Catalytic Generation and Use of Ketyl Radical from Unactivated Aliphatic Carbonyl Compounds

Generation of a ketyl radical from unactivated aliphatic carbonyl compounds is an important strategy in organic synthesis. Herein, catalytic generation and use of a ketyl radical for the reductive coupling of aliphatic carbonyl compounds and styrenes by organic photoredox catalysis is described. The method is applicable to both aliphatic ketones and aldehydes to afford the corresponding tertiary and secondary alcohols in continuous flow and batch. Preliminary mechanistic investigation suggests the catalytic formation of a ketyl radical intermediate.


General Procedures
All reactions were performed under an inert atmosphere of argon with the exclusion of moisture from reagents and glassware unless otherwise noted. Analytical thin-layer chromatography (TLC) was performed on 0.2 mm coated Science silica gel (EM 60 F254) plates. Visualization was accomplished with UV light (254 nm) and exposure to either ceric ammonium molybdate (CAM), para-anisaldehyde, or potassium permanganate solution followed by heating. Column chromatography was carried out on a Biotage Isolera flash chromatography system using ReadiSep ® Normal-phase Silica Flash Columns (silica gel, average particle size 35-70 µm spherical).

Materials
Methyl benzoate (99%, Sigma-Aldrich) was used as an internal standard for quantification. Commercially available chemicals were purchased from Sigma-Aldrich Chemical Company (Milwaukee, WI), Alfa Aesar (Ward Hill, MA), Acros Organics (Pittsburgh, PA), or TCI America (Portland, OR). All solvents were degassed by sparging with nitrogen and dried by passage through a column of activated alumna on an SG Water solvent purification system. Distilled water was obtained from an in-house supply.

Instrumentation
Proton nuclear magnetic resonance ( 1 H NMR) spectra and carbon nuclear magnetic resonance ( 13 C NMR) spectra were obtained on a Bruker 400 MHz NMR instrument (400 and 101 MHz, respectively). Chemical shifts for proton are reported in parts per million (ppm) downfield from tetramethylsilane (δ = 0.00 ppm) and are referenced to residual protium in the NMR solvent (CDCl3, 7.26 ppm; DMSO, 2.50 ppm; D2O, 4.79 ppm; C6D6, 7.16 ppm). Chemical shifts for carbon are reported in ppm downfield from tetramethylsilane (δ = 0.00 ppm) and are referenced to residual carbon in the NMR solvent (CDCl3, 77.0 ppm; DMSO, 39.5 ppm). Fluorine nuclear magnetic resonance ( 19 F NMR) spectra were recorded on a Bruker 400 MHz (376 MHz) spectrometer; chemical shifts are reported in ppm and are referenced to α,α,α-trifluorotoluene (δ = -63.7 ppm). The following designations are used to describe multiplicities: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad). IR spectra were obtained on an Agilent Cary 630 FT-IR spectrometer equipped with an ATR (attenuated total reflectance) accessory. The following designations are used to describe intensities: s (strong), m (medium), w (weak), br (broad). Highresolution mass spectrometry data were acquired in the Department of Chemistry Instrumentation Facility, Massachusetts Institute of Technology on a JEOL AccuTOF DART. Gas chromatography (GC) was performed on an Agilent 5870 GC (HP-5 column) with a flame ionization detector.

Entry
Conditions Trifluoroacetic acid (4 equiv) as a proton source instead of H2O n.d.

Beeler's Continuous Flow Photochemistry System:
As shown in Figure S1, a Harvard Apparatus PHD2000 syringe pump was used to deliver the reagent solution (syringe 1) from a SGE gas-tight syringe, which was connected to the perfluoroalkoxy (PFA) tubing (ID 0.04''). The reagent solution was introduced to a PFA coil reactor (OD 1/16", ID 0.04", volume = 2.7 mL). The tubing reactor was wrapped within the helical grooves around a cone-shaped frame. The cone reactor was cooled by circulating water at room temperature. The cone reactor was irradiated by collimated light beam of 500W Hg(Xe) arc lamp. A UV Hot Mirror and longpass filter were placed between the UV source and the cone reactor. The entire reactor was covered by black cardboard. The final exiting stream was collected into a flask. Figure S1. Setup of the continuous flow Beeler's photochemistry system

Photochemistry Setup in Batch
The reagent solution was transferred to a quartz tube and the tube was placed in front of the collimated beam of UV light ( Figure S2). The reaction mixture was allowed to stir for 2 h. The general procedure in continuous flow was followed using styrene (1, 104 mg, 1.0 mmol) and tetrahydro-4H-pyran-4-one (2, 0.277 mL, 3.0 mmol). The residue was purified by column chromatography (ReadiSep ® Normal-phase Silica Flash Columns 12 g, 2-30% ethyl acetate in hexanes) to afford the coupled product 3 (82 mg, 0.4 mmol, 99% yield) as a white solid. IR (neat, cm

S25
The 1 H and 13 C NMR spectra are in agreement with those reported in the literature. 2 Electrochemical potentials were obtained with a standard set of conditions to main internal consistency. Cyclic voltammograms were collected with a Gamry Interface 1010 B Potentiostat/Galvanostat/ZRA. Samples were prepared with 0.03 mmol of substrate in 20 mL of 0.1 M tetra-n-butylammonium hexafluorophosphate in dry, degassed DMF. Measurements employed a glassy carbon working electrode, platinum wire counter electrode, 3.5 M NaCl silversilver chloride reference electrode, and a scan rate of 100 mV/s. Reductions were measured by scanning potentials in the negative direction. The glassy carbon electrode was polished between each scan. To a one-neck 250 mL round-bottomed flask equipped with a septum pierced with a needle and a stir bar was added pyridinium chlorochromate (4.3 g, 20 mmol) and DCM (30 mL) with stirring. 5-Hexen-1-ol (1.2 mL, 10 mmol) was added all at once via syringe, and the reaction turned dark brown and thick. The reaction was stirred at rt for 2 h until complete by TLC, followed by addition of Et2O (100 mL) and silica gel (50 g). The suspension was stirred for 30 min, filtered through a pad of silica gel with Et2O washings, and then concentrated under reduced pressure to yield the aldehyde as a light yellow oil (735 mg, 75%). The crude product was carried on without further purification. 3 The general procedure in continuous flow was followed using 4-vinylanisole (0.133 mL, 1.0 mmol) and hex-5-enal (0.196 mL, 3.0 mmol) with residence time of 17 min. The product solution OH as a proton source under the condition, which provides a proton for the protonation of the benzylic anion intermediate in the absence of H2O.