# The Piancatelli rearrangement of AMF (5-azidomethylfurfural) derivatives: a biobased opportunity for the synthesis of nitrogenous cyclopentenones

Clémentine Mayet, Jérôme Bignon, Jean-François Betzer

► To cite this version:

Clémentine Mayet, Jérôme Bignon, Jean-François Betzer. The Piancatelli rearrangement of AMF (5-azidomethylfurfural) derivatives: a biobased opportunity for the synthesis of nitrogenous cyclopentenones. Green Chemistry, 2025, 27 (22), pp.6420-6429. 10.1039/D4GC06306F. hal-05094524

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# The Piancatelli rearrangement of AMF (5-azidomethylfurfural) derivatives: a biobased opportunity for the synthesis of nitrogenous cyclopentenones

Clémentine Mayet, Jérôme Bignon and Jean-François Betzer*

Institut de Chimie des Substances Naturelles (ICSN), CNRS-UPR2301, Université Paris-Saclay, Gif-sur-Yvette, France. E-mail: jean-francois.betzer@cnrs.fr

In the field of renewable material to substitute petroleum-based products, one of the main areas of research is the study and transformation of small molecules derived from biomass into high added-value compounds. In this context, we report the preparation of 4-(azidomethyl)-cyclopentenones starting from AMF (5-azidomethylfurfural) derivatives, directly obtained from the well-known biosourced renewable material CMF (5-chloromethylfurfural). The Piancatelli rearrangement of these AMF derivatives, catalyzed by Dy(OTf)₃ and under microwave activation affords substituted cyclopentenones with two contiguous stereogenic centres, one of which is quaternary, with high diastereoselectivities. We were able to exploit the azidomethyl side chain to produce cyclopentenones with other nitrogenous functionalities, such as amine or triazole moieties. Moreover, these 4-(azidomethyl)-cyclopentenones exhibited relevant cytotoxic activities against HCT116 and HL60 cancer cell lines with nanomolar IC₅₀ values.

## Introduction

In recent decades, increased attention within scientific and industrial communities has been focused on decreasing the dependence of oil-based fossil raw material. Given the environmental impact, fossil fuels significantly contribute to carbon dioxide and other greenhouse gas emissions, and their extraction generates pollutants that degrade air and water quality. Thus, replacing fossil fuels with renewable materials is indeed a key element in developing a green and circular economy. The use of renewable biomass resources for the production of fuels, chemicals, and materials offers a valuable alternative to the fossil-based industry.¹ The two main lines of research in this field focus firstly, on the transformation of biomass into molecular building blocks and secondly, the conversion of these building blocks into high value-added compounds for many applications such as precursors for pharmaceutical compounds, 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%).² For this lignocellulosic biomass transformation, the production of furfural (FFR), furfuryl alcohol (FA), and 5-hydroxymethyl-furfural (HMF) provides versatile sustainable and valuable substitutes for petrochemical building blocks.³ HMF is regarded by the scientific community as a versatile building block platform and is considered as one of the "Top 14" bio-based building blocks listed by the US Department of Energy.⁴

Despite significant interest and the synthetic potential of HMF to replace petroleum-based products, this compound suffer from significant drawbacks. First, HMF is a polar and hydrophilic molecule that is not easily extracted from the aqueous media. Second, HMF is sensitive to the acidic conditions under which it is produced, leading to the formation of numerous by-products. Among their number, we can mentioned the OBMF, resulting from HMF dimerization, as already observed by Ananikov⁵ and Afonso.⁶ Another major drawback side reaction is the formation of levulinic acid associated to the concomitant release of formic

acid.⁷ 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 are formed by multiple combination of HMF hydrolyzed product and HMF itself to produce dark-colored solids material.⁸

In this context, other versatile sustainable and valuable substitutes of petrochemical compound have been prospected to identify biomass molecular building blocks for chemical applications, and the conversion of these building blocks into high value-added compounds. These studies have allowed to establish a more convenient and stable derivative of HMF, namely 5-(chloromethyl)furfural (CMF) 1.⁹ Among the benefits of CMF over HMF, CMF is produced in high yield under mild conditions directly from raw biomass, and its stability and hydrophobicity markedly facilitate isolation.¹⁰ Very recently, a comparative study of the potential between HMF and CMF was reported, clearly highlighting the advantages of CMF in terms of ease of production, stability, and reactivity.¹¹

Different synthetic transformations have been described, supporting the versatility of CMF as a building block platform.¹² From them, we have highlighted the substitution reaction of chloromethyl group into azidomethyl function in quantitative yield by substitution reaction, described for the first time by Mascal,¹³ thus providing a nitrogenous biobased furan derivative AMF 2.

