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Application of a robustness screen for the evaluation of synthetic organic methodology

Nature Protocols volume 9, pages 1348–1353 (2014)Cite this article

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Abstract

This protocol provides a rapid method for evaluating the tolerance of a given set of reaction conditions to a wide range of functional groups, as well as the stability of functional groups to the reaction conditions. This information is highly desirable when considering the application of a given protocol in the preparation of complex compounds, including natural products or biologically active molecules. By using a contemporary Rh(III)-catalyzed C-H activation protocol for the preparation of indole derivatives as a demonstrative example, here we describe a simple process that uses batch reaction preparation, small-scale parallel reaction techniques, simplified gas chromatography (GC) calibration techniques and GC analysis to undertake this evaluation in a rapid and cost-effective manner. This analysis provides quantitative data for a large number of functional groups and heterocycles, and it is readily adaptable to investigate structural motifs of choice, such as common moieties or functional groups within a given medicinal or agrochemical project or within a family of natural products. Twenty chosen additives plus controls can be evaluated in ∼3 d depending on the reaction time, with actual reaction setup and analysis taking 12–24 h depending on the reaction.

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Figure 1: Standard reaction to be investigated by using the robustness screen.
Figure 2: Filtration equipment for GC sample preparation.

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Acknowledgements

Generous financial support by the Deutsche Forschungsgemeinschaft (DFG) (SFB 858 and Leibniz award) and the Alfried Krupp von Bohlen und Halbach Foundation is gratefully acknowledged. We thank D.-B. Zhao for helpful discussions and K. Gottschalk for support in compiling the manuscript.

Author information

Authors and Affiliations

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

    Karl D Collins, Andreas Rühling & Frank Glorius

Authors
  1. Karl D Collins
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  2. Andreas Rühling
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  3. Frank Glorius
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Contributions

K.D.C. and F.G. designed the concept and the protocol. A.R. performed all experimental work. All authors co-wrote the paper.

Corresponding author

Correspondence to Frank Glorius.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Methods

Images of non-commercial equipment. (PDF 12206 kb)

Supplementary Data 1

Example of reporting the Robustness screen. (PDF 584 kb)

Supplementary Data 2

Robustness screen template for calculations (includes and original data set). (XLSX 22 kb)

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Collins, K., Rühling, A. & Glorius, F. Application of a robustness screen for the evaluation of synthetic organic methodology. Nat Protoc 9, 1348–1353 (2014). https://doi.org/10.1038/nprot.2014.076

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