Download PDF
Synthesis 2024; 56(05): 860-870
DOI: 10.1055/a-2206-5900
paper

Synthesis of All Regioisomers of 2-Arylazaindole-3-acetic Acid Derivatives

Taewook Kim‡
a   Department of Chemistry, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea
,
Ju Hyeon Park‡
a   Department of Chemistry, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea
,
Cheol Jeong‡
b   Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Daejeon 34114, Republic of Korea
c   Graduate School of New Drug Discovery and Development, Chungnam National University, 99 Daehak-ro, Daejeon 34134, Republic of Korea
,
Eunjoon Park
a   Department of Chemistry, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea
,
Jong Mu Kim
a   Department of Chemistry, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea
,
You-Jin Kim
b   Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Daejeon 34114, Republic of Korea
c   Graduate School of New Drug Discovery and Development, Chungnam National University, 99 Daehak-ro, Daejeon 34134, Republic of Korea
,
Jung-Nyoung Heo∗
b   Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology, 141 Gajeong-ro, Daejeon 34114, Republic of Korea
c   Graduate School of New Drug Discovery and Development, Chungnam National University, 99 Daehak-ro, Daejeon 34134, Republic of Korea
,
Cheol-Hong Cheon  ∗
a   Department of Chemistry, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 02841, Republic of Korea
› Author AffiliationsThis work was supported by the National Research Foundation of Korea­ (NRF) grants funded by the Korean Government {NRF-2021R1A2C1012984, NRF-2021R1A5A6002803 (Center for New Directions­ in Organic Synthesis)} for CHC, and by the Bio&Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIT) (NRF-RS-2023-00235550) for JNH.
› Further Information
    Permissions and Reprints All articles of this category


Abstract

A novel protocol was developed for synthesizing 2-aryl-substituted azaindole-3-acetic acid derivatives from 2-aminoazacinnamic acid derivatives and aryl aldehydes through an imino-Stetter reaction. Condensation of 2-aminoazacinnamic acid derivatives with aldehydes forms the corresponding aldimines, which are then treated with cyanide to yield the desired 2-aryl-substituted azaindole-3-acetic acid derivatives. Notably, this protocol could be employed for the synthesis of all regioisomers of azaindole-3-acetic acid derivatives by using the appropriate azacinnamic acid derivatives.

Key words

azaindoles - regioisomers - azacinnamic acid derivatives - imino-Stetter reaction - cyanide

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/a-2206-5900.
  • Supporting Information


Publication History

Received: 19 September 2023

Accepted after revision: 08 November 2023

Accepted Manuscript online:
08 November 2023

Article published online:
02 January 2024

© 2023. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References


      • For reviews of azaindoles, see:
    • 1a Song JJ, Reeves JT, Gallow F, Tan Z, Yee NK, Senanayake CH. Chem. Soc. Rev. 2007; 36: 1120
      CrossrefPubMed
    • 1b Merour J.-Y, Buron F, Ple K, Bonnet P, Routier S. Molecules 2014; 19: 19935
      CrossrefPubMed
    • 1c Motati DR, Amaradhi R, Ganesh T. Bioorg. Med. Chem. 2020; 28: 115830
      CrossrefPubMed
    • 1d Motati DR, Amaradhi R, Ganesh T. Org. Chem. Front. 2021; 8: 466
      Crossref

      For examples of the comparison of bioactivities between indoles and azaindoles, see:
    • 2a Garai S, Kulkarni PM, Schaffer PC, Leo LM, Brandt AL, Zagzoog A, Tallan B, Lin X, Hurst DP, Janero DR, Abood ME, Zimmowitch A, Straiker A, Pertwee RG, Kelly M, Szczesniak A.-M, Denovan-Wright EM, Mackie K, Hohmann AG, Reggio PH, Laprairie RB, Thakur GA. J. Med. Chem. 2020; 63: 542
      CrossrefPubMed
    • 2b Urvashi JB, Kumar S, Das P, Tandon V. J. Med. Chem. 2022; 65: 6454
      CrossrefPubMed

      For selected examples of the syntheses of indoles and azaindoles using the same protocol, see:
    • 3a Jeanty M, Blu J, Suzenet F, Guillaumet G. Org. Lett. 2009; 11: 5142
      CrossrefPubMed
    • 3b Livecchi M, Calvet G, Schmidt F. J. Org. Chem. 2012; 77: 5006
      CrossrefPubMed
    • 3c Pires MJ. D, Poeira DL, Purificação SI, Marques MM. B. Org. Lett. 2016; 18: 3250
      CrossrefPubMed
    • 3d Purificação SI, Pires MJ. D, Rippel R, Santos AS, Marques MM. B. Org. Lett. 2017; 19: 5118
      CrossrefPubMed
    • 3e Qiu Y, Dlugosch M, Liu X, Khan F, Ward JS, Lan P, Banwell MG. J. Org. Chem. 2018; 83: 12023
      CrossrefPubMed
  • 4 A limited number of examples of the synthesis of all regioisomers of azaindole derivatives using a single protocol have been reported. However, the efficiency of these protocols strongly relies on the position of the nitrogen atom in the starting materials; consequently, the substrate scope of certain azaindole regioisomers is limited. For selected examples, see refs. 3c and 3d.

