# Evaluation of Aquivion® as Recyclable Superacid Solid Catalyst in the Oxidation of Furfurylamines with Hydrogen Peroxide to 3-Hydroxypyridines

Antoine Richieu, Philippe Bertrand

► To cite this version:

Antoine Richieu, Philippe Bertrand. Evaluation of Aquivion® as Recyclable Superacid Solid Catalyst in the Oxidation of Furfurylamines with Hydrogen Peroxide to 3-Hydroxypyridines. ChemistrySelect, 2023, 8 (42), 10.1002/slct.202303423. hal-05023037

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# Evaluation of Aquivion® as Recyclable Superacid Solid Catalyst in the Oxidation of Furfurylamines with Hydrogen Peroxide to 3-Hydroxypyridines

Antoine Richieu[a] and Philippe Bertrand*[a]

Furfurylamines are converted to 3-hydroxypyridines by 1) oxidation with hydrogen peroxide to ring-opened intermediates, with 2) a subsequent acid-mediated cyclization/aromatization catalysed by the acidic and recyclable Aquivion catalyst eliminating neutralization steps. For substituted furfurylamines,

the electronic effect of the substituents influence the conversion rate and this effect was correlated with Hammet's constants. Conversions up to 60% were obtained for the most reactive furfurylamines.

## Introduction

Pyridines are important building blocks in various applications. Although medicinal chemistry is probably the most important,[1] pyridines can be found in sustainable[2] or conductive[3] polymers, oxidants as the well-known pyridinium chlorochromate, pesticides, dyes[4] and cosmetics (oxidative hair dyes). Some examples of important bioactive compounds containing pyridine are presented in Figure 1, as well as compounds used in other applications. From an industrial point of view the production of niacin (Figure 1) from renewable resources remains a challenge.[5] The syntheses of pyridines are known from decades, with the Chichibabin synthesis using aldehydes and ammonia.[6] Other methods involve the reactions of primary amines with convenient (conjugated) carbonyl derivatives or intramolecular cyclization of advanced intermediates, requiring several steps or with limited sustainability.

A sustainable approach to pyridine can be to use furfurylamine (FURA) obtained from the furfural platform with various catalytic methods[7] or directly from the biomass.[8] The biotransformation of substituted furfurals was also described with transaminases.[9] The simplest transformation of FURA derivatives to pyridines is the HCl-catalysed oxidation with H₂O₂. This method works well and was often used to convert FURA to 3-hydroxypyridine but requires a work-up complicated by the high water solubility of the pyridine and starting material. It proves anyway useful for preparing labelled compounds.[10] Alternative transformations of furfural derivatives to pyridine include the conversion of 2-acylfurans with a source of nitrogen,[11–13] the use of dioxygen in dichloromethane with photoooxygenation,[14] the use of 2-hydroxymethyl-5-aminomethylfurans under electrochemical conditions,[15] or FURA and formol with concentrated HCl in water.[16] The HCl/H₂O₂ method was used in the field of surfactants where alkylpyridinium were obtained from 2-(furfurylamino) acetate,[17] showing that the method supports N-alkylated furfurylamines to give pyridinium salts. A sustainable approach to produce pyridinium salts from 5-hydroxymethylfurfural (HMF) was also described recently.[18] The mechanism of this atom-economy reaction has been established by several groups. Starting from furfural derivatives 1, a reductive amination can give the FURA derivatives 2 (Scheme 1). The oxidation of the furan ring to a 2,5-dihydroxy intermediate 3 is the most studied step. A more detailed mechanism for this oxidation was proposed involving hydroxyl radicals generated from H₂O₂ in the presence of vanadyl sulphate.[19]

<figure><img src="image_3.png" /><figcaption>Figure 1. Examples of pyridine-containing compounds.</figcaption></figure>

The formation of a 4,5-epoxydihydrofuran 4 was also proposed for the oxidation of furfural to malic acid with an additional Bayer-Villiger (BV) oxidation to remove the formyl group.[20] The BV reaction may occur as the first step.[21] Using dioxygen Kuo et al. proposed a trioxabicyclic intermediate 5 for this oxidation.[14] These three pathways give after rearrangement the same key intermediate 6 where the amine group finally reacts with the carbonyl group at the opposite end,

