# Evaluation of C3-substituents on pyrazoles as remote directing groups in palladium-catalyzed direct arylation

Besma Saoudi, Norman Le Floch, Henri Doucet

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Besma Saoudi, Norman Le Floch, Henri Doucet. Evaluation of C3-substituents on pyrazoles as remote directing groups in palladium-catalyzed direct arylation. Tetrahedron, 2025, 184, pp.134783. 10.1016/j.tet.2025.134783. hal-05167546

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# Evaluation of C3-substituents on pyrazoles as remote directing groups in palladium-catalyzed direct arylation

Besma Saoudi<sup>a,b</sup>, Norman Le Floch<sup>b</sup>, Henri Doucet<sup>b,*</sup>

## ARTICLE INFO

**Keywords:**

C-H bond activation

Direct arylation

Homogeneous catalysis

Palladium

Pyrazoles

## ABSTRACT

The palladium-catalyzed C-H bond functionalization of pyrazoles frequently presents significant challenges in terms of control of the selectivity of the reaction. This is due to the similar reactivity of their C4 and C5 positions, which frequently leads to the formation of mixtures of C4- and C5-mono-arylated pyrazoles, as well as C4,C5-di-arylated pyrazoles. This study demonstrates that the incorporation of suitable substituents at the C3-position of pyrazoles, such as trifluoromethyl or formyl, can result in the regioselective formation of the C5-arylated pyrazoles. These reactions demonstrate a high degree of tolerance for a variety of substituents on the aryl bromide. Moreover, our procedure utilizes an air-stable palladium catalyst that is readily available and a cost-effective base. In contrast, the presence of nitrile or bromo substituents at the C3-position of pyrazoles resulted in the formation of mixtures of products.

## 1. Introduction

In pharmaceutical chemistry, C5-aryl-substituted pyrazole derivatives that incorporate a functional group at the C3 position are frequently employed [1]. A notable example is Celecoxib, featuring a 3-trifluoromethyl substituent on the pyrazole unit (Fig. 1, left). Celecoxib is a COX-2 inhibitor and nonsteroidal anti-inflammatory drug. Deracoxib, which contains a difluoromethyl C3-substituent, is used in dogs for the treatment of pain and inflammation (Fig. 1, right). Consequently, the regioselective introduction of aryl units at the C5-position of pyrazoles that contain specific functional groups at the C3-position by straightforward methods remains an important area of research in organic synthesis.

The metal-catalyzed C-H bond functionalization of heteroarenes is currently regarded as one of the most effective methods for their arylation [2,3]. In contrast to the intermolecular direct arylation of carbocyclic arene systems which frequently resulted in mixtures of isomers, the inherent electronic bias of the heterocycle itself — such as with thiophenes, furans, or pyrroles — allows for the control of the regioselectivity of the direct arylation reaction in favor of their C2- or C5-positions [3]. In 2009, Sames and coworkers determined the regioselectivity of the Pd-catalyzed C-H arylation of pyrazoles [4]. In contrast to the high regioselectivities observed in thiophenes, furans, and

pyrroles arylations, they demonstrated that pyrazole arylation can take place at either the C4-position or the C5-position, with a preference for the latter (Scheme 1, a). As a consequence, the Pd-catalyzed C-H arylation of pyrazole generally results in the formation of mixtures of C4 and C5 mono-arylated pyrazoles, as well as 4,5-diarylated pyrazoles [5]. For example, 1-methylpyrazole (2 equiv.) and 4-bromobenzonitrile (1 equiv.) in the presence of 1 mol% Pd(OAc)₂ catalyst led to a mixture of the C5, C4 and C4,C5-(di)arylated pyrazoles, with a ratio of 70:10:20 (Scheme 1, b) [5b]. In several cases, regioselective palladium-catalyzed direct arylations of pyrazoles have been achieved through the use of blocking groups, such as halides, positioned at the C4- or C5-positions of the pyrazole unit [6–8]. To the best of our knowledge, the influence of C3-substituents on the pyrazole unit on the selectivity of their direct arylation reaction has not been fully elucidated. Among the rare examples, Gaulier and coworkers employed a pyrazole bearing a trifluoromethyl substituent at the C3-position, resulting in the synthesis of C5-arylated pyrazole with a yield of 66 % (Scheme 1, c) [9]. Itami, Torii and coworkers also performed a C5-position arylation of a trifluoromethyl C3-substituted pyrazole using Pd(OAc)₂/Binap as the catalyst [10]. However, the selectivity of the reaction was not clearly determined in both cases, and to the best of our knowledge, the influence of other C3-substituents on pyrazoles has not been investigated. Consequently, the impact of such substituents at the C3-position on

<figure><img src="image_3.png" /></figure>

<footnote><sup>a</sup> University of Constantine 1 - Frère Mentouri, Constantine, Algeria</footnote>

<footnote><sup>b</sup> Univ Rennes, CNRS, ISCR-UMR 6226, 35000, Rennes, France</footnote>

<footnote>* Corresponding author.
E-mail address: henri.doucet@univ-rennes1.fr (H. Doucet).</footnote>
<figure><img src="image_4.png" /><figcaption>**Fig. 1.** Pharmaceuticals containing a C3-substituent on a 5-arylpyrazole unit.</figcaption></figure>

<figure><img src="image_5.png" /><figcaption>**Scheme 1.** Regioselectivity of the Pd-catalyzed direct arylation of pyrazoles with free C4 and C5 positions.</figcaption></figure>

pyrazoles needed to be examined, given their potential to function as remote directing groups. Here we report on i) the selectivity of a set of C3-substituted pyrazoles which have both unsubstituted C4- and C5-positions in the Pd-catalyzed C–H arylation, ii) on the scope of the reaction, when good selectivities in C5-arylation were obtained (Scheme 1, d).

