Enantioselective radical conjugate additions driven by a photoactive intramolecular iminium-ion-based EDA complex

The photochemical activity of electron donor–acceptor (EDA) complexes provides a way to generate radicals under mild conditions. This strategy has found application in chemical synthesis and recently in enantioselective catalysis. Reported methods classically relied on the formation of intermolecular EDA complexes, generated upon aggregation of two suitable reagents. Herein, we further expand the synthetic utility of this strategy demonstrating that an intramolecular EDA complex can trigger a photochemical catalytic enantioselective radical process. This approach enables radical conjugate additions to β-substituted cyclic enones to form quaternary carbon stereocenters with high stereocontrol using visible light irradiation. Crucial for success is the use of an amine catalyst, adorned with a carbazole moiety, which generates, upon condensation with enones, chiral iminium ions that show a broad absorption band in the visible region. This optical property originates from an intramolecular charge transfer π–π interaction between the electron-rich carbazole nucleus and the electron-deficient iminium double bond.


Synthesis of catalyst 3e
Procedure for the aza-Michael addition.
To an oven dried, argon purged 2-neck round bottomed flask fitted with an argon inlet and septum was added the substituted carbazole (1 equiv) and anhydrous THF (0.05 M). The reaction mixture was cooled to 0 o C and n-BuLi (1.05 equiv) was added dropwise. The reaction was stirred at 0 ºC for 30 minutes, and then 1-nitrocyclohex-1-ene (1.2 equiv) was added to the cold solution. The solution was allowed to slowly reach ambient temperature and stirred until full consumption of the carbazole, as inferred by TLC analysis (hexane/ethyl acetate 20:1). The reaction was then quenched with saturated aqueous NH4Cl solution and extracted with EtOAc. The organic phase was washed with water and brine, dried over MgSO4 and concentrated. The crude material (syn/anti = 5:1) was continued to the next step without further purification.

Procedure for the epimerization from syn to anti.
To the crude nitroalkane (1 equiv) in a round bottomed flask was added THF (0.1 M) and triethylamine (2 equiv). The reaction mixture was heated to 60 o C until epimerization was complete, as determined by 1 H NMR analysis of the epimeric protons (usually two days were necessary). The reaction mixture was then concentrated to dryness. The crude material was continued to the next step.

Procedure for the reduction of the nitroalkane.
To the crude anti nitroalkane (1 equiv), suspended in a solution of EtOAc/i-PrOH (1:3) in a Parr hydrogenation flask, was added Raney nickel (commercial slurry in water, 2 tsps per mmol of nitroalkane). The flask was then charged with a hydrogen atmosphere (3-3.5 bar) and shook for 24 hours. The reaction mixture was filtered through celite and rinsed with ethyl acetate (CAUTION: Raney nickel oxidizes exothermically, the filter cake must not be allowed to become dry) and concentrated. The residue was purified by flash chromatography (2% MeOH in DCM) to obtain the racemic aminocatalyst 3e as a whiteyellow solid (average 60% yield over 3 steps).

Procedure for the resolution of the racemic catalyst.
To an oven dried, argon purged, round-bottomed flask was added rac-3e (1.37 mmol, 1 equiv) and anhydrous tetrahydrofuran (5 mL). The solution was cooled to 0 ºC and anhydrous pyridine (154 μL, 1.92 mmol, 1.4 equiv) was added followed by dropwise addition of (1R)-(-)-menthyl chloroformate (0.35 mL, 1.64 mmol). The reaction was then stirred overnight at ambient temperature. The reaction was diluted with CH2Cl2 and washed with 2 M HCl solution, water and then brine. The organic phase was then dried over MgSO4, and concentrated to an off-white solid. The residue containing both menthyl carbamates of (S,S)-3e and (R,R)-3e was separated by flash chromatography (hexane:DCM 1:1) to afford both of the enantiopure menthyl carbamates of (R,R)-3e (first fraction, 492 mg) and (S,S)-3e (second fraction, 413 mg).

Synthesis of the Organic Silane Substrates
General procedure for the synthesis of carbazole or aniline derived organic silanes 4 or 9 To a stirred solution of the opportune carbazole or aniline substrate (10 mmol), dissolved in 5 mL of anhydrous THF, was added anhydrous DMF (or HMPA for aniline substrate, 5 mL). After cooling to -78 o C, n-BuLi (2.5 M in hexane, 1.0 equiv) was added slowly, and the reaction mixture was allowed to reach ambient temperature. After cooling again to -78 o C degree, 1.5 equiv of ClCH2SiMe2Ph were added. The reaction mixture was warmed to ambient temperature and stirring continued overnight. After consumption of the carbazole or aniline substrate, as inferred by GC-MS or TLC analysis, the reaction mixture was quenched by adding EtOAc and washed with H2O three times. The organic phase were washed with brine, dried over Mg2SO4, filtered and concentrated. The crude mixture was purified by silica gel (for aniline derived silane 9, neutral silica gel was used) column chromatography to afford the desired products.