<footnote>[a] Dr. A. Richieu, Dr. P. Bertrand
team MediaCat, University of Poitiers IC2MP UMR CNRS 7285
4, rue Michel Brunet - TSA 51106. B27, 86073 Poitiers cedex 9 - France
E-mail: Philippe.bertrand@univ-poitiers.fr
Homepage: https://ic2mp.labo.univ-poitiers.fr/membres/bertrand-philippe/

Supporting information for this article is available on the WWW under
https://doi.org/10.1002/slct.202303423

© 2023 The Authors. ChemistrySelect published by Chemistry Europe and
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_4.png" /></figure>

<figure><img src="image_5.png" /><figcaption>**Scheme 1.** Proposed mechanisms for the oxidation and ring opening/closing of furfural derivatives to 3-hydroxypyridines</figcaption></figure>

usually an aldehyde, to afford the cyclic aminal **7** which upon dehydration gives the intermediate **8**. A final tautomerism yields the 3-hydroxypyridine **9**. Finally Gruber et al. used ethanolic ammonia with a catalytic amount of ammonium salt and proposed the enaminoimine **10** as an intermediate.

In our laboratory the oxidation of furfural has been used to prepare malic acid with $H_2O_2$ as the oxidant and an acidic catalyst.[22] The recyclable acid catalyst Aquivion® PFSA, per-fluorinated solid superacid ($H_0 = -12$),[23,24] was used in several transformations of furan derivatives with hydroxyl or ketone groups to produce furan ethers as biofuel additives,[25] to transform glycerol in oligomers[26] or alkyl glycosides.[27,28] The proton mobility in Aquivion® matrix is also exploited in the field of fuel cells.[29] The use of Aquivion® supported on silica to prepare aryl diazo compounds was demonstrated by Paris et al.[30] but its use alone for converting aliphatic amine was never described. Regarding oxidative conditions and the choice of amines, several methods have been described for the oxidation of amines to oximes or N-oxides with $H_2O_2$ and an additional negatively charged (per)oxometallic catalyst suggesting that $H_2O_2$ alone cannot oxidize the amine.[31] In light of these data we hypothesized that Aquivion® could be a valuable catalyst to replace HCl in the transformation of FURA to 3-hydroxypyridine (Scheme 2) and we report herein our study with Aquivion® prepared with several shapes and acidic

activities,[32] with $H_2O_2$ as the oxidant. The reaction was also investigated with substituted furfurylamines to measure the impact on the conversion rate of electron withdrawing and donating substituents.

## Results and Discussion

### Influence of the reaction conditions

The reference reaction (Scheme 2) with $H_2O_2$ 30%, HCl 3 N and FURA **2a** gave 100% conversion to pyridine **9a** in two hours. This method requires a neutralization step introducing more water and leading to a long extraction process due to the water solubility of the products. Replacing HCl that needs a work-up by a recyclable acidic solid catalyst like Aquivion® could simplify this work-up and fits better with sustainability conditions. Experiments with Aquivion® used alone gave no reaction and $H_2O_2$ used alone gave oxidation products not corresponding to the expected pyridine.

Regarding the postulated mechanism (Scheme 1) the mobility of the proton in the reaction media obtained with aqueous HCl is important for a fast conversion. With Aquivion® the pH of the reacting medium is around 7–8 due to FURA pKa, indicating that the protons are trapped in the matrix of the catalyst, possibly reducing the conversion rate. We speculated that this lower proton concentration in the reaction media may be compensated by the most acidic form of Aquivion® catalyst. Several morphologies and acidic loads of Aquivion® were available for this study (Table 1) and we started our study with the most acidic Aquivion PW72S (1.4 mmol $H^+/g$).

