N-(3-(tert-Butyl)-1-methyl-1H-pyrazol-5-yl)-4-methyl-N-tosylbenzenesulfonamide

Abstract

N-(3-(tert-Butyl)-1-methyl-1H-pyrazol-5-yl)-4-methyl-N-tosylbenzenesulfonamide was efficiently synthesized in good yield through a triethylamine-mediated sulfonamidation reaction of 3-(tert-butyl)-1-methyl-1H-pyrazol-5-amine with 4-methylbenzenesulfonyl chloride in acetonitrile at room temperature. The pyrazole-based benzenesulfonamide was fully characterized using FT-IR, NMR, and HMRS techniques.

1. Introduction

Pyrazole is a five-membered N-heterocyclic compound characterized by the presence of two adjacent nitrogen atoms. Due to its structural versatility, pyrazole and its derivatives have been widely explored across multiple scientific and industrial fields, including in polymer, material, and supramolecular chemistry fields [1,2], as well as in cosmetic, food, and agrochemical applications [1,3]. Furthermore, these compounds play a crucial role in coordination chemistry [4], catalysis [5], and chemosensing for the detection of cations and anions [6]. Their broad spectrum of biological and pharmacological properties has positioned pyrazole derivatives as valuable scaffolds in medicinal chemistry and drug discovery [7,8,9]. This versatility enables their interaction with a variety of biological targets, contributing to their presence in natural bioactive molecules with significant therapeutic potential [10]. Moreover, the pyrazole core serves as a privileged pharmacophore in numerous FDA-approved drugs, including Fomepizole, Lonazolac, Mepirizole, Rimonabant, Difenamizole, Betazole, and Tepoxalin, highlighting its central role in modern drug development and clinical applications [11,12].

As a result, the functionalization of pyrazole derivatives has gathered significant attention in recent decades, driving the development of diverse synthetic methodologies aimed at enhancing their biological profiles [8,9,13,14]. Notably, the incorporation of a sulfonamide group into the pyrazole framework has contributed to the advancement of several clinically approved drugs. For example, Celecoxib and Deracoxib are anti-inflammatory agents that selectively inhibit cyclooxygenase-2 (COX-2) [15], Sulfaphenazole is used to treat urinary tract infections [16], and Encorafenib is approved for treating metastatic melanoma, colorectal, and non-small cell lung cancer with BRAF V600E or V600K mutations [17], among others.

Beyond these examples, various pyrazole–sulfonamide hybrids have demonstrated promising anticancer activity [18,19,20]. For instance, Gundla’s group reported the synthesis of pyrazole-4-sulfonamide derivatives and evaluated their anticancer activity against the U937 human monocytic leukemia cell line [19]. Among them, compound (I) exhibited the highest potency, with a GI₅₀ value of 1.7 µM and an LC50 value exceeding 100 µM (Figure 1). Similarly, Khalil’s group synthesized a series of pyrazole–sulfonamide hybrids and evaluated them against HCT-116, HT-29, and SW-620 colon cancer cell lines, using 5-fluorouracil (5-FU) as the reference drug [20]. Among them, compound (II) exhibited the greatest potency against HCT-116, HT-29, and SW-620 cell lines, with IC₅₀ values of 25.01 μM, 8.99 μM, and 3.27 μM, respectively, compared to 5-FU (IC₅₀ = 3.70 μM, 12.36 μM, and 14.80 μM, respectively) (Figure 1).

Despite these advances, the development of novel pyrazole–sulfonamide hybrids with promising anticancer activity remains a significant challenge. In this context, we report the synthesis of a new pyrazole-based benzenesulfonamide 3 via a classical sulfonamidation reaction between 5-aminopyrazole 1 and 4-methylbenzenesulfonyl chloride 2 using triethylamine as the base (Scheme 1).

2. Results and Discussion

The N-sulfonylation reaction was then evaluated using 5-aminopyrazole 1, 4-methylbenzenesulfonyl chloride 2, and triethylamine in a stoichiometric ratio of 1:2:2 in acetonitrile at room temperature for 12 h (Scheme 1). Upon completion, the reaction mixture was extracted with a water/ethyl acetate mixture and purified by column chromatography on silica gel using dichloromethane as the eluent, affording the pyrazole-based benzenesulfonamide 3 in 88% yield. Notably, compound 3 is not listed in the Reaxys database, indicating that its synthesis and structural characterization have not been previously reported. To confirm its structure, a comprehensive structural analysis was performed using FT-IR, NMR, and HRMS, as detailed in the Section 3.

In the ¹H NMR spectrum of compound 3, a singlet at 1.24 ppm was assigned to the tert-butyl group (

Table 1. One- and two-dimensional NMR assignments and correlations of 3.

