Accelerated and Scalable C(sp³)–H Amination via Decatungstate Photocatalysis Using a Flow Photoreactor Equipped with High-Intensity LEDs

Abstract

Carbon–nitrogen bonds are ubiquitous in biologically active compounds, prompting synthetic chemists to design various methodologies for their preparation. Arguably, the ideal synthetic approach is to be able to directly convert omnipresent C–H bonds in organic molecules, enabling even late-stage functionalization of complex organic scaffolds. While this approach has been thoroughly investigated for C(sp 2 )–H bonds, only few examples have been reported for the direct amination of aliphatic C(sp 3 )–H bonds. Herein, we report the use of a newly developed flow photoreactor equipped with high intensity chip-on-board LED technology (144 W optical power) to trigger the regioselective and scalable C(sp 3 )–H amination via decatungstate photocatalysis. This high-intensity reactor platform enables simultaneously fast results gathering and scalability in a single device, thus bridging the gap between academic discovery (mmol scale) and industrial production (>2 kg/day productivity). The photocatalytic transformation is amenable to the conversion of both activated and nonactivated hydrocarbons, leading to protected hydrazine products by reaction with azodicarboxylates. We further validated the robustness of our manifold by designing telescoped flow approaches for the synthesis of pyrazoles, phthalazinones and free amines.

α-C–H Photoalkylation of a Glucose Derivative in Continuous Flow

“…We observed that when the light output was reduced, the conversion dropped significantly, in an almost linear fashion. (30) Subsequently, the reaction was performed at different substrate concentrations. It was found that there was no significant change in conversion when the concentration of the substrate was either increased or decreased.…”

Scale-Up of a Heterogeneous Photocatalytic Degradation Using a Photochemical Rotor–Stator Spinning Disk Reactor

“…Ranging from the numbering up of micro- and millireactors to the design of completely novel reactor types, the productivities of photochemical reactors have seen tremendous growth over the past years. 14 − 16 …”

Reconciling Imbalanced Transition State Effects with Nonadiabatic CPET Reactions

“…9,[24][25][26][27][28][29][30][31] The influence of offdiagonal free energies is well precedented in organic hydrogen atom transfer reactions, 32 but their relevance in the broader class of CPET reactions has implications for the mechanism and selectivity of many biological and synthetic systems. [33][34][35][36][37] A central paradox that has recently emerged is how the influence of off-diagonal thermodynamic elements, which is rooted in semiclassical transition state theory, can be reconciled with CPET reactions which are widely acknowledged to be nonclassical or nonadiabatic (Figure 1, right). 16,[38][39][40][41] The specific formulations for how ΔG °PT and ΔG °ET can affect CPET reactivity vary, but are commonly supported by DFT optimized transition states 9,24,27,28 and invoke textbook physical organic concepts such as nonperfect synchronization, imbalanced transition states, and More O'Ferral-Jencks diagrams.…”