Late-stage trifluoromethylthiolation of benzylic C-H bonds

The benzylic positions in drugs are sites that readily react with cytochrome P450 oxidases via single-electron oxidation. New synthetic methodologies to incorporate a fluoroalkyl group at the benzylic site are continually being developed, and in this paper, we report a metal-free and site-selective organophotoredox-catalyzed trifluoromethylthiolation of benzylic C-H bonds for a wide variety of alkyl arenes and heteroarenes. The precise and predictive regioselectivity among various C(sp3)-H bonds originates from an inner-sphere benzylic radical initiation mechanism, and avoids the use of external oxidants or hydrogen atom abstractors. Its practicality stems from the trifluoromethylthiolation of a series of drugs and complex organic molecules, which is overwhelmingly selective for benzyl groups. This operationally simple protocol can provide a general and practical access to structurally diverse benzylic trifluoromethyl sulfides produced from ubiquitous benzylic C-H bonds. Large scale trifluoromethylthiolation can be achieved with continuous flow photoredox technology.


The parallel experiments under the present condition and the previous condition
The selected examples 1a and 1k were conducted under the optimal conditions and the previous condition, respectively. To our delight, the present method shows an excellent selectivity and efficiency for benzylic C-H trifluoromethylthiolation of 1a ( Fig. S9-a). In addition, 1k could undergo C(sp 3 )-H trifluoromethylthiolation, but with a much lower conversion and selectivity than the present condition ( Fig. S9-b). These experiments perfectly exhibit the advantages in compatibility and selectivity by innersphere radical initiation mechanism in comparison with outer-sphere radical initiation mechanism [Qing's work: Org. Lett. 16, 3372-3375 (2014); Glorius's work: J. Am. To elucidate the possible reaction mechanism, electron paramagnetic resonance (EPR) 28 experiments with N-tert-Butyl-α-phenylnitrone (PBN) as electron-spin trapping reagent were carried out. As shown in Fig S20-

Parallel competition
Following the general procedure, D 8 -toluene ( To determine whether a reductive or oxidative quenching cycle is operative in the reaction, fluorescence quenching studies were conducted. Based on the above data, photoexcited 4CzIPN* can be quenched by 1a, involved a reductive quenching cycle.

Quantum yield measurement
The quantum yield (ф) was determined by the known ferrioxalate actinometry method. A ferrioxalate actinometry solution was prepared by following the Hammond variation of the Hatchard and Parker procedure outlined in Handbook of Photochemistry. Hence, the irradiated light intensity was estimated to 3.93 x 10 -8 einstein S -1 by using K 3 [Fe(C 2 O 4 ) 3 ] as an actinometer. For seven clean tubes, according to the general procedure, the 0.1 mmol scale model reaction solution was irradiated with two 45 W blue LEDs for specified time intervals (10 min, 20 min, 30 min, 40 min, 50 min, 60 min and 70 min). The moles of products formed were determined by GC yield with acetophenone as reference standard. The number of moles of products (y axis) per unit time is related to the number of photons (x axis, calculated from the light intensity). The slope gives the quantum yield (Φ) of the 31 photoreaction, 0.33 (33%). Thus, a radical chain pathway may be ruled out.
Supplementary Figure 28. The UV-Vis spectra and data of quantum yield measurement.

Cyclic Voltammetry (CV) measurements
Cyclic Voltammetry were collected using CHI660E from Shanghai Chenhua Instruments Limited (SCHI). Sample 0.001 M and tetrabutylammonium hexafluorophosphate 0.1 M in anhydrous MeCN were used for tests. Measurements were run using glassy carbon working electrode, platinum wire counter electrode, and 0.01 M AgNO 3 silver-silver chloride reference electrode in a scan rate of 0.1 V/s. In addition, ferrocene was used as an internal reference to SCE. In order to elucidate the possibility of SET between 4CzIPN and alkyl arenes, we again gained the CV data of 4CzIPN and toluene. To our delight, the small part overlap between the excited 4CzIPN 2 with Toluene was observed. Thus, the first sluggish oxidation of alkyl arenes is reasonable, which is consist with the luminescence experiments. E 1/2 (P*/P -) = E 0-0 + E 1/2 (P/P -), E 0-0 = 2.53 V V vs SCE

UV-Vis absorption study
All the UV spectra were measured in MeCN (I-V). It is also interesting to find that the introduction of SCF 3 into 1a could make the the max UV-Vis absorption peak red-shift (V). It is clear to see that photocatalyst 4CzIPN has a visible light absorption range from 400-470 nm (our blue LEDs, IV). All the other compounds (1a, Phth-SCF 3 , 3a) don't have obvious absorption in visible-light region (>400 nm).  128.5, 117.2, 79.4, 67.3, 25.4, 21.2. Procedure F: