PDF herunterladen
Synlett 2015; 26(16): 2261-2266
DOI: 10.1055/s-0035-1560462
letter
© Georg Thieme Verlag Stuttgart · New York

Regioselective Friedel–Crafts Reactions of N-Substituted Glyoxylamide with Indoles Catalyzed by Brønsted Acid

Zhen Zhan
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Department of Medicinal Chemistry West China School of Pharmacy, Sichuan University, Chengdu 610041, P. R. of China   eMail: wyong@scu.edu.cn
,
Renjun Li
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Department of Medicinal Chemistry West China School of Pharmacy, Sichuan University, Chengdu 610041, P. R. of China   eMail: wyong@scu.edu.cn
,
Yang Zheng
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Department of Medicinal Chemistry West China School of Pharmacy, Sichuan University, Chengdu 610041, P. R. of China   eMail: wyong@scu.edu.cn
,
Yan Zhou
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Department of Medicinal Chemistry West China School of Pharmacy, Sichuan University, Chengdu 610041, P. R. of China   eMail: wyong@scu.edu.cn
,
Li Hai
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Department of Medicinal Chemistry West China School of Pharmacy, Sichuan University, Chengdu 610041, P. R. of China   eMail: wyong@scu.edu.cn
,
Yong Wu*
Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Department of Medicinal Chemistry West China School of Pharmacy, Sichuan University, Chengdu 610041, P. R. of China   eMail: wyong@scu.edu.cn
› Institutsangaben
Weitere Informationen

Publikationsverlauf

Received: 10. Juni 2015

Accepted after revision: 17. Juli 2015

Publikationsdatum:
25. August 2015 (online)

    Lizenzen und Reprints Alle Artikel dieser Rubrik


Dedicated with admiration to Professor K. Peter C. Vollhardt

Abstract

An efficient regioselective Friedel–Crafts reaction of a series of N-substituted glyoxylamide with indoles catalyzed by Brønsted acid was developed. The reactions proceeded smoothly at room temperature and the corresponding N-substituted 2-hydroxy-2-(1H-indol-3-yl) acetamides were afforded in moderate to good yields (up to 89%). When 2 M HCl was used, the bisindole compounds were obtained in good to excellent yield (up to 91%) resulting from a double Friedel–Crafts reaction.

Key words

regioselective Friedel–Crafts reaction - Brønsted acid - N-substituted glyoxylamide - indole - N-substituted 2-hydroxy-2-(1H-indol-3-yl) acetamide - bisindole compound

Supporting Information

    Supporting information for this article is available online at http://dx.doi.org/10.1055/s-0035-1560462.
  • Supporting Information
 

  • References and Notes


      • N-Substituted glyoxylamides 1 were prepared according to the reported procedures, see:
    • 11a Chen WS, Liu YZ, Chen ZR. Eur. J. Org. Chem. 2005; 1665
    • 11b Wu WB, Yuan XQ, Hu J, Wu XX, Wei Y, Liu ZW, Lu JZ, Ye JX. Org. Lett. 2013; 15: 17
      Suche in Google Scholar

      Indoles 2 were purchased from ASTATECH and J&K Scientific Ltd. except ethyl 2-[(1-methyl-1H-indol-6-yl)oxy]acetate and 2-[(1-methyl-1H-indol-6-yl) oxy]acetamide. Ethyl 2-[(1-methyl-1H-indol-6-yl)oxy]acetate was synthesized according to the literature procedures, see:
    • 12a Finefield JM, Williams RM. J. Org. Chem. 2010; 75: 2785
      CrossrefSuche in Google Scholar
    • 12b Akao A, Nonoyama N, Mase T, Yasuda N. Org. Process Res. Dev. 2006; 10: 1178
      CrossrefSuche in Google Scholar
    • 12c Choy PY, Lau CP, Kwong FY. J. Org. Chem. 2011; 76: 80
      CrossrefSuche in Google Scholar
    • 12d Ontoria JM, Marco SD, Conte I, Francesco ME. D, Gardelli C, Koch U, Matassa VG, Poma M, Steinkühler C, Volpari C, Harper S. J. Med. Chem. 2004; 47: 6443
      CrossrefPubMedSuche in Google Scholar

