Enantioselective propargylic [1,3]-rearrangements: copper-catalyzed O-to-N migrations toward C–N bond formation

We have identified an enantioselective copper-catalyzed O-to-N formal [1,3]-rearrangement to form N-propargylic-2-pyridones.


General Procedure for Synthesis of Propargyloxylpyridines
NaH (2.0 eq of a 60% dispersion in mineral oil) was added into the oven-dried flask with a stir bar. The flask was evacuated and refilled with N 2 three times. THF was transferred to the flask via syringe and the reaction was cooled to 0 ºC. In another flask, propargylic alcohol (1.2 eq) was dissolved in THF (1.0 M) and added dropwise to the above suspension at 0 °C. After 10 min, the cooling bath was removed to reach room temperature and the mixture was stirred for a further 20 min. Then a solution of 2-chloro-3,5-dinitropyridine (1.0 eq) in THF (1.0 M) was added dropwise to the above solution at 0 ºC. After addition is complete, the brown solution was allowed to room temperature and continue to stir for 2 h. Then the mixture was poured into ice/water in a beaker. The mixture was extracted with EtOAc three times. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Hexane/ethyl acetate as eluent) to give the corresponding propargyloxypyridine.

6-(3,5-Dinitro-2-pyridyloxy)-7-octynal (4i).
A 100 mL round-bottom flask with a 1.5 cm stir bar was evacuated and refilled with N 2 three times. (COCl) 2 (0.28 mL, 3.3 mmol) and CH 2 Cl 2 (5 mL) was added via syringe. The flask was cooled to -78 ºC. A solution of DMSO (0.47 mL, 6.6 mmol) in CH 2 Cl 2 (5 mL) was added to the flask by syringe at -78 ºC. After addition, the mixture was stirred at this temperature for 10 min before a solution of alcohol (927 mg, 3.0 mmol) in CH 2 Cl 2 (5 mL) was added dropwise. The mixture was stirred at -78 ºC for further 0.5 h. Then Et 3 N (2.0 mL, 15.6 mmol) was added once. After that, the cooling bath was removed and the mixture was allowed to reach room temperature. H 2 O (20 mL) was added and the aqueous phase was extracted twice with CH 2 Cl 2 (60 mL). The combined organic phases were washed with brine, dried over MgSO 4 , filtered and then concentrated under reduced pressure. The crude oil was purified by silica gel chromatography (hexane/EtOAc = 3:1) to afford the product as a colorless oil (600 mg, 65% yield).

General Procedure for Rearrangement
CuTC (7.6 mg, 0.040 mmol) and (R)-Tol-BINAP (33.0 mg, 0.048 mmol) were added in turn to a 4 mL vial with a 1 cm stir bar. The vial was capped with a PTFE-lined cap and then it was evacuated and refilled with N 2 three times. Then toluene (1.0 mL) was added via 2 mL syringe. The mixture was stirred at room temperature for 1 h. The vial was then cooled down to -40 ºC using a cooling bath and a solution of 3,5-dinitropropargyloxypyridine (0.4 mmol) in toluene (1.0 mL) was added dropwise. After the addition is complete, the reaction mixture was stirred at -40 ºC for 18 h. Then the mixture was transferred to a 25 mL round-bottom flask via pipette and solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to afford the corresponding pyridones.
A second run was performed using (S)-Tol-BINAP.

Non-linear Effect Experiments
CuTC (3.6 mg, 0.02 mmol), (R)-Tol-BINAP and (S)-Tol-BINAP (according to the bellowing ratio, total 0.024 mmol) were added in turn to a 4 mL vial with a 1 cm stir bar. The vial was capped with a PTFE-lined cap and then it was evacuated and refilled with N 2 three times. Then toluene (1.0 mL) was added via 2 mL syringe and the mixture was stirred at room temperature for 1 h. 0.5 mL of the above solution was transferred to another vial under the N 2 atmosphere and the vial was then cooled down to -40 ºC using a cooling bath. A solution of 3,5dinitro-2-(1-phenethyl-2-propynyloxy)pyridine (32.7 mg, 0.1 mmol) in toluene (0.5 mL) was added dropwise. After the addition is complete, the reaction mixture was stirred at -40 ºC for 18 h. The reaction mixture was filtered through a pad of silica gel (a pipette with about 5 cm silica gel) and washed with ethyl acetate (10 mL). The filtrate was concentrated under reduced pressure. The residue was dissolved in CDCl 3 and CH 2 Br 2 (0.1 mmol) was added as internal standard for 1 H NMR analysis. The er was determined by Chiral HPLC. was filtered through a pad of silica gel (a pipette with about 5 cm silica gel) and washed with ethyl acetate (10 mL). The filtrate was concentrated under reduced pressure. The residue was dissolved in CDCl 3 and CH 2 Br 2 (0.1 mmol) was added as internal standard for 1 H NMR analysis to determine the reaction conversion (70%).

2-Chloro-3,5-dinitropyridine-4-d (S-2).
A 4 mL glass vial was charged with 2-(methoxy-d 3 )-3,5dinitropyridine-4-d (216 mg, 1.06 mmol, 1 eq.) and a 1 cm stir bar. The vial was fitted with a PTFE-lined cap and evacuated and refilled with N 2 three times through a needle. DMF (1.25 mL) was added via a 2 mL syringe, followed by POCl 3 (250 μL, 2.66 mmol, 2.5 eq.). The mixture was heated to 80 °C and stirred for 12 h. The reaction was allowed to cool to room temperature, diluted with phosphate buffer (10 mL, pH 7) and extracted with EtOAc (2 x 10 mL). The combined organic extracts were washed with saturated aqueous NaOAc (10 mL), separated, dried over MgSO 4 and concentrated under reduced pressure to afford the title compound as a yellow S-23 oil that solidified on standing (142 mg, 65%, 97 atom% D at C4). The product was used in the next step without further purification.

