Accessing trifluoromethylated SuFEx-able pyrazole via distortion-accelerated 1,3-dipolar cycloadditions

Abstract

Fluorinated pyrazoles are valuable scaffolds with wide-ranging applications in medicinal chemistry, agrochemistry and materials science. We report the 1,3-dipolar cycloaddition of 2,2,2-trifluorodiazoethane and 1-bromoethene-1-sulfonyl fluoride for the concise synthesis of 5-(trifluoromethyl)-1H-pyrazole-3-sulfonyl fluoride. Computational analysis revealed that lowered distortion energies account for increased reactivity relative to other stabilized diazo compounds. The resulting trifluoromethylated pyrazole contains a SuFEx-able click handle, enabling orthogonal diversification pathways for diversity-oriented clicking. Together, these features support rapid functionalization and efficient access to structurally diverse analogs, offering a versatile platform for expansion of chemical space geared towards the development of bioactive molecules.

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Introduction

Pyrazoles, a class of five-membered nitrogen-containing heterocycles, are valued for their structural versatility and broad applicability in synthetic organic chemistry.^1,2 Their ability to engage in hydrogen bonding, π-stacking, and metal coordination has made them indispensable in medicinal chemistry, agrochemicals, and materials science.^3–7 Pyrazole motifs are present in numerous pharmaceuticals, dyes, metal complexes, and supramolecular systems, highlighting their role as privileged scaffolds in molecular design.^7–16 Their prevalence across diverse fields reflects not only their synthetic accessibility but also their adaptability to a wide range of functionalization strategies and biological targets.^17,18

Among its derivatives, fluorinated pyrazoles have garnered significant attention for their enhanced pharmacological properties.^14,15 The unique characteristics of fluorine, such as high electronegativity, small atomic radius, and strong carbon–fluorine bond,^19,20 can significantly improve metabolic stability, lipophilicity, and target binding affinity.^21–24 These attributes make fluorinated pyrazoles valuable in drug discovery,^25–27 agrochemistry,²⁸ and as ligands in coordination and organometallic chemistry (Fig. 1).^29–32

Fig. 1 (A) Commercially available bioactive compounds with fluorinated pyrazole motifs in their structures. (B) Examples of bioactive compounds containing all three motifs: CF₃, pyrazole, and sulfonyl group.

Fluorinated pyrazoles remain a focal point of research across multiple scientific domains as a result of their unique characteristics and broad applicability. As such, the design and synthesis of structurally diverse, selectively fluorinated pyrazoles remain a critical strategy for modulating reactivity, tuning physicochemical properties, and enabling targeted applications. Due to our interest in the electronic tuning of 1,3-dipolar cycloadditions through the incorporation of fluorine and other heteroatoms,^33–45 we sought to generate a fluorinated pyrazole containing a SuFEx-able handle for diversity-oriented click strategies.^46–48 As a robust and orthogonal click transformation, SuFEx offers a reliable platform to enable modular diversification.^49–54

Herein, we report a rapid synthesis of 5-(trifluoromethyl)-1H-pyrazole-3-sulfonyl fluoride, a novel fluorinated pyrazole, through a mild 1,3-dipolar cycloaddition between 2,2,2-trifluorodiazoethane and 1-bromoethene-1-sulfonyl fluoride (Br-ESF). This scaffold is structurally significant, containing the sulfonyl fluoride as a clickable reactive handle, as well as the trifluoromethyl group (CF₃) and the pyrazole ring—pharmacophores frequently found in bioactive molecules (Scheme 1).^55–57 The presence of these motifs within a single framework highlights their potential relevance in drug discovery.

Scheme 1 Our strategy for the synthesis of SuFEx-able fluorinated pyrazole via 1,3-dipolar cycloaddition of diazo derivative with Br-ESF and subsequent diversification.

