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Synlett 2019; 30(19): 2148-2152
DOI: 10.1055/s-0039-1690724
letter
© Georg Thieme Verlag Stuttgart · New York

Acetic Acid Catalysed One-Pot Synthesis of Pyrrolo[1,2-a]quinoxaline Derivatives

Pia N. M. Allan
,
Martyna I. Ostrowska
,
Bhaven Patel  ∗
We thank London Metropolitan University for funding.
Further Information

Publication History

Received: 11 September 2019

Accepted after revision: 07 October 2019

Publication Date:
22 October 2019 (online)

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Abstract

An efficient acetic acid catalysed reaction has been developed for the synthesis of 4-aryl substituted pyrrolo[1,2-a]quinoxalines from readily available starting materials. A range of structures have been synthesised in very good to excellent yields. The one-pot reaction proceeds through imine formation, cyclisation followed by air oxidation.

Key words

pyrrolo[1,2-a]quinoxaline - catalysis - Pictet–Spengler reaction - 1-(2-aminophenyl)pyrroles - biological heterocycles

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/s-0039-1690724.
  • Supporting Information
 

  • References and Notes

    • 1a Escude C, Nguyen CH, Kukreti S, Janin Y, Sun JS, Bisagni E, Garestier T, Helene C. Proc. Natl. Acad. Sci. U.S.A. 1998; 95: 3591
      CrossrefPubMed
    • 1b Deady LW, Kaye AJ, Finlay GJ, Baguley BC, Denny WA. J. Med. Chem. 1997; 40: 2040
      CrossrefPubMed
    • 1c Huang A, Ma C. Mini-Rev. Med. Chem. 2013; 13: 607
      CrossrefPubMed
    • 1d Rodrigues FA. R, Bomfim ID. S, Cavalcanti BC, Pessoa CD. O, Wardell JL, Wardell SM. S. V, Pinheiro AC, Kaiser CR, Nogueira TC. M, Low JN, Gomes LR, Souza MV. N. D. Bioorg. Med. Chem. Lett. 2014; 24: 934
      CrossrefPubMed
    • 2a Parrino B, Carbone A, Ciancimino C, Spano V, Montalbano A, Barraja P, Cirrincione G, Diana P, Sissi C, Palumbo M, Pinato O, Pennati M, Beretta G, Folini M, Matyus P, Balogh B, Zaffaroni N. Eur. J. Med. Chem. 2015; 94: 149
      CrossrefPubMed
    • 2b Desplat V, Geneste A, Begorre MA, Guillon J. J. Enzyme Inhib. Med. Chem. 2008; 23: 648
      PubMed
    • 2c Alleca S, Corona P, Lorigo M, Paglietti G, Loddo R, Mascia V, Busonera B, La Colla P. Farmaco 2003; 58: 639
      CrossrefPubMed
    • 2d Lv W, Budke B, Pawlowski M, Connell PP, Kozikowski AP. J. Med. Chem. 2016; 59: 4511
      CrossrefPubMed
    • 2e Aiello F, Carullo G, Giordano F, Spina E, Nigro A, Garofalo A, Tassini S, Costantino G, Vincetti p, Bruno A, Radi M. ChemMedChem 2017; 12: 1279
      CrossrefPubMed
    • 2f You W, Rotili D, Li T.-M, Kambach C, Meleshin M, Schutkowski M, Chua KF, Mai A, Steegborn C. Angew. Chem. Int. Ed. 2017; 56: 1007
      CrossrefPubMed
    • 3a Guillon J, Cohen A, Gueddouda NM, Das RN, Moreau S, Ronga L, Savrimoutou S, Basmaciyan L, Monnier A, Monget M, Rubio S, Garnerin T, Azas N, Mergny J.-L, Mullie C, Sonnet P. J. Enzyme Inhib. Med. Chem. 2017; 32: 547
      CrossrefPubMed
    • 3b Ronga L, Del Favero M, Cohen A, Soum C, Le Pape P, Savrimoutou S, Pinaud N, Mullie C, Daulouede S, Vincendeau P, Farvacques N, Agnamey P, Pagniez F, Hutter S, Azas N, Sonnet P, Guillon J. Eur. J. Med. Chem. 2014; 81: 378
      CrossrefPubMed
    • 3c Guillon J, Mouray E, Moreau S, Mullie C, Forfar I, Desplat V, Belisle-Fabre S, Pinaud N, Ravanello F, Le-Naour A, Leger JM, Gosmann G, Jarry C, Deleris G, Sonnet P, Grellier P. Eur. J. Med. Chem. 2011; 46: 2310
      CrossrefPubMed
    • 4a Desplat V, Moreau S, Gay A, Fabre SB, Thiolat D, Massip S, Macky G, Godde F, Mossalayi D, Jarry C, Guillon J. J. Enzyme Inhib. Med. Chem. 2010; 25: 204
      CrossrefPubMed
    • 4b Desplat V, Moreau S, Belisle-Fabre S, Thiolat D, Uranga J, Lucas R, de Moor L, Massip S, Jarry C, Mossalayi DM, Sonnet P, Déléris G, Guillon J. J. Enzyme Inhib. Med. Chem. 2011; 26: 657
      CrossrefPubMed
  • 5 Guillon J, Borgne ML, Rimbault C, Moreau S, Savrimoutou S, Pinaud N, Baratin S, Marchivie M, Roche S, Bollacke A, Pecci A, Alvarez L, Desplat V, Jose J. Eur. J. Med. Chem. 2013; 65: 205
    CrossrefPubMed
  • 6 Guillon J, Dallemagne P, Pfeiffer B, Renard P, Manechez D, Kervran A, Rault S. Eur. J. Med. Chem. 1998; 33: 293
    Crossref
  • 7 Campiani G, Morelli E, Gemma S, Nacci V, Butini S, Hamon M, Novellino E, Greco G, Cagnotto A, Goegan M, Cervo L, Valle FD, Fracasso C, Caccia S, Mennini T. J. Med. Chem. 1999; 42: 4362
    CrossrefPubMed
    • 8a Jacobsen EJ, Stelzer LS, Belonga KL, Carter DB, Im WB, Sethy VH, Tang AH, Von Voigtlander PF, Petke JD. J. Med. Chem. 1996; 39: 3820
      CrossrefPubMed
    • 8b Colotta V, Cecchi L, Catarzi D, Filacchioini G, Martini C, Tacchi P, Lucacchini A. Eur. J. Med. Chem. 1995; 30: 133
  • 9 Gemma S, Colombo L, Forloni G, Savini L, Fracasso C, Caccia S, Salmona M, Brindisi M, Joshi BP, Tripaldi P, Giorgi G, Taglialatela-Scafati O, Novellino E, Fiorini I, Campiani G, Butini S. Org. Biomol. Chem. 2011; 9: 5137
    CrossrefPubMed
    • 10a Kalinin AA, Mamedov VA. Chem. Heterocycl. Compd. 2011; 46: 1423 ; and references therein
      Crossref
    • 10b Mamedov VA, Kalinin AA. Chem. Heterocycl. Compd. 2010; 46: 641 ; and references therein
      Crossref
  • 11 Kalinin AA, Islamova LN, Fazleeva GM. Chem. Heterocycl. Compd. 2019; 55: 584 ; and references therein
    Crossref
  • 12 Pereira MF, Thiéry V. Org. Lett. 2012; 14: 4754
    CrossrefPubMed
