Ⅲ. Chapter 3. Electrochemical C(sp 3 )-H Functionalization of ɣ-Lactams based on Hydrogen
3.11 Faradaic efficiency
60
M) was added BH3-SMe2 (10.0 equiv.) dropwise at 0 °C, and then the mixture was stirred at room temperature. Once the reaction was determined to be completed by TLC, MeOH (0.05 M) was added, and the solvent was removed under reduced pressure. The product 8d was purified through the flash chromatography. Structural assignments were made with additional information from gHSQC, gHMBC and NOESY experiments
61
Figure 3-10. Transition state of reaction with 6a, 6b and 6c.
3.13 Experimental data
Methyl 2-((5aS,6S)-5-methyl-4-oxo-4,5,5a,6-tetrahydrodibenzo[cd,f]indol-6-yl)acetate (8a)
At 150 °C (microwave). 12.3 mg, 80% yield, d.r. = 10:1, yellow oil; The dr value was determined by 1H NMR using the integral of methyl groups; The major product configuration was determined via analysis of 1D NOE (Figure S11); racemic mixture; 1H NMR (400 MHz, CDCl3) δ 7.83 – 7.80 (m, 1H), 7.78 – 7.73 (m, 2H), 7.55 (t, J = 7.6 Hz, 1H), 7.44 – 7.39 (m, 2H), 7.32 (t, J = 7.5 Hz, 1H), 4.61 (d, J = 6.0 Hz, 1H), 3.90 (dt, J = 8.7, 5.8 Hz, 1H), 3.54 (s, 3H), 3.18 (s, 3H), 2.02 (dd, J = 15.9, 5.5 Hz, 1H), 1.70 (dd, J = 15.8, 8.7 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 172.2, 170.4, 140.4, 137.8, 132.0, 131.5, 130.5, 130.4, 129.9, 128.9, 128.8, 125.0, 124.2, 122.5, 60.0, 51.7, 38.5, 32.4, 28.4; HRMS calcd for C19H18NO3+ 308.1281, observed 308.1288 [M+H]+
5-Methyldibenzo[cd,f]indol-4(5H)-one (8b)
62
At 250 °C (microwave). 5.9 mg, 51% yield, yellow solid; 1H NMR (400 MHz, CDCl3) δ 8.59 (d, J = 8.1 Hz, 1H), 8.55 – 8.51 (m, 1H), 8.10 (d, J = 7.1 Hz, 1H), 7.89 – 7.81 (m, 2H), 7.62 – 7.55 (m, 2H), 7.10 (s, 1H), 3.52 (s, 3H); The compound was identified by spectral comparison with literature data.65
1-Phenyl-1,9b-dihydro-3H-pyrrolo[2,1-a]isoindole-3,5(2H)-dione (8c)
6.0 mg, 58% yield, d.r. = 2:1; The dr value was determined by 1H NMR using the integral of methine proton; The product configuration was determined via analysis of NOESY (Figure S12 and S13).
Isomer 1 (major); (1S,9bR)-1-Phenyl-1,9b-dihydro-3H-pyrrolo[2,1-a]isoindole-3,5(2H)-dione; white solid, m.p. 200-210 °C; racemic mixture; 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 7.2 Hz, 1H), 7.58 – 7.38 (m, 7H), 7.07 (d, J = 7.2 Hz, 1H), 5.32 (d, J = 10.3 Hz, 1H), 3.43 (ddd, J = 12.8, 10.2, 7.1 Hz, 1H), 3.28 (dd, J = 16.8, 12.8 Hz, 1H), 3.08 (dd, J = 16.7, 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 170.6, 164.6, 144.6, 136.9, 134.1, 131.5, 129.5, 129.4, 128.3, 127.5, 126.0, 123.0, 67.2, 48.2, 44.9;
HRMS calcd for C17H14NO2+ 264.1019, observed 264.1020 [M+H]+