Considering the derivatization of AMF 2, and taking advantage of azidomethyl, aldehyde and furan functionalities, only few selective synthetic transformations have been described. The aldehyde group could undergo participate in condensation reaction with ammonia for carbon–nitrogen bond formation (Fig 1a), to produce diamine derivatives after reduction.¹⁴ This same aldehyde group could also undergo a change in oxidation state, to the carboxylic acid or alcohol functionalities. For instance, Ananikov has described the transformation of AMF 2 into methyl 5-(azidomethyl)furan-2-carboxylate under the Corey-Gilman-Ganem oxidative esterification process using NaCN/MnO₂/MeOH, AcOH (Fig 1b).¹⁵ The same Ananikov has also benefited of the azide function to perform copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) to produce 1,4-substituted 1,2,3-triazole derivatives (Fig 1c).¹⁶ The use of bis-
terminal alkyne allowed the formation of bis-(1,2,3-triazolyl) aldehyde derivatives (not shown).¹⁷ The furan ring itself is able to undergo [4 + 2] cycloaddition with singlet oxygen to produce a 1,2,4-trioxolane intermediate, which is known to decompose into the corresponding butenolide derivatives. In this way, starting from AMF **2**, Mascal¹³ has described the two steps the synthesis of δ-aminolevulinic (Fig 1d), an effective non-toxic biodegradable herbicide and insecticide,¹⁸ but also a precursor for biosynthesis of tetrapyrroles, the core structure of porphyrins.¹³

<figure><img src="image_2.png" /><figcaption>**Fig. 1** Transformation of bio-sourced CMF **1** into AMF **2**, and aldehyde, azide and the furan ring reactivities of AMF **2**.</figcaption></figure>

Taking advantage of the great synthetic potential of AMF **2**, this compound, or its close furanic derivatives, could be converted into cyclopentenone with 4-(azidomethyl) and 4-hydroxy functionalities via a Piancatelli rearrangement.¹⁹ Despite the recent number of studies on the Piancatelli rearrangement and the effectiveness of this process to produce cyclopentenones from 2-furylcarbinols,²⁰ the C-5 substituted 2-furylcarbinol substrates have scarcely been explored. Except for the favoured intramolecular version with a tethered nucleophile at the C-5 position, the intermolecular Piancatelli rearrangement with C-5 substituted 2-furylcarbinol was only described with substrates containing a methyl,²¹ a phenyl²² and an ethoxymethyl group.²³ The challenge in using C-5 substituted 2-furylcarbinol as starting material for Piancatelli rearrangement is due to this C-5 substitution thereby significantly reducing the reactivity during the elementary step of catalytic cycle for the C-5 addition on furanoxonium ion intermediate.²⁰ In previous studies, we have shown that HMF derivatives, that means with a hydroxymethyl C-5 substitution, can deliver cleanly 5-substituted-4-hydroxymethyl-4-hydroxycyclopentenones.²⁴ 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. In this study, we would like to extend this synthetic methodology for the preparation of 5-substituted-4-(azidomethyl)-4-hydroxycyclopentenones, starting from (5-(azidomethyl)furan-2-yl)-carbinol derivatives.

## Results and discussion

Initial studies were conducted by examining the Piancatelli rearrangement directly on AMF **2** and on its simple reduced derivative **4** obtained in one step by selective reduction of aldehyde function into carbinol using sodium borohydride in 95% yield. The implemented experimental conditions for this Piancatelli rearrangement are those optimized for the transformation of furfuryl alcohol (FA) into the 4-hydroxy-2-cyclopentenone (HCP), that means the use of microwave (MW) activation. The use of MW irradiations allows to perform this rearrangement within a short time, thus leading to an efficient rearrangement while minimizing side reactions and the formation of humins.²⁵ Attempt to transform directly AMF **2**, or its hydrated form which could be generated *in situ* in the reaction medium, into cyclopentenone failed (Scheme 1). Under these conditions, no reaction was observed and the starting material was cleanly recovered unchanged. Only traces of a few new products could be observed, but none correspond to a cyclopentenic core structure. In contrast, with the use of carbinol derivative **4** we have observed a complete conversion of the starting material and the formation of the desired 4-(azidomethyl)-4-hydroxycyclopentenone **5** in 37% yield.

<figure><img src="image_3.png" /><figcaption>**Scheme 1** Attempted of Piancatelli rearrangement on AMF **1** and on its reduced derivative **4**. Piancatelli rearrangement performed on 1 mmol scale in t-BuOH/H₂O 1:5 mixture at 0.1 M under microwave (MW) heating for 5 min. NR = no reaction.</figcaption></figure>

Encouraged by this first result and in order to apply this methodology to the preparation of 5-substituted-4-(azidomethyl)-4-hydroxycyclopentenones, we next turned our attention reactions involving (5-(azidomethyl)furan-2-yl)-α-substituted carbinol derivatives. The first reaction pathway to introduce a phenyl substituent on aldehyde moiety of AMF **2** was performed with phenylmagnesium bromide. The desired carbinol adduct was obtained in a 85% yield, in the yield range of Grignard 1,2-addition reaction on carbonyl function for substrates bearing also an azide function.²⁶ Actually, it is well-known in the literature that organic azides may act as nitrogen sources for electrophilic amination reactions for organometallic species such as Grignard reagents leading to secondary amines.²⁷ For these reasons, we would like to take advantage of alternative milder conditions involving a transition metal-catalyzed 1,2-addition of arylboronic acids.

To identify the best reaction conditions of this 1,2-addition of benzeneboronic acid on AMF **2**, we have firstly used the conditions described by Miyaura, which implies the use of a rhodium(I) as catalyst combined with the bidentate phosphine
1,1'-bis(diphenylphosphanyl)ferrocene as ligand. The use of $Rh(acac)(CO)_2$ led to no reaction (Table 1, entry 1),²⁸ while the use of more labile ligand on rhodium, that means the use of $Rh(acac)(coe)_2$,²⁹ led to a low conversion but without any formation of desired product **6a** (entry 2).

<table><caption>**Table 1** Phenylmagnesium bromide addition and screening of transition metal-catalyzed 1,2-addition of benzene boronic acid onto AMF 2</caption><thead><tr><th>Entry</th><th>Catalyst</th><th>Ligand</th><th>Base</th><th>T (°C)</th><th>Time (h)</th><th>Conv. (%)</th><th>Yield 6a (%)<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>18</td><td>0</td><td>NA</td></tr><tr><td>2<sup>c</sup></td><td>Rh(acac)(coe)<sub>2</sub><br>(3 mol%)</td><td>dppf<br>(3 mol%)</td><td>-</td><td>80</td><td>18</td><td>30</td><td>0</td></tr><tr><td>3<sup>d</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>(1 eq.)</td><td>80</td><td>2</td><td>0</td><td>NA</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>(1 eq.)</td><td>90</td><td>0.5</td><td>100</td><td>0</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>(1 eq.)</td><td>60</td><td>24</td><td>70</td><td>&lt;5</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>100</td><td>20</td></tr><tr><td>7<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>20</td><td>16</td><td>80</td><td>60</td></tr></tbody></table>

The same reaction was then attempted with the use of rhodium(III) as catalyst combined with 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,³⁰ but no reaction was observed (entry 3). This 1,2-addition reaction was also described by Gois with the use of dirhodium(II) complexes with axial N-heterocyclic carbene (NHC) ligands,³¹ but while a total conversion was observed, any identified product could be isolated from the crude reaction mixture (entry 4). We next turned our attention to the use of palladium as catalyst, firstly described by Ohta with the use of Pd<sub>2</sub>(dba)<sub>3</sub>.CHCl<sub>3</sub>/PPh<sub>3</sub>³² and investigated by Wu and Cheng with the use of PdCl<sub>2</sub>/P(1-Naphtyl)<sub>3</sub>.³³ In the optimized conditions described by these authors, the use of Pd<sub>2</sub>(dba)<sub>3</sub>.CHCl<sub>3</sub>/PPh<sub>3</sub> led to the desired compound **6a** in low yield despite a satisfactory conversion (entry 5), while the use of PdCl<sub>2</sub>/P(1-Naphtyl)<sub>3</sub> led to a complete conversion but the desired compound **6a** was isolated in only 20% yield (entry 6). Gratifyingly, by changing the literature described conditions, that means to achieve the reaction at lower temperature, a cleaner reaction was observed

and the compound **6a** was isolated in a satisfactory 60% yield (entry 7). Thus, this study demonstrated that it is possible to perform 1,2-addition reactions of boronic acids on AMF, opening up a wide range of possibilities considering the large number of commercially available boronic acid derivatives.

The reactivity control of substrate **6a** for a Piancatelli rearrangement is a real challenge that requires overcoming three major difficulties. First, the low reactivity of furan substrate substituted at the C-5 position. Second, the control of the diastereoselectivity of the two newly formed stereogenic centers, including one quaternary center. And finally, preserving the stability and integrity of the alkyl azide functional group. First, we examined the reactivity of substrate **6a**, in the same microwave conditions (MW-190) applied on the unsubstituted substrate **4**, but despite a total conversion, only the decomposition of this substrate was observed (Part II in the ESI†, Table S1, entry 1). In contrast, under milder microwave conditions (MW-100), no reaction was observed and the starting material was cleanly recovered unchanged (Table 2, entry 1).