Results and discussion

Synthesis of a SuFEx-able trifluoromethylated pyrazole

The synthesis of the SuFEx-able fluorinated pyrazole harnessed the in situ generation of 2,2,2-trifluorodiazoethane due to its known propensity to react violently.^29,58,59 Initial attempts focused on conditions we reported previously for the 1,3-dipolar cycloadditions stabilized diazoacetates and diazoacetamides with Br-ESF.^46,48 Combining 2,2,2-trifluoroethan-1-amine hydrochloride 1, sodium nitrite, and Br-ESF 2 in methylene chloride in one pot failed to yield the desired product. Varying the order of addition—first reacting the amine salt 1 with sodium nitrite in DCM, followed by the addition of Br-ESF 2—also proved unsuccessful, with no product detected after 2 or 12 hours (Table 1, entries 1 and 2). Additionally, changing the solvent to acetonitrile or using excess sodium nitrite in DCM had no significant effect (entries 3 and 4). The 1,3-dipolar cycloaddition reaction of in situ generated trifluorodiazoethane 3 with Br-ESF required modification of the conditions we previously reported.^46,48

Table 1 Optimization of reaction conditions for the synthesis of 5-(trifluoromethyl)-1H-pyrazole-3-sulfonyl fluoride

Entry	1 (equiv.)	NaNO2 (equiv.)	4 (equiv.)	Solvent	t, h	Yield^a, %
a Isolated yield, unless otherwise stated.b Determined by TLC.
1	0.9	0.9	1.0	DCM	2	—
2	0.9	0.9	1.0	DCM	12	—
3	0.9	0.9	1.0	MeCN	12	—
4	3.0	5.0	1.0	DCM	2	—
5	3.0	5.0	1.0	DCM/H2O	12	Trace^b
6	6.0	10.0	1.0	Toluene/H2O	12	72
7	2.0	2.0	1.0	Toluene/H2O	12	53

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A new product formed when a small amount of water was added to the reaction mixture, as determined by thin-layer chromatography. This finding suggested that the desired pyrazole 4 could be forming, which was later confirmed by the retention factor upon isolation. Based on this observation, we employed a biphasic solvent system of toluene and water (5 : 1) and increased the equivalents of diazo precursor 1 and NaNO₂ (relative to Br-ESF 2). We also separated the organic phase from the aqueous phase and dried it over magnesium sulfate prior to the introduction of Br-ESF 2. Under these optimized conditions, the reaction yielded 72% after 12 hours (entry 6). In contrast, using equal quantities of starting materials (1 and NaNO₂) in the biphasic solvent resulted in a drop in yield (entry 7), highlighting the importance of reagent stoichiometry and solvent composition. The optimized overall yield is similar to that found for stabilized diazo compounds with Br-ESF 2,^46,48 suggesting efficient formation of trifluorodiazoethane 3.

Computational analysis

Insights into the 1,3-dipolar cycloaddition reactivity of the CF₃-substituted diazo compound (CF₃-diazo) were provided by DFT calculations. Geometry optimizations of ground state and transition state structures were performed using Gaussian 16 at the M06-2X/6-31G(d) level of theory, followed by single-point energy calculations at the M06-2X/6-311++G(d,p) level of theory with a PCM solvation model for toluene.^60,61 The reaction with Br-ESF was compared against N-methyldiazoacetamide (NMe-diazo) and methyl diazoacetate (OMe-diazo)—simplified models of two synthetically useful dipoles also bearing electron-withdrawing substituents.^{36,44,46,62,63} We focused on stereoelectronic factors contributing to their reactivities throughout the reaction coordinate,^35,45,62,64 as well as the energetic trade-off of molecular distortions during bond formation.⁶⁵

Despite possessing a lower-energy HOMO—which would typically disfavor a normal electron demand (NED) pathway—CF₃-diazo (ΔE^‡ = 7.9 kcal mol⁻¹) undergoes the cycloaddition with Br-ESF more readily than NMe-diazo (ΔE^‡ = 9.6 kcal mol⁻¹) and OMe-diazo (11.7 kcal mol⁻¹). This counterintuitive reactivity trend suggests that electronic effects beyond the primary HOMO–LUMO interaction play a critical role.

