# On Reuben G. Jones synthesis of 2-hydroxypyrazines

Pierre Legrand, Yves Janin

► To cite this version:

Pierre Legrand, Yves Janin. On Reuben G. Jones synthesis of 2-hydroxypyrazines. Journées de Chimie Organique 2022, Nov 2022, Palaiseau, France. . hal-03932333

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Submitted on 10 Jan 2023

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Distributed under a Creative Commons Attribution 4.0 International License
# On Reuben G. Jones synthesis of 2-hydroxypyrazines

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Institut Pasteur

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Pierre Legrand, Yves L. Janin

Synchrotron SOLEIL, L'Orme des Merisiers, 91190 Saint-Aubin, France.

Structure et Instabilité des Génomes (StrlNG), Muséum National d'Histoire Naturelle, INSERM, CNRS, Alliance Sorbonne Université, 75005 Paris, France.

## A double condensation between 1,2-dicarbonyls and α-aminoamides upon treatment with sodium hydroxide at low temperature to give hydroxypyrazines, which is "plagued with regioselectivity issues"

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Jones, R.G. *J. Am. Chem. Soc.* **1949**, *71*, 78-81

Karmas, G.; Spoerri, P.E. *J. Am. Chem. Soc.* **1952**, *74*, 1580-1584

Konakahara, T.; Takagi, Y. *Heterocycles* **1978**, *9*, 1733-1739

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But, from α-ketoaldehyde, there is a degree of selectivity

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ORTEP of 4{1,2}

## A counter-intuitive regioselectivity

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## Hydroxypyrazines are "under-represented in chemical libraries"

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Coutant, E.P.; Gagnot, G.; Hervin, V.O.; Baatallah, R.; Goyard, S.; Jacob, Y.; Rose, T.; Janin, Y.L. *Chem. Eur. J.* **2020**, *26*, 948-958

## Optimization and mechanism insights

→ Solvent, base, concentration, addition speed, temperature, reaction time...

<figure><img src="image_13.png" /><figcaption>Table 1, condensation between 1{1} and 2{1}</figcaption></figure>

1) Stirring in solvent (S), 2) Addition of base (B) with a (N) concentration, at speed s (mmol/min) and temperature T (°C), 3) Stirring for t (h) (from T back to 20 °C), 4) Addition of 4 eq. of 37% HCl, 5) Work up (neutralization and extraction) and chromatography. All reactions run at a 13.1 mmol scale in 35 mL of solvent.