We then applied the conditions previously developed for the Piancatelli rearrangement for the C-5 substituted 2-furylcarbinol substrates that means the use of a catalytic amount of DyCl<sub>3</sub> and under microwave activation in a mixture of t-BuOH/H<sub>2</sub>O,²⁴ but a low conversion was observed associated to a poor NMR yield and modest diastereoisomeric ratio.

In order to improve this conversion reaction, the use of Dy(OTf)<sub>3</sub> as dysprosium catalyst,²¹b,²³,³⁴ and under microwave activation²⁴ was performed and allowed the formation of the desired cyclopent-2-enone **7a** with a satisfactory 46% yield and high diastereoselectivity still, despite an incomplete conversion (entry 3). All attempts to achieve completion that means the increase of catalyst loading, time, temperature, conventional heating (CH) and also the use of TFA as co-catalyst since a combination of Lewis and Brønsted acids has well-known to improve the yield of these rearrangements,²¹b and also the change of counteranion failed (Part II in the ESI†, Table S1, entries 6-11). We considered other lanthanide catalysts used for Piancatelli rearrangement like ytterbium³⁵ or cerium,³⁶ but no improvement was observed (entries 4-5), either under the described conditions or under our microwave conditions.

We next turned out our screening with the use of transition metal as catalyst for this Piancatelli rearrangement with the most commonly catalyst used, that means Sc(OTf)<sub>3</sub>,²¹b,³⁴a but once again an incomplete reaction was observed and unfortunately associated to a poor diastereoselectivity (entry 6). This lack of stereoselectivity can be attributed to the high reactivity of scandium triflate.³⁷ In order to moderate this reactivity, scandium trichloride, a milder catalyst, was considered for the first time to promote a Piancatelli rearrangement. With the use of ScCl<sub>3</sub> as catalyst, we have observed an incomplete but clean reaction, and the desired cyclopent-2-enone **7a** was obtained in 37% isolated yield with high diastereoselectivity (entry 7). An increasing of temperature or the use of scandium triflimide did not improve the conversion of the reaction (Part II in the ESI†, Table S1, entries 17-18). The use of the transition metal from the row below, yttrium,³⁸ as well as other transition metals previously used with success for

<footnote><sup>a</sup> Isolated yield.
<sup>b</sup> Reaction performed in a DME/H<sub>2</sub>O 1:1.6 mixture at 0.2 M.
<sup>c</sup> Reaction performed in a DME/H<sub>2</sub>O 3:2 mixture at 0.2 M.
<sup>d</sup> Reaction performed in a DME/H<sub>2</sub>O 4:1 mixture at 0.2 M.
<sup>e</sup> Reaction performed in a DME/H<sub>2</sub>O 5:1 mixture at 0.3 M.
<sup>f</sup> Reaction performed in Toluene at 0.3 M.
<sup>g</sup> Reaction performed in THF at 0.2 M.
Acac = acetylacetonate. Dppf = 1,1'-bis(diphenylphosphino)ferrocene. Coe = cyclooctene. IPrHCl = 1,3-bis(2,6-diisopropylphenyl) imidazolium chloride. Pfb = perfluorobutyrate. P(1-Nap)<sub>3</sub> = tri-1-naphthylphosphine.</footnote>
Piancatelli rearrangement in the literature, namely iron,³⁹ cobalt,⁴⁰ or even gold,⁴¹ did not improve the efficiency of the rearrangement of **6a** (entries 8-11).

The use of non-noble metals also known to trigger Piancatelli rearrangement, such as aluminum,³⁶ zinc,⁴² indium³⁶ and bismuth⁴³ also led to disappointing results for the formation of compound **7a** (entries 12-15). The use of alkaline earth metals, such as calcium⁴⁴ or barium,⁴⁵ are also well-known to promote Piancatelli rearrangement, but inadequate for our substrate **6a**, whether in standard conditions or under our microwave conditions (entries 16-17).

We have speculated that using a non-metallic Lewis acid such as B(C₆F₅)₃, applied recently in literature for Piancatelli rearrangement,⁴⁵⁻⁴⁶ might be more compatible with the azide function, but its use also led to a low reaction conversion associated with a low yield in the formation of compound **7a** (entry 18). Brønsted acids such as (C₆HF₄)B(OH)₂,⁴⁷ BINOL-derived phosphoric acid⁴⁸ or TFA,³⁴b,³⁵ were also considered, but despite the high level of conversion of substrate **6a** compound **7a** was formed in very low yield (entries 19-21).

