Download PDF
Synlett 2022; 33(15): 1519-1522
DOI: 10.1055/a-1865-2556
letter

Construction of Indole Skeletons through Direct Catalytic Three-Component Domino Reactions of Vinylarenes, Aldehydes, and Pronucleophiles

Fuka Hori
,
Tomoyuki Yoshimura 
,
Jun-ichi Matsuo  ∗
We are grateful for financial support from JSPS (KAKENHI Grant Number JP19K05473 and 22K06500).
› Further Information
    Permissions and Reprints All articles of this category


Abstract

A synthesis of 3-alkyl-2-arylindoles was performed by sequential oxidation and reduction of 2-(2-nitrophenyl)ethanols that were prepared by base-catalyzed three-component reactions of vinylarenes, aldehydes, and various pronucleophiles, including nitroalkanes, thiols, and malonates. In addition to indoles, a selective synthesis of an N-hydroxyindole was accomplished. The highly nucleophilic character of transient benzylic anions in DMSO was also clarified for the three-component reactions.

Key words

indole - multicomponent reaction - catalytic reaction - direct reaction - domino reaction

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/a-1865-2556.
  • Supporting Information


Publication History

Received: 09 May 2022

Accepted after revision: 31 May 2022

Accepted Manuscript online:
31 May 2022

Article published online:
23 June 2022

© 2022. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References and Notes

  • 1 Lal S, Snape TJ. Curr. Med. Chem. 2012; 19: 4828
    CrossrefPubMed
    • 2a Komm BS, Kharode YP, Bodine PV. N, Harris HA, Miller CP, Lyttle CR. Endocrinology 2005; 146: 3999
      CrossrefPubMed
    • 2b Mylavarapu R, Kondaiah GC. M, Reddy LA, Dubey MK, Jasmine, Mukkanti K, Bandichhor R. Chem. Biol. Interface 2015; 5: 137
  • 3 Dinnell K, Chicchi GG, Dhar MJ, Elliott JM, Hollingworth GJ, Kurtz MM, Ridgill MP, Rycroft W, Tsao K.-L, Williams AR, Swain CJ. Bioorg. Med. Chem. Lett. 2001; 11: 1237
    CrossrefPubMed
  • 4 Chu L, Hutchins JE, Weber AE, Lo J.-L, Yang Y.-T, Cheng K, Smith RG, Fisher MH, Wyvratt MJ, Goulet MT. Bioorg. Med. Chem. Lett. 2001; 11: 509
    CrossrefPubMed
    • 5a La Regina G, Bai R, Coluccia A, Famiglini V, Pelliccia S, Passacantilli S, Mazzoccoli C, Ruggieri V, Verrico A, Miele A, Monti L, Nalli M, Alfonsi R, Di Marcotullio L, Gulino A, Ricci B, Soriani A, Santoni A, Caraglia M, Porto S, Da Pozzo E, Martini C, Brancale A, Marinelli L, Novellino E, Vultaggio S, Varasi M, Mercurio C, Bigogno C, Dondio G, Hamel E, Lavia P, Silvestri R. J. Med. Chem. 2015; 58: 5789
      CrossrefPubMed
    • 5b Chu L, Lo J.-L, Yang Y.-T, Cheng K, Smith RG, Fisher MH, Wyvratt MJ, Goulet MT. Bioorg. Med. Chem. Lett. 2001; 11: 515
      CrossrefPubMed
    • 5c Trotter BW, Quigley AG, Lumma WC, Sisko JT, Walsh ES, Hamann CS, Robinson RG, Bhimnathwala H, Kolodin DG, Zheng W, Buser CA, Huber HE, Lobell RB, Kohl NE, Williams TM, Graham SL, Dinsmore CJ. Bioorg. Med. Chem. Lett. 2001; 11: 865
      CrossrefPubMed
    • 6a Van Order RB, Lindwall HG. Chem. Rev. 1942; 30: 69
      Crossref
    • 6b Robinson B. Chem. Rev. 1969; 69: 227
      Crossref
    • 7a Madelung W. Ber. Dtsch. Chem. Ges. 1912; 45: 1128
      Crossref
    • 7b Houlihan WJ, Parrino VA, Uike Y. J. Org. Chem. 1981; 46: 4511
      Crossref
    • 8a Larock RC, Yum EK. J. Am. Chem. Soc. 1991; 113: 6689
      CrossrefPubMed
    • 8b Larock RC, Yum EK, Refvik MD. J. Org. Chem. 1998; 63: 7652
      Crossref
    • 9a Bartoli G, Palmieri G, Bosco M, Dalpozzo R. Tetrahedron Lett. 1989; 30: 2129
      Crossref
    • 9b Bartoli G, Bosco M, Dalpozzo R, Palmieri G, Marcantoni E. J. Chem. Soc., Perkin Trans. 1 1991; 2757
      Crossref
  • 10 Batcho AD, Leimgruber W. Org. Synth. Coll. Vol. VII . Wiley; London: 1990: 34
    Google Scholar
  • 11 Reissert A. Ber. Dtsch. Chem. Ges. 1897; 30: 1030
    Crossref

