# Efficient Piancatelli rearrangement of HMF derivatives under microwave activation or subcritical water conditions to produce functionalized hydroxylated cyclopentenones

Sparta Youssef-Saliba, Clémentine Mayet, Elsa Van Elslande, Géraldine Le Goff, Jean-François Betzer

► To cite this version:

Sparta Youssef-Saliba, Clémentine Mayet, Elsa Van Elslande, Géraldine Le Goff, Jean-François Betzer. Efficient Piancatelli rearrangement of HMF derivatives under microwave activation or subcritical water conditions to produce functionalized hydroxylated cyclopentenones. Organic & Biomolecular Chemistry, 2025, 23 (11), pp.2683-2690. 10.1039/D4OB01899K. hal-05035266

HAL Id: hal-05035266

https://hal.science/hal-05035266v1

Submitted on 15 Apr 2025

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

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

Distributed under a Creative Commons Attribution 4.0 International License
# Efficient Piancatelli rearrangements of HMF derivatives under microwave activation or subcritical water conditions to produce functionalized hydroxylated cyclopentenones

Sparta Youssef-Saliba, Clémentine Mayet, Elsa Van Elslande, Géraldine Le Goff* and Jean-François Betzer*

HMF (5-hydroxymethylfurfural), a renewable raw material from biomass, was used as starting material to provide 5-aryl-4-hydroxymethyl-4-hydroxycyclopentenones with functionalized aryl groups. In a first time, arylic substituents were added to the aldehyde moiety of HMF under rhodium- or palladium-catalyzed 1,2-addition of arylboronic acids, in mild conditions to respect the very sensitive HMF reactivity. In a second time, these non-symmetrical furan-2,5-dicarbinols, through Piancantelli rearrangement, provided the desired cyclopentenones under microwave activation or subcritical water conditions (100 °C and 100 bars) using the Zippertex technology, in regio- and diastereoselective manner. These synthetized bis-hydroxylated cyclopentenone derivatives exhibited significant antimicrobial activities against gram-positive bacteria *Micrococcus luteus*, *Bacillus subtilis* and gram-negative bacteria *Echerichia coli*.

## Introduction

Replacing fossil fuels with renewable materials is a key element in developing a green and circular economy. Considering the environmental impact, fossil fuels are major contributors to carbon dioxide and other greenhouse gas emissions, and their extraction also produce pollutants that harm air and water quality. For consequences in terms of sustainability, renewable materials are more sustainable, as they can be replenished naturally over short periods contrasting with fossil fuels, which take millions of years to form and are being depleted rapidly and irremediably.

The use of biomass as renewable materials is crucial to the development of sustainable economy. To meet these technological, economic and societal challenges, the scientific community is seriously mobilized considering the huge number of research articles and reviews in this research area (more than 2.800 reviews in 2023 for "biomass" as keyword, source ISI Web of Knowledge). The two main lines of research in this field focus firstly, on the transformation of biomass into molecular building blocks and secondly, the selective conversion of these building blocks into high value-added compounds for many applications such as precursors for pharmaceutical compounds, cosmetics industry, monomer for polymer synthesis, surfactants, lubricants, paints, plasticizers, paper additives and biocarburants.

In the field of renewable materials, lignocellulosic biomass is the cheaper and the most abundant material. This sustainable lignocellulose is composed of cellulose (50%), hemicellulose (30%), and polyphenolic lignins (20%).¹ For this lignocellulosic biomass transformation, the production of furfural (FFR), furfuryl alcohol (FA), and 5-hydroxymethyl-furfural (HMF) provide versatile sustainable and valuable substitutes for petrochemical building blocks.² More specifically, HMF is considered as one of the "Top 14" bio-based building blocks listed by the US Department of Energy.³

HMF is regarded by the scientific community as a crucial component for transitioning from a fossil-based economy to a sustainable one.⁴ Taking advantage of the primary hydroxyl, aldehyde and furan functionalities, numerous synthetic transformations have been described, supporting the versatility

of HMF as a building block platform.⁵ The synthetic potential of HMF is directly correlated to the number of reaction sites for this small molecule, which makes the criterion of chemoselectivity highly challenging and also cause biorefinery production difficulties, reasons why HMF has been assessed as a "sleeping giant".⁴,⁶ Indeed, the selective transformation of HMF into value-added products was complicated by the formation of numerous by-products due to the high reactivity of HMF (Fig 1).

<figure><img src="image_2.png" /><figcaption>Fig. 1 HMF and its more common side-products. In background, in light-grey coloured, a generic molecular structure of humins as condensation by-product. HMF: 5-hydroxymethyl-furfural. OBMF: 5,5'-[oxy-bis(methylene)]bis-2-furfural. DHH: 2,5-dioxo-6-hydroxy-hexanal.</figcaption></figure>

Among their number, we can mentioned the OBMF, resulting from HMF dimerization, as already observed by Ananikov⁷ and Afonso.⁸ Another major drawback side reaction is the formation of levulinic acid associated to the concomitant release of formic acid.⁹ But the major difficulties encountered when using HMF as starting material are the formation of oligomeric and polymeric materials, that are commonly called humins. These humins result from the multiple combination of 2,5-dioxo-6-hydroxyhexanal (DHH), formed by hydrolytic ring-opening of HMF, and its condensation with recombination of HMF to form these humins as dark-colored solids material.¹⁰

Despite these difficulties, which must be overcome to take full advantage of the high potential of HMF as starting material,
HMF has been the object of numerous studies on its use in fine chemical synthesis.⁵b,⁵c In this topic, we are the first to use HMF derivatives as starting material for Piancatelli rearrangement to produce 5-substituted-4-hydroxymethyl-4-hydroxycyclopentenones.¹¹ The challenge in using HMF derivatives as starting material for Piancatelli rearrangement is due to the hydroxymethyl C-5 substitution thereby significantly reducing the reactivity during the elementary step of catalytic cycle for the C-5 addition on furanoxonium ion intermediate.¹² For that reason, only three C-5 substituted substrates have been reported in literature for Piancatelli rearrangement, and involved exclusively the unfunctionalized methyl,¹³ phenyl¹⁴ or ethoxymethyl¹⁵ C-5 substitution.