<table><caption>Table 2, condensation between 1{1} and 2{2}</caption><thead><tr><th>Entry</th><th>T (°C)</th><th>eq.</th><th>N</th><th>B</th><th>S</th><th>s</th><th>t (h)</th><th>Comments</th><th>%3</th><th>%4</th></tr></thead><tbody><tr><td>1</td><td>-78</td><td>2.5</td><td>6</td><td>NaOH</td><td>MeOH</td><td>65</td><td>2</td><td></td><td>52</td><td>4</td></tr><tr><td>2</td><td>-78</td><td>2.5</td><td>6</td><td>NaOH</td><td>MeOH</td><td>3.6</td><td>2</td><td></td><td>68</td><td>3</td></tr><tr><td>3</td><td>-78</td><td>2.5</td><td>2</td><td>NaOH</td><td>MeOH</td><td>2.3</td><td>2</td><td></td><td>71</td><td>4</td></tr><tr><td>4</td><td>-78</td><td>2.5</td><td>6</td><td>NaOH</td><td>MeOH</td><td>4.0</td><td>1</td><td></td><td>61</td><td>2</td></tr><tr><td>5</td><td>-78</td><td>2.5</td><td>6</td><td>NaOH</td><td>MeOH</td><td>4.6</td><td>4</td><td></td><td>70</td><td>4</td></tr><tr><td>6</td><td>-78</td><td>2.5</td><td>6</td><td>NaOH</td><td>MeOH</td><td>3.6</td><td>2</td><td>NH<sub>4</sub>Cl quench</td><td>60</td><td>1</td></tr><tr><td>7</td><td>20</td><td>2.5</td><td>-</td><td>NEt<sub>3</sub></td><td>MeOH</td><td>-</td><td>18</td><td></td><td>0</td><td>11</td></tr><tr><td>8</td><td>reflux</td><td>2.5</td><td>-</td><td>NEt<sub>3</sub></td><td>MeOH</td><td>-</td><td>22</td><td></td><td>0</td><td>8</td></tr><tr><td>9</td><td>-78</td><td>1.5</td><td>2</td><td>NaOH</td><td>MeOH</td><td>3.6</td><td>2</td><td>1.5 eq. of NaOH</td><td>34</td><td>18</td></tr><tr><td>10</td><td>-78</td><td>2.5</td><td>1.4</td><td>NEt<sub>3</sub>OH</td><td>MeOH</td><td>2.2</td><td>2</td><td></td><td>76</td><td>3</td></tr><tr><td>11</td><td>-78</td><td>2.5</td><td>2</td><td>NaOH</td><td>MeOH</td><td>3.6</td><td>2</td><td>1 eq. of 1{1}, 0.5 eq. of 2{1}</td><td>85</td><td>1</td></tr><tr><td>12</td><td>-78</td><td>2.5</td><td>2</td><td>NaOH</td><td>MeOH</td><td>3.6</td><td>2</td><td>0.5 eq. of 1{1}, 1 eq. of 2{1}</td><td>74</td><td>3</td></tr></tbody></table>