To elucidate the origin of the increased cycloaddition reactivity of the CF₃-diazo relative to the conjugated diazo compounds, we performed detailed distortion–interaction (DI) analysis throughout the intrinsic reaction coordinate (IRC),⁶⁵ and Natural Bond Orbital (NBO) analysis.⁶⁶

Distortion–interaction (DI)/strain–activation analysis.. DI analysis provides a computational framework for dissecting (1,3-dipolar cycloaddition) reactivity by quantifying the energetic cost of distorting the reactants in isolation (ΔE^‡_dist or ΔE^‡_strain), which is offset by stabilizing interaction energies (ΔE^‡_interaction) between reactants as the reaction proceeds.⁶⁵ Previous studies attribute relative cycloaddition reactivity to the differences in distortion energies of the 1,3-dipole.^67,68 Consistent with this, comparison of distortion energies highlights a distinct difference for the CF₃-substituted diazo (Fig. 2A). At the TS, the CF₃-diazo exhibits the lowest overall distortion energy (ΔE^‡_dist = 21.6 kcal mol⁻¹; diazo: 13.4 kcal mol⁻¹, Br-ESF: 8.2 kcal mol⁻¹), whereas NMe- and OMe-diazo require significantly higher total distortion energies (25.9 and 26.8 kcal mol⁻¹, respectively). Geometrically, this reduction results from a less strained diazo group in CF₃-diazo, as indicated by its ∼1.5° larger bond angle relative to NMe- and OMe-diazos. These trends are expected due to the relatively weaker hyperconjugative versus interactions in the acetamide and acetate. While such differences at the TS are well established, a fuller picture requires examining how strain/activation energies evolve along the IRC to reveal the trajectory of structural and electronic adjustments leading to the TS.

Fig. 2 Computational analysis for the 1,3-dipolar cycloaddition transition state between diazo compounds (CF₃-diazo, NMe-diazo, OMe-diazo) and Br-ESF performed at the M06-2X/6-311++G(d,p)-PCM(toluene)//M06-2x/6-31G(d) level of theory. (A) Optimized transition state geometries, NBO charges (italics), free energies of activation (kcal mol⁻¹), and distortion–interaction (strain–activation) analysis. (B) Distortion–interaction (strain–activation) analysis along the intrinsic reaction coordinate.

In parallel, analysis of the interaction component reveals an important trade-off: CF₃-diazo exhibits the least stabilizing interaction energy (ΔE^‡_interaction = −13.7 kcal mol⁻¹) among the three models. The reduced distortion cost offsets this weaker stabilization, aligning with the previous findings where activation energy is governed not solely by interaction strength but by the energetic feasibility of achieving the TS geometry.^65,69–71 This balance reflects the nature of the CF₃-diazo system—weaker interactions are compensated by the formation of new bonds at an earlier stage in the reaction, leading to an earlier TS (vide infra).

The enthalpy (ΔH) profiles reveal the presence of pre-reaction complexes for all diazo systems (Fig. S2).⁷² Both NMe- and OMe-diazo form slightly deeper enthalpic wells (ΔH = −9.5 and −7.2 kcal mol⁻¹) than CF₃-diazo (−4.5 kcal mol⁻¹). Additionally, their geometries are less aligned with the transition state, leading to greater reorganization during bond formation. In contrast, the CF₃-diazo pre-complex is geometrically pre-organized along the reaction coordinate, positioning the reacting centres of the diazo and Br-ESF moieties in a near-TS orientation. This improved preorganization reduces the translational and rotational adjustments required to reach the TS, lowering the effective distortion energy and contributing to the smaller pre-complex → TS enthalpic gap observed for CF₃-diazo. Together, these features rationalize its enhanced cycloaddition reactivity relative to the more stabilized yet less efficiently oriented NMe- and OMe-diazo systems.

