4.2. Synthesis of Chiral Acrylamides
To a solution of (R)-(-)-2-phenylglycinol 1 (1.45 mmol) in CH2Cl2 (2 mL) was added K2CO3 (2.18 mmol) in H2O (2 mL), then was stirred. After acryloyl chloride, 2 or 3 ( 2.00 mmol) was added dropwise. The reaction was stirred for 2.0 h at room temperature and monitored by TLC (CH2Cl2:MeOH, 95:5). When the reaction ended, extractions were carried out with CH2Cl2 (3 x 15 mL). The organic phase was dried with anhydrous Na2SO4, filtered, and subsequently the solvent was concentrated under reduced pressure. The residue was purified by column chromatography on SiO2 (CH2Cl2:MeOH, 80:20).
(
R)-
N-(2-Hydroxy-1-phenylethyl)acrylamide
4 in 90% yield as white solid, melting point 120-123 °C, [a]
D20 -119.0 (
c 1, CH
2Cl
2).
1H NMR (500 MHz, CDCl
3) δ ppm 3.88 (d,
J = 5.0 Hz, 2H-CH
2), 5.10 (dd,
J = 5.5, 12.5 Hz, 1H-Bn), 5.66 (d,
J = 11.5 Hz, 1H-CH
2), 6.12 (dd,
J = 10.5 Hz, 17.0 Hz, 1H-CH), 6.29 (d,
J = 15.5 Hz, 1H-CH
2), 6.51 (d,
J = 7.0 Hz, 1H-NH), 7.26 (m, 5H-Ph) (
Figure S1).
13C NMR (150 MHz, CDCl
3) δ ppm 56.0, 66.4, 126.8, 127.4, 128.0, 128.9, 130.4, 138.8, 166.0 (
Figure S2). IR: 1537, 1626, 3307 cm
-1 (
Figure S3).
(
R,
E)-3-(4-Fluorophenyl)-
N-(2-hydroxy-1-phenylethyl)acrylamide
5 in 85% yield as white solid, melting point 157-160 °C, [a]
D20 +19.4 (
c 1, CH
2Cl
2).
1H NMR (500 MHz, CDCl
3) δ ppm 2.91 (s, 1H-OH), 3.93 (m, 2H-CH
2), 5.19 (dd,
J = 6.0, 11.0 Hz, 1H-Bn), 6.39 (d,
J = 15.5 Hz, 1H-CH), 6.43 (d,
J = 7.0 Hz, 1H-NH), 7.03 (t,
J = 8.5 Hz, 2H-Ar), 7.30 (m, 5H-Ph), 7.45 (dd, 5.5, 9.0 Hz, 2H-Ar), 7.60 (d,
J = 15.5 Hz, 1H-CH) (
Figure S4).
13C NMR (150 MHz, CDCl
3) δ ppm 56.3, 66.8, 115.9, 116.1 119.8, 126.8, 128.1, 129.0, 129.7, 129.8, 130.8, 138.7, 140.8, 166.3 (
Figure S5). IR: 698, 1224, 1657, 3308 cm
-1 (
Figure S6).
4.3. Synthesis of Methyl 2-(4R)-3-acryloyl-4-phenyloxazolidin-2-yl)acetates
To a solution of chiral acrylamide, 4 or 5 (3.5 mmol) in CH3CN (10 mL) at 0°C was added DABCO (10 mol%) in CH3CN (2 mL), and the mixture was stirred. Then, methyl propiolate 6 (5.26 mmol) was added dropwise. The reaction was stirred for 2.0 h at 0°C and monitored by TLC (SiO2, CH2Cl2:MeOH, 95:5). When the reaction ended, the solvent was evaporated under reduced pressure. Then, the mixture was purified by column chromatography (SiO2, Hexane:AcOEt, 70:30).
Methyl 2-((4
R)-3-acryloyl-4-phenyloxazolidin-2-yl)acetate
7(a,b) in 86 % yield as a yellow pale oil, d.r. 74:26.
1H NMR (500 MHz, CDCl
3) δ ppm 2.72 (m, H-CH
2), 3.31 (d,
J = 15.5 Hz, 1H-CH
2), 3.44 (d,
J = 15.0 Hz, 1H-CH
2), 3.73 (s, H-OMe), 3.95 (d,
J = 9.0 Hz, 1H-CH
2), 4.06 (dd,
J = 3.0, 8.5 Hz, 1H-CH
2), 4.34 (dd,
J = 6.5, 8.5 Hz, 1H-Bn), 4.48 (d,
J = 6.0, 8.5 Hz, 1H-Bn), 5.02 (m, 1H-CH
2), 5.48 (dd,
J = 2.0, 10.5 Hz, 1H-CH
2), 5.58 (d,
J = 10.0 Hz, 1H-CH
2), 5.88 (d,
J = 7.5 Hz, 1H-CH
2), 6.05 (dd,
J = 10.5, 17.0 Hz, 1H-CH), 6.15 (dd,
J = 2.5, 8.0 Hz, 1H-CH
2), 6.25 (d, 16.5 Hz, 1H-CH
2), 6.36 (d,
J = 17.0 Hz, 1H-CH
2), 7.21 (m, H-Ph) (
Figure S7).
