# Ring-opening of 3-substituted azetidines as an entry to triazolodiazepines

Melvin Raulin, Bruno Drouillat, Jérome Marrot, François Couty, Karen Wright

► To cite this version:

Melvin Raulin, Bruno Drouillat, Jérome Marrot, François Couty, Karen Wright. Ring-opening of 3-substituted azetidines as an entry to triazolodiazepines. Tetrahedron Letters, 2026, 177, pp.155975. 10.1016/j.tetlet.2026.155975. hal-05507181

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# Ring-Opening of 3-substituted Azetidines as an Entry to Triazolodiazepines

Melvin Raulin, Bruno Drouillat, Jérome Marrot, François Couty and Karen Wright*

Université Paris-Saclay, UVSQ, CNRS, UMR 8180, Institut Lavoisier de Versailles, 78000, Versailles, France

**Abstract:** Prochiral 3-substituted azetidines bearing a chiral *N*-substituent may undergo ring-opening reactions with electrophiles, such as benzyl or propargyl bromide, to generate diastereomeric products with moderate selectivity. In the case of the resulting 3-bromo-*N*-propargylamines, reaction with sodium azide followed by intramolecular azide-alkyne cycloaddition led to substituted tetrahydro triazolodiazepine derivatives. These findings expand the utility of azetidine scaffolds for the construction of more complex nitrogen-containing heterocycles.

## Introduction

Azetidines are highly strained yet bench-stable four-membered nitrogen heterocycles which offer substantial synthetic utility in both diversity-oriented synthesis and medicinal chemistry. Recent advances have enabled the synthesis of azetidines with a wide variety of substitution patterns, including enantioenriched derivatives.¹ The inherent ring strain in these molecules facilitates nucleophilic ring-opening reactions, which can be harnessed for the construction of structurally complex, biologically relevant scaffolds. Previous studies have shown that *N*-alkyl azetidines may react to give azetidinium ions² (e.g. with chloroformates, alkyl halides, alkyl sulfonates, triphosgene, cyanogen bromide) which can then evolve further by ring cleavage or ring-expansion reactions.³ Enantioselective ring-opening was observed when a SPINOL-derived phosphonate ligand acted as a chiral counteranion for azetidinium cations substituted at C-3.⁴ Approaches using chiral *N*,*N*-dioxide, urea or squaramide catalysts to direct azetidinium-opening selectively have also been successful.⁵

It is rather well known that ring-opening can be a competing side reaction during synthetic transformations of azetidines in the presence of electrophiles. Following this observation, a systematic study of these reactions was carried out, but did not address possible stereochemical outcomes.⁶ª This reactivity has been exploited to access functionalised linear amines. ⁶ᵇ,ᶜ We recently reported that *N*-alkyl azetidines bearing a chiral substituent at the nitrogen atom and a variable substituent at C-3, acting as a prochiral centre, may undergo von Braun ring-opening reactions with cyanogen bromide in a diastereoselective manner (up to 80:20 d.r.), yielding 3-bromo-*N*-alkyl cyanamides (Scheme 1a) without any additional chiral auxiliary.²,⁷ These compounds could be exploited as versatile intermediates for subsequent functionalization.⁸ Encouraged by these results, we continued to explore analogous desymmetrization reactions of 3-substituted azetidines using various electrophiles, such as benzyl, allyl or propargyl bromide.⁹ We report here the preparation of polyfunctional tertiary amines that could then serve as bifunctional electrophilic building blocks. This is illustrated for various 3-bromo-*N*-propargylamines that, after azide substitution and Huisgen intramolecular cycloaddition, gave access to novel triazolo[1,5-*a*][1,4]diazepine scaffolds (Scheme 1b).
a. Previous work: von Braun reaction

<figure><img src="image_2.png" /></figure>

b. This work

<figure><img src="image_3.png" /><figcaption>**Scheme 1.** (a) von Braun reaction of achiral C-3 substituted azetidines (b) overview of the present work.</figcaption></figure>

**Results and Discussion**

*N*-(S)-1-Arylethyl azetidines **1-3**, **19-22**, **29** and **31-35** bearing 3-*O*, 3-*N*, 3-*C* or 3-*S* substituents were chosen as prochiral substrates to conduct this study, and were prepared as described previously.⁷ Briefly, 3-hydroxy azetidines were prepared by reaction of (S)-arylethylamines with epichlorohydrin by Gaertner's method,¹⁰ then derivatized by tosylation and nucleophilic substitution. The esters **3** and **22**, carrying a second stereocenter, were prepared by esterification of **1** with *N*-Cbz-L-phenylalanine in the presence of EDC and DMAP.

