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6.2 Experimental Section
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6.2.2 Synthesis of Optically Pure (R)-5-Benzyl-1-vinyl-2-pyrrolidinone The chiral monomers were synthesized as reported procedure.21,22
Scheme 6-2-1 Synthesis of (R)-5-benzyl-1-vinyl-2-pyrrolidinone.
(R)-t-Butoxycarbonyl-L-phenylalanine (2). A solution of 5 g (30 mmol) of L-phenylalanine (1) in 200 mL of 1:1 THF/H2O was stirred vigorously at 25°C. Then, 7.2 g (33 mmol) of di-t-butyl dicarbonate and 2.4 g (60 mmol) of NaOH were added into reaction mixture. After being stirred for 12 h at 25°C, THF was removed under vacuo. Then, 100 mL of CH2Cl2 was added into the mixture before acidified with the dropwise addition of 1 M HCl to obtain pH 4 solution.
Then, the aqueous layer was separated by funnel, the organic layer was washed with water 50 ml three times and brine. Then, it was dried over anhydrous Na2SO4. The solvent was removed in vacuo to obtain 7.5 g of colorless thick liquid. This compound was used in the following step without further purification. 1H-NMR (400 MHz, CDCl3) δ: 7.37-7.18 (m, 5H), 6.41(broad, 1H), 5.00 (d, J = 8 Hz, 1H), 4.64- 4.59 (m, 1H), 3.17 (dd, J = 13.6, 5.2 Hz, 1H), 3.06 (dd, J = 13.8, 5.6 Hz, 1H), 1.41 (s, 9H)
(R)-t-Butyl-1-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-1-oxo-3-phenylpropan-2-ylcarbamate (3). A solution of 7.5 g of compound 2, 6.5 g (45 mmol) of Meldrum’s acid, and 5.5 g (45 mmol) of 4-(dimethylamino)pyridine (DMAP) in 50 ml of CH2Cl2 under N2 was cooled to 0 °C over an ice-water bath. To the mixture, a solution of 6.3 g (30.6 mmol) of N,N’-dicyclohexylcarbodiimide (DCC) in 50 ml of CH2Cl2 was added dropwise. After being stirred for 10 h under N2 at 25°C, the obtained white precipitate was collected by filtration, and washed with 100 ml of 5% HCl and then water, dried under vacuo to obtain 10.5 g of yellowish solid compound. This compound was used in the following step without further purification. 1 H-NMR (400 MHz, CDCl3) δ: 7.35-7.20 (m, 5H), 6.59 (broad, 1H), 5.01 (d, J = 8 Hz, 1H),
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4.65- 4.63 (m, 1H), 3.20 (dd, J = 14.4, 5.6 Hz, 1H), 3.09 (dd, J = 14, 6.4 Hz, 1H), 1.44 (s, 9H), 1.30 (d, J = 1.6 Hz, 6H)
(R)-t-Butyl-1-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-3-phenylpropan-2-ylcarbamate (4). To a cold (0 °C) solution of compound 3 in 100 ml of CH2Cl2 under N2 were added 10.3 ml (180 mmol) of acetic acid and 2.8 g (75 mmol) of NaBH4. The solution was stirred at 0 °C for 3 h and at 25 °C for 6 h, diluted with water, and extracted with CH2Cl2 (20 ml × 3 times).
The combined organic layers were washed with water and brine. The combined organic layers were washed with water and brine, then dried over anhydrous Na2SO4. The solvent was removed under vacuum to give yellow oil which was precipitated from diethyl ether. The white solid was washed with cold diethyl ether to give 8.3 g (73% yield for 3 steps) of compound 4.
