CC BY ND NC 4.0 · SynOpen 2018; 02(01): 0025-0029
DOI: 10.1055/s-0037-1609082
letter
Copyright with the author

Cycloaddition of Benzyne with Alkoxy-Substituted Pyrroline-N-oxides­: Unexpected Rearrangement to an N-Phenylpyrrole

Department of Chemistry ‘Ugo Schiff’, University of Florence, Via della Lastruccia 13, 50019 Sesto Fiorentino (FI), Italy   Email: franca.cordero@unifi.it   Email: alberto.brandi@unifi.it
Consorzio Interuniversitario Nazionale per le Metodologie e Processi Innovativi di Sintesi (C.I.N.M.P.I.S), Bari, Italy
,
Bhushan B. Khairnar
Department of Chemistry ‘Ugo Schiff’, University of Florence, Via della Lastruccia 13, 50019 Sesto Fiorentino (FI), Italy   Email: franca.cordero@unifi.it   Email: alberto.brandi@unifi.it
,
Anna Ranzenigo
Department of Chemistry ‘Ugo Schiff’, University of Florence, Via della Lastruccia 13, 50019 Sesto Fiorentino (FI), Italy   Email: franca.cordero@unifi.it   Email: alberto.brandi@unifi.it
Consorzio Interuniversitario Nazionale per le Metodologie e Processi Innovativi di Sintesi (C.I.N.M.P.I.S), Bari, Italy
,
Department of Chemistry ‘Ugo Schiff’, University of Florence, Via della Lastruccia 13, 50019 Sesto Fiorentino (FI), Italy   Email: franca.cordero@unifi.it   Email: alberto.brandi@unifi.it
Consorzio Interuniversitario Nazionale per le Metodologie e Processi Innovativi di Sintesi (C.I.N.M.P.I.S), Bari, Italy
› Author Affiliations
The authors thank the Italian Ministry of Education, University and Research (MIUR-Rome), for financial support (PRIN20109Z2XRJ). C.I.N.M.P.I.S. is acknowledged for partial financial support of a Fellowship for A. R. Mrs. Nesrin Yumitkan, an Erasmus Placement student from Uludağ University (Turkey), is acknowledged for her contribution to this work.
Further Information

Publication History

Received: 04 December 2017

Accepted after revision: 04 January 2018

Publication Date:
31 January 2018 (online)

Abstract

Reaction of enantiopure 3,4-dialkoxy-pyrroline N-oxides with benzyne affords the expected tetrahydrobenzo[d]pyrrolo[1,2-b]isoxazoles along with an unexpected 2,3-disubstitued-N-phenyl-pyrrole derived from an unprecedented rearrangement of the adduct of nitrone with two molecules of benzyne. A mechanism for the unusual rearrangement is proposed. The benzo[d]isoxazolidine derivatives are conveniently converted into 2-(2-hydroxyphenyl)-3,4-dialkoxypyrrolidines by reductive opening of the N–O bond.

Supporting Information

 
  • References

    • 1a Dubrovskiy AV. Markina NA. Larock RC. Org. Biomol. Chem. 2013; 11: 191
    • 1b Wu C. Shi F. Asian J. Org. Chem. 2013; 2: 116
    • 1c Gampe CM. Carreira EM. Angew. Chem. Int. Ed. 2012; 51: 3766
    • 1d Tadross PM. Stoltz BM. Chem. Rev. 2012; 112: 3550
    • 1e Pellissier H. Santelli M. Tetrahedron 2003; 59: 701
    • 1f Wenk HH. Winkler M. Sander W. Angew. Chem. Int. Ed. 2003; 42: 502
    • 2a Himeshima Y. Sonoda T. Kobayashi H. Chem. Lett. 1983; 1211
    • 2b For a modified procedure, see: Peña D. Cobas A. Préz D. Guitián E. Synthesis 2002; 1454