      • For recent indole synthesis progress and applications, see:
    • 12a Humphrey GR, Kuethe JT. Chem. Rev. 2006; 106: 2875
      CrossrefPubMed
    • 12b Taber DF, Tirunahari PK. Tetrahedron 2011; 67: 7195
      CrossrefPubMed
    • 12c Heravi MM, Rohani S, Zadsirjan V, Zahedi N. RSC Adv. 2017; 7: 52852
      Crossref
    • 12d Neto JS. S, Zeni G. Org. Chem. Front. 2020; 7: 155
      Crossref
  • 13 Tsuji Y, Kotachi S, Huh KT, Watanabe Y. J. Org. Chem. 1990; 55: 580
    CrossrefPubMed
    • 14a Morita S, Yoshimura T, Matsuo J. Green Chem. 2021; 23: 1160
      Crossref
    • 14b Morita S, Yoshimura T, Matsuo J. Tetrahedron 2021; 94: 132329
      Crossref
    • 15a Dale WJ, Strobel CW. J. Am. Chem. Soc. 1954; 76: 6172
      Crossref
    • 15b Gnanasekaran KK, Yoon J, Bunce RA. Tetrahedron Lett. 2016; 57: 3190
      Crossref
  • 16 Siperko LG, Smith FX. Synth. Commun. 1979; 9: 383
    Crossref
  • 17 Pratihar S. Org. Biomol. Chem. 2014; 12: 5781
    CrossrefPubMed
  • 18 Nicolaou KC, Estrada AA, Freestone GC, Lee SH, Alvarez-Mico X. Tetrahedron 2007; 63: 6088
    CrossrefPubMed
  • 19 Diethyl {3-Hydroxy-2-(2-nitrophenyl)-3-[2-(trifluoromethyl)phenyl]propyl}(methyl)malonate (4j); Typical Procedure A mixture of diethyl methylmalonate (104.5 mg, 0.6 mmol), a 0.5 M solution of KHMDS in toluene (0.06 mL, 0.03 mmol), and anhyd DMSO (0.5 mL) was added to a stirred solution of 2-nitrostyrene (89.5 mg, 0.60 mmol) and 2-(trifluoromethyl)benzaldehyde (52.2 mg, 0.30 mmol) in dry DMSO (0.5 mL) at rt. The resulting solution was stirred at rt for 18 h, and then the reaction was quenched by addition of sat. aq NH4Cl. The mixture was extracted with EtOAc, and the organic extracts were washed with H2O, dried (Na2SO4), filtered, and concentrated. The crude product was purified by column chromatography [silica gel, hexane–EtOAc (5:1)] to give a yellow solid; yield: 107.7 mg (0.216 mmol, 72%); mp 98.3–99.0 °C (CHCl3). IR (CHCl3): 3602, 3029, 2987, 1725, 1608, 1527, 1351 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.80 (d, J = 8.0 Hz, 1 H), 7.67–7.60 (m, 3 H), 7.44–7.35 (m, 3 H), 7.28 (d, J = 8.0 Hz, 1 H), 5.18 (t, J = 6.0 Hz, 1 H), 4.12–4.00 (m, 3 H), 3.98–3.77 (m, 1 H), 3.67–3.59 (m, 1 H), 2.65 (d, J = 5.2 Hz, 1 H), 2.55 (dd, J = 14.4, 10.8 Hz, 1 H), 2.20 (dd, J = 14.4, 2.8 Hz, 1 H), 1.19–1.15 (m, 6 H), 1.07 (t, J = 6.8 Hz, 3 H).13C NMR (100 MHz, CDCl3): δ = 172.0, 171.4, 151.6, 140.9, 134.8, 132.0, 132.0, 130.1, 128.0, 127.7, 127.7 (q, split by C–F coupling, J = 29.6 Hz), 127.6, 125.6 (q, split by C–F coupling, J = 5.7 Hz), 124.3 (q, split by C–F coupling, J = 272.7 Hz), 124.0, 73.2, 61.5, 61.1, 52.8, 40.9, 37.4, 19.9, 13.8, 13.7. HRMS (DART+): m/z [M + H]+ calcd for C24H27F3NO7: 498.1740; found: 498.1732.
