Chromium photocatalysis: accessing structural complements to Diels–Alder adducts with electron-deficient dienophiles

A Cr-photocatalyzed [4 + 2] cycloaddition between dienes and electron-deficient alkenes is reported, accessed by up to three converging pathways to yield the “meta” adducts.

SC), Strem (Newburyport, MA) and TCI America (Portland, OR). Qualitative TLC analysis was performed on 250 mm thick, 60 Å, glass backed, F254 silica (Silicycle, Quebec City, Canada). Visualization was accomplished with UV light and exposure to p-anisaldehyde or KMnO 4 solution followed by heating. Flash chromatography was performed using Silicycle silica gel (230-400 mesh). Reactions under NUV irradiation were performed in a Luzchem chamber reactor equipped with 10 lamps of wavelengths 419, 350, and 300 nm. Irradiation with visible light was performed in a sealed box using a 23 W compact fluorescent light bulb (EcoSmart 23 W bright white CFL spiral light bulb, 1600 lumens). NMR spectra were acquired at the University of Georgia Chemical Sciences Magnetic Resonance Facility on a Varian Mercury Plus 400 MHz NMR. 1 H NMR spectra were acquired at 400 MHz and are reported relative to SiMe 4 (δ 0.00). 13 C NMR spectra were acquired at 100 MHz and are reported relative to SiMe 4 (δ 0.00). IR spectra were obtained on a Shimadzu IRPrestige-21 FT-IR. High resolution mass spectrometry data were acquired by the Proteomics and Mass Spectrometry Facility at the University of Georgia on a Thermo Orbitrap Elite. Absorption spectra were obtained with a Hewlett-Packard 8453 spectrometer in quartz cuvettes with a 1 cm path length. Emission spectra were obtained with an Aviv automated titrating differential/ratio spectrofluorometer (model ATF105).
Quantum yields and chain lengths were determined in a similar manner reported by Cismesia and Yoon. 3 Actinometry experiments were performed using a Newport TLS-300XU tunable light source, which includes a 200 watt Xe arc lamp, a Cornerstone 130 monochromator, and a motorized filter wheel; this instrument provides a wavelength range of 250-2400 nm and a wavelength selectivity of ±0.7 nm. Electrochemical experiments were performed in 0.1 M solutions of Bu 4 NPF 6 in CH 3 CN and CH 3 NO 2 . Cyclic voltammograms (CVs) and square-wave voltammograms Supporting Information: Stevenson,Higgins,Shores,and Ferreira S4 (SWVs) were recorded with a CH Instruments potentiostat (Model 1230A or 660C) using a 0.25 mm Pt disk or 0.25 mm glassy carbon disk working electrode, Ag + /Ag reference electrode and a Pt wire auxiliary electrode. Scans were collected at a rate of 100 mV/s. Reported potentials are referenced to the [Cp 2 Fe] + /[Cp 2 Fe] redox couple (abbreviated Fc + /Fc, where Cp = cyclopentadienyl), and were determined by adding ferrocene (which was sublimed before use) as an internal standard at the conclusion of each electrochemical experiment. Oxygenated experiments were performed by bubbling O 2 into the experimentation vessel for 10 seconds prior to data collection. Dark experiments were performed by removing the vessel from all light for 20 minutes before and during scans. To minimize electrode interactions with possible superoxide species present, the working electrode was polished before each set of experiments were performed. The surface of the working electrode was also cleaned with a Kimwipe before each scan to help provide a clean surface of the electrode.
TLC: R f = 0.52 in 3:1 hexanes/EtOAc, stained yellow with p-anisaldehyde.      Table   Table S1. Selected optimization experiments.         ox " defined here as the onset potential for the oxidation wave occurring when scanning the potential in the positive direction. d Data acquired with 3 equiv isoprene added. e Data acquired with 2 equiv isoprene added. f Data acquired with 6 equiv isoprene added.