Synthesis of Iminium Ion A-2
To a solution of isophorone (20.0 mmol, 1.0 equiv) and pyrrolidine (20.0 mmol, 1.0 equiv) in 25 mL benzene were added ammonium hexafluorophosphate (20.0 mmol, 1.0 equiv). 3 The suspension was refluxed overnight with continuous removal of the formed water (using a Dean-Stark apparatus). Then, the solvent was evaporated under reduced pressure to afford a yellow crude solid. After washing it with dry diethyl ether and acetonitrile, the iminium ion A-2 (3.56 g, 53%) were obtained as a white solid. 1

Mechanism studies
Radical Trapping Experiment with Ethene-1,1-diyldibenzene A 15 mL Schlenk tube was charged with the racemic primary amine catalyst 3e (13.3 mg, 0.04 mmol, 20 mol%), salicylic acid (5.5 mg, 0.08 mmol, 40 mol%), 9-((dimethyl(phenyl)silyl)methyl)-9H-carbazole 4d (47.3 mg, 0.15 mmol, 150 mol%), H2O (0.2 mmol, 200 mol%), 3-methylcyclohex-2-en-1-one 1a (11.0 mg, 0.1 mmol, 100 mol%), ethene-1,1-diyldibenzene 5 (27.0 mg, 0.15 mmol, 150 mol%), and 200 μL CH3CN. The mixture was placed under an atmosphere of argon, cooled to -78 °C, and degassed via vacuum evacuation (5 min), backfilled with argon, and warmed to ambient temperature. The freeze-pump-thaw cycle was repeated three times, and then the Schlenk tube was sealed with Parafilm and placed into a 3Dprinted plastic support mounted on an aluminium block fitted with a 420 nm high-power single LED (λ = 420 nm). The irradiance was fixed at 15±2 mW/cm 2 , as controlled by an external power supply and measured using a photodiode light detector at the start of each reaction; the temperature was kept at 35 °C with a chiller connected to the irradiation plate (the setup is the same as in Supplementary Figure 1). Stirring was maintained for 48 hours, and then the irradiation was stopped. The reaction mixture was analyzed by NMR and GC-MS spectroscopic analysis, confirming the formation of radical addition product 6 in 37% NMR yield (using 0.1 mmol trichloroethylene as the internal standard). The use of semi-preparative HPLC method enabled us to get the pure product 6 as a white solid. 1 ), backfilled with argon, and warmed to room temperature. The freeze-pump-thaw cycle was repeated three times, and then the Schlenk tube was sealed with parafilm and placed into a 3D-printed plastic support mounted on an aluminium block fitted with a 420 nm high-power single LED (λ = 420 nm). The irradiance was fixed at 15±2 mW/cm 2 , as controlled by an external power supply and measured using a photodiode light detector at the start of each reaction; the temperature was kept at 35 °C with a chiller connected to the irradiation plate (the setup is the same as in Supplementary Figure 1). Stirring was maintained for 48 hours, and then the irradiation was stopped. The reaction mixture was analyzed by NMR (using 0.1 mmol of trichloroethylene as the internal standard) and GC-MS spectroscopic analysis, confirming the formation of radical addition product 2a (45% NMR yield) and 3-methylcyclohexan-1-one 7 (33% NMR yield). Both the NMR and GC-MS spectroscopic traces of 7 are in accordance with the authentic sample, bought from Sigma-Aldrich Company. In order to check the enantiomeric excess of product 7, 4-methylbenzenesulfonohydrazine (37.2 mg, 0.2 mmol) and 1 mL MeOH was added to the reaction mixture, and then stirred for two hours. The crude material was purified by flash column chromatography on silicon gel (hexane/ethyl acetate: gradient from 10:1 to 4:1), to afford the corresponding cyclic hydrazone product (white solid, Z/E = 1:1). The enantioselectivity of the hydrazone was measured by Waters ACQUITY ® UPC 2 instrument (condition: UPC 2 , Trefoil AMY-1 column, 100% CO2 to 60/40 CO2/MeCN over 4 minutes, flow rate: 3.00 mL/min, λ = 230 nm, τMajor (

