Reaction Procedures of -Oxygenation of Tertiary Amines

The reaction setup consisted of a self-constructed light source configuration, made up of a crystallizing dish with a diameter of 140 mm. Inside of the crystallizing dish, a commercially available 5 m LED-Strip was glued with separable LED elements. In the designed setup, 3 m LED strip was used in a crystallizing dish, with a total power of 24 W. Light intensity of the light source could be adjusted by a self-constructed dimmer. Construction of the reaction setup and the dimmer was performed by the electronic services of the faculty for chemistry of the Georg-August-Universität Göttingen. Cooling of the setup was performed by a commercially available 120 mm computer fan. To ensure a constant room temperature, the dimmer setting was used at 50 % (12 W). During the first experiment the temperature was monitored inside the crystallizing dish and did not exceed the room temperature (25–30 °C). Magnetic stirring was performed with 250 rpm. It should be noted that the reaction temperature will increase if the higher power (more than 12 W) was employed.

Figure 5.2.1 LED reaction setup for photocatalytic reactions.

Measurement of Wavelength about Blue LED

The emission spectra of the light setup were measured with a UV-Vis probe from Ocean optics (P200-5-UV-Vis). The emission spectra showed a clear wavelength band between 404 and 553 nm with a maximum at 456 nm (Figure 5.2.2).^[122]

400 600 800

0 10000 20000 30000 40000 50000 60000

 / nm

AU

Emission spectra of blue LED setup

Figure 5.2.2 Wavelength of blue LED.

General Procedure for The Oxygenation of Tertiary Amines

A dry 10 mL two-necked flask containing a stirring bar was charged with 0.30 mmol of substrate and 0.009 mmol of rose bengal. The flask was degassed three times (5 min each) under nitrogen in the dark, oxygen atmosphere was incorporated through an O2 balloon subsequently. Finally, dry DMF (1.0 mL) and a dry DBN solution (1 mol/L in DMF) were added. The resulting mixture was stirred for 16–48 h under 12 W blue LED irradiation (the progress was monitored via GC-MS or TLC).

Figure 5.2.3 A: preparation of the reaction; B: reaction setup under vacuum; C:

transferring DBN from Schlenk tube with syringe under nitrogen; D: Injecting DBN into the flask through the septum; E: Starting the magnetic stirring, cooling fan, and LED light.^[122]

Then, the resulting mixture was subjected to an aqueous workup (using distilled

water; or brine in case of slurry phase separation) and was extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Products were purified via silica gel chromatography or GPC (see details of products) with ethyl acetate and n-hexane as solvents (Figure 5.2.3).

Synthesis of N-Phenyl-tetrahydroisoquinoline

A typical procedure is described as following for the synthesis of N-phenyl-tetrahydroisoquinoline: Copper(I) iodide (1.0 mmol, 10 mol%), and potassium phosphate (20 mmol, 2.0 eq.) were added to a Schlenk tube. The tube was evacuated and back filled with nitrogen. 2-Propanol (10 mL), ethylene glycol (20 mmol, 2.0 eq.), 1,2,3,4-tetrahydroisoquinoline (2.0 g, 15 mmol, 1.5 eq.) and iodobenzene (10 mmol, 1.0 eq.) were added successively at room temperature. The reaction mixture was heated at 90 °C and kept for 24 h and then allowed to cool to room temperature.

Diethyl ether (20 mL) and water (20 mL) were then added. The aqueous layer was extracted with diethyl ether (2×20 mL). The combined organic phases were washed with brine and dried over magnesium sulfate. The solvent was removed via rotary evaporation, and the remaining residue was purified via flash column chromatography to give the desired product with 72% yield. The products were obtained and the analytical data were consistent with those given in literature.^[125]

Synthesis of N-Ethyl-tetrahydroisoquinoline and Derivatives

A typical procedure is described as following for the synthesis of N-phenyl-tetrahydroisoquinoline: tetrahydroisoquinolines (10 mmol, 1.0 eq.), bromides (12 mmol, 1.2 eq.), and sodium carbonate (20 mmol, 2.0 eq.) were added into THF (50 mL). Afterwards, diethyl ether (20 mL) and water (20 mL) were added. The aqueous layer was extracted with diethyl ether (2×20 mL). The combined organic phases were washed with brine and dried over magnesium sulfate. The solvent was removed via rotary evaporation, and the remaining residue was purified via flash column chromatography to give the desired product with medium yields. The products were obtained and the analytical data were consistent with those given in literature.^[126]