1H-NMR (400 MHz, CDCl3) δ: 7.32-7.20 (m, 5H), 5.90 (broad, 1H), 5.02 (broad, 1H), 3.18 (broad, 1H), 2.88 (broad, 1H), 1.75 (s, 3H), 1.65 (s, 3H), 1.36 (s, 9H)
(R)-t-Butyl-5-benzyl-2-oxopyrrolidine-1-carboxylate (5). A solution of 8.3 g (22 mmol) of compound 4 in 100 ml of dried toluene under N2 was heated to reflux for 6 hours, cooled to room temperature, concentrated over a rotary evaporator and then under vacuo to obtain 6 g of compound 5 as a yellow oil. This material was used in the subsequent step without further purification. 1H-NMR (400 MHz, CDCl3) δ: 7.55-7.18 (m, 5H), 4.35(m, 1H), 3.11 (dd, J = 12, 3 Hz, 1H), 2.70 (m, 1H), 2.30 (m, 4H), 1.96 (m, 2H), 1.59 (s, 9H)
(R)-5-Benzylpyrrolidin-2-one (6). A solution of compound 5 in 150 mL of 10%
trifluoroacetic acid (TFA)/dichloromethane was stirred at 25 °C for 4 h, diluted with dichloromethane, washed with an aqueous solution of NaHCO3, then water and brine, dried (MgSO4), concentrated to give 3.8 g (99% yield) of 3.6 g of yellowish oil as a compound 6.
This material was used in the subsequent step without further purification. 1H-NMR (400 MHz, CDCl3) δ: 7.34-7.17 (m, 5H), 5.64 (broad, 1H), 3.85 (m, 1H), 2.85 (dd, J = 13.2, 5.6 Hz, 1H), 2.69 (m, 1H), 2.35 (m, 1H)
(R)-5-Benzyl-1-vinylpyrrolidin-2-one (7). To a solution of 1 g (5.7 mmol) of compound 6 in 50 ml of vinyl acetate under N2, were added 0.2 g of 4Å molecular sieves, 1.3 g (4.3 mmol) of
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Na2PdCl4, and 2.4 g (17.1 mmol) of K2CO3. The mixture was stirred at 65 °C under N2 for 12 hours, cooled to 25 °C, filtered, and concentrated under vacuum, and column chromatographed on silica gel using a mixture of hexane and ethyl acetate (3:2) as an eluent, concentrated over a rotary evaporator. The resulting brownish oil was washed with ethyl acetate to give 0.3 g (26% yield for 3 steps) of pure compound 7 as a yellowish oil. 1H-NMR (400 MHz, CDCl3) δ: 7.34-7.23 (m, 3H), 7.18-7.14 (m, 2H), 7.09 (m, 1H), 4.65- 4.58 (m, 2H), 4.22-4.16 (m, 1H), 3.01 (dd, J = 3.2, 13.7 Hz, 1H), 2.82 (dd, J = 7.8, 13.7 Hz, 1H), 2.26-1.90 (m, 4H) ; 13C-NMR (400 MHz, CDCl3) δ : 173.6, 137.0, 129.2, 128.8, 128.3, 127.0, 95.1, 56.8, 36.4, 29.9, 22.7; HRMS (EI+) m/z: calcd. for C13H15NO 201.1154; found 201.1154
The (S)-5-benzyl-1-vinylpyrrolidin-2-one was prepared with the same procedure as S-monomer with total yield of 23%. HRMS (EI+) m/z: calcd for C13H15NO 201.1154; found 201.1153
6.2.3 Synthesis of Optically Pure (S)-5-Methyl-1-vinyl-2-pyrrolidinone
The synthesis of methyl substituted N-(vinyl-2-pyrrolidone) was applied from those of benzyl substituted N-(vinyl-2-pyrrolidone).
Scheme 6-2-2 Synthesis of (S)-5-methyl-1-vinyl-2-pyrrolidinone.
(S)-tert-Butoxycarbonyl-L-alanine (2). A solution of 2.7 g (30 mmol) of L-alanine (1) in 200 mL of 3:1 dioxane/H2O was stirred vigorously under room temperature. Then, 7.2 g (33 mmol) of di-tert-butyl dicarbonate and 1.6 g (40.5 mmol) of NaOH were added into reaction mixture.
After the reaction mixture was stirred for 12 h under 25 °C, dioxane was removed under vacuo.
Then, 100 mL of ethylacetatewas added into the mixture before acidified with the dropwise addition of 1 M HCl to obtain pH 4 solution. Then, it was extracted with ethylacetate three times. The combined organic layers were washed with water and brine, dried (anhydrous
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Na2SO4). The solvent was removed under vacuo to obtain 5.7 g of colorless thick liquid. This compound was used in the following step without further purification. 1H-NMR (400 MHz, CDCl3) δ: 7.78 (s, 1H), 5.08(s, 1H), 2.11 (s, 9H), 2.11 (s, 3H).