## 2. Results and discussion

Our initial study focused on the outcome of the coupling reaction between 1-methyl-3-(trifluoromethyl)pyrazole and 4-bromoacetophenone (Table 1). The reaction was catalyzed by 2 mol% Pd(OAc)₂ catalyst associated with a KOAc base in DMA at 150 °C. This specific set of conditions had previously been determined to be highly effective for the Pd-catalyzed direct arylation of 1-methylpyrazole [5a]. The formation of a mixture of C4- and C5-monoarylation products (1a and 1b) and 4, 5-diarylated pyrazole (1c) was observed, with a ratio of 93:5:2. The isolation of 1a was achieved with an 85 % yield (Table 1, entry 1). The

use of KOPiv and NaOAc bases instead of KOAc resulted in highly analogous mixtures in products 1a, 1b and 1c and yields of 1a (Table 1, entries 2 and 3). The use of carbonate base Cs₂CO₃ was found to be ineffective, exhibiting a poor conversion of 4-bromoacetophenone (Table 1, entry 4). Conversely, a high selectivity in favor of the formation of 1a (94 %) was observed when employing K₂CO₃ as a base (Table 1, entry 5). The influence of a few phosphine ligands on the selectivity of the reaction was also examined; however, no significant changes compared to the phosphine-free Pd(OAc)₂ catalyst were observed. In the presence of PPh₃ as the ligand, the selectivity in products 1a:1b:1c was 91:9:0 (Table 1, entry 6). When dppb and dppf were used as the ligands, selectivities ranging from 90 to 93 % were obtained for 1a (Table 1, entries 7–9). The two polar solvents NMP and DMF solvents were found to be compatible with this reaction, with selectivities in target product 1a of 92 % (Table 1, entries 10 and 11). In contrast, a low conversion of 4-bromoacetophenone was observed in the less polar solvent xylene. Furthermore, the selectivity in product 1a was only 72 % (see Table 1, entry 12). The better results obtained in polar solvents may be attributable to the more efficient formation of anionic palladium species. Finally, a lower reaction temperature of 120 °C instead of 150 °C proved ineffective, due to a low conversion of 4-bromoacetophenone (Table 1, entry 13).

The scope of the C5-arylation of 1-methyl-3-(trifluoromethyl)pyrazole was investigated, using a variety of (hetero)aryl bromides and 2 mol% Pd(OAc)₂ catalyst associated to KOAc base in DMA at 150 °C as the reaction conditions (Scheme 2). The use of electron-deficient para-substituted aryl bromides, bearing nitrile, ester, chloro, formyl, and benzoyl substituents, has resulted in the successful synthesis of the desired products 2a-6a. These products were obtained with selectivities ranging from 80 % to 94 % and yields ranging from 74 % to 80 %. The reaction also exhibited tolerance for aryl bromides bearing trifluoromethyl and trifluoromethoxy para-substituents, which resulted in the production of products 7a and 8a with selectivities of 82 % and 79 %, respectively, and satisfactory yields. 4-Fluorobenzene was also identified as a suitable substrate, resulting in the formation of product 9a with a selectivity of 92 % and a yield of 79 %. Under the same reaction conditions, the more electron-rich 4-tert-butylbromobenzene gave the desired product 10a in a very low yield, due to a poor conversion of this aryl bromide. In contrast, the use of 5 mol% of the more stable palladium catalyst PdCl(C₃H₅)(dppb), afforded product 10a in 94 % selectivity and 44 % yield. These conditions were also effective for the reaction with 4-bromoanisole, affording product 11a in 92 % selectivity and in 41 % yield.

Aryl bromides with nitrile, acetyl, or ester meta-substituents were also found to be effective in the synthesis of C5-arylated pyrazoles (12a-14a), exhibiting selectivities that range from good to high. In the case of the more congested 2-bromobenzonitrile, only the formation of the C5-arylated pyrazole 15a was observed by GC/MS analysis of the crude mixture. The reaction of 1-bromonaphthalene with 1-methyl-3-(trifluoromethyl)pyrazole resulted in the formation of product 16a, with a yield of 74 % and a selectivity of 84 %. The N-containing heterocycle 4-bromopyridine also led to a regioselective arylation of the pyrazole unit, with the formation of 17a in 83 % selectivity and 74 % yield.

We also investigated the impact of the presence of an ester substituent at the C3-position of the pyrazole unit on the outcome of the Pd-catalyzed direct arylation reaction, using again 2 mol% Pd(OAc)₂ catalyst associated to KOAc base in DMA for a duration of 16 h (Scheme 3). However, under these conditions, at temperatures of 100 or 130 °C, the reaction of methyl 1-methylpyrazole-3-carboxylate with 4-bromobenzonitrile as the coupling partner was unsuccessful, and the starting materials were recovered. At 150 °C, the formation of the desired coupling product 18a was again not detected, but a complete decomposition of methyl 1-methylpyrazole-3-carboxylate was observed. In contrast, at 150 °C using 5 mol% of PdCl(C₃H₅)(dppb) catalyst, a shorter reaction time of 1 h led to the formation of desired product 18a in low yield, due to a partial conversion of 4-bromobenzonitrile. It was
<caption>**Table 1**</caption>

Influence of the reaction conditions on the Pd-catalyzed coupling of 1-methyl-3-(trifluoromethyl)pyrazole with 4-bromoacetophenone. [a]

<figure><img src="image_6.png" /></figure>

<table><thead><tr><th>Entry</th><th>Catalyst</th><th>Solvent</th><th>Base</th><th>Conv. (%)</th><th>Ratio 1a:1b:1c</th><th>Yield in 1a (%)</th></tr></thead><tbody><tr><td>1</td><td>Pd(OAc)<sub>2</sub></td><td>DMA</td><td>KOAc</td><td>100</td><td>93:5:2</td><td>85</td></tr><tr><td>2</td><td>Pd(OAc)<sub>2</sub></td><td>DMA</td><td>KOPiv</td><td>100</td><td>92:5:3</td><td>83</td></tr><tr><td>3</td><td>Pd(OAc)<sub>2</sub></td><td>DMA</td><td>NaOAc</td><td>100</td><td>94:5:1</td><td>83</td></tr><tr><td>4</td><td>Pd(OAc)<sub>2</sub></td><td>DMA</td><td>Cs<sub>2</sub>CO<sub>3</sub></td><td>40</td><td>–</td><td>&lt;5</td></tr><tr><td>5</td><td>Pd(OAc)<sub>2</sub></td><td>DMA</td><td>K<sub>2</sub>CO<sub>3</sub></td><td>100</td><td>94:6:0</td><td>78</td></tr><tr><td>6</td><td>PdCl(C<sub>3</sub>H<sub>5</sub>)(dppb)</td><td>DMA</td><td>KOAc</td><td>100</td><td>90:7:3</td><td>83</td></tr><tr><td>7</td><td>Pd(OAc)<sub>2</sub>/dppb</td><td>DMA</td><td>KOAc</td><td>100</td><td>92:6:2</td><td>80</td></tr><tr><td>8</td><td>Pd(OAc)<sub>2</sub>/2 PPh<sub>3</sub></td><td>DMA</td><td>KOAc</td><td>100</td><td>91:9:0</td><td>76</td></tr><tr><td>9</td><td>Pd(OAc)<sub>2</sub>/dppf</td><td>DMA</td><td>KOAc</td><td>100</td><td>93:7:0</td><td>83</td></tr><tr><td>10</td><td>Pd(OAc)<sub>2</sub></td><td>DMF</td><td>KOAc</td><td>100</td><td>92:8:0</td><td>80</td></tr><tr><td>11</td><td>Pd(OAc)<sub>2</sub></td><td>NMP</td><td>KOAc</td><td>100</td><td>92:8:0</td><td>78</td></tr><tr><td>12</td><td>Pd(OAc)<sub>2</sub></td><td>Xylene</td><td>KOAc</td><td>30</td><td>72:28:0</td><td>–</td></tr><tr><td>13</td><td>Pd(OAc)<sub>2</sub></td><td>DMA</td><td>KOAc</td><td>22</td><td>87:13:0</td><td>[b]</td></tr></tbody></table>