Supplementary Methods
The NMR spectra were recorded at 400 MHz or 500 MHz for 1 H, 101 or 126 MHz for 13 C, 286 MHz for 19 F, and 162 MHz for 31 P. The chemical shift (δ) for 1 H and 13 C are given in ppm relative to residual signals of the solvents (CHCl3 @ 7.26 ppm 1 H NMR and 77.16 ppm 13 C NMR, or CD3OD @ 3.31 ppm 1 H NMR and 49.00 ppm 13 C NMR, and tetramethylsilane @ 0 ppm). Coupling constants are given in Hertz. The following abbreviations are used to indicate the multiplicity: s, singlet; d, doublet; q, quartet; p, pentet; sept, septet; m, multiplet; br, broad signal. NMR yields were determined by adding trichloroethylene (Cl2=ClH,  = 6.44 ppm) as an internal standard to the crude reaction mixtures and by integration of diagnostic signals. High-resolution mass spectra (HRMS) were obtained from the ICIQ High Resolution Mass Spectrometry Unit on MicroTOF Focus and Maxis Impact (Bruker Daltonics) with electrospray ionization. UV-vis measurements were carried out on a Shimadzu UV-2401PC spectrophotometer equipped with photomultiplier detector, double beam optics and D2 and W light sources. Cyclic voltammetry studies were carried out on an IJ-Cambria HI-730 Bipotentiostat using a three-electrode cell, offering compliance voltage up to ± 100 V (available at the counter electrode), ± 10 V scan range and ± 2 A current range.
General Procedures. All reactions were set up under an argon atmosphere in oven-dried glassware using standard Schlenk techniques, unless otherwise stated. Synthesis grade solvents were used as purchased. Anhydrous solvents were taken from a commercial SPS solvent dispenser. Chromatographic purification of products was accomplished using force-flow chromatography (FC) on silica gel (35-70 mesh). For thin layer chromatography (TLC) analysis throughout this work, Merck pre-coated TLC plates (silica gel 60 GF254, 0.25 mm) were employed, using UV light as the visualizing agent. Organic solutions were concentrated under reduced pressure on a Büchi rotary evaporator (in vacuo at 40 ºC, ~5 mbar).

Determination of Enantiomeric Purity: HPLC analysis on chiral stationary phase was performed on an
Agilent 1200-series instrument, employing Daicel Chiralpak ID and IC-3 columns, or on a Waters ACQUITY ® UPC 2 instrument, using a Trefoil AMY1, IB, CEL1 chiral column. The exact conditions for the analyses are specified within the characterization section. HPLC traces were compared to racemic samples prepared performing the reaction in the presence of the racemic carbazole-derived primary amine catalyst 3d.

Materials.
Commercial grade reagents and solvents were purchased from Sigma-Aldrich, Fluka, Alfa Aesar, and Fluorochem at the highest commercial quality and used without further purification, unless otherwise stated. Starting material, including 3-methyl-2-cyclohexenone 1a, 3-methyl-2-cyclopentenone, linear enones 1q-r, ClCH2SiMe2Ph, and N-phenylglycine were purchased from commercial source and used as received. All other cyclic enones 1 were prepared following a literature procedure. 4,5 The preparation of carbazole substituted silanes 4 and aniline-derived silanes 9 is detailed in Supplementary Note 1. The chiral primary amine catalysts 3a-3d were prepared according to procedures reported in the literature. 1,6 (Benzyloxy)methyl substituted dihydropyridine 13 was prepared according to a reported literature precedure. 7

Light Illumination System and General Procedure
A 15 mL Schlenk tube was charged with the chiral carbazole-derived primary amine catalyst (R,R)-3e (0.04 mmol, 20 mol%), acid (0.08 mmol, 40 mol%, salicylic acid for substrate 4 and benzoic acid for substrates 9), the organic silane 4 or 9 (0.15 mmol, 150 mol%), enone 1 (0.1 mmol, 100 mol%), H2O (0.2 mmol, 200 mol%) and 200 μL of CH3CN. The mixture was placed under an atmosphere of argon, cooled with liquid nitrogen, and degassed via vacuum evacuation (5 min), backfilled with argon, and warmed to room temperature. The freeze-pump-thaw cycle was repeated three times, and then the Schlenk tube was placed into a 3D-printed plastic support mounted on an aluminium block fitted with a 420 nm high-power single LED (λ = 420 nm). The irradiance was regulated at 15±2 mW/cm 2 , as controlled by an external power supply and measured using a photodiode light detector at the start and the end of each reaction; the temperature was kept at 35 °C with a chiller connected to the irradiation plate (the setup is detailed in Supplementary Figure 1). This setup secured a reliable irradiation and temperature while keeping a distance of 1 cm between the reaction vessel and the light source. Stirring was maintained for the indicated time (generally 48 hours), and then the irradiation was stopped. The reaction volatiles were removed in vacuum and the residue was purified by column chromatography to give the products 2 or 10 in the stated yield and enantiomeric purity. The reported yield and ee are average of two runs per substrate.