A flow chemistry route to 2-phenyl-3-(1H-pyrrol-2-yl)propan-1-amines

Abstract

The Knoevenagel condensation of pyrrole-2-carboxaldehyde (1) with a range of substituted benzyl nitriles (2a–e) afforded rapid access to a family of α,β-unsaturated nitriles (3a–e) in good yields (67–78%). Flow hydrogenation (ThalesNano H-cube™) at 60 °C, 50 bar H₂ pressure, 1.0 mL/min through a 10% Pd-C catalyst selectively, and quantitatively, hydrogenated the olefin double bond (4a–e). Use of a Raney Nickel catalyst at 70 °C, 70 bar H₂ pressure and flow rates of 0.5–1.0 mL/min afforded quantitative conversion into the corresponding saturated amines with the reduction of both the olefin and nitrile bonds (5a–e). The versatility of this approach was further exemplified by reaction of 5a and 5c with norcantharidin to afford acid amide norcantharidin analogues 7 and 8 as novel protein phosphatase 1 and 2A inhibitors