      For a selection of recent studies on the synthesis of alkaloids codonopsinine and radicamine and analogous, see:
    • 3a Choi YJ. Kim YC. Park SJ. Jung JM. Kim YS. Kim IS. Jung YH. Tetrahedron 2017; 73: 4458
    • 3b Lingamurthy M. Jagadeesh Y. Ramakrishna K. Rao BV. J. Org. Chem. 2016; 81: 1367
    • 3c Kim J.-S. Kim G.-W. Kang J.-C. Myeong I.-S. Jung C. Lee Y.-T. Choo G.-H. Park S.-H. Lee G.-J. Ham W.-H. Tetrahedron: Asymmetry 2016; 27: 171
    • 3d Li Y.-X. Iwaki R. Kato A. Jia Y.-M. Fleet GW. J. Zhao X. Xiao M. Yu C.-Y. Eur. J. Org. Chem. 2016; 1429
    • 3e Dharuman S. Palanivel AK. Vankar YD. Org. Biomol. Chem. 2014; 12: 4983
  • 4 Khangarot RK. Kaliappan KP. Eur. J. Org. Chem. 2012; 5844
  • 5 Brandi A. Cardona F. Cicchi S. Cordero FM. Goti A. Org. React. 2017; 94: 1
    • 6a Brandi A. Cardona F. Cicchi S. Cordero FM. Goti A. Chem. Eur. J. 2009; 15: 7808
    • 6b Cicchi S. Höld I. Brandi A. J. Org. Chem. 1993; 58: 5274
    • 6c Cordero FM. Bonanno P. Neudeck S. Vurchio C. Brandi A. Adv. Synth. Catal. 2009; 351: 1155
    • 6d Cordero FM. Bonanno P. Khairnar BB. Cardona F. Brandi A. Macchi B. Minutolo A. Grelli S. Mastino A. ChemPlusChem 2012; 77: 224
    • 7a Yao T. Ren B. Wang B. Zhao Y. Org. Lett. 2017; 19: 3135
    • 7b Okuma K. Hirano K. Shioga C. Nagahora N. Shioji K. Bull. Chem. Soc. Jpn. 2013; 86: 615
    • 7c Li P. Wu C. Zhao J. Li Y. Xue W. Shi F. Can. J. Chem. 2013; 91: 43
    • 7d Dennis N. In Organic Reaction Mechanisms 2012 . Knipe C. Wiley; Weinheim: 2015: 433
    • 7e Lu C. Dubrovskiy AV. Larock RC. J. Org. Chem. 2012; 77: 2279
    • 7f Wu K. Chen Y. Lin Y. Cao W. Zhang M. Chen J. Lee AW. M. Tetrahedron 2010; 66: 578
    • 7g Dai M. Wang Z. Danishefsky SJ. Tetrahedron Lett. 2008; 49: 6613
    • 7h Khanapure SP. Bhawal BM. Biehl ER. Heterocycles 1991; 32: 1773
    • 7i Abramovitch RA. Shinkai I. J. Am. Chem. Soc. 1974; 96: 5265