determined that a reaction time of 3 h was required to achieve a high conversion of 4-bromobenzonitrile of 73 %. Under these conditions, the desired product **18a** was obtained in 100 % selectivity and in 36 % yield.

Conversely, 1-methylpyrazole-3-carbaldehyde was found to be a more suitable substrate (Scheme 4). Using 2 mol% Pd(OAc)₂ catalyst with KOAc base in DMA at a temperature of 150 °C, it's reaction with 4-bromobenzonitrile resulted in the formation of the C5-arylated pyrazole **19a** with complete selectivity and in 80 % yield. Furthermore, the use of 4-bromobenzotrifluoride, 3-bromobenzonitrile, and 3-bromo-1-chlorobenzene resulted in good selectivities of 80–90 % in favor of the C5-arylation products **20a**, **21a**, and **22a**. 4-Bromopyridine was also well tolerated and afforded the product **23a** in 93 % selectivity and in 76 % yield.

Under the same reaction conditions, the Pd-catalyzed direct arylation of 1-methylpyrazole-3-carbonitrile was found to be poorly selective. A mixture of mono-arylated products (**24a** and **24b**) and diarylated product (**24c**) was obtained in a ratio of 54:24:22 (Scheme 5).

The reactivity of 3-bromo-1-methylpyrazole in Pd-catalyzed direct arylation using 4-bromobenzonitrile as the reaction partner was also examined. This reaction was conducted at a temperature of 120 °C rather than 150 °C. This adjustment was made to prevent the cleavage of the pyrazole C–Br bond. However, the presence of a bromo substituent at the C3 position of the pyrazole was observed to be an ineffective strategy for the control of selectivity, as a mixture of products **25a**, **25b** and **25c** was obtained with a ratio of 40:30:30 (Scheme 6).

The dissimilar selectivities of these coupling reactions using various C3-substituents on pyrazole could be explained by the steric hindrance of these C3-substituents. The A-values [11] of nitrile (0.17) and bromo (0.38) are much lower than for formyl (0.8), ester (1.27) or trifluoromethyl (2.1), indicating that there is a less important steric hindrance with nitrile and bromo substituents. For the bromine substituent, the C–Br bond, which is longer than the C–C bond, is responsible for this low A-value.

### 3. Conclusion

In summary, the use of appropriate C3-substituents on pyrazoles

allow to control the selectivity of the Pd-catalyzed direct arylation if favor of the C5-position. A high degree of regioselectivity has been observed for the C5-arylation process involving 1-methyl-3-(trifluoromethyl)pyrazole. The incorporation of an aldehyde substituent at the C3 position of pyrazole was also identified as a particularly advantageous approach, providing again enhanced regioselectivity control in favor of pyrazole C5-arylation in comparison to unsubstituted 1-methylpyrazole. The reactions with these two pyrazole derivatives exhibit a high degree of tolerance for a wide variety of substituents on the aryl bromide. Moreover, this procedure utilizes an air-stable palladium catalyst associated to with a cost-effective base. Conversely, the presence of an ester C3-substituent on pyrazole proved ineffective in yielding the desired coupling product, and the presence of nitrile and bromo C3-substituents resulted in the formation of mixtures of coupling products that lacked practical utility. Thus, despite the lack of predictability in the selectivity of the reaction, we believe that the use C3-substituents on pyrazoles as remote directing groups constitutes an efficacious methodology for the regioselective access to specific 5-arylpyrazoles.

### 3.1. Experimental section

**General:** Pd(OAc)₂ (98 %) was purchased from Aldrich. DMA (99+%) extra pure and KOAc (99 %), were purchased from Acros. 1-Methyl-3-(trifluoromethyl)pyrazole (97 %), methyl 1-methylpyrazole-3-carboxylate (95 %), 1-methylpyrazole-3-carbaldehyde (97 %) 1-methylpyrazole-3-carbonitrile (97 %) and 3-bromo-1-methylpyrazole (95 %) were purchased from Doug Discovery. These compounds were not purified before use. All reagents were weighed and handled in air. All reactions were carried out under an inert atmosphere with standard Schlenk techniques. ¹H, ¹⁹F and ¹³C NMR spectra were recorded on a Bruker Avance III 400 MHz spectrometer. Melting points were determined with a Kofler hot bench system. High-resolution mass spectra were measured on a Thermo Fisher Q-Exactive spectrometer.