The reaction of 3-*O* substituted *N*-((S)-1-phenylethyl) azetidines **1-3** was investigated first under standard conditions (0.2 M of the azetidine in acetonitrile for 24h at 5°C, 1.5 equiv. of alkylating agent, Scheme 2). Ring-opening reactions led to a diastereomeric mixture of products with a diastereomeric ratio ranging from 50:50 to 70:30 (Table 1). No specific correlation could be deduced from the size or the nature of the functional groups at the 3-position on the selectivity of the reaction, although the substrate **3** bearing the bulky *N*-Cbz-L-phenylalaninate ester did show some advantage over **1** and **2**. The nature of the electrophile did not appear to systematically influence selectivity either; for example benzyl bromide gave a diastereomeric ratio of 50:50 for **1** and 70:30 for **3**. Allyl bromide was the only electrophile which displayed no selectivity in any case.

<figure><img src="image_4.png" /><figcaption>**Scheme 2.** Reaction of 3-*O* substituted *N*-((S)-1-phenylethyl) azetidines with electrophiles</figcaption></figure>
<table><caption>**Table 1.** Reaction of 3-O substituted N-((S)-1-phenylethyl) azetidines with electrophiles. <sup>a</sup> From <sup>1</sup>H NMR spectra, rounded down to nearest 5%. <sup>b</sup> Reaction at room temperature (no reaction observed at 5°C). <sup>c</sup> Yield after acetylation.</caption><thead><tr><th>Entry</th><th>Substrate</th><th>R</th><th>R'</th><th>Product</th><th>Yield (%)</th><th>d.r. (%)<sup>a</sup></th></tr></thead><tbody><tr><td>1</td><td>1</td><td>H</td><td>CH<sub>2</sub>Ph</td><td>4</td><td>49</td><td>50:50</td></tr><tr><td>2<sup>b</sup></td><td>1</td><td>H</td><td>CH<sub>2</sub>CN</td><td>5</td><td>80</td><td>50:50</td></tr><tr><td>3</td><td>1</td><td>H</td><td>CH<sub>2</sub>COOEt</td><td>6<sup>c</sup></td><td>54</td><td>55:45</td></tr><tr><td>4<sup>b</sup></td><td>1</td><td>H</td><td>CH<sub>2</sub>C≡CH</td><td>7</td><td>77</td><td>55:45</td></tr><tr><td>5<sup>b</sup></td><td>1</td><td>H</td><td>CH<sub>2</sub>CH=CH<sub>2</sub></td><td>8</td><td>37</td><td>50:50</td></tr><tr><td>6</td><td>2</td><td>Bn</td><td>CH<sub>2</sub>Ph</td><td>9</td><td>89</td><td>65:35</td></tr><tr><td>7</td><td>2</td><td>Bn</td><td>CH<sub>2</sub>CN</td><td>10</td><td>100</td><td>60:40</td></tr><tr><td>8</td><td>2</td><td>Bn</td><td>CH<sub>2</sub>COOEt</td><td>11</td><td>82</td><td>50:50</td></tr><tr><td>9</td><td>2</td><td>Bn</td><td>CH<sub>2</sub>C≡CH</td><td>12</td><td>88</td><td>55:45</td></tr><tr><td>10</td><td>2</td><td>Bn</td><td>CH<sub>2</sub>CH=CH<sub>2</sub></td><td>13</td><td>61</td><td>50:50</td></tr><tr><td>11</td><td>3</td><td>N-Cbz-L-Phe</td><td>CH<sub>2</sub>Ph</td><td>14</td><td>89</td><td>70:30</td></tr><tr><td>12</td><td>3</td><td>N-Cbz-L-Phe</td><td>CH<sub>2</sub>CN</td><td>15</td><td>79</td><td>70:30</td></tr><tr><td>13</td><td>3</td><td>N-Cbz-L-Phe</td><td>CH<sub>2</sub>COOEt</td><td>16</td><td>73</td><td>70:30</td></tr><tr><td>14</td><td>3</td><td>N-Cbz-L-Phe</td><td>CH<sub>2</sub>C≡CH</td><td>17</td><td>60</td><td>60:40</td></tr><tr><td>15</td><td>3</td><td>N-Cbz-L-Phe</td><td>CH<sub>2</sub>CH=CH<sub>2</sub></td><td>18</td><td>53</td><td>50:50</td></tr></tbody></table>