  • 20 Diethyl Methyl({2-[2-(trifluoromethyl)phenyl]-1H-indol-3-yl}methyl)malonate (5j) and Diethyl ({1-Hydroxy-2-[2-(trifluoromethyl)phenyl]-1H-indol-3-yl}methyl)(methyl)malonate (7j); Typical Procedure PCC (43.1 mg, 0.20 mmol) was added to a stirred suspension of 4j (24.8 mg, 0.05 mmol) and Celite (27.7 mg) in CH2Cl2 (2.0 mL) at 0 °C, and the mixture was stirred at rt for 24 h. The mixture was then filtered through a silica gel pad by washing with Et2O, and the filtrate was concentrated to give a crude product (26.5 mg) that was used in the next step without purification. To a stirred solution of the resulting ketone (26.5 mg) in CH2Cl2 (1.0 mL) were added Zn (49 mg) and AcOH (0.08 mL, 1.40 mmol) at 0 °C. The resulting mixture was refluxed for 3 h, cooled to rt, and filtered through Celite pad. Sat. aq NaHCO3 was added, and the mixture was extracted with CH2Cl2. The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated. The crude product was purified by preparative TLC (benzene–EtOAc, 10:1) to give 5j as a yellow oil [yield: 19.5 mg (43.6 μmol, 87% for 2 steps)] and 7j as a white solid [yield: 0.9 mg (1.94 μmol, 4% for 2 steps)]. 5j IR (CHCl3): 3471, 2985, 2938, 1725, 1606 cm–1. 1H NMR (CDCl3, 400 MHz): δ = 8.16 (br s, 1 H), 7.81 (d, J = 7.2 Hz, 1 H), 7.65–7.52 (m, 4 H), 7.34 (d, J = 7.6 Hz, 1 H), 7.23–7.10 (m, 2 H), 4.04–3.96 (m, 2 H), 3.89–3.82 (m, 2 H), 3.54 (s, 2 H), 1.13 (s, 3 H), 1.08 (t, J = 6.8 Hz, 6 H). 13C NMR (CDCl3, 100 MHz): δ = 172.2, 135.4, 133.7, 133.2, 131.8, 131.5, 129.4 (q, split by C–F coupling, J = 30.5 Hz), 128.9, 128.6, 126.6 (q, split by C–F coupling, J = 4.7 Hz), 123.9 (q, split by C–F coupling, J = 272.7 Hz), 122.5, 119.7, 119.6, 110.7, 109.2, 61.1, 54.8, 29.3, 19.9, 13.7. HRMS (FAB+): m/z [M+] calcd for C24H24F3NO4: 447.1657; found: 447.1652. 7j mp 174.0–175.0 °C (MeOH). IR (CHCl3): 3029, 2985, 1724 cm–1. 1H NMR (CD3OD, 400 MHz): δ = 7.83 (d, J = 7.6 Hz, 1 H), 7.74–7.63 (m, 2 H), 7.50–7.46 (m, 2 H), 7.37 (d, J = 8.4 Hz, 1 H), 7.17 (t, J = 8.4 Hz, 1 H), 7.03 (t, J = 6.8 Hz, 1 H), 4.05–3.90 (m, 3 H), 3.86–3.78 (m, 1 H), 3.48 (d, J = 14.8 Hz, 1 H), 3.20 (d, J = 14.8 Hz, 1 H), 1.13–1.04 (m, 9 H). 13C NMR (CD3OD, 100 MHz): δ = 173.8, 173.7, 135.8, 135.4, 134.9, 132.4, 132.0 (q, split by C–F coupling, J = 30.5 Hz), 130.5, 130.3, 127.6 (q, split by C–F coupling, J = 4.8 Hz), 125.3 (q, split by C–F coupling, J = 272.7 Hz), 125.3, 123.1, 120.2, 120.2, 109.3, 105.3, 62.5, 62.4, 56.0, 31.0, 20.8, 14.1, 14.1. HRMS (FAB+): m/z [M+] calcd for C24H24F3NO5: 463.1607; found: 463.1598.