## Results and discussion

In our previous study, we have shown that non-symmetrical furan-2,5-dicarbinols (FDC), derived from HMF, can produce cleanly 5-substituted-4-hydroxymethyl-4-hydroxycyclopentenones. We have highlighted that the combination of microwave activation and the use of a catalytic amount of DyCl₃ was necessary to provide high chemical yields and to ensure control of the relative configuration of the two stereogenic centers that are created in the rearrangement.¹¹ To overcome the well-known bottlenecks and drawbacks of the Piancatelli rearrangement on large-scale synthesis, we have also performed studies on this rearrangement under subcritical water conditions (100 °C and 100 bars) using the Zippertex technology. The Zippertex technology, with its specific operating process combining temperature and pressure activations, has been originally designed for extraction of natural bio-resources.¹⁶ We were the first to apply this technology for the replacement of microwave irradiation for a relevant chemical transformation on a large scale synthesis. Using the Zippertex technology, and under subcritical water conditions, the Piancatelli rearrangement proceeds smoothly to deliver cleanly the desired cyclopentenones while limiting the formation of side-product and insoluble dark brown humins.¹⁷ In this study, we would like to extend this synthetic approach to 5-substituted-4-hydroxymethyl-4-hydroxycyclopentenones, starting from α-arylsubstituted-furan-2,5-dicarbinol, obtained in one step from HMF, with aryl-functionalized substrates and compare the Piancatelli rearrangement under microwave and subcritical water conditions.

The incorporation of an aryl moiety to HMF, described in literature by us¹¹ and other,¹⁸ were previously performed by addition of an excess of organomagnesium or organolithium reagents. In this study, we would like to take advantage of an alternative synthetic pathway which implies the transition metal-catalyzed 1,2-addition of arylboronic acids to aldehydes. The use of a transition metal catalyst allows transmetalation between boron and the metal catalyst, followed by the 1,2-addition reaction onto carbonyl moiety and the release of the metal catalyst. The use of readily commercially available, safe and nontoxic organoboron reagents and especially the mild conditions to these transition metal-catalyzed additions seems quite appropriate to the very sensitive HMF reactivity.

To identify the best reaction conditions, this 1,2-addition of boronic acid on HMF **1** was firstly screened with the benzeneboronic acid **2a**. We started our screening with the firstly reaction conditions described by Miyaura, which implies the use [Rh(acac)(CO)₂] as rhodium catalyst and the bidentate phosphine 1,1'-bis(diphenylphosphanyl)ferrocene as ligand.¹⁹ Unfortunately, in these conditions we observed only the decomposition of the starting material (entry 1). The same reaction was then attempted with the use of RhCl₃·3H₂O as rhodium catalyst and the N-heterocyclic carbene IPr (1,3-bis(2,6-diisopropylphenyl-imidazol-2-ylidene) as ligand, easily generated in basic media from its corresponding imidazolium salts, under reaction conditions described by Fürstner.²⁰ As previously observed with the use of rhodium(I) complex, the use rhodium(III) salt also led to complete decomposition of the starting material (entry 2).

<figure><img src="image_3.png" /><figcaption>**Table 1** Screening of metal catalyst and conditions for metal-catalyzed 1,2-addition of benzeneboronic acid to HMF</figcaption></figure>

<table><thead><tr><th>Entry</th><th>Catalyst</th><th>Ligand</th><th>Base</th><th>T (°C)</th><th>Time (h)</th><th>3a Yield (%)<sup>a</sup></th></tr></thead><tbody><tr><td>1<sup>b</sup></td><td>Rh(acac)(CO)<sub>2</sub><br>(3 mol%)</td><td>dppf<br>(3 mol%)</td><td>-</td><td>80</td><td>16</td><td>decomp</td></tr><tr><td>2<sup>c</sup></td><td>RhCl<sub>3</sub>·3H<sub>2</sub>O<br>(3 mol%)</td><td>IPrHCl<br>(3 mol%)</td><td>NaOMe<br>(2 eq.)</td><td>80</td><td>2</td><td>decomp</td></tr><tr><td>3<sup>d</sup></td><td>[Rh<sub>2</sub>(pfb)<sub>4</sub>]<br>(3 mol%)</td><td>IPrHCl<br>(3 mol%)</td><td>KOtBu<br>(2 eq.)</td><td>55</td><td>1.5</td><td>26</td></tr><tr><td>4<sup>e</sup></td><td>[Rh<sub>2</sub>(OAc)<sub>4</sub>]<br>(3 mol%)</td><td>IPrHCl<br>(3 mol%)</td><td>KOtBu<br>(2 eq.)</td><td>90</td><td>0.5</td><td>98</td></tr><tr><td>5<sup>f</sup></td><td>Pd<sub>2</sub>(dba)<sub>3</sub>·CHCl<sub>3</sub><br>(5 mol%)</td><td>PPh<sub>3</sub><br>(5 mol%)</td><td>CS<sub>2</sub>CO<sub>3</sub><br>(2 eq.)</td><td>60</td><td>24</td><td>NR</td></tr><tr><td>6<sup>g</sup></td><td>PdCl<sub>2</sub><br>(5 mol%)</td><td>P(1-Nap)<sub>3</sub><br>(5 mol%)</td><td>K<sub>2</sub>CO<sub>3</sub><br>(3 eq.)</td><td>65</td><td>16</td><td>72</td></tr></tbody></table>