Intrinsic reaction coordinate (IRC) analysis. To examine how interaction and distortion energies evolve prior to the TS, we calculated the intrinsic reaction coordinate (IRC) profiles⁶⁹ for all the systems (Fig. 2B). At a consistent forming-bond length (∼2.27 Å), all systems have similar distortion energies (CF₃-diazo: 21.6 kcal mol⁻¹, NMe-diazo: 20.9 kcal mol⁻¹, OMe-diazo: 22.7 kcal mol⁻¹); however, interaction energies differed more significantly, with CF₃-diazo showing the strongest stabilizing value (−13.7 kcal mol⁻¹). Strain energies accumulate similarly across the system, but the more favorable early-stage interaction in CF₃-diazo indicates a better preorganization or early-stage orbital alignment, allowing the system to cross the intrinsic barrier earlier along the reaction coordinate. In line with Hammond's postulate,⁷³ the more exergonic cycloaddition of CF₃-diazo (ΔG = −18.0 kcal mol⁻¹) correlates with an earlier, less distorted TS, compared to the NMe- (−14.3 kcal mol⁻¹) and OMe-diazo dipoles (−9.6 kcal mol⁻¹; Table S1).^34,40,70,74 Thus, the apparent trade-off between weaker stabilizing interactions at the TS and lower activation energies arises because bond formation is initiated sooner, thereby reducing the distortion penalty. Overall, reactivity is modulated not only by the magnitude of strain or interaction but also by the timing and the efficiency of their buildup along the reaction coordinate.

Insights into the origin of the interaction energy were obtained by examining charge transfer between reactants using NBO charges, electrostatic interactions from Coulombic energies between the vinylic hydrogen of Br-ESF and the diazo substituent's heteroatoms, and steric exchange from interactions between Br lone pairs and either the F lone pairs (CF₃-diazo) or the carbonyl π orbitals (NMe- and OMe-diazo) at a consistent forming-bond length (∼2.27 Å; Fig. S3 and Table S3). Charge transfer was similar across the series, indicating minimal differences in orbital interactions. In contrast, electrostatic stabilization decreased significantly for CF₃-diazo (E_ES = 23.0 kcal mol⁻¹) compared to NMe- and OMe-diazo (35.1 and 31.8 kcal mol⁻¹, respectively), consistent with the reduced dipolar character. The steric (Pauli) component exhibited the opposite trend, with CF₃-diazo exhibiting slightly higher steric energy (E_steric = 1.4 kcal mol⁻¹) than NMe- and OMe-diazo (≈0.4 kcal mol⁻¹), reflecting a closer Br–F distance in the TS. Overall, the reduced ΔE_interaction of CF₃-diazo arises primarily from weaker electrostatic stabilization rather than differences in charge transfer, and the enhanced cycloaddition reactivity is driven by minimized distortion.

Frontier molecular orbitals (FMO) and natural bond orbital (NBO) analysis. The cycloadditions proceed via an NED pathway—where the HOMO of the diazo compound donates into the LUMO of Br-ESF.^10,15 However, the observed reactivity trend (CF₃-diazo > NMe-diazo > OMe-diazo) is not fully explained by HOMO–LUMO energy gaps alone (Fig. 3A). Although CF₃-diazo shows the highest reactivity, its HOMO–LUMO gap with Br-ESF is relatively large. Instead, secondary orbital interactions and electronic delocalization, revealed by NBO analysis,⁶⁶ provide a clearer explanation.

Fig. 3 CF₃-diazo harnesses secondary orbital interactions to accelerate cycloaddition reaction with Br-ESF. (A) Frontier molecular orbital energies, and (B) stereoelectronic interactions in the CF₃-diazo during its cycloaddition with Br-ESF, calculated at M06-2X/6-311++G(d,p)-PCM(toluene) level of theory. ^aEnergies correspond to the LUMO+1 of OMe-diazo and the LUMO+2 of NMe- and CF₃-diazo (see: Fig. S1). ^bSum of interaction energies.

