title: Development of an Intermittent-Flow Enantioselective Aza-Henry Reaction Using an Arylnitromethane and Homogeneous Brønsted Acid-Base Catalyst with Recycle.
abstract: A stereoselective aza-Henry reaction between an arylnitromethane and Boc-protected aryl aldimine using a homogeneous Brønsted acid-base catalyst was translated from batch format to an automated intermittent-flow process. This work demonstrates the advantages of a novel intermittent-flow setup with product crystallization and slow reagent addition which is not amenable to the standard continuous equipment: plug flow tube reactor (PFR) or continuous stirred tank reactor (CSTR). A significant benefit of this strategy was the integration of an organocatalytic enantioselective reaction with straightforward product separation, including recycle of the catalyst, resulting in increased intensity of the process by maintaining high catalyst concentration in the reactor. A continuous campaign confirmed that these conditions could effectively provide high throughput of material using an automated system while maintaining high selectivity, thereby addressing nitroalkane safety and minimizing catalyst usage.
authors.affiliation: Small Molecule Design and Development, Eli Lilly and Company, Indianapolis, Indiana 46285, Unites States; Department of Chemistry and Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37235, United States.
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Tsukanov
authors.affiliation: Small Molecule Design and Development, Eli Lilly and Company, Indianapolis, Indiana 46285, Unites States.
authors.forename: Martin D
authors.initials: MD
authors.lastname: Johnson
authors.affiliation: Small Molecule Design and Development, Eli Lilly and Company, Indianapolis, Indiana 46285, Unites States.
authors.forename: Scott A
authors.initials: SA
authors.lastname: May
authors.affiliation: Small Molecule Design and Development, Eli Lilly and Company, Indianapolis, Indiana 46285, Unites States.
authors.forename: Morgan
authors.initials: M
authors.lastname: Rosemeyer
authors.affiliation: Small Molecule Design and Development, Eli Lilly and Company, Indianapolis, Indiana 46285, Unites States.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Watkins
authors.affiliation: Small Molecule Design and Development, Eli Lilly and Company, Indianapolis, Indiana 46285, Unites States.
authors.forename: Stanley P
authors.initials: SP
authors.lastname: Kolis
authors.affiliation: Small Molecule Design and Development, Eli Lilly and Company, Indianapolis, Indiana 46285, Unites States.
authors.forename: Matthew H
authors.initials: MH
authors.lastname: Yates
authors.affiliation: Department of Chemistry and Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37235, United States.
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Johnston
keywords: asymmetric catalysis or synthesis; aza-Henry reaction; continuous processes; flow chemistry; organocatalysis; sustainable or green chemistry