Using the reference reaction (Scheme 2), a first set of experiments was designed to modulate the ratios of FURA/$H_2O_2$ or FURA/Catalyst. In a typical experiment 50 µL of FURA (0.61 mmol) are mixed with 85 µL $H_2O_2$ (33% = 110 volume $O_2$, 4.6 eq. $H_2O_2$), diluted with 0.5 mL $H_2O$. To this solution was added an amount of catalyst corresponding to 10% mol $H^+$ relative to FURA (43.6 mg for PW72S, Table 2 entry 1). The reaction was heated at 100 °C and followed by HPLC (see experimental section, Figure 7). The profiles of the reactions described in Table 2 are presented in Figure 2. The results showed that after one hour the conversion reached a plateau. Although reaction times longer than 4 hours were sometimes performed, most of the experiments were stopped at 4 hours. As expected the reduction of the oxidant (Table 2 entry 2) lowered the conversion. The plateau observed after one hour of

<figure><img src="image_6.png" /><figcaption>**Scheme 2.** The reference reaction with furfurylamine.</figcaption></figure>

<table><caption>**Table 1.** Shapes and acidities of Aquivion® used in this study.</caption><thead><tr><th>Type</th><th>PW72S</th><th>PW79S</th><th>PW87S</th><th>mPW98</th><th>PW98</th></tr></thead><tbody><tr><td>H<sup>+</sup> [mmol/g]</td><td>1.40</td><td>1.27</td><td>1.13</td><td>1.03</td><td>1.0</td></tr><tr><td>Morphology</td><td>graphite-like</td><td>graphite-like</td><td>fine powder</td><td>micro pellets</td><td>pellets</td></tr></tbody></table>

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

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

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

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

<figure><img src="image_11.png" /></figure>
<figure><img src="image_12.png" /></figure>

<table><caption>**Table 2.** Influence of reaction conditions with Aquivion® PW72S as catalyst.</caption><thead><tr><th>Entry</th><th>FURA [mmol]</th><th>H<sub>2</sub>O<sub>2</sub></th><th>[% volume]</th><th>[µL]</th><th>[mmol (eq.)]</th><th>H<sup>+</sup> [mmol (%)]</th><th>H<sub>2</sub>O [mL]</th><th>time [h]</th><th>Conversion %</th><th>TOF [h<sup>-1</sup>]<sup>[e]</sup></th></tr></thead><tbody><tr><td>1</td><td>0.61</td><td>33</td><td>85</td><td>2.8 (4.6)</td><td>0.061 (10)</td><td>0.5</td><td>4</td><td>50.7</td><td>7,5</td><td></td></tr><tr><td>2</td><td>0.61</td><td>33</td><td>42.5</td><td>1.4 (2.6)</td><td>0.061 (10)</td><td>0.5</td><td>4</td><td>32.6</td><td>1,8</td><td></td></tr><tr><td>3</td><td>0.61</td><td>33</td><td>85</td><td>2.8 (4.6)</td><td>0.01525×4<sup>[b]</sup> (10)</td><td>0.5</td><td>4.5</td><td>44.3</td><td>4,9</td><td></td></tr><tr><td>4</td><td>0.61</td><td>33</td><td>170</td><td>5.6 (9.2)</td><td>0.305 (50)</td><td>0.8<sup>[c]</sup></td><td>4</td><td>42</td><td>4,3</td><td></td></tr><tr><td>5</td><td>3.05</td><td>33</td><td>425</td><td>14 (4.6)</td><td>0.305 (10)</td><td>0.85</td><td>4</td><td>36.3<sup>[d]</sup></td><td>2,6</td><td></td></tr><tr><td>6</td><td>0.61</td><td>33</td><td>85×4<sup>[a]</sup></td><td>2.8 (4.6)</td><td>0.061 (10)</td><td>5</td><td>4</td><td>45.5</td><td>6,6</td><td></td></tr><tr><td>7</td><td>0.61</td><td>33</td><td>85</td><td>2.8 (4.6)</td><td>0.122 (20)</td><td>5</td><td>4</td><td>35.3</td><td>4,6</td><td></td></tr></tbody></table>

[a] 85 µL more were added after 30 minutes over 1.5 hours (total 4 loads). [b] Started with 2.5% and 2.5% fractions more every 30 minutes over 1.5 hours.

[c] more water was added to have sufficient volume for the catalyst; [d] 60% after 5 days more at 20°C. [e] TOF is calculated at initial catalyst activity.

