The Photochemical Activity of a Halogen-Bonded Complex Enables the Microfluidic Light-Driven Alkylation of Phenols

A mild light-driven protocol for the direct alkylation of phenols is reported. The process is driven by the photochemical activity of a halogen-bonded complex formed upon complexation of the in situ generated electron-rich phenolate anion with the α-iodosulfone. The reaction proceeds rapidly (10 min) under microfluidic conditions, delivering a wide variety of ortho-alkylated products (27 examples, up to 97% yield, >20:1 regioselectivity, on a gram scale), including densely functionalized bioactive phenol derivatives

The following spectrum is reported in the Kessil website (www.kessil.com/science/PR160L.php). The wavelengths used in the current study were set at 370 and 456 nm.  Figure S2 shows a schematic representation of the microfluidic circuit employed in the present study. Reaction mixtures are introduced in continuous flow into the micro-photoreactor via a double syringe pump (Syrris Atlas, see general information). The microfluidic reactor consists of a transparent TFE capillary (BGB®; internal diameter: 800 μm; inner volume: 210 μL; microreactor tubing length: 42 cm). The microreactor is then irradiated by the selected light source. The crude is collected in a vial, connected to the exit of the microreactor. Figure S2. Schematic representation of the micro-photoreactor setup. Figure S3 shows the assembled microfluidic reactor (left side) and the general setup of a reaction using a Kessil lamp (right side). The lamp is placed at a fixed distance of 1 cm. Aluminium foil is used to avoid undesired irradiation of the tubing. To maintain a stable reaction temperature, a fan is placed at 3 cm from the reactor.
4m was synthesized following a method previously reported in the literature. [7] The characterization data matched with the reported one. •
Boc-Tyr-OH (S3) was synthesized following a method previously reported in the literature. [8] The characterization data matched with the reported one. 4n was synthesized from S3, following a method previously reported in the literature. [9] The characterization data matched with the reported one.