We chose to retain the two conditions using Dy(OTf)₃ as lanthanide catalyst and ScCl₃ as transition metal catalyst under microwave activation. These two selected optimized conditions have been applied to a 1 mmol scale with sodium dithionite (in a 3 mass percentage). Sodium dithionite (Na₂S₂O₄) is a well-known additive, for HMF derivatives reactions, acting as a reductive agent able to avoid oxidative pathways which are involved in the oligomerization of HMF derivatives and the resulting humins formation.⁶b

For this 1 mmol scale experiment performed with Dy(OTf)₃ as lanthanide catalyst, the high diastereoselectivity was maintained but the yield decreased slightly to 34% yield. But more interestingly, we were able to recover 37% yield of the starting material **6a**, thus leading to **7a** in a 54% corrected yield, based on conversion of **6a** (entry 22).

For this same 1 mmol scale experiment performed with ScCl₃ as transition metal catalyst and Na₂S₂O₄ as additive, the yield is severely reduced to 18% (entry 23).

<figure><img src="image_4.png" /><figcaption>**Table 2** Screening and optimization reaction for Piancatelli rearrangement on (5-(azidomethyl)furan-2-yl)phenyl-carbinol **6a**ª</figcaption></figure>

<table><thead><tr><th>Entry</th><th>Catalyst</th><th>Conv. (%)</th><th>NMR Yield (%)<sup>b</sup></th><th>Isolated Yield (%)</th><th>d.r.<sup>c</sup><br><b>7a/8a</b></th></tr></thead><tbody><tr><td>1</td><td>-</td><td>0</td><td>-</td><td>-</td><td>-</td></tr><tr><td>2</td><td>DyCl<sub>3</sub></td><td>40</td><td>10</td><td>ND</td><td>80:20</td></tr><tr><td>3</td><td>Dy(OTf)<sub>3</sub></td><td>60</td><td>50</td><td>46</td><td>&gt;95:5</td></tr><tr><td>4</td><td>Yb(OTf)<sub>3</sub></td><td>70</td><td>30</td><td>ND</td><td>85:15</td></tr><tr><td>5</td><td>Ce(OTf)<sub>3</sub></td><td>80</td><td>20</td><td>ND</td><td>ND</td></tr><tr><td>6</td><td>Sc(OTf)<sub>3</sub></td><td>75</td><td>35</td><td>ND</td><td>80:20</td></tr><tr><td>7</td><td>ScCl<sub>3</sub></td><td>70</td><td>40</td><td>37</td><td>95:5</td></tr><tr><td>8</td><td>Y(OTf)<sub>3</sub></td><td>65</td><td>35</td><td>ND</td><td>90:10</td></tr><tr><td>9</td><td>Fe(OTf)<sub>3</sub></td><td>80</td><td>20</td><td>ND</td><td>90:10</td></tr><tr><td>10</td><td>Co(OTf)<sub>3</sub></td><td>70</td><td>30</td><td>ND</td><td>85:15</td></tr><tr><td>11</td><td>HAuCl<sub>4</sub>.3H<sub>2</sub>O</td><td>100</td><td>10</td><td>ND</td><td>ND</td></tr><tr><td>12</td><td>Al(OTf)<sub>3</sub></td><td>85</td><td>25</td><td>ND</td><td>85:15</td></tr><tr><td>13</td><td>Zn(OTf)<sub>3</sub></td><td>65</td><td>10</td><td>ND</td><td>ND</td></tr><tr><td>14</td><td>In(OTf)<sub>3</sub></td><td>80</td><td>20</td><td>ND</td><td>90:10</td></tr><tr><td>15</td><td>Bi(OTf)<sub>3</sub></td><td>75</td><td>15</td><td>ND</td><td>ND</td></tr><tr><td>16</td><td>Ca(NTf)<sub>2</sub></td><td>0</td><td>NA</td><td>NA</td><td>NA</td></tr><tr><td>17</td><td>Ba(OTf)<sub>3</sub></td><td>70</td><td>20</td><td>ND</td><td>ND</td></tr><tr><td>18</td><td>B(C₆F₅)<sub>3</sub></td><td>50</td><td>25</td><td>ND</td><td>90:10</td></tr><tr><td>19<sup>d</sup></td><td>(C₆HF₄)B(OH)<sub>2</sub></td><td>70</td><td>0</td><td>NA</td><td>NA</td></tr><tr><td>20<sup>e</sup></td><td>BINOL.PA</td><td>90</td><td>25</td><td>ND</td><td>ND</td></tr><tr><td>21<sup>f</sup></td><td>TFA</td><td>100</td><td>15</td><td>ND</td><td>90:10</td></tr><tr><td>22<sup>g</sup></td><td>Dy(OTf)<sub>3</sub></td><td>60</td><td>50</td><td>34<sup>h</sup></td><td>&gt;95:5</td></tr><tr><td>23<sup>g</sup></td><td>ScCl<sub>3</sub></td><td>65</td><td>25</td><td>18</td><td>95:5</td></tr></tbody></table>