<figure><img src="image_13.png" /><figcaption>**Figure 2.** Profiles of the reactions described in Table 2.</figcaption></figure>

reaction may be due to a deactivation of the catalyst. Indeed the catalyst becomes dark in the reaction media after one hour at 100°C suggesting that an organic shell is formed possibly limiting the catalyst efficacy. We evaluated the addition of the 10%mol. catalyst in several 2.5%mol. loads (Table 2, entry 3) but the results were not conclusive. Adding more oxidant and more catalyst (Table 2, entry 4) did not improve the conversion. In fact more oxidant generated more side products lowering the selectivity and the conversion of FURA to PYR.

Scaling-up the reaction 5 fold (Table 2 entry 5) gave a conversion of 36% to be compared to 50% with lower amount. More water was added for this scale-up experiment to allow better mixing of the catalyst. When used in higher amounts the graphite-like morphology of PW72S makes it sticking to the glass vessel and upon heating appeared to behave as a supernatant, both properties leading to lower efficacy. Two other experiments were performed in more dilute conditions to manage this catalyst behaviour (Table 2 entries 6–7) with minor impact on the conversion. Overall these experiments showed that the conversion after 4 h at 100°C is between 30 and 50%.

For calculating the TOF we evaluated “the number of molecules reacting per active site per time”.[33] The proton

conductivity of Aquivion is highly dependent on the water content in its matrix,[34] that contributes to the formation of SO₃H clusters[35] where two populations of protons may exist, with fast and low diffusion properties that may affect the surface activity.[36] Indeed working in a water environment may give a better catalyst activity. In contrast the oxidative environment of our reaction may affect the catalyst activity over time.[29] Swelling over time in water and the number of uses may also impact the activity[37] that can be improved by reinforcing PFSA ionomer stability.[38] Having observed a diminishing activity we evaluated the TOF using the tangent method at initial conversion rate and extrapolated to one hour to have a per hour result. The protons in the Aquivion being strongly trapped in the matrix, the number of catalytic sites considered here was the number of protons per gram of catalysts as described by the Aquivion provider (e.g. 1.4 mmol H⁺/g for PW72S). Considering the initial conversion extrapolated at one hour the formula used for these calculations was nₚ/nₐ at one hour, with nₚ the number of moles of product formed (e.g. the pyridinol) and nₐ the number of catalyst active sites equal to the number of moles of H⁺ introduced with the catalyst. For table 1, entry 1, we obtain 75% for the extrapolated conversion corresponding to nₚ = 0.4575 mmol for nₐ = 0.061 mmol active site. The TOF calculated this way is thus 7.5 h⁻¹. This raw result does not consider if the substrate is able or not to diffuse within the catalyst matrix. If it was not the case and the reaction is limited to the surface of the solid the TOF value may be higher.

## Recycling of Aquivion®

Attempt to reuse the PW72S catalyst showed that after 4 cycles (including the first run) with conditions from Table 1, line 1, one hour reaction, the activity remains around 25% conversion (36.5, 25.5, 20.2 and 27.4, Figure 3). The catalyst became darker and darker with the number of tests to finally transform into a highly viscous liquid at 100°C after the last run. As mentioned previously, the swelling of the catalyst in water environment may explain this observation, not reported for reactions in water-free environments.[28]
<figure><img src="image_14.png" /></figure>

<figure><img src="image_15.png" /><figcaption>**Figure 3.** Percentage of pyridine produced after 4 use of recycled PW72S catalyst.</figcaption></figure>

## Comparison of Aquivion's®

The catalysts described in Table 1 were compared using the best conditions found for PW72S:FURA/Oxidant 1:4.6 (mol ratio) and 10% mol H⁺ relative to FURA for the Aquivion® catalyst. The conversion profile (time 0, 1 and 4 hours) are presented in Figure 4. The experiments were also made at higher scale and global concentrations with the aim of isolating the final product. Thus for 0.25 mL of FURA, 0.425 mL of H₂O₂ 33% were used, diluted with 0.425 mL H₂O. The amounts of catalysts were 218 mg for PW72S, 240 mg for PW79S, 270 mg for PW87S, 296 mg for mPW98 and 305 mg for PW98. After 1 hour the best conversion was found for PW98 (pellets, 1 mmol H⁺/g) > PW79S > mPW98 > PW72S > PW87S. The TOFs at initial conversion were respectively of 4,3 (PW98), 3,3 (PW79S), 2,6 (mPW98) and 1,6 (PW72S and PW87S). After 4 h of treatment the evolution of the conversion for PW98 appeared