      • 2-[(1-methyl-1H-indol-6-yl) oxy]acetamide was synthesized from ethyl 2-[(1-methyl-1H-indol-6-yl)oxy]acetate according to the literature procedures, see:
    • 12e Kreutter KD, Lu TB, Lee L, Giardino EC, Patel S, Huang H, Xu GZ, Fitzgerald M, Haertlein BJ, Mohan V, Crysler C, Eisennagel S, Dasgupta M, McMillan M, Spurlino JC, Huebert ND, Maryanoff BE, Tomczuk BE, Damiano BP, Player MR. Bioorg. Med. Chem. Lett. 2008; 18: 2865
      CrossrefSuche in Google Scholar
  • 13 N-Substituted 2-Hydroxy-2-(1H-indol-3-yl) Acetamides 3; General Procedure To a stirred mixture of N-substituted glyoxylamide (1.0 mmol), indoles (1.1 mmol) in dioxane (8 mL) was added AcOH (5.0 mmol) at 25 °C for 0.5 h. After the completion of the reaction (monitored by TLC), the mixture was diluted with H2O and extracted with EtOAc (4 × 20 mL). The organic layer was washed with sat. brine, dried over anhydrous Na2SO4, and the solvent was evaporated to dryness. The crude residue was purified by flash chromatography on silica gel (CH2Cl2–MeOH, 80:1) to afford pure N-substituted 2-hydroxy-2-(1H-indol-3-yl) acetamides 3 (61–89% yield). 2,2-Di(1H-indol-3-yl)-N,N-phenyl Acetamide Derivatives 4; General Procedure To a stirred mixture of N-substituted glyoxylamide (1.0 mmol), indoles (2.0 mmol) in dioxane (8 mL) was added HCl (2 mol/L, 0.1 mmol) at 25 °C for 0.5 h. After completion of the reaction (monitored by TLC), the mixture was diluted with H2O and extracted with EtOAc (3 × 20 mL). The organic layer was washed with sat. brine, dried over anhydrous Na2SO4, and the solvent was evaporated to dryness. The crude residue was purified by flash chromatography on silica gel (CH2Cl2–MeOH, 100:1) to afford pure 2,2-di(1H-indol-3-yl)-N,N-phenyl acetamide derivatives 4 (69–91% yield). Analytical Data of Some Typical Compounds 2-Hydroxy-2-(1H-indol-3-yl)-N-phenylacetamide (3a) Yield 84%; yellow solid, mp 150–152 °C. 1H NMR (400 MHz, DMSO-d 6): δ = 11.00 (s, 1 H), 9.90 (s, 1 H), 7.70 (s, 3 H), 7.33–7.28 (m, 4 H), 7.03–6.96 (m, 3 H), 6.08 (s, 1 H), 5.32 (s, 1 H). 13C NMR (150 MHz, DMSO-d 6): δ = 171.9, 138.9, 136.6, 128.8, 128.0, 126.0, 124.3, 123.6, 121.4, 119.9, 118.9, 114.8, 111.7, 68.9. ESI-HRMS: m/z [M + Na+] calcd for C16H14N2O2Na: 289.0947; found: 289.0961. Anal. Calcd: C, 72.17; H, 5.30; N, 10.52. Found: C, 72.10; H, 5.35; N, 10.53. 2,2-Di(1H-indol-3-yl)-N-phenylacetamide (4a) Yield 89%; yellow solid, mp 139–141 °C. 1H NMR (400 MHz, DMSO-d 6): δ = 10.90 (s, 2 H), 10.34 (s, 1 H), 7.65–7.57 (m, 4 H), 7.35 (m, 2 H), 7.28 (t, J = 8.0 Hz, 2 H), 7.19 (s, 2 H), 7.07–7.00 (m, 3 H), 6.95 (t, J = 8.0 Hz, 2 H) 5.55 (s, 1 H). 13C NMR (150 MHz, DMSO-d 6): δ = 171.0, 138.9, 137.0, 128.8, 126.9, 126.1, 124.1, 121.5, 120.4, 119.3, 118.0, 112.8, 111.0, 42.0. ESI-HRMS: m/z [M + Na+]: calcd for C24H19N3ONa: 388.1420; found: 388.1425. Anal. Calcd: C, 78.88; H, 5.24; N, 11.50. Found: C, 78.79; H, 4.23; N, 9.49. 2-[(3-{2-[(4-chlorophenyl)amino]-1-(1H-indol-3-yl)-2-oxoethyl}-1-methyl-1H-indol-6-yl)oxy]acetate (3d′) Yield 84%; brown solid, mp 194–196 °C. 1H NMR (600 MHz, DMSO-d 6): δ = 10.92 (s, 1 H), 10.47 (s, 1 H), 7.67 (d, J = 8.4 Hz, 2 H), 7.57 (d, J = 8.4 Hz, 1 H), 7.47 (d, J = 8.4 Hz, 1 H), 7.36–7.18 (m, 2 H), 7.18 (m, 1 H), 7.07–7.04 (m, 2 H), 6.96–6.94 (m, 2 H), 6.69–6.67 (m, 1 H), 5.48 (s, 1 H), 4.77 (s, 2 H), 4.17 (q, J = 7.2 Hz, 2 H), 3.67 (s, 3 H), 1.21 (t, J = 7.2 Hz, 3 H). 13C NMR (150 MHz, DMSO-d 6): δ = 171.9, 169.2, 154.5, 139.3, 137.8, 136.9, 132.5, 131.0, 128.5, 127.0, 122.9, 122.1, 121.6, 121.0, 120.7, 119.8, 112.5, 109.9, 98.6, 65.6, 42.6, 40.7, 32.4, 14.2. ESI-HRMS: m/z [M + Na+] calcd for C29H26ClN3O4Na: 538.1504; found: 538.1501. Anal. Calcd: C, 67.50; H, 5.08; N, 8.14. Found: C, 67.56; H, 5.00; N, 8.19.