºC; ¹H NMR (300 MHz, CDCl₃): δ (ppm) 2.17 (s, 3H, CH₃), 2.66 (s, 3H, CH₃), 7.35-7.45 (m, 4H, ArH); ¹³C NMR (75 MHz, CDCl₃): δ (ppm) 11.8, 12.2 (2CH₃), 115.5 (C4), 126.4, 129.4, 129.7, 131.5, 131.8, 134.3 (6C, Ph), 139.7, (C5), 150.7 (C3), 167.0 (C=O); IR (KBr) ν_max/cm^-1: 3065, 2969, 2922, 2855, 1715, 1587, 1335, 924, 734, 651; MS (EI, 70 eV): m/z (%) = 268 (M⁺, 1), 233 (50), 139 (100), 111 (38), 75 (21). Anal. Calc. for C₁₂H₁₀Cl₂N₂O: C, 53.55; H, 3.75; N, 10.41. Found: C, 53.61; H, 3.79; N, 10.34.

3,5-Dimethyl-1-tosyl-1H-pyrazole (3q)²⁷

White solid, mp 95 ºC; ¹H NMR (300 MHz, CDCl₃): δ (ppm) 2.20 (s, 3H, CH₃), 2.40 (s, 3H, CH₃), 2.49 (s, 3H, CH₃), 5.90 (s, 1H, CH), 7.30 (d, 2H, J 8.1 Hz, ArH), 7.83 (d, 2H, J 8.2 Hz, ArH); ¹³C NMR (75 MHz, CDCl₃): δ (ppm) 13.1, 13.8, 21.6 (3CH₃), 110.8 (C4), 127.5, 129.9, 135.3, 144.1 (6C, Ph), 145.2 (C5), 153.4 (C3); IR (KBr) ν_max/cm^-1: 3041, 2928, 2863, 1656, 1580, 1372, 1292, 1186, 1120, 809, 668, 591, 534.

4-Chloro-3,5-dimethyl-1-tosyl-1H-pyrazole (3r)

White solid, mp 126-127 ºC; ¹H NMR (300 MHz, CDCl₃): δ (ppm) 2.17 (s, 3H, CH₃), 2.38 (s, 3H, CH₃), 2.45 (s, 3H, CH₃), 7.29 (d, 2H, J 8.2 Hz, ArH), 7.80 (d, 2H, J 8.4 Hz, ArH); ¹³C NMR (75 MHz, CDCl₃): δ (ppm) 11.2, 11.9, 21.7 (3CH₃), 113.5 (C4), 127.7, 130.1, 134.7, 139.3 (6C, Ph), 145.7 (C5), 150.9 (C3); IR (KBr) ν_max/cm^-1: 3067, 2927, 2859, 1581, 1451, 1374, 1188, 1151, 669; MS (EI, 70 eV): m/z (%) = 284 (M⁺, 4), 220 (30), 129 (8), 91 (100), 65 (30). Anal. Calc. for C₁₂H₁₃ClN₂O₂S: C, 50.61; H, 4.60; N, 9.84. Found: C, 50.63; H, 4.65; N, 9.87.

(5-Hydroxy-3,5-dimethyl-4,5-dihydro-1H-pyrazol-1-yl)(phenyl)methanone (4)²⁸

Colorless oil; ¹H NMR (300 MHz, CDCl₃): δ (ppm) 1.92 (s, 3H, CH₃), 1.94 (s, 3H, CH₃), 2.76 (d, 1H, J 18.4 Hz, CH₂), 2.99 (d, 1H, J 18.4 Hz, CH₂), 5.30 (s, 1H, OH), 7.33-7.44 (m, 3H, ArH), 7.82-7.84 (m, 2H, ArH); IR (KBr) ν_max/cm^-1: 3445, 3063, 2983, 2930, 1695, 1626, 1438, 1340, 1224, 1120, 918, 706.

3-Methyl-1,5-diphenyl-1H-pyrazole (3s) and 5-methyl-1,3-diphenyl-1H-pyrazole (3s')¹⁵

(3s): colorless oil; ¹H NMR (300 MHz, CDCl₃): δ (ppm) 2.39(s, 3H, CH₃), 6.31 (s, 1H, CH₃), 7.21-7.30 (m, 10H, ArH); ¹³C NMR (75 MHz, CDCl₃): δ (ppm) 13.6 (CH₃), 107.8 (C4), 125.1, 127.1, 128.1, 128.4, 128.7, 128.9, 130.8, 140.2 (12C, 2Ph), 143.7 (C5), 149.5 (C3); IR (KBr) ν_max/cm^-1: 3057, 2925, 2866, 1597, 1550, 1500, 1450, 1419, 1369, 763, 694.; (3s'): ¹H NMR (300 MHz, CDCl₃): δ (ppm) 2.38(s, 3H, CH₃), 6.41 (s, 1H, CH₃), 7.30-7.39 (m, 10H, ArH).

Acknowledgments

We are grateful to the National Natural Science Foundation of China (No. 20676123) and Natural Science Foundation of Zhejiang Province (Y4080107) for financial support.

Supplementary Information

Supplementary data are available free of charge at http://jbcs.sbq.org.br, as PDF file.

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Received: August 25, 2008

Web Release Date: January 22, 2009

SUPPLEMENTARY INFORMATION

Publication Dates

• Publication in this collection
  27 Feb 2009
• Date of issue
  2009

History

• Received
  25 Aug 2008
• Accepted
  22 Jan 2009