First Example of Alkyl-Aryl Negishi Cross-Coupling in Flow: Mild, Efficient and Clean Introduction of Functionalized Alkyl Groups

• Brecht Egle²
• Juan de Muñoz¹
• Nerea Alonso¹
• Wim M. De Borggraeve²
• Antonio de la Hoz³
• Angel Díaz-Ortiz³
• Jesús Alcázar¹

• ¹Janssen Research and Development Department of Medicinal Chemistry Janssen-Cilag, Toledo Spain
• ²Department of Chemistry, Molecular Design and Synthesis University of Leuven, Heverlee Belgium
• ³Universidad de Castilla-La Mancha Facultad de Ciencias y Tecnologías Químicas, Spain

The first example of an alkyl–aryl Negishi coupling in a practical, sustainable, and high-yielding process using a silica-supported catalyst in flow is described. Excellent conversions and good functional group compatibility were obtained under very mild conditions. Functionalized alkyl groups were also introduced to provide access to synthetically useful molecules and to demonstrate the versatility of the method. The scalability was assessed, and a throughput of 7.5 mmol/h of processed substrate was achieved. All crude products were free from phosphine derivatives and ready for use in subsequent reaction steps.

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