# Direct Palladium-Catalyzed C5-Arylation of 1,3,4-Oxadiazoles with Aryl Chlorides Promoted by Bis(di- iso propylphosphino) Ferrocene

Loris Gelin, Henri Sabbadin, Hélène Cattey, Paul Fleurat-Lessard, Jean-cyrille Hierso, Julien Roger

<figure><img src="image_1.png" /></figure>

## ► To cite this version:

Loris Gelin, Henri Sabbadin, Hélène Cattey, Paul Fleurat-Lessard, Jean-cyrille Hierso, et al., Direct Palladium-Catalyzed C5-Arylation of 1,3,4-Oxadiazoles with Aryl Chlorides Promoted by Bis(di- iso propylphosphino) Ferrocene. European Journal of Organic Chemistry, 2024, 27 (21), pp.16824-16832.
10.1002/ejoc.202400212. hal-05020889

HAL Id: hal-05020889

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Submitted on 4 Apr 2025

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# Direct Palladium-Catalyzed C5-Arylation of 1,3,4-Oxadiazoles with Aryl Chlorides Promoted by Bis(di-isopropylphosphino) Ferrocene

Loris Gelin,[a] Henri Sabbadin,[a] Hélène Cattey,[a] Paul Fleurat-Lessard,[a] Jean-Cyrille Hierso,*[a] and Julien Roger*[a]

The direct palladium-catalyzed C—H arylation of 1,3,4-oxadiazoles with challenging aryl chloride substrates is promoted by the use of a specifically designed electron-rich ferrocenyl diphosphane. This protocol employs 0.5 to 1.0 mol % catalyst loading without any additives such as copper or ammonium

salts, and equally tolerates electron-donating and electron-withdrawing substituents on the (heteroaryl)aryl halides, as illustrated by the efficient synthesis in 86 % yield of the anti-tubercular agent PHOXPY (2-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazine) by a late-stage arylation using 2-chloropyrazine.

## Introduction

1,3,4-Oxadiazoles are an important class of five-membered heterocycles with valuable applications in the field of pharmaceuticals, including examples of anti-tubercular (PHOXPY) and anti-hypertensive (Nesapidil®) agents, an endothelin receptor antagonist (Zibotentan®), and a selective SK2 inhibitor.[1] Oxadiazoles undergo retro-Diels-Alder cycloaddition with alkenes and alkynes with the extrusion of a nitrogen molecule.[2] Some of them are also known as ester and amide bioisosteres.[3] In organic or organometallic materials, oxadiazole derivatives have proven to be very effective as acceptors in improving the injection and transport of electrons,[4] necessary in OLED and phosphorescent materials (PHOLED, (Scheme 1).[5]

The direct C—H bond activation/functionalization of (hetero)aryls, catalyzed by transition metals, has emerged as a sustainable alternative to the cross-coupling reactions that employs costly and/or polluting organometallic reagents.[6]

The synthesis of 2,5-diarylated oxadiazoles was reported using copper catalysts in the presence of iodoarenes,[7] and diaryliodonium salts.[8] Seminal works on the C5-arylation with palladium catalysts were described using a 1 % molar of NHC-Pd complexes with 4-bromotoluene on two different 2-aryl-1,3,4-oxadiazoles, LiOtBu as the base in dimethoxyethane (DME) at 100 °C (Scheme 2).[9] Kapdi and coworkers reported the

<figure><img src="image_3.png" /><figcaption>**PHOXPY**
Anti-tubercular agent</figcaption></figure>

<figure><img src="image_4.png" /><figcaption>examples in material sciences</figcaption></figure>

<figure><img src="image_5.png" /><figcaption>**Nesapidil**
Anti-hypertensive agent</figcaption></figure>

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

<figure><img src="image_7.png" /><figcaption>**Zibotentan**
Endothelin receptor antagonist</figcaption></figure>

