# Mechanochemical Suzuki-Miyaura Cross-Coupling with Natural Deep Eutectic Solvent as Liquid-Assisted Grinding Additive: Merging Two Fields for a Greener Strategy

Emilie Thiery, Pierre-olivier Delaye, Jérôme Thibonnet, Leslie

Boudesocque-delaye

► To cite this version:

Emilie Thiery, Pierre-olivier Delaye, Jérôme Thibonnet, Leslie Boudesocque-delaye. Mechanochemical Suzuki-Miyaura Cross-Coupling with Natural Deep Eutectic Solvent as Liquid-Assisted Grinding Additive: Merging Two Fields for a Greener Strategy. European Journal of Organic Chemistry, 2023, 26 (37), pp.e202300727. 10.1002/ejoc.202300727. hal-04969276

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# Mechanochemical Suzuki-Miyaura Cross-Coupling with Natural Deep Eutectic Solvent as Liquid-Assisted Grinding Additive: Merging Two Fields for a Greener Strategy

Emilie Thiery,*[a] Pierre-Olivier Delaye,*[a] Jérôme Thibonnet,[a] and
Leslie Boudesocque-Delaye[a]

The use of volatile solvents for organic synthesis is nowadays questioned due to their negative impact on the environnement. To develop sustainable and environmentally friendly methodologies, we propose to combine two green chemistry concepts: the use of bioinspired solvents: natural deep eutectic solvents (NaDES), and mechanochemistry. Using the Suzuki-Miyaura

coupling as a model reaction, we described an efficient mechanochemical method with NaDES as a LAG (liquid-assisted grinding) additive with short reaction times and without any ligand or additional heating. A mechanochemical extraction was also used to reduce the amounts of extraction solvents and the total time of the synthesis process.

## Introduction

The development of more environmentally friendly synthetic methodologies is today a major challenge for researchers. The twelve principles of green chemistry highlighted by Anastas et al. have inspired many works and underline the importance of the choice of catalysts, reagents, and solvents.[1] Indeed, the volatile organic solvents commonly used in academic and industrial organic synthesis for their solubilizing power, have toxic and environmentally harmful properties. The fifth principle states that “the use of auxiliary substances should be made unnecessary as far as possible and harmless when used”.

Solvent-free reactions are an interesting alternative. Developed within the framework of mechanochemistry, they are taking an increasingly important place in research.[2] By shearing, grinding, and milling, the use of large volumes of solvents can be avoided. In the solid state, new reactivities can also be discovered.[3] However, some mechanochemical reactions cannot completely proceed without solvent and are assisted by a small amount of solvent (LAG for liquid-assisted grinding).[4]

The use of a green solvent to replace common organic solvents is also an attractive possibility. Thus, for years, deep

eutectic solvents (DES) are seen as an alternative to organic solvents and are used in many fields such as extraction, electro-chemistry, biomedical applications and organic synthesis.[5] In the literature, several definitions of DES co-exist. Originally defined as mixtures of Lewis/Bronsted acids and bases, the most widespread definition is based on a mixture of several compounds, including at least one hydrogen bond donor (HBD) and one hydrogen bond acceptor (HBA). More recently, some authors have proposed a broader definition based solely on thermodynamic properties, encompassing a wider range of DES based on compounds that are neither acids nor bases.[6] In DES, the charge delocalization occurring by hydrogen bonding between components is responsible for the decrease in the melting point of the mixture compared to the melting points of individual components. When the components come from natural resources, they are called NaDES (Natural Deep Eutectic Solvent). These solvents meet the objectives of green chemistry thanks to their non-flammable nature, biodegradability and low toxicity. However, their high viscosity makes homogeneous stirring of the reaction medium difficult, and it is often necessary to heat.[5c] Indeed in our laboratory, we worked on the use of NaDES as solvent for Suzuki-Miyaura cross-coupling reaction applied to heterocycles. The reaction conditions were simple, ligand free, but the viscosity of the medium required heating to 90 °C and vigorous stirring.[7]

To improve the quality of the agitation and the homogenization of the reactions in NaDES medium and to avoid heating, we were interested in the use of ball mills usually employed in mechanochemistry. To our best of knowledge, the association of the use of NaDES as a solvent and mechanical agitation in a ball mill has not yet been considered in synthesis. On the other hand, some examples of extraction method using deep eutectic solvents for mechanochemical extraction have been successfully developed.[8] In order to explore the efficiency of this NaDES-mechanochemistry association, we focused on Suzuki-Miyaura cross-coupling.

The first Suzuki-Miyaura in a low melting point mixture was described by Konig et al. in 2006.[9] The cross-coupling between

<footnote>[a] Dr. E. Thiery, Dr. P.-O. Delaye, Prof. J. Thibonnet, Prof. L. Boudesocque-Delaye
Laboratoire Synthèse et Isolement de Molécules
Bioactives (SIMBA, EA 7502)
Université de Tours, Faculté de Pharmacie
Parc de Grandmont, 31 avenue Monge
37200 Tours (France)
E-mail: emilie.thiery@univ-tours.fr
pierre-olivier.delaye@univ-tours.fr
Homepage: https://simba.univ-tours.fr/</footnote>

<footnote>Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202300727</footnote>