ª Reactions performed on 0.2 mmol scale at 0.1 M. ᵇ Yield determined by ¹H NMR with trimethoxybenzene as internal standard added at the end of the reaction. ᶜ The diastereoisomeric ratio (d.r.) was determined by ¹H NMR on the crude mixture. ᵈ (C₆HF₄)B(OH)₂ (20 mol%) at CH-90 for 24 h. ᶠ CH-50 for 18 h. ᶠ TFA (20 mol%), ᵉ 1 mmole scale and sodium dithionite (Na₂S₂O₄) in a 3 mass percentage was added. ᵉh 37% of the starting material **6a** was recovered. MW = microwave heating. CH = conventional heating. ND = not determined. NA = not applicable.

The *trans* relative stereochemistry of cyclopentenone **7a** is the result of relative stabilities of pentadienyl cations intermediates and the pericyclic conrotatory 4π-electrocyclization process, closely related to the Nazarov reaction (Part III in the ESI†, Scheme S1).⁴⁹ This *trans* relative stereochemistry was assigned based upon NMR NOESY 2D-experiments (Part IX in the ESI†). Thus, for the continuation of our study, we examined the scope of (5-(azidomethyl)furan-2-yl)-α-substituted carbinol derivatives **6**. These substrates were prepared starting from AMF **2**, using the two identified conditions in Table 1, that means the use of Grignard reagents or the palladium-catalyzed 1,2-addition of boronic acids. The details of these preparations are provided in Supporting Information (Part VI in the ESI†).

Under the optimized reaction conditions for Piancatelli rearrangement (Table 2, entry 3), that means Dy(OTf)₃ 10 mol%, t-BuOH/H₂O 5:1, microwave heating, 100 °C, 1.5 h, the variety of (5-(azidomethyl)furan-2-yl)-α-substituted carbinols **6a-n** delivered the expected C5-substituted 4-(azidomethyl)-4-hydroxycyclopentenone **7a-n** in moderate to good isolated yields (Scheme 2). The rearrangement of carbinols **6a-f** into cyclopentenones **7a-f** does not appear to depend on the steric hindrance of the substituent R, same range as yields was observed, along with good diastereoselectivities. The best yield was obtained with substrate **6d** containing a 9-phenanthrenyl substituent that provides cyclopentenone **7d** in 62% yield.

The reaction was proven to be quite general, since both electron-withdrawing and electron-donating groups were tolerated on the aromatic substituent of **6**, affording products **7**.
in a same range of yields. However, with electron-withdrawing group a slight decrease of diastereoselectivity was observed, decrease that can be attributed to the higher acidity of the proton in the benzylic position, specifically for compound **7j**

with the perfluorophenyl substation. The high level of diastereoselectivity was maintained with electron-donating groups for compounds **7k-m**.

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

AMF
2

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

<figure><img src="image_7.png" /></figure>

6a-n

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

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

7a-n

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

**7a**, 46% yield
> 95:5 d.r.

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

**7b**, 20% yield
> 95:5 d.r.

<figure><img src="image_12.png" /></figure>

**7c**, 25% yield
> 95:5 d.r.

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

**7d**, 62% yield
> 95:5 d.r.

<figure><img src="image_14.png" /></figure>

**7e**, 40% yield
> 95:5 d.r.

<figure><img src="image_15.png" /></figure>

**7f**, 28% yield
> 95:5 d.r.

<figure><img src="image_16.png" /></figure>

**7g**, 33% yield
> 95:5 d.r.

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

**7h**, 35% yield
75:25

<figure><img src="image_18.png" /></figure>

**7i**, 22% yield
95:5 d.r.

<figure><img src="image_19.png" /></figure>

**7j**, 36% yield
> 80:20 d.r.

<figure><img src="image_20.png" /></figure>

**7k**, 42% yield
95:5 d.r.

<figure><img src="image_21.png" /></figure>

**7l**, 29% yield
> 95:5 d.r.

<figure><img src="image_22.png" /></figure>

**7m**, 34% yield
> 95:5 d.r.

<figure><img src="image_23.png" /></figure>

**7n**, 31% yield
50:50 d.r.

<caption>**Scheme 2** Substrate scope in the Dy(OTf)₃-catalyzed MW-100 °C Piancatelli rearrangement of (5-(azidomethyl)furan-2-yl)-α-substituted carbinols **6a-n**.</caption>