      • For examples of the bioactivities of 2-aryl-substituted indole-3-acetic acid derivatives, see:
    • 5a Schultz C, Link A, Leost M, Zaharevitz DW, Gussio R, Sausville EA, Meijer L, Kunick C. J. Med. Chem. 1999; 42: 2909
      CrossrefPubMed
    • 5b Boucherle B, Haudecoeur R, Queiroz EF, Waard MD, Wolfender J.-L, Robins RJ. Nat. Prod. Rep. 2016; 33: 1034
      CrossrefPubMed
    • 5c Curtin NJ. Cancers 2020; 12: 564
      CrossrefPubMed
    • 5d Yeo M, Chen Y, Jiang C, Chen G, Wang K, Chandra S, Bortsov A, Lioudyno M, Zeng Q, Wang P, Wang Z, Buscigilo J, Ji R.-R, Liedtke W. Nat. Commun. 2021; 12: 6208
      CrossrefPubMed
  • 6 Only one example of the synthesis of a 2-aryl-substituted azaindole-3-acetic acid derivative has been reported. However, the protocol used in this study has never been explored for the synthesis of other 2-aryl-substituted indole-3-acetic acid derivatives. See: Power DP, Lozach O, Meijer L, Gravson DH, Connon SJ. Bioorg. Med. Chem. Lett. 2010; 20: 4940
    CrossrefPubMed
  • 7 For a seminal report on the cyanide-catalyzed imino-Stetter reaction, see: Lee SJ, Seo H.-A, Cheon C.-H. Adv. Synth. Catal. 2016; 358: 1566
    Crossref
  • 8 For a review on the cyanide-catalyzed imino-Stetter reaction, see: Park E, Jeon J, Cheon C.-H. Chem. Rec. 2018; 18: 1474
    CrossrefPubMed

      • For selected examples of the application of the imino-Stetter reaction to natural product total synthesis, see:
    • 9a Bae C, Park E, Cho C.-G, Cheon C.-H. Org. Lett. 2020; 22: 2354
      CrossrefPubMed
    • 9b Jeon J, Kim HJ, Cheon C.-H. J. Org. Chem. 2020; 85: 8149
      CrossrefPubMed
    • 9c Park E, Bae C, Cho C.-G, Cheon C.-H. J. Org. Chem. 2021; 86: 4497
      CrossrefPubMed
    • 9d Jeon J, Lee SE, Cheon C.-H. Org. Lett. 2021; 23: 2169
      CrossrefPubMed
    • 9e Park J, Cheon C.-H. J. Org. Chem. 2022; 87: 4813
      CrossrefPubMed
    • 9f Jeon J, Cheon C.-H. Org. Lett. 2022; 24: 7128
      CrossrefPubMed
  • 10 For a review of bioactivity of 7-azaindole derivatives, see: Sharma N. Anurag, Mini-Rev. Med. Chem. 2019; 19: 727
    CrossrefPubMed

      • For examples of bioactivities of 7-azaindole derivatives, see:
    • 11a Bollag G, Hirth P, Tsai J, Zhang J, Ibrahim PN, Cho H, Spevak W, Zhang C, Zhang Y, Habets G, Burton EA, Wong B, Tsang G, West BL, Powell B, Shellooe R, Marimuthu A, Nguyen H, Zhang KY. J, Artis DR, Schlessinger J, Su F, Higgins B, Iyer R, D’Andrea K, Koehler A, Stumm M, Lin PS, Lee RJ, Grippo J, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, Chapman PB, Flaherty KT, Xu X, Nathanson KL, Nolop K. Nature 2010; 467: 596
      CrossrefPubMed
    • 11b Lamb YN. Drugs 2019; 79: 1805
      CrossrefPubMed
  • 12 We developed a protocol for the synthesis of 2-aminocinnamic acid derivatives via the Heck reaction of 2-iodoanilines with acrylic acid derivatives; see ref. 9b.
  • 13 For the effect of reaction media on the efficiency of Heck coupling, see: Yoon J, Cheon C.-H. Asian J. Org. Chem. 2019; 8: 1631
    CrossrefPubMed
  • 14 Blackburn C, Guan B. Tetrahedron Lett. 2000; 41: 1495
    Crossref
  • 15 For an example of the synthesis of 3-azacinnamic acid derivatives via the Wittig reaction, see: Allen JR, Amegadzie A, Andrews KL, Brown J, Chen JJ, Chen N, Harrington EH, Liu Q, Nguyen TT, Pickrell AJ, Qian W, Rumfelt S, Rzasa RM, Yuan CC, Zhong W. U.S. Patent 20130225552A1, 2013
    PubMed
  • 16 Because cyanide is regenerated after the imino-Stetter reaction of these substrates, we expected that the imino-Stetter reactions for the syntheses of 4-, 5- and 6-azaindole-3-acetic acid derivatives would proceed with a catalytic amount of cyanide. For details, see ref. 8.
  • 17 Product 16bc underwent transesterification to form the corresponding methyl ester during column chromatography on silica gel using methanol as an eluent. To prevent this, we used ethanol instead of methanol as the eluent during the column separation.