This 1,2-addition reaction was also described by Gois with the use of dirhodium(II) complexes with axial N-heterocyclic carbene ligands.²¹ The reaction on HMF was first attempted with the most efficient catalyst, that means the [Rh₂(pfb)₄] with a perfluorobutyrate as bridging ligand. Under these mild conditions, we were pleased to isolate the desired α-phenylfuran-2,5-dicarbinol **3a** in 26% isolated yield (entry 3). Gratifyingly, the use of [Rh₂(OAc)₄] described as less efficient catalyst for this reaction, allowed the formation of **3a** in nearly quantitative yield (entry 4). This high 98% yield may be attributed to the less reactive [Rh₂(OAc)₄] catalyst, associated to a satisfactory tolerance of this catalyst towards the HMF

<footnote><sup>a</sup> Isolated yield. <sup>b</sup> Reaction performed in a DME/H₂O 1:1.6 mixture at 0.2 M. <sup>c</sup> Reaction performed in aqueous DME at 0.2 M. <sup>d</sup> Reaction performed in t-amylalcohol at 0.2 M. <sup>e</sup> Reaction performed in a DME/H₂O 4:1 mixture at 0.2 M. <sup>f</sup> Reaction performed in toluene at 0.2 M. <sup>g</sup> Reaction performed in THF at 0.1 M. <sup>h</sup> Acac = acetylacetonate. Dppf = 1,1'-bis(diphenylphosphino)ferrocene. IPrHCl = 1,3-bis(2,6-diisopropylphenyl) imidazolium chloride. Pfb = perfluorobutyrate. P(1-Nap)<sub>3</sub> = tri-1-naphthylphosphine.</footnote>
functional groups. Beyond this clean process to produce **3a**, during the chromatography purification we are able to isolate the catalyst dirhodium tetraacetate carbenoid [Rh₂(OAc)₄](IPr). The molecular structure of this dirhodium organometallic complex has been assigned at first by NMR spectroscopy, identified as C₃₅H₄₈N₂O₈Rh₂ such as molecular formula by HRMS and unambiguously established by single-crystal X-ray crystallography analysis (see ESI Part V†).²² This dirhodium tetraacetate carbenoid [Rh₂(OAc)₄](IPr) was previously described by Jang²³ for allylic oxidation alkenes and Gois²⁴ during studies on arylation of aldehydes with arylboronic acids. The ORTEP drawing of this active catalyst [Rh₂(OAc)₄](IPr) with NHC ligand is shown in Fig. 2. This stable isolated [Rh₂(OAc)₄](IPr) catalyst may be reused for another reaction cycle with comparable efficiency.

<figure><img src="image_4.png" /><figcaption>**Fig. 2** ORTEP view of dirhodium tetraacetate carbenoid [Rh₂(OAc)₄](IPr). Hydrogen atoms have been excluded for clarity (CCDC deposit number 2383332).</figcaption></figure>

In spite of this efficient formation of **3a** under rhodium catalysis, this 1,2-addition of benzeneboronic acid on HMF **1** was also attempted under palladium catalysis, firstly described by Ohta²⁵ and developed by Wu.²⁶ With the conditions developed by Ohta, that means the use of Pd₂(dba)₃·CHCl₃ as catalyst and PPh₃ as ligand, any reaction was observed and HMF was recovered unchanged (entry 5). In contrast, with the conditions developed by Wu, which implies the use of bulky and electron-rich P(1-Nap)₃, allowed the formation of **3a** in 72% yield (entry 6).

Thus, for the continuation of our study, and for the preparation of functionalized of α-aryl-substituted-furan-2,5-dicarbinol from HMF, we chose to retain the two conditions with dirhodium complexes as catalyst (conditions of entries 3 and 4) and the last condition with palladium as catalyst (conditions of entry 6). We have applied these three conditions on four functionalized arylboronic acid with *p*-methoxy, *p*-(*t*-butyldimethylsilyl)oxy, *p*-methoxymethyl, and *p*-(*t*-butoxycarbonyl)amino moieties. Depending of functional group onto the boronic acid, we observed very different results according to the catalytic system. For the *p*-methoxy and *p*-methoxymethyl functional groups and the synthesis of adducts **3b** and **3d**, the best results were obtained using the dirhodium [Rh₂(OAc)₄] catalyst (entries 2 and 8). In contrast, for the OTBS group, these conditions (entry 5) led to a poor yield of compound **3d**, while the use [Rh₂(pfb)₄] and PdCl₂ gave satisfactory 55% (entry 4) and 54% (entry 6) yields, respectively. For the NHBoc group, only the use of PdCl₂ gave satisfactory 58% yield (entry 12).

Thus, this study confirms that it is challenging to control the reactivity of HMF **1** towards this 1,2-addition reaction of boronic acids. However, **Cond. B** (use of [Rh₂(OAc)₄] catalyst and NHC ligand) appear to be the most general and effective for the formation of the desired furan-2,5-dicarbinols **3**.

