Research ArticleORGANIC CHEMISTRY

Borate esters: Simple catalysts for the sustainable synthesis of complex amides

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Science Advances  22 Sep 2017:
Vol. 3, no. 9, e1701028
DOI: 10.1126/sciadv.1701028
  • Fig. 1 Approaches to amide bond formation.

    (A) Conventional methods for amidation proceeding via an activated carboxylic acid. (B) Recent catalytic amidations using group IV metal or boronic acid catalysts. THF, tetrahydrofuran. (C) Borate ester–catalyzed amide bond formation. TAME, tert-amyl methyl ether; PhMe, toluene.

  • Fig. 2 Towards a borate-catalyzed amide coupling.

    (A) Proposed catalytic cycle for amidation. (B) Catalyst selection. (C) Time course of borate amidation with different boron catalysts.

  • Fig. 3 Scope of borate-catalyzed amide bond formation.

    (A) Secondary amides. (B) Tertiary amides. (C) Challenging amides. (D) Amino acid amides. mol %, mole percent; Boc, tert-butoxycarbonyl. Reactions run according to general procedure A for 24 hours unless stated otherwise. *Amide synthesized using 20 mole percent (mol %) B(OCH2CF3)3. †Reaction performed in PhMe instead of TAME. ‡Amide synthesized using 1 mol % B(OCH2CF3)3. §Amide synthesized using 5 mol % B(OCH2CF3)3.

  • Fig. 4 Chemoselective amide bond formation from amino acids.

    (A) Chemoselective amino acid couplings. (B) Sequential amidation/condensation to form imidazolidinones. dr, diastereomeric ratio. Reactions run according to general procedures B and C for 24 hours unless stated otherwise. *Using 30 mol % B(OCH2CF3)3. †Using 2 equiv. of amine. ‡Using 1.2 equiv. of benzylamine.

  • Fig. 5 Application to the synthesis of APIs.

    Reactions run according to general procedures A or B for 24 hours unless stated otherwise. *Using 1.5 equiv. of homopiperazine. †Using 2 equiv. of H-Gly-OttBu. ‡Using 1.0 equiv. of B(OCH2CF3)3.

  • Fig. 6 Environmental metrics for catalytic amidation reactions.

    (A) PMI calculations for a selection of catalytic amide bond formation processes. MIBA, 5-methoxy-2-iodophenylboronic acid. (B) Improved PMIs of large-scale borate-catalyzed amidation procedures.

  • Fig. 7 Mechanism of the amidation reaction.

    (A) Proposed mechanism. (B) Low reactivity of a trifluoroethyl ester acylating agent. Sol, solvent.

Supplementary Materials

  • Supplementary material for this article is available at http://advances.sciencemag.org/cgi/content/full/3/9/e1701028/DC1

    General methods

    Optimization of reaction parameters

    General procedures

    Resin capacity in varying solvents

    PMI calculations

    Mechanistic studies

    Spectroscopic data

    1H and 13C NMR spectra

    Chiral HPLC traces for enantiopurity measurements

    1H and 13C NMR spectra for enantiopurity measurements

    table S1. Solvent screen for general amidation.

    table S2. Screening of borate reagents in amino acid amidation.

    table S3. Varying time, catalyst loading, and equivalents of amine.

    table S4. Varying concentration.

    table S5. Reaction troubleshooting.

    table S6. Solvent screen for resin workup.

    table S7. Raw data for PMI calculations for amidation product 10.

    table S8. PMI calculations for amidation product 10.

    table S9. Raw data for PMI calculations.

    table S10. PMI calculations.

    table S11. Raw data for determination of order in catalyst.

    table S12. Raw data for determination of order in catalyst.

    table S13. Raw data for determination of order in catalyst.

    table S14. Raw data for determination of order in amine.

    table S15. Raw data for determination of order in amine.

    table S16. Raw data for determination of order in amine.

    table S17. Raw data for determination of order in acid.

    table S18. Raw data for determination of order in acid.

    table S19. Raw data for determination of order in acid.

    table S20. Raw data for determination of order in acid.

    table S21. Raw data for determination of order in acid.

    fig. S1. Representative example of a Dean-Stark reaction setup.

    fig. S2. Representative examples of a Dean-Stark setup with adaptor for the addition of ketone/aldehyde.

    fig. S3. Representative example of a resin workup.

    fig. S4. Green metrics for catalytic amidation protocols.

    fig. S5. 19F NMR spectra of the crude reaction mixture (top) and the Dean-Stark (bottom) with fluorobenzene as an internal standard.

    fig. S6. 11B NMR spectra of B(OCH2CF3)3 (top) and reaction mixture (bottom two) at 4- and 24-hour intervals.

    References (4766)

  • Supplementary Materials

    This PDF file includes:

    • General methods
    • Optimization of reaction parameters
    • General procedures
    • Resin capacity in varying solvents
    • PMI calculations
    • Mechanistic studies
    • Spectroscopic data
    • 1H and 13C NMR spectra
    • Chiral HPLC traces for enantiopurity measurements
    • 1H and 13C NMR spectra for enantiopurity measurements
    • table S1. Solvent screen for general amidation.
    • table S2. Screening of borate reagents in amino acid amidation.
    • table S3. Varying time, catalyst loading, and equivalents of amine.
    • table S4. Varying concentration.
    • table S5. Reaction troubleshooting.
    • table S6. Solvent screen for resin workup.
    • table S7. Raw data for PMI calculations for amidation product 10.
    • table S8. PMI calculations for amidation product 10.
    • table S9. Raw data for PMI calculations.
    • table S10. PMI calculations.
    • table S11. Raw data for determination of order in catalyst.
    • table S12. Raw data for determination of order in catalyst.
    • table S13. Raw data for determination of order in catalyst.
    • table S14. Raw data for determination of order in amine.
    • table S15. Raw data for determination of order in amine.
    • table S16. Raw data for determination of order in amine.
    • table S17. Raw data for determination of order in acid.
    • table S18. Raw data for determination of order in acid.
    • table S19. Raw data for determination of order in acid.
    • table S20. Raw data for determination of order in acid.
    • table S21. Raw data for determination of order in acid.
    • fig. S1. Representative example of a Dean-Stark reaction setup.
    • fig. S2. Representative examples of a Dean-Stark setup with adaptor for the addition of ketone/aldehyde.
    • fig. S3. Representative example of a resin workup.
    • fig. S4. Green metrics for catalytic amidation protocols.
    • fig. S5. 19F NMR spectra of the crude reaction mixture (top) and the Dean-Stark (bottom) with fluorobenzene as an internal standard.
    • fig. S6. 11B NMR spectra of B(OCH2CF3)3 (top) and reaction mixture (bottom two) at 4- and 24-hour intervals.
    • References (47–66)

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