**General procedure:** for the preparation of products **1a-23a:** As a typical experiment, the reaction of the pyrazole derivative (1.5 or 2 mmol) (see schemes), aryl bromide (1 mmol) and KOAc (0.196 g, 2 mmol) at 120 or 150 °C (see schemes) during 3 or 16 h (see schemes) in

<footnote>a [Pd] (0.02 equiv.), 1-methyl-3-(trifluoromethyl)pyrazole (1.5 equiv.), 4-bromoacetophenone (1 equiv.), base (2 equiv.), 150 °C, 16 h, conversion of 4-bromoacetophenone, 1a:1b:1c ratios determined by ¹H NMR and GC/MS analysis of the crude mixtures, isolated yields.</footnote>

<footnote>b 120 °C.</footnote>
<figure><img src="image_7.png" /><figcaption>**Scheme 2.** Pd-catalyzed C5-arylations of 1-methyl-3-(trifluoromethyl)pyrazole with a set of aryl bromides.</figcaption></figure>

<figure><img src="image_8.png" /><figcaption>**Scheme 3.** Reactivity of methyl 1-methylpyrazole-3-carboxylate in Pd-catalyzed direct arylation.</figcaption></figure>

<figure><img src="image_9.png" /><figcaption>**Scheme 4.** Pd-catalyzed direct C5-arylations of 1-methylpyrazole-3-carbaldehyde with a set of aryl bromides.</figcaption></figure>

<figure><img src="image_10.png" /><figcaption>**Scheme 5.** Selectivity of the Pd-catalyzed direct arylations of 1-methylpyrazole-3-carbonitrile.</figcaption></figure>

<figure><img src="image_11.png" /><figcaption>**Scheme 6.** Selectivity of the Pd-catalyzed direct arylations of 3-bromo-1-methylpyrazole.</figcaption></figure>
DMA (4 mL) in the presence of Pd(OAc)₂ (4.5 mg, 0.02 mmol) or PdCl(C₃H₅)(dppb) (30.5 mg, 0.05 mmol) (see schemes) under argon affords the coupling product after evaporation of the solvent and purification on silica gel column chromatography.

### 3.1.1. 1-(4-(1-Methyl-3-(trifluoromethyl)pyrazol-5-yl)phenyl)ethan-1-one (1a)

From 1-methyl-3-(trifluoromethyl)pyrazole (0.225 g, 1.5 mmol) and 4-bromoacetophenone (0.199 g, 1 mmol), **1a** was obtained in 85 % yield (0.228 g) as a colorless oil.

¹H NMR (400 MHz, CDCl₃): δ 8.10 (d, *J* = 8.1 Hz, 2H), 7.56 (d, *J* = 8.1 Hz, 2H), 6.65 (s, 1H), 3.98 (s, 3H), 2.68 (s, 3H).

¹⁹F NMR (376 MHz, CDCl₃): δ -62.0.

¹³C NMR (100 MHz, CDCl₃): δ 197.4, 144.0, 141.8 (q, *J* = 38.5 Hz), 137.4, 133.6, 129.0, 128.9, 121.1 (q, *J* = 268.6 Hz), 104.9 (q, *J* = 1.9 Hz), 38.3, 26.7.

HRMS calcd for [M+H]⁺ C₁₃H₁₂F₃N₂O 269.0896, found: 269.0896.

### 3.1.2. 4-(1-Methyl-3-(trifluoromethyl)pyrazol-5-yl)benzonitrile (2a)

From 1-methyl-3-(trifluoromethyl)pyrazole (0.225 g, 1.5 mmol) and 4-bromobenzonitrile (0.182 g, 1 mmol), **2a** was obtained in 74 % yield (0.186 g) as a colorless oil.

¹H NMR (400 MHz, CDCl₃): δ 7.83 (d, *J* = 8.1 Hz, 2H), 7.56 (d, *J* = 8.1 Hz, 2H), 6.66 (s, 1H), 3.98 (s, 3H).

¹⁹F NMR (376 MHz, CDCl₃): δ -62.0.

¹³C NMR (100 MHz, CDCl₃): δ 143.1, 142.0 (q, *J* = 38.5 Hz), 133.6, 132.8, 129.4, 121.0 (q, *J* = 268.5 Hz), 118.0, 113.2, 105.2 (q, *J* = 1.9 Hz), 38.3.

HRMS calcd for [M+H]⁺ C₁₂H₉F₃N₃ 252.0743, found: 252.0742.

### 3.1.3. Ethyl 4-(1-methyl-3-(trifluoromethyl)pyrazol-5-yl)benzoate (3a)

From 1-methyl-3-(trifluoromethyl)pyrazole (0.225 g, 1.5 mmol) and ethyl 4-bromobenzoate (0.229 g, 1 mmol), **3a** was obtained in 75 % yield (0.223 g) as a colorless oil.

¹H NMR (400 MHz, CDCl₃): δ 8.19 (d, *J* = 8.3 Hz, 2H), 7.53 (d, *J* = 8.3 Hz, 2H), 6.64 (s, 1H), 4.45 (q, *J* = 7.2 Hz, 2H), 3.97 (s, 3H), 1.45 (t, *J* = 7.2 Hz, 3H).

¹⁹F NMR (376 MHz, CDCl₃): δ -62.1.

¹³C NMR (100 MHz, CDCl₃): δ 165.8, 144.1, 141.8 (q, *J* = 38.5 Hz), 133.4, 131.2, 130.1, 128.7, 121.1 (q, *J* = 268.6 Hz), 104.8 (q, *J* = 1.9 Hz), 61.4, 38.3, 14.3.

Anal. Calcd. for C₁₄H₁₃F₃N₂O₂: C, 56.38; H, 4.39. Found: C, 56.59; H, 4.17.

### 3.1.4. 5-(4-Chlorophenyl)-1-methyl-3-(trifluoromethyl)pyrazole (4a) [12]

From 1-methyl-3-(trifluoromethyl)pyrazole (0.225 g, 1.5 mmol) and 1-bromo-4-chlorobenzene (0.192 g, 1 mmol), **4a** was obtained in 77 % yield (0.200 g) as a colorless oil.

¹H NMR (400 MHz, CDCl₃): δ 7.49 (d, *J* = 8.5 Hz, 2H), 7.37 (d, *J* = 8.5 Hz, 2H), 6.57 (s, 1H), 3.93 (s, 3H).

¹⁹F NMR (376 MHz, CDCl₃): δ -62.1.

¹³C NMR (100 MHz, CDCl₃): δ 143.9, 141.7 (q, *J* = 38.2 Hz), 135.6, 130.1, 129.2, 127.8, 121.2 (q, *J* = 268.5 Hz), 104.7, 38.0.

HRMS calcd for [M+H]⁺ C₁₁H₉ClF₃N₂ 261.0401, found: 261.0400.

