The N-protected cis-4-aminocyclohexanol derivatives have proven to be valuable intermediates
in the syntheses of active pharmaceutical ingredients (APIs). A novel continuous flow
process for hydrogenation of N-protected 2-oxa-3-azabicyclo[2.2.2]oct-5-ene cycloadducts
to the corresponding cis-4-aminocyclohexanols has been reported using H-Cube Pro.
A > 99% selectivity towards the desired product was obtained using Raney nickel catalyst
cartridge. Under carefully selected hydrogenation parameters the reduction could stop
at the also valuable 2-oxa-3-azabicyclo[2.2.2] octane intermediate, with a selectivity
of >99%. The N-protected 2-oxa-3-azabicyclo[2.2.2]oct-5-ene producing nitroso hetero-Diels–Alder
cycloaddition was also accomplished in a flow system using an Omnifit column packed
with MnO2. The two flow reactions were successfully merged in a system, thus the product
was obtained in a multistep flow synthesis without any isolation or purification steps.
Compared with the previously reported batch processes, the present multistep procedure
facilitates an efficient cis selective preparation of numerous synthetically valuable
4-aminocyclohexanol derivatives.