(S)-tert-Butyl-(1-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-1-oxopropan-2-yl)carbamate (3). A solution of 5.7 g of compound 2, 4.8 g (33 mmol) of Meldrum’s acid, and 5.5 g (45 mmol) of 4-(dimethylamino)pyridine (DMAP) in 50 ml of CH2Cl2 under N2 was cooled to 0oC over an ice-water bath. To the mixture, a solution of 6.9 g (36 mmol) of N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC•HCl) in 50 ml of CH2Cl2
was added dropwise. The mixture was stirred for 12 hours under N2. The reaction mixture was washed with 100 ml of 5% KHSO4 and then water, dried under vacuo to obtain 9.4 g of yellowish solid. This compound was used in the following step without further purification.
1H-NMR (400 MHz, CDCl3) δ: 5.51 (m, 1H), 5.08 (broad, 1H), 1.78 (s, 1H), 1.76 (s, 3H), 1.74 (s, 3H), 1.46 (d, J = 7.6 Hz, 3H), 1.43 (s, 9H)
(S)-tert-Butyl-(1-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-1-propan-2-yl)carbamate (4).
To a cold (0°C) solution of compound 3 (9.4 g) in 100 ml of CH2Cl2 under N2 were added 15.5 ml (270 mmol) of acetic acid and 2.5 g (66 mmol) of NaBH4. The solution was stirred at 0°C for three hours and at 25°C for 6 hours, diluted with water, and extracted with CH2Cl2 three times. The combined organic layers were washed with water and brine, dried (anhydrous Na2SO4), concentrated to give a yellow oil, which was precipitated from diethyl ether. The white solid was washed with cold diethyl ether to give 5.7 g (63% yield for 3 steps) of compound 4 as a white solid. 1H-NMR (400 MHz, CDCl3) δ: 4.48 (broad, 1H), 4.02 (m, 2H), 2.20 (m, 2H), 1.81 (s, 3H), 1.75 (s, 3H), 1.40 (s, 9H), 1.24 (d, J = 6.8 Hz, 3H)
(S)-tert-Butyl-5-methyl-2-oxopyrrolidine-1-carboxylate (5). A solution of 5.7 g (19 mmol) of compound 4 in 100 ml of dried toluene under N2 was heated to reflux for 6 hours, cooled to room temperature, concentrated over a rotary evaporator and then under vacuo to obtain 3.7 g of compound 6 as a yellow oil. This material was used in the subsequent step without further purification. 1H-NMR (400 MHz, CDCl3) δ: 4.24(m, 1H), 2.59 (m, 1H), 2.46 (m, 1H), 2.19 (m, 1H), 1.50 (s, 9H), 1.32 (d, J = 6.4 Hz, 3H)
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(S)-5-Methylpyrrolidin-2-one (6). A solution of compound 5 in 150 mL of 10%
trifluoroacetic acid (TFA)/dichloromethane was stirred at 25°C for 1 h. The reaction mixture was placed under reduced pressure in order to removal of TFA and CH2Cl2. The compound 6 was obtained as 1.8 g of a yellowish oil. This material was used in the subsequent step without further purification. 1H-NMR (400 MHz, CDCl3) δ: 7.60 (broad, 1H), 3.92(m, 1H), 2.50 (m, 2H), 2.32 (m, 1H), 1.29 (d, J = 6 Hz, 3H)
(S)-5-Methyl-1-vinylpyrrolidin-2-one (7). To a solution of 1 g (10 mmol) of compound 6 in 100 ml of vinyl acetate under N2, were added 0.4 g of 4 Å molecular sieves, 202 mg (7.5 mmol) of Na2PdCl4, and 4.2 g (30 mmol) of K2CO3. The mixture was stirred at 65°C under N2 for 12 hours, cooled to 25°C, filtered, and concentrated under vacuo, and column chromatographed on silica gel using a mixture of hexane and ethyl acetate (3:2) as an eluent, concentrated over a rotary evaporator. The resulting brownish oil was washed with ethyl acetate to give 0.6 g (51% yield for 3 steps) of pure compound 7 as a yellowish oil. 1H-NMR (400 MHz, CDCl3) δ : 6.98 (m, 1H), 4.50-4.41 (m, 2H), 4.11-4.01 (m, 1H), 2.62-2.51 (m, 1H), 2.43-2.35(m, 1H), 2.27-2.14 (m. 1H), 1.79-1.69 (m, 1H), 1.25 (d, J = 6.4 Hz, 1H) ; 13C-NMR (400 MHz, CDCl3) δ : 173.1, 128.0, 94.9, 51.9, 29.9, 26.1, 18.0; HRMS (EI+) m/z: calcd for C7H11NO 125.0841;
