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Synlett 2017; 28(20): 2859-2864
DOI: 10.1055/s-0036-1589105
letter
© Georg Thieme Verlag Stuttgart · New York

One-Pot Michael Addition/Radical Cyclization Reaction of N-Acryloyl Indoles

Lauren C. Irwin
Department of Chemistry, The University of Western Ontario, London, ON, N6A 5B7, Canada   eMail: makerr@uwo.ca
,
Michael A. Kerr*
Department of Chemistry, The University of Western Ontario, London, ON, N6A 5B7, Canada   eMail: makerr@uwo.ca
› InstitutsangabenWe are grateful to the Natural Sciences and Engineering Research Council of Canada (NSERC) for generous funding of this research. LCI is a recipient of an OGS scholarship.
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Publikationsverlauf

Received: 29. Juli 2017

Accepted after revision: 11. August 2017

Publikationsdatum:
21. September 2017 (online)

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Abstract

From N-acryloyl indoles, ten examples of 1,2-annulated ­indole products were generated in a one-pot procedure via a Michael addition and radical cyclization mediated by Mn(OAc)3.

Key words

indoles - radical reaction - heterocycles - alkaloids - Michael addition

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/s-0036-1589105.
  • Supporting Information
 

  • References and Notes

    • 1a Samala S. Arigela RK. Kant R. Kundu B. J. Org. Chem. 2014; 79: 2491
      CrossrefPubMed
    • 1b Sessler JL. Cho D.-G. Lynch V. J. Am. Chem. Soc. 2006; 128: 16518
      CrossrefPubMed
    • 1c Zhang M.-Z. Chen Q. Yang G.-F. Eur. J. Med. Chem. 2015; 89: 421
      CrossrefPubMed
    • 1d Hamann MT. Waseem G. Life. Sci. 2005; 78: 442
      CrossrefPubMed
    • 1e Gul W. Hamann MT. Life Sci. 2005; 78: 442
      CrossrefPubMed

      Tronocarpine:
    • 2a Sim K.-M. Lim T.-M. Kam T.-S. Tetrahedron Lett. 2000; 41: 2733
      Crossref
    • 2b Sapeta K. Kerr MA. Org. Lett. 2009; 11: 2081
      CrossrefPubMed
    • 2c Torres-Ochoa RO. Reyes-Gutierrez PE. Martinez R. Eur. J. Org. Chem. 2014; 48
    • 3a Ervataine: Jin Y.-S. Du J.-L. Chen H.-S. Jin L. Liang S. ­Fitoterapia 2010; 81: 63
      PubMed
    • 3b Chippiinne: Van Beek TA. Verpoorte R. Baerheim Svendsen A. Fokkens R. J. Nat. Prod. 1985; 48: 400
      CrossrefPubMed
    • 4a Abubakar IB. Lim K.-H. Kam TS. Loh H.-S. Phyto­chemistry 2017; 30: 74
    • 4b Raja VJ. Lim K.-H. Leong C.-O. Kam T.-S. Bradshaw TD. Invest. New Drugs 2014; 32: 838
      CrossrefPubMed
    • 4c Low Y.-Y. Lim K.-H. Choo Y.-M. Pang H.-S. Etoh T. Hayashi M. Komiyama K. Kam T.-S. Tetrahedron Lett. 2010; 51: 269
      Crossref

      For other examples of radical chemistry to functionalize indoles, see:
    • 5a Chuang C.-P. Wang S.-F. Tetrahedron Lett. 1994; 35: 1283
      Crossref
    • 5b Bhat V. Mackay JA. Rawal VH. Org. Lett. 2011; 13: 3214
      CrossrefPubMed
    • 5c Tsai A.-I. Lin C.-H. Chuang C.-P. Hetero­cycles 2005; 65: 2381
    • 5d Lopchuk JM. Montgomery WL. Jasinski JP. Gorifard S. Gribble GW. Tetrahedron Lett. 2013; 54: 6142
      Crossref
    • 5e Baciocchi E. Muraglia E. J. Org. Chem. 1993; 58: 7610
      Crossref