<table><caption>**Table 2** Rhodium- and palladium-catalyzed addition reactions of arylboronic acids to HMF</caption><thead><tr><th></th><th>Cond. A : [Rh<sub>2</sub>(pfb)<sub>4</sub>] (3 mol%)<br>IPrHCl (3 mol%)<br>KOtBu (1 equiv.)</th><th>IPrHCl =</th></tr></thead><tbody><tr><td></td><td>Cond. B : [Rh<sub>2</sub>(OAc)<sub>4</sub>] (3 mol%)<br>IPrHCl (3 mol%)<br>KOtBu (1 equiv.)</td><td></td></tr><tr><td></td><td>Cond. C : PdCl<sub>2</sub> (5 mol%)<br>P(1-Nap)<sub>3</sub> (5 mol%)<br>K<sub>2</sub>CO<sub>3</sub> (3 equiv.)</td><td>P(1-Nap)<sub>3</sub> =</td></tr></tbody></table>
<table><thead><tr><th>Entry</th><th>R</th><th>Boronic acid (2 equiv.)</th><th>Cond.</th><th>Product</th><th>3b-e Yield (%)<sup>a</sup></th></tr></thead><tbody><tr><td>1</td><td>OMe</td><td><b>2b</b></td><td>A</td><td><b>3b</b></td><td>19</td></tr><tr><td>2</td><td>OMe</td><td><b>2b</b></td><td>B</td><td><b>3b</b></td><td>55</td></tr><tr><td>3</td><td>OMe</td><td><b>2b</b></td><td>C</td><td><b>3b</b></td><td>0</td></tr><tr><td>4</td><td>OTBS</td><td><b>2c</b></td><td>A</td><td><b>3c</b></td><td>55</td></tr><tr><td>5</td><td>OTBS</td><td><b>2c</b></td><td>B</td><td><b>3c</b></td><td>12</td></tr><tr><td>6</td><td>OTBS</td><td><b>2c</b></td><td>C</td><td><b>3c</b></td><td>54</td></tr><tr><td>7</td><td>OMOM</td><td><b>2d</b></td><td>A</td><td><b>3d</b></td><td>20</td></tr><tr><td>8</td><td>OMOM</td><td><b>2d</b></td><td>B</td><td><b>3d</b></td><td>82</td></tr><tr><td>9</td><td>OMOM</td><td><b>2d</b></td><td>C</td><td><b>3d</b></td><td>45</td></tr><tr><td>10</td><td>NHBoc</td><td><b>2e</b></td><td>A</td><td><b>3e</b></td><td>0</td></tr><tr><td>11</td><td>NHBoc</td><td><b>2e</b></td><td>B</td><td><b>3e</b></td><td>14</td></tr><tr><td>12</td><td>NHBoc</td><td><b>2e</b></td><td>C</td><td><b>3e</b></td><td>58</td></tr></tbody></table>

Conditions A: reaction performed in t-amylalcohol at 0.2 M. Conditions B: reaction performed in a DME/H₂O 4:1 mixture at 0.2 M. Conditions C: reaction performed in toluene at 0.2 M. a Isolated yield.

With these new non-symmetrical furan-2,5-dicarbinols **3b-e** in hand, we turned our attention to their application in Piancatelli rearrangement under Dy-catalyzed with microwave activation¹¹ and under subcritical water conditions²⁷ (100 °C and 100 bars) using the Zippertex technology.¹⁷

For the substrate **3b** with the *p*-methoxy group and under microwave conditions, the desired cyclopentenone **4b** was isolated in 46% yield with high level of diastereoselectivity (entry 1). The same reaction, carried out on a larger scale on Zippertex, led to **4b** in a very good 82% yield, albeit a slightly lower diastereoselectivity was observed (entry 2). Compare to *p*-methoxy group, the Piancatelli rearrangement on substrate **3c** with the *p*-(t-butyldimethylsilyl)oxy performed under microwave conditions on the same previous scale, that means 0.30 mmol scale, led to a lower 32% yield (entry 3). It should be noted that the same reaction carried out on a 0.60 mmol scale led to a further drop in yield (entry 4). These limitation when increasing the scale is something commonly encountered for these rearrangements and this is the reason why we have developed these rearrangements on Zippertex. In Zippertex conditions and on 1.4 mmole scale, cyclopentenone **4c** was isolated in 30% yield with also the formation of 5% yield of the cyclopentenone **5** with the deprotected phenolic moiety entry 5). In order to improve the efficiency of this rearrangement and the yield for the formation of **4c**, we have realized this reaction in Zippertex conditions using sodium dithionite (in a 4 mass percentage). Sodium dithionite (Na₂S₂O₄) is a well-known additive, for reaction of HMF derivatives, acting as a reductive

agent able to avoid the oxidative pathways which are involved in the oligomerization of HMF derivatives and the resulting humins formation.⁸b With the use of Na₂S₂O₄ as additive, we have observed a decrease for the formation of **4c** but associated to a very sharp increase of **5** with the deprotected phenolic moiety, isolated in 41% yield with good diastereoselectivity (entry 6). This concomitant Piancatelli rearrangement/TBS removing can be useful for the preparation of free phenolic derivatives.

Intrigued by this unusual deprotection of the OTBS group, the same experimental conditions were applied to 4-(*t*-butyldimethylsilyloxy)biphenyl, that means microwave activation or Zippertex conditions, and any deprotection could be observed on the phenolic moiety (scheme 1). This observation suggests that TBS deprotection occurs on one of the cationic intermediate, furanoxonium or pentadienyl cation,¹² during Piancatelli rearrangement and not just as a result of experimental conditions.

