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Rhodium-catalyzed, P-directed selective C7 arylation of indoles

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Science Advances  14 Dec 2018:
Vol. 4, no. 12, eaau6468
DOI: 10.1126/sciadv.aau6468
  • Fig. 1 Development of a Rh(I)-catalyzed protocol for the P-directed C7 arylation of indoles.

    (A) Nature products containing 7-arylindole moiety. (B) Rh(I)-catalyzed, phosphorous-directed C7 arylation of indoles. (C) Indole-based commercially available ligands.

  • Fig. 2 Relevant steps in overall transformation.

    Reaction conditions: 1a (0.20 mmol), 2 (0.40 mmol), Rh(PPh3)3Cl (6.0 mol%), and LiOtBu (3.0 equiv) in m-xylene (1.0 ml) at 150°C, 24 hours, under Ar. DG, directing group.

  • Fig. 3 Application as a key step in the synthesis of dictyodendrin B.

    Reaction conditions: (a) MeNO2, LiHMDS, 51%; (b) Pd(OAc)2 (2 mol %), Phen (4 mol %), CO (1 atm), DMF, 110°C, 93%; (c) tBu2PCl, or cHex2PCl, nBuLi, 92 to 95%; (c′) after procedure (c), then H2O2, 99%; (d) Rh(PPh3)3Cl (10 mol %), LiOtBu (3.0 equiv), 2d (10.0 equiv), m-xylene, 160°C, then add dilute HCl, 10 min, 72%; (d′) Pd(OAc)2 (10 mol %), 2-Cl-pyridine (20 mol %), Cu(OTf)2 (0.5 equiv), Ag2O (2.0 equiv), CuO (1.0 equiv), dioxane, 120°C, Ar, trace in gas chromatography–mass spectrometry.

  • Fig. 4 Preliminary investigation of the developed ligands in Suzuki-Miyaura couplings of aryl chlorides.

    Reaction conditions: 11 (0.20 mmol), 12 (0.40 mmol), Pd2(dba)3 (1.0 mol%), ligand (2.0 mol%), and K3PO4 (3.0 equiv) in m-xylene (1.0 ml) and H2O (1.0 ml) at 100°C, 24 hours, under Ar.

  • Fig. 5 Deuterium labeling experiments and the study of kinetic isotope effect.

    n.d., not detected.

  • Fig. 6 Plausible reaction pathways.
  • Table 1 Reaction optimization.

    Reaction conditions: 1a (0.20 mmol), 2 (0.30 mmol), base (3.0 equiv), solvent (1.0 ml), 24 hours, under Ar. CCDC, Cambridge Crystallographic Data Centre.

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    1X[Rh] (mol %)BaseSolventT (°C)Yield (%)*
    1Br (2a)Rh(PPh3)3Cl (6.0)Cs2CO3Toluene11010
    2Br (2a)Rh(PPh3)3Cl (6.0)tBuONaToluene11033
    3Br (2a)Rh(PPh3)3Cl (6.0)tBuOLiToluene11084
    4Br (2a)Rh(PPh3)3Cl (6.0)tBuOLiPhCl11089
    5Br (2a)Rh(PPh3)3Cl (6.0)tBuOLiPhCF311091
    6Br (2a)Rh(PPh3)3Cl (6.0)tBuOLim-Xylene11094
    7Br (2a)Rh(PPh3)3Cl (6.0)tBuOLim-Xylene8096
    8Br (2a)Rh(PPh3)3Cl (6.0)tBuOLim-Xylene6015
    9Cl (2a′)Rh(PPh3)3Cl (6.0)tBuOLim-Xylene11084
    10I (2a″)Rh(PPh3)3Cl (6.0)tBuOLim-Xylene110Trace
    11Br (2a)Rh(PPh3)3Cl (3.0)tBuOLim-Xylene8081
    12Br (2a)Rh(PPh3)3Cl (1.0)tBuOLim-Xylene8064
    13Br (2a)[Rh(cod)Cl]2 (3.0)tBuOLim-Xylene8011
    14Br (2a)[Rh(cod)Cl]2 (3.0)tBuOLim-Xylene8064
    15Br (2a)tBuOLim-Xylene800

    *Isolated yields.

    †With 10 mol % PPh3.

    • Table 2 Scope for the N-PtBu–directed C7-(hetero)arylation of indoles.

      Reaction conditions: 1a (0.20 mmol), 2 (0.40 mmol), Rh(PPh3)3Cl (6.0 mol%), LiOtBu (3.0 equiv) in m-xylene (1.0 ml) at 150°C, 24 hours, under Ar, isolated yields.


      Embedded Image

      *80°C.

      †100°C.

      ‡130°C.

      §Using 1t (0.10 mmol), 2 (0.40 mmol), Rh(PPh3)3Cl (12.0 mol%), and LiOtBu (6.0 equiv) in m-xylene (1.0 ml) at 100°C.

      • Table 3 Scope for the N-PcHex–directed C7 arylation of indoles.

        Reaction conditions: 1 (0.20 mmol), 2a (0.40 mmol), Rh(PPh3)3Cl (6.0 mol %), and LiOtBu (3.0 equiv) in m-xylene (1.0 ml) at 150°C, 24 hours, under Ar, isolated yields.


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      Supplementary Materials

      • Supplementary material for this article is available at http://advances.sciencemag.org/cgi/content/full/4/12/eaau6468/DC1

        Fig. S1. Test the indole N-PPh2–directed C7 arylation reaction.

        Fig. S2. General procedure for the investigation of the developed ligands in Suzuki-Miyaura coupling.

        Fig. S3. Single-crystal x-ray structure determination of compound 3aa (CCDC no. 1838725).

        Table S1. Deuteration experiments with indole 1a.

        Table S2. Deuteration experiments with indole D7-1a.

        Table S3. Study of kinetic isotope effect.

        Data file S1. Characterization of isolated compounds.

        Data file S2. X-ray crystal data of 3aa.

        Data file S3. 1H, 13C, 31P, and 19F NMR spectra.

      • Supplementary Materials

        This PDF file includes:

        • Fig. S1. Test the indole N-PPh2–directed C7 arylation reaction.
        • Fig. S2. General procedure for the investigation of the developed ligands in Suzuki-Miyaura coupling.
        • Fig. S3. Single-crystal x-ray structure determination of compound 3aa (CCDC no. 1838725).
        • Table S1. Deuteration experiments with indole 1a.
        • Table S2. Deuteration experiments with indole D7-1a.
        • Table S3. Study of kinetic isotope effect.
        • Data file S1. Characterization of isolated compounds.
        • Data file S2. X-ray crystal data of 3aa.
        • Data file S3. 1H, 13C, 31P, and 19F NMR spectra.

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