  • 13 Sun Q, Liu L, Yang Y, Zha Z, Wang Z. Chin. Chem. Lett. 2019; 30: 1379
    Crossref
    • 15a Wang C, Li Y, Guo R, Tian J, Tao C, Cheng B, Wang H, Zhang J, Zhai H. Asian J. Org. Chem. 2015; 4: 866
      Crossref
    • 15b Xie C, Feng L, Li W, Ma X, Liu Y, Ma C. Org. Biomol. Chem. 2016; 14: 8529
      CrossrefPubMed
    • 16a Guillon J, Forfar I, Mamani-Matsuda M, Desplat V, Saliege M, Thiolat D, Massip S, Tabourier A, Léger J. -M, Dufaure B. Bioorg. Med. Chem. 2007; 15: 194
      CrossrefPubMed
    • 16b Cheeseman GW. H, Tuck B. J. Chem. Soc. (C) 1966; 852
    • 17a Kamal A, Babu KS, Kovvuri J, Manasa V, Ravikumar A, Alarifi A. Tetrahedron Lett. 2015; 56: 7012
      Crossref
    • 17b Preetam A, Nath M. RSC Adv. 2015; 5: 21843
      Crossref
    • 17c Wang C, Li Y, Zhao J, Cheng B, Wang H, Zhai H. Tetrahedron Lett. 2016; 57: 3908
      Crossref
  • 18 Verma AK, Jha RR, Kasi Sankar V, Aggarwal T, Singh R, Chandra R. Eur. J. Org. Chem. 2011; 6998
  • 19 Huo H.-R, Tang X.-Y, Gong Y.-F. Synthesis 2018; 50: 2727
    Article in Thieme Connect
  • 20 Krishna T, Reddy TR, Laxminarayana E, Kalita D. ChemistrySelect 2019; 4: 250
    Crossref
    • 21a An Z, Jiang Y, Guan X, Yan R. Chem. Commun. 2018; 54: 10738
      CrossrefPubMed
    • 21b An Z, Zhao L, Wu M, Ni J, Qi Z, Yu G, Yan R. Chem. Commun. 2017; 53: 11572
      CrossrefPubMed
    • 21c Lade JJ, Patil BN, Vhatkar MV, Vadagaonkar KS, Chaskar AC. Asian J. Org. Chem. 2017; 6: 1579
      Crossref
    • 21d Lade JJ, Patil BN, Sathe PA, Vadagaonkar KS, Chetti P, Chaskar AC. ChemistrySelect 2017; 2: 6811
      Crossref
  • 22 Typical Procedure for the Synthesis of Pyrrolo[1,2-a]quinoxaline 3a: To a solution of 2-(1H-pyrrol-1-yl)aniline (1 equiv) in methanol (5 mL) were added benzaldehyde (1 equiv) and acetic acid (0.1 equiv) and the mixture was heated to 60 °C for 8 h. The reaction mixture was allowed to cool to room temperature and the solvent was removed under reduced pressure. The crude reaction mixture was purified by column chromatography to give 2-substituted pyrrolo[1,2-a]quinoxaline 3a as a pale-yellow solid; mp 118–120 °C. IR (neat): 2929 (CH) cm–1. 1H NMR (500 MHz, CDCl3): δ = 8.07 (dd, J = 7.7, 1.4 Hz, 1 H, ArH), 7.99–8.04 (m, 5 H, 5 × ArH), 7.88 (dd, J = 8.0, 1.4 Hz, 1 H, ArH), 7.01 (dd, J = 3.8, 1.3 Hz, 1 H, ArH), 6.90 (dd, J = 3.9, 2.7 Hz, 1 H, ArH). 13C (126 MHz, CDCl3): δ = 154.4 (C), 138.4 (C), 136.2 (C), 130.2 (CH), 129.7 (CH), 128.6 (2 × CH), 128.5 (2 × CH), 127.4 (CH), 127.1 (C), 125.3 (C), 125.2 (CH), 114.5 (CH), 113.9 (CH), 113.6 (CH), 108.7 (CH). MS: m/z (%) = 244 (100) [M + H]+.
  • 23 Woon KL, Ariffin A, Ho KW, Chen S.-A. RSC Adv. 2018; 8: 9850
    Crossref