Ionic liquid-supported sulfonyl hydrazine: a useful reagent for traceless synthesis of pyrazoles

Abstract

Ionic liquid-supported sulfonyl hydrazine has been synthesized and used as a soluble support for the traceless synthesis of highly substituted pyrazoles from two different routes. Various substituted pyrazoles were synthesized in high yields. A key feature of the protocol is an easy and convenient purification process that avoids chromatographic separation of products and thus makes the method eco-friendly and economical.

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Introduction

Nitrogen-containing heterocycles are of great chemical and biological significance. In particular, pyrazole is a popular synthetic target for pharmaceutical, material and agrochemical industries.^1,2 Numerous compounds containing the pyrazole moiety are known to exhibit biological activities such as analgesic,³ antimicrobial,⁴ anti-convulsant,⁵ antidepressant,⁶ anti-inflammatory,^7,8 anti-arthritics,⁹ cannabinoid-1 (CB1) receptor antagonists,^10–12 Iκβ kinase β (IKKβ or IKK-2) inhibition¹³ and HIV-1 reverse transcriptase inhibition.¹⁴ Pyrazole constitutes the basic framework of several drug molecules. Structures of some important pyrazole containing drugs such as Celecoxib (selective COX-2 inhibition, 1), Zaleplon (insomnia, 2), Zoniporide (selective human NHE-1 inhibition, 3), Sildenafil (erectile dysfunction, 4), and Acomplia (selective CB1 receptor blocker, 5) are depicted in Fig. 1.

Fig. 1 Structure of some drugs containing the pyrazole ring.

Owing to the attractive biological properties of pyrazoles, considerable attention has been focused on developing methods for the preparation of diversely substituted pyrazoles.^15–22 The most common methods for preparing pyrazoles are (a) the reaction of 1,3-diketones with hydrazines or its derivatives,^23–25 (b) the reaction of α,β-unsaturated aldehydes and ketones with hydrazines followed by oxidation,²⁶ and (c) [3 + 2]-cycloaddition of diazo compounds with alkynes.²⁷ Formation of two regioisomers by the condensation of 1,3-diketones or unsaturated aldehydes and ketones with hydrazine or arylhydrazines is an inevitable drawback of the first two methods. On the other hand, preparing toxic and potentially explosive diazo compounds and handling reactive 1,3-dipolar compounds limit the synthetic utility of the third method. With the aim to solve the handling problem in diazo compounds, Aggarwal et al. reported a one-pot method for the preparation of pyrazoles by 1,3-dipolar cycloaddition of in situ generated diazo compounds from tosylhydrazones of aldehydes in the presence of a base.²⁸ Wu et al. also synthesized 3,5-disubstituted pyrazoles by the reaction of aldehydes with tosylhydrazine followed by cycloaddition with terminal alkynes.²⁹ Recently, the Tang group applied this protocol for the synthesis of 1,3,5-trisubstituted-1H-pyrazoles from N-alkylated tosylhydrazones to increase the range of substrates and demonstrated excellent tolerance to a variety of substituents, including both electron-donating and electron-withdrawing groups.³⁰ This approach solved some of the traditional problems inherent in the [3 + 2]-cycloaddition of diazo compounds to alkynes for the synthesis of pyrazoles. However, purification of pyrazoles from the co-product tosylsulfonamide remains a challenge and requires extensive chromatographic separation.

We recently synthesized ionic liquid-supported sulfonyl azide and it has proven to be a highly effective and safe diazotransfer reagent for active methylene compounds. The diazo compounds could be easily separated from the co-product sulfonamide without chromatographic separation. We envisioned that the use of ionic liquid-supported sulfonyl hydrazine could solve the problem of separation in the synthesis of pyrazoles and thus designed two routes to synthesize pyrazoles using ionic liquid-supported sulfonyl hydrazine as a soluble support (Scheme 1). The first one is by the condensation of α,β-unsaturated carbonyl compounds to ionic liquid-supported sulfonyl hydrazine 6 followed by cyclization in the presence of a base and the second one by the 1,3-dipolar cycloaddition of alkynes with ionic liquid-supported sulfonyl hydrazones 10, which were obtained by reacting 6 with the corresponding aldehydes. In this article, we report our results on traceless synthesis of pyrazoles using ionic liquid-supported sulfonyl hydrazine.