The use of 2-thienyl as heteroaryl group resulted in a loss of diastereoselectivity for compound **7n**. We would like also to mention that when the aryl group was changed by an alkyl substituent, such as *n*-butyl, *t*-butyl or cyclopropyl substituent, no reaction was observed and the starting material was cleanly recovered unchanged. The same Piancatelli rearrangements were also performed on carbinols **6** with optimized reaction conditions for ScCl₃ as catalyst (Table 2, entry 7). However, as observed for compound **6a**, slightly lower yields were observed for the formation of cyclopentenones **7** compare to the use of Dy(OTf)₃ as catalyst (Part VII in the ESI†).

In the case of substrate **6l**, in addition to the formation of cyclopentenone **7l**, we also observed the formation of aldehyde compound **9** in 5% yield, which is the outcome from the decomposition of the primary alkyl azide followed by alpha

hydrogen deprotonation to generate an aldimine which, upon hydrolysis, releases the aldehyde function (Scheme 3). This oxidative conversion of primary azides to aldehydes, useful for the installation of aldehydes from a non-oxygenated precursory functional group, were previously described using molybdenum xanthate⁵⁰ or iron(III) chloride⁵¹ in harsh reaction conditions, and more recently under milder conditions involving the use of metalloproteins such as cytochrome P450s and myoglobin.⁵²
<figure><img src="image_24.png" /><figcaption>**Scheme 3** Denitrogenative reaction of 6l leading to the formation of aldehyde compound 9.</figcaption></figure>

To confirm the relative stability of this alkyl azide function under our reaction conditions, the azide function has been set to a sp²-hybridized carbon center, both on the aromatic and vinylic parts of the cyclopentenone, leading to better yields in the Piancatelli rearrangement (Part IV† the ESI). To overcome this issue of azide function stability, other nitrogen functions such as aliphatic or aromatic amines, and protected amine function in phthalimide derivative have been considered, but all attempts for Piancatelli rearrangement on these substrates failed (Part V† the ESI).

To showcase the synthetic versatility of the obtained cyclopentenones **7** with the azidomethyl side chain, further functional group elaborations were performed (Scheme 4). First, the carbonyl function was selectively reduced towards the double bond and azide function under Luche⁵³ conditions to provide the secondary alcohol **10** in 76% yield, without stereoselectivity as previously observed in literature for similar substrate.⁵⁴ Azide and double reduction was performed *via* the mild catalytic hydrogenation in the presence of Boc₂O,⁵⁵ which gave the cyclopentanone **11** with the *N*-Boc-protected-methyl side chain in 40% yield.

Moreover, subjecting **7a** and **7e** to the conditions of copper-catalyzed azide-alkyne cycloaddition (CuAAC)⁵⁶ with phenylacetylene resulted in the formation of cyclopentenones with a triazole-methyl side chain **12** and **13** in 88% and 99%, respectively.

<figure><img src="image_25.png" /><figcaption>**Scheme 4** Synthetic transformation of 4-(azidomethyl)-cyclopentenones 7.</figcaption></figure>

As some natural products with a hydroxylated cyclopentenone scaffold, such as the marine natural products trichodenone A⁵⁷ or didemnenone D⁵⁸ and Terrein⁵⁹ from the fungi *Aspergillus terreus* exhibited significant cytotoxicity against cancer cell

lines, we have evaluated the cytotoxicity activities of the newly synthesized compounds **7a-n**. Moreover, we also intend to take benefit of the azidomethyl side chain as many well-known chemotherapeutic drugs contain these metabolically active azide groups.⁶⁰

Biological preliminary results are highly promising as compounds **7a-n** displays antiproliferative effects at nanomolar concentrations for two different tumor cell lines. Concentrations inducing 50% cell growth inhibition (IC₅₀) are given in Table 3 and 4. The first observation must be noticed is that substitution by an aromatic moiety on C5 position of cyclopentenone is necessary, as the unsubstituted compound **5** does not exhibit cytotoxic activity.

For all the C5 substituted compounds, the antiproliferative effects are more pronounced on HL60 non adherent leukemia cell line. Moreover, some compounds such as **7c-d** and **7h** behave differently towards these two tumor cell lines, which may indicate some tissue specific antiproliferative activity of these molecules.

