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J Org Chem. 2017 Apr 7;82(7):3741-3750. doi: 10.1021/acs.joc.7b00201. Epub 2017 Mar 15.

A Method for Identifying and Developing Functional Group Tolerant Catalytic Reactions: Application to the Buchwald-Hartwig Amination.

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Discovery Chemistry Research and Technologies, Eli Lilly and Company Limited, Erl Wood Manor, Windlesham, Surrey GU20 6PH, United Kingdom.
Discovery Chemistry Research and Technologies, Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
Translational Research Office Drug Discovery Group, University College London School of Pharmacy , 29-39 Brunswick Square, London WC1N 1AX, United Kingdom.
Penn/Merck Laboratory for High-Throughput Experimentation, Department of Chemistry, University of Pennsylvania , 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States.


Transition-metal catalysis has revolutionized organic synthesis, but difficulties can often be encountered when applied to highly functionalized molecules, such as pharmaceuticals and their precursors. This results in discovery collections that are enriched in substances possessing less desirable properties (high lipophilicity, low polar surface area). Masking groups are often employed to circumvent this problem, which is in opposition to the inherent ideality of these methods for green chemistry and atom economy. A general screening methodology, related to robustness screening described by Glorius et al., builds a broad understanding of the impact of individual functional groups on the success of a transformation under various conditions and provides a simple framework for identifying new conditions that tolerate challenging functional groups. Application of this approach to profile the conditions for the Buchwald-Hartwig amination and rapidly identify bespoke conditions for challenging substrate classes is described.


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