Synthesis of N-Benzyl Piperidine

Adapting a known procedure, ^[127] piperidine (12.5 mmol, 2.5 equiv.) was added at 0

°C to a solution of benzyl bromide (5 mmol, 1.0 equiv.) in CH2Cl2 (25 mL). Afterwards, Et3N (7.5 mmol, 1.5 equiv.) was add into the solution slowly. The reaction mixture was stirred overnight at room temperature, then concentrated in vacuo and aqueous HCl (20 mL, 2M) was added. The mixture was extracted with n-hexane (3 x 40 mL). The aqueous layer was made strongly basic by adding solid sodium hydroxide and the resulting solution was extracted with diethyl ether (3 x 40 mL). The combined organic phase was dried over MgSO4, filtered and solvents were removed in vacuo. The products were isolated by flash column chromatography (n-hexane/EtOAc 80:20) to give the desired product with 88% yield. The products were obtained and the analytical data were consistent with those given in literature.^[127]

Synthesis of 1-(Furan-2-ylmethyl)piperidine and 1-(Thiophen-2-ylmethyl)piperidine

Adapting a known procedure,^[128] a 25 mL Schlenk tube containing a stir bar was charged with 5.0 mol % Cs2CO3 (0.15 mmol). Subsequently, amides (3.0 mmol, 1.0 eq.) and PhSiH3(3.0 mmol, 1.0 eq.) were added. The mixture was stirred at room temperature for 24 h. Dichloromethane (0.5 mL) was added to the mixture. The mixture was purified on a short silica gel column to give the products. The products were obtained and the analytical data were consistent with those given in literature.

[128]

Those tertiary amines were synthesized in accordance with a known procedure.^[126]

To a 50-mL round-bottom flask fitted with a reflux condenser were added the reactants including the secondary amines (5.0 mmol, 1.0 equiv.), acetonitrile (15 mL), aliphatic bromides (8.5 mmol, 1.7 equiv.), and triethylamine (12.5 mmol, 2.5 equiv.), respectively. The reaction was heated to reflux overnight. After cooling to room temperature, the mixture was partitioned between water (20 mL) and DCM (20 mL).

The organic layer was washed with an additional portion of water (20 mL), dried over

MgSO4, filtered, and concentrated under reduced pressure. Then the remaining residue was purified via flash column chromatography to give the desired products with medium yields. The products were obtained and the analytical data were consistent with those given in literature.^[126]

18O-labelling and KIE Experiments

Oxidation of 1-Benzylpiperidine in Presence of ¹⁸O-labeled Oxygen.

The ¹⁸O-labeling experiment was performed with ¹⁸O2 (Sigma Aldrich, ¹⁸O atom 99.7%), and analyzed with ESI-HRMS and GC showing the ¹⁸O-labeled product with a yield of 91% (88% of isolated yield). The result showed that the origin of the oxygen atom in the desired product 222c was only from oxygen gas since no ¹⁶O-labeled 25 mL two-necked flask. After purging the flask three times with vacuum/N2, 7.5 mL of dry DMSO-d6 was added and the reaction mixture was stirred at 80 °C for 2 h.

The reaction was quenched with water and the product was extracted with ethyl acetate. The solution was dried over Na2SO4 and the solvent was removed under reduced pressure providing the product in > 95 atom% D and 99% yield which was used without further purification.

KIE: Oxidation of Deuterium-labeled 1-Benzylpiperidine.

Deuterium-labeled 1-benzylpiperidine was oxidized by the general procedure.

under O2 atmosphere. After 4 h, the yield was determined by GC using n-dodecane as internal standard and compared with a non-deuterated sample under the same conditions. The calculated KIE is a result of the average (the average of three runs with a standard deviation of 1.5) of three independent runs, which strongly suggested the C–H bond cleavage in the rate-determining step. The signal of D2O was also detected by NMR.

𝑘_H

𝑘_D~ 𝑛(𝑃_H)

𝑛(𝑃_D) = 0.0922

0.0283= 3.2