lower than for its micro pellet version mPW98, the latter being equivalent to PW72S. Considering the conversion at 4 h all catalysts gave similar results except PW87S. The conversion with PW98 being at the end lower than expected regarding the initial slope of the curve, this suggests that the lower surface activity for this morphology is more sensitive to organic deposition. Indeed PW98 is obtained as a "blob" of catalyst and dark glue. The same can be said for PW79S whereas the other catalysts darkened and were glued but remains as separated particles. Despite these defaults PW98 is more practical to use compared to PW72S that is floating at the surface of the reaction mixture. The final aspect of the catalysts can be explained again by the known swelling effect or by amines or basic side products trapped in the catalyst's matrix.

## Effect of the temperature

It was demonstrated[39] that the decomposition of H₂O₂ is temperature dependent, 50% decomposition occurring at 70 °C after 4 h, the duration of our experiments. At 100 °C one can expect a faster decomposition and more hydroxyl radical formation. PW98 was selected for these experiments for its best conversion after 1 hour. The experiments at various temperatures (70, 80 and 90 °C, Figure 5) showed clearly the temperature dependence of the conversion rate, which can be attributed to less hydroxyl radical formation but with no reduction in the formation of side products. The slope of the curve suggests that working at higher temperature than 100 °C could slightly improve the conversion but it wasn't possible in our conditions.

## Effect of the furfurylamine substitution

As for any aromatic compound, the presence of substituents with their donating/withdrawing effects may have an impact on the furan reactivity. Electron donating groups (EDG) improve

<figure><img src="image_16.png" /><figcaption>**Figure 4.** Compared of Aquivion's® activities at 100 °C</figcaption></figure>

<figure><img src="image_17.png" /><figcaption>**Figure 5.** Relation between the % of conversion and the reaction temperature.</figcaption></figure>
<figure><img src="image_18.png" /></figure>

<figure><img src="image_19.png" /><figcaption>Figure 6. Correlation of conversion and σp Hammet constants.</figcaption></figure>

carboxypyridinol **9e**, as confirmed by adding again the reference acid (Figure S1, supplementary information, 2nd line).

Indeed an unknown di-substituted aromatic compound **9x**, similar to **9d**, is formed. The signal at 8.3 ppm being typical of a R₁CH=NR₂ imine function we speculated the possible formation of an imine resulting from the partial oxidation of the hydroxymethyl group to a formyl group. A small signal is observed at 9.3 ppm that could be an aldehyde. The oxidation of hydroxymethylfuran with H₂O₂ was described but with various catalysts[43,44] whereas other derivatives were oxidized with MnO₂[45,46] or SeO₂. It appeared that the chemical shifts for the unknown aromatic compound **9x** and for the alkenes in **2x** or **2y** were insensitive to pH variations suggesting pH stable compounds. The formation of the aldehyde in our reaction conditions was assessed by treating the reference hydroxymethylpyridinol with H₂O₂ in water. After 1 h 30 treatment a small peak at 9.3 ppm appeared that could correspond to the aldehyde, as observed in the reaction mixture with HMFA (Figure S2, supporting information). Unfortunately, after 4 h the product was completely degraded. This result suggested that over-oxidation of the hydroxymethyl group could occur after the cyclization. For **2d**, the conversion showed in Figure 6 considers the transformation to both **9d** and **9x**. Beside the starting material **2d** two other major compounds **2x,y** have proton chemical shifts in the 6–6.5 pm range indicating two other furans or the opened intermediates **6** (Scheme 1). The observed chemicals shifts are also similar to the reported but-2-en-1,4-diones prepared by oxidation of furans[47] and the formation of cyclized compounds similar to the intermediate **7** can also be postulated.[48] The ratio of **2d–2x–2y–9d–9x** was determined by ¹H NMR to be 1.3–1.0–0.5–0.6–1.0, suggesting a conversion of furan to pyridine for **2d** of approximatively 36% with a modest 14% conversion to the expected pyridinol **9d**.