Isomer 2 (minor); (1R,9bR)-1-Phenyl-1,9b-dihydro-3H-pyrrolo[2,1-a]isoindole-3,5(2H)-dione; white solid, m.p. 190-200 °C; racemic mixture; 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 7.7 Hz, 1H), 7.42 (d, J = 7.6 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.23 (d, J = 7.7 Hz, 1H), 7.07 (m, 3H), 6.94 (d, J = 7.3 Hz, 2H), 5.62 (d, J = 6.5 Hz, 1H), 4.05 (t, J = 7.1 Hz, 1H), 3.50 (dd, J = 17.4, 7.6 Hz, 1H), 2.99 (d, J = 17.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 172.0, 165.1, 143.1, 137.7, 133.5, 131.9, 128.9, 128.7, 127.6, 127.0, 125.6, 123.9, 66.0, 44.1, 43.0; HRMS calcd for C17H14NO2+ 264.1019, observed 264.1020 [M+H]+
63
1-Phenyl-2,3,5,9b-tetrahydro-1H-pyrrolo[2,1-a]isoindole (8d)
11 mg, 47% yield (racemic mixture), clear oil; The product configuration was determined via analysis of HSQC, HMBC and 1D NOE (Figure S14-16). 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 7.2 Hz, 2H), 7.41 (t, J = 7.6 Hz, 2H), 7.31 (m, 3H), 7.19 (d, J = 7.4 Hz, 1H), 6.98 (d, J = 7.4 Hz, 1H), 4.95 (d, J = 7.8 Hz, 1H), 4.77 (d, J = 15.2 Hz, 1H), 4.34 (d, J = 15.2 Hz, 1H), 3.75 (dd, J = 10.3, 6.5 Hz, 1H), 3.29 (dt, J = 11.2, 7.5 Hz, 1H), 3.11 (td, J = 11.4, 5.5 Hz, 1H), 2.67 (ddt, J = 18.7, 12.2, 6.6 Hz, 1H), 2.30 (dd, J = 12.7, 6.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 140.7, 140.6, 134.7, 129.0, 128.5, 128.4, 128.0, 127.3, 122.6, 122.4, 85.6, 69.5, 64.4, 53.9, 35.4; HRMS calcd for C17H18N+ 236.1434, observed 236.1438 [M+H]+
Methyl 3-(2-methyl-3-oxoisoindolin-1-yl)-3-phenylpropanoate (3aa)
Prepared according to the general procedure (A) using 2-methylisoindolin-1-one 1a (0.1 mmol, 1.0 equiv.) and methyl cinnamate 2a (1.5 equiv.). 12.6 mg, 82% yield, 1 h, d.r. = 1.1:1; The dr value was determined by 1H NMR using the integral of methyl groups. The major product configuration was determined via analysis of HSQC and HMBC (Figure S17 and S18); The relative stereochemistry could not be assigned.
Isomer 1 white solid, m.p. 150-155 °C; 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 7.4 Hz, 1H), 7.41 (t, J = 7.3 Hz, 3H), 7.33 (m, 2H), 7.29 – 7.25 (m, 2H), 6.55 (d, J = 7.6 Hz, 1H), 4.68 (d, J = 3.8 Hz, 1H), 4.13 (dd, J = 9.7, 5.0 Hz, 1H), 3.57 (s, 3H), 3.26 (s, 3H), 2.30 (dd, J = 16.0, 9.8 Hz, 1H), 2.18 (dd, J = 16.0, 5.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 172.2, 168.6, 141.9, 138.3, 132.9, 130.8, 128.8, 128.5, 128.1, 127.6, 123.5, 123.3, 66.5, 51.9, 41.3, 30.7, 28.0; HRMS calcd for C19H20NO3+ 310.1438, observed 310.1436 [M+H]+
Isomer 2 white solid, m.p. 120-125 °C; 1H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 7.5 Hz, 1H), 7.61 (d, J = 7.5 Hz, 1H), 7.56 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.3 Hz, 1H), 7.14 – 7.10 (m, 3H), 6.90 – 6.84 (m, 2H), 4.72 (d, J = 3.5 Hz, 1H), 4.00 (ddd, J = 8.5, 6.0, 3.5 Hz, 1H), 3.63 (s, 3H), 3.03 (s, 3H), 2.93 (dd,
64
J = 16.1, 8.5 Hz, 1H), 2.78 (dd, J = 16.1, 6.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 172.1, 168.5, 143.0, 137.5, 133.1, 131.1, 128.5, 128.3, 127.7, 127.4, 123.7, 122.7, 65.8, 52.0, 43.1, 34.9, 28.8; HRMS calcd for C19H20NO3+ 310.1438, observed 310.1439 [M+H]+
