A robustness screen for the rapid assessment of chemical reactions

Journal name:
Nature Chemistry
Volume:
5,
Pages:
597–601
Year published:
DOI:
doi:10.1038/nchem.1669
Received
Accepted
Published online

Abstract

In contrast to the rapidity with which scientific information is published, the application of new knowledge often remains slow, and we believe this to be particularly true of newly developed synthetic organic chemistry methodology. Consequently, methods to assess and identify robust chemical reactions are desirable, and would directly facilitate the application of newly reported synthetic methodology to complex synthetic problems. Here, we describe a simple process for assessing the likely scope and limitations of a chemical reaction beyond the idealized reaction conditions initially reported. Using simple methods and common analytical techniques we demonstrate a rapid assessment of an established chemical reaction, and also propose a simplified analysis that may be reported alongside new synthetic methodology.

At a glance

Figures

  1. A typical palladium-catalysed Suzuki–Miyaura cross-coupling.
    Figure 1: A typical palladium-catalysed Suzuki–Miyaura cross-coupling.

    The scope of this reaction would traditionally be investigated by assessing the nature of R and R′ in terms of their electronic influence (that is, electron-donating functional groups (OMe, NMe2) and electron-withdrawing functional groups (CO2Me, NO2)) and their steric influence by varying the position of a given substituent (ortho, meta or para) on the reactive centre.

  2. Results of the preparation of multifunctional substrates to validate the predictions of the robustness screen.
    Figure 2: Results of the preparation of multifunctional substrates to validate the predictions of the robustness screen.

    Reaction conditions were identical to those used in the screen. Yields are for isolated compounds. SM, starting material. ‘✓’ (above 66%), ‘−’ (34−66%), and ‘⨯’ (below 34%).

Compounds

9 compounds View all compounds
  1. 3-Bromoanisole
    Compound 1 3-Bromoanisole
  2. Morpholine
    Compound 2 Morpholine
  3. 4-(3-Methoxyphenyl)morpholine
    Compound 3 4-(3-Methoxyphenyl)morpholine
  4. 4-(3-(Pent-4-en-1-yloxy)phenyl)morpholine
    Compound 4 4-(3-(Pent-4-en-1-yloxy)phenyl)morpholine
  5. 4-(3-((2-((1H-Pyrrol-1-yl)methyl)benzyl)oxy)phenyl)morpholine
    Compound 5 4-(3-((2-((1H-Pyrrol-1-yl)methyl)benzyl)oxy)phenyl)morpholine
  6. 4-(3-(Pent-4-yn-1-yloxy)phenyl)morpholine
    Compound 6 4-(3-(Pent-4-yn-1-yloxy)phenyl)morpholine
  7. Methyl 4-((3-((3-morpholinophenoxy)methyl)benzyl)oxy)benzoate
    Compound 7 Methyl 4-((3-((3-morpholinophenoxy)methyl)benzyl)oxy)benzoate
  8. 4-((3-((3-Morpholinophenoxy)methyl)benzyl)oxy)benzonitrile
    Compound 8 4-((3-((3-Morpholinophenoxy)methyl)benzyl)oxy)benzonitrile
  9. 5-(3-Morpholinophenoxy)pentan-2-one
    Compound 9 5-(3-Morpholinophenoxy)pentan-2-one

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Affiliations

  1. Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstrasse 40, 48149 Münster, Germany

    • Karl D. Collins &
    • Frank Glorius

Contributions

F.G. and K.D.C. conceived the concept and experiments. K.D.C. performed all experiments. Both authors discussed the results and co-wrote the paper.

Competing financial interests

The authors declare no competing financial interests.

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