<footnote>© 2023 The Authors. 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.</footnote>
<figure><img src="image_3.png" /></figure>

phenylboronic acid and bromobenzenes was catalyzed by palladium acetate in the presence of sodium carbonate in a sugar-urea-salt melt at 90 °C. The reaction was carried out on three examples with good yields and seems very promising. Since then, studies have focused on the use of other eutectic solvents and the DES choline chloride/glycerol (1:2, mol/mol), also known as glyceline or choline chloride/ethylene glycol (1:2, mol/mol) are very often used for Suzuki-Miyaura coupling.[10] A strong interest was also focused on the use of ligand to allow the recycling of the system. For example, Ramón *et al.* reported the use of pyridiniophosphine ligands with palladium chloride[11] or a bipyridine-palladium derivative[12] for cross-coupling reaction, including the Suzuki-Miyaura reaction, in DES. Chakraborty *et al.* proposed a facile process for Suzuki-Miyaura coupling reaction catalyzed by metallized DNA (Pd-DNA-Fe₂O₃). This catalytic system was recycled 5 times while the catalyst was easily separated using a magnet.[13] Some other examples demonstrated that palladium acetate as a catalyst without an associated ligand in glyceline was able to recycle over at least 4 cycles without loss of activity.[7,14] Overall, in the literature, the reactions were mainly described on aromatic derivatives of boronic acid and aromatic halides but some examples of couplings from aryltrifluoroborates[14] and halogenated heterocycles[7,15,16] have also been reported.

At the same time, Suzuki-Miyaura mechanochemical cross-coupling has been also developed. The first coupling between aryl halides and phenylboronic acids in a planetary mill was reported in 2000 by Peters *et al.*[17] Since then, there has been growing interest in the Suzuki-Miyaura reaction under mechanochemical conditions.[18] For example, in 2009, Ondruschka *et al.* showed that many parameters such as revolution per minute (rpm), milling time, grinding material, size and number of milling balls, influence the yield of the Suzuki-Miyaura reaction.[19] Using liquid rather than solid aryl halides results in better yields. The use of additives such as ligands, solid supports, or a solvent, allows to widen the scope of reactions. For example, Ondruschka *et al.* described an efficient mechanochemical method of the Suzuki-Miyaura reaction in the presence of an inorganic solid support (KF-Al₂O₃).[20] In 2016, Su *et al.* investigated the effect of liquid-assisted grinding (LAG) on the coupling of aryl chlorides and boronic acids.[21] The addition of a small quantity of methanol to the reaction catalyzed by palladium acetate in the presence of tricyclohexylphosphine as ligand and potassium carbonate as base allowed the improvement of the yield by more than 55%. Ethanol has also been used as LAG-additive for the coupling of aryl halides with phenylboronic acids catalyzed by palladium milling ball.[22] This addition significantly increased the kinetics of the reaction. In 2019, Ito *et al.* showed that the addition of olefins such as 1,5-cyclooctadiene accelerated the Suzuki-Miyaura reaction and allowed the coupling of many solid aryl halides.[23] More recently, they have developed triphenylphosphine ligands with a PEG-chain that allow the coupling between polyaromatic halides and *p*-methoxyphenylboronic acids with very good yields.[24] Finally, we can cite the work of Liu *et al.* on the use of electromagnetic mill for mechanochemical solid-state Suzuki-

Miyaura coupling.[25] The reaction was realized solvent-free without additive and catalyzed by small amounts of palladium and DavePhos ligand. The relatively high reaction temperature, between 67 and 74 °C would be generated by the collision of the ferromagnetic rods.

Thus, considering the literature and our previous work, we describe here the study of the potential of using NaDES *i.e.*, glyceline, as a solvent or LAG additive for the Suzuki-Miyaura coupling reaction in mechanochemistry.

## Results and Discussion

According to the conditions previously described by our team,[7] the Suzuki-Miyaura cross-coupling between bromobenzene **1a** and *p*-methoxyboronic acid **2a** was first realized using palladium acetate in the presence of sodium carbonate as base in glyceline under mechanochemical conditions (Table 1).

During the reaction, there was an increase in the temperature of the reaction medium between 35 and 40 °C. After 10 minutes, the NaDES phase was extracted with ethyl acetate and the conversion of boronic acid **2a** and yield were calculated by NMR. Initially, we were interested in the optimization of the rotation frequency (Entries 1–5). The increase of the rotation speeds up to 2000 rpm improved the yield of the reaction. Beyond 2000 rpm, a slight decrease was observed. We then turned our attention to the amount of catalyst (Entries 6–8). Without palladium, no conversion was observed. Between 1 and 5 mol% palladium acetate, NMR yields of at least 80% were obtained. Then we decided to keep 1 mol% of catalyst for the next steps, in accordance with green chemistry guidelines. The amount of glyceline was then considered (Entries 9–14). Under solid state conditions, the NMR yield was only 7%. There was no degradation since the starting products were fully recovered in the crude. The addition of NaDES accelerated the reaction. Indeed, with 250 mg of glyceline, an NMR yield of 69% was obtained. Further optimization with glyceline amounts between 500 mg and 4 g provided NMR yields of at least 75%. The calculation of the parameter *η* which corresponds to the ratio between the volume of additive liquid (µL) and the mass of reactants (mg) allows to locate the nature of the reaction medium between the solid state and the solution.[26] For values of *η* between 0 and 2 µL/mg, the reaction is considered as liquid-assisted grinding (LAG). Under these conditions (entry 12), in the presence of 0.5 g (422 µL) of glyceline, the *η* parameter is approximately 1, placing them in the LAG category. The reaction was also carried out with ethanol as an additive solvent instead of glyceline since it had shown interesting results in recent work.[21] We then examined the quantity of milling balls (Entries 15–18). Without balls, the reaction taked place but an NMR yield of only 50% was obtained. In the presence of 5–30 g of balls, NMR yields between 80 and 86% were obtained. It is noteworthy that smaller (diameter: 0.8 mm) and larger (diameter: 20 mm) balls were also tested with similar NMR yields. The presence of balls is therefore very favorable to the reactivity of the reaction but in this case, the size and quantity do not seem to have an
<figure><img src="image_4.png" /></figure>