Methyl 3-(2-methyl-3-oxoisoindolin-1-yl)-3-(p-tolyl)propanoate (3ab)
Prepared according to the general procedure (A) using 2-methylisoindolin-1-one 1a (0.1 mmol, 1.0 equiv.) and methyl (E)-3-(p-tolyl)acrylate 2b (1.5 equiv.). 28.7 mg, 89% yield, 1 h, d.r. = 1:1, yellow oil; The dr value was determined by 1H NMR using the integral of methyl groups; The relative stereochemistry could not be assigned; 1H NMR (400 MHz, CDCl3, two diastereomers are reported together) δ 7.80 (d, J = 7.5 Hz, 1H), 7.71 (d, J = 7.5 Hz, 1H), 7.61 (d, J = 7.5 Hz, 1H), 7.55 (td, J = 7.4, 1.1 Hz, 1H), 7.42 (dt, J = 12.6, 7.4 Hz, 2H), 7.32 (td, J = 7.5, 1.1 Hz, 1H), 7.21 (d, J = 7.9 Hz, 2H), 7.16 (d, J = 8.0 Hz, 2H), 6.92 (d, J = 7.8 Hz, 2H), 6.74 (d, J = 7.9 Hz, 2H), 6.60 (d, J = 7.6 Hz, 1H), 4.70 (d, J = 3.6 Hz, 1H), 4.66 (d, J = 3.8 Hz, 1H), 4.09 (dt, J = 9.5, 4.6 Hz, 1H), 3.97 (m, 1H), 3.63 (s, 3H), 3.56 (s, 3H), 3.25 (s, 3H), 3.02 (s, 3H), 2.91 (dd, J = 16.0, 8.8 Hz, 1H), 2.76 (dd, J = 16.0, 6.8 Hz, 1H), 2.38 (s, 3H), 2.27 (dd, J = 16.0, 9.9 Hz, 1H), 2.21 (s, 3H), 2.16 (dd, J = 16.0, 5.3 Hz, 1H); 13C NMR (100 MHz, CDCl3, two diastereomers are reported together) δ 172.3, 172.1, 168.6, 168.5, 143.1, 142.0, 137.2, 137.0, 135.1, 134.4, 133.2, 132.9, 131.0, 130.8, 129.5, 129.0, 128.4, 128.4, 127.9, 127.6, 123.6, 123.5, 123.4, 122.7, 66.5, 65.8, 51.9, 51.9, 42.8, 40.9, 35.1, 30.7, 28.8, 27.9, 21.1, 20.9; HRMS calcd for C20H22NO3+ 324.1594, observed 324.1596 [M+H]+
Methyl 3-(4-methoxyphenyl)-3-(2-methyl-3-oxoisoindolin-1-yl)propanoate (3ac)
Prepared according to the general procedure (A) using 2-methylisoindolin-1-one 1a (0.1 mmol, 1.0 equiv.) and methyl (E)-3-(4-methoxyphenyl)acrylate 2c (1.5 equiv.). 30.2 mg, 89% yield, 1 h, d.r. = 1:1;
The dr value was determined by 1H NMR using the integral of methyl groups; The relative stereochemistry could not be assigned.
65
Isomer 1 clear oil; 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 7.5 Hz, 1H), 7.41 (t, J = 7.4 Hz, 1H), 7.33 (t, J = 7.5 Hz, 1H), 7.18 (d, J = 8.6 Hz, 2H), 6.94 (d, J = 8.7 Hz, 2H), 6.61 (d, J = 7.6 Hz, 1H), 4.64 (d, J = 3.8 Hz, 1H), 4.08 (m, 1H), 3.84 (s, 3H), 3.57 (s, 3H), 3.25 (s, 3H), 2.21 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 172.3, 168.6, 158.9, 142.0, 132.9, 130.8, 130.1, 129.1, 128.4, 123.5, 123.3, 114.2, 66.5, 55.3, 51.9, 40.6, 31.0, 28.0; HRMS calcd for C20H22NO4+ 340.1543, observed 340.1553 [M+H]+ Isomer 2 clear oil; 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 7.5 Hz, 1H), 7.60 (d, J = 7.5 Hz, 1H), 7.55 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.4 Hz, 1H), 6.75 (d, J = 8.7 Hz, 2H), 6.63 (d, J = 8.6 Hz, 2H), 4.68 (d, J = 3.6 Hz, 1H), 3.95 (ddd, J = 8.5, 6.9, 3.6 Hz, 1H), 3.70 (s, 3H), 3.64 (s, 3H), 3.05 (s, 3H), 2.91 (dd, J = 16.0, 8.5 Hz, 1H), 2.79 (dd, J = 16.0, 6.9 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 172.1, 168.5, 158.7, 143.0, 133.2, 131.0, 129.2, 128.7, 128.5, 123.7, 122.7, 113.6, 65.7, 55.1, 52.0, 42.4, 35.5, 28.7;