General Procedure for Deviations from Standard Conditions
To convert the potentials from V vs. Fc + /Fc to V vs. SCE, 0.35 was added to the potentials taken in CH 3 NO 2 , and 0.40 was added to the potentials taken in CH 3 Figure S4. Static emission (λ ex = 340 nm, bandwidth = 2 nm) of 4-methoxychalcone (1) in acetonitrile at 0.0016 M. The λ em centered at 443 nm was reproduced on two separate samples that were degassed for ~45 min before the measurement was performed. A sample of acetonitrile revealed no increase in emission intensity over the wavelength range tested.       All spectroscopic data were consistent with previously reported values. 9
All spectroscopic data were consistent with previously reported values. 10 Ester S5. To a solution of triethyl phosphonoacetate (5.46 mL, 27.5 mmol) in THF (31.0 mL) at 0 °C was added NaH (1.06 g, 60% dispersion in mineral oil, 26.5 mmol). The reaction mixture was stirred at 0 °C for 45 min, then aldehyde S24 (3.04 mL, 25.0 mmol) was added dropwise. The mixture was allowed to warm to ambient temperature and maintained for 15 h. The reaction mixture was then diluted with brine (30 mL), and the THF was removed by rotary evaporation. The mixture was extracted with CH 2 Cl 2 (3 x 20 mL), and the combined organic layers were washed with brine (50 mL), then dried over MgSO 4 . The solvent was removed by rotary evaporation, and the crude residue was purified by flash chromatography (100% hexanes → 4:1 hexanes/EtOAc) to afford ester S5 (4.14 g, 80% yield) as a white solid.
All spectroscopic data were consistent with previously reported values. 11 Carboxylic acid S6. To a solution of ester S5 (1.00 g, 4.85 mmol) in EtOH (9.70 mL) at 23 °C was added 10% aq.
NaOH (19.0 mL). The flask was stoppered, and the reaction mixture was stirred at ambient temperature for 45 h. The reaction mixture was diluted with 1 M aq. HCl (25 mL). EtOAc was added until the white solid was completely dissolved (ca. 75 mL) . The layers were separated, and the aqueous layer was extracted with EtOAc (3 x 25 mL). The combined organic layers were washed with brine (60 mL) and dried over MgSO 4 . The solvent was removed by rotary evaporation to afford carboxylic acid S6 (0.864 g, quantitative) as a white solid. The crude residue was sufficiently pure by 1 H NMR and therefore was used without further purification.
All spectroscopic data were consistent with previously reported values. 12 Alcohol S28. To a solution of ester S5 (1.50 g, 7.27 mmol) in hexane (58.0 mL) at 0 °C was added DIBAL (14.6 mL, 1.0 M in hexane) dropwise with an addition funnel. The reaction mixture was stirred at 0 °C for 2 h, then was allowed to warm to ambient temperature and stirred an additional 20 min. The reaction mixture was then diluted with sat. aq.

MeO
Rochelle salt (75.0 mL) and stirred overnight. The layers were separated, and the aqueous layer was extracted with CH 2 Cl 2 (3 x 50 mL). The combined organic layers were washed with brine (50 mL), then dried over MgSO 4 . The volatile materials were removed by rotary evaporation to afford alcohol S28 as a white solid, which was used in subsequent reactions without further purification. All spectroscopic data were consistent with previously reported values. 13 Aldehyde S7. To a solution of alcohol S28 (0.739 g, 4.50 mmol) in hexanes (22.5 mL) was added MnO 2 (7.82 g, 90.0 mmol). The reaction mixture was stirred for 3 h, and then was filtered through a short plug of silica (5 cm high x 3 cm wide EtOAc eluent). The filtrate was concentrated by rotary evaporation, and the crude residue was purified by flash chromatography (100% hexanes → 3:1 hexanes/EtOAc eluent) to afford aldehyde S7 (0.387 g, 53% yield) as a white solid.
All spectroscopic data were consistent with previously reported values. 6 Nitroalkene S8. To a solution of NH 4 OAc (0.848 g, 11.0 mmol) in nitromethane (14.0 mL, 0.71 M with respect to S12) at 23 °C was added aldehyde S24 (1.22 mL, 10.0 mmol). The reaction flask was equipped with a reflux condenser (open to air) and the mixture was heated at 100 °C for 4 h. The reaction was allowed to cool to ambient temperature, and the nitromethane was removed by rotary evaporation. The resulting residue was dissolved in CH 2 Cl 2 (20 mL), and the organic layer was washed sequentially with H 2 O (20 mL) and brine (20 mL), then dried over   All spectroscopic data were consistent with previously reported values. 16 Diene S10. To a solution of alcohol S11 (0.168 g, 1.50 mmol) and acetic anhydride (0.170 mL, 1.80 mmol) in THF (15. and was allowed to warm to ambient temperature. The layers were separated, and the aqueous layer was washed with Et 2 O (3 x 30 mL). The combined organic layers were washed with brine (50 mL) and dried over MgSO 4 . The solvent was removed by rotary evaporation, and the crude residue was purified by flash chromatography (100% hexanes → 3:1 hexanes/EtOAc eluent) to afford diene S11 (1.57 g, 56% yield) as a colorless oil.
All spectroscopic data were consistent with previously reported values. 18 Diene S12. To a solution of myrcene (S33) (0.860 mL, 5.00 mmol) in CH 2 Cl 2 (6.90 mL) at 0 °C was added m-CPBA (1.25 g, 5.05 mmol). The reaction mixture was stirred at 0 °C for 10 min, and then was diluted with 10% aq. NaOH (10 mL). The reaction mixture was allowed to warm to ambient temperature. The layers were separated, and the aqueous layer was extracted with CH 2 Cl 2 (3 x 10 mL). The combined organic layers were washed sequentially with H 2 O (20 mL) and brine (20 mL), then dried over MgSO 4 . The solvent was removed by rotary evaporation to afford diene S12 (0.767 g, quantitative) as a colorless oil which was used without further purification. All spectroscopic data were consistent with previously reported values. 19 Ester S36. To a solution of ylide S35 (8.36 g, 25.0 mmol) in CH 2 Cl 2 (62.5 mL) at 23 °C was added aldehyde S34 (2.00 mL, 30.0 mmol). The reaction mixture was stirred for 45 h, and then was filtered through a plug of silica (5 cm high x 3 cm wide, CH 2 Cl 2 eluent). The filtrate was concentrated by rotary evaporation, and the crude residue was purified by flash chromatography (100% hexanes → 9:1 hexanes/EtOAc eluent) to afford ester S36 (0.891 g, 32% yield) as a colorless oil. Alcohol S37. To a solution of ester S36 (0.516 g, 4.60 mmol) in CH 2 Cl 2 (7.70 mL) at -78 °C was added DIBAL (9.70 mL, 1.0 M in hexanes, 9.70 mmol). The reaction mixture was allowed to warm to 23 °C, and was stirred for 3.5 h.

