# A New and Efficient Ring Contraction of Dihydrobenzopyran to Dihydrobenzofuran Derivatives

Sophie Chasset-Boye, Marie-Claude Viaud-Massuard, Franck Suzenet, Gerald Guillaumet

► To cite this version:

Sophie Chasset-Boye, Marie-Claude Viaud-Massuard, Franck Suzenet, Gerald Guillaumet. A New and Efficient Ring Contraction of Dihydrobenzopyran to Dihydrobenzofuran Derivatives. Revista de Chimie, 2010, 61 (4), pp.404-406. [hal-00614893](https://hal.science/hal-00614893v1)

HAL Id: hal-00614893

https://hal.science/hal-00614893v1

Submitted on 13 Dec 2023

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

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

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

Distributed under a Creative Commons CC BY 4.0 - Attribution - International License
# A New and Efficient Ring Contraction of Dihydrobenzopyran to Dihydrobenzofuran Derivatives

SOPHIE CHASSET-BOYE<fnref n="1" />, MARIE-CLAUDE VIAUD-MASSUARD<fnref n="2" />, FRANCK SUZENET<fnref n="1" />, GÉRALD GUILLAUMET<fnref n="1" />*

A simple and efficient synthesis of benzofuran from benzopyran is described. The ring contraction takes place in the presence of Lewis acid. BBr₃ in dichloromethane have proven to be the best conditions. A mechanism via an aziridinium intermediate is proposed.

Keywords: benzofuran, benzopyran, Lewis acid, ring contraction

In connection with our studies on heterocyclic derivatives with potential biological activity [1-7], we now report on an unusual ring contraction reaction of benzopyran to benzofuran derivatives [8-16]. This phenomenon is well recognized in benzothiopyranic series [17]. Indeed, the formation of benzothiophenes by the ring contraction of benzothiopyrans is facilitated by the presence of suitable leaving groups at position 3. Benzopyrans, on the other hand, are not known to undergo a similar transformation possibly because of their inability to form the presumed bicyclo-oxiranium intermediate. However, Descotes and Missos first related the preparation of benzofurans from benzopyranic halohydrins [17]. Later, it was reported in moderate yield below 40%, and unusual ring contraction reaction of benzopyrans to benzofurans under basic conditions in the course of their work on the synthesis of structural analogues of cromakalim [18].

In this paper, we describe the one-pot synthesis of benzofurans by a Lewis acid mediated ring contraction. This study concerned essentially benzopyranic derivatives of type A which were substituted at position 3 with amino groups. Indeed, treatment of this compounds A with the appropriate Lewis acid led to the corresponding benzofuranic isomers of type B (scheme 1).

## Experimental part

<figure><img src="image_2.png" /><figcaption>Scheme 1. Benzopyran to benzofuran ring contraction</figcaption></figure>

## General procedure for the ring contraction

Method A. A solution of boron tribromide (0.05 mL, 0.55 mmol) in dry CH₂Cl₂ (2 mL) was added dropwise to a stirred solution of the appropriate benzopyran (0.5 mmol) in dry CH₂Cl₂ under argon. The reaction mixture was then refluxed for 24 h. After cooling, the reaction mixture was hydrolyzed. The aqueous phase was basified with a saturated solution of NaHCO₃ and extracted with dichloromethane. The combined organic layers were dried over anhydrous MgSO₄. The solvent was removed in vacuo and the residue was purified by flash column chromatography, eluting with CH₂Cl₂/MeOH (100:0 to 90:10) to afford the corresponding benzofuran. Yields of the products are reported in Table 1.

Method B. Reactions were performed as mentioned above, excepted that 2.1 equiv. (1.05 mmol) of boron tribromide were used and that the reaction was refluxed 48 h.

