Diastereoselective synthesis of cis-N-Boc-4-aminocyclohexanol with reductive ring opening method using continuous flow

• Published in: Journal of flow chemistry Vol. 9; no. 1; pp. 13 - 17
• Main Authors: Szabó, Balázs, Tamás, Bálint, Faigl, Ferenc, Éles, János, Greiner, István
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 15.03.2019
• Subjects: Chemistry; Chemistry and Materials Science; Chemistry/Food Science; Communications; Green Chemistry; Industrial Chemistry/Chemical Engineering; Inorganic Chemistry; Nanochemistry; Organic Chemistry; Nitroso-Diels-Alder cycloaddition; Diastereomer selective; Flow chemistry; Reductive ring opening
• ISSN: 2062-249X; 2063-0212
• DOI: 10.1007/s41981-018-00028-3

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 MnO 2 . 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.