<table><caption>**Table 3** In vitro anti-proliferative activity (IC₅₀) of compounds 5 and 7a-n for HCT116 cancer cell line (human colon cancer cell line)</caption><thead><tr><th>Compound</th><th>IC<sub>50</sub> (nM)<sup>a</sup></th><th>Compound</th><th>IC<sub>50</sub> (nM)<sup>a</sup></th></tr></thead><tbody><tr><td><strong>5</strong></td><td>&gt; 10000</td><td><strong>7h</strong></td><td>2462 ± 316</td></tr><tr><td><strong>7a</strong></td><td>2607 ± 243</td><td><strong>7i</strong></td><td>742 ± 16</td></tr><tr><td><strong>7b</strong></td><td>1570 ± 241</td><td><strong>7j</strong></td><td>811 ± 43</td></tr><tr><td><strong>7c</strong></td><td>2700 ± 222</td><td><strong>7k</strong></td><td>294 ± 129</td></tr><tr><td><strong>7d</strong></td><td>1080 ± 144</td><td><strong>7l</strong></td><td>3163 ± 243</td></tr><tr><td><strong>7e</strong></td><td>491 ± 16</td><td><strong>7m</strong></td><td>1320 ± 16</td></tr><tr><td><strong>7f</strong></td><td>3295 ± 880</td><td><strong>7n</strong></td><td>568 ± 29</td></tr><tr><td><strong>7g</strong></td><td>3724 ± 465</td><td></td><td></td></tr></tbody></table>

<table><caption>**Table 4** In vitro anti-proliferative activity (IC₅₀) of compounds 5 and 7a-n for HL60 cancer cell line (human leukemia cell line)</caption><thead><tr><th>Compound</th><th>IC<sub>50</sub> (nM)<sup>a</sup></th><th>Compound</th><th>IC<sub>50</sub> (nM)<sup>a</sup></th></tr></thead><tbody><tr><td><strong>5</strong></td><td>10200 ± 180</td><td><strong>7h</strong></td><td>126 ± 3.7</td></tr><tr><td><strong>7a</strong></td><td>145 ± 4.3</td><td><strong>7i</strong></td><td>144 ± 64</td></tr><tr><td><strong>7b</strong></td><td>220 ± 33</td><td><strong>7j</strong></td><td>194 ± 19</td></tr><tr><td><strong>7c</strong></td><td>136 ± 10.6</td><td><strong>7k</strong></td><td>535 ± 43</td></tr><tr><td><strong>7d</strong></td><td>131 ± 8.4</td><td><strong>7l</strong></td><td>149 ± 7.5</td></tr><tr><td><strong>7e</strong></td><td>104 ± 1.5</td><td><strong>7m</strong></td><td>190 ± 16</td></tr><tr><td><strong>7f</strong></td><td>264 ± 64</td><td><strong>7n</strong></td><td>330 ± 10</td></tr><tr><td><strong>7g</strong></td><td>160 ± 2.8</td><td></td><td></td></tr></tbody></table>

## Conclusions

In conclusion, we have shown for the first time that AMF (5-azidomethylfurfural) derivatives, a biosourced renewable material directly obtained from CMF (5-chloromethylfurfural), could lead to nitrogenous cyclopentenones with an azidomethyl side chain. These cyclopentenones with two contiguous stereogenic centres, one of which is quaternary, were in moderate to good yields with high diastereoselectivities *via* a Piancatelli rearrangement. The use of ScCl₃ as transition metal catalyst was used for the first time to catalyse this

<footnote>a Data are the mean ± standard error (SEM) of three independent experiments.</footnote>

<footnote>a Data are the mean ± standard error (SEM) of three independent experiments.</footnote>
rearrangement, even better results were obtained using lanthanide Dy(OTf)₃ as catalyst.

The introduction of this azido group is particularly innovative in these Piancatelli rearrangements. On the one hand, it allows taking advantage of the high synthetic potential of this functional group, which can be derivatized into a wide variety of other functionalities and for the synthesis of a range of nitrogen-based scaffolds of biologically active compounds and functional materials. Moreover, these 4-(azidomethyl)-cyclopentenones 7 exhibited relevant cytotoxic activities against HCT116 and HL60 cancer cell lines with nanomolar IC₅₀ values.

This work has led to the first proof of concept that a nitrogen-
containing substrate can be involved in a Piancatelli
rearrangement. We have no doubt that this methodology,
based on Piancatelli rearrangement on substrate with azido
function, will subsequently be used to construct other nitrogen
derivatives with multiple applications.

Author Contributions

JFB designed the experiments and supervised the project. CM
performed all chemical synthesis and characterization data of
compounds. JB carried out the bioassays for cytotoxicity
activities. JFB wrote the manuscript 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. The dose-response curves were plotted with Graph Prism
software and the IC50 values were calculated from these
polynomial curves with the same software.

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).

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