### 3.1.5. 4-(1-Methyl-3-(trifluoromethyl)pyrazol-5-yl)benzaldehyde (5a)

From 1-methyl-3-(trifluoromethyl)pyrazole (0.225 g, 1.5 mmol) and 4-bromobenzaldehyde (0.185 g, 1 mmol), **5a** was obtained in 77 % yield (0.196 g) as a colorless oil.

¹H NMR (400 MHz, CDCl₃): δ 10.11 (s, 1H), 8.03 (d, *J* = 8.1 Hz, 2H), 7.64 (d, *J* = 8.1 Hz, 2H), 6.67 (s, 1H), 3.99 (s, 3H).

¹⁹F NMR (376 MHz, CDCl₃): δ -61.5.

¹³C NMR (100 MHz, CDCl₃): δ 191.2, 143.8, 141.8 (q, *J* = 38.5 Hz), 136.5, 134.9, 130.1, 129.4, 121.1 (q, *J* = 268.7 Hz), 105.1 (q, *J* = 1.9 Hz), 38.4.

HRMS calcd for [M+H]⁺ C₁₂H₁₀F₃N₂O 255.0738, found: 255.0740.

### 3.1.6. (4-(1-Methyl-3-(trifluoromethyl)pyrazol-5-yl)phenyl)(phenyl)methanone (6a)

From 1-methyl-3-(trifluoromethyl)pyrazole (0.225 g, 1.5 mmol) and 4-bromobenzophenone (0.261 g, 1 mmol), **6a** was obtained in 80 % yield (0.264 g) as a colorless oil.

¹H NMR (400 MHz, CDCl₃): δ 7.95 (d, *J* = 8.1 Hz, 2H), 7.85 (d, *J* = 8.1 Hz, 2H), 7.65 (t, *J* = 7.8 Hz, 1H), 7.57 (d, *J* = 8.1 Hz, 2H), 7.54 (t, *J* = 7.7 Hz, 2H), 6.67 (s, 1H), 4.00 (s, 3H).

¹⁹F NMR (376 MHz, CDCl₃): δ -61.5.

¹³C NMR (100 MHz, CDCl₃): δ 195.7, 144.0, 141.8 (q, *J* = 38.2 Hz), 138.2, 137.1, 132.9, 132.8, 130.5, 130.0, 128.7, 128.5, 121.1 (q, *J* = 268.5 Hz), 104.9 (q, *J* = 1.9 Hz), 38.3.

HRMS calcd for [M+H]⁺ C₁₈H₁₄F₃N₂O 331.1053, found: 331.1052.

### 3.1.7. 1-Methyl-3-(trifluoromethyl)-5-(4-(trifluoromethyl)phenyl)pyrazole (7a)

From 1-methyl-3-(trifluoromethyl)pyrazole (0.225 g, 1.5 mmol) and 4-bromobenzotrifluoride (0.225 g, 1 mmol), **7a** was obtained in 75 % yield (0.220 g) as a colorless oil.

¹H NMR (400 MHz, CDCl₃): δ 7.79 (d, *J* = 8.1 Hz, 2H), 7.57 (d, *J* = 8.1 Hz, 2H), 6.64 (s, 1H), 3.97 (s, 3H).

¹⁹F NMR (376 MHz, CDCl₃): δ -62.1, -62.9.

¹³C NMR (100 MHz, CDCl₃): δ 143.6, 141.8 (q, *J* = 38.4 Hz), 132.8, 131.4 (q, *J* = 32.8 Hz), 129.2, 126.0 (q, *J* = 3.9 Hz), 123.6 (q, *J* = 272.1 Hz), 121.1 (q, *J* = 268.6 Hz), 104.9, 38.2.

HRMS calcd for [M+H]⁺ C₁₂H₉F₆N₂ 295.0664, found: 295.0666.

### 3.1.8. 1-Methyl-5-(4-(trifluoromethoxy)phenyl)-3-(trifluoromethyl)pyrazole (8a)

From 1-methyl-3-(trifluoromethyl)pyrazole (0.225 g, 1.5 mmol) and 1-bromo-4-(trifluoromethoxy)benzene (0.241 g, 1 mmol), **8a** was obtained in 72 % yield (0.223 g) as a colorless oil.

¹H NMR (400 MHz, CDCl₃): δ 7.47 (d, *J* = 7.8 Hz, 2H), 7.36 (d, *J* = 7.8 Hz, 2H), 6.59 (s, 1H), 3.94 (s, 3H).

¹⁹F NMR (376 MHz, CDCl₃): δ -57.8, -62.2.

¹³C NMR (100 MHz, CDCl₃): δ 149.9, 143.7, 141.7 (q, *J* = 38.5 Hz), 130.5, 127.9, 121.3, 120.8 (q, *J* = 268.6 Hz), 120.5 (q, *J* = 258.0 Hz), 104.6 (q, *J* = 2.1 Hz), 38.1.

Anal. Calcd. for C₁₂H₈F₆N₂O: C, 46.46; H, 2.60. Found: C, 46.58; H, 2.70.

### 3.1.9. 5-(4-Fluorophenyl)-1-methyl-3-(trifluoromethyl)pyrazole (9a)

From 1-methyl-3-(trifluoromethyl)pyrazole (0.225 g, 1.5 mmol) and 1-bromo-4-fluorobenzene (0.175 g, 1 mmol), **9a** was obtained in 79 % yield (0.193 g) as a colorless oil.

¹H NMR (400 MHz, CDCl₃): δ 7.45 (dd, *J* = 8.8, 5.3 Hz, 2H), 7.21 (t, *J* = 8.5 Hz, 2H), 6.56 (s, 1H), 3.92 (s, 3H).

¹⁹F NMR (376 MHz, CDCl₃): δ -62.0, -111.4.

¹³C NMR (100 MHz, CDCl₃): δ 163.2 (d, *J* = 250.2 Hz), 144.1, 141.6 (q, *J* = 38.2 Hz), 130.8 (d, *J* = 8.4 Hz), 125.4 (d, *J* = 3.2 Hz), 121.2 (q, *J* = 268.6 Hz), 116.1 (d, *J* = 22.0 Hz), 104.5, 38.0.

HRMS calcd for [M+H]⁺ C₁₁H₉F₄N₂ 245.0696, found: 245.0696.