found 125.0840
The (R)-5-Methyl-1-vinylpyrrolidin-2-one was prepared with the same procedure as S-monomer with total yield of 12%. HRMS (EI+) m/z: calcd for C7H11NO 125.0841; found 125.0841
6.2.4 General Procedure for Chiral Polymers Synthesis
To the 10 ml round-bottom flask, both chiral monomer and N-vinyl pyrrolidone with the mole ratio of 1:4 were diluted in solvent. After the mixture was deaerated by freeze-pump-thaw cycles, the deaerated solution was stirred under 75 °C for 10 min, before the reaction was
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initiated by addition of initiator (H2O2 and/or AIBN). The reaction was stirred under 75 °C for 12h. The resulting polymer was purified by precipitation with hexane. The amount of chiral monomer unit was quantified by 1H-NMR. The polymer molecular weight was determined by GPC analysis. A calibration curve was obtained using poly(N-vinylpyrrolidone) standards, and LiBr (10 mM) in DMF was used as an eluent.
6.2.5 Preparation of Polymers-stabilized Gold Nanoclusters
The small size of AuNCs were prepared by conventional batch method.23 The molar ratio of tetrachloroauric acid (HAuCl4): polymers: sodium tetraborohydride (NaBH4) was set as 1:100:10. To a 10 ml 1:1 ratio of EtOH: H2O solution of polymer (0.625 mmol) was added 6.25 mol of HAuCl4(50 mM, 125 μL). The mixture was stirred at 0 °C for 5 min. Then, the aqueous solution of 0.0625 mmol of NaBH4 (100 mM, 2.5 mL) was rapidly added into the mixture under vigorous stirring. The color of the mixture immediately turned from pale yellow to dark brown.
For large size of gold nanoclusters, it was prepared by using seed-mediated growth method.24 The mixture of 1:1 ratio of EtOH: H2O solution of 5.97 μmol HAuCl4 (50 mM, 119.3 μL) and 17.9 μmol Na2SO3(90 mM, 119 μL) were quickly added to that of 0.284 μmol of small size gold nanoclusters and 28.4 μmol of polymer. The reaction mixture was stirred for 3 h under N2 at 300 K. The color of the mixture immediately turned from pale yellow to red.
The resulting colloidal AuNCs was dialyzed three times to remove the inorganic impurities such Na+ and Cl− by centrifugal ultrafiltration at 4800 rpm by using a membrane with a proper molecular weight cut off using 10 ml of water. The resulting solution mixture was washed with pure water 3 times. The purified AuNCs was kept as a solid form in a dry place after freeze-drying by using Freeze Dryer (EYELA FDU-2200).
6.2.6 General Procedure for Aerobic Intramolecular Hydroamination of Toluenesulfonamide Catalyzed by Au:PVP
The reaction was carried out according to the reported procedure.25 To a test tube (30 mmϕ), toluenesufoamide substrate (0.025 mmol), Cs2CO3 (24.4 mg, 0.075 mmol), and dried
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Au:PVP (5 atom%) in EtOH (7.5 mL) was added. The reaction mixture was vigorously stirred (1300 rpm) at 50oC for 16 h. The reaction mixture was extracted with ethyl acetate (10 mL ×3).
Then the combined organic layers were washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. The product yield was quantified as NMR yield. The enantioselectivity was determined as %ee from the integration of peak area obtained from chiral SFC resolution.