      For reviews on Mn(OAc)3 chemistry, see:
    • 6a Mondal M. Bora U. RCS Adv. 2013; 3: 18716
    • 6b Snider BB. Chem. Rev. 1996; 96: 339
      CrossrefPubMed
    • 6c Snider BB. Cole BM. J. Org. Chem. 1995; 60: 5376
      Crossref
    • 6d Snider BB. Tetrahedron 2009; 65: 10735
      PubMed
    • 6e Mohan R. Kates SA. Domroski MA. Snider BB. Tetrahedron Lett. 1987; 28: 854
    • 7a Artis DR. Cho I.-S. Muchowski JM. Can. J. Chem. 1992; 70: 1838
      Crossref
    • 7b Artis DR. Cho I.-S. Jaime-Figueroa S. Muchowski JM. J. Org. Chem. 1994; 59: 2456
      Crossref
  • 8 Magolan J. Kerr MA. Org. Lett. 2006; 8: 4561
    CrossrefPubMed
  • 9 Magolan J. Carson CA. Kerr MA. Org. Lett. 2008; 10: 1437
    CrossrefPubMed
  • 10 Kandukuri SR. Schiffner JA. Oestreich M. Angew. Chem. Int. Ed. 2012; 51: 1265
    CrossrefPubMed
    • 11a Michael A. J. Prakt. Chem. 1887; 35: 349
      Crossref
    • 11b Liu X. Chen X. Mohr JT. Chem. Eur. J. 2016; 22: 2274
      CrossrefPubMed
    • 11c Alcaide B. Almendros P. Aragoncillo C. J. Org. Chem. 2001; 66: 1612
      CrossrefPubMed
    • 11d Wu B. Gao X. Yan Z. Chen M.-W. Zhou Y.-G. Org. Lett. 2015; 17: 6134
      CrossrefPubMed
  • 12 General Experimental Procedure: One-Pot Michael Addition, Radical Cyclization (15a–j, 16) To an argon-flushed round-bottom flask was added half of the total volume of THF (0.15 M) required followed by NaH (60% dispersed in mineral oil, 1.5 equiv). The 1,3-dicarbonyl species (1.5 equiv) was added dropwise via syringe with stirring under argon. The resultant mixture was stirred for 15 min at which point the desired indole (1 equiv), dissolved in the other half-volume of THF, was added via syringe or cannula. The Michael addition was monitored by TLC. Once TLC confirmed complete consumption of starting indole, Mn(OAc)3(7 equiv) was added to the round-bottom flask followed by AcOH (0.12 M). The flask was equipped with a reflux condenser and put back under an argon atmosphere. The reaction was brought to 110 °C and refluxed until the mixture changed color from a dark brown to now containing obvious white solid in a yellow/orange solution. At this point, TLC analysis always indicated complete consumption of starting materials. The crude reaction mixture was allowed to cool to r.t. and then diluted with a large excess of EtOAc. The solution was vacuum filtered through a thick pad of Celite and then flushed with even more EtOAc. The solvent was removed under reduced pressure with added toluene to aid in the removal of AcOH. The obtained dried crude product was purified with flash column chromatography (EtOAc in hexanes). The desired fractions of the column were collected to a separatory funnel and washed twice with 1 M NaOH solution and then followed with a brine wash. The organic layer was collected, dried with MgSO4, and concentrated in vacuo to yield product. Product 15a Following the general experimental procedure, 15a was synthesized from acyl-indole 14a (0.30 g, 1.51 mmol), NaH (0.091g, 2.27 mmol), dimethyl malonate (0.30 g, 2.27 mmol, 0.26 mL) in 10 mL of THF then Mn(OAc)3 (2.80 g, 10.6 mmol) in AcOH (13 mL). Compound 15a was isolated as a yellow solid (0.33 g, 65%); Rf = 0.40 (20% EtOAc in hexanes); mp 126–129 °C. 1H NMR (400 MHz, CDCl3): δ = 8.50 (d, J = 8.2 Hz, 1 H), 7.50 (d,   = 7.7 Hz, 1 H), 7.35 (t, J = 7.7 Hz, 1 H), 7.30 (t, J = 7.5 Hz, 1 H), 3.83 (s, 3 H), 3.79 (s, 3 H), 2.90 (ddq, J = 12.6, 6.5, 6.3 Hz, 1 H), 2.84 (dd, J = 13.0, 4.4 Hz, 1 H), 2.39 (t, J = 13.0 Hz, 1 H), 2.16 (s, 3 H), 1.42 (d, J = 6.8 Hz, 3 H). 13C NMR (101 MHz, CDCl3): δ = 170.9, 170.4, 169.0, 134.5, 131.1, 128.2, 125.7, 124.0, 118.6, 117.9, 116.8, 55.7, 53.6, 37.5, 35.4, 15.7, 9.2 IR 3027, 2954, 1785, 1702, 1456, 1386, 1385, 1308, 1245, 751. HRMS: m/z calcd for C18H19NO5: 329.1263; found [M+]: 329.12682. Product 15d Following the general experimental procedure, 15d was synthesized from acryloyl indole 14d (0.25 g, 1.35 mmol), dimethyl malonate (0.27 g, 2.02 mmol, 0.23 mL), NaH (0.081 g, 2.02 mmol) in 9 mL of THF. Following completion of the Michael addition was then added Mn(OAc)3 (2.53 g, 9.40 mmol) and AcOH (11 mL). Compound 15d was isolated as a pale orange solid (0.18 g, 45%); Rf = 0.27 (20% EtOAc in hexanes); mp 109–113 °C. 1H NMR (400 MHz, CDCl3): δ = 8.48 (d, J = 8.2 Hz, 1 H), 7.52 (d, J = 8.4 Hz, 1 H), 7.39–7.31 (m, 1 H), 7.28 (m, 1 H), 6.68 (s, 1 H), 3.89 (s, 3 H), 3.77 (s, 3 H), 2.80 (ddd, J = 13.3, 6.7, 4.5 Hz, 1 H), 2.72 (dd, J = 13.6, 4.5 Hz, 1 H), 2.51 (t, J = 13.5 Hz, 1 H), 1.43 (d, J = 6.8 Hz, 3 H). 13C NMR (101 MHz, CDCl3): δ = 171.0, 169.6, 168.8, 135.4, 133.0, 129.3, 125.5, 124.3, 120.8, 116.8, 109.2, 55.7, 53.7, 42.0, 36.4, 35.3, 15.9. IR: 2956, 2923, 2852, 1746, 1708, 1437, 1300, 1144, 1063, 836 cm–1. HRMS: m/z calcd for C17H17NO5: 315.11067; found [M+]: 315.11120.
  • 13 Cai G.-X. Wen J. Lai T.-T. Xie D. Zhou C.-H. Org. Biomol. Chem. 2016; 14: 2390
    CrossrefPubMed

      • For other indoline to indole oxidations involving Mn, see:
    • 14a Ketcha DM. Tetrahedron Lett. 1988; 29: 2151
      Crossref
    • 14b Gourdoupis CG. Stamos IK. Synth. Commun. 1993; 23: 2241
      Crossref