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<table><thead><tr><th>Entry</th><th>T (°C)</th><th>eq.</th><th>N</th><th>B</th><th>S</th><th>s</th><th>t (h)</th><th>Comments</th><th>%3</th><th>%4</th></tr></thead><tbody><tr><td>1</td><td>-78</td><td>2.05</td><td>6</td><td>NaOH</td><td>MeOH</td><td>2.9</td><td>2</td><td></td><td>40</td><td>4</td></tr><tr><td>2</td><td>-78</td><td>2.5</td><td>6</td><td>NaOH</td><td>MeOH</td><td>3.5</td><td>2</td><td></td><td>45</td><td>3</td></tr><tr><td>3</td><td>-78</td><td>2.5</td><td>6</td><td>NaOH</td><td>MeOH</td><td>0.5</td><td>2</td><td>Very slow addition</td><td>45</td><td>3</td></tr><tr><td>4</td><td>-78</td><td>2.5</td><td>6</td><td>NaOH</td><td>MeOH</td><td>2.7</td><td>2</td><td>Addition of water before 37% HCl</td><td>45</td><td>5</td></tr><tr><td>5</td><td>-78</td><td>2.5</td><td>2</td><td>NaOH</td><td>MeOH</td><td>3.1</td><td>2</td><td></td><td>51</td><td>7</td></tr><tr><td>6</td><td>-78</td><td>2.5</td><td>1</td><td>NaOH</td><td>MeOH</td><td>1.7</td><td>2</td><td>freezing at -78°C</td><td>58</td><td>3</td></tr><tr><td>7</td><td>-78</td><td>2.5</td><td>2</td><td>NaOH</td><td>EtOH</td><td>2.7</td><td>2</td><td>freezing at -78°C</td><td>33</td><td>2</td></tr><tr><td>8</td><td>-78</td><td>2.5</td><td>2</td><td>NaOH</td><td>iPrOH</td><td>2.7</td><td>2</td><td>freezing at -78°C</td><td>21</td><td>2</td></tr><tr><td>9</td><td>-78</td><td>2.5</td><td>2</td><td>LiOH</td><td>MeOH</td><td>1.6</td><td>2</td><td></td><td>56</td><td>6</td></tr><tr><td>10</td><td>-78</td><td>2.5</td><td>2</td><td>KOH</td><td>MeOH</td><td>3.1</td><td>2</td><td></td><td>54</td><td>4</td></tr><tr><td>11</td><td>-78</td><td>2.5</td><td>2</td><td>NEt<sub>3</sub></td><td>MeOH</td><td>3.0</td><td>2</td><td></td><td>0</td><td>6</td></tr><tr><td>12</td><td>reflux</td><td>2.5</td><td>2</td><td>EtONa/EtOH</td><td>MeOH</td><td>2.0</td><td>2</td><td>1 mm needle</td><td>38</td><td>25</td></tr><tr><td>13</td><td>-78</td><td>2.5</td><td>2.7</td><td>NB<sub>4</sub>OH</td><td>MeOH</td><td>0.9</td><td>2</td><td>Base diluted in water, freezing at -78°C</td><td>67</td><td>2</td></tr><tr><td>14</td><td>-78</td><td>2.5</td><td>0.75</td><td>NB<sub>4</sub>OH</td><td>MeOH</td><td>0.7</td><td>2</td><td>Base diluted in methanol</td><td>64</td><td>2</td></tr><tr><td>15</td><td>-78</td><td>2.5</td><td>0.75</td><td>NaOH</td><td>MeOH</td><td>2.7</td><td>2</td><td>Addition at 20°C</td><td>11</td><td>8</td></tr><tr><td>16</td><td>20</td><td>2.5</td><td>6</td><td>NaOH</td><td>MeOH</td><td>2.7</td><td>2</td><td>Fast addition at 20°C</td><td>55</td><td>2</td></tr><tr><td>17</td><td>20</td><td>2.5</td><td>1.4</td><td>NB<sub>4</sub>OH</td><td>MeOH</td><td>75</td><td>2</td><td></td><td>61</td><td>2</td></tr><tr><td>18</td><td>-78</td><td>2.5</td><td>2.8</td><td>NEt<sub>3</sub>OH</td><td>MeOH</td><td>1.1</td><td>2</td><td></td><td>65</td><td>3</td></tr><tr><td>19</td><td>-78</td><td>2.5</td><td>1.4</td><td>NEt<sub>3</sub>OH</td><td>MeOH</td><td>2.0</td><td>2</td><td></td><td>66</td><td>3</td></tr><tr><td>20</td><td>-78</td><td>2.5</td><td>1.4</td><td>NEt<sub>3</sub>OH</td><td>MeOH</td><td>2.0</td><td>3</td><td>1 eq. of 1{1}, 0.5 eq. of 2{2}</td><td>77</td><td>2</td></tr><tr><td>21</td><td>-78</td><td>2.5</td><td>1.4</td><td>NEt<sub>3</sub>OH</td><td>MeOH</td><td>2.0</td><td>2</td><td>0.5 eq. of 1{1}, 1 eq. of 2{2}</td><td>70</td><td>4</td></tr><tr><td>22</td><td>-78</td><td>2.5</td><td>1.4</td><td>NEt<sub>3</sub>OH</td><td>MeOH</td><td>2.0</td><td>2</td><td></td><td>65</td><td>3</td></tr><tr><td>23</td><td>-20</td><td>2.5</td><td>1.4</td><td>NEt<sub>3</sub>OH</td><td>MeOH</td><td>2.0</td><td>2</td><td>Addition at -20°C</td><td></td><td></td></tr></tbody></table>

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Minor

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strong base

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- H₂O

→ + H₂O

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R₂

R₂

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Major

## Side reactions (the base counter ion seems important)

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(water soluble)

(water soluble)

## Isomers are separable by chromatography, but at 60°C...

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Legrand, P.; Janin, Y. L. *Beilstein J. Org. Chem.* **2022**, *18*, 935-943

This project benefited from the Valoexpress funding calls of the Institut Pasteur. We thank Dr. Ahmed Haouz of the PF6 core facility of the Institut Pasteur for crystal freezing and data collection. We acknowledge SOLEIL (Saint-Aubin, France) for provision of synchrotron radiation facilities and we would like to thank the staff of PROXIMA-2 for assistance in using beamline.