<figure><img src="image_5.png" /><figcaption>**Figure 1.** X-ray crystal structure of (1'S, 2S)-10</figcaption></figure>

The major diastereoisomer of **10** could be purified by crystallization from a chromatographically inseparable mixture, allowing the determination of its (1'S, 2S) configuration by X-ray crystallography (Figure 1).<sup>11</sup>

The influence of the *N*-substituent of the azetidine ring in the reaction of 3-O substituted azetidines with benzyl and propargyl bromides was investigated next. Increasing the bulk of the *N*-substituent with a 1- or 2-naphthyl group gave again only moderate diastereomeric ratios, of up to 65:35. No advantage could be seen in using these groups apart from substrate **19** with an *N*--(S)-1-(naphthalen-1-yl)ethyl group which gave a better *d.r.* than the corresponding *N*--(S)-1-phenylethyl substrate **1** (Scheme 3).
<figure><img src="image_6.png" /></figure>

<figure><img src="image_7.png" /><figcaption>**Scheme 3.** Reaction of 3-O substituted azetidines with benzyl and propargyl bromides (d.r. determined from ¹H NMR spectra, rounded down to nearest 5%).</figcaption></figure>

<figure><img src="image_8.png" /><figcaption>**Scheme 4.** Reaction of 3-azido substituted azetidine 29 with propargyl bromide</figcaption></figure>

The reactions of 3-C, 3-N and 3-S substituted *N*-((S)-1-phenylethyl) azetidines were also considered. When the 3-azido azetidine **29** was reacted with propargyl bromide, the expected linear product was not isolated, but only the tetrahydro triazolopyrazine **30**, formed *via* a spontaneous intramolecular azide-alkyne Huisgen cycloaddition (Scheme 4).¹² This cyclisation product was obtained in a good yield, but with a low *d.r.* This result encouraged us to focus on ring-opening reactions with propargyl bromide, with a view to forming the corresponding tetrahydro triazolodiazepines from the 3-bromo-*N*-propargylamine products. Triazolodiazepines are relatively little explored heterocycles in comparison to their benzo-fused analogues, which have demonstrated interesting pharmacological properties.¹³ Approaches to their syntheses have been reported by several groups over the last fifteen years, with intramolecular triazole formation as a final step being a common feature¹⁴. Thermal conditions, using either conventional or microwave heating, were used for this cycloaddition reaction to form 1,5-triazoles.¹⁴,¹⁵

The azetidines **31-35** bearing a variety of functional groups reacted with propargyl bromide to give the desired 3-bromo-*N*-propargylamines in moderate to good yields, but with low or no diastereoselectivity (Scheme 5). In the case of the 3-cyano substituted azetidine **31**, an elimination product was also isolated (in 5% yield).
<figure><img src="image_9.png" /><figcaption>**Scheme 5.** Reaction of 3-C, 3-N and 3-S substituted N-((S)-1-phenylethyl) azetidines with propargyl bromide (d.r. determined from ¹H NMR spectra, rounded down to nearest 5%).</figcaption></figure>

