Dye-incorporated coordination polymers for direct photocatalytic trifluoromethylation of aromatics at metabolically susceptible positions

Abstract

Direct trifluoromethylation of unactivated aromatic rings at metabolically susceptible positions is highly desirable in pharmaceutical applications. By incorporating thiophenes into the backbone of triphenylamine to enlarge its π-system, a new approach for constructing coordination polymers is reported for direct trifluoromethylation without prefunctionalization of the aryl precursors. The improved light-harvesting ability and well-modulated excited state redox potential of the designed polymers endow the generated CF₃ radicals with suitable reactivity and enhance radical adduct oxidation in pores. The well-configurated interactions between the organic ligands distort the coordination geometry to create active interaction sites within the coordination polymer; thus, the substrates could be docked near the photoredox-active centres. The synergistic electronic and spatial effects in the confined pores balance the contradictory demands of electronic effects and reaction dynamics, achieving regio- and diastereoselective discrimination among reaction sites with unremarkable electronic/steric differences.

Fig. 1

Schematic illustration of the composition and structure of Zn–TCTA. a The components. b The top view of the undulating monolayer with a virtual plane. c The intralayer cage showing the potential substrate binding site. d The packing pattern and open channels along the a- or b-axis. Green, Zn; yellow, S; red, O; blue, N; gray, C. Hydrogen atoms and solvent molecules are omitted for clarity

Fig. 2

The host–guest interactions between Zn–TCTA and substrate/reagent. a Normalized absorption and emission spectra of Zn–TCTA (ν^0–0 = 19,274 cm⁻¹, E^0–0 = 2.39 eV) and MOF−150 (ν^0–0 = 23,468 cm⁻¹, E^0–0 = 2.91 eV) excited at 390 and 350 nm, respectively. b Fluorescence spectrum of Zn–TCTA upon the addition of trifluoromethanesulfonyl chloride (TfCl) and the corresponding simulated Stern–Volmer curve (inset of b) excited at 390 nm; the intensity was recorded at 546 nm. c ¹H NMR spectrum of the crystals of Zn−TCTA and 1a@Zn−TCTA (digested in DMSO-d₆/DCl). Peaks marked with inverted red triangles represent the aromatic signals of the encapsulated substrate 1a. d Comparison of the infrared (IR) spectrum of 1a (red line), Zn−TCTA (black line), and 1a@Zn−TCTA (blue line)

Fig. 3

Schematic illustration of the photocatalytic site-specific trifluoromethylaion. a Potential reaction paths of the in vivo enzymatic aryl oxidative metabolism of (2H)-pyridone. Complementary approaches to the protection of metabolically susceptible sites by trifluoromethylation using b fac-Ir(Fppy)₃ or c Zn–TCTA as the photocatalyst, respectively. d Crystal structure of 1a@Zn–TCTA showing the multiple interactions between 1a and the Zn–TCTA scaffold and the potential reaction paths e and f for the reaction

Fig. 4

Characterization of reaction dynamics and photocatalyst recyclability. a The kinetics of the ingress and egress of substrate 1a on Zn–TCTA block crystals in an acetonitrile suspension and the time-dependent conversion plots of the photocatalytic transformation with the insert showing the enlarged ingress/egress curves. b Histograms of the time-course reactions of excess 1a (2.5 mmol, 10 equiv) in the presence of Zn–TCTA and fac-Ir(Fppy)₃ (6.25 μmol, 2.5 mol%) as photocatalysts, respectively. c Time-conversion plots of three rounds of the reaction using recycled catalyst Zn–TCTA. d A magnified TEM image of a crystalline powder of the photocatalyst Zn–TCTA after three rounds of reaction, showing the step-like cross-section of the laminated thin layers (inset, scale bar, 20 nm)

Fig. 5

Scope of photocatalytic trifluoromethylation of aromatics by Zn–TCTA. Reaction conditions: 1 (0.25 mmol, 1.0 equiv), RfCl (fluoroalkylation reagent as specified, 2.0 equiv), base additive (2.0 equiv), Zn–TCTA (0.025 equiv), MeCN (1 mL), 23 W household light, N₂ atmosphere, room temperature, 24 h. Isolated yields. ^†15 mmol-scale reaction. ^‡3.0 equiv of TfCl and collidine. ^*Only major regioisomers are shown. The minor regioisomeric sites are labelled with their carbon atom numbers

Fig. 6

Photocatalytic alkenyl trifluoromethylation-arylation by Zn–TCTA. Conditions were the same as those in Fig. 5. Isolated yield. ^†1.5 or ^‡3.0 equiv of TfCl and collidine

Fig. 7

Illustration of the interactions between the encapsulated substrates and Zn–TCTA. a Structure of 3a@Zn–TCTA. b Structure of 3f@Zn–TCTA. c The plausible mechanistic interpretation of the role of substrate encapsulation in diastereocontrol