      For examples of 1,3-DC of chiral cyclic nitrones with arynes, see: Ref 4 and
    • 8a Reidl TW. Son J. Wink DJ. Anderson LL. Angew. Chem. Int. Ed. 2017; 56: 11579
    • 8b Son J. Kim KH. Mo D.-L. Wink DJ. Anderson LL. Angew. Chem. Int. Ed. 2017; 56: 3059
    • 9a Ali SA. Wazeer MI. M. Tetrahedron 1993; 49: 4339
    • 9b Nagasawa K. Georgieva A. Nakata T. Tetrahedron 2000; 56: 187
    • 9c Shimokawa J. Ishiwata T. Shirai K. Koshino H. Tanatani A. Nakata T. Hashimoto Y. Nagasawa K. Chem. Eur. J. 2005; 11: 6878
    • 9d Morozov DA. Kirilyuk IA. Komarov DA. Goti A. Bagryanskaya IY. Kuratieva NV. Grigorev IA. J. Org. Chem. 2012; 77: 10688
  • 10 General Procedure for the Cycloaddition Reaction: A mixture of nitrone 1 (300 mg), 2 (1.5 equiv), and Bu4NF (1 M in THF, 1.2 equiv) in anhydrous DMF (final nitrone concentration of 0.09–0.1 M) was stirred at room temperature for 2.5 h. The DMF was evaporated under a flow of nitrogen and the crude residue was purified by chromatography on silica gel
  • 11 Compound 3a: Rf  = 0.33 (EtOAc/petroleum ether, 1:16); [α]D 24 = –90.6 (c = 0.25, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 7.25 (dm, J = 7.4 Hz, 1 H, 9-H), 7.17–7.12 (m, 1 H, 7-H), 6.90 (pseudo dt, J = 0.9, 7.4 Hz, 1 H, 8-H), 6.73 (br d, J = 8.0 Hz, 1 H, 6-H), 4.77 (br s, 1 H, 9b-H), 4.13–4.10 (m, 1 H, 1-H), 3.96 (ddd, J = 6.0, 4.9, 3.6 Hz, 1 H, 2-H), 3.58 (dd, J = 11.6, 4.9 Hz, 1 H, 3-Ha), 3.16 (ddm, J = 11.6, 6.0 Hz, 1 H, 3-Hb), 1.29 (s, 9 H, 3 × CH3), 1.06 (s, 9 H, 3 × CH3). 13C NMR (CDCl3, 50 MHz): δ = 156.3 (s, C-5a), 128.5 (d, C-7), 127.1 (s, C-9a), 123.4 (d, C-9), 120.9 (d, C-8), 107.1 (d, C-6), 82.0 (d, C-1), 76.6 (d, C-2), 75.6 (d, C-9b), 74.5 (s, CMe3), 73.6 (s, CMe3), 62.1 (t, C-3), 28.7 (q, 3C, 3 × CH3), 28.3 (q, 3C, 3 × CH3). IR (CDCl3): 2977, 2871, 1597, 1480, 1456, 1390, 1365, 1253, 1190, 1099, 1079 cm–1. MS (+ESI): m/z = 306 [M+H]+, 250 [M+H–(isobutene)]+, 194 [M+H–2(isobutene)]+. C18H27NO3 (305.41): calcd. C, 70.79; H, 8.91; N, 4.59; found: C, 70.56; H, 8.69; N, 4.98
