Nitroreductase-triggered indazole formation

Biocatalysis contributes significantly to the development of more sustainable synthetic pathways by using mild reaction conditions and water as a solvent. However, many relevant classes of compounds, including privileged groups in drug design, are not yet accessible via enzymatic pathways. In this context, the development of an enzymatic route to indazoles remains an unmet challenge. Here, we present the first example of nitroreductase-triggered indazole formation, in which 2-nitrobenzylamine derivatives are converted to reactive nitrosobenzylamine intermediates that spontaneously cyclize and aromatize to indazoles. Two nitroreductases, NfsA and BaNTR1, were found to accept a series of 2-nitrobenzylamine derivatives with excellent conversions (up to >99 %). In the case of N-substituted nitrosobenzylamines, 2H-indazoles were formed, whereas other derivatives led to 1H-indazoles. The synthetic value of the nitroreductase-triggered indazole formation was further demonstrated by successful coupling with an imine reductase (IRED15) in a sequential cascade reaction. With this cascade, N-methyl-2Hindazole was accessible from cheap 2-nitrobenzaldehyde and methylamine, resulting in 62 % isolated yield.