<figure><img src="image_5.png" /><figcaption>**Scheme 1** Control experiments for TBS deprotection of 4-(*t*-butyldimethylsilyloxy)biphenyl under microwave and Zippertex conditions. For condition details, see Table 3.</figcaption></figure>
<figure><img src="image_6.png" /><figcaption>**Table 3** Piancatelli studies on compounds **3b-e** under microwave activation and subcritical water conditions using the Zippertex technology.</figcaption></figure>

<table><thead><tr><th>Entry</th><th>R</th><th>Substrate</th><th>Cond.</th><th>Scale (mmole)</th><th>Additive (weight%)</th><th>Product</th><th>4b-e Yield (%)<sup>a</sup></th><th>4b-e d.r.<sup>b trans/cis</sup></th><th>5 Yield (%)<sup>a</sup></th><th>5 d.r.<sup>b trans/cis</sup></th></tr></thead><tbody><tr><td>1</td><td>OMe</td><td><b>3b</b></td><td>MW-100</td><td>0.3</td><td>-</td><td><b>4b</b></td><td>46</td><td>&gt; 95:5</td><td>-</td><td>-</td></tr><tr><td>2</td><td>OMe</td><td><b>3b</b></td><td>Zippertex</td><td>12.0</td><td>-</td><td><b>4b</b></td><td>82</td><td>90:10</td><td>-</td><td>-</td></tr><tr><td>3</td><td>OTBS</td><td><b>3c</b></td><td>MW-100</td><td>0.3</td><td>-</td><td><b>4c</b></td><td>32</td><td>&gt; 95:5</td><td>-</td><td>-</td></tr><tr><td>4</td><td>OTBS</td><td><b>3c</b></td><td>MW-100</td><td>0.6</td><td>-</td><td><b>4c</b></td><td>19</td><td>&gt; 95:5</td><td>-</td><td>-</td></tr><tr><td>5</td><td>OTBS</td><td><b>3c</b></td><td>Zippertex</td><td>1.4</td><td>-</td><td><b>4c</b></td><td>30</td><td>&gt; 95:5</td><td>5</td><td>&gt; 95:5</td></tr><tr><td>6</td><td>OTBS</td><td><b>3c</b></td><td>Zippertex</td><td>1.6</td><td>Na<sub>2</sub>S<sub>2</sub>O<sub>4</sub> (4)</td><td><b>4c</b></td><td>16</td><td>&gt; 95:5</td><td>41</td><td>&gt; 95:5</td></tr><tr><td>7</td><td>OMOM</td><td><b>3d</b></td><td>MW-100</td><td>0.3</td><td>-</td><td><b>4d</b></td><td>10</td><td>&gt; 95:5</td><td>-</td><td>-</td></tr><tr><td>8</td><td>OMOM</td><td><b>3d</b></td><td>Zippertex</td><td>1.9</td><td>Na<sub>2</sub>S<sub>2</sub>O<sub>4</sub> (4)</td><td><b>4d</b></td><td>66</td><td>92:8</td><td>10</td><td>&gt; 95:5</td></tr><tr><td>9</td><td>NHBoc</td><td><b>3e</b></td><td>MW-100</td><td>0.3</td><td>-</td><td><b>4e</b></td><td>60</td><td>90:10</td><td>-</td><td>-</td></tr><tr><td>10</td><td>NHBoc</td><td><b>3e</b></td><td>Zippertex</td><td>2.1</td><td>Na<sub>2</sub>S<sub>2</sub>O<sub>4</sub> (4)</td><td><b>4e</b></td><td>-</td><td>-</td><td>-</td><td>-</td></tr></tbody></table>

With the substrate **3d**, with the *p*-methoxymethyl group, the microwave conditions led to a complete conversion reaction but associated to a messy crude reaction mixture and only 10% yield of cyclopentenone **4d** can be isolated (entry 7). Gratifyingly, the use of Zippertex conditions led to clean conversion of substrate **3d** and the desired cyclopentenone **4d** was isolated in 66% yield (entry 8) with the formation of the deprotected phenolic **5** on 10% yield. In contrast to what was observed with substrates **3b-d** bearing OMe, OTBS, and OMOM substituents, the Piancatelli rearrangement performed on the substrate **3f** with an unprotected phenol functionality did not lead to the desired cyclopentenone (see ESI Part III†).

With the nitrogen substrate **3e**, with the NHBoc group, the microwave conditions led to a clean reaction and the desired desired cyclopentenone **4e** was isolated in 60% yield (entry 9). Unfortunately, the use of Zippertex conditions led to a complete conversion reaction but associated to a messy crude reaction mixture and any product could be isolated or identified from this crude reaction mixture (entry 10).

As some natural products with a hydroxylated cyclopentenone scaffold, such as isonitrin,²⁸ terrein,²⁹ pentenomycins³⁰ and EA-2801 compound isolated by our group from *Trichoderma atroviridae* as a symbiont of *Taxus baccata* tree,³¹ exhibited significant antimicrobial activities, we have evaluated the antimicrobial activities of the newly synthetized compounds **3b-3e**, **4b-4e** and **5** on a panel of pathogenic microorganisms, that means the gram-positive *Micrococcus luteus* ATCC.10240 and *Bacillus subtilis* ATCC.6633 and also gram-negative *Echerichia coli* ATCC.25922 using the inhibition zone technique (Kirby-Bauer Disk Diffusion Susceptibility Test; for the numeric values, see ESI Part VI†). The furanic compounds **3b**, **3c**, **3d**, and cyclopentenone derivatives **4d** and **5** exhibited a moderate broad-spectrum antimicrobial activity against *Micrococcus luteus*, *Bacillus subtilis* and *Echerichia coli*. Compound **3e**

showed a moderate antimicrobial activity only against gram-positive bacteria (*M. luteus* and *B. subtilis*), whereas cyclopentenones **4c** and **4e** were not active. The most promising antibiotic properties was observed for compound **4b**, which exhibited a significant and even more importantly selective inhibition against gram-negative *E. coli.*, suggesting the importance of the substitution onto the aromatic ring to modulate antimicrobial activities of cyclopentenones **4b-e** and **5**.