Number	δH (Mult, J in Hz)	δC (ppm)	COSY	NOESY	HMBC
t-Bu	1.24 (s)	30.4
Cq (t-Bu)		32.4			t-Bu (2J)
MeN	3.40 (s)	35.6
Me	2.48 (s)	21.9		Hm	Hm (3J)
3		160.9			H–4 (2J) t-Bu (3J)
4	5.74 (s)	103.7
5		130.9			H–4 (2J) MeN (3J)
i		135.8			Hm (3J)
o	7.78 (d, J = 8.0)	129.0	Hm (3J)	Hm
m	7.34 (d, J = 8.0)	129.8	Ho (3J)	Ho Me	Me (3J)
p		145.9			Me (2J) Ho (3J)

and Figure S1). Two additional singlets at 2.48 ppm and 3.40 ppm corresponded to the methyl substituents on the phenyl and pyrazole rings, respectively. In the aromatic region, the H–4 proton of the pyrazole ring appeared as a singlet at 5.74 ppm, while the phenyl ring exhibited two doublets at 7.34 ppm and 7.78 ppm, assigned to the Hm and Ho protons, respectively. The absence of a broad singlet typically associated with the –NH₂ group confirmed the completion of the double N-sulfonylation reaction. Further structural elucidation by ¹³C NMR and DEPT-135 spectroscopy revealed signals at 21.9, 30.4, and 35.6 ppm, corresponding to two magnetically equivalent methyl groups on phenyl rings, the three equivalent methyl groups of the tert-butyl group, and a methyl group attached to nitrogen (MeN), respectively. Additionally, methine carbon signals were observed at 103.7 (C–4), 129.0 (Co), and 129.8 ppm (Cm), and five quaternary carbons were identified at 32.4 (Cq of t-But), 130.9 (C–5), 135.8 (Ci), 145.9 (Cp), and 160.9 ppm (C–3) (Figure S2). Complete assignment of all proton and carbon signals was supported by 2D NMR experiments (Table 1 and Figures S3–S6).

Figure S7 illustrates the FT-IR spectrum of compounds 3, highlighting strong absorption bands at 1363 cm⁻¹ and 1170 cm⁻¹, corresponding to the asymmetric and symmetric SO₂ stretching vibrations, respectively. The S–N and S–C stretching vibrations were assigned at 892 cm⁻¹ and 676 cm⁻¹, respectively. The C=C and C=N stretching vibrations were found to overlap at 1595 cm⁻¹. The exact mass (m/z 462.1516) of the pseudo-molecular ion ([M + H]⁺) and its elemental formula (C₂₂H₂₈N₃O₄S₂⁺) were confirmed by HRMS analysis, yielding a mass error of −1.30 ppm (Figure S8).

3. Materials and Methods

3.1. General Information

The progress of the reaction was monitored using thin-layer chromatography and assessed under a UV lamp at 254 or 365 nm. Flash column chromatography was performed with silica gel 60 (230–400 mesh) (Alfa Aesar, Tewksbury, MA, USA). The infrared spectrum was recorded at ambient temperature using a Shimadzu FTIR 8400 spectrophotometer (Scientific Instruments Inc., Seattle, WA, USA) equipped with an ATR accessory. NMR spectra were acquired in CDCl₃ using a Bruker Avance 400 spectrophotometer (Bruker BioSpin GmbH, Rheinstetten, Germany). Chemical shifts are reported in ppm (δ) and coupling constants in Hz (J). The residual non-deuterated signal (δ = 7.26 ppm) and the deuterated solvent signal (δ = 77.16 ppm) were used as internal references for ¹H and ¹³C NMR spectra, respectively. High-resolution mass spectrometry (HRMS) was performed using a Q-TOF 6520 spectrometer (Agilent Technologies Inc., Santa Clara, CA, USA) with electrospray ionization (ESI, 4000 V). 3-(tert-Butyl)-1-methyl-1H-pyrazol-5-amine 1 was synthesized according to previously reported procedures [21,22].

3.2. Synthesis of N-(3-(tert-Butyl)-1-methyl-1H-pyrazol-5-yl)-4-methyl-N-tosylbenzenesulfonamide 3

A mixture of 3-(tert-butyl)-1-methyl-1H-pyrazol-5-amine 1 (76 mg, 0.50 mmol), 4-methylbenzenesulfonyl chloride 2 (190 mg, 1.0 mmol), and triethylamine (167 µL, 1.2 mmol) in 2.0 mL of acetonitrile was stirred at room temperature for 12 h. The solvent was then evaporated under reduced pressure, and 5.0 mL of distilled water was added. The resulting mixture was extracted twice with 5.0 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulphate, filtered, and the solvent was evaporated under reduced pressure. Finally, the crude product was purified by column chromatography on silica gel using dichloromethane as the eluent, affording compound 3 as colourless amorphous solid (203 mg, 88%). Rf = 0.58 (CH₂Cl₂). M.p. 116–117 °C. FTIR–ATR: 2957 (v C–H_pyrazole and v C–H_benzene), 2901, 2862, 1595 (v C = N_pyrazole and C = C_benzene), 1527, 1454, 1380, 1363 (v_a SO₂), 1300, 1170 (v_s SO₂), 1084, 892 (v S–N), 818, 676 (v S–C), 653, 534 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ = 1.24 (s, 9H, t-Bu), 2.48 (s, 6H, 2Me), 3.40 (s, 3H, MeN), 5.74 (s, 1H, H–4), 7.34 (d, J = 8.0 Hz, 4H, Hm), 7.78 (d, J = 8.0 Hz, 4H, Ho) ppm. ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 21.9 (2Me), 30.4 (3Me, t-Bu), 32.4 (Cq, t-Bu), 35.6 (MeN), 103.7 (CH, C–4), 129.0 (4CH, Co), 129.8 (4CH, Cm), 130.9 (Cq, C–5), 135.8 (2Cq, Ci), 145.9 (2Cq, Cp), 160.9 (Cq, C–3) ppm. HRMS (ESI+): calcd for C₂₂H₂₈N₃O₄S₂⁺, 462.1516 [M + H]⁺; found, 462.1510.