**2-(N,N-Dipropylaminomethyl)-2,3-dihydrobenzo[b]furan(2).** Yellow oil; IR (film) 1230 (C-O-C) cm⁻<fnref n="1" />; ¹H NMR (CDCl₃) δ: 0.86(t, J = 7.3 Hz, 6H, CH₂-CH₃), 1.39-1.55 (m, 4H, CH₂-CH₃), 2.47 (t, J = 7.3 Hz, 4H, N'-CH₂-CH₃), 2.60 (dd, J = 5.9 Hz, *J* = 13.2 Hz, 1H, CH(H)-NPr₂), 2.79 (dd, *J* = 6.6 Hz, *J* = 13.2 Hz, 1H, CH(H)-NPr₂), 2.97 (dd, *J* = 7.3 Hz, *J* = 15.4 Hz, 1H, H₃a), 3.24 (dd, *J* = 8.8 Hz, *J* = 15.4 Hz, 1H, H₃b), 4.84-4.89 (m, 1H, H₂), 6.76 (d, *J* = 7.4 Hz, 1H, H₇), 6.80 (t, *J* = 7.4 Hz, 1H, H₅), 7.08 (t, *J* = 7.4 Hz, 1H, H₆), 7.14 (d, *J* = 7.4 Hz, 1H, H₄); ¹³C NMR (CDCl₃) δ: 11.8 (2 CH₃), 20.2 (2 CH₂-CH₂), 33.5 (C₃), 57.0 (2 N-CH₂-CH₂), 58.7 (CH₂-NPr₂), 81.5 (C₅), 109.4 (C₇), 120.1 (C₅), 124.9 (C₄), 126.6 (C₃a), 127.8 (C₆), 159.5 (C₇a); MS (Cl/NH₃) m/z 234 (M+1). Anal. Calcd for C₁₃H₂₃NO: C, 77.19; H, 9.95; N, 6.00. Found: C, 77.37; H, 10.06; N, 5.88.

**2-(Methylpyrrolidin)-2,3-dihydrobenzo[b]furan(6).** Yellow oil; IR (film) 1220 (C-O-C) cm⁻<fnref n="1" />; ¹H NMR (CDCl₃) δ: 1.76-1.86 (m, 4H, H₃), 2.58-2.70 (m, 5H, C-CH(H)-N- and H₃), 2.90 (dd, *J* = 7.8 Hz, *J* = 12.8 Hz, 1H, C-CH(H)-N-), 2.96 (dd, *J* = 7.9 Hz, *J* = 15.6 Hz, 1H, H₃a), 3.28 (dd, *J* = 9.1 Hz, *J* = 15.6 Hz, 1H, H₃b), 4.88-4.99 (m, 1H, H₇); 6.77-7.17 (m, 4H, H₃), 13C NMR (CDCl₃) δ: 23.5 (2N-CH₂-CH₂), 34.1 (C₃), 54.8 (2N-CH₂-CH₂), 61.1 (C₂-CH₂), 81.6 (C₅), 109.6 (C₆), 120.3 (C₅), 124.9 (C₄), 126.5 (C₃a), 128.0 (C₆), 159.5 (C₇a); MS (Cl/NH₃) m/z 204 (M+1). Anal. Calcd for C₁₃H₂₃NO: C, 76.79; H, 8.45; N, 6.89. Found: C, 76.67; H, 8.54; N, 7.02.

**2-N-Propylaminomethyl)-2,3-dihydrobenzo[b]furan(8).** Yellow oil; IR (film) 1220 (C-O-C), 3320 (N-H) cm⁻<fnref n="1" />; ¹H NMR (CDCl₃ + D₂O) δ: 0.94 (t, *J* = 7.4 Hz, 3H, C-CH(H), 1.50-1.64 (m, 2H, C-CH₂-CH₃), 2.68 (t, *J* = 7.4 Hz, 2H, N'-CH₂-CH₂-CH₃), 2.84-2.99 (m, 3H, C-CH₂-NHPr, H₃a), 3.29 (dd, *J* = 9.2 Hz, *J* = 15.6 Hz, 1H, H₃b), 4.92-5.02 (m, 1H, H₇), 6.77 and 7.14 (2d, *J* = 7.4 Hz, 2H, H₄, H₇), 6.83 and 7.09 (2t, *J* = 7.4 Hz, 2H, H₅, H₇); ¹³C NMR (CDCl₃) δ: 11.3 (CH₃), 19.4 (CH₂-CH₃), 33.8 (C₃), 49.9, 50.8 (CH₂-N-CH₂), 77.6 (C₃), 110.3 (C₇), 121.3 (C₅), 124.9, 125.1 (C₄, C₃a), 128.5 (C₆), 158.2 (C₇); MS (Cl/NH₃) m/z 192 (M+1). Anal. Calcd for C₁₂H₁₇NO: C, 75.34; H, 8.98; N, 7.32. Found: C, 75.44; H, 8.81; N, 7.39.