**Scheme 1.** Selected applications of 1,3,4-oxadiazoles.

efficiency of the monophosphane phosphatiazene butane sultonate (PTABS) to couple (hetero)aryl bromides with oxadiazoles with 1 % of the Pd/PTABS catalyst with haloarenes (X=I or Br).[10] In 2012, Van der Eycken et al. demonstrated the efficiency of the diphosphane Xantphos, used with copper and palladium catalyst in the presence of aryl halides (also exclusively X=I, Br) or triflates to specifically promote the direct arylation of thiadiazoles.[11] They demonstrated the efficiency of the diphosphine compared to monophosphines such as PPh₃, CyJohnphos, or even directly with the precursor [Pd(PPh₃)Cl₂]. Recently, Patil et al. reported also the high activity of bipyridine ligand (phenanthroline, 30 mol %) with the association of PPh₃ (20 mol %).[12] With this combination approach, the [Pd₂(dba)₃] (2.5 mol%) promote the C5-arylation of oxadiazole using aryl bromides and iodides into a mixture of solvents (DMF/1,4-dioxane/1/1). While the direct Palladium-arylation of various heteroaryls has been well-studied before with mechanism insights,[6,13] the use of other pertinent classes of chelating ligands to promote the direct palladium C5-arylation of oxadiazoles has not been reported. This is especially pertinent when the significantly more challenging aryl chlorides are targeted. Notably, aryl chlorides are cheaper and much more functionally-diversified among the haloarenes (X=I, Br, Cl), while conversely the Csp²—Cl bond is the strongest and most difficult
State of the art

Van der Eycken et al., 2012, J. Org. Chem.

<figure><img src="image_8.png" /></figure>

Jin et al., 2019, Tetrahedron

<figure><img src="image_9.png" /></figure>

Kapdi et al., 2019, Asian JOC

<figure><img src="image_10.png" /></figure>

Patil et al., 2024, Tetrahedron

<figure><img src="image_11.png" /></figure>

This work: ferrocenyl diphosphanes in C5–H direct arylation with ArCl

<figure><img src="image_12.png" /><figcaption>33 examples</figcaption></figure>

**Scheme 2.** Efficient catalytic systems available for palladium-catalyzed C5-arylation of 1,3,4-oxadiazoles and thiadiazoles from haloarenes and triflates and the first system for coupling aryl chlorides.

to activate. Therefore, the assistance of a suitable ligand may be decisive.

To this end, ferrocenyl polyphosphanes ligands demonstrated their highly activities in the palladium C—H bonds activation of (hetero)aryls with aryl chlorides derivatives, and many bulky aryl bromides.[14] Based on these performances, we hypothesised that some ferrocenyl diphosphanes might be effective auxiliary in the direct C5-arylation of 1,3,4-oxadiazoles with demanding aryl chloride reagents.[15,16]

Results and Discussion

Chelating diphosphane ligands based on the ferrocenyl platform are useful auxiliaries in a number of synthetic approaches.[16,17] Our group reported the diastereoselective synthesis of di-tert-butylated bis(phosphino)ferrocenes in which subsequent phosphination and lithiation sequences favoured rac sterorochemistry in the final diphosphane ligand.[17] These species promoted the silver-mediated nucleophilic fluorination of chloroquinolines heteroarenes. By combination with gold salts they achieve various coordination species (gold mono-, di-

or tetranuclear) for which the catalytic selectivity towards enyne cycloisomerization reaction can be finely controlled.[18] As auxiliaries in palladium catalysis, they were found useful to the C—S bond formation from thiophenol substrates, leading to heteroaryl thioethers in high yield, ready for further sulfoxidation and sulfonylation reactions.[19]

In the first approach for palladium-catalyzed direct C5-arylation of 2-(4-methoxyphenyl)-1,3,4-oxadiazole with 1-fluoro-4-chlorobenzene as the coupling partner, we explored several phosphane auxiliaries in various conditions (Table 1).