NBO analysis highlights the role of intramolecular stabilization and reorganization across the diazo dipoles. In CF₃-diazo, strong hyperconjugation (39.0 kcal mol⁻¹ in the SM) weakens significantly at the TS (25.6 kcal mol⁻¹), consistent with early polarization and reorganization. Simultaneously, the delocalization (234.2 kcal mol⁻¹ in SM) diminishes significantly at the TS (135.1 kcal mol⁻¹), indicating substantial lone pair redistribution that facilitates new bond formation (Fig. 3B). In contrast, NMe- and OMe-diazo are dominated by strong delocalization in the SM (87.3 and 95.3 kcal mol⁻¹, respectively), which diminishes quickly at the TS (51.2 and 57.4 kcal mol⁻¹), increasing their reorganization penalty. Their interactions, while substantial, are slightly weaker at the TS (132.0 and 128.9 kcal mol⁻¹) compared to CF₃-diazo (Table S2).

Altogether, the CF₃-group reduces the reorganization penalty by limiting the loss of stabilizing interactions while maintaining strong delocalization within the diazo moiety. Thus, while HOMO–LUMO overlap defines the primary interaction in this NED pathway, the enhanced reactivity of CF₃-diazo originates from stereoelectronic effects: ground-state σ_CF hyperconjugation that is traded off with minimal energetic cost, combined with efficient electron density redistribution into π_NN delocalization at the TS. These features lower the energetic penalty required to distort the CF₃-diazo and stabilize an earlier TS, resulting in an acceleration of the cycloaddition beyond what FMO gaps alone would predict.

SuFEx-based derivatization

We next explored the scope of nucleophiles compatible with this fluorinated pyrazolyl SuFEx hub using previously optimized conditions.^46,75 We began by evaluating various nitrogen-containing nucleophiles, which readily afforded the corresponding sulfonamides (Fig. 4). When 5-(trifluoromethyl)-1H-pyrazole-3-sulfonyl fluoride 4 was reacted with aniline in the presence of DABCO as a base and Ca(NTf₂)₂ as an additive, efficient substitution at the sulfur(VI)–fluoride bond afforded sulfonamide 5a in excellent yield. Similarly, substituted arylamines and benzylamine underwent smooth conversion to the corresponding sulfonamides 5b and 5c under identical conditions. Morpholine, a representative secondary amine, also delivered the expected sulfonamide product in excellent yield. In addition, aliphatic amines were found to be viable partners in this SuFEx transformation. For example, tert-butylamine reacted with compound 4 to afford sulfonamide 5f in 76% yield. To further highlight the applicability of this method to biologically relevant substrates, we reacted an amino acid derivative, which furnished the desired sulfonamide product 5g in 74% yield.

Fig. 4 Synthesis of pyrazolyl sulfonamides via SuFEx reaction, illustrating the scope of the reported fluorinated SuFEx-able pyrazole.

We also explored the reactivity of oxygen-containing nucleophiles with the SuFEx-able fluorinated pyrazole 4. Substituted aryl alcohols underwent SuFEx reactions efficiently at room temperature, providing the corresponding aryl sulfonates (6a–e) in excellent yields (Fig. 5). Similarly, the heteroaromatic alcohol 2-methylpyridin-3-ol reacted smoothly with 4 to yield sulfonate 6f in 81% yield. In contrast, representative aliphatic alcohols, including cyclohexanol, methanol, and tert-butyl alcohol, were largely unreactive under the standard conditions, with starting materials recovered. Attempts to enhance reactivity by increasing the reaction temperature or adding excess base and additive did not result in product formation.

Fig. 5 Synthesis of pyrazolyl sulfonates via SuFEx reaction, illustrating the scope of the reported fluorinated SuFEx-able pyrazole.

