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

# Palladium-Catalyzed C4,C5-Diarylation of Isoxazole-3-Carboxylate by Double C–H Bond Functionalization

Rabeb Ben Romdhane,[a, b] Linhao Liu,[a] Ridha Ben Salem,[*b] and Henri Doucet*[a]

The Pd-catalyzed C4-arylation of 3,5-disubstituted isoxazoles via C–H bond functionalization has been largely described. By contrast, the reactivity of isoxazoles in C–H bond functionalization with both unsubstituted C4 and C5 positions remains largely unexplored. Herein, we report on the reactivity in Pd-catalyzed double C–H bond arylation of an isoxazole with unsubstituted C4 and C5 positions. Conditions for the palladium-catalyzed direct C4,C5-diarylation of ethyl isoxazole-3-carboxylate using aryl bromides as the aryl source are reported.

This procedure tolerates several useful substituents on the aryl bromide such as nitrile, acetyl, formyl, benzoyl, alkoxycarbonyl, chloro, fluoro, trifluoromethyl, trifluoromethoxy, cyanomethyl, tertbutyl and methoxy at *para*- and *meta*-positions. Conversely, with *ortho*-substituted aryl bromides, mixtures of mono- and di-arylated isoxazoles were generally obtained. This methodology provides a simple one pot access to a wide variety of C4,C5-diarylated isoxazoles from commercially available substrates allowing to modify easily their biological properties.

## Introduction

Isoxazole units bearing aryl substituents at C3-, C4- and/or C5-positions are widely used in medicinal chemistry.[1] For example, Parecoxib is an anti-inflammatory drug and 4,5-diaryl isoxazole Luminespib is an experimental drug candidate for the treatment of cancer (Figure 1). Therefore, the discovery of simple methods for the access to polyarylated isoxazoles is an important research topic in medicinal chemistry.

When C–H bonds of heteroarenes can be directly functionalized via catalytic reactions, it provides straightforward methods for the synthesis of heteroaromatic derivatives. The arylation via palladium-catalyzed C–H bond functionalization also called “direct arylation”[2] of isoxazoles, pioneered by Nakamura, Tajima and Sakai[3] and of several other heteroarenes reported by Ohta et al. is one of the most effective tool for the access to arylated heteroarenes.[4] In addition, in many cases sustainable reaction conditions could be employed for such Pd-catalyzed couplings.[5] When this Pd-catalyzed C–H bond arylation methodology can be applied to the late-stage functionalization of useful building blocks, it provides a very powerful tool for the fast screening of biological properties of a class of compounds.

The Pd-catalyzed direct C4-arylation of 3,5-disubstituted isoxazoles has been largely described (Scheme 1a).[3,6] By contrast,

<figure><img src="image_2.png" /><figcaption>Figure 1. Structures of Parecoxib and Luminespib.</figcaption></figure>

Previous work: C4- or C5-monoarylation

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

<figure><img src="image_4.png" /></figure>

<figure><img src="image_5.png" /></figure>

d) This work: One pot 4,5-diarylation

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

* Double C-H arylation in one operation

* Silver free base

* Aryl bromides as coupling partners

* Wide functional group tolerance

<caption>Scheme 1. Pd-catalyzed C–H arylations of isoxazoles.</caption>

[a] Ms. R. Ben Romdhane, Dr. L. Liu, Dr. H. Doucet
Univ Rennes, CNRS, ISCR-UMR 6226, F-35000 Rennes, France
E-mail: henri.doucet@univ-rennes.fr

[b] Ms. R. Ben Romdhane, Prof. R. Ben Salem
Laboratoire de Chimie Organique LR 17ES08, Faculté des Sciences de Sfax,
Université de Sfax, BP 1171, Route de la Soukra km 4, 3038 Sfax, Tunisia
E-mail: ridhabensalem@yahoo.fr

Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202401036

© 2024 The Author(s). European Journal of Organic Chemistry published by
Wiley-VCH GmbH. This is an open access article under the terms of the
Creative Commons Attribution License, which permits use, distribution and
reproduction in any medium, provided the original work is properly cited.
<figure><img src="image_7.png" /></figure>

the C5-arylation of 3,4-disubstituted isoxazoles has only been described by two groups (Scheme 1b).[7] In addition, the reactivity of isoxazoles with both unsubstituted C4- and C5-positions has attracted very little attention. To our knowledge, only a single example of direct arylation of a C3-substituted isoxazole has been described.[8] For this coupling, Shigenobu, Takenaka and Sasai employed PdCl₂(MeCN)₂ 5 mol% with DPPBz 10 mol% [DPPBz: 1,2-bis(diphenylphosphino)benzene] as catalyst associated to AgF as the base and 4-iodotoluene as the aryl source. Although an excess of 4-iodotoluene (2 equiv.) was employed, the mono C5-arylated product was obtained in 64% yield, while the formation of C4,C5-diarylated isoxazole was produced in only 7% yield. (Scheme 1c). To our knowledge, no examples of direct C4,C5-diarylation of isoxazoles as the major product have been reported to date. Moreover, currently, very few methods allow the synthesis of such 4,5-diarylisoxazole-3-carboxylates and they require multi step synthesis such as using 4-halo-5-arylisoxazoles intermediates which have subsequently been used in Suzuki couplings.[9,10] Therefore, the reactivity of isoxazoles with both unsubstituted C4- and C5-positions in Pd-catalyzed C–H diarylation needed to be investigated. Herein, we report reaction conditions for the palladium-catalyzed direct C4,C5-diarylation of ethyl isoxazole-3-carboxylate and on the substrate scope of the reaction (Scheme 1d).

## Results and Discussion

We first examined the reactivity of ethyl isoxazole-3-carboxylate based on our previous results on the Pd-catalyzed direct arylation of isoxazoles.[6b,e] Using 1 equiv. of ethyl isoxazole-3-carboxylate and 3 equiv. of 4-bromo-1-chlorobenzene in the presence of PdCl(C₃H₅)(dppb)[11] catalyst (5 mol%) and KOAc base at 120 °C in DMA, a 11:89 mixture of C5-arylated isoxazole **1a** and C4,C5-diarylated isoxazole **1c** was obtained, and **1c** was isolated in 80% yield (Table 1, entry 1). Under these conditions, the C4-arylated isoxazole **1b** was not detected by GC/MC analysis of the crude mixture. Moreover, the reaction proceeded without cleavage of the C–Cl bond of the arene allowing further transformations. By contrast, the use of a 1.5:1 ratio of ethyl isoxazole-3-carboxylate and 4-bromo-1-chlorobenzene afforded the **1a**, **1b** and **1c** products in 39:12:49 ratio indicating that the C5-arylation of isomer **1b** is easier than the C4-arylation of **1a** (Table 1, entry 2). The influence of a few other bases was examined. Complete conversions of ethyl isoxazole-3-carboxylate were observed using NaOAc and KOPiv as the bases, but the selectivities in favor of product **1c** were only 35% and 62%, respectively (Table 1, entries 3 and 4). Carbonate bases Na₂CO₃ and K₂CO₃ also led to low selectivities in **1c** (Table 1, entries 5 and 6). By contrast, Cs₂CO₃ base gave no coupling products **1a–1c**, and a large amount of 4-bromo-1-chlorobenzene was recovered (Table 1, entry 7). Since Cs₂CO₃ is a stronger base than Na₂CO₃ and K₂CO₃, it could result in

