Copper-Nitroxyl-Catalyzed α-Oxygenation of Cyclic Secondary Amines Including Application to Late-Stage Functionalization

Abstract

Cyclic secondary amines are prominent subunits in pharmaceutical compounds. Methods for direct functionalization of N-unprotected/unsubstituted piperidines and related heterocycles have limited precedent despite their potential to impact medicinal chemistry and organic synthesis. Herein, we report a Cu/nitroxyl co-catalyzed method for direct conversion of cyclic secondary amines to the corresponding lactams via aerobic dehydrogenation and oxidative coupling with water. The mild reaction conditions tolerate diverse functional groups, enabling application to molecules that cover broad chemical space. The method is showcased in selective functionalization of building blocks and complex molecules, including late-stage functionalization of bromodomain inhibitors.

Figure 1.

(A) Reaction optimization for 4-phenylpiperidine using 20 mol % catalyst loading (Cu/ligand/nitroxyl/additive). Yield determined by UPLC (int. std. = 1,3,5-trimethoxybenzene). (B) Reaction conducted with 90% enriched H₂¹⁸O. ¹⁸O incorporation measured by HRMS. Note: THF was used instead of DCE to achieve a homogeneous reaction mixture.

Figure 2.

(A) Distribution of medicinally relevant amine building blocks analyzed by t-SNE, used to select diverse substrates for evaluation in the aerobic α-oxygenation reaction conditions. Similar assessment, using principal component analysis, is provided in the supporting information (see Figure S11). (B) Representative screening data (see section 5 in the Supporting Information). 10 μmol scale, 20 mol % catalyst loading at 0.2 M, 24 h, 1 atm O₂. Reaction yields were assessed by UPLC-MS (int. std. = 1,3,5-trimethoxybenzene).

Figure 3.

Substrate scope for copper-nitroxyl co-catalyzed amine oxygenation of 6-membered alicyclic amines. ^awith CuPF₆•4MeCN as copper catalyst. ^bwith 1,2-dichloroethane as solvent. ^cwith acetonitrile as solvent. ^dat 1.0 M concentration. ^ewith CuOTf as copper catalyst. ^fyield determined by gas chromatography.

Figure 4.

Substrate scope for copper-nitroxyl co-catalyzed amine oxygenation of pyrrolidines and azepanes. ^awith CuPF₆•4MeCN as copper catalyst. ^bwith 1,2-dichloroethane as solvent. ^cat 1.0 M concentration. ^dwith 1,8-diazabicyclo(5.4.0)undec-7-ene as base additive. ^eyield determined by gas chromatography.

Figure 5.

Direct, one-pot oxygenation of amine salts, including synthesis of the drug metabolite, oxovarenicline 38b.

Figure 6.

Late-stage functionalization (LSF) of biologically relevant molecules.

Scheme 1.

Context for the development of a copper-nitroxyl co-catalyzed α-oxygenation of cyclic amines.