Scheme 1 Synthetic approach for the synthesis of pyrazoles from ionic liquid-supported sulfonyl hydrazine.

Results and discussion

Our investigations commenced with the synthesis of ionic liquid-supported sulfonyl hydrazones 9 and 10 by the reaction of ionic liquid-supported sulfonyl hydrazine 6 with α,β-unsaturated carbonyl compounds 7 and aryl aldehydes 8, respectively (Scheme 2). The reaction of 6 with 1-phenylbut-2-en-1-one 7a in ethanol for 5 h at 40 °C followed by evaporation of ethanol, washing of the ionic liquid layer with an ethyl acetate–hexane mixture (1 : 1 v/v) and drying under vacuum gave 9a in excellent yield (86%) with high purity. The structure and purity of ionic liquid-supported hydrazones 9a were confirmed by ¹H and ¹³C NMR data. In ¹H NMR of 9a the characteristic peak for CH₃–C=N proton appeared at 2.08 ppm as a singlet and C=N carbon appeared at around 154.49 ppm in the ¹³C NMR spectrum.

Scheme 2 Synthesis of ionic liquid-supported sulfonyl hydrazones 9 and 10.

As can be seen from Table 1, the reaction has wide substrate scope. Reaction of 6 with 7 or 8 bearing both electron-withdrawing and/or electron donating substituents resulted in the corresponding ionic liquid-supported sulfonyl hydrazones 9a–o & 10a–g in good to excellent yields (54–92%). The ¹H and ¹³C NMR spectra of all the sulfonyl hydrazones 9 & 10 were in agreement with the structure (ESI).

Table 1 Preparation of ionic liquid-supported sulfonyl hydrazones 9 and 10 using 6^a

Entry	Ar	R	Product 9 or 10	Yield^b (%)
a Reaction conditions: 6 (1 mmol), 7 or 8 (1.1 mmol), EtOH (10 mL), 40 °C for 5 h. b Isolated yield.
1	C6H5	CH3	9a	86
2	2-FC6H4	CH3	9b	83
3	2-ClC6H4	CH3	9c	81
4	3-ClC6H4	CH3	9d	84
5	3-NO2C6H4	CH3	9e	79
6	4-ClC6H4	CH3	9f	74
7	4-BrC6H4	CH3	9g	87
8	2,6-(Cl)2C6H3	CH3	9h	80
9	3-OCH3C6H4	CH3	9i	54
10	4-CH3C6H4	CH3	9j	67
11	4-OCH3C6H4	CH3	9k	92
12	3,4-(OCH3)2C6H3	CH3	9l	71
13	C4H3S	CH3	9m	89
14	C4H3O	CH3	9n	88
15	C6H5	H	9o	59
16	C6H5	—	10a	88
17	3-ClC6H4	—	10b	76
18	4-ClC6H4	—	10c	72
19	4-BrC6H4	—	10d	79
20	2,6-(Cl)2C6H3	—	10e	77
21	4-CH3C6H4	—	10f	89
22	C4H3S	—	10g	88

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In an initial experiment for the synthesis of pyrazoles, we performed the cyclization of 9g in the presence of K₂CO₃ at 100 °C in water. The reaction afforded pyrazole 11g in 72% yield after 24 h. After screening various bases viz. K₂CO₃, Cs₂CO₃, KOH and NaOH, and solvents it was found that the best yield (88%) of 11g was achieved by employing 3 N NaOH in water (Table 2, entry 5). Almost similar yields of 11g were obtained in DMF in the presence of 3 N NaOH at 150 °C and water using 5 equiv. Cs₂CO₃ at 100 °C (Table 2, entries 7 & 13).