<table><caption>**Table 1.** Influence of the reaction conditions for the palladium-catalyzed direct coupling of ethyl isoxazole-3-carboxylate with 4-bromo-1-chlorobenzene.</caption><thead><tr><th>Entry</th><th>Catalyst (mol %)</th><th>Base</th><th>Solvent</th><th>Temp. (°C)</th><th>Ratio 1a:1b:1c</th><th>Yield in 1c (%)</th></tr></thead><tbody><tr><td>1</td><td>PdCl(C<sub>3</sub>H<sub>5</sub>)(dppb) (5)</td><td>KOAc</td><td>DMA</td><td>120</td><td>11:0:89</td><td>80</td></tr><tr><td>2</td><td>PdCl(C<sub>3</sub>H<sub>5</sub>)(dppb) (5)</td><td>KOAc</td><td>DMA</td><td>120</td><td>39:12:49</td><td>41<sup>[a]</sup></td></tr><tr><td>3</td><td>PdCl(C<sub>3</sub>H<sub>5</sub>)(dppb) (5)</td><td>NaOAc</td><td>DMA</td><td>120</td><td>48:17:35</td><td>nd</td></tr><tr><td>4</td><td>PdCl(C<sub>3</sub>H<sub>5</sub>)(dppb) (5)</td><td>KOPiv</td><td>DMA</td><td>120</td><td>38:0:62</td><td>54</td></tr><tr><td>5</td><td>PdCl(C<sub>3</sub>H<sub>5</sub>)(dppb) (5)</td><td>Na<sub>2</sub>CO<sub>3</sub></td><td>DMA</td><td>120</td><td>54:20:26</td><td>nd</td></tr><tr><td>6</td><td>PdCl(C<sub>3</sub>H<sub>5</sub>)(dppb) (5)</td><td>K<sub>2</sub>CO<sub>3</sub></td><td>DMA</td><td>120</td><td>47:0:53</td><td>nd</td></tr><tr><td>7</td><td>PdCl(C<sub>3</sub>H<sub>5</sub>)(dppb) (5)</td><td>Cs<sub>2</sub>CO<sub>3</sub></td><td>DMA</td><td>120</td><td>0:0:0</td><td>0</td></tr><tr><td>8</td><td>PdCl(C<sub>3</sub>H<sub>5</sub>)(dppb) (5)</td><td>KOAc</td><td>xylene</td><td>120</td><td>100:0:0</td><td>0<sup>[b]</sup></td></tr><tr><td>9</td><td>PdCl(C<sub>3</sub>H<sub>5</sub>)(dppb) (5)</td><td>KOAc</td><td>NMP</td><td>120</td><td>18:8:74</td><td>61</td></tr><tr><td>10</td><td>PdCl(C<sub>3</sub>H<sub>5</sub>)(dppb) (5)</td><td>KOAc</td><td>DMF</td><td>120</td><td>20:1:79</td><td>69</td></tr><tr><td>11</td><td>Pd(OAc)<sub>2</sub> (5)</td><td>KOAc</td><td>DMA</td><td>120</td><td>22:5:73</td><td>58</td></tr><tr><td>12</td><td>PdCl(C<sub>3</sub>H<sub>5</sub>)(dppb) (2)</td><td>KOAc</td><td>DMA</td><td>120</td><td>17:3:80</td><td>72</td></tr><tr><td>13</td><td>PdCl(C<sub>3</sub>H<sub>5</sub>)(dppb) (5)</td><td>KOAc</td><td>DMA</td><td>120</td><td>20:4:76</td><td>67<sup>[c]</sup></td></tr><tr><td>14</td><td>PdCl(C<sub>3</sub>H<sub>5</sub>)(dppb) (5)</td><td>KOAc</td><td>DMA</td><td>150</td><td>0:0:0</td><td>0<sup>[d]</sup></td></tr></tbody></table>

Conditions: Ethyl isoxazole-3-carboxylate (1 mmol), 4-bromo-1-chlorobenzene (3 mmol), base (3 mmol), 16 h, isolated yields, nd: not determined. [a] Ethyl isoxazole-3-carboxylate (1.5 mmol), 4-bromo-1-chlorobenzene (1 mmol). [b] Yield in **1a** < 5%. [c] 4-Bromo-1-chlorobenzene (2.5 mmol). [d] A large amount of 4-bromo-1-chlorobenzene was recovered unreacted; whereas, a complete conversion or decomposition of ethyl isoxazole-3-carboxylate, and decomposition of **1a**, **1b** and **1c** was observed.
<figure><img src="image_8.png" /></figure>