The C—H bond activation/functionalization failed using [Pd-(OAc)₂] without any phosphane (entry 1). The addition of the monophosphane PPh₃, or 1-naphthyl diphenylphosphine (NaphPPh₂, **L1**), or 2-(diphenylphosphino)-10-(4-methoxyphenyl) naphthalene (**L2**),[20] or the long-chain chelating diphenylphosphane butane (dppb) with 1% of the catalyst [Pd(OAc)₂] did not improve significantly the rate of the reaction (entries 2-5). Conversely, the addition of the ferrocenyl diphosphanes bearing phenyl (dppf) or isopropyl groups (dippf) on the phosphorus atom allowed to reach 74 % and 94 % of 2-(4-fluorophenyl)-5-(4-methoxyphenyl)-1,3,4-oxadiazole **1**, respectively (Table 1, entries 6 and 7). The introduction of t-butyl groups on the ferrocenyl platform for further rigidification of the catalytic system, and improved stability, achieved a significant improvement at 1 % molar of [Pd(OAc)₂] (Table 1, entries 6-7, 74 % vs 94 % conversion), and demonstrated an even stronger and decisive beneficial effect at lower catalytic amount (0.5 mol %); especially the system combining tBudippf and Pd compared to its counterpart dippf and Pd (Table 1, entries 10 and 11, 60 % vs 5 % conversion, respectively). The use of other bases (CsOAc and KOtBu) instead of Cs₂CO₃ and solvents (toluene instead of DMF) did not improve the yield of the C5-arylation (Table 1, entries 10-12). Thus, using 1 mol % of [Pd(OAc)₂], tBudippf (1 mol %), 2 equiv. of Cs₂CO₃ as the base (in DMF at 100 °C for 13 h, give 96 % isolated yield of the arylated 1,3,4-oxadiazole **1**.

We further investigated the scope of functionalized aryl chlorides as coupling partners with the 2-(4-methoxyphenyl)-1,3,4-oxadiazole under the optimized conditions (Table 2).

The reaction was successfully extended to the 1-chloro-4-trifluoromethylbenzene with a 90 % isolated yield for **2** at 1 mol % Pd(OAc)₂, and 33 % isolated yield at 0.5 mol % of catalyst. Lower isolated yields were obtained with nitrile and nitro substituents in the *para*-position on the aryl group yielding 62 % and 42 %, for **3** and **4**, respectively. The unsubstituted chlorobenzene was coupled to the oxadiazole to give 84 % isolated yield for **5**. Electron-donating groups are also tolerated for the direct Pd-arylation reaction. **6** (methyl) and **7** (methoxy) were obtained in 80 % and 70 % respectively at 1 mol % of catalyst and 64 % and 50 % respectively at 0.5 mol % of [Pd(OAc)₂]. At 1 mol % of [Pd(OAc)₂], the 2-naphthyl group furnished 88 % isolated yield for **8** and still 58 % at 0.5 mol%, when the bulkiest 1-naphthyl furnished 33 % for **9** at 1 mol%. With aryl chlorides functionalized in *ortho*-position (fluoro, nitrile and methoxy groups), a moderate isolated yield was obtained for **10**, **11** and **12** with 44 %, 40 % and 64 % isolated yields, respectively. The reaction was successfully extended to
<figure><img src="image_13.png" /><figcaption>**Table 1.** Optimization of the Pd-catalyzed C5-arylation of 2-(4-methoxyphenyl)-1,3,4-oxadiazole with 1-fluoro-4-chlorobenzene.[a]</figcaption></figure>

<table><thead><tr><th>Entry</th><th>[Pd(OAc)2] (mol%)</th><th>[L] (mol%)</th><th>Base (2 equiv.)</th><th>Solvent [0.1 M]</th><th>Conv. (%)</th></tr></thead><tbody><tr><td>1</td><td>1</td><td>-</td><td>Cs<sub>2</sub>CO<sub>3</sub></td><td>DMF</td><td>0</td></tr><tr><td>2</td><td>1</td><td>PPh<sub>3</sub></td><td>Cs<sub>2</sub>CO<sub>3</sub></td><td>DMF</td><td>3</td></tr><tr><td>3</td><td>1</td><td><b>L1</b></td><td>Cs<sub>2</sub>CO<sub>3</sub></td><td>DMF</td><td>5</td></tr><tr><td>4</td><td>1</td><td><b>L2</b></td><td>Cs<sub>2</sub>CO<sub>3</sub></td><td>DMF</td><td>5</td></tr><tr><td>5</td><td>1</td><td>dppb</td><td>Cs<sub>2</sub>CO<sub>3</sub></td><td>DMF</td><td>5</td></tr><tr><td>6</td><td>1</td><td>dppf</td><td>Cs<sub>2</sub>CO<sub>3</sub></td><td>DMF</td><td>74</td></tr><tr><td>7</td><td>1</td><td>dippf</td><td>Cs<sub>2</sub>CO<sub>3</sub></td><td>DMF</td><td>94</td></tr><tr><td>8</td><td>1</td><td>tBudippf</td><td>Cs<sub>2</sub>CO<sub>3</sub></td><td>DMF</td><td>73</td></tr><tr><td><b>9</b></td><td><b>1</b></td><td><b>tBudippf</b></td><td><b>Cs<sub>2</sub>CO<sub>3</sub></b></td><td><b>DMF</b></td><td><b>98 (96)</b></td></tr><tr><td>10</td><td>0.5</td><td>tBudippf</td><td>Cs<sub>2</sub>CO<sub>3</sub></td><td>DMF</td><td>60</td></tr><tr><td>11</td><td>0.5</td><td>dippf</td><td>Cs<sub>2</sub>CO<sub>3</sub></td><td>DMF</td><td>5</td></tr><tr><td>12</td><td>1</td><td>tBudippf</td><td>CsOAc</td><td>DMF</td><td>24</td></tr><tr><td>13</td><td>1</td><td>tBudippf</td><td>KO<sub>t</sub>Bu</td><td>DMF</td><td>0</td></tr><tr><td>14</td><td>1</td><td>tBudippf</td><td>Cs<sub>2</sub>CO<sub>3</sub></td><td>Toluene</td><td>7</td></tr></tbody></table>

