Difluoroalkylation of Anilines via Photoinduced Methods

The development of sustainable and mild protocols for the fluoroalkylation of organic backbones is of current interest in chemical organic synthesis. Herein, we present operationally simple and practical transition-metal-free methods for the preparation of difluoroalkyl anilines. First, a visible-light organophotocatalytic system working via oxidative quenching is described, providing access to a wide range of difluoroalkyl anilines under mild conditions. In addition, the formation of an unprecedented electron donor–acceptor (EDA) complex between anilines and ethyl difluoroiodoacetate is reported and exploited as an alternative, efficient, and straightforward strategy to prepare difluoroalkyl derivatives.


Reaction Workflow for the Synthesis of Difluoroalkylanilines
All photoredox reactions were performed with blue and green LED PR160L Kessil ® (light-emitting diode, λmax = 427 nm and λmax = 525 nm respectively) employed at a distance of ~4 cm from the reaction vials. A fan was used to ensure reactions remained near room temperature within a ventilated fume hood. A typical reaction setup is shown below for 0.1-0.3 mmol and 1.0 mmol scale.

Characterization of Compound 29
During the chromatographic purification of compound 25, it converted to compound 29.

UV-Vis Studies
A 0.1 M solution of 1a, 0.13 M solution of 2b and a mixture 1:1.3 of 1a:2b in DMSO were prepared. UV-Vis absorption spectra were measured in a 1 cm quartz cuvette.
Absorption spectra of individual reaction components and mixtures thereof were recorded. A bathochromic shift was observed for a mixture of aniline 1a and fluorinated 2b in DMSO, which was a visibly intense yellow in color (inset in Figure S2). This indicates the formation of an electron donor-acceptor (EDA) complex ( Figure S2, orange band).

Quantum yield
The quantum yield of the reaction was determined using the procedure reported previously: 4 1a, reagent 2b, and Na2CO3 were used as model substrates to determinate the quantum yield of this transformation, using 1,3,5-trimethoxybenzene as internal standard in a proportion 1:1 with 1a. The yield of the reaction after 1 h irradiation was 30%.
The quantum yield of the reaction is defined as: Φ(reaction at 427 nm) = mol of formed product mol of photon flux · t · f (1) where Φ is the quantum yield of the reaction, t is the time of the reaction (s), and f is the incident light absorbed by the EDA complex at 438 nm. The photon flux is calculated by standard ferrioxalate actinometry 5 (see below).

Incident light absorbed by the EDA complex
The fraction of light, f, absorbed was determined according to equation 2:

The photoredox reaction
The photoredox transformation was developed using the general procedure for 60 min (3600 s). Afterwards, 1,3,5-trimethoxybenzene was added as internal standard, and the reaction was worked up. The yield of the reaction was determined by 1 H NMR, where 0.03 mmols (30%) of the desired compound were obtained.

Photon flux at 438 nm
Standard ferrioxalate actinometry was used to determine the photon flux of the spectrophotometer using equations 3 and 4. For the ferrioxalate actinometer, the production of iron(II) ions proceeds by the following reactions: 5 The moles of Fe +2 formed are determined spectrophotometrically by development with 1,10-phenanthroline (phen) to form the red [Fe(phen)3] +2 moiety (λ = 510 nm). 3 The photon flux is defined as shown in equation 3: where Φ is the quantum yield for the ferrioxalate actinometer (1.01 at λ = 438 nm), 4 t is the time (s), f ~1, and the mol of Fe +2 are calculated according to equation 4.
where V is the total volume of the solution, ΔA is the difference in absorbance between irradiated and nonirradiated solutions, l is the path length (1.0 cm), and ε is the molar absorptivity at 510 nm (11110 L mol -1 cm -1 ). 5

Experimental
The following solutions were prepared in the dark (flasks were wrapped in aluminum foil) and stored in the dark at room temperature:  Ferrioxalate solution (0.15 M): Potassium ferrioxalate hydrate (0.65 g) was added to a flask wrapped in aluminum foil containing H2SO4 (10 mL, 0.05 M). The flask was stirred for complete solvation of the green solid in complete darkness. It is noteworthy that the solution should not be exposed to any incident light.
The absorbance of the non-irradiated sample. The buffered solution of phen (350 µL) was added to a ferrioxalate solution (2.0 mL) in a vial that had been covered with aluminum foil and with the lights of the laboratory switched off. The vial was capped and allowed to rest for 1 h and then transferred to a cuvette. The absorbance of the non-irradiated solution was measured at 510 nm to be 0.02 (see Figure S4).