Photocatalytic Hydrogenation of Quinolines to Form 1,2,3,4-Tetrahdyroquinolines Using Water as the Hydrogen Atom Donor

Abstract

The design of a sequential process combining hydrogenation and a subsequent stereomutation is an attractive strategy for the stereoselective reduction of cyclic disubstituted π-systems to access the thermodynamically more stable trans isomer, which would be the minor compound considering a kinetically controlled cis hydrogenation process. Herein, we demonstrate stereoselective photocatalytic phosphine-mediated quinoline reductions with water as the hydrogen atom source under mild conditions to afford the corresponding 1,2,3,4-tetrahydroquinolines with complete selectivity towards reduction of the heteroaromatic part. The method shows broad functional group tolerance and provides access to trans-2,3-disubstituted tetrahydroquinolines with moderate to excellent diastereoselectivity. These trans isomers are not readily obtained using established methods, as transition-metal-catalyzed regioselective quinoline hydrogenations provide the corresponding cis-2,3-disubstituted isomers with high selectivity. Mechanistic studies reveal that the hydrogenation of the 2,3-disubstituted quinolines proceeds through a cascade process comprising an initial cis selective photocatalytic hydrogenation of the heteroarene core of the quinoline, followed by a trans selective photoisomerization.

Keywords: Hydrogen atom transfer; Hydrogenation; Isomerization; Photocatalysis; Water activation.

Figure 1

a) Chemical modification of quinolines through peripheral and skeletal editing as well as through photocycloaddition reactions. b) State of the art in the quinoline hydrogenation and (c, d) suggested cis selective hydrogenation of quinolines through radical hydrogenation by phosphine‐mediated water activation, followed by epimerization.

Figure 2

Radical hydrogenation of differently substituted quinolines. All reactions were conducted using a quinoline or its HCl‐salt (1.0 equiv., 0.2 mmol). Applying method A, quinoline HCl‐salts were used as the starting materials, see the Supporting Information for further details. Isolated yields are provided. The trans/cis ratio was determined by ¹H‐NMR spectroscopy. ^[a] The hydrogenation was accompanied by the formation of the corresponding indole as the byproduct, see Supporting Information for details. ^[b] Conducted with (p‐CF₃C₆H₄)₃P in place of (p‐MeOC₆H₄)₃P. ^[c] Yields and trans/cis ratios obtained through extending reaction time to 36 h.

Figure 3

Mechanism investigation. ^[a] Yields were determined by ¹H‐NMR spectroscopy.