<figure><img src="image_7.png" /><figcaption>**Fig. 3** Microbial growth inhibition of compounds **3b-e**, **4b-e** and **5** towards the gram-positive *Micrococcus luteus* ATCC.10240 and *Bacillus subtilis* ATCC.6633 and also gram-negative *Echerichia coli* ATCC.25922 determined by the disk inhibition zone technique. Antimicrobial activity is expressed as the percentage of the inhibition obtained for various antibiotics (chloramphenicol *M. luteus* and *E. coli*, and penicillin for *B. subtilis*).</figcaption></figure>

<footnote><sup>a</sup> Isolated yield. <sup>b</sup> The *trans/cis* diastereoisomeric ratio (d.r.) was determined by ¹H NMR in the crude mixture.</footnote>
## Conclusions

In summary we have demonstrated that HMF, an essential and crucial renewable building block derived from biomass resources, can deliver non-symmetrical furan-2,5-dicarbinols under rhodium- or palladium-catalyzed 1,2-addition of aryboronic acids and in mild conditions to respect the very sensitive HMF reactivity. Under rhodium catalysis, the catalyst dirhodium tetraacetate carbenoid $[Rh_2(OAc)_4](IPr)$ prepared in situ with $[Rh_2(OAc)_4]$ and IPrHCl in basic media can be isolated at the end reaction and may be reused for another reaction cycle with comparable efficiency. These non-symmetrical furan-2,5-dicarbinols can be suitably used as starting materials for the Piancatelli rearrangement to produce highly functionalized cyclopentenones in a regio- and diastereoselective manner. The implementation of this Piancatelli rearrangement was realized on two experimental conditions, that means under Dy-catalyzed with microwave activation or under subcritical water conditions (100 °C and 100 bars) using the Zippertex technology. Depending of these two conditions for Piancatelli rearrangement, divergent but complementary results were obtained. This study implements the high synthetic potential of HMF as renewable raw starting material from biomass and other applications are under studies.

These synthetized bis-hydroxylated cyclopentenone derivatives exhibited significant antimicrobial activities against gram-positive bacteria *Micrococcus luteus*, *Bacillus subtilis* and gram-negative bacteria *Echerichia coli*. Most importantly, one of the synthetized cyclopentenone derivative display totally selective activities towards *Echerichia coli*, a gram-negative bacteria difficult to target, opens up new opportunities for the development of new antimicrobial agents.

## Author Contributions

JFB and GLG designed the experiments and supervised the project. GLG has provided Zippertex technology. SYS and CM performed chemical synthesis and characterization data of compounds. EVE performed single crystal X-ray analysis and interpreted the structural data. SYS carried out the Antibacterial assays. JFB wrote the manuscript and GLG, SYS and CM revised the manuscript. All the authors have given approval to the final version of the manuscript.

## Data availability

The authors confirm that the data supporting this article and the findings of this study have been included as part of the ESI.† The software used for drawing chemical structures is ChemDraw 23.0.

## Conflicts of interest

There are no conflicts to declare.

## Acknowledgements

The authors acknowledge the support of the "Centre National de la Recherche Scientifique" (CNRS) the "Institut de Chimie des Substances Naturelles" (ICSN) and the "Agence Nationale de la Recherche" (ANR) for financial support (AntiCyp project, Grant N° ANR-21-CE07-0055).

## Notes and references

1. C. Liu, H. Wang, A. M. Karim, J. Sun and Y. Wang, Catalytic fast pyrolysis of lignocellulosic biomass, *Chem. Soc. Rev.*, 2014, **43**, 7594-7623.

2. S. Chen, R. Wojcieszak, F. Dumeignil, E. Marceau and S. Royer, How Catalysts and Experimental Conditions Determine the Selective Hydroconversion of Furfural and 5-Hydroxymethylfurfural, *Chem. Rev.*, 2018, **118**, 11023-11117.

3. J. J. Bozell and G. R. Petersen, Technology development for the production of biobased products from biorefinery carbohydrates-the US Department of Energy's "Top 10" revisited, *Green Chem.*, 2010, **12**, 539-554.

4. K. I. Galkin and V. P. Ananikov, When Will 5-Hydroxymethylfurfural, the "Sleeping Giant" of Sustainable Chemistry, Awaken?, *ChemSusChem*, 2019, **12**, 2976-2982.

5. (a) R.-J. van Putten, J. C. van der Waal, E. de Jong, C. B. Rasrendra, H. J. Heeres and J. G. de Vries, Hydroxymethylfurfural, A Versatile Platform Chemical Made from Renewable Resources, *Chem. Rev.*, 2013, **113**, 1499-1597; (b) W. Fan, C. Verrier, Y. Queneau and F. Popowycz, 5-Hydroxymethylfurfural (HMF) in Organic Synthesis: A Review of its Recent Applications Towards Fine Chemicals, *Curr. Org. Synth.*, 2019, **16**, 583-614; (c) F. Chacón-Huete, C. Messina, B. Cigana and P. Forgione, Diverse Applications of Biomass-Derived 5-Hydroxymethylfurfural and Derivatives as Renewable Starting Materials, *ChemSusChem*, 2022, **15**, e202200328.

6. (a) M. Bicker, D. Kaiser, L. Ott and H. Vogel, Dehydration of D-fructose to hydroxymethylfurfural in sub- and supercritical fluids, *J. Supercrit. Fluids*, 2005, **36**, 118-126; (b) A. Corma, S. Iborra and A. Velty, Chemical Routes for the Transformation of Biomass into Chemicals, *Chem. Rev.*, 2007, **107**, 2411-2502; (c) A. A. Turkin, E. V. Makshina and B. F. Sels, Catalytic Hydroconversion of 5-HMF to Value-Added Chemicals: Insights into the Role of Catalyst Properties and Feedstock Purity, *ChemSusChem*, 2022, **15**, e202200412.

7. K. I. Galkin, E. A. Krivodaeva, L. V. Romashov, S. S. Zalesskiy, V. V. Kachala, J. V. Burykina and V. P. Ananikov, Critical Influence of 5-Hydroxymethylfurfural Aging and Decomposition on the Utility of Biomass Conversion in Organic Synthesis, *Angew Chem Int Ed Engl*, 2016, **55**, 8338-8342.

8. (a) A. Páez, H. A. Rojas, O. Portilla, G. Sathicq, C. A. M. Afonso, G. P. Romanelli and J. J. Martínez, Preyssler Heteropolyacids in the Self-Etherification of 5-Hydroxymethylfurfural to 5,5'-[Oxybis(methylene)]bis-2-furfural Under Mild Reaction Conditions, *ChemCatChem*, 2017, **9**, 3322-3329; (b) R. F. A. Gomes, Y. N. Mitrev, S. P. Simeonov and C. A. M. Afonso, Going Beyond the Limits of the Biorenewable Platform: Sodium Dithionite-Promoted Stabilization of 5-Hydroxymethylfurfural, *ChemSusChem*, 2018, **11**, 1612-1616.

9. (a) C. Rosenfeld, J. Konnerth, W. Sailer-Kronlachner, P. Solt, T. Rosenau and H. W. G. van Herwijnen, Current Situation of the Challenging Scale-Up Development of Hydroxymethylfurfural Production, *ChemSusChem*, 2020, **13**, 3544-3564; (b) M. Sajid, U. Farooq, G. Bary, M. M. Azim and X. Zhao, Sustainable production of levulinic acid and its derivatives for fuel additives and
chemicals: progress, challenges, and prospects, *Green Chem.*, 2021, **23**, 9198-9238.

10. (a) S. K. R. Patil and C. R. F. Lund, Formation and Growth of Humins via Aldol Addition and Condensation during Acid-Catalyzed Conversion of 5-Hydroxymethylfurfural, *Energy Fuels*, 2011, **25**, 4745-4755; (b) N. Shi, Q. Liu, X. He, G. Wang, N. Chen, J. Peng and L. Ma, Molecular Structure and Formation Mechanism of Hydrochar from Hydrothermal Carbonization of Carbohydrates, *Energy Fuels*, 2019, **33**, 9904-9915; (c) S. Constant, C. S. Lancefield, W. Vogelzang, R. K. Pazhavelikkakath Purushothaman, A. E. Frissen, K. Houben, P. de Peinder, M. Baldus, B. M. Weckhuysen, D. S. van Es and P. C. A. Bruijnincx, Molecular structure and composition elucidation of an industrial humin and its fractions, *Green Chem.*, 2024, **26**, 7739-7751.

11. F. Cacheux, G. Le Goff, J. Ouazzani, J. Bignon, P. Retailleau, A. Marinetti, A. Voituriez and J.-F. Betzer, The Piancatelli rearrangement of non-symmetrical furan-2,5-dicarbinols for the synthesis of highly functionalized cyclopentenones, *Org. Chem. Front.*, 2021, **8**, 2449-2455.

12. (a) C. Piutti and F. Quartieri, The Piancatelli rearrangement: new applications for an intriguing reaction, *Molecules*, 2013, **18**, 12290-12312; (b) C. Verrier, S. Moebs-Sanchez, Y. Queneau and F. Popowycz, The Piancatelli reaction and its variants: recent applications to high added-value chemicals and biomass valorization, *Org. Biomol. Chem.*, 2018, **16**, 676-687.

13. (a) G. Piancatelli, A. Scettri, G. David and M. D'Auria, A new synthesis of 3-oxocyclopentenes, *Tetrahedron*, 1978, **34**, 2775-2778; (b) D. Fisher, L. I. Palmer, J. E. Cook, J. E. Davis and J. Read de Alaniz, Efficient synthesis of 4-hydroxycyclopentenones: dysprosium(III) triflate catalyzed Piancatelli rearrangement, *Tetrahedron*, 2014, **70**, 4105-4110.

14. M. D'Auria, F. D'Onofrio, G. Piancatelli and A. Scettri, A convenient synthesis of 2-bromo-4-hydroxy-2-cyclopenten-1-ones and 3-bromo-4-hydroxy-2-cyclopenten-1-ones, *Gazz. Chim. Ital.*, 1986, **116**, 173-175.

15. A. Bredihhin, S. Luiga and L. Vares, Application of 5-Ethoxymethylfurfural (EMF) for the Production of Cyclopentenones, *Synthesis*, 2016, **48**, 4181-4188.

