Application of a robustness screen for the evaluation of synthetic organic methodology.
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.
Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Münster, Germany.
Karl D
KD
Collins
Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Münster, Germany.
Andreas
A
Rühling
Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Münster, Germany.
Frank
F
Glorius
D002384:Catalysis; D002616:Chemical Engineering / Q000379:methods*; D060326:Chemistry Techniques, Synthetic / Q000379:methods*; D007211:Indoles / Q000737:chemistry; D007700:Kinetics; D015394:Molecular Structure; D009930:Organic Chemicals / Q000737:chemistry*
D007211:Indoles; D009930:Organic Chemicals