Table 2 Optimization of reaction conditions for the synthesis of 11g from 9g^a

Entry	Base	Solvent	T (°C)	Yield^a (%)
a Isolated yields. b No product isolated.
1	NaOH (1 N)	Water	100	71
2	NaOH (2 N)	Water	100	76
3	KOH (2 N)	Water	100	66
4	NaOH (3 N)	Water	30	—^b
5	NaOH (3 N)	Water	100	88
6	NaOH (3 N)	DMSO	150	47
7	NaOH (3 N)	DMF	150	85
8	NaOH (3 N)	CH3CN	80	52
9	NaOH (3 N)	CH3OH	60	30
10	NaOH (5 N)	Water	100	85
11	K2CO3 (1 eq)	Water	100	72
12	K2CO3 (2 eq)	Water	100	67
13	Cs2CO3 (5 eq)	Water	100	87
14	Cs2CO3 (3 eq)	Water	100	54

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With the optimized conditions in hand, we next investigated the scope and generality of the cyclization, and the results are summarized in Table 3. Various electron-withdrawing and electron-donating groups on the aryl ring of ionic liquid-supported hydrazones 9 were well tolerated in this reaction. It was observed that compound 9 with electron-withdrawing groups (Table 3, entries 1–4 and 6–8) furnished the target pyrazoles in slightly better yields compared to electron-rich groups (Table 3, entries 9–12). Remarkably, thiophene and furan-substituted pyrazoles 9m & 9n could also be obtained under the given conditions in good to moderate yields (Table 3, entries 13 and 14). Ionic liquid-supported sulfonyl hydrazone of cinnamaldehyde 9o resulted in the corresponding pyrazole 11o in moderate yields (Table 3, entry 15). In all cases the product was isolated by simple extraction with an ethyl acetate–hexane mixture (1 : 1 v/v). It is worth mentioning that the pyrazoles 11 were highly pure and no further chromatographic separation was required. The chemical structures of 11 were determined by ¹H and ¹³C NMR and data for known pyrazoles were in agreement with the reported values. In the ¹H NMR spectra of 11a, a characteristic singlet peak appeared around 6.3 ppm for C₄-protons of the pyrazole ring along with other protons and a peak corresponding to C₄-carbon of the pyrazole ring appeared around 102 ppm in the ¹³C NMR. However, signals for quaternary C₃- and C₅-carbons of some 3,5-disubsituted pyrazoles could not be observed due to their longer relaxation time, which is a consequence of the neighboring nitrogen atoms present in the highly conjugated pyrazole ring.^28,31

Table 3 Yields of 3,5-disubstituted pyrazoles 11 formed by cyclization of ionic liquid-supported sulfonyl hydrazones 9^a

Entry	9	Ar	R	Product	Yield^b (%)
a Reaction conditions: 9 (1 mmol), 3 N NaOH (2 mL), 100 °C for 24 h. b Isolated yield.
1	9a	C6H5	CH3	11a	70
2	9b	2-FC6H4	CH3	11b	77
3	9c	2-ClC6H4	CH3	11c	70
4	9d	3-ClC6H4	CH3	11d	76
5	9e	3-NO2C6H4	CH3	11e	33
6	9f	4-ClC6H4	CH3	11f	83
7	9g	4-BrC6H4	CH3	11g	88
8	9h	2,6-(Cl)2C6H3	CH3	11h	93
9	9i	3-OCH3C6H4	CH3	11i	57
10	9j	4-CH3C6H4	CH3	11j	62
11	9k	4-OCH3C6H4	CH3	11k	60
12	9l	3,4-(OCH3)2C6H3	CH3	11l	27
13	9m	C4H3S	CH3	11m	80
14	9n	C4H3O	CH3	11n	57
15	9o	C6H5	H	11o	65

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These results encouraged us to further explore an alternative protocol for the synthesis of 3,5-disubstituted pyrazoles by 1,3-dipolar cycloaddition of ionic liquid-supported tosylhydrazones 10 to alkynes 12. To our delight the reaction of tosylhydrazone 10d with phenylacetylene 12a in the presence of 5 N NaOH at 60 °C afforded 3-(4-bromophenyl)-5-phenyl-1H-pyrazole 13da in 85% yield. It is important to mention that the yield of 13da was low when 3 N NaOH and other bases were used in this reaction.