Having in hand a series of 3-bromo-*N*-propargylamines, we investigated the formation of tetrahydro triazolodiazepines at first *via* a two-step synthesis (Scheme 6, method A). As a model sequence, 3-bromo-*N*-propargylamine **7** (*R* = OH) was stirred at 70°C for 2 days in MeCN with an excess of sodium azide to afford the corresponding azido derivative **41** in 73% yield. Heating of **41** at 100°C for 24h in toluene then gave the tetrahydro triazolodiazepine **48** in 71% yield (52% over 2 steps). The same protocol was applied to **12** (*R* = OBn) to give the corresponding azido compound **42** in 79% yield, and the tetrahydro triazolodiazepine **49** in 60% yield (48% over 2 steps). The *N*-Cbz-phenylalaninate ester **17** and *N*-phthalimide **38** gave the azido compounds **43** and **45** in quantitative yields, while substitution of the ethyl ester **37** gave **44** in only 66% yield. As it had been previously reported that microwave dielectric heating could be advantageous for copper-free intramolecular azide-alkyne cycloadditions,¹⁴,¹⁵ a one-pot procedure using this method was attempted. The 3-bromo-*N*-propargylamine **7** was heated at 100°C for 6h in isopropanol with an excess of sodium azide under microwave irradiation to give directly the tetrahydro triazolodiazepine **48** in 55% yield (Scheme 6, method B). The same process applied to **12** afforded **49** in 57% yield. For comparison, conventional heating of **7** under these conditions gave 60% of **48** after 48h. Performing both steps of this process under microwave irradiation significantly reduced the reaction time, but did not give better yields than the two-step procedure. A diastereoisomer of **48** could be crystallized, allowing the determination of its configuration (Figure 2).¹⁶
Method A: two-step synthesis

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

Method B: one-pot synthesis

<figure><img src="image_11.png" /><figcaption>**Scheme 6.** Preparation of tetrahydro triazolodiazepines. (A) yield over two steps.</figcaption></figure>

<figure><img src="image_12.png" /><figcaption>**Figure 2.** X-ray crystal structure of (1'S, 7R)-48</figcaption></figure>

When the S-pMeOBn propargylamine **40** was reacted with sodium azide under conditions **Ai**, a complex mixture of products was formed. Treatment of **40** at room temperature for 24h in DMF with excess sodium azide, gave a mixture of 3-azido-*N*-propargylamine **46** and tetrahydro triazolopyrazine **47** in 51% and 27% yield, respectively. A nucleophilic displacement of the halide had evidently occurred, involving the formation of a thiiranium ion intermediate (Scheme 7). Opening of this ion with sodium azide presumably gave a mixture of the possible 2- and 3-azido regioisomers. The 2-azido-*N*-propargylamine could then cyclize spontaneously to give **47**, in the same way that **29** had given the triazolopyrazine **30**. Heating of **46** at 100°C for 24h in toluene gave the expected triazolodiazepine **53**.
in quantitative yield. When compound **40** was subjected to conditions **B**, a 60:40 mixture of compounds **53** and **47** was isolated in 84% yield.

Deprotection of the *N*-(**(S)**)-1-phenylethyl group of a diastereomer of **48** by hydrogenation in the presence of Pd(OH)₂/C under 2 bars H₂ pressure gave the expected deprotected product **54** in quantitative yield.

<figure><img src="image_13.png" /><figcaption>**Scheme 7.** Proposed mechanism for the formation of tetrahydro triazolopyrazine **47** under conditions **Ai**.</figcaption></figure>

In conclusion, we have demonstrated that *N*-alkyl azetidines featuring a chiral substituent at the nitrogen atom, and a prochiral substituent at the C-3 position undergo ring-opening reactions with a range of electrophiles to yield polyfunctional tertiary amines. In spite of the moderate diastereoselectivities observed, the resulting intermediates may serve as building blocks for the synthesis of more complex molecular frameworks. This was illustrated by the efficient and modular synthesis of triazolodiazepine derivatives *via* intramolecular azide-alkyne cycloaddition, starting from 3-bromo-*N*-propargylamine substrates. This type of 7-substituted tetrahydro triazolodiazepines has not been reported previously to our knowledge. The simplicity and functional group tolerance of these transformations make this approach attractive for accessing diverse heterocycles from readily available azetidine precursors.

**Declaration of Competing Interest**

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

**Acknowledgments**

The University of Versailles St-Quentin-en-Yvelines, University Paris-Saclay and the CNRS are acknowledged for financial support. MR thanks the Ministère de l'Enseignement Supérieur de la Recherche et de l'Innovation for a PhD fellowship.

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16. The structure of compound (1'S, 7R)-48 has been deposited at the CCDC Cambridge database and has been allocated the number 2488297. For structural details, see supplementary material.