  • 12 Compound 4a: Rf  = 0.23 (EtOAc/petroleum ether, 1:16). [α]D 21 = –12.7 (c = 0.22, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 7.32 (br d, J = 7.5 Hz, 1 H, 9-H), 7.17 (pseudo tm, J = 8.0 Hz, 1 H, 7-H), 6.91 (pseudo dt, J = 0.8, 7.4 Hz, 1 H, 8-H), 6.76 (br d, J = 8.1 Hz, 1 H, 6-H), 4.87 (d, J = 6.8 Hz, 1 H, 9b-H), 4.24 (pseudo t, J = 7.2 Hz, 1 H, 1-H), 3.82 (pseudo q, J = 7.9 Hz, 1 H, 2-H), 3.49 (dd, J = 14.0, 7.6 Hz, 1 H, 3-Ha), 3.23 (dd, J = 14.0, 8.6 Hz, 1 H, 3-Hb), 1.28 (s, 9 H, 3 × CH3), 1.11 (s, 9 H, 3 × CH3). 13C NMR (CDCl3, 50 MHz): δ = 157.2 (s, C-5a), 128.4 (d, C-7), 125.9 (d, C-9), 125.2 (s, C-9a), 120.8 (d, C-8), 107.2 (d, C-6), 77.6 (d, C-1), 74.3 (s, CMe3), 73.7 (s, CMe3), 73.0 (d, C-2), 68.4 (d, C-9b), 62.5 (t, C-3), 28.5 (q, 6C, 6 × CH3). IR (CDCl3): 2977, 2935, 1593, 1474, 1458, 1390, 1365, 1236, 1192, 1119 cm–1. MS (ESI): m/z = 306 [M+H]+, 250 [M+H–(isobutene)]+, 194 [M+H–2(isobutene)]+. C18H27NO3 (305.41): calcd. C, 70.79; H, 8.91; N, 4.59; found: C, 70.51; H, 9.12; N, 4.56
    • 13a Ishikawa T. Tajima Y. Fukui M. Saito S. Angew. Chem. Int. Ed. Engl. 1996; 35: 1863
    • 13b Cardona F. Faggi E. Liguori F. Cacciarini M. Goti A. Tetrahedron Lett. 2003; 44: 2315
    • 13c Liautard V. Christina AE. Desvergnes V. Martin OR. J. Org. Chem. 2006; 71: 7337
  • 14 Compound 5a: Rf  = 0.35 (EtOAc/petroleum ether, 1:32), one orange spot with p-anisaldehyde stain. Mp = 110–112 °C. 1H NMR (CDCl3, 400 MHz): δ = 8.18 (s, 1 H, OH, disappears on addition of D2O), 7.30–7.25 (m, 2 H, HAr), 7.24–7.18 (m, 1 H, HAr), 7.11–7.01 (m, 4 H, HAr), 6.84 (d, J = 3.2 Hz, 1 H, 5-H), 6.60–6.51 (m, 2 H, HAr), 6.14 (d, J = 3.2 Hz, 1 H, 4-H), 1.23 (s, 9 H, 3 × CH3). 13C NMR (CDCl3, 100 MHz): δ = 153.7 (s, CAr), 140.7 (s, CAr), 139.5 (s, CAr), 130.8 (d, CHAr), 128.9 (d, 2C, CHAr), 128.0 (d, CHAr), 126.3 (d, CHAr), 125.3 (d, 2C, CHAr), 122.4 (d, C-5), 120.9 (s, CAr), 119.6 (d, CHAr), 119.0 (s, CAr), 118.3 (d, CHAr), 105.1 (d, C-4), 81.6 (s, CMe3), 28.0 (q, 3C, 3 × CH3). C/H coupled 13C NMR (CDCl3, 100 MHz): δ = (selection of signals) = 122.4 (dd, J = 187.6, 7.0 Hz, C-5), 105.1 (dd, J = 173.3, 7.2 Hz, C-4). IR (CDCl3): 3255 (broad), 3075, 2981, 2934, 1599, 1556, 1502, 1352, 1235, 1164 cm–1. MS (+ESI): m/z = 330 [M+Na]+. MS (ESI): m/z = 307 [M]. HRMS (+ESI): m/z [MH]+ calcd for C20H22NO2 +: 308.16451; found: 308.16444
    • 15a McNab H. Monahan LC. J. Chem. Soc., Perkin Trans. 2 1991; 1999