### 3.1.10. 5-(4-(tert-Butyl)phenyl)-1-methyl-3-(trifluoromethyl)pyrazole (10a)

From 1-methyl-3-(trifluoromethyl)pyrazole (0.225 g, 1.5 mmol) and 1-bromo-4-tert-butylbenzene (0.213 g, 1 mmol), **10a** was obtained in 44 % yield (0.124 g) as a colorless oil.

¹H NMR (400 MHz, CDCl₃): δ 7.53 (d, *J* = 8.4 Hz, 2H), 7.37 (d, *J* = 8.4 Hz, 2H), 6.55 (s, 1H), 3.95 (s, 3H), 1.39 (s, 9H).

¹⁹F NMR (376 MHz, CDCl₃): δ -62.0.

¹³C NMR (101 MHz, CDCl₃): δ 152.5, 145.2, 141.5 (q, *J* = 38.2 Hz), 128.5, 126.4, 125.9, 121.4 (q, *J* = 268.6 Hz), 104.2 (q, *J* = 1.9 Hz), 38.1, 34.8, 31.2.

HRMS calcd for [M+H]⁺ C₁₅H₁₈F₃N₂ 283.1417, found: 283.1415.
### 3.1.11. 5-(4-Methoxyphenyl)-1-methyl-3-(trifluoromethyl)pyrazole (11a)

From 1-methyl-3-(trifluoromethyl)pyrazole (0.225 g, 1.5 mmol) and 4-bromoanisole (0.187 g, 1 mmol), **11a** was obtained in 41 % yield (0.105 g) as a colorless oil.

¹H NMR (400 MHz, CDCl₃) δ 7.36 (d, *J* = 8.7 Hz, 2H), 7.03 (d, *J* = 8.7 Hz, 2H), 6.52 (s, 1H), 3.92 (s, 3H), 3.89 (s, 3H).

¹⁹F NMR (376 MHz, CDCl₃) δ -62.1.

¹³C NMR (101 MHz, CDCl₃) δ 160.3, 145.0, 141.5 (q, *J* = 38.1 Hz), 130.2, 121.6, 121.3 (d, *J* = 268.6 Hz), 114.4, 104.0 (d, *J* = 2.2 Hz), 55.4, 37.9.

HRMS calcd for [M+H]⁺ C₁₂H₁₂F₃N₂O 257.0896, found: 257.0894.

### 3.1.12. 3-(1-Methyl-3-(trifluoromethyl)pyrazol-5-yl)benzonitrile (12a)

From 1-methyl-3-(trifluoromethyl)pyrazole (0.225 g, 1.5 mmol) and 3-bromobenzonitrile (0.182 g, 1 mmol), **12a** was obtained in 65 % yield (0.163 g) as a colorless oil.

¹H NMR (400 MHz, CDCl₃): δ 7.79 (dt, *J* = 7.1, 1.6 Hz, 1H), 7.75 (s, 1H), 7.71–7.63 (m, 2H), 6.64 (s, 1H), 3.96 (s, 3H).

¹⁹F NMR (376 MHz, CDCl₃): δ -62.0.

¹³C NMR (100 MHz, CDCl₃): δ 142.6, 142.0 (q, *J* = 38.5 Hz), 133.0, 132.7, 132.2, 130.7, 130.0, 121.0 (q, *J* = 268.6 Hz), 117.8, 113.6, 105.1 (q, *J* = 1.9 Hz), 38.2.

HRMS calcd for [M+H]⁺ C₁₂H₁₂F₃N₃ 252.0743, found: 252.0742.

### 3.1.13. 1-(3-(1-Methyl-3-(trifluoromethyl)pyrazol-5-yl)phenyl)ethan-1-one (13a)

From 1-methyl-3-(trifluoromethyl)pyrazole (0.225 g, 1.5 mmol) and 3-bromoacetophenone (0.199 g, 1 mmol), **13a** was obtained in 81 % yield (0.217 g) as a colorless oil.

¹H NMR (400 MHz, CDCl₃): δ 8.12–7.97 (m, 2H), 7.67–7.58 (m, 2H), 6.63 (s, 1H), 3.96 (s, 3H), 2.68 (s, 3H).

¹⁹F NMR (376 MHz, CDCl₃): δ -62.1.

¹³C NMR (100 MHz, CDCl₃): δ 197.1, 144.1, 141.7 (q, *J* = 38.4 Hz), 137.8, 133.1, 129.9, 129.4, 129.1, 128.5, 121.2 (q, *J* = 268.5 Hz), 104.7 (q, *J* = 1.9 Hz), 38.1, 26.7.

HRMS calcd for [M+H]⁺ C₁₃H₁₂F₃N₂O 269.0896, found: 269.0896.

### 3.1.14. Methyl 3-(1-methyl-3-(trifluoromethyl)pyrazol-5-yl)benzoate (14a)

From 1-methyl-3-(trifluoromethyl)pyrazole (0.225 g, 1.5 mmol) and methyl 3-bromobenzoate (0.215 g, 1 mmol), **14a** was obtained in 71 % yield (0.202 g) as a colorless oil.

¹H NMR (400 MHz, CDCl₃): δ 8.16 (dt, *J* = 7.1, 1.8 Hz, 1H), 8.12 (s, 1H), 7.65–7.57 (m, 2H), 6.63 (s, 1H), 3.98 (s, 3H), 3.96 (s, 3H).

¹⁹F NMR (376 MHz, CDCl₃): δ -62.1.

¹³C NMR (100 MHz, CDCl₃): δ 166.2, 144.0, 141.7 (q, *J* = 38.4 Hz), 133.0, 131.1, 130.3, 129.9, 129.6, 129.2, 121.2 (q, *J* = 268.5 Hz), 104.7 (q, *J* = 1.9 Hz), 52.5, 38.1.

HRMS calcd for [M+H]⁺ C₁₃H₁₂F₃N₂O₂ 285.0845, found: 285.0846.

### 3.1.15. 2-(1-Methyl-3-(trifluoromethyl)pyrazol-5-yl)benzonitrile (15a)

From 1-methyl-3-(trifluoromethyl)pyrazole (0.225 g, 1.5 mmol) and 2-bromobenzonitrile (0.182 g, 1 mmol), **15a** was obtained in 83 % yield (0.208 g) as a colorless oil.