16. (a) M. Bourjot, C. Apel, M.-T. Martin, P. Grellier, V. H. Nguyen, F. Guéritte and M. Litaudon, Antiplasmodial, Antitrypanosomal, and Cytotoxic Activities of Prenylated Flavonoids Isolated from the Stem Bark of Artocarpus styracifolius, *Planta Med*, 2010, **76**, 1600-1604; (b) G. Marti, V. Eparvier, M. Litaudon, P. Grellier and F. Guéritte, A New Xanthone from the Bark Extract of Rheedia acuminata and Antiplasmodial Activity of Its Major Compounds, *Molecules*, 2010, **15**, 7106-7114; (c) A. Leverrier, M. E. T. H. Dau, P. Retailleau, K. Awang, F. Guéritte and M. Litaudon, Kingianin A: A New Natural Pentacyclic Compound from Endiandra kingiana, *Org. Lett.*, 2010, **12**, 3638-3641; (d) C. Rabhi, G. Arcile, L. Cariel, C. Lenoir, J. Bignon, J. Wdzieczak-Bakala and J. Ouazzani, Antiangiogenic-Like Properties of Fermented Extracts of Ayurvedic Medicinal Plants, *J. Med. Food*, 2015, **18**, 1065-1072; (e) A. Gallego, I. Metón, I. V. Baanante, J. Ouazzani, E. Adelin, J. Palazon, M. Bonfill and E. Moyano, Viability-reducing activity of Corylus avellana L. extracts against human cancer cell lines, *Biomed. Pharmacother.*, 2017, **89**, 565-572.

17. G. Arcile, J. Ouazzani and J.-F. Betzer, Efficient Piancatelli rearrangement on a large scale using the Zippertex technology under subcritical water conditions, *React. Chem. Eng.*, 2022, **7**, 1640-1649.

18. (a) R. Rajmohan, S. Gayathri and P. Vairaprakash, Facile synthesis of 5-hydroxymethylfurfural: a sustainable raw material for the synthesis of key intermediates toward 21,23-dioxaporophyrins, *RSC Advances*, 2015, **5**, 100401-100407; (b) C. A. Sutton, A.

Polykarpov, K. Jan van den Berg, A. Yahkind, L. J. Lea, D. C. Webster and M. P. Sibi, Novel Biobased Furanic Diols as Potential Alternatives to BPA: Synthesis and Endocrine Activity Screening, *ACS Sustainable Chem. Eng.*, 2020, **8**, 18824-18829.

19. M. Sakai, M. Ueda and N. Miyaura, Rhodium-Catalyzed Addition of Organoboronic Acids to Aldehydes, *Angew. Chem. Int. Ed.*, 1998, **37**, 3279-3281.

20. A. Fürstner and H. Krause, Practical Method for the Rhodium-Catalyzed Addition of Aryl- and Alkenylboronic Acids to Aldehydes, *Adv. Synth. Catal.*, 2001, **343**, 343-350.

21. P. M. P. Gois, A. F. Trindade, L. F. Veiros, V. André, M. T. Duarte, C. A. M. Afonso, S. Caddick and F. G. N. Cloke, Tuning the Reactivity of Dirhodium(II) Complexes with Axial N-Heterocyclic Carbene Ligands: The Arylation of Aldehydes, *Angew. Chem. Int. Ed.*, 2007, **46**, 5750-5753.

22. Crystallographic data for this compound have been deposited at the CCDC, Cambridge, UK, with the deposit number 2383332. The supplementary crystallographic data can be obtained free of charge from The Cambridge Crystallographic Data Centre via URL www.ccdc.cam.ac.uk/data_request/cif.

23. S. J. Na, B. Y. Lee, N.-N. Bui, S.-i. Mho and H.-Y. Jang, A new dirhodium tetraacetate carbenoid: Synthesis, crystal structure and catalytic application, *J. Organomet. Chem.*, 2007, **692**, 5523-5527.

24. A. F. Trindade, P. M. P. Gois, L. F. Veiros, V. André, M. T. Duarte, C. A. M. Afonso, S. Caddick and F. G. N. Cloke, Axial Coordination of NHC Ligands on Dirhodium(II) Complexes: Generation of a New Family of Catalysts, *J. Org. Chem.*, 2008, **73**, 4076-4086.

25. T. Yamamoto, T. Ohta and Y. Ito, Palladium-Catalyzed Addition of Arylboronic Acids to Aldehydes, *Org. Lett.*, 2005, **7**, 4153-4155.

26. C. Qin, H. Wu, J. Cheng, X. a. Chen, M. Liu, W. Zhang, W. Su and J. Ding, The Palladium-Catalyzed Addition of Aryl- and Heteroarylboronic Acids to Aldehydes, *J. Org. Chem.*, 2007, **72**, 4102-4107.

27. A. G. Carr, R. Mammucari and N. R. Foster, A review of subcritical water as a solvent and its utilisation for the processing of hydrophobic organic compounds, *Chem. Eng. J.*, 2011, **172**, 1-17.

28. A. Massarotti, F. Brunelli, S. Aprile, M. Giustiniano and G. C. Tron, Medicinal Chemistry of Isocyanides, *Chem. Rev.*, 2021, **121**, 10742-10788.

29. J. Goutam, G. Sharma, V. K. Tiwari, A. Mishra, R. N. Kharwar, V. Ramaraj and B. Koch, Isolation and Characterization of "Terrein" an Antimicrobial and Antitumor Compound from Endophytic Fungus Aspergillus terreus (JAS-2) Associated from Achyranthus aspera Varanasi, India, *Front. Microbiol.*, 2017, **8**.

30. S. A. Zisopoulou, S. Bousis, J. Haupenthal, J. Herrmann, R. Müller, A. K. H. Hirsch, D. Komiotis, J. K. Gallos and C. I. Stathakis, Synthesis and Biological Evaluation of Novel 2-Substituted -Analogues of (-)-Pentenomycin I, *Synlett*, 2020, **31**, 475-481.

31. E. Adelin, G. Le Goff, P. Retailleau, M. Bonfill and J. Ouazzani, Isolation of the antibiotic methyl (R,E)-3-(1-hydroxy-4-oxocyclopent-2-en-1-yl)-acrylate EA-2801 from Trichoderma atroviridae, *J. Antibiot.*, 2017, **70**, 1053-1056.