Visible-light photoredox catalysis enabled bromination of phenols and alkenes

Summary A mild and efficient methodology for the bromination of phenols and alkenes has been developed utilizing visible light-induced photoredox catalysis. The bromine was generated in situ from the oxidation of Br− by Ru(bpy)3 3+, both of which resulted from the oxidative quenching process.


Introduction
Bromophenols serve as important synthetic intermediates for a variety of naturally occurring biologically active compounds and are also important constituents of industrial chemicals [1][2][3][4][5]. Thus, numerous methods were developed for the electrophilic bromination of phenols. The typical approaches include direct electrophilic halogenation by using molecular bromine or N-bromosuccinimide (NBS) [6][7][8], organometallic catalystpromoted bromination [9][10][11][12], and the oxidative bromination of phenols [13][14][15]. Nevertheless, most of the methods suffer from several drawbacks such as toxic reagents, harsh conditions, low yields, and low chemo-and regioselectivity. Hence, the development of an environmentally friendly methodology for the bromination of phenols with high chemoselectivity under mild and operationally simple conditions is still appealing.

Results and Discussion
Our initial investigation was carried out on protected 4-methoxyphenol 1a and CBr 4 in dried CH 3 CN in the presence of Ru(bpy) 3 Cl 2 (5.0 mol %) with visible light irradiation (blue LEDs, λ max = 435 nm) for 6 hours. The corresponding 2-bromo-4-methoxyphenol (2a) was obtained in 78% yield (Table 1, entry 1), whereas 3-bromo-4-methoxyphenol was not observed. The optimization of the reaction conditions were conducted by screening selected solvents and the amount of the photoredox catalyst using 1a as the representative substrate. As can be seen in Table 1, the solvent had a significant effect on the reaction efficiency. The reaction did not work well in DMF, MeOH, THF, CH 2 Cl 2 , EtOAc, CH 3 CN with 10 equivalents of H 2 O or 1,4-dioxane ( With the optimized conditions in hand, we prepared a variety of phenols which were subjected to the photocatalytic reaction. In general, both electron-withdrawing and electron-donating groups were tolerated as substituents R 2 in this process. Interestingly, the substrates protected with TMS (trimethylsilyl), TBS (tert-butyldimethylsilyl), MOM (methoxymethyl) and THP (tetrahydropyranyl) groups led to the corresponding bromophenols via a Tandem bromination/deprotection reaction ( Table 2, entries 1-8, 12, 13, and 15), among which the cases with substituents at paraand ortho-position afforded 2-and 4-bromophenol, respectively, in good to excellent yields ( Table 2, entries 1-5 and 12). The compound substituted with a methoxy group at the meta-position (1b) led to both 2-and 4-bromophenols 2b and 2b' with a ratio of 2:1 ( Table 2, entry 8). Without any substituent at the phenol moiety mono-and dibromophenols were obtained with a ratio of 3:2 ( Table 2,  entries 6 and 7). Notably, 1-bromonaphthalen-2-ol and 1-bromo-2-methoxynaphthalene could be prepared in good yields with high regioselectivity from TMS and methyl protected naphthalen-2-ol (   The bromination of phenols could be controlled by the amount of CBr 4 . For example, when TMS protected 3-methoxyphenol was treated with 2 equivalents of CBr 4 under similar conditions (Table 2), a dibromophenol product was directly obtained in a high yield (95%) (Scheme 2), which also could be prepared from the same starting materials in two steps ( Table 2).
We also conducted a control experiment by reacting stilbene with CBr 4 (1 equiv) in dry CH 3 CN in the presence of Ru(bpy) 3 Cl 2 (5.0 mol %) with visible-light irradiation (blue LEDs, λ max = 435 nm) for 72 hours, which led to the anti-1,2-dibromo-1,2-diphenylethane in 92% yield. This result is in accordance with the direct bromination of stilbene from liquid bromine [47]. Based on this result, our protocol provides an easily manageable and environment-friendly pathway to the bromination of alkenes. We further examined the scope of the reaction, and the results are summarized in Scheme 3. The 1,2-dibromo products were obtained in moderate to high yields.

Conclusion
In summary, we have developed a mild and operationally simple method for the in situ preparation of bromine utilizing a visible-light photoredox catalyst. The reaction proceeds with high chemical yield and regioselectivity for the bromination of phenols and alkenes. Further development of photoredox catalysis in the context of radical chemistry and its application in other reactions are currently underway in our laboratory.

Bromination of diketones
To a 10 mL round bottom flask equipped with a magnetic stir bar were added 5 (0.4 mmol), CBr 4 (133 mg, 0.4 mmol), dry CH 3 CN (2 mL) and Ru(bpy) 3 Cl 2 (15 mg, 0.02 mmol). The mixture was irradiated with blue LEDs (1 W) at room temperature open to air until the starting material was largely consumed (monitored by TLC). After the reaction was completed the solvent was concentrated in vacuo. The residue was purified by flash column chromatography to give the final product 6.

Synthesis of bromofuran
To a 10 mL round bottom flask equipped with a magnetic stir bar were added 7 (0.13 mmol), CBr 4 (43 mg, 0.13 mmol), LiBr (11 mg, 0.13 mmol), dry CH 3 CN (1 mL) and Ru(bpy) 3 Cl 2 (4.5 mg, 0.006 mmol). The mixture was irradiated with blue LEDs (1 W) at room temperature open to air until the starting material disappeared completely (monitored by TLC). After the reaction was completed the solvent was concentrated in vacuo. The residue was purified by flash column chromatography to give the final product 8.

Supporting Information
Supporting Information File 1 1 H and 13 C NMR spectra for products.