<table><caption>**Table 1.** Optimization of the Suzuki-Miyaura coupling in glyceline between bromobenzene (1a) and *p*-methoxyphenylboronic acid (2a).<sup>[a]</sup></caption><thead><tr><th>Entry</th><th>Pd(OAc)<sub>2</sub></th><th>Glyceline<br>1a<br>(1 equiv.)</th><th>Balls</th><th>rpm</th><th>Conv. (2a)<sup>[b]</sup></th><th>NMR Yield<sup>[b]</sup></th></tr></thead><tbody><tr><td>1</td><td>2.5 mol%</td><td>2,5 g</td><td>20 g</td><td>650</td><td>100%</td><td>65%</td></tr><tr><td>2</td><td>2.5 mol%</td><td>2,5 g</td><td>20 g</td><td>1000</td><td>100%</td><td>76%</td></tr><tr><td>3</td><td>2.5 mol%</td><td>2,5 g</td><td>20 g</td><td>1525</td><td>100%</td><td>78%</td></tr><tr><td>4</td><td><b>2.5 mol%</b></td><td><b>2,5 g</b></td><td><b>20 g</b></td><td><b>2000</b></td><td>100%</td><td><b>87%</b></td></tr><tr><td>5</td><td>2.5 mol%</td><td>2,5 g</td><td>20 g</td><td>2400</td><td>100%</td><td>76%</td></tr><tr><td>6</td><td>-</td><td>2,5 g</td><td>20 g</td><td>2000</td><td>87%</td><td>-</td></tr><tr><td>7</td><td><b>1 mol%</b></td><td><b>2,5 g</b></td><td><b>20 g</b></td><td><b>2000</b></td><td>100%</td><td><b>80%</b></td></tr><tr><td>4</td><td>2.5 mol%</td><td>2,5 g</td><td>20 g</td><td>2000</td><td>100%</td><td>87%</td></tr><tr><td>8</td><td>5 mol%</td><td>2,5 g</td><td>20 g</td><td>2000</td><td>100%</td><td>86%</td></tr><tr><td>9</td><td>1 mol%</td><td>-</td><td>20 g</td><td>2000</td><td>50%</td><td>7%</td></tr><tr><td>10</td><td>1 mol%</td><td>0.25 g</td><td>20 g</td><td>2000</td><td>85%</td><td>69%</td></tr><tr><td>11</td><td>1 mol%</td><td>0.35 g</td><td>20 g</td><td>2000</td><td>85%</td><td>70%</td></tr><tr><td>12</td><td><b>1 mol%</b></td><td><b>0.5 g</b></td><td><b>20 g</b></td><td><b>2000</b></td><td><b>100%</b></td><td><b>82%</b></td></tr><tr><td>13</td><td>1 mol%</td><td>1 g</td><td>20 g</td><td>2000</td><td>100%</td><td>76%</td></tr><tr><td>7</td><td>1 mol%</td><td>2.5 g</td><td>20 g</td><td>2000</td><td>100%</td><td>80%</td></tr><tr><td>14</td><td>1 mol%</td><td>4 g</td><td>20 g</td><td>2000</td><td>100%</td><td>75%</td></tr><tr><td>15</td><td>1 mol%</td><td>0.5 g</td><td>-</td><td>2000</td><td>71%</td><td>50%</td></tr><tr><td>16</td><td>1 mol%</td><td>0.5 g</td><td>5 g</td><td>2000</td><td>95%</td><td>80%</td></tr><tr><td>17</td><td><b>1 mol%</b></td><td><b>0.5 g</b></td><td><b>10 g</b></td><td><b>2000</b></td><td>100%</td><td><b>86%</b></td></tr><tr><td>12</td><td>1 mol%</td><td>0.5 g</td><td>20 g</td><td>2000</td><td>100%</td><td>82%</td></tr><tr><td>18</td><td>1 mol%</td><td>0.5 g</td><td>30 g</td><td>2000</td><td>100%</td><td>85%</td></tr></tbody></table>

[a] Conditions: 1a (1 mmol), 2a (1 mmol), Pd(OAc)<sub>2</sub> (0-5 mol%), Na<sub>2</sub>CO<sub>3</sub> (1.25 mmol), Glyceline (0-4 g), milling balls (ZrO<sub>2</sub>, Ø 5 mm, 0-30 g), milled at 650-2400 rpm for 10 minutes. [b] determined by NMR with trimethoxybenzene as internal reference.

influence. For the rest of the study, we decided to use 10 g of 5 mm diameter milling balls.