    • 15b Zhang M. Fang X. Neumann H. Beller M. J. Am. Chem. Soc. 2013; 135: 11384
  • 16 Compound 6a: Rf  = 0.31. Mp = 124–125 °C. [α]D 21 = –43.4 (c = 0.43, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 7.13 (pseudo dt, J = 1.7, 7.7 Hz, 1 H, HAr), 7.00 (dd, J = 7.5, 1.7 Hz, 1 H, HAr), 6.80 (dd, J = 8.1, 1.1 Hz, 1 H, HAr), 6.74 (pseudo dt, J = 1.1, 7.4 Hz, 1 H, HAr), 4.08 (dd, J = 7.9, 5.3 Hz, 1 H, 3-H), 3.99 (dd, J = 7.4, 5.3 Hz, 1 H, 4-H), 3.94 (d, J = 7.9 Hz, 1 H, 2-H), 3.30 (dd, J = 10.6, 7.4 Hz, 1 H, 5-Ha), 3.01 (dd, J = 10.6, 4.4 Hz, 1 H, 5-Hb), 1.19 (s, 9 H, 3 × CH3), 0.93 (s, 9 H, 3 × CH3). 13C NMR (CDCl3, 100 MHz): δ = 158.0 (s, CAr), 129.6 (d, CHAr), 128.7 (d, CHAr), 123.3 (s, CAr), 118.4 (d, CHAr), 116.7 (d, CHAr), 80.7 (d, C-3), 76.3 (d, C-4), 74.6 (s, CMe3), 73.8 (s, CMe3), 66.6 (d, C-2), 50.9 (t, C-5), 28.7 (q, 3C, 3 × CH3), 28.6 (q, 3C, 3 × CH3). IR (CDCl3): 2977, 2935, 1589, 1489, 1392, 1367, 1257, 1190, 1106, 1068 cm–1. MS (+ESI): m/z = 308 [M+H]+. MS (ESI): m/z = 306 [M–H]. C18H29NO3 (307.43): calcd. C, 70.32; H, 9.51; N, 4.56; found: C, 70.53; H, 9.66; N, 4.17
  • 17 Compound 6b: Rf  = 0.15 (EtOAc/petroleum ether, 1:4). Mp = 162–164 °C. [α]D 27 = –57.4 (c = 1.0, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 8.08–8.03 (m, 2 H, HBz), 8.96–7.91 (m, 2 H, HBz), 7.63–7.58 (m, 1 H, HBz), 7.57–7.52 (m, 1 H, HBz), 7.50–7.44 (m, 2 H, HBz), 7.43–7.37 (m, 2 H, HBz), 7.23 (dd, J = 7.6, 1.6 Hz, 1 H, HAr), 7.18 (pseudo dt, J = 1.6, 7.7 Hz, 1 H, HAr), 6.88 (dd, J = 8.2, 1.2 Hz, 1 H, HAr), 6.80 (pseudo dt, J = 1.2, 7.4 Hz, 1 H, HAr), 5.71 (dd, J = 4.3, 1.6 Hz, 1 H, 3-H), 5.62 (pseudo dt, J = 5.5, 1.6 Hz, 1 H, 4-H), 4.68 (d, J = 4.3 Hz, 1 H, 2-H), 3.70 (dd, J = 12.1, 5.5 Hz, 1 H, 5-Ha), 3.44 (dm, J = 12.1 Hz, 1 H, 5-Hb). 13C NMR (CDCl3, 100 MHz): δ = 165.7 (s, CO), 165.3 (s, CO), 157.8 (s, CAr), 133.5 (d, CHBz), 133.3 (d, CHBz), 129.9 (d, 2C, CHBz), 129.7 (d, 2C, CHBz), 129.3 (s, CBz), 129.2 (s, CBz), 129.1 (d, CHAr), 128.5 (d, 2C, CHBz), 128.4 (d, CHAr), 128.3 (d, 2C, CHBz), 121.1 (s, CAr), 119.2 (d, CHAr), 117.4 (d, CHAr), 83.0 (d, C-3), 77.3 (d, C-4), 67.0 (d, C-2), 51.2 (t, C-5). IR (CDCl3): 3348, 3065, 2959, 2858, 1719, 1602, 1585, 1491, 1451, 1278, 1258, 1110 cm–1. MS (+ESI): m/z = 404 [M+H]+. MS (ESI): m/z = 402 [M–H]. C24H21NO5 (403.43): calcd. C, 71.45; H, 5.25; N, 3.47; found: C, 71.08; H, 5.07; N, 3.44