3,5-Dinitro-2-((5-phenylpent-1-yn-3-yl-1-d)oxy)pyridine-4-d (4a-D).
A flame-dried 10 mL round-bottom flask was charged with NaH (55 mg, 1.36 mmol, 60% dispersion in mineral oil, 2 eq.) and a 1 cm stir bar. The flask was fitted with a rubber septum and evacuated and refilled with N 2 three times. THF (0.5 mL) was added to the flask via syringe and the resulting suspension cooled to 0 °C. A solution of 5-phenyl-1-pentyn-3-ol (131 mg, 0.82 mmol, 1.2 eq.) in THF (1.1 mL) was prepared in a separate flask and added dropwise to the above solution over 3 minutes. The mixture was stirred at 0 °C for 5 minutes and then allowed to warm to room temperature over 20 minutes. The flask was cooled to 0 °C and a solution of 2-chloro-3,5-dinitropyridine-4-d (139 mg, 0.68 mmol, 1 eq.) in THF (1.4 mL) was added dropwise over 3 minutes. The resulting solution was allowed to warm to room temperature and stirred for 2 hours. The reaction was quenched by the dropwise addition of D 2 O (3 mL).
Spectroscopic data were identical to those obtained previously.
Additional information on the 'cross-over' experiments: The rearrangement of deuterated substrate 4a-D was performed in d 8 -toluene and followed by 1 H NMR; product 5a-D was observed, bearing a terminal proton and no terminal deuteron-contiaining products were observed. The rearrangement of non-deuterated substrate 4a was performed in d 8 -toluene and gave a comparable results with no alkyne deuteration observed. Under no circumstances was pyridone-exchange observed during 'cross-over' experiments, indicating unambiguously that pyridone exchange does not occur.
Exchange of the alkyne deuteron was rationalized by the presence of adventurous moisture, despite repeated S-25 efforts to remove moisture from the system -nevertheless, the alkyne-D/H exchange does not cange the conclusion relating to pyridone exchange.

Kinetics Experiments
CuTC (X mmol, Y eq.) and (R)-tol-BINAP (X mmol, Y eq.) were added in turn to a 4 mL vial equipped with a 1 cm stir bar. The vial was fitted with a PTFE-lined cap and evacuated and refilled with N 2 three times.
Toluene-d8 (0.5 mL) was added via a 1 mL syringe and the mixture was stirred at room temperature for 1 h. In a separate vial 3,5-dinitro-2-(1-phenethyl-2-propynyloxy)pyridine 4a (65.4 mg, 0.2 mmol, 1 eq.) and 1,3,5trimethoxybenzene (11.1 mg, 0.066 mmol, 0.33 eq., internal standard) were dissolved in toluene-d 8 (0.5 mL). An NMR tube was equipped with a septum and evacuated and refilled with N 2 three times. The solution containing catalyst was transferred to the NMR tube via 1 mL syringe and cooled to −78 °C in a CO 2 (s)/acetone bath. The solution of starting material 4a was then added dropwise down the side of the NMR tube over 2 minutes. The NMR tube was immediately transferred to an NMR spectrometer at −40 °C. 1 H NMR spectra were recorded each minute over 2 h. The disappearance of starting material was measured using the integral of the peak for the propargylic proton at 5.45 ppm, relative to the internal standard. S-26 6. Derivations of the Product (R)-2-Nitro-1-(1-phenethyl-2-propynylamino)-1-ethanone, (S)-9. 3 In the air, to an oven-dried 40 mL vial with a 1.5 cm stir bar was added (R)-5a (310 mg, 0.95 mmol). The vial was closed with a PTFE septum cap, and then it was evacuated and back-filled with nitrogen three times. CH 3 OH (15 mL) was added to the vial, followed by cyclohexanone (0.2 mL, 1.9 mmol) and ammonia (7 M  (R)-1-phenethylprop-2-ynylamine. In the air, to an oven-dried 50 mL flask with a 1.5 cm stir bar was added (R)-2-Nitro-1-(1-phenethyl-2-propynylamino)-1-ethanone (148 mg, 0.6 mmol). Then aq HCl (3 M, 10 mL) was added to the flask and the reaction was heated at 90 ºC for 24 h. After the reaction was cooled to room temperature, K 2 CO 3 was added as small portions to neutralize the acid until pH > 10. The product was extracted with EtOAc (20 mL × 3) and the combined organic phase was washed with brine, dried over NaSO 4 , concentrated. The crude material was purified by silica gel chromatography (ethyl acetate/methanol = 95:5) to afford the title compound as a yellow oil (73 mg, 76% yield).  (S)-1-phenethylprop-2-ynylamine was also synthesized using the same method.

NMR Parameter Value
(R)-1-Phenethyl-2-propynylamino 2,2-dimethylpropionate, (S)-10. 4 In the air, to an oven-dried 4 mL vial with a 1.0 cm stir bar was added (R)-1-phenethylprop-2-ynylamine (29 mg, 0.18 mmol). The vial was closed with a PTFE septum cap, and then it was evacuated and back-filled with nitrogen three times. DCM (1.0 mL) was added to the vial, followed by NaHCO 3 (30 mg, 0.36 mmol) and Boc 2 O (59 mg, 0.27 mmol). The resulting solution was then stirred at room temperature over night. Then the solid was removed by filtration and filtrate was concentrated under reduced pressure. The crude material was purified by silica gel chromatography (hexanes/ethyl acetate = 12:1) to afford the title compound as a white solid (205 mg, 88% yield).