The scope of the reaction was evaluated with regard to the structure of aldehydes and alkynes. As shown in Table 4, various substituted aldehydes worked well with alkynes to provide the corresponding 3,5-disubstituted-1H-pyrazoles 13 in moderate to excellent yields. The reaction could tolerate alkynes and aldehydes with various steric and electronic properties. In general, the electronic effect on the aldehydes had little influence on the reaction; both electron-withdrawing and electron-donating substituents gave good to excellent yields with simple phenylactylene 12a and 4′-methylphenylacetylene 12b. We also found that the reaction could tolerate heteroaryl motifs (Table 4, entry 11). However, for the disubstituted alkynes the yields of the corresponding pyrazole were poor (Table 4, entries 2 and 6). The chemical structures of the synthesized pyrazoles 13 were elucidated using ¹H and ¹³C NMR data (ESI).

Table 4 Yields of 3,5-disubstituted pyrazoles 13 formed by cyclization of ionic liquid-supported sulfonyl hydrazones 10^a

Entry	10	Ar	12	R	R^1	Product	Yield^b (%)
a Reaction conditions: 10 (1 mmol), 12 (1.5 mmol), 5 N NaOH (2 mL), 60 °C for 24 h. b Isolated yield.
1	10a	C6H5	12a	C6H5	H	13aa	90
2	10a	C6H5	12a′	C6H5	CH3	13aa′	15
3	10b	3-ClC6H4	12a	C6H5	H	13ba	87
4	10c	4-ClC6H4	12a	C6H5	H	13ca	87
5	10d	4-BrC6H4	12a	C6H5	H	13da	85
6	10d	4-BrC6H4	12a′	C6H5	CH3	13da′	14
7	10e	2,6-(Cl)2C6H3	12a	C6H5	H	13ea	78
8	10e	2,6-(Cl)2C6H3	12b	4-CH3C6H4	H	13eb	74
9	10f	4-CH3C6H4	12a	C6H5	H	13fa	80
10	10f	4-CH3C6H4	12b	4-CH3C6H4	H	13fb	83
11	10g	C4H3S	12a	C6H5	H	13ga	41

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In summary, a facile and economical approach for the traceless synthesis of highly substituted pyrazoles has been developed using ionic liquid-supported sulfonyl hydrazine. A key feature of the protocol is an easy and convenient purification process that avoids chromatographic separation of products and thus makes the method ecofriendly and economical.

Experimental

General information

The NMR spectra were recorded on 300 MHz, 400 MHz and 500 MHz spectrometers using CDCl₃ and DMSO-d₆ as solvents. The chemical shifts were expressed in ppm. Reactions were monitored by thin-layer chromatography (TLC) carried out on silica-coated aluminum plates (60F-254) using UV light as a visualizing agent. Melting points were determined on an open capillary tube on automated melting point apparatus and are uncorrected. All the chemicals and reagents were purchased at the highest commercial quality and were used without further purification, unless otherwise stated. Ionic liquid-supported sulfonyl hydrazine was prepared from ionic liquid-supported sulfonic acid which was prepared by the reaction of 1,4-butanesultone with 1,2-dimethylimidazole followed by acidification with trifluoromethane sulfonic acid.³²

General procedure for the synthesis of ionic liquid-supported sulfonyl hydrazones 9a–o & 10a–g

To the ionic liquid-supported sulfonyl hydrazine (6, 1 mmol) in ethanol, α,β-unsaturated carbonyl compounds (7, 1.1 mmol) or aldehydes (8, 1.1 mmol) were added and the resulting solution was stirred at room temperature vigorously for 5 h. After completion of the reaction, ethanol was removed and the resulting mixture was washed with an ethyl acetate–hexane mixture (1 : 1 v/v) and dried under reduced pressure to obtain the pure product.