  • 18 Compound 7b: Rf  = 0.34 (EtOAc/petroleum ether, 1:4). Mp = 60–62 °C. [α]D 26 = –45.3 (c = 0.5, CHCl3). 1H NMR (CDCl3, 400 MHz): δ = 8.11–8.07 (m, 2 H, HBz), 7.97–7.93 (m, 2 H, HBz), 7.66–7.60 (m, 1 H, HBz), 7.54–7.47 (m, 3 H, HBz), 7.40–7.35 (m, 2 H, HBz), 7.08–7.00 (m, 2 H, HAr), 6.76 (dd, J = 8.2, 1.2 Hz, 1 H, HAr), 6.72 (pseudo dt, J = 1.2, 7.4 Hz, 1 H, HAr), 5.77 (dd, J = 4.7, 1.1 Hz, 1 H, 3-H), 5.55 (dm, J = 5.1 Hz, 1 H, 4-H), 4.97 (d, J = 4.7 Hz, 1 H, 2-H), 3.85 (dd, J = 12.6, 5.1 Hz, 1 H, 5-Ha), 3.35 (dd, J = 12.6, 2.3 Hz, 1 H, 5-Hb). 13C NMR (CDCl3, 100 MHz): δ = 165.3 (s, CO), 165.2 (s, CO), 159.2 (s, CAr), 133.6 (d, CHBz), 133.2 (d, CHBz), 129.9 (d, 2C, CHBz), 129.8 (d, 2C, CHBz), 129.3 (s, CBz), 129.1 (s, CBz +d, CHAr), 128.6 (d, 2C, CHBz), 128.5 (d, CHAr), 128.3 (d, 2C, CHBz), 118.8 (d, CHAr), 118.4 (s, CAr), 117.1 (d, CHAr), 78.8 (d, C-3), 77.1 (d, C-4), 65.0 (d, C-2), 50.3 (t, C-5). IR (CDCl3): 3366, 3065, 2958, 2871, 1721, 1601, 1586, 1492, 1452, 1316, 1260, 1109 cm–1. MS (+ESI): m/z = 404 [M+H]+. MS (ESI): m/z = 402 [M–H]. C24H21NO5 (403.43): calcd. C, 71.45; H, 5.25; N, 3.47; found: C, 71.44; H, 5.13; N, 3.37
  • 19 Compound 5b: Rf  = 0.52 (EtOAc/petroleum ether, 1:4), one red spot with p-anisaldehyde stain. Mp = 135–137 °C (dec). 1H NMR (CDCl3, 400 MHz): δ = 8.15–8.09 (m, 2 H, HBz), 7.62–7.56 (m, 1 H, HBz), 7.49–7.42 (m, 2 H, HBz), 7.31–7.11 (m, 6 H, HAr), 7.03 (d, J = 3.2 Hz, 1 H, 5-H), 6.93 (dm, J = 8.2 Hz, 1 H, HAr), 6.88 (dd, J = 7.6, 1.6 Hz, 1 H, HAr), 6.76–6.69 (m, 1 H, HAr), 6.44 (d, J = 3.2 Hz, 1 H, 4-H), 6.06 (br s, 1 H, OH). 13C NMR (CDCl3, 100 MHz): δ = 165.8 (s, CO), 154.8 (s, CAr), 139.6 (s, CAr), 136.8 (s, CAr), 133.6 (d, CHBz), 132.1 (d, CHAr), 130.3 (d, 2C, CHBz), 130.1 (d, CHAr), 129.0 (d, 2C, CHAr), 128.9 (s, CHBz), 128.5 (d, 2C, CHBz), 126.8 (d, CHAr), 124.9 (d, 2C, CHAr), 121.6 (d, C-5), 120.1 (d, CHAr), 117.3 (s, CAr), 116.4 (s, CAr), 116.1 (d, CHAr), 103.3 (d, C-4). IR (CDCl3): 3072, 2927, 1726, 1600, 1502, 1356, 1267, 1228, 1068, 1025 cm–1. MS (+ESI): m/z = 356 [M+1]+. MS (ESI): m/z = 354 [M–1]. HRMS (+ESI): m/z [MH]+ calcd for C23H18NO3 +: 356.12812; found: 356.12788