degrading the isoxazole moiety in the starting material and/or coupling products. The influence of a few solvents was also studied. Xylene was ineffective resulting in a very low conversion of ethyl isoxazole-3-carboxylate (Table 1, entry 8). Conversely, both NMP and DMF led to good selectivities and good yields in the desired 4,5-diarylated isoxazole **1c** (Table 1, entries 9 and 10). Phosphine-free catalyst Pd(OAc)₂[12] was found to be less selective than PdCl(C₃H₅)(dppb) with the formation of a larger amount (22%) of mono-arylated isoxazole **1a** (Table 1, entry 11). A lower catalyst loading of 2 mol% instead of 5 mol% of PdCl(C₃H₅)(dppb) also resulted in the formation of a larger amount (17%) of **1a** (Table 1, entry 12). A lower excess of 4-bromo-1-chlorobenzene (2.5 equiv. instead of 3 equiv.) also leads to a lower yield in **1c**, once again due to the formation of a larger quantity of **1a** (Table 1, entry 13). Finally, the use of a reaction temperature of 150°C instead of 120°C caused decomposition and the **1a-c** products were not detected (Table 1, entry 14).

The scope of the 4,5-diarylation of ethyl isoxazole-3-carboxylate using a set of aryl bromides was investigated using 5 mol% PdCl(C₃H₅)(dppb) catalyst associated to KOAc base at 120 °C in DMA (Scheme 2). First, the influence of several *para*-substituents on aryl bromide on the reactivity and selectivity was studied. Aryl bromides bearing the electron-withdrawing substituents acetyl, propionyl, formyl, benzoyl, nitrile, ethoxycarbonyl, trifluoromethyl or trifluoromethoxy were well tolerated affording the desired 4,5-diarylated isoxazoles **2-9** in 70-80% yields. Synthesis of **8** on a larger scale (from 5 mmol ethyl isoxazole-3-carboxylate instead of

1 mmol) resulted in very similar yield. An acetonitrile *para*-substituent was also found to be accepted providing the product **10** in a moderate yield of 48% due to the presence of a mono-arylated isoxazole. Slightly electron-deficient 4-fluorobromobenzene reacted nicely to give the expected product **11** in 70% yield. Using 4-bromobiphenyl, a good yield in the 4,5-diarylated product **12** was also obtained. Conversely, the more electron-rich 4-tert-butylbromobenzene gave the desired coupling product **13** in only 51% yield, due to the presence of a significant amount of a mono-arylated isoxazole.

Then, the influence some *meta*-substituents on the aryl bromide was evaluated. Again, electron-withdrawing nitrile, methoxycarbonyl, acetyl and formyl substituents were well tolerated, delivering the target products **14-17** in 74-79% yields. Both trifluoromethyl and trifluoromethoxy *meta*-substituted aryl bromides also gave to the desired products **18** and **19** in good yields. 1-Bromo-3-chlorobenzene afforded the expected product **20** in 76% yield, without cleavage of the C–Cl bond. A 3-fluoro substituent was also well accepted yielding product **21** in 68% yield. Conversely, although a *meta*-OMe substituent on benzene is a slightly withdrawing group, a large amount of two monovalent products was detected by GC/MS analysis of the crude mixture, and the desired 4,5-diarylation product **22** was only isolated in 28% yield. Finally, the disubstituted 3,5-bis(trifluoromethyl)bromobenzene gave the 4,5-arylated isoxazole **23** in 88% yield and 2-bromonaphthalene provided product **24** in 58% yield.

We also studied the reactivity of some *ortho*-substituted aryl bromides, as the steric hindrance of some of them could hamper the second arylation (Scheme 3). With 2-bromobenzonitrile, the desired 4,5-diarylated isoxazole **25c** was obtained in a lower yield of 61% than with 3- and 4-bromobenzonitriles (see Scheme 2). In the course of this reaction a significant amount of the two monovalent isoxazoles **25a** and **25b** (32%, ratio **25a:****25b** 27:5) was detected by GC/MS analysis of the crude mixture. 2-fluorobromo-

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

*: Reaction using 5 mmol of isoxazole derivative instead of 1 mmol.