In our previous work on Suzuki-Miyaura coupling in NaDES, palladium acetate was found to be the best performing catalyst.[7] Under mechanochemical conditions, it was shown by other groups that palladium acetate was also the best source of palladium for the ligand-free Suzuki-Miyaura reaction.[27] To check whether this was also the case in our system, we tested several palladium sources. Indeed, palladium acetate was found to be the best source of palladium for the Suzuki-Miyaura cross-coupling between bromobenzene 1a and *p*-methoxyboronic acid 2a in the presence of sodium carbonate in glyceline under NaDES LAG mechanochemical conditions (Table 2, entry 1). Good yield was also obtained with palladium chloride (Entry 2). On the other hand, the presence of ligands (Entry 3) or other sources of palladium (II) (Entry 4) or (0) (Entries 5–6) ended with lower yields (55%, 45%, 28%, 27% respectively).

We then tested different LAG solvents (Table 3). First, we selected NaDES based on glycerol or choline chloride (Entries 1–4). They were used under the conditions optimized with glyceline, i. e., a mass of 0.5 g for *η* of around 1 (Entry 1). Choline chloride/ethylene glycol (1:2, mol/mol) gave a good NMR yield

<table><caption>**Table 2.** Optimization of the catalyst.[a]</caption><thead><tr><th></th><th></th><th>[Pd]</th><th></th></tr><tr><th>Entry</th><th>[Pd] [mol %]</th><th>Na<sub>2</sub>CO<sub>3</sub> (1.25 equiv.)<br>Glyceline (0.5 g)<br>Balls (10 g), 10 minutes<br>Milling (2000 rpm)</th><th>OMe</th></tr></thead><tbody><tr><td>1</td><td>Pd(OAc)<sub>2</sub> (1 mol%)</td><td></td><td>86%</td></tr><tr><td>2</td><td>PdCl<sub>2</sub> (1 mol%)</td><td></td><td>78%</td></tr><tr><td>3</td><td>Pd(OAc)<sub>2</sub> (1 mol%)/PPh<sub>3</sub> (2 mol%)</td><td></td><td>55%</td></tr><tr><td>4</td><td>PdCl<sub>2</sub>dppf (1 mol%)</td><td></td><td>45%</td></tr><tr><td>5</td><td>Pd<sub>2</sub>dba<sub>3</sub> (0.5 mol%)</td><td></td><td>28%</td></tr><tr><td>6</td><td>Pd/C (10% wt) (1 mol%)</td><td></td><td>27%</td></tr></tbody><tfoot><tr><td colspan="4"><b>[a]</b> Conditions: 1a (1 mmol), 2a (1 mmol), [Pd] (0.5-1 mol%), Na<sub>2</sub>CO<sub>3</sub> (1.25 mmol), Glyceline (0.5 g), milling balls (ZrO<sub>2</sub>, Ø 5 mm, 10 g), milled at 2000 rpm for 10 minutes. [b] determined by NMR with trimethoxybenzene as internal reference.</td></tr></tfoot></table>

of 77% (Entry 2), while the urea based NaDES, choline chloride/urea (2:1, mol/mol) and glycerol/urea (4:1, mol/mol), lead to moderate yields of 47% and 48% respectively (Entries 3 and 4).
<figure><img src="image_5.png" /></figure>

<table><caption>**Table 3.** Optimization of LAG additive.[a]</caption><thead><tr><th>Entry</th><th>LAG</th><th>m or V</th><th>η (μL/mg)</th><th>NMR Yield [%]</th></tr></thead><tbody><tr><td>1</td><td>Glyceline</td><td>0.5 g</td><td>0.95</td><td>86%</td></tr><tr><td>2</td><td>choline chloride/ ethylene glycol (1:2, mol/mol)</td><td>0.5 g</td><td>1.08</td><td>77%</td></tr><tr><td>3</td><td>Choline chloride/urea (1:2, mol/mol)</td><td>0.5 g</td><td>0.95</td><td>47%</td></tr><tr><td>4</td><td>Glycerol/urea (4:1, mol/mol)</td><td>0.5 g</td><td>0.93</td><td>48%</td></tr><tr><td>5</td><td>Glycerol</td><td>0.5 g</td><td>0.90</td><td>58%</td></tr><tr><td>6</td><td>EtOH</td><td>44 μL</td><td>0.1</td><td>10%</td></tr><tr><td>7</td><td>EtOH</td><td>442 μL</td><td>1</td><td>37%</td></tr><tr><td>8</td><td>1,5-cyclooctadiene</td><td>53 μL</td><td>0.12</td><td>0%</td></tr><tr><td>9</td><td>1,5-cyclooctadiene</td><td>442 μL</td><td>1</td><td>0%</td></tr></tbody></table>

[a] Conditions: **1a** (1 mmol), **2a** (1 mmol), Pd(OAc)₂ (1 mol%), Na₂CO₃ (1.25 mmol), LAG, milling balls (ZrO₂, Ø 5 mm, 10 g), milled at 2000 rpm for 10 minutes. [b] determined by NMR with trimethoxybenzene as internal reference.

The use of glycerol alone gave compound **3aa** in 58% NMR yield (Entry 5). We then turned our attention to LAG additives previously used for Suzuki-Miyaura coupling in the literature.[22,23] Ethanol and 1,5-cyclooctadiene were used as LAG additives in the proportions optimized in the literature (respectively η=0.1 and η=0.12, Entries 6 and 8) and under optimized conditions for NaDES (η=1, Entries 7 and 9). Ethanol led to compound **3aa** with low NMR yields of 10% and 38%. However, when 1,5-cyclooctadiene was used, the coupling product was not observed. Among the various additives tested, glyceline was the best LAG additive for Suzuki-Miyaura coupling under these conditions.

