N-Arylphenothiazines as strong donors for photoredox catalysis – pushing the frontiers of nucleophilic addition of alcohols to alkenes

A new range of N-phenylphenothiazine derivatives was synthesized as potential photoredox catalysts to broaden the substrate scope for the nucleophilic addition of methanol to styrenes through photoredox catalysis. These N-phenylphenothiazines differ by their electron-donating and electron-withdrawing substituents at the phenyl group, covering both, σ and π-type groups, in order to modulate their absorbance and electrochemical characteristics. Among the synthesized compounds, alkylaminylated N-phenylphenothiazines were identified to be highly suitable for photoredox catalysis. The dialkylamino substituents of these N-phenylphenothiazines shift the estimated excited state reduction potential up to −3.0 V (vs SCE). These highly reducing properties allow the addition of methanol to α-methylstyrene as less-activated substrate for this type of reaction. Without the help of an additive, the reaction conditions were optimized to achieve a quantitative yield for the Markovnivkov-type addition product after 20 h of irradiation.

S2 to 220 °C. Measurements were performed in split-split mode using hydrogen as the carrier gas (flow rate 30 mL/min).
For the calculation of the GC yields a concentration series with (2-methoxypropan-2yl)benzene (17) and 2-bromotoluol (8.77 µmol/mL) as internal standard was prepared. The R-value of the series was determined to be 0.91. To analyze the catalysis mixture, 100 µL of the crude reaction mixture, 174.6 µL of a stock solution of 2-bromotoluol (8.77 µmol/mL) and 724.6 µL ethyl acetate were mixed and shaken vigorously. Then, a volume of 300 µL of the resulting solution was transferred to an GC vial.
Irradiation of the photochemical reactions was carried out using a setup which was designed and manufactured by the University of Regensburg and the workshop of the Institute for Physical Chemistry at KIT Karlsruhe. We warmly thank Dieter Waltz and Klaus Stree for their kind support with manufacturing the irradiation hardware. A Nichia NVSU233A LED was applied for 365 nm irradiation and the photoreactions were irradiated from the bottom. The temperature during the reaction time was controlled using a LAUDA Alpha R8 thermostat. High resolution mass spectrometry was performed on a Finnigan Modell MAT 95 using an electron impact ionization source or on a Q Exactive Plus Orbitrap from Thermo Scientific. MALDI mass spectra were recorded on a Bruker Daltonics Biflex-IV spectrometer, operated in linear negative mode with 3-hydroxy-2-pyridinecarboxylic acid as a matrix. GC-MS coupling was recorded using a Varian 431 GC with a capillary column FactorFourTM VF-5 ms (30 m × 0.25 mm × 0.25 μm) and a Varian 210 ion trap mass detector. Thin layer chromatography was performed using Fluka silica gel 60 F254 coated aluminium foil. Flash chromatography was carried out on silica gel 60 supplied by Sigma Aldrich (43-60 μm. Spectroelectrochemical measurements were carried out using a Varian Cary 50 spectrometer at room temperature and a HORBIA-Scientific S3 Fluoromax-4 spectrofluorometer with an AC 200 thermostat from Thermo Scientific and the FluoroEssence software V3.5 in semi-micro quartz glass cuvettes (width 1 cm, volume 1.4 mL) from Starna.
The cyclic voltammetry measurements were carried out with complete exclusion of air and moisture. We warmly thank Prof. Dr. Frank Breher for sharing his CV infrastructure. The working electrode and the counter electrode were made of platinum. Reference electrode serving as the potential zero point was made of silver.
For the electrolysis solution, a 0.05 M solution of tetrabutylammonium hexafluorophosphate in dry DCM or in dry MeCN was prepared. Figure S1: Modular LED irradiation setup and cooling blocks.

Synthetic procedures
General procedure A -synthesis of N-phenylphenothiazines. N-phenylphenothiazines were synthesized similarily to the reported procedure [S2]. Phenothiazine (1.00 equiv) was dissolved in anhydrous toluene (0.51 M). Bromobenzene (1.22 equiv), KOt-Bu (1.29 equiv) and (t-Bu) 3 PHBF 4 (6 mol %) were added, followed by Pd 2 dba 3 (3 mol % as 6 mol % Pd). The reaction mixture was degassed using three freeze-pump-thaw cycles and finally stirred under reflux for 20 °h. After reaching room temperature, 100 mL EtOAc and 50 mL water were added to the reaction mixture. After phase separation, the aqueous phase was extracted additionally with 3 × 100 mL EtOAc. The combined organic phases were dried over Na 2 SO 4 , the solvent evaporated and the crude product purified by column chromatography.

General procedure B -synthesis of N-phenylphenothiazines. N-Phenothiazine
(1.00 equiv), aryl halide (1.50 equvi), sodium tert-butoxide (2.50 equiv), Pd 2 dba 3 (0.05 equiv/5 mol %) and tricyclohexylphosphine (0.07 equiv) were dissolved in anhydrous toluene (0.26 M). The reaction mixture was then stirred under reflux under inert atmosphere overnight. The reaction mixture was cooled to room temperature and 50 mL water were added. The reaction mixture was extracted with EtOAc (3 × 100 mL). The combined organic phases were dried over MgSO 4 , the solvent removed and the crude product purified by column chromatography.
The product was isolated as yellow powder (595 mg
The product was isolated as colorless powder (939 mg

UV-vis absorption
The UV-vis absorption spectra were recorded at 20 °C in acetonitrile (HPLC grade, Fisher Scientific) or dichloromethane (HPLC grade, Fisher Scientific) using slit 2 nm.               S89