B.2. PREPARATION OF α-IODOSULFONES
B.2.1. Synthesis of 5a-d and 5f-h STEP 1, according to a modified literature procedure. [10] A mixture of thiol S4 (10 mmol, 1 equiv.), Oxone (25 mmol, 2.5 equiv.), KCl (10 mmol, 1 equiv.) and water (30 mL) was vigorously stirred at room temperature for 2 hours. The aqueous phase was extracted with ethyl acetate (4 × 50 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography (cyclohexane) affording the desired product (R = Cl: 90% yield, R = cyclohexyl: 83% yield). The characterization data matched with the reported one. STEP 2, according to a literature procedure. [2] The corresponding sulfonyl chloride S5 (7 mmol, 1 equiv.) was dissolved in water (25 mL). Sodium sulfite (11.2 mmol, 1.6 equiv.) and sodium bicarbonate (11.2 mmol, 1.6 equiv.) were added and the reaction mixture was refluxed for 3 hours in an oil bath. Water was evaporated and ethanol was added to the residue. The suspension was heated for 10 minutes, cooled and filtered. This procedure was repeated twice using the residue of the filtration. The ethanol fractions were combined and the solvent was evaporated under reduced pressure. Sodium sulfinate was used without any further purification (R = F: 93%, R = Cl: 92% yield, R = Br: 88% yield, R = cyclohexyl: 75% yield, R = naphthalenyl: 72% yield). The characterization data matched with the reported one. STEP 3, according to a literature procedure. [2] A solution of sodium sulfinate S6 (5 mmol, 1 equiv.) in DMF (20 mL, 0.25 M) was stirred at room temperature for 15 minutes. Diiodomethane (6 mmol, 1.2 equiv.) was added dropwise and the solution was heated up to 80 ºC (heat source: oil bath) and stirring was continued over 17 hours. The reaction was quenched by the addition of water (100 mL). The solution was then transferred to a separatory funnel and extracted with ethyl acetate (3 x 50 mL). The organic phases were combined and washed with brine (50 mL), saturated solution of sodium thiosulfate (50 mL) and then dried over sodium sulfate before concentration in vacuo. The residue was purified by flash column chromatography (cyclohexane/ethyl acetate) to afford the desired α-iodo sulfones 5a-d and 5f-h. Iodo(methylsulfonyl)methane (5f) 5f was synthesized according to the general procedure B.2.1 from sodium methanesulfinate (510 mg, 5 mmol). The final α-iodosulfone 5f was obtained as a white solid (746 mg, 68% yield). 1 H NMR (400 MHz, CDCl3) δ 4.39 (s, 2H), 3.17 (s, 3H). The characterization data matched with the reported one. [2] ((Iodomethyl)sulfonyl)cyclohexane (5g) 5g was synthesized according to the general procedure B.2.1 from cyclohexanethiol (1.22 mL, 10 mmol). The final α-iodo sulfone 5g was obtained as a white solid (504 mg, 35% yield  [12] B.2.2. Synthesis of the secondary α-iodo sulfone 5e STEP 1, according to a modified literature procedure. [2] To a solution of commercially available 3-chloro butanone S7 (5 mmol, 1 equiv.) in DMF (10 mL, 0.5 M) was added the sodium sulfinate S6 (5 mmol, 1 equiv.) in one portion. The reaction mixture was stirred at room temperature for 24 hours. The reaction was quenched by the addition of water (50 mL), the mixture was extracted with ethyl acetate (3 x 35 mL), dried over sodium sulfate and the solvent was removed under reduced pressure. The corresponding adduct was used without any further purification (R = phenyl: 85% yield, R = 4-fluorophenyl: 82% yield). STEP 2, according to a modified literature procedure. [2] To a dioxane-water (1:1, 0.5 M) solution of the starting material S8 (2.5 mmol, 1 equiv.) and iodine (10 mmol, 4 equiv.) in the presence of potassium iodide (20 mmol, 8 equiv.), 1 M solution of NaOH is added under stirring at room temperature until decoloration of the excess of iodine occurred. After 20 minutes stirring, the reaction mixture was diluted with water and extracted with DCM (3 x 20 mL). The final α-iodo sulfone 5e. The phenol derivative (4a-o) (3 equiv, 3 mmol) and the α-iodosulfone (5a-h) (1 equiv, 1 mmol) were introduced into a vial and dissolved in 2 mL of acetonitrile (MeCN), unless otherwise stated. The mixture was degassed with Argon (Ar) for 1 minute. Then, 1,1,3,3-tetramethylguanidine (TMG, 3 equiv, 3 mmol) was added to the vial under Ar atmosphere. The reaction mixture was connected to the flow setup ( Figure S3 in Section A.2) and introduced in continuous-flow with a flow rate of 21.3 µL/min (residence time, tR = 10 min). The crude was collected in a vial connected to the exit of the microreactor (collected volume = 1.5 mL ca.). To a 300 µL of the crude were added 2 mL of a saturated solution of ammonium chloride (NH4Cl), and the organic layer was extracted with dichloromethane (DCM) three times. The organic layer was then separated, dried over magnesium sulfate (MgSO4) and filtered. The solvent was removed under reduced pressure. 300 µL of an internal standard solution (trichloroethylene 0.5 M in CDCl3) were added to the dried crude and the NMR yield was determined.

Characterization
Another 1 mL of the crude (0.5 mmol, unless otherwise stated) was subsequently extracted as described. The final residue was purified by flash column chromatography on silica gel to afford the ortho-alkylated phenols 7a-7aa as the major regioisomer, in the stated yield. The regioselective ratio was determined by 1 H-NMR-analysis of the reaction crude.

F.1. DESULFONYLATION OF THE PRODUCTS 7a, 7d AND 7o
According to a modified literature procedure: [13] To a round-bottom flask containing freshly activated Mg (30 equiv) under N2, it was added dry MeOH (0.05 M) followed by the sulfonylated phenol 7 (1 equiv) and anhydrous NiCl2 (0.05 equiv, 50 mol%). The mixture was stirred vigorously at 60 ºC for 6 h, in an oil bath. The reaction was quenched by adding an aqueous solution of HCl (1 M). The crude mixture was then transferred to a separatory funnel and extracted with ethyl acetate (x3 times). The organic phases were combined and dried over Mg2SO4 before concentration in vacuo. The mixture was purified by flash column chromatography (hexane/ethyl acetate 9:1) to give the product 8 in the state yield.