General procedure for the synthesis of pyrazoles 11a–o from ionic liquid-supported sulfonyl hydrazones 9a–o

To the ionic liquid-supported sulfonyl hydrazones 9 (1 mmol) 2 mL of 3 N NaOH was added and the reaction mixture was heated at 100 °C for 24 h. The progress of the reaction was monitored by thin-layer chromatography. After completion of the reaction, the product was extracted in ethyl acetate (2 × 10 mL) and dried over sodium sulfate. The combined organic layers were evaporated under reduced pressure to obtain pure compound 11.

5-Methyl-3-phenyl-1H-pyrazole (11a). Yield 70%; light brown solid; mp 121–122 °C (lit.³³ 124–126 °C); ¹H NMR (300 MHz, CDCl₃) δ 10.62 (s, 1H), 7.70 (d, J = 7.3 Hz, 2H), 7.31 (dt, J = 22.7, 7.7 Hz, 3H), 6.32 (s, 1H), 2.25 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 150.0, 132.5, 128.7, 127.8, 125.7, 102.1, 11.7.

3-(2-Fluorophenyl)-5-methyl-1H-pyrazole (11b). Yield 77%; colorless liquid; ¹H NMR (300 MHz, DMSO-d₆) δ 12.77 (s, 1H), 7.91 (t, J = 7.7 Hz, 1H), 7.40–7.28 (m, 1H), 7.24 (dd, J = 8.9, 4.9 Hz, 2H), 6.40 (d, J = 3.8 Hz, 1H), 2.28 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ 159.5 (d, J = 247.3 Hz), 129.4 (d, J = 8.3 Hz), 128.3 (d, J = 3.9 Hz), 125.0 (d, J = 3.3 Hz), 116.5 (d, J = 22.0 Hz), 104.7 (d, J = 8.7 Hz), 11.5.

3-(2-Chlorophenyl)-5-methyl-1H-pyrazole (11c). Yield 70%; light yellow liquid; ¹H NMR (300 MHz, DMSO-d₆) δ 12.75 (s, 1H), 7.75 (s, 1H), 7.50 (d, J = 7.1 Hz, 1H), 7.42–7.27 (m, 2H), 6.48 (s, 1H), 2.28 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ 131.3, 130.7, 130.6, 129.2, 127.6, 107.2, 105.2, 10.8.

3-(3-Chlorophenyl)-5-methyl-1H-pyrazole (11d). Yield 76%; white solid; mp 141–144 °C; ¹H NMR (500 MHz, CDCl₃) δ 11.01 (brs, 1H), 7.69 (s, 1H), 7.56 (d, J = 6.4 Hz, 1H), 7.23 (d, J = 5.9 Hz, 2H), 6.29 (s, 1H), 2.22 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 149.4, 142.5, 134.7, 134.6, 129.9, 127.7, 125.8, 123.8, 102.3, 11.3.

3-(3-Nitrophenyl)-5-methyl-1H-pyrazole (11e). Yield 33%; white solid; mp 139–141 °C; ¹H NMR (300 MHz, DMSO-d₆) δ 12.83 (s, 1H), 8.55 (s, 1H), 8.19 (d, J = 7.6 Hz, 1H), 8.12 (d, J = 8.0 Hz, 1H), 7.69 (t, J = 8.0 Hz, 1H), 6.64 (s, 1H), 2.30 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ 148.7, 140.7, 136.2, 131.7, 130.7, 122.1, 119.4, 102.1, 10.9.

3-(4-Chlorophenyl)-5-methyl-1H-pyrazole (11f). Yield 83%; brownish white solid; mp 135–139 °C; ¹H NMR (500 MHz, CDCl₃) δ 7.65 (d, J = 8.3 Hz, 2H), 7.34 (d, J = 8.3 Hz, 2H), 6.32 (s, 1H), 2.32 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 132.5, 130.3, 129.2, 127.8, 126.8, 125.8, 101.0, 10.2.