<footnote n="1">¹Institut de Chimie Organique et Analytique (ICOA), UMR-CNRS 6005, FR CNRS 2708, LRC CEA M09, Université d'Orléans, Rue de Chartres, BP 6759, 45067 Orléans Cedex 2, France</footnote>

<footnote n="2">²UMR CNRS 6239 - Genetique, Immunotherapie, Chimie et Cancer, UFR des Sciences Pharmaceutiques, Université de Tours, 31 avenue de Monge, 37200 Tours, France</footnote>

<footnote>* email: gerald.guillaumet@univ-orleans.fr. Tel.: +33 2 38 49 45 76</footnote>
**2-(N,N-Dipropylaminomethyl)-2,3-dihydronaphto[1,2-b]furan (11).** Yellow oil; IR (film) 1230 (C-O-C) cm⁻¹; ¹H NMR (CDCl₃) δ: 0.89 (t, *J* = 7.4 Hz, 6H, -CH₂-CH₃, 1.42-1.56 (m, 4H, -CH₂-CH₃), 2.53 (t, *J* = 7.4 Hz, 4H N(CH₂-CH₃), 2.71 (dd, ³*J* = 6.0 Hz, ²*J* = 13.5 Hz, 1H, -CH(H)-NP₂), 2.89 (dd, *J* = 6.7 Hz, *J* = 13.5 Hz, 1H, -CH(H)-NP₂), 3.25 (dd, *J* = 7.1 Hz, *J* = 15.5 Hz, 1H, H₃a), 3.54 (dd, ³*J* = 9.5 Hz, ²*J* = 15.5 Hz, 1H, H₃b).503-5.15 (m, 1H, H₂), 7.07-7.82 (m, 6H, H₃, H₅, H₆, H₇, H₈, H₉, H₁₀); ¹³C NMR (CDCl₃) δ: 11.9 (2 CH₃), 20.2 (2 CH₂-CH₃), 32.8 (C₃), 57.1 (2 N-CH₂-CH₃), 59.0 (CH₃-NPr₂), 82.3 (C₂), 112.2, 118.2, 122.7, 125.8, 126.5, 128.7, 128.8; 129.1, 130.9, 157.1; MS (Cl/NH₃) m/z 284 (M+1). Anal. Calcd for C₁₉H₂₅NO: C, 80.50; H, 8.91; N, 4.94. Found: C, 80.59; H, 8.78; N, 4.90.

**2-Aminomethyl-2,3-dihydrobenzo[b]furan (14).** oil; IR (KBr) 1230 (C-O-C), 3300 (N-H) cm⁻¹; ¹H NMR (CDCl₃) δ: 1.57 (br s, 2H, NH₃), 2.79 (m, 1H, H₃, CH(H)-NH₃), 3.28 (dd, 1H, CH(H)-NH₃, *J* = 8.8 Hz, *J* = 15.4 Hz, 1H, H₃b), 4.84-4.89 (m, 1H, H₂), 6.77 (d, ³*J* = 7.4 Hz, 1H, H₇), 6.83 (t, *J* = 7.4 Hz, 1H, H₄), 7.11 (t, *J* = 7.4 Hz, 1H, H₆), 7.15 (d, *J* = 7.4 Hz, 1H, H₄); ¹³C NMR (CDCl₃) δ: 32.5 (C₃), 43.1 (CH₂-NH₃), 79.9 (C₄), 109.5 (C₇), 120.9 (C₅), 125.4 (C₄), 126.6 (C₃a), 128.1 (C₆), 158.6 (C₇); MS (Cl/NH₃) m/z 150 (M+1). Anal. Calcd for C₉H₁₁NO: C, 72.46; H, 7.43; N, 9.39. Found: C, 72.51; H, 7.36; N, 9.48.

## Results and discussions

As far as we know, the formation of benzofurans from benzopyrans mediated ring contraction reaction *via* Lewis acid has only been described in the literature by our group [19]. In the present paper, results of the performed reaction are presented and a possible mechanism is proposed.