G.4. QUANTUM YIELD MEASUREMENT
A ferrioxalate actinometry solution was prepared by following the Hammond variation of the Hatchard and Parker procedure outlined in Handbook of Photochemistry. [17] Ferrioxalate actinometer solution measures the decomposition of ferric ions to ferrous ions, which are complexed by 1,10-phenanthroline (complete complexation takes about an hour) and monitored by UV/Vis absorbance at 510 nm. [18] The moles of iron-phenanthroline complex formed are related to moles of photons absorbed.
The following solutions were prepared and stored in the dark: 1. Potassium ferrioxalate solution: 589.5 mg of potassium ferrioxalate (commercially available from Alfa Aesar) and 278 μL of sulfuric acid (96%) were added to a 100 mL volumetric flask and filled to the mark with water (MilliQ grade).

3.
Buffer solution: to a 100 mL volumetric flask 4.94 g of NaOAc and 1 mL of sulfuric acid (96%) were added and filled to the mark with water (MilliQ grade).

4.
Model reaction solution I: the mixture between phenol 4a and α-iodosulfone 5a was added to a 1 mL volumetric flask, using the described reaction conditions (see Section C) and dibromomethane as internal standard, and filled to the mark with acetonitrile (HPLC grade).

5.
Model reaction solution II: a mixture between phenol 4l and α-iodosulfone 5a was added to a 1 mL volumetric flask, using the described reaction conditions (see Section C) and dibromomethane as internal standard, and filled to the mark with acetonitrile (HPLC grade).
The actinometry measurements were done as follows: A1. 365 nm LED: 1 mL of the actinometer solution was added to a quartz cuvette (l = 10 mm). The actinometry solution (placed 2 cm away from the lamp) were irradiated with 3 W 365 nm LED for specified time intervals (0, 10, 20, 30) seconds.

B.
After irradiation all the actinometer solution was removed and placed in a 10 mL volumetric flask. 0.5mL of 1,10-phenanthroline solution and 2 mL of buffer solution was added to this flask and filled to the mark with water (MilliQ grade).
C. The UV-Vis spectra of actinometry samples were recorded for each time interval ( Figure S23 and Figure S24). The absorbance of the actinometry solution was monitored at 510 nm. where V1 is the irradiated volume (1 mL), V2 is the aliquot of the irradiated solution taken for the determination of the ferrous ions (1 mL), V3 is the final volume after complexation with phenanthroline (10 mL), l is the optical path-length of the irradiation cell (1 cm), ΔA(510 nm) the optical difference in absorbance between the irradiated solution and that taken in the dark, ε(510 nm) is the molar extinction coefficient of the complex Fe(phen)3 2+ (11100 L mol -1 cm -1 ).
E. The moles of Fe 2+ formed (N) are plotted as a function of time (t) ( Figure S25 and Figure S26).
The slope is a product of the photon flux (F) and the quantum yield for Fe 2+ (φFe 2+ = 1.21 for λ = 365 nm; and φFe 2+ = 0.9 for λ = 456 nm), [17] since F = N/ΦFe 2+ t. The F was determined to be:   Since the ferrioxalate actinometer absorbance at 365 nm is 1.50 and at 456 nm is 0.26, and inferior to 2 in both cases (if it is major than 2 at the wavelength used, it can be assumed that the entire incident light is absorbed), a correction factor (C) based on the fraction of light absorbed by the actinometer has to be considered to calculate the photon flux and the final quantum yield of the reaction [17] (note that is also needed if the absorbance of the reaction under study at the optimized concentration is inferior to 2 at the wavelength used). Thus, according to the definition of quantum yield: [19] Φ 2+ = the photon flux (F) previously found has to be divided by the appropriate correction factor C. F. The reaction solutions I and II described at point 4 and 5, respectively, were irradiated using the same system, and the moles of product formed for the reaction of interest are described below. The moles of product formed were determined by 1 H-NMR analysis using dibromomethane as internal standard. The moles of product formed per unit of time were related to the number of photons absorbed. Figure S27. Moles of product formed after irradiation with 365 nm light as a function of the moles of emitted photons.

Reaction solution I
The absorbance of the reaction at the irradiation wavelength (365 nm) is A365nm> 2, hence no correction factor must be applied since it can be assumed that the entire incident light is absorbed. The quantum yield (φ) corresponding to the registered slope is 1.95 ( Figure S27).