N-Substituted Auxiliaries for Aerobic Dehydrogenation of Tetrahydro-isoquinoline: A Theory-Guided Photo-Catalytic Design

Savithra Jayaraj,Abraham K Badu-Tawiah

doi:10.1038/s41598-019-47735-y

Abstract

Visible-light mediated aerobic dehydrogenation of N-heterocyclic compounds is a reaction with enormous potential for application. Herein, we report the first complete aerobic dehydrogenation pathway to large-scale production of isoquinolines. The discovery of this visible light photoredox reaction was enabled through the combination of mathematical simulations and real-time quantitative mass spectrometry screening. The theoretical calculations showed that hyper-conjugation, the main underlying factor hindering the aerobic oxidation of tetrahydroisoquinolines, is relieved both by π- and σ-donating substituents. This mechanistic insight provided a novel photocatalytic route based on N-substituted auxiliaries that facilitated the conversion of tetrahydroisoquinolines into the corresponding isoquinolines in just three simple steps (yield 71.7% in bulk-solution phase), using unmodified Ru(bpy)3Cl2 photocatalyst, sun energy, atmospheric O2, and at ambient temperature.

Highlights

To contribute to the emerging field of accelerated droplet reaction screening[19,20,21,22], the current study applies a theory-guided photoreaction screening approach to investigate the underlying mechanistic difference between the reactivity of THQ and THiQ
Owing to the fact that the isoquinoline moiety is more common in pharmaceutical compounds than the quinoline counterpart, we sought to develop a much cleaner and milder photocatalytic strategy based on the use of safe solar photons, ambient air and temperature
We carried out our studies using the photoreaction screening platform shown in Fig. 1a, which consisted of a nano-electrospray ionization source fitted with a portable laser source (450 nm, 5 mW)

Summary

Introduction

To contribute to the emerging field of accelerated droplet reaction screening[19,20,21,22], the current study applies a theory-guided photoreaction screening approach to investigate the underlying mechanistic difference between the reactivity of THQ and THiQ. In spite of the recent progress with iridium-based catalysts[30], the development of methods that involve the use of milder reaction conditions (e.g., ambient temperature) and that which utilizes more abundant, inexpensive, and renewable reagents for the dehydrogenation of N-heterocycles is highly desirable. In this regard, iron pincer complexes have been proposed[31]. A comparison of this theoretical insight and real-time experimental results, in turn, enabled us to rationally design a novel bulk-phase photocatalytic strategy based on three simple steps: (i) N-substitution of a suitable auxiliary to reduce hyper-conjugation, (ii) photoredox oxidation of the N-substituted THiQ using Ru(bpy)3Cl2, and (iii) removal of N-substituted auxiliary to generate isoquinolines

Methods

Results

Conclusion