¹H NMR (400 MHz, CDCl₃): δ 7.85 (d, *J* = 8.4 Hz, 1H), 7.76 (td, *J* = 7.7, 1.4 Hz, 1H), 7.64 (td, *J* = 7.7, 1.2 Hz, 1H), 7.51 (d, *J* = 8.4 Hz, 1H), 6.72 (s, 1H), 3.89 (s, 3H).

¹⁹F NMR (376 MHz, CDCl₃): δ -61.5.

¹³C NMR (100 MHz, CDCl₃): δ 141.8 (q, *J* = 38.5 Hz), 140.8, 133.7, 133.1, 132.6, 131.0, 130.1, 121.0 (q, *J* = 268.2 Hz), 117.0, 113.3, 106.2 (q, *J* = 1.9 Hz), 38.0.

HRMS calcd for [M+H]⁺ C₁₂H₁₂F₃N₃ 252.0743, found: 252.0742.

### 3.1.16. 1-Methyl-5-(naphthalen-1-yl)-3-(trifluoromethyl)pyrazole (16a)

From 1-methyl-3-(trifluoromethyl)pyrazole (0.225 g, 1.5 mmol) and 1-bromonaphthalene (0.207 g, 1 mmol), afford **16a** in 74 % yield (0.204 g) as a colorless oil.

¹H NMR (400 MHz, CDCl₃): δ 8.02 (d, *J* = 8.0 Hz, 1H), 7.98 (d, *J* = 7.9 Hz, 1H), 7.63–7.53 (m, 4H), 7.49 (dd, *J* = 7.1, 1.3 Hz, 1H), 6.67 (s, 1H), 3.72 (s, 3H).

¹⁹F NMR (376 MHz, CDCl₃): δ -61.9.

¹³C NMR (100 MHz, CDCl₃): δ 143.2, 141.7 (q, *J* = 38.2 Hz), 133.6, 132.0, 130.2, 128.6, 128.5, 127.4, 126.7, 126.6, 125.2, 124.9, 121.4 (q, *J* = 268.6 Hz), 106.0 (q, *J* = 1.9 Hz), 37.7.

Anal. Calcd. for C₁₅H₁₁F₃N₂: C, 65.22; H, 4.01. Found: C, 65.47; H, 3.80.

### 3.1.17. 4-(1-Methyl-3-(trifluoromethyl)pyrazol-5-yl)pyridine (17a)

From 1-methyl-3-(trifluoromethyl)pyrazole (0.225 g, 1.5 mmol) and 4-bromopyridine (0.158 g, 1 mmol), **17a** was obtained in 74 % yield (0.168 g) as a colorless oil.

¹H NMR (400 MHz, CDCl₃): δ 7.78 (d, *J* = 6.1 Hz, 2H), 7.38 (d, *J* = 6.1 Hz, 2H), 6.70 (s, 1H), 4.01 (s, 3H).

¹⁹F NMR (376 MHz, CDCl₃): δ -62.2.

¹³C NMR (100 MHz, CDCl₃): δ 150.6, 142.4, 142.1 (q, *J* = 38.1 Hz), 136.8, 122.9, 121.0 (q, *J* = 268.0 Hz), 105.2 (q, *J* = 1.9 Hz), 38.5.

HRMS calcd for [M+H]⁺ C₁₀H₉F₃N₃ 228.0743, found: 228.0741.

### 3.1.18. Methyl 5-(4-cyanophenyl)-1-methylpyrazole-3-carboxylate (18a)

From methyl 1-methylpyrazole-3-carboxylate (0.210 g, 1.5 mmol) and 4-bromobenzonitrile (0.182 g, 1 mmol), **18a** was obtained in 36 % yield (0.087 g) as a colorless oil.

¹H NMR (600 MHz, CDCl₃): δ 7.82 (d, *J* = 8.3 Hz, 2H), 7.58 (d, *J* = 8.3 Hz, 2H), 6.96 (s, 1H), 4.01 (s, 3H), 3.98 (s, 3H).

¹³C NMR (151 MHz, CDCl₃): δ 162.4, 143.2, 142.8, 133.9, 132.7, 129.3, 118.1, 113.0, 109.7, 52.2, 38.6.

HRMS calcd for [M+H]⁺ C₁₃H₁₂N₃O₂ 242.0924, found: 242.0922.

### 3.1.19. 4-(3-Formyl-1-methylpyrazol-5-yl)benzonitrile (19a)

From 1-methylpyrazole-3-carbaldehyde (0.220 g, 2 mmol) and 4-bromobenzonitrile (0.182 g, 1 mmol), **19a** was obtained in 80 % yield (0.169 g) as a white solid: mp 167–169 °C.

¹H NMR (400 MHz, CDCl₃): δ 10.00 (s, 1H), 7.82 (d, *J* = 8.4 Hz, 2H), 7.59 (d, *J* = 8.4 Hz, 2H), 6.92 (s, 1H), 4.03 (s, 3H).

¹³C NMR (100 MHz, CDCl₃): δ 186.1, 150.6, 143.8, 133.8, 132.8, 129.4, 118.0, 113.2, 106.6, 38.7.

HRMS calcd for [M+H]⁺ C₁₂H₁₀N₃O 212.0818, found: 212.0817.

### 3.1.20. 1-Methyl-5-(4-(trifluoromethyl)phenyl)pyrazole-3-carbaldehyde (20a)

From 1-methylpyrazole-3-carbaldehyde (0.220 g, 2 mmol) and 4-bromobenzotrifluoride (0.225 g, 1 mmol), **20a** was obtained in 76 % yield (0.193 g) as a white solid: mp 79–81 °C.

¹H NMR (400 MHz, CDCl₃): δ 10.01 (s, 1H), 7.79 (d, *J* = 8.4 Hz, 2H), 7.59 (d, *J* = 8.4 Hz, 2H), 6.91 (s, 1H), 4.02 (s, 3H).

¹⁹F NMR (376 MHz, CDCl₃): δ -62.9.

¹³C NMR (100 MHz, CDCl₃): δ 186.3, 150.6, 144.3, 133.0, 131.4 (q, *J* = 32.9 Hz), 129.2, 127.0 (q, *J* = 3.8 Hz), 123.7 (q, *J* = 272.2 Hz), 106.4, 38.5.

HRMS calcd for [M+H]⁺ C₁₂H₁₀F₃N₂O 255.0740, found: 255.0739.

