Highly enantioselective synthesis of both tetrahydroquinoxalines and dihydroquinoxalinones via Rh–thiourea catalyzed asymmetric hydrogenation

Chiral tetrahydroquinoxalines and dihydroquinoxalinones represent the core structure of many bioactive molecules. Herein, a simple and efficient Rh–thiourea-catalyzed asymmetric hydrogenation for enantiopure tetrahydroquinoxalines and dihydroquinoxalinones was developed under 1 MPa H2 pressure at room temperature. The reaction was magnified to the gram scale furnishing the desired products with undamaged yield and enantioselectivity. Application of this methodology was also conducted successfully under continuous flow conditions. In addition, 1H NMR experiments revealed that the introduction of a strong Brønsted acid, HCl, not only activated the substrate but also established anion binding between the substrate and the ligand. More importantly, the chloride ion facilitated heterolytic cleavage of dihydrogen to regenerate the active dihydride species and HCl, which was computed to be the rate-determining step. Further deuterium labeling experiments and density functional theory (DFT) calculations demonstrated that this reaction underwent a plausible outer-sphere mechanism in this new catalytic transformation.


Synthesis of quinoxalinone substrates
A mixture of o-phenylenediamine (5 mmol), ethyl 2-oxoacetate (6 mmol) and ethanol (20 mL) in a dried 50 mL round-bottom flask was stirred at reflux for 1 hour. After the completion (as indicated by TLC), the reaction mixture was filtered, washed with ethanol and then dried to give quinoxalinone 1. Subsequently, A mixture of quinoxalinone 1, K2CO3 (1.2 equiv.), corresponding halogenoalkane (1.6 equiv.) and DMF (20 ml) in a dried 50 mL round-bottom flask was stirred at room temperature overnight. After the completion (as indicated by TLC), the mixture was then extracted with ethyl acetate and the collected organic layer was washed with brine, dried with MgSO4. The solvent was removed under reduced pressure, and the crude product was further purified by silica gel column chromatography (200-300 mesh silica gel, PE/EA = 5:1) to afford desired substrates 2. 3 To an oven-dried sealed tube charged with substrates 2 (800 mg, 1.0 equiv.), KOH (840 mg 3.0 equiv.), and trimethylsufoxonium iodide (2a) (3.3 g, 3.0 equiv.) was added H2O (5 mL) at room temperature under air. The reaction mixture was allowed to stir at 100 o C for 2 h. The reaction mixture was cooled to room temperature and filtered through a bed of Na2SO4. The solid bed was washed with a mixture of CH2Cl2 and MeOH (9:1). The filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (CH2Cl2/acetone = 97:3) to afford 3 in 85% yield. 4

General procedure for asymmetric hydrogenation of quinoxaline/quinonalinone chlorides
In the nitrogen-filled glovebox, solution of [Rh(cod)Cl]2 (1.25 mg, 0.0025 mmol) and ligand (4.4 mg, 0.005 mmol) in 2.0 ml anhydrous solvent was stirred at room temperature for 30 min. A specified volume of the resulting solution (1 mL, 0.5% Rh catalyst) was transferred by syringe to a Score-Break ampule charged with substrate solution (0.25 mmol in 0.5 mL). The ampule was placed into an autoclave, which was then charged with 1 MPa H2. The autoclave was stirred at room temperature for the indicated period of time. After release of H2, the resulting mixture was concentrated under vacuum. Saturated potassium carbonate solution and dichloromethane was added and the mixture was stirred for 30 min. The organic layer was dried with anhydrous sodium sulfate. After removal of solvent, the crude product was analysed by 1 H NMR to determine the conversion. The enantiomeric excess was determined by HPLC analysis of the crude product. Table S1. Scope of quinoxaline derivatives Reaction conditions: 1 (0.25 mmol) in 4 mL dry DCM, 1/[Rh(cod)Cl]2/ L1 ratio = 100/0.5/1; yield was determined with isolated products; ee was determined by HPLC.

Result of deuterium labeling experiments
Following standard hydrogenation procedure, deuterium labeling experiments were conducted with specific modification.

General procedure for asymmetric hydrogenation under continuous flow
All process parts, including fittings, tubes, valves and junctions that hold pressure were purchased from Shenzhen Yizheng Technology Co., LTD. The specification of the reaction coil is 0.5ml/m. The information of other main components is summarized in Table S3.

Mixer
Shenzhen yizheng technology CO. LTD, (0.6 mL, 1000 psi) In the nitrogen-filled glovebox, solution of [Rh(cod)Cl]2 (5.6 mg, 0.0113 mmol) and ligand (19.5mg, 0.0226 mmol) in 2.0 ml anhydrous DCM was stirred at room temperature for 30 min. Then the substrate 3j (645mg, 2.26mmol) was dissolved in 45 mL anhydrous DCM and mixed with the above solution. The resulting mixture was filtered and the filtrate was added into a flask. The process was washed by anhydrous DCM at a liquid flow rate of 5 mL/min and gas flow rate of 10 sccm (avoid back flow of liquid to gas flow meter) for 10 minutes and then pressurized the BPR. After the reactor was pressurized to 2 MPa, the aforehand reaction medium was pumped instead of solvent. Liquid flow rate was set at 0.4 mL/min and gas flow rate was keeping 10 sccm. The liquid holding capacity of the reaction coil can be adjusted according to the needs. The conversion and ee value were analyzed by NMR and HPLC. When reaction finished, system was depressurized by releasing the gas of Equilibar BPR slowly, and washed the whole system by pumping DCM for 10 minutes.

The influence of H + and Clrespectively
In the nitrogen-filled glovebox, solution of [Rh(cod)Cl]2 (1.25 mg, 0.0025 mmol) and ligand (4.4 mg, 0.005 mmol) in 2.0 ml anhydrous solvent was stirred at room temperature for 30 min. A specified volume of the resulting solution (1 ml, 0.5% Rh catalyst) was transferred by syringe to a Score-Break ampule charged with substrate solution (0.25 mmol in 0.5 ml). Corresponding additives are added and then the ampule was placed into an autoclave, which was then charged with 1 MPa H2. The autoclave was stirred at room temperature for the indicated period of time.
After release of H2, the resulting mixture was concentrated under vacuum. Saturated potassium carbonate solution and dichloromethane was added and the mixture was stirred for 30 min. The organic layer was dried with anhydrous sodium sulfate. After removal of solvent, the crude product was analyzed by 1 H NMR to determine the conversion. The enantiomeric excess was determined by HPLC analysis of the crude product. This result indicated that the HCl salt is crucial for ees and yields (Table S6, entries   1-3). Moreover, in order to obtain more insights into H + and Clrole for ees and yields respectively, detailed more additional experiments were also conducted. It was observed that the amount of HCl had an obvious influence on ees and yields (

Method for DFT calculation
All quantum chemistry calculations were conducted using Gaussian 09 packages 8 at China National Supercomputing Center in Shenzhen with Density functional theory (DFT) method. B3LYP functional was used for optimization of all geometries 9, 10 . SDD basis set was used for Rh and Fe 11 , and 6-31g* basis set was used for other elements 9,12 . Then frequency calculations (at 298.15 K) were performed on the optimized geometries to confirm the local minimums (without imaginary frequency) and the transition states (with one imaginary frequency). Solvent effect was included employing SMD solvation model with dichloromethane as the solvent 13 . In the above figure, the transition energy TS3-N1 is slightly lower than intermediate 7 while the electronic energy is inverse. We considered this because the transition state leads to an increase in the enthalpy and a decrease in the Gibbs energy. We calculated these two electronic energies through the PCM solvation method and IRC analysis to further prove this mechanism route.