[a] Conditions: 2-(4-methoxyphenyl)-1,3,4-oxadiazole (0.5 mmol, 1 equiv., Oxa), 1-fluoro-4-chlorobenzene (2 equiv), [Pd(OAc)2] (0.5 to 1 mol %), [L] (Pd/L: 1/4 ratio for PPh3; 1/2 ratio for the diphosphanes), base (2 equiv.), in solvent [0.1 M based on Oxa] at 100 °C, 13 h under argon. ¹H NMR yield based on the oxadiazole, isolated yield under brackets. L1: 1-naphthyl diphenylphosphine; L2: 2-(diphenylphosphino)-10-(4-methoxyphenyl) naphthalene; [20] dppb: diphenylphosphine butane; dppf: diphenylphosphine ferrocene; dippf: diisopropylphosphine ferrocene.

heteroaryl chlorides, 2-chlorothiophene and 4-chloropyridine were both successfully employed to give the corresponding products **13** and **14**, respectively, in 84% isolated yield each.

This protocol was further extended to other 2-(aryl)-1,3,4-oxadiazoles. With the unsubstituted 2-phenyloxadiazole, the targeted heteroarenes **5** and **15-18** were obtained in moderate to high yields (68-58%). The 2-(4-methoxyphenyl)-5-phenyl-1,3,4-oxadiazole **7** was obtained in 46% yield starting from 2-phenyl-oxadiazole. It was formed in 64% isolated yield starting from the 4-methoxyphenyl-oxadiazole. The synthesis of the anti-tubercular agents PHOXPY (**18**) was successfully achieved with 86% isolated using 1 mol % of [Pd(OAc)2] and 2 mol % of tBudippf and 22% with only 0.5 mol % of [Pd(OAc)2] and 1 mol % of tBudippf. With the 2-(4-methoxyphenyl)-1,3,4-oxadiazole in hands, the chlorinated arenes bearing electron-withdrawing groups (fluorine, high trifluoromethyl, nitrile) reacted to give moderate yields (62%, 64% and 44%, respectively) or even lower yields with the electron-donating

methoxy in *para*-position (20% for **10**). The use of the 2-(4-chlorophenyl)-1,3,4-oxadiazole was found to be troublesome, with side reactions occurring at the chlorine atom (homocoupling and dechlorination for instance), and only 20% yield of the targeted heteroarene **24** was isolated.

In order to overpass these limitations, we further investigated the scope of the direct C—H arylation of the 2-(4-chlorophenyl)-1,3,4-oxadiazole using brominated aryl reagents (Table 3), and we also extended the study to other oxadiazole partners. Using 1-bromo-trifluoromethylbenzene the C5-arylation was clean and **24** was isolated in high 89% yield. To benefit from this higher activity, we reduced the catalyst loading to 0.5 mol %. nevertheless, the reaction proceeded with only 13% isolated yield. Pleasingly, these conditions preserved the chlorine atom, presumably because of a better reactivity of the brominated electrophilic reagent. The extension to substrates incorporating electron-donating groups, such as the diphenylamine or methoxy groups, produces 96% and 65% of
<figure><img src="image_14.png" /><figcaption>**Table 2.** Pd-catalyzed C5-arylation of 2-aryl-1,3,4-oxadiazole with aryl chlorides.[a]</figcaption></figure>