3-(4-Bromophenyl)-5-methyl-1H-pyrazole (11g). Yield 88%; white solid; mp 136–139 °C; ¹H NMR (500 MHz, CDCl₃) δ 7.57 (d, J = 8.5 Hz, 2H), 7.47 (d, J = 8.5 Hz, 2H), 6.31 (s, 1H), 2.29 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 131.7, 127.2, 121.7, 102.1, 11.4.

3-(2,6-Dichlorophenyl)-5-methyl-1H-pyrazole (11h). Yield 93%; colorless solid; mp 168–171 °C; ¹H NMR (300 MHz, DMSO-d₆) δ 12.71 (s, 1H), 7.54 (d, J = 7.9 Hz, 2H), 7.46–7.38 (m, 1H), 6.06 (s, 1H), 2.28 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 144.7, 141.7, 136.0, 132.0, 129.8, 128.0, 106.0, 11.3.

3-(3-Methoxyphenyl)-5-methyl-1H-pyrazole (11i). Yield 57%; white solid; mp 133–135 °C; ¹H NMR (500 MHz, CDCl₃) δ 7.29 (d, J = 5.2 Hz, 3H), 6.86 (dd, J = 7.9, 3.8 Hz, 1H), 6.34 (s, 1H), 3.82 (s, 3H), 2.32 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 159.9, 133.9, 129.7, 118.2, 113.7, 110.8, 102.2, 55.2, 11.7.

5-Methyl-3-(p-tolyl)-1H-pyrazole (11j). Yield 62%; white solid; mp 199–203 °C; ¹H NMR (500 MHz, CDCl₃) δ 7.58 (d, J = 8.1 Hz, 2H), 7.18 (d, J = 7.9 Hz, 2H), 6.31 (s, 1H), 2.36 (s, 3H), 2.31 (s, 3H); ¹³C NMR (126 MHz, CDCl₃) δ 137.7, 129.4, 129.4, 128.0, 127.9, 125.5, 101.9, 21.2, 11.9.

3-(4-Methoxyphenyl)-5-methyl-1H-pyrazole (11k). Yield 60%; brown solid; mp 106–109 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.64 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 6.29 (s, 1H), 3.85 (s, 3H), 2.32 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 159.4, 149.5, 143.3, 126.93, 125.2, 114.1, 101.5, 55.3, 11.8.

3-(3,4-Dimethoxyphenyl)-5-methyl-1H-pyrazole (11l). Yield 27%; white solid; mp 76–79 °C; ¹H NMR (300 MHz, CDCl₃) δ 7.21 (s, 1H), 7.15 (dd, J = 8.3, 1.4 Hz, 1H), 6.78 (d, J = 8.3 Hz, 1H), 6.20 (s, 1H), 3.82 (s, 3H), 3.79 (s, 3H), 2.22 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 150.0, 149.1, 148.9, 142.9, 125.6, 118.2, 111.2, 108.8, 101.6, 55.9, 55.8, 11.7.

5-Methyl-3-(thiophen-2-yl)-1H-pyrazole (11m). Yield 80%; white solid; mp 125–128 °C; ¹H NMR (300 MHz, DMSO-d₆) δ 12.54 (s, 1H), 7.39 (d, J = 4.6 Hz, 1H), 7.31 (d, J = 2.9 Hz, 1H), 7.08–7.02 (m, 1H), 6.31 (s, 1H), 2.24 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ 128.0, 124.7, 123.7, 101.5, 11.1.

3-(Furan-2-yl)-5-methyl-1H-pyrazole (11n). Yield 57%; black solid; mp 85–87 °C; ¹H NMR (300 MHz, DMSO-d₆) δ 12.67 (s, 1H), 7.65 (s, 1H), 6.64 (d, J = 2.9 Hz, 1H), 6.53 (s, 1H), 6.25 (s, 1H), 2.24 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ 142.3, 111.9, 105.5, 101.3, 11.3.