Our initial studies of this process were focused on the 3-aminochromanic derivative **1** [1] which was chosen as model (scheme 2).

Attempts to obtain compound **2** from **1** by ring contraction reaction were carried out in the presence of different Lewis acids and one Brönsted acid in similar conditions using 1.1 equivalent of acid in refluxing dichloromethane for 2 h (*Method A*). The complexed Lewis acids such as boron trifluoride/diethyl etherate and boron tribromide/methyl sulfide as well as Brönsted acids such as the camphorsulfonic acid did not give the expected reaction. In contrast, Lewis acids such as titanium tetrachloride, aluminium trichloride and boron tribromide allowed us to isolate the benzofuran **2** respectively in 63%, 83% and 88% yield. The structure of this compound has

<figure><img src="image_3.png" /></figure>

<table><caption>Scheme 2. Evaluation of few Lewis acids</caption><thead><tr><th>Lewis Acid</th><th>Yields of 1 (%)</th><th>Yield of 2 (%)</th></tr></thead><tbody><tr><td>AlCl<sub>3</sub></td><td>-</td><td>83</td></tr><tr><td>BBr<sub>3</sub></td><td>-</td><td>88</td></tr><tr><td>BBr<sub>3</sub>•Me<sub>2</sub>S</td><td>100</td><td>-</td></tr><tr><td>BF<sub>3</sub>•Et<sub>2</sub>O</td><td>100</td><td>-</td></tr><tr><td>TiCl<sub>4</sub></td><td>23</td><td>63</td></tr><tr><td>Camphorsulfonic acid</td><td>100</td><td>-</td></tr></tbody></table>

been elucidated and confirmed by ¹H and ¹³C NMR spectroscopic data and two-dimensional NMR experiments.

In the light of these results, boron tribromide was retained to evaluate the scope and limitations of the reaction.

As shown in scheme 3, formation of the benzofuran **2** can be explained in terms of complexation between the oxygen of the methoxy moiety and the boron (III) bromide. At this stage, the increased polarization of the carbon-oxygen bond allows an intramolecular nucleophilic attack by the amine function. The resulting azinidinium ion is then subsequently opened to provide, after neutralization, the benzofuran **2**. In this tetrahedral system, in term of Baldwin rules, the cyclisation occurs in a favored 5-exo-tet process whereas the other possible six-endo-tet is disfavoured [20]. This phenomenon was also observed in recent works in piperidine series [21,22].

<figure><img src="image_4.png" /><figcaption>Scheme 3. Possible mechanism for the ring contraction</figcaption></figure>

In order to generalize this methodology, the experimental parameters, previously established (*Method A*: 1.1 equiv of BBr₃, CH₂Cl₂, reflux, 2h) were applied to benzopyranic and naphtopyranic derivatives, which present from the pattern compounds a variation of the substitution on the nitrogen atom or on the homocycle. To optimize the reaction, the number of equivalents of boron tribromide and the time of the reaction were increased simultaneously (*Method B*: 2.1 equiv of BBr₃, CH₂Cl₂, reflux, 24h) (table 1).

As depicted in table 1, benzopyranic and naphtopyranic derivatives **5** (obtained by alkylation of aminochromane **4** with 1,4-dibromobutane in the presence of triethylamine in DMF) and **10** (obtained by reduction of 3-nitro-2H-benzo[h] chromene [23] and N-alkylation with 1-iodopropene in the presence of K₂CO₃ in DMF), respectively led in high yields to the corresponding furans **6** and **11** (run 3 and 6). On the other hand, compounds **4** [24] and **7** [25] did not allow the formation of the expected products. Nevertheless, using method B with benzopyran **7**, benzofuran product **8** was isolated in a poor yield and the starting material was predominantly recovered. It should be noted that no ring contraction reaction occurred with compounds **3** [1-3] and **9** [22] bearing a nitro or acetamido group. This result is in agreement with the suggested mechanism.

In order to find an efficient route that would allow the preparation of benzofurans **8** and **14**, we investigated the ring contraction reaction from 3-aminochromans **12** and **13** (scheme 4) which were respectively alkylated on the nitrogen atom by reacting aminochromans **4** and **7** with benzyl bromide in DMF at 60°C in the presence of K₂CO₃ and a catalytic amount of potassium iodide in 72% and 93% yields.