We then focused on studying the conversion kinetics during Suzuki-Miyaura coupling (Figure 1). The reaction rate increases sharply in the first few minutes of reaction, reaching a steady state at around 10 minutes. When the reaction was performed at 40 °C with conventional heating, the NMR yield was 47% after 10 minutes of reaction. We thus observed an activation under mechanochemical conditions.

In organic synthesis, the product extraction step is generally one of the most solvent-intensive and time-consuming steps.

Moreover, when it comes to NaDES, solvent with high viscosity, every transfer step is tedious and quickly lead to increasing extraction solvent consumption. As a first step, the NMR yield of product **3aa** was evaluated prior to extraction. Thus, after 10 minutes of reaction, the reaction crude was completely dissolved in DMSO-d6 and trimethoxybenzene was added as an internal reference. Compound **3aa** was observed in 86% NMR yield. This indicates that the conventional extraction procedure recovers the entire product formed in the organic phase, since an NMR yield of 86% is also obtained after extraction (Scheme 1). To reduce the amount of solvent and optimize extraction time, we tested the possibility of carrying out extraction directly in the reaction bowl using the same ball mill. Thus, after the reaction, 5 mL of ethyl acetate was added directly to the milling jar and the mixture was ground at 2000 rpm for 2 minutes. The ethyl acetate, immiscible with NaDES, can easily be collected. The operation was realized 4 times and the solvent was evaporated. Compound **3aa** was obtained with an NMR yield of 96%. This process allowed to obtain a better yield with 3 times less extraction solvent and a time saving on the whole process.[28] This result suggests that the reaction continues in the milling bowl during extraction, thereby increasing the reaction yield. Unfortunately, a one-pot process

<figure><img src="image_6.png" /><figcaption>**Figure 1.** Kinetic study under NaDES LAG mechanochemical conditions.</figcaption></figure>

<figure><img src="image_7.png" /><figcaption>**Scheme 1.** Comparison of extraction processes.</figcaption></figure>
<figure><img src="image_8.png" /></figure>

(reaction and extraction at the same time) was not possible since when the same reaction was carried out in the presence of 5 mL ethyl acetate, only traces of coupling product **3aa** were obtained. While the addition of ethyl acetate does not stop the reaction, it does significantly slow down its reactivity.

We then investigated the recycling capacity of the NaDES phase containing our catalytic system (Figures 2 & 3). The first test was performed under the previously optimized conditions. After a first cycle, bromobenzene **1a**, *p*-methoxyboronic acid **2a**, and sodium carbonate were added to the NaDES phase. The NMR yield was only 36%. A third run was performed but the NaDES phase completely dissolved in ethyl acetate upon extraction, highlighting a potential degradation of glyceline after repeated contacts with an excess of EtOAc. <sup>13</sup>C NMR analysis of glyceline in DMSO-d<sub>6</sub> after 10 minutes at 2000 rpm in the presence of EtOAc shows that ethyl acetate remains after removal of the “organic” phase. Moreover, after evaporation of the EtOAc, NMR reveals that some glycerol is extracted by the EtOAc. This suggests that repeated extractions using this extraction methodology would alter the proportions between glycerol and choline chloride, leading to the dissolution of DES in EtOAc as observed. This prompted us to perform a second test by increasing the amount of glyceline, to increase glyceline/EtOAc ratio. Although the NaDES phase was maintained, a decrease in yield was observed from the second run, invalidating our first hypothesis. Since we previously described that this catalytic system could be recycled under conventional conditions,<sup>[7]</sup> we assumed that the high stirring intensity observed at 2000 rpm in the ball mill could contribute to the damage of the

catalytic system. Thus, we considered decreasing the revolution per minute at 650 rpm to see if it affected the catalyst activity. As expected, considering Table 1, a lower NMR yield was observed in the first cycle, but also a decrease in the second cycle. Thus, the rotation speed does not seem to be responsible for the loss of catalytic activity. Finally, a last test was performed to see if the mechano-assisted extraction step could affect the NaDES phase. In assay 4, after 10 minutes of reaction, the reaction medium was again loaded with substrates **1a** and **2a**, and base, without intermediate extraction. Extraction was then performed at the end of the second cycle. The NMR yield obtained for the two consecutive cycles was 67%, which corresponds to the average yield of the two cycles in assay 1 (96% and 40%). Therefore, mechano-assisted extraction is also not the factor that can explain the loss of activity from the second cycle. We then decided to move forward to the scope investigation. Further experiments will be carried out in the laboratory to understand why the catalytic system in the NaDES phase was recyclable after conventional stirring and heating, whereas it rapidly lost its activity under mechanochemical conditions.

