Research ArticleChemistry

Ketones and aldehydes as alkyl radical equivalents for C─H functionalization of heteroarenes

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Science Advances  11 Oct 2019:
Vol. 5, no. 10, eaax9955
DOI: 10.1126/sciadv.aax9955
  • Fig. 1 The combination of PCET and an RNR class I reaction enables heteroarene C─H alkylation using ketones and aldehydes as alkyl radical equivalents.

    (A) The polarity of the C═O bond. HAT, hydrogen atom transfer. (B) A new catalyst system for reductive PCET. (C) The RNR class I reaction. (D) The method reported herein.

  • Fig. 2 Proposed mechanism for direct alkylation of heteroaromatic using ketones and aldehydes as alkyl radical sources.

  • Fig. 3 Mechanistic studies in support of the proposed pathway.

    (A) Ir[dF(CF3)ppy]2(dtbbpy)PF6 emission quenching with TTMS. (B) Proof of the corresponding α-oxy radicals. (C) Mechanistic studies support the spin-center shift elimination pathway. (D) Confirmation of the source of hydrogen atoms at the benzylic position of product. rt, room temperature.

  • Table 1 Optimization of conditions for alkylation of 4-hydroxyquinazoline with acetone.

    Reaction conditions: 4-hydroxyquinazoline (0.3 mmol), photocatalyst (0.003 mmol), reductant (0.6 mmol), TFA (0.6 mmol), and acetone (3.0 ml) under Ar atmosphere. The yield was determined by 1H NMR spectroscopy using dibromomethane as the internal standard. Reaction was performed in the absence of light for entry 9. Reaction was performed in the absence of photocatalyst for entry 10. Reaction was performed in the absence of TTMS for entry 11. Reaction was performed in the absence of TFA for entry 12. rt, room temperature; NR, no reaction; DIPEA, N,N-diisopropylethylamine; HEH, diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate.


    Embedded Image
    EntryPhotocatalystReductantYield (%)
    1Ir[dF(CF3)ppy]2(dtbbpy)PF6TTMS96
    2Ir(ppy)3TTMSNR
    3[Ru(bpy)3](PF6)2TTMSNR
    4Eosin-YTTMSNR
    5Ir[dF(CF3)ppy]2(dtbbpy)PF6Et3SiH82
    6Ir[dF(CF3)ppy]2(dtbbpy)PF6Ph3SiHNR
    7Ir[dF(CF3)ppy]2(dtbbpy)PF6DIPEANR
    8Ir[dF(CF3)ppy]2(dtbbpy)PF6HEH40
    9Ir[dF(CF3)ppy]2(dtbbpy)PF6TTMSNR
    10TTMSNR
    11Ir[dF(CF3)ppy]2(dtbbpy)PF6NR
    12Ir[dF(CF3)ppy]2(dtbbpy)PF6TTMSNR
  • Table 2 Exploration of substrate scope.

    Reactions were performed on a 0.3-mmol scale, unless otherwise noted. Isolated yields are given. We used Hantzsch dihydropyridine as reductant for 48. See the Supplementary Materials for experimental details.


    Embedded Image

Supplementary Materials

  • Supplementary material for this article is available at http://advances.sciencemag.org/cgi/content/full/5/10/eaax9955/DC1

    Section S1. General information

    Section S2. Reaction optimization

    Section S3. Investigation of the mechanism

    Section S4. Experimental procedures and product characterization

    Section S5. Copies of 1H NMR and 13C NMR spectra for new compounds

    Table S1. Screening of different solvents.

    Table S2. Screening of the amount of cyclohexanone.

    Table S3. Light on and off experiments.

    Table S4. Control experiments of intermediate 66.

    Fig. S1. Control experiments.

    Fig. S2. Emission quenching experiments (Stern-Volmer studies).

    References (33, 34)

  • Supplementary Materials

    This PDF file includes:

    • Section S1. General information
    • Section S2. Reaction optimization
    • Section S3. Investigation of the mechanism
    • Section S4. Experimental procedures and product characterization
    • Section S5. Copies of 1H NMR and 13C NMR spectra for new compounds
    • Table S1. Screening of different solvents.
    • Table S2. Screening of the amount of cyclohexanone.
    • Table S3. Light on and off experiments.
    • Table S4. Control experiments of intermediate 66.
    • Fig. S1. Control experiments.
    • Fig. S2. Emission quenching experiments (Stern-Volmer studies).
    • References (33, 34)

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