[a] Conditions: 2-aryl-1,3,4-oxadiazole (0.5 mmol, 1 equiv), aryl chloride (2 equiv.), [Pd(OAc)₂] (1 mol %), tBudippf (2 mol %), Cs₂CO₃ (2 equiv), in DMF [0.1 M based on Oxa] at 100°C, 13 h under argon. Isolated yield. [b] [Pd(OAc)₂] (0.5 mol %), tBudippf (1 mol %). [c] Several side products were detected.

heteroarenes **25** and **26**, respectively (49 % yield for **24** at 0.5 mol % Pd). The 2-naphthyl bromide was coupled in 80 % at 1 mol % and 60 % at 0.5 mol % Pd (**27**). With the its 1-brominated counterparts, 2.5 mol % of catalyst was necessary to improved the yield for **28** with 66 % (only 33 % with 1 mol % Pd). Similar isolated yields were obtained for the substrate incorporating methoxy groups in *para*-position (**29**) but using 1 mol % of palladium catalyst. Globally, the use of bromoarenes as coupling partners with the 2-aryl-1,3,4-oxadiazole provided either similar or higher isolated yields compared to using chloroarenes. At 1 mol % [Pd(OAc)₂], the 2-(4-methoxyphenyl)-1,3,4-oxadiazole was successfully coupled with the 4-bromo anisole, 4-bromotriphenylamine, the 2-bromonaphthyl and the 2-bromo anisole to give 74 % (**7**), 88 % (**30**), 86 % (**8**) and 91 % (**30**) isolated yields. This allowed us, to test lower catalyst loading conditions with only 0.5 mol %, **30**, **8** and **12** were isolated in 42%, 74% and 22% respectively.

With the 2-phenyl-1,3,4-oxadiazole, the trifluoromethyl groups in *para*-position gave **16** in 66 % isolated yield. The 2,5-diphenyl-1,3,4-oxadiazole **17** was obtained in 80 % yield and

<figure><img src="image_15.png" /><figcaption>**Table 3.** Pd-catalyzed C5-arylation of 2-(aryl)-1,3,4-oxadiazoles with aryl bromides.[a]</figcaption></figure>

[a] Conditions: 2-aryl-1,3,4-oxadiazole (0.5 mmol, 1 equiv), aryl bromide (2 equiv.), [Pd(OAc)₂] (1 mol %), tBudippf (2 mol %), Cs₂CO₃ (2 equiv), in DMF [0.1 M based on Oxa] at 100°C, 13 h under argon. Isolated yield. [b] [Pd(OAc)₂] (0.5 mol %), tBudippf (1 mol %). [c] [Pd(OAc)₂] (2.5 mol %), tBudippf (5 mol %). [d] [Pd(OAc)₂] (0.1 mol %), tBudippf (0.2 mol %).

the 2-(4-methoxyphenyl)-5-phenyl-1,3,4-oxadiazole **5** in 66 % yield. Using 2-(2-fluorophenyl)-1,3,4-oxadiazole as the coupling partner, compounds **21** and **22** were obtained in 86 % and 55 %, respectively (26 % for **21** at 0.5 mol % Pd). Compound **10** was obtained in good isolated yield (80 %) using 1 mol % of Pd, and 42 % using only 0.5 mol % of Pd from the brominated reagent. 20 % yield had been obtained from the chlorinated arene under similar conditions.

The coupling of aryl iodides was also successfully promoted using our conditions (Table 4). With the 2-(4-chlorophenyl)-1,3,4-oxadiazole, the C5-arylation took place cleanly in the presence of 4-iodoanisole with 88 % isolated yield for **26** using 1 mol % of Pd-catalyst. The bis(4-methoxyphenyl)-1,3,4-oxadiazole was obtained in 72 % isolated yield. The extension to substrates incorporating electron-withdrawing groups, and electron-donating groups was achieved on the 2-(2-fluorophenyl)-1,3,4-oxadiazole with 46 % (**20**), 76 % (**21**), 37 % (**22**), 67 % (**10**) and 79 % (**31**) isolated yields. The reaction was found more challenging with the 1-naphthyl iodide and 2-iodoanisole and required 2.5 mol % of [Pd(OAc)₂] to reach satisfying yields (70% and 68% isolated yields for **32** and **33** respectively).
<figure><img src="image_16.png" /><figcaption>**Table 4.** Pd-catalyzed C5-arylation of 2-(aryl)-1,3,4-oxadiazoles with aryl iodides.[a]</figcaption></figure>