To investigate the scope of mechanochemical Suzuki-Miyaura cross-coupling with glyceline as LAG additive, the reaction was carried out with various liquid aryl bromides and solid boronic acids (Scheme 2). We first performed the coupling

<figure><img src="image_9.png" /><figcaption>**Figure 2.** Reaction medium after a mechanochemical cycle.</figcaption></figure>

<figure><img src="image_10.png" /><figcaption>**Figure 3.** Recycling tests. **1:** Glyceline (0.5 g), 2000 rpm/2: Glyceline (2.5 g), 2000 rpm/3: Glyceline (2.5 g), 650 rpm/4: Glyceline (2.5 g), 2000 rpm, no extraction after cycle 1, extraction after cycle 2.</figcaption></figure>

<figure><img src="image_11.png" /><figcaption>**Scheme 2.** Synthesis of biaryls **3** by Mechanochemical Suzuki-Miyura Cross-Coupling with glyceline as LAG additive. Conditions: **1** (1 mmol), **2** (1 mmol), Pd(OAc)<sub>2</sub> (1 mol%), Na<sub>2</sub>CO<sub>3</sub> (1.25 mmol), Glyceline (0.5 g), milling balls (ZrO<sub>2</sub>, Ø 5 mm, 10 g), milled at 2000 rpm for 10 min.*Isolated yield.</figcaption></figure>
<figure><img src="image_12.png" /></figure>

between bromobenzene **1a** and various substituted phenyl-
boronic acids **2**. Phenylboronic acids substituted in *para* (2*a*-d),
*meta* (2*e*-f) or *ortho* (2*g*) with electron-donor or withdrawing
groups led to the obtain of biphenyls **3a-g** in moderate to
good, isolated yields (50–79%). Coupling of bromobenzene **1a**
with phenylboronic acid **2h** led to the compound **3ah** in 65%
yield. In contrast, in the case of a hindered substrate such as
2,4,6-trimethoxyphenylboronic acid **2i**, no conversion was
observed. Then, *para*-, *ortho*- and *meta*-bromotoluenes **1b**, **1c**
and **1d** were coupled with *para*-methoxyboronic acid. With
*ortho*-bromotoluene **1c**, biphenyl **3ca** is isolated in slightly
lower yield, compared to *meta*- and *para*-bromotoluene (**3ca**:
52%, **3ba**: 66%, **3da**: 67%, respectively). To compare the
reactivity of aryl halides, the reaction was carried out with 4-
chlorotoluene and 2-iodotoluene. In the case of the chlorinated
derivative, no conversion was observed. Biphenyl **3ca** was
obtained with a slightly lower yield (**3ca**: 46%) from the
iodinated derivative than from the brominated derivative (**3ca**:
52%). Subsequently, couplings of 4-bromoanisole **1e** with *para*-
, *meta*-, *ortho*-substituted phenylboronic acids led to the
corresponding biphenyls **3ea**, **3eb** and **3ef** in moderate to
good yields. In contrast, with benzyl- and hexyl-boronic acids **2j**
and **2k**, no coupling reaction was observed. Last, 1-bromo-
naphthalene **1f** furnished the desired coupling product **3fa**
with good yield (69%).

Our interest then turned to the use of solid aryl bromides,
generally considered as challenging substrates (Scheme 3). We
were delighted to see that 2-bromonaphthalene, 9-bromoan-
thracene and 1-bromopyrene respectively led to the desired
coupling products with good yields (76–82%). It is noteworthy
that these yields are generally better than those obtained from
liquid aryl bromides.

Finally, the coupling reaction was carried out under gram-scale
conditions. The work of Kubota and Ito has demonstrated the
efficiency of mechanochemical versus solution conditions for the
synthesis of compound **3ha** (Scheme 4).[23] In order to compare
our methodology with this previous work, we performed the
coupling on 8 mmol of 9-bromoanthracene **1h** and *p*-meth-
oxyboronic acid **2a** in a 25 mL grinding bowl in the presence of
10 g of balls, palladium acetate (1 mol%), sodium carbonate

<figure><img src="image_13.png" /><figcaption>**Scheme 4.** Suzuki-Miyura Cross-Coupling on the gram scale.</figcaption></figure>

(1.25 equiv.) and glycine (η = 0.8 µL/mg). After just 20 minutes of reaction, compound **3ah** was obtained in 90% yield. Typical metrics applied at First Pass, according to the CHEM21 Metrics Toolkit developed by Clark *et al.*[29] have been calculated for this process. The CHEM21 toolkit enables the sustainability of reactions and their ecological character to be assessed according to quantitative and qualitative criteria. Reaction mass efficiency (RME) 62.5, atom economy (AE) 69.5, optimum efficiency (OE) 89.9, process mass intensity (PMI) 97.2 g g⁻¹, space time yield (STY) 488 and the E-factor 81.9 were calculated. Production costs of **3ha**, for raw materials only, are 21.6 €/g. Quantitative and qualitative CHEM21 criteria and production costs were compared with those of Kubota and Ito's solid-state process where data were available (for details, see Supporting Information). These values show an ecological and economic improvement of the methodology. This result once again demonstrates the effectiveness of mechanochemistry coupled with NaDES as LAG additive in the development of robust methodologies, as well as the performance of our process.

Conclusions

In conclusion, we have reported an efficient and sustainable
method for Suzuki-Miyaura Cross-Coupling. The association of
mechanochemical conditions and NaDES as LAG additive
allowed to obtain the coupling products with good yields with
very short reaction times and without additional heating or
ligand. Mechano-assisted extraction also made it possible to
reduce the quantities of extraction solvents and the overall
time of the synthesis process and reduced the unitary operation
of the process. This first mechanochemical reaction with NaDES
as LAG additive opens the door to further studies for
sustainable chemistry as it also demonstrated good perform-
ances with solid substrates.