3-Phenyl-1H-pyrazole (11o). Yield 65%; brown viscous liquid; ¹H NMR (300 MHz, DMSO-d₆) δ 12.88 (s, 1H), 7.81 (d, J = 7.1 Hz, 2H), 7.41 (t, J = 7.4 Hz, 3H), 7.35–7.23 (m, 1H), 6.71 (d, J = 1.8 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 148.1, 132.2, 131.0, 127.7, 127.0, 124.7, 101.7.

General procedure for the synthesis of pyrazole 13 from ionic liquid-supported sulfonyl hydrazones 10a–g

Alkyne (1.5 mmol) and 2 mL of 5 N NaOH were added to the ionic liquid-supported sulfonyl hydrazone 10 (1.0 mmol) at room temperature. The resulting solution was stirred for 24 h at 60 °C and the progress of the reaction was monitored by thin-layer chromatography. After completion of the reaction, the product was extracted in ethyl acetate (2 × 10 mL) and dried over sodium sulfate. The combined organic layers were evaporated under reduced pressure to obtain a pure compound.

3,5-Diphenyl-1H-pyrazole (13aa). Yield 90%; yellow solid; mp 195–198 °C (lit.³⁴ 197–198.5 °C); ¹H NMR (300 MHz, DMSO-d₆) δ 13.38 (s, 1H), 7.85 (s, 4H), 7.46 (t, J = 6.8 Hz, 4H), 7.36 (d, J = 6.8 Hz, 2H), 7.19 (s, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ 129.3, 128.5, 128.2, 128.0, 125.6, 100.0.

4-Methyl-3,5-diphenyl-1H-pyrazole (13aa′). Yield 15%; yellow solid; mp 79–81 °C; ¹H NMR (300 MHz, DMSO-d₆) δ 13.06 (s, 1H), 7.62 (s, 4H), 7.48 (d, J = 6.2 Hz, 4H), 7.39 (d, J = 6.3 Hz, 2H), 2.27 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ 157.1, 129.1, 127.8, 109.9, 10.6.

3-(3-Chlorophenyl)-5-phenyl-1H-pyrazole (13ba). Yield 87%; white solid; mp 180–182 °C (lit.²⁹ 158–162 °C); ¹H NMR (300 MHz, DMSO-d₆) δ 13.50 (s, 1H), 7.93 (s, 1H), 7.89–7.79 (m, 3H), 7.48 (d, J = 5.3 Hz, 3H), 7.39 (d, J = 6.5 Hz, 2H), 7.31 (s, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 134.8, 130.1, 129.0, 128.6, 128.1, 125.8, 125.5, 123.7, 100.4

3-(4-Chlorophenyl)-5-phenyl-1H-pyrazole (13ca). Yield 87%; white solid; mp 217–219 °C (lit.³¹ 214–215 °C); ¹H NMR (300 MHz, DMSO-d₆) δ 13.46 (s, 1H), 7.86 (d, J = 11.3 Hz, 4H), 7.50 (d, J = 6.1 Hz, 4H), 7.37 (s, 1H), 7.23 (s, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ 150.6, 144.0, 133.0, 132.4, 132.4, 129.4, 129.1, 128.6, 127.2, 125.6, 100.3.

3-(4-Bromophenyl)-5-phenyl-1H-pyrazole (13da). Yield 85%; white solid; mp 211–213 °C (lit.³¹ 212–214 °C); ¹H NMR (300 MHz, DMSO-d₆) δ 13.47 (s, 1H), 7.82 (d, J = 6.4 Hz, 4H), 7.65 (d, J = 7.7 Hz, 2H), 7.47 (t, J = 6.5 Hz, 2H), 7.37 (t, J = 6.7 Hz, 1H), 7.23 (s, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ 160.9, 132.2, 130.7, 129.3, 128.4, 127.5, 125.6, 121.2, 100.4, 31.1.