Intermolecular C–N coupling

After evaluating the effectiveness of SuFEx chemistry with various nucleophiles, we turned our attention to the N-functionalization of pyrazole (Fig. 6). Initially, we tested the N-alkylation of 5-(trifluoromethyl)-1H-pyrazole-3-sulfonyl fluoride 4 using benzyl bromide in the presence of various bases. While bases like triethylamine, diisopropylethylamine, and sodium hydroxide proved ineffective, potassium carbonate (K₂CO₃) significantly improved the reaction, yielding high conversion and excellent isolated yields. DMSO was chosen as the solvent due to its ability to solvate larger alkali metal cations (such as K⁺), as well as its high solubility for the reactants.^76,77 With the optimized conditions established, we explored N-substitution on the pyrazole scaffold using five representative substrates, obtaining consistently good yields (7a–e).

Fig. 6 N-alkylation of 5-(trifluoromethyl)-1H-pyrazole-3-sulfonyl fluoride with alkyl halides under basic conditions, affording N-alkylated products (7a–e).

Following our success with N-alkylation, we sought to explore the intermolecular N-arylation of 5-(trifluoromethyl)-1H-pyrazole-3-sulfonyl fluoride as a route to further diversify the core scaffold. Initial attempts using Ullmann-type and Buchwald–Hartwig couplings proved ineffective, with minimal conversion and sluggish reactivity under standard conditions. Given the elevated temperatures and ligand-dependence typically required for these methods, we turned our attention to milder Chan–Lam-type couplings employing arylboronic acids.

Despite extensive screening (see Table S4), copper-mediated Chan–Lam conditions consistently afforded only low yields of the desired N-aryl products. The best outcome was observed using 1.5 equivalents of copper(II) acetate and excess triethylamine in methanol at room temperature, which furnished the N-arylated products in detectable but poor yields (Fig. 7). Three representative N-aryl derivatives (8a–c) were successfully isolated under these conditions, highlighting the generality of the transformation despite its limited efficiency. The lack of efficient reactivity likely stems from the combined effects of electron-withdrawing trifluoromethyl and sulfonyl fluoride substituents on the pyrazole ring, reducing the nucleophilicity of the nitrogen and altering its coordination behaviour. These findings suggest that the substrate presents intrinsic challenges under Chan–Lam-type conditions.

Fig. 7 Chan–Lam coupling of 5-(trifluoromethyl)-1H-pyrazole-3-sulfonyl fluoride with arylboronic acids afforded N-aryl products (8a–c) in low yields under mild conditions.

Conclusion

In conclusion, we have developed a concise and modular route to access 5-(trifluoromethyl)-1H-pyrazole-3-sulfonyl fluoride via a 1,3-dipolar cycloaddition between an in situ-generated diazo compound and Br-ESF. DFT and orbital analyses reveal that the exceptional 1,3-dipolar cycloaddition reactivity of CF₃-substituted diazo arises from its reduced distortion energy, early-stage orbital preorganization, and intramolecular electronic reorganization, which together overcome a less favorable primary HOMO–LUMO interaction to enable an earlier, less strained transition state formation. Subsequent sulfur(VI) fluoride exchange (SuFEx) reactions with diverse nitrogen- and oxygen-based nucleophiles furnished the corresponding sulfonamides and sulfonates in good yields. Further functionalization of the pyrazole core was demonstrated through N-alkylation and N-arylation. N-alkylation proceeded efficiently under mild conditions, while N-arylation via Chan–Lam coupling led to low yields despite extensive optimization. These results highlight both the synthetic utility and current limitations of this scaffold, offering a foundation for future development of functionally diverse molecules with potential relevance in medicinal chemistry and materials science.

Experimental

1-Bromoethene-1-sulfonyl fluoride (Br-ESF) (2)

1-Bromoethene-1-sulfonyl fluoride (Br-ESF) (2) was prepared according to previously reported procedures.^53,78–80

5-(Trifluoromethyl)-1H-pyrazole-3-sulfonyl fluoride (4)