**Experimental Section**

**General procedure for the mecanochemical Suzuki-Miyaura**
**coupling:** Glyceline (0.5 g), boronic acid (1 mmol), sodium
carbonate (1.25 mmol, 132.5 mg), palladium acetate (0.01 mmol,
2.2 mg), aryl halogenated (1 mmol) and balls (10 g) were introduced
in a ball milling bowl (25 mL). The bowl was placed in the ball mill
(*Hauschild*® SpeedMixer DAC 400.1 FVZ, 10 min at 2000 rpm). The
reaction mixture was then extracted with EtOAc (4×5 mL) in the

<figure><img src="image_14.png" /><figcaption>**Scheme 3.** Mechanochemical Suzuki-Miyura Cross-Coupling with glycine as LAG additive between solid aryl bromides and *p*-methoxyboronic acid (2a). Conditions: **1** (1 mmol), **2a** (1 mmol), Pd(OAc)₂ (1 mol%), Na₂CO₃ (1.25 mmol), Glyceline (0.5 g), milling balls (ZrO₂, Ø 5 mm, 10 g), milled at 2000 rpm for 10 min (3ga and 3ia) or 20 min (3ha).*Isolated yield.</figcaption></figure>
<figure><img src="image_15.png" /></figure>

ball mill (4x2 min at 2000 rpm). The organic phases were combined and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with cyclohexane/EtOAc or cyclohexane/CH₂Cl₂ as eluent to afford the expected compound.

**Procedure for the mecanochemical Suzuki-Miyaura coupling on the gram scale:** Glyceline (4 g), 4-methoxyphenylboronic acid (8 mmol, 1.215 g), sodium carbonate (10 mmol, 1.06 g), palladium acetate (0.08 mmol, 18 mg), 9-bromoanthracene (8 mmol, 2.06 g) and balls (10 g) were introduced in a ball milling bowl (25 mL). The bowl was placed in the ball mill (Hauschild® SpeedMixer DAC 400.1 FVZ, 20 min at 2000 rpm). The reaction mixture was then partitioned between water and EtOAc (30 mL/45 mL). The phases were separated, and the aqueous phase was extracted with EtOAc (3×45 mL). The organic phases were combined, dried over MgSO₄ and concentrated under reduced pressure. The crude NMR analysis revealed that the compound **3ha** did not need further purification (2.05 g, yield = 90%).

## Supporting Information

The authors have cited additional references within the Supporting Information.[30,36]

## Acknowledgements

We thank Emmanuelle Etiemble from MP2E solutions for fruitful discussion and technical support.

## 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:** mechanochemistry · natural deep eutectic solvent · sustainable chemistry · Suzuki-Miyaura cross-coupling

[1] P. T. Anastas, M. M. Kirchhoff, T. C. Williamson, *Appl. Catal. A.: Gen.* **2001**, *221*, 3–13.

[2] J. Andersen, J. Mack, *Green Chem.* **2018**, *20*, 1435–1443.

[3] J. G. Hernández, C. Bolm, *J. Org. Chem.* **2017**, *82*, 4007–4019.

[4] G. A. Bowmaker, *Chem. Commun.* **2013**, *49*, 334–348.

[5] a) E. L. Smith, A. P. Abbott, K. S. Ryder, *Chem. Rev.* **2014**, *114*, 11060–11082; b) A. Paiva, R. Craveiro, I. Aroso, M. Martins, R. L. Reis, A. R. C. Duarte, *ACS Sustainable Chem. Eng.* **2014**, *2*, 1063–1071; c) J. García-Álvarez, *Eur. J. Inorg. Chem.* **2015**, *5147–5157*; d) D. A. Alonso, A. Baeza, R. Chinchilla, G. Guillena, I. M. Pastor, D. J. Ramón, *Eur. J. Org. Chem.* **2016**, 612–632; e) Y. Liu, J. B. Friesen, J. B. McAlpine, D. C. Lankin, S.-N. Chen, G. F. Pauli, *J. Nat. Prod.* **2018**, *81*, 679–690; f) B. B. Hansen, S.

Spittle, B. Chen, D. Poe, Y. Zhang, J. M. Klein, A. Horton, L. Adhikari, T. Zelovich, B. W. Doherty, B. Gurkan, E. J. Maginn, A. Ragauskas, M. Dadmun, T. A. Zawodzinski, G. A. Baker, M. E. Tuckerman, R. F. Savinell, J. R. Sangoro, *Chem. Rev.* **2021**, *121*, 1232–1285.

[6] D. O. Abranches, J. A. P. Coutinho, *Ann. Rev. Chem. Biomol. Eng.* **2023**, *14*, 141–163.

[7] P.-O. Delaye, M. Pénichon, L. Boudesocque-Delaye, C. Enguehard-Gueiffier, A. Gueiffier, *SynOpen* **2018**, *2*, 306–311.

[8] a) M. Wang, J. Wang, Y. Zhou, M. Zhang, Q. Xia, W. Bi, D. D. Y. Chen, *ACS Sustainable Chem. Eng.* **2017**, *5*, 6297–6303; b) J. Wang, Y. Zhou, M. Wang, W. Bi, H. Li, D. D. Y. Chen, *Anal. Chem.* **2018**, *90*, 3109–3117.

