Aerobic titania photocatalysis: selective oxidative dehydrogenation of tetrahydroisoquinoline and related amines

Abstract

3,4-Dihydroisoquinolines are high-value chemicals, both as medicinally relevant compounds and as intermediates for the synthesis of 1,2,3,4-tetrahydroisoquinoline derivatives, which are widely regarded as privileged scaffolds in drug discovery. Though envisaged as a direct route, the partial oxidation of 1,2,3,4-tetrahydroisoquinolines to 3,4-dihydroisoquinolines is, however, very challenging due to the inherent tendency of these substrates toward over-oxidation to the aromatic isoquinolines. Herein, we have used 1,2,3,4-tetrahydroisoquinoline (THIQ) as a model substrate for its selective oxidative dehydrogenation to 3,4-dihydroisoquinoline (DHIQ) under heterogeneous photochemical conditions with titania-based photocatalysts. Among the materials tested, TiO2-P25 and CuNPs/TiO2-P25 have been found to be the best photocatalysts in terms of conversion and selectivity upon irradiation (369 nm) in acetonitrile, with oxygen as a terminal oxidant. Notably, high conversion and selectivity were also attained with TiO2-P25 in the presence of Cs2CO3 under air. Although pristine TiO2-P25 represents the simplest and most readily available photocatalyst, CuNPs/TiO2-P25 is clearly superior from a reusability standpoint, maintaining high conversions (97-96%) and excellent selectivities (97:3-96:4) over the first four cycles, and consistently outperforming TiO2-P25 in the oxidation of other amines. A detailed characterisation of this catalyst, combined with comprehensive mechanistic studies, supports a strong substrate-surface interaction that facilitates single-electron transfer oxidation of the former; accordingly, a consistent reaction mechanism has been proposed. A meticulous green chemistry assessment shows that, while TiO2-P25 displays the most favourable risk-factor score, CuNPs/TiO2-P25 provides the most balanced overall sustainability profile when risk factors, waste generation and recyclability are considered, and benchmarks favourably against previously reported photocatalytic methodologies. Overall, this study introduces an efficient and sustainable photocatalytic method that not only overcomes key limitations of previous systems, but also underscores the effectiveness and practicality of heterogeneous photochemical approaches under mild aerobic conditions.