Chemoselective Quinoline and Isoquinoline Reduction by Energy Transfer Catalysis Enabled Hydrogen Atom Transfer

Abstract

(Hetero)arene reduction is one of the key avenues for synthesizing related cyclic alkenes and alkanes. While catalytic hydrogenation and Birch reduction are the two broadly utilized approaches for (hetero)arene reduction across academia and industry over the last century, both methods have encountered significant chemoselectivity challenges. We hereby introduce a highly chemoselective quinoline and isoquinoline reduction protocol operating through selective energy transfer (EnT) catalysis, which enables subsequent hydrogen atom transfer (HAT). The design of this protocol intelligently bypasses the conventional metric of reduction reaction, i.e., the reductive potential, but instead, relies on chemical moieties’ triplet energies and kinetic barriers of energy and hydrogen atom transfer events. Many reducing labile functional groups which were incompatible with previous (hetero)arene reductions, are retained in this work. We anticipate this protocol to trigger further advancement of chemoselective arene reductions and enable the current arene‐rich drug space escaping from flatland.

Late-Stage Saturation of Drug Molecules

“…33 Likewise, a photocatalysis-hydrogenation sequential protocol was applied to saturate Boc-OSI-930 and a Fmoc-quinisocaine analogue in a highly selective fashion, thus smoothly leading to the reduced products 48 and 49, respectively. 34 It is noteworthy that the photocatalyzed conditions selectively reduced the benzene ring rather than the pyridine in these (iso)quinolines. Furthermore, LSS can dramatically improve the synthetic efficiency and complement retrosynthetic strategies (Figure 4c).…”

High Performance Polyoxometalate-Stabilizing Pt Nanocatalysts for Quinoline Hydrogenation with Water-Mediated Dynamic Hydrogen

“…D 2 O can accept an active hydrogen from H 2 dissociation and then release one D atom to form HDO; the HDO continued to exchange with the dissociated H 2 to generated H 2 O (Figure 7b). 65 Overall, the reaction between H 2 and D 2 O can generated liquid components HDO and H 2 O, which can be determined quantitatively by 1 H NMR spectra (Figures S30−S34). Similarly, the reaction between H 2 and CH 3 CH 2 OD was also carried out (Figures S35−S39).…”

“…N-heterocycles, especially tetrahydroquinoline derivative, play important roles in the production of fine chemicals, agrochemicals and pharmaceuticals. − The direct hydrogenation of quinolines into a tetrahydroquinoline derivative with H 2 was a 100% atomic economy reaction and was considered to be a highly promising approach. In this process, the adsorption and activation of H 2 is the critical step in the hydrogenation reaction. − Homolytic dissociation and heterolytic dissociation are the common dissociation methods of H 2 .…”

Photochemical Reduction of Quinolines with γ-Terpinene

“…In particular, we were interested in capture of the excited state with H atom donors to result in the formation of reduced products . Very recently, Ma demonstrated a related process that results in the reduction of the benzene ring of quinoline . Herein, we demonstrate that photochemically induced hydrogenation of quinolines can be achieved with the use of widely available γ-terpinene.…”

“…This suggests that the reduction may occur via the singlet excited state under direct excitation conditions, and that reaction with a photosensitizer, which likely operates by a triplet excited state (based on previous work), leads to formation of the same product with 9 . In Ma’s report, reduction occurs at the other ring. The basis for the switch in reduction is not clear at this time, but may be due to differing substrates and singlet vs triplet reduction pathway.…”