13C NMR (150 MHz, CDCl
3) δ ppm 37.4, 38.9, 51.9, 52.0, 60.3, 60.3, 73.7, 74.0, 87.8, 88.0, 125.8, 125.9, 128.2, 128.4, 128.6, 129.2, 129.2, 129.4, 139.9, 141.3, 163.7, 165.1, 170.1, 170.3 (
Figure S8). IR: 699, 1423, 1649, 1735 cm
-1 (
Figure S9).
Methyl 2-((4
R)-3-((
E)-3-(4-fluorophenyl)acryloyl)-4-phenyloxazolidin-2-yl)acetate
8(a,b) in 81 % yield as a yellow pail oil, d.r. 67:33.
1H NMR (500 MHz, CDCl
3) δ ppm 2.77 (dd,
J = 8.5, 16.0 Hz, H-CH
2), 3.34 (dd,
J = 3.0, 16.0 Hz, 1H-CH
2), 3.46 (d,
J = 15.5 Hz, 1H-CH
2), 3.74 (s, 3H-OMe), 3.75 (s, 3H-OMe), 3.93 (d,
J = 5.0 Hz, 1H-CH), 3.99 (dd,
J = 2.0, 9.0 Hz, 1H-CH
2), 4.08 (dd,
J = 4.0, 9.0 Hz, 1H-CH
2), 4.37 (dd,
J = 6.5, 8.5 Hz, 1H-Bn), 4.51 (dd,
J = 6.0, 8.5 Hz, 1H-Bn), 5.09 (m, H-CH
2), 5.95 (d,
J = 7.0 Hz, 1H-CH), 6.19 (dd,
J = 3.0, 8.0 Hz, 1H-CH), 6.25 (d,
J = 7.5 Hz, 1H-CH
2), 6.05 (dd,
J = 10.5, 17.0 Hz, 1H-CH), 6.15 (dd,
J = 2.5, 8.0 Hz, 1H-CH
2), 6.25 (d, 15.5 Hz, 1H-CH), 6.30 (d,
J = 15.0 Hz, 1H-CH), 6.46 (d,
J = 15.5 Hz, 1H-CH), 6.93 (m, H-Ph), 7.18 (m, H-Ar), 4.27 (m, H-Ph) (
Figure S10).
13C NMR (150 MHz, CDCl
3) δ ppm 37.5, 39.0, 51.9, 52.0, 56.1, 60.4, 60.6, 66.4, 73.7, 74.1, 87.9, 88.1, 115.8, 115.8, 115.8, 115.9, 116.0, 116.0, 118.0, 118.6, 120.3, 120.3, 139.2, 140.0, 140.2, 141.3, 141.4, 142.1, 162.5, 162.6, 162.7, 164.0, 164.5, 164.6, 164.7, 165.4, 166.2, 170.2, 170.3 (
Figure S11). IR: 700, 1508, 1650, 1734 cm
-1 (
Figure S12).
Methyl 2-((2
S,4
R)-3-acryloyl-4-phenyloxazolidin-2-yl)acetate
7b, [a]
D20 -49.5 (
c 0.5, CH
2Cl
2)..
1H NMR (500 MHz, CDCl
3) δ ppm 2.72 (dd,
J = 8.5, 16.0 Hz, 1H-CH
2), 3.32 (dd,
J = 2.5, 15.5 Hz, 1H-CH
2), 3.75 (s, 3H-OMe), 3.96 (dd,
J = 2.5, 9.0 Hz, 1H-CH
2), 4.47 (dd,
J = 6.0, 9.0 Hz, 1H-Bn), 5.00 (d,
J = 6.5 Hz, 1H-CH
2), 5.47 (d,
J = 10.5 Hz, 1H-CH
2), 6.04 (dd,
J = 10.5, 16.5 Hz, 1H-CH), 6.15 (dd,
J = 3.0, 8.0 Hz, 1H-O-CH-N), 6.26 (d,
J = 16.5 Hz, 1H-CH
2), 7.21 (5H-Ph) (
Figure S13).
13C NMR (150 MHz, CDCl
3) δ ppm 29.7, 37.4, 51.9, 60.3, 73.7, 88.0, 125.8, 128.2, 128.5, 128.6, 129.1, 141.3, 163.7, 170.2 (
Figure S14). See COSY and NOESY spectra in
Figures S14 and S15 respectively.