Thus, ring contraction process followed by hydrogenolysis could lead to the expected benzofurans. Indeed, treatment of compound **12** with 2.1 equiv. of boron tribromide in refluxing dichloromethane during 24 hours followed by hydrogenolysis led to the 2-amino-
<table><caption>**Table 1**
SCOPE AND LIMITATIONS OF THE RING CONTRACTION</caption><thead><tr><th>Run</th><th>Starting Benzopyrans</th><th>Methods<sup>a</sup></th><th>Products</th><th>Yield (%)</th></tr></thead><tbody><tr><td rowspan="2">1</td><td rowspan="2">C<sub>6</sub>H<sub>5</sub>NO<sub>2</sub></td><td>A</td><td rowspan="2">no product</td><td><sup>b</sup></td></tr><tr><td>B</td><td><sup>b</sup></td></tr><tr><td rowspan="2">2</td><td rowspan="2">C<sub>6</sub>H<sub>5</sub>NH<sub>2</sub></td><td>A</td><td rowspan="2">no product</td><td><sup>c</sup></td></tr><tr><td>B</td><td><sup>c</sup></td></tr><tr><td rowspan="2">3</td><td rowspan="2">C<sub>6</sub>H<sub>5</sub>NH<sub>2</sub></td><td>A</td><td rowspan="2">6</td><td>54</td></tr><tr><td>B</td><td>80</td></tr><tr><td rowspan="2">4</td><td rowspan="2">C<sub>6</sub>H<sub>5</sub>NHPr</td><td>A</td><td rowspan="2">8</td><td><sup>b</sup></td></tr><tr><td>B</td><td>26</td></tr><tr><td rowspan="2">5</td><td rowspan="2">C<sub>6</sub>H<sub>5</sub>NHAc</td><td>A</td><td rowspan="2">no product</td><td><sup>b</sup></td></tr><tr><td>B</td><td><sup>b</sup></td></tr><tr><td rowspan="2">6</td><td rowspan="2">C<sub>6</sub>H<sub>5</sub>NPr<sub>2</sub></td><td>A</td><td rowspan="2">11</td><td>68</td></tr><tr><td>B</td><td>85</td></tr></tbody></table>

methylbenzofuran **14** in 86 % yield. Under similar conditions but during 48 hours, benzopyran **13** led to benzofuran **8** in 90% yield.

**Conclusions**

In conclusion, the few examples described here suggest that the Lewis acid mediated ring contraction reaction represents a new and potentially useful methodology for the formation of benzofuranic derivatives from the corresponding benzopyranic isomers.

*Acknowledgments: We are grateful to the Laboratories Servier for financial support. We also thank Mrs. M.M. Le Floch for typing the manuscript.*

**References**

1. PODONA, T., GUARDIOLA-LEMAITRE, B., CAIGNARD, D.-H., ADAM, G., PFEIFFER, B., RENARD, P., GUILLAUMET, G., J. Med. Chem., **37**, 1994, p. 1779

2. MAROT, C., COMOY, C., VIAUD, M.C., RETTORI, M.C., PFEIFFER, B., MORIN-ALLORY L., GUILLAUMET, G., Bioorg. Med. Chem. Lett., **6**, 1996, p. 1077

3. COMOY, C., MAROT, C., PODONA, T., BAUDIN, M. L., MORIN-ALLORY L., GUILLAUMET, G., PFEIFFER, B., CAIGNARD, D.-H., RENARD, P., RETTORI, M.C., ADAM, G., GUARDIOLA-LEMAITRE, B., J. Med. Chem., **39**, 1996, p. 4285

4. BADARAU, E., SUZENET, F., BOJARSKI, A.J., FINARU, A.L., GUILLAUMET, G., Bioorg. Med. Chem. Lett., **19**, 2009, p. 1600

5. GRIG-ALEXA, I.C., FINARU, A.L., ROUTIER, S., BAILLY, C., CAUBERE, P., GUILLAUMET, G., Rev. Chim. (Bucharest), **59**, no. 3, 2008, p. 266