3-(4-Bromophenyl)-4-methyl-5-phenyl-1H-pyrazole (13da′). Yield 14%; white solid; mp 118–121 °C; ¹H NMR (300 MHz, DMSO-d₆) δ 13.16 (s, 1H), 7.76–7.34 (m, 9H), 2.26 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ 131.9, 129.7, 127.9, 10.5.

3-(2,6-Dichlorophenyl)-5-phenyl-1H-pyrazole (13ea). Yield 78%; off white solid; mp 150–153 °C; ¹H NMR (300 MHz, DMSO-d₆) δ 13.43 (s, 1H), 7.85 (d, J = 7.4 Hz, 2H), 7.61 (d, J = 7.8 Hz, 2H), 7.47 (dd, J = 16.9, 8.8 Hz, 3H), 7.39–7.30 (m, 1H), 6.83 (s, 1H); ¹³C NMR (75 MHz, DMSO-d₆) δ 135.6, 131.6, 129.7, 129.3, 129.1, 128.8, 128.3, 126.1, 125.5, 104.0.

3-(2,6-Dichlorophenyl)-5-(p-tolyl)-1H-pyrazole (13eb). Yield 74%; off white solid; mp 137–142 °C; ¹H NMR (300 MHz, DMSO-d₆) δ 7.72 (d, J = 2.2 Hz, 2H), 7.60 (d, J = 4.4 Hz, 2H), 7.49 (d, J = 5.6 Hz, 1H), 7.26 (d, J = 3.6 Hz, 2H), 6.77 (s, 1H), 2.34 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ 135.6, 129.9, 128.8, 125.5, 103.6, 21.3.

5-Phenyl-3-(p-tolyl)-1H-pyrazole (13fa). Yield 80%; off white solid; mp 179–181 °C (lit.³¹ 170–172 °C); ¹H NMR (300 MHz, DMSO-d₆) δ 13.30 (s, 1H), 7.84 (d, J = 7.3 Hz, 2H), 7.73 (d, J = 8.1 Hz, 2H), 7.45 (t, J = 7.5 Hz, 2H), 7.33 (t, J = 7.3 Hz, 1H), 7.26 (d, J = 8.0 Hz, 2H), 7.13 (s, 1H), 2.34 (s, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 138.1, 132.1, 131.6, 129.5, 128.8, 128.1, 125.6, 125.5, 99.8, 21.2.

3,5-Di-p-tolyl-1H-pyrazole (13fb). Yield 83%; white solid; mp 174–175 °C; ¹H NMR (300 MHz, DMSO-d₆) δ 13.22 (s, 1H), 7.73 (d, J = 7.0 Hz, 4H), 7.25 (d, J = 7.5 Hz, 4H), 7.07 (s, 1H), 2.33 (s, 6H); ¹³C NMR (101 MHz, CDCl₃) δ 138.2, 129.5, 128.6, 125.4, 99.6, 21.3.

5-Phenyl-3-(thiophen-2-yl)-1H-pyrazole (13ga). Yield 41%; brown solid; mp 160–164 °C (lit.³¹ 187–188 °C); ¹H NMR (300 MHz, DMSO-d₆) δ 13.33 (s, 1H), 7.81 (d, J = 6.7 Hz, 2H), 7.46 (d, J = 5.7 Hz, 4H), 7.36 (t, J = 6.6 Hz, 1H), 7.12 (s, 1H), 7.05 (s, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 130.2, 128.9, 128.5, 127.6, 125.5, 124.9, 124.1, 100.2.

Acknowledgements

We gratefully acknowledge the Council for Scientific and Industrial Research (CSIR), New Delhi for the financial support (02(0115)/13/EMR-II) to carry out this work. SC and MKM thank CSIR, New Delhi for a senior research fellowship (SRF).

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Footnote

† Electronic supplementary information (ESI) available: NMR data of ionic liquid-supported sulfonyl hydrazones 9, copies of ¹H NMR and ¹³C NMR of ionic liquid-supported sulfonyl hydrazones 9, and pyrazoles 11 & 13. See DOI: 10.1039/c4qo00092g

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