Photochemical [2+2] Cycloaddition
An independent synthesis of vinylcyclobutane 6 was devised in order to determine its structure and perform additional experiments to confirm its role as a reaction intermediate. The reaction mixture was stirred at 0 °C for 1.5 h, then was allowed to warm to ambient temperature and stirred for 10 h. At this time, the vinylcyclobutane (S41) was not yet consumed, so additional sulfur trioxide pyridine complex (27.5 mg, 0.173 mmol) and Et 3 N (0.024 mL, 0.173 mmol) were added. The reaction was stirred for 3 d total. The reaction mixture was then diluted with H 2 O (2 mL) and CH 2 Cl 2 (2 mL). The layers were separated, and the aqueous layer was extracted with CH 2 Cl 2 (2 x 5 mL). The combined organic layers were washed with brine (10 mL) and dried over Na 2 SO 4 . The volatile materials were then removed by rotary evaporation, and the residue was purified by flash chromatography (100% hexanes → 9:1 hexanes/EtOAc eluent) to afford pure vinylcyclobutane 6 (16.4 mg, 77% yield) as a colorless oil.

Decoupling Experiment
The stereochemistry of the 1-substituted diene products was determined through structural modification of cyclohexene 24 and a 1 H NMR decoupling experiment.
Cyclohexane S42. To a solution of cyclohexene 24 (37.6 mg, 93.0 µmol) in MeOH (0.900 mL) at 23 °C was added Pd/C (10% w/w, 9.9 mg, 9.30 µmol). The flask was sealed with a rubber septum, and H 2 was bubbled through the solution for 1 min using a balloon and needle outlet. The needle outlet was removed, and the reaction mixture was left under positive pressure of H 2 and stirred for 9 h. The crude reaction mixture was passed through a short plug of celite Supporting Information: Stevenson,Higgins,Shores,and Ferreira S62 the solution was washed with H 2 O (2 x 3.00 mL) and dried over Na 2 SO 4 . The solvent was removed by rotary evaporation, and the crude residue was purified by flash chromatography (100% hexanes → 9:1 hexanes/EtOAc eluent) to afford nitrobenzoate S43 (16.6 mg, 78% yield) as a colorless oil.
TLC: R f = 0.50 in 9:1 hexanes/EtOAc, visualized by UV. Decoupling of proton H c (2.45 ppm) of cyclohexane S43 resulted in peak H b changing from a doublet of doublets (J = 11.5, 4.6 Hz) to just a doublet (J = 11.5 Hz) ( Figure S8). From this data, we can conclude that the coupling constant between H a and H b is 11.5 Hz, corresponding to an anti relationship, and the coupling constant between H b and H c is 4.6 Hz, corresponding to a syn relationship. The reaction mixture was stirred for 46 h, then was diluted with H 2 O (2 mL) and CH 2 Cl 2 (2 mL). The layers were separated, and the aqueous layer was extracted with CH 2 Cl 2 (2 x 5 mL). The combined CH 2 Cl 2 layers were passed through a short plug of silica (EtOAc eluent). The volatile materials were removed by rotary evaporation, and the crude product was purified by flash chromatography (4:1 → 2:1 hexanes/EtOAc eluent) to afford carboxylic acid S47 (5.4 mg, 65% yield) as a colorless oil. The NMR spectrum of the major diastereomer is reported.