6. DAVON, Y., GUILLAUMET, G., LAFOSSE, M., LESUR, B., MEROUR, J.Y., FINARU, A.L. Rev. Chim. (Bucharest), **57**, no. 8, 2006, p. 850

7. BASSENE, C.E., SUZENET, F., HENNUYER, N., STAELS, B., CAIGNARD, D.H., DACQUET, C., RENARD, P., GUILLAUMET, G., Bioorg. Med. Chem. Lett., **16**, 2006, p. 4528

<figure><img src="image_5.png" /><figcaption>Scheme 4. Improved synthesis to benzofurans 8 and 14</figcaption></figure>

8. HOFMANN, H., SALBECK, G., Angew. Chem. Int. Ed., **8**, 1969, p. 456

9. MACNICOL, D.D., MCKENDRICK, J.J., Tetrahedron Lett., **28**, 1973, p. 2593

10. MACKENZIE, N.E., THOMSON, R.H., J. Chem. Soc. Perkin Trans., **1**, 1982, p. 395

11. COZZI, P., PILLAN, A., J. Heterocyclic Chem., **25**, 1988, p. 1613

12. SMITH, D.G, J. Chem. Soc. Perkin Trans., **1**, 1990, p. 3187

13. ISTRATI, D., POPESCU, A., PARVULESCU, L., ANDREI, E., DRAGHICI, C., CIUCULESCU, C., Rev. Chim. (Bucharest), **59**, no. 5, 2008, p. 564

14. CAPROIU, M.T., DUMITRASCU, F., CAIRA M.R., Rev. Chim. (Bucharest), **59**, no. 11, 2008, p. 1242

15. CONDRAT, D., CRISAN, F., SZABO, M.-R., CHAMBREE, D.-R., LUPEA A.-X., Rev. Chim. (Bucharest), **60**, no. 11, 2009, p. 1129

16. LIMBAN, C., MISSIR, A.-V., CHIRITA, I.C., CAPROIU, M.T., DRAGHICI, C., NITULESCU, G.M., Rev. Chim. (Bucharest), **60**, no. 12, 2009, p. 1313

17. DESCOTES, G., MISSOS, D., Bull. Soc. Chim. Fr., **2**, 1972, p. 696

18. BUCKLE, D.R., FALLER, A., PINTO, I.L., SMITH, D.G., Tetrahedron Lett., **33**, 1992, p. 1109

19. BOYÉ, S., PFEIFFER, B., RENARD, P., RETTORI, M.C., GUILLAUMET, G., VIAUD, M.C., Bioorg. Med. Chem., **7**, 1999, p. 335

20. BALDWIN, J.E., J. Chem. Soc., Chem. Commun., 1976, p. 734

21. TEHRANI, K.A., VAN SYNGEL, K., BOELENS, M., CONTRERAS, J., DE KIMPE, N., KNIGHT, D.W., Tetrahedron Lett., **41**, 2000, p. 2507

22. ALONSO, E.R., TEHRANI, K.A., BOELENS, M., KNIGHT, D.W., Yu, V., DE KIMPE, N., Tetrahedron Lett., **42**, 2001, p. 3921

23. AL NEIRABEYEH, M., KOUSSINI, R., GUILLAUMET, G., Synth. Comm., **20**, 1990, p. 783

24. SARDA, N., GROUILLIE, A., PACHECO, H., Eur. J. Med. Chem., **11**, 1976, p. 251

25. VAN VLIET, L.A., RODENHUIS, N., WIKSTROEM, M., PUGSLEY, T.A., SERPA, K.A., MELTRER, L.T., HEFFNER, T.G., WISE, L.D., LAJINESS, M.E., HUFF, R.M., SVENSSON, K., HAENEN, G.R., BAST, A., J. Med. Chem., **43**, 2000, p. 3549

Manuscript received: 27. 07.2009

<footnote><sup>a</sup> Method A: 1.1 equiv. BBr<sub>3</sub>, CH<sub>2</sub>Cl<sub>2</sub>, reflux, 2h. Method B: 2.1 equiv. BBr<sub>3</sub>, CH<sub>2</sub>Cl<sub>2</sub>, reflux, 24h. <sup>b</sup> Starting material was recovered. <sup>c</sup> Degradation products were observed.</footnote>