[a] Conditions: 2-aryl-1,3,4-oxadiazole (0.5 mmol, 1 equiv.), aryl iodide (2 equiv.), [Pd(OAc)₂] (1 mol %), tBudippf (2 mol %), Cs₂CO₃ (2 equiv.), in DMF [0.1 M based on Oxa] at 100 °C, 13 h under argon. Isolated yield.
[b] [Pd(OAc)₂] (2.5 mol %), tBudippf (5 mol %).

## Conclusions

Sterically constrained ferrocenyl diphosphanes combined with Pd promotes the direct C—H arylation of 1,3,4-oxadiazoles with challenging aryl chlorides employing low catalyst loading (0.5 to 1 mol % Pd). This protocol does not need any other metal reagent (copper salt) and tolerates electron-donating and withdrawing substituents on the (heteroaryl)aryl halides, allowing ultimately the access to relevant molecules such as the anti-tubercular agent PHOXPY in excellent isolated yield.

## Experimental Section

Deposition Number(s) 2332971 (tBudippf) contain(s) the supplementary crystallographic data for this paper. These data are provided free of charge by the joint Cambridge Crystallographic Data Centre and Fachinformationszentrum Karlsruhe "Access Structures" service.

## Materials and Methods

All reagents were purchased from commercial suppliers and used without purification except for the 2-aryl-1,3,4-oxadiazoles, which were synthesized according to the literature.[21] The diphosphanes tBudippf et tBudippf were synthesized according to literature reports.[17] All experiments were carried out under an atmosphere of argon in oven-dried glassware using Schlenk and vacuum-line techniques. Flash chromatography was performed on silica gel (40-63 µm). ¹H (500 MHz), ¹³C (125 MHz), ¹⁹F (470 MHz) spectra were recorded in CDCl₃ using a 500 MHz Bruker Avance NEO. Chemical shifts are reported in ppm relative to CDCl₃ (¹H: 7.26 ppm and ¹³C: 77.16 ppm) and coupling constants *J* are given in Hz. High Resolution Mass Spectra (HRMS) were obtained on a ThermoFischer ISQ-EM with ESI source. Exact Masses were obtained on a ThermoScientific FlashSmart.

## General Procedure for the Pd-catalyzed C5-arylation of 2-(aryl)-1,3,4-oxadiazole

As a typical experiment, in a Schlenk tube equipped with a magnetic stirring bar was charged with 2-arylated 1,3,4-oxadiazole (1 equiv, 0.5 mmol), aryl halides (2 equiv.), [Pd(OAc)₂] (0.5-2.5 mol %), tBudippf ([Pd]/L: 1/2) and Cs₂CO₃ (2 equiv) in DMF [0.1 M/Oxa] under argon. The mixture was heated at 100 °C during 13 h. After cooling down at room temperature, the solvent was removed under vacuum and the residue was analyzed by ¹H NMR to determine the conversion of the targeted product. The crude mixture was purified by silica gel column chromatography using an appropriate ratio of eluent (pentane/ethyl acetate) to afford the targeted product.

## Acknowledgements

This work was supported by the CNRS, the Université de Bourgogne, the Conseil Régional Bourgogne-Franche-Comté, and the Fonds Européen de Développement Régional (FEDER). This work was also supported by the French Agence Nationale de la Recherche via the ANR-JCJC program 2018 FIT-FUN (ANR-18-CE07-0015) and ANR PRC program 2021 Pi-Aza (ANR-21-CE07-0024-02). Thanks is due to the PACSMUB platform for analyses (SATT SAYENS) especially M.-J. Penouilh, Q. Bonnin and T. Régnier.

## Data Availability Statement

The data that support the findings of this study are available in the supplementary material of this article.

**Keywords:** aryl chlorides · C—H activation · ferrocenyl ligands · oxadiazoles · palladium

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