## Using furfurylamine hydrochlorides

Amines can be found as hydrochloride salts for better stability on storage. This was the case for compounds **2e** and **2f**. The presence of the hydrochloric acid may be viewed as potentially accelerating the reaction. These two compounds were thus treated with carbonate salts prior starting the reaction. The furylethylamine **2f** was first treated with NaHCO₃ or K₂CO₃ (1 eq.) resulting in a pH of the starting solution of 6–7 and 8–9 respectively. The treatment with K₂CO₃ gave a pH similar to the one obtained for FURA itself, suggesting that this treatment is better suited to compare the reaction of **2f** with the previous ones. As expected the reaction performed with hydrochloride neutralization by NaHCO₃ was faster with a final conversion >70% (HPLC) whereas the initial hydrochloride neutralization with K₂CO₃ gave a lower final conversion of 14%. The corresponding selectivity and TOFs were correlated with this pH dependence of the conversion. The hydrochloride salt of the carboxylfurfurylamine **2e** was treated with 1 equivalent of K₂CO₃ prior starting the reaction. The final neutralized product may be a zwitterion due to the proton transfer of the COOH group to the NH₂ group and may thus also have an impact on the reaction. In this case the final conversion was found around 5% (NMR) only indicating that the electronic effect of the carboxyl group (or carboxylate) is as important as the final pH.

## Improving the work-up

FURA and pyridin-3-ol are highly soluble in water making their work-up difficult with water as the solvent. In the reference work a long extraction in continuous mode was performed with diethyl ether to afford the hydroxypyridine. Prior to the compound recovery eliminating the water used for the reaction is a key step. Searching for green solvent to extract these compounds we investigated the use of methyl tetrahydrofuran (MeTHF) which can be obtained from sustainable resources. Fortunately, MeTHF makes an azeotrope with water (10.4% water, boiling point at 71 °C) equivalent to the water-toluene azeotrope. We settled up a Dean-Stark apparatus and were able to eliminate almost all the water content. The final MeTHF solution was dried (MgSO₄) and HPLC analysis showed a profile similar to the crude reaction mixture.

## Conclusions

Aquivion® has been evaluated as a potential substitute for HCl as an acidic catalyst in the conversion of furfurylamines to pyridin-3-ols. By nature, this catalyst maintains the proton in its matrix to perform surface reactions even if the reaction medium is slightly basic. Indeed the lower proton mobility lowers the reaction rate compared to water soluble acids. When used with furfurylamines bearing oxidation-stable substituents the conversion can be up to 60% in our reaction conditions. As expected the use of hydrochloride salt of amines accelerate the reaction for substituents with EDG effect. As reported previously
<figure><img src="image_20.png" /></figure>

in other studies, the presence of EWG strongly reduces the reactivity of the furan ring. In the case of HMFA, the hydroxymethyl group introduces some instability regarding the oxidation conditions.

A deeper study is needed to better rationalize the results for HMFA, with the possible use of protecting groups as hydroxymethyl ethers to limit the oxidation or using oxidants that will not react with the hydroxymethyl group, like mCPBA (Scheme 1). The renewable preparation of 3-hydroxypyridine deserves particular attention as an intermediate toward a sustainable synthesis of niacin. The 3-hydroxyl group may be converted to a sulfonate leaving group to be used in Buchwald-type reaction.[49] Several patents describe a Sonogashira reaction to access 3-substituted pyridines bearing an alkyne group[50] useful for many transformations including eventually the conversion to a carboxamide group.

Experimental

Materials and methods

Furfurylamine was purchased from Aldrich and distilled before use. 3-hydroxypyridine was purchased from Aldrich. All other furfuryl-amines and hydroxypyridines were purchased from Enamines and used directly. EA: ethyl acetate; PE: petroleum ether; DCM: dichloro-methane. Solvents were used without purification. Osmosed water at 18 mS was used for all experiments. 35–70 µm silica was used for flash chromatography and preparative TLC. 250 µm silica gel plates were used for TLC analysis. All reactions were conducted under nitrogen, and concentrations were performed under reduced pressure using a rotary evaporator.