[9] G. Imperato, S. Höger, D. Lenoir, B. König, *Green Chem.* **2006**, *8*, 1051–1055.

[10] S. E. Hooshmand, R. Afshari, D. J. Ramón, R. S. Varma, *Green Chem.* **2020**, *22*, 3668–3692.

[11] X. Marset, A. Khoshnood, L. Sotorrios, E. Gómez-Bengoa, D. A. Alonso, D. J. Ramón, *ChemCatChem* **2017**, *9*, 1269–1275.

[12] B. Saavedra, N. González-Gallardo, A. Meli, D. J. Ramón, *Adv. Synth. Catal.* **2019**, *361*, 3868–3879.

[13] S. Chakraborty, M. Halanur Mruthunjayappa, K. Aruchamy, N. Singh, K. Prasad, D. Kalpana, D. Ghosh, N. S. Kotrappanavar, D. Mondal, *ACS Sustainable Chem. Eng.* **2019**, *7*, 14225–14235.

[14] G. Dilauro, S. M. García, D. Tagarelli, P. Vitale, F. M. Perna, V. Capriati, *ChemSusChem* **2018**, *11*, 1–8.

[15] P. Thiyagamurthy, F. R. N. Khan, *ChemistrySelect* **2020**, *5*, 2610–2617.

[16] R. Mancuso, M. Lettieri, R. Stangis, P. Russo, A. P. Piccionello, S. De Angelis, B. Gabriele, *Asian J. Org. Chem.* **2022**, *11*, e202200353.

[17] S. F. Nielsen, D. Peters, O. Axelsson, *Synth. Commun.* **2000**, *30*, 3501–3509.

[18] K. Kubota, H. Ito, *Trends in Chemistry* **2020**, *2*, 1066–1081.

[19] F. Schneider, A. Stolle, B. Ondruschka, H. Hopf, *Org. Process Research & Development* **2009**, *13*, 44–48.

[20] F. Schneider, B. Ondruschka, *ChemSusChem* **2008**, *1*, 622–625.

[21] Z.-J. Jiang, Z.-H. Li, J.-B. Yu, W.-K. Su, *J. Org. Chem.* **2016**, *81*, 10049–10055.

[22] W. Pickhardt, C. Beaković, M. Mayer, M. Wohlgemuth, F. J. L. Kraus, M. Etter, S. Grätz, L. Borchardt, *Angew. Chem. Int. Ed.* **2022**, *61*, e202205003.

[23] T. Seo, T. Ishiyama, K. Kubota, H. Ito, *Chem. Sci.* **2019**, *10*, 8202–8210.

[24] T. Seo, K. Kubota, H. Ito, *J. Am. Chem. Soc.* **2023**, *145*, 6823–6837.

[25] X. Li, Y. Liu, L. Zhang, Y. Dong, Q. Liu, D. Zhang, L. Chen, Z. Zhao, H. Liu, *Green Chem.* **2022**, *24*, 6026–6035.

[26] P. Ying, J. Yu, W. Su, *Adv. Synth. Catal.* **2021**, *363*, 1246–1271.

[27] L. M. Klingensmith, N. E. Leadbeater, *Tetrahedron Lett.* **2003**, *44*, 765–768.

[28] In each case, TLC monitoring of the extraction allowed to optimize the number of extractions while ensuring that no organic compounds was left in the aqueous phase.

[29] C. R. McElroy, A. Constantinou, L. C. Jones, L. Summerton, J. H. Clark, *Green Chem.* **2015**, *17*, 3111–3121.

[30] J.-H. Na, X. Liu, J.-W. Jing, J. Wang, X.-Q. Chu, M. Ma, H. Xu, X. Zhou, Z.-L. Shen, *Org. Lett.* **2023**, *25*, 2318–2322.

[31] F. Mäsing, Harald Nüsse, J. Klingauf, A. Studer, *Org. Lett.* **2018**, *20*, 752–755.

[32] M. Ravbar, A. Koler, M. Paljevac, P. Krajnc, M. Kolar, J. Iskra, *ACS Omega* **2022**, *7*, 12610–12616.

[33] Z. Luo, L. Xiong, T. Liu, Y. Zhang, S. Lu, Y. Chen, W. Guo, Y. Zhu, Z. Zeng, *J. Org. Chem.* **2019**, *84*, 10559–10568.

[34] G. Zhang, X. Luo, C. Guan, Y. Cui, C. Ding, *Eur. J. Org. Chem.* **2023**, *26*, e202300114.

[35] C. Li, Y. Shi, Q. Chen, K. Zhang, G. Yang, *J. Org. Chem.* **2023**, *88*, 2306–2313.

[36] K. Manna, R. Jana, *Org. Lett.* **2023**, *25*, 341–346.
<figure><img src="image_16.png" /></figure>

RESEARCH ARTICLE

The combination of two green chemical domains: an efficient and sustainable method for Suzuki-Miyaura mechanochemical cross-coupling reaction with NaDES as LAG additive. The synthesis process is fast and does not require ligand or heating.

<figure><img src="image_17.png" /></figure>

Dr. E. Thiery*, Dr. P.-O. Delaye*, Prof. J. Thibonnet, Prof. L. Boudesocque-Delaye

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Mechanochemical Suzuki-Miyaura Cross-Coupling with Natural Deep Eutectic Solvent as Liquid-Assisted Grinding Additive: Merging Two Fields for a Greener Strategy