In the mixture of water and the corresponding organic solvent (toluene), sodium nitrite (2.6 g, 10.0 equiv., 37.64 mmol) and 2,2,2-trifluoroethylamine hydrochloride (3.0 g, 6.0 equiv., 22.14 mmol) were added. The resulting mixture was stirred vigorously for 1 hour. Then, the organic layer was separated and dried over MgSO₄. To this layer, 1-bromoethene-1-sulfonyl fluoride (812 mg, 1.0 equiv., 3.69 mmol) was added and stirred overnight at room temperature. The solvent was evaporated, and the dry residue was fractioned upon silica and purified by flash chromatography eluting with hexane/EtOAc mixture 10 : 1 to afford the titled product 4 (1.16 g, 7.379 mmol, 72%) as a light-yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 11.71 (br, 1H), 7.32 (s, 1H). ¹³C{1H} NMR (126 MHz, CDCl₃) δ 143.2 (d, J = 37.6 Hz), 138.3 (d, J = 43.2 Hz), 119.0 (q, J = 270.2 Hz), 109.3. ¹⁹F NMR (471 MHz, CDCl₃) δ 66.6, −61.1. HRMS (ESI-TOF) m/z: [M − H]⁻ Calcd for C₄H₂F₄N₂O₂S 216.9701; found 216.9693.

General procedure for SuFEx

In a 3 mL vial, 5-(trifluoromethyl)-1H-pyrazole-3-sulfonyl fluoride 4 (1.0 equiv.), a nucleophile (1.0–1.1 equiv.), calcium bis((trifluoromethyl)sulfonyl)amide (1.4 equiv.), DABCO (2.1–3.0 equiv.), and 1 mL of acetonitrile were combined. The reaction was stirred at room temperature until the starting material was completely consumed, as confirmed by TLC. The solvent was removed under reduced pressure, and the resulting residue was dry loaded onto silica gel and purified by column chromatography using a hexanes/EtOAc mixture for elution. The titled product was obtained after further solvent removal under reduced pressure.

General procedure for N-alkylation

In a vial equipped with a magnetic stir bar, 5-(trifluoromethyl)-1H-pyrazole-3-sulfonyl fluoride 4 (1.0 equiv.), the corresponding alkyl bromide (1.05–1.1 equiv), and potassium carbonate (2.0 equiv.) were combined in DMSO (1 mL). The reaction mixture was stirred at 0 °C for 5–10 minutes, then allowed to warm to room temperature and stirred until complete consumption of the starting material, as monitored by TLC. The reaction was quenched with cold water and extracted with ethyl acetate. The organic layer, after drying over MgSO₄, was concentrated under reduced pressure. The resulting residue was dry loaded onto silica gel and purified by column chromatography using a hexane/EtOAc mixture for elution. The titled product was obtained after further solvent removal under reduced pressure.

General procedure for N-arylation

In a round-bottom flask containing MeOH, Cu(OAc)₂ (1.5 eq.) and NEt₃ (3.0 eq.) were added and stirred for 5–10 minutes. To this solution, 5-(trifluoromethyl)-1H-pyrazole-3-sulfonyl fluoride (1.0 eq.) was added and stirred for another 10 minutes. After 10 minutes, the corresponding aryl boronic acid (0.8 eq.) was added and stirred at room temperature (open flask) until completion. The reaction mixture was washed with water and extracted twice with ethyl acetate, dried over MgSO_4, and fractionated upon silica for purification via column chromatography using a mixture of ethyl acetate and hexanes. The titled product was obtained after further solvent removal under reduced pressure.

Author contributions

Bipin Khanal: conceptualization, experimental investigation, methodology, data curation, writing – review and editing; Mark Aldren M. Feliciano: computational investigation, writing – review and editing; Brian Gold: conceptualization, supervision, funding acquisition/project administration, data curation, writing – review and editing.

Conflicts of interest

There are no conflicts to declare.

Data availability

The data supporting this article have been included as part of the supplementary information (SI). Supplementary information: ¹H and ¹³C NMR specta of synthesized compounds, together with their spectral data, as well as computational details, coordinates, and total energies. See DOI: https://doi.org/10.1039/d5ra07095c.

Acknowledgements

This work was supported by start-up funds from New Mexico State University and by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P20GM103451.

Notes and references

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