### 3.1.21. 3-(3-Formyl-1-methylpyrazol-5-yl)benzonitrile (21a)

From 1-methylpyrazole-3-carbaldehyde (0.220 g, 2 mmol) and 3-bromobenzonitrile (0.182 g, 1 mmol), **21a** was obtained in 78 % yield (0.165 g) as a colorless oil.

¹H NMR (400 MHz, CDCl₃): δ 10.01 (s, 1H), 7.79 (dt, *J* = 7.2, 1.7 Hz, 1H), 7.75 (s, 1H), 7.70 (dt, *J* = 7.9, 1.7 Hz, 1H), 7.65 (t, *J* = 7.9 Hz, 1H), 6.90 (s, 1H), 4.01 (s, 3H).

¹³C NMR (100 MHz, CDCl₃): δ 186.1, 150.6, 143.3, 133.0, 132.7, 132.1, 130.9, 130.0, 117.8, 113.6, 106.5, 38.5.

HRMS calcd for [M+H]⁺ C₁₂H₁₀N₃O 212.0818, found: 212.0816.
### 3.1.22. 5-(3-Chlorophenyl)-1-methylpyrazole-3-carbaldehyde (22a)

From 1-methylpyrazole-3-carbaldehyde (0.220 g, 2 mmol) and 1-bromo-3-chlorobenzene (0.192 g, 1 mmol), **22a** was obtained in 71 % yield (0.156 g) as a white solid: mp 111–113 °C.

¹H NMR (400 MHz, CDCl₃) δ 9.99 (s, 1H), 7.56–7.39 (m, 3H), 7.39–7.18 (m, 1H), 6.86 (s, 1H), 3.99 (s, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 186.3, 150.5, 144.3, 135.0, 131.1, 130.3, 129.4, 128.9, 127.0, 106.1, 38.5.

HRMS calcd for [M+H]⁺ C₁₁H₁₀ClN₂O 221.0476, found: 221.0474.

### 3.1.23. 1-Methyl-5-(pyridin-4-yl)pyrazole-3-carbaldehyde (23a)

From 1-methylpyrazole-3-carbaldehyde (0.220 g, 2 mmol) and 4-bromopyridine (0.158 g, 1 mmol), **23a** was obtained in 76 % yield (0.142 g) as a white solid: mp 139–141 °C.

¹H NMR (400 MHz, CDCl₃) δ 10.01 (s, 1H), 8.79 (d, *J* = 6.1 Hz, 2H), 7.39 (d, *J* = 6.1 Hz, 2H), 6.97 (s, 1H), 4.07 (s, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 186.1, 150.7, 150.6, 143.0, 137.0, 122.8, 106.6, 38.8.

HRMS calcd for [M+H]⁺ C₁₀H₁₀N₃O 188.0818, found: 188.0817.

### 3.1.24. 5-(4-Cyanophenyl)-1-methylpyrazole-3-carbonitrile (24a)

From 1-methylpyrazole-3-carbonitrile (0.214 g, 2 mmol) and 4-bromobenzonitrile (0.182 g, 1 mmol), **24a** was obtained in 33 % yield (0.069 g) as a white solid: mp 200–202 °C.

¹H NMR (400 MHz, CDCl₃) δ 7.84 (d, *J* = 8.5 Hz, 2H), 7.57 (d, *J* = 8.5 Hz, 2H), 6.79 (s, 1H), 3.98 (s, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 143.1, 132.9, 132.8, 129.5, 124.5, 117.8, 113.7, 113.6, 111.9, 38.7.

HRMS calcd for [M+H]⁺ C₁₂H₉N₄ 209.0822, found: 209.0823.

### 3.1.25. 4-(3-Bromo-1-methylpyrazol-5-yl)benzonitrile (25a)

From 3-bromo-1-methylpyrazole (0.322 g, 2 mmol) and 4-bromobenzonitrile (0.182 g, 1 mmol), **25a** was obtained in 24 % yield (0.061 g) as a white solid: mp 137–139 °C.

¹H NMR (400 MHz, CDCl₃) δ 7.80 (d, *J* = 8.4 Hz, 2H), 7.55 (d, *J* = 8.4 Hz, 2H), 6.41 (s, 1H), 3.89 (s, 3H).

¹³C NMR (101 MHz, CDCl₃) δ 143.8, 133.8, 132.7, 129.3, 125.4, 118.1, 113.0, 109.3, 38.0.

HRMS calcd for [M+H]⁺ C₁₁H₉BrN₃ 261.9974, found: 261.9976.

## CRediT authorship contribution statement

**Besma Saoudi:** Writing – original draft, Methodology, Investigation, Funding acquisition, Formal analysis, Conceptualization.
**Norman Le Floch:** Methodology, Investigation.
**Henri Doucet:** Writing – review & editing, Writing – original draft, Project administration, Conceptualization.

## Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

## Acknowledgments

We thank CNRS and "Rennes Metropole" for providing financial support. We also thank the University of Frère Mentouri Constantine – 1, Algeria for providing an internship program.

## Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.tet.2025.134783.

## Data availability

Data will be made available on request.

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[7] For Pd-catalyzed direct C4-arylations of 5-substituted pyrazoles, T. Yan, L. Chen, C. Bruneau, P.H. Dixneuf, H. Doucet, J. Org. Chem. 77 (2012) 7659–7664.

[8] For Pd-catalyzed direct C4-arylations of pyrazoles without C5-substituents; X. Shi, E.D. Sosa Carrizo, M. Cordier, J. Roger, N. Pirio, J.-C. Hierso, P. Fleurat-Lessard, J.-F. Soule, H. Doucet, Chem. Eur. J. 27 (2021) 5546–5554.

[9] For Pd-catalyzed direct C5-arylations of 3-trifluoromethyl-substituted pyrazole, S. M. Gaulier, R. McKay, N.A. Swain, Tetrahedron Lett. 52 (2011) 6000–6002.

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[11] For A-values see, J.A. Hirsch, Topics in Stereochemistry, John Wiley & Sons, Inc., New York, 1967, pp. 199–222.

[12] S. Fustero, R. Roman, J.F. Sanz-Cervera, A. Simon-Fuentes, A.C. Cunat, S. Villanova, M. Murguia, J. Org. Chem. 73 (2008) 3523–3529.