Synthetic procedures

General procedure for the conversion of furfurylamines to 3-hydroxypyridines. To a solution of furfurylamine (0.25 mL, 2.8 mmol) in H₂O (0.425 mL; osmosed 18.2 mS) in a 5 mL flask was added Aquivion® (weight corresponding to 10% mol H⁺: 305 mg for Aquivion® PW98). To this mixture was added 0.425 mL of H₂O₂ 33%. The solution was stirred at 300 rpm and heated at 100 °C with a temperature controller for 4 h. 10 µL aliquots were taken at fixed times and diluted with osmosed water to 1.5 mL in order to have a solution at 1 mg/mL average as samples for HPLC. After 4 hours reaction, the reaction was cooled and the solid catalyst was filtered off and washed with methanol 3 times and finally water.

For the preparation of 3-hydroxypyridine itself the final water solution can be concentrated under vacuum in a rotary evaporator to yield a solid. The catalyst was eventually reused for recycling studies.

General procedure for synthesis and purification of compound 9a. Treatment with CH₂Cl₂ of the solid obtained after elimination of the water removes mainly the remaining furfurylamine and better purification of the hydroxypyridine can be achieved by flash chromatography (SiO₂) with MeOH:CH₂Cl₂ 10:90 as the eluent.

Analyses

HPLC analyses were performed on a Hitachi Chromaster series 5000 equipped with a DAD detector and a temperature controlled oven. Data were acquired with the detection wavelength between 200

<figure><img src="image_21.png" /><figcaption>Figure 7. Chromatographic calibration of furfurylamine, 3-hydroxypyridine and reaction at 220 nm. left FURA, middle PYR, right typical 2D plot of UV detection and chromatogram of the reaction mixture. Top: typical UV response, Bottom: chromatogram in full spectrum mode (all wavelengths integrated). At the same concentrations PYR responds 1.587 times less than FURA.</figcaption></figure>

and 400 nm and the calibration and analytic wavelength was fixed at 220 nm. Calibration curves gave the linear AU responses per µmol of product. This data was used to calculate the HPLC yields after 4 h reaction and the corresponding selectivity. The chromatographic conditions were: column Waters Spherisorb S3 NH2 4.6×150 mm. Mobile phase for FURA: iPrOH:CH₃CN:H₂O (0,07% HClO₄) 95:2.5:2.5. Flow 1 mL/min (160 bar). Stop time 15 min. Mobile phase for other amines: same eluent with 0.5% TFA, 0.5 mL/min (80 bar). Retention times for FURA: 1.2 min; PYR: 1.4–1.5 min. Typical chromatograms for the conversion of furfurylamine to 3-hydroxypyridine are shown in Figure 7.

The calibration curves for FURA and 3-hydroxypyridine gave a response coefficient FURA:PYR of 1:0.63 for identical injected concentrations. All the percentages of conversion for experiments with FURA and PYR were calculated based on the HPLC data and areas for PYR were corrected by the response factor 1/0.63. The coefficient for the other couple of substituted FURA and PYR was calculated as well based on HPLC response at equivalent concentration and used for all calculations.

Supporting Information

HPLC chromatograms and eluting methods for all derivatives 2 and 9, calculations of relative UV response for all the couple of compounds, HPLC chromatograms at selected reaction times, ¹H NMR spectra reference compounds and of selected crude products from the reactions at 4 hours. Figure S1 and S2 cited in the manuscript.

Acknowledgements

Authors thanks FNS (Fond National Suisse) for funding A. R. postdoc, Ligue Contre le Cancer Comité Charente Maritime for financial support, CNRS and University of Poitiers.

Conflict of Interests

The authors declare no conflict of interest.
<figure><img src="image_22.png" /></figure>

Data Availability Statement

The data that support the findings of this study are available
from the corresponding author upon reasonable request.

Keywords: Catalyst • Furfurylamine • Hydroxypyridine • Acid • Oxidation

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Manuscript received: September 1, 2023