Development of a Stepwise Reductive Deoxygenation Process by Ru-Catalysed Homogeneous Ketone Reduction and Pd-Catalysed Hydrogenolysis in the Presence of Cu Salts

Authors

  • Dr. Damian M. Grainger,

    Corresponding author
    1. Johnson Matthey, Catalysis and Chiral Technologies, Cambridge Science Park, Unit 28, Cambridge, CB4 0FP (United Kingdom), Fax: (+44) 01223-438037
    • Johnson Matthey, Catalysis and Chiral Technologies, Cambridge Science Park, Unit 28, Cambridge, CB4 0FP (United Kingdom), Fax: (+44) 01223-438037
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  • Dr. Antonio Zanotti-Gerosa,

    1. Johnson Matthey, Catalysis and Chiral Technologies, Cambridge Science Park, Unit 28, Cambridge, CB4 0FP (United Kingdom), Fax: (+44) 01223-438037
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  • Dr. Kevin P. Cole,

    Corresponding author
    1. Chemical Product Research and Development, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285 (USA), Fax: (+1) 317-276-4507
    • Chemical Product Research and Development, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285 (USA), Fax: (+1) 317-276-4507
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  • Dr. David Mitchell,

    1. Chemical Product Research and Development, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285 (USA), Fax: (+1) 317-276-4507
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  • Dr. Scott A. May,

    1. Chemical Product Research and Development, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285 (USA), Fax: (+1) 317-276-4507
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  • Patrick M. Pollock,

    1. Chemical Product Research and Development, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285 (USA), Fax: (+1) 317-276-4507
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  • Joel R. Calvin

    1. Chemical Product Research and Development, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285 (USA), Fax: (+1) 317-276-4507
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Abstract

A stepwise catalytic reduction of ketone 1 to alcohol 2 and subsequently to aryl(imidazo[1,2-b]pyridazinyl)methane 3 is described, which provides synthetically useful chemoselectivity at acceptably low catalyst loadings. Undesired reactive sites include an aryl chloride, heteroarylchloride and benzylic amine group. The presence of these functional groups presents a significant challenge to chemoselectivity for both reduction steps. For selective C[DOUBLE BOND]O reduction of highly functionalised 1, high chemoselectivity was observed at low catalyst loading by using Wills’ tethered Ru transfer-hydrogenation catalyst 13. The selective hydrogenolysis of 2 was then accomplished under acidic hydrogenation conditions by using a Pd/C catalyst in the presence of Cu salts. This procedure has been demonstrated on a multi-gram scale, which makes this approach a viable method to use a combination of homogeneous and heterogeneous catalysis.

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