**: Ratio of diarylation product (22) 35%, two mono arylation products 65% (ratio 47/53).

<figure><img src="image_10.png" /><figcaption>**Scheme 3.** Scope of the Pd-catalyzed direct C5-arylation of ethyl isoxazole-3-carboxylate using various *ortho*-substituted aryl bromides and 3-bromoquinoline.</figcaption></figure>
<figure><img src="image_11.png" /></figure>

benzene also provided the 4,5-diarylated isoxazole 26c in quite good yield (53%), but again the formation of a significant amount of the mono-arylated isoxazoles 26a and 26b was observed. 2-chlorobromobenzene and 2-bromobenzotrifluoride also led to mixtures of mono- and di-aryl isoxazoles, with the C5-monoarylated compounds 27a and 28a being obtained with selectivities of 60% and 76%, respectively. Using 2-bromobiphenyl or 3-bromoquinoline, the reaction led specifically to the mono C5-arylated isoxazoles 29a and 30a, which were isolated in 74% and 79% yield, respectively. These selectivities in favor of mono-arylation might be due to the steric hindrance of these (hetero)arenes. In order to determine the potential of this monoarylation reaction for the synthesis of Luminespib (Figure 1), the coupling of ethyl isoxazole-3-carboxylate with 2-bromophenol and 2-bromoanisole was attempted, but in both cases the desired coupling product was not observed.

## Conclusions

In summary, we report herein on the reactivity of ethyl isoxazole-3-carboxylate which has both unsubstituted C4 and C5 positions in Pd-catalyzed direct arylation by aryl bromides. The C5-position was found to be more reactive than the C4, but using appropriate reaction conditions, both positions could be arylated. Therefore, in the presence of an excess of aryl bromide, the C4,C5-diarylated isoxazoles could be obtained in good yields. The reaction tolerates aryl bromides bearing useful functional groups such as nitrile, acetyl, propionyl, formyl, benzoyl, alkoxycarbonyl, cyanomethyl, chloro, fluoro, trifluoromethyl, trifluoromethoxy, tertbutyl and methoxy. This methodology which employs commercially available substrates, an inexpensive base, and an air-stable catalyst provides a straightforward access 4,5-diarylated isoxazoles in only one step allowing to tune or modify easily their properties.

## Supporting Information Summary

Experimental procedures and characterization data are available in Supporting Information. The authors have cited additional references within the Supporting Information (Ref. [13]).

## Acknowledgements

We are grateful to the Scientific Ministry of Higher Education and Research of Tunisia for providing financial support to R. B. R. and to the CSC for a grant to L. L.

## Conflict of Interests

The authors declare no conflict of interest.

## Data Availability Statement

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

**Keywords:** C–H bond functionalization · Direct arylation · Homogeneous catalysis · Isoxazoles · Palladium

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RESEARCH ARTICLE

<figure><img src="image_12.png" /><figcaption>Double C-H bond arylation in one operation</figcaption></figure>

28 examples
Yields up to 80%

Conditions for the palladium-catalyzed C4,C5-diarylation of ethyl isoxazole-3-carboxylate through double C–H bond activation are reported. This methodology, which employs commercially available sub-

strates, an inexpensive base and an
air-stable catalyst, provides simple
one-pot access to a wide variety of
C4,C5-diarylated isoxazoles, allowing
straightforward tuning of their prop-
erties.

Ms. R. Ben Romdhane, Dr. L. Liu, Prof. R. Ben Salem*, Dr. H. Doucet*

1 – 5

Palladium-Catalyzed C4,C5-Diaryla-
tion of Isoxazole-3-Carboxylate by
Double C–H Bond Functionalization

<figure><img src="image_13.png" /></figure>