HRMS calcd for C20H22NO4+ 340.1543, observed 340.1557 [M+H]+
Methyl 3-(3-methoxyphenyl)-3-(2-methyl-3-oxoisoindolin-1-yl)propanoate (3ad)
Prepared according to the general procedure (A) using 2-methylisoindolin-1-one 1a (0.1 mmol, 1.0 equiv.) and methyl 3-(3-methoxyphenyl)acrylate 2d (1.5 equiv.). 28.5 mg, 84% yield, 1 h, d.r. = 1:1, clear oil; The dr value was determined by 1H NMR using the integral of methyl groups; The relative stereochemistry could not be assigned; 1H NMR (400 MHz, CDCl3, two diastereomers are reported together) δ 7.81 (d, J = 7.5 Hz, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.57 (t, J = 7.4 Hz, 1H), 7.43 (dt, J = 14.8, 7.4 Hz, 2H), 7.33 (t, J = 7.8 Hz, 2H), 7.05 (t, J = 7.9 Hz, 1H), 6.87 (t, J = 7.0 Hz, 2H), 6.82 (s, 1H), 6.67 (d, J = 7.9 Hz, 1H), 6.62 (d, J = 7.6 Hz, 1H), 6.51 (d, J = 7.6 Hz, 1H), 6.34 (s, 1H), 4.73 (d, J = 3.5 Hz, 1H, isomer 2), 4.69 (d, J = 3.7 Hz, 1H, isomer 1), 4.10 (dt, J = 9.4, 4.5 Hz, 1H, isomer 1), 3.98 (ddd, J = 9.5, 7.0, 3.3 Hz, 1H, isomer 2), 3.82 (s, 3H, isomer 1), 3.64 (s, 3H, isomer 2), 3.59 (s, 3H, isomer 2), 3.58 (s, 3H, isomer 1), 3.25 (s, 3H, isomer 1), 3.03 (s, 3H, isomer 2), 2.91 (dd, J = 16.1, 8.7 Hz, 1H, isomer 2), 2.76 (dd, J = 16.1, 6.8 Hz, 1H, isomer 2), 2.27 (dd, J = 16.1, 9.8 Hz, 1H, isomer 1), 2.16 (dd, J = 16.1, 5.2 Hz, 1H, isomer 1); 13C NMR (100 MHz, CDCl3, two diastereomers are reported together) δ 172.2, 172.0, 168.6, 168.5, 159.9, 159.3, 143.0, 141.9, 140.0, 139.2, 133.2, 132.9, 131.1, 130.8, 129.8, 129.3, 128.5, 128.5, 123.7, 123.5, 123.4, 122.7, 120.3, 114.3, 113.4, 112.9, 112.6, 66.4, 65.6, 55.3, 55.0, 52.0, 51.9, 43.1, 41.2, 35.1, 30.7, 28.8, 27.9; HRMS calcd for C20H22NO4+ 340.1543, observed 340.1558 [M+H]+
66
Methyl 3-(2-methoxyphenyl)-3-(2-methyl-3-oxoisoindolin-1-yl)propanoate (3ae)
Prepared according to the general procedure (A) using 2-methylisoindolin-1-one 1a (0.1 mmol, 1.0 equiv.) and methyl (E)-3-(2-methoxyphenyl)acrylate 2e (1.5 equiv.). 31.9 mg, 94% yield, 1 h, d.r. = 2.6:1, yellow oil; The dr value was determined by 1H NMR using the integral of methyl groups; The relative stereochemistry could not be assigned; 1H NMR (400 MHz, CDCl3, two diastereomers are reported together) δ 7.82 (d, J = 7.5 Hz, 1H), 7.66 (d, J = 7.5 Hz, 0.4H, isomer 2), 7.58 (t, J = 7.4 Hz, 0.4H, isomer 2), 7.49 – 7.29 (m, 4H), 7.22 (t, J = 7.8 Hz, 1H), 7.10 (d, J = 7.2 Hz, 1H), 7.05 – 6.97 (m, 2H), 6.95 – 6.89 (m, 1H), 6.82 (t, J = 7.5 Hz, 0.4H, isomer 2), 6.66 (d, J = 7.6 Hz, 1H, isomer 1), 4.85 (m, 0.4H, isomer 2), 4.78 (m, 1H, isomer 1), 4.48 (m, 1H, isomer 1), 4.47 (m, 0.4H, isomer 2), 3.96 (s, 3H, isomer 1), 3.92 (s, 1.2H, isomer 2), 3.54 (s, 3H, isomer 1), 3.51 (s, 1.2H, isomer 2), 3.27 (s, 3H, isomer 1), 2.86 (s, 1.2H, isomer 2), 2.76 (dd, J = 16.1, 10.0 Hz, 0.4H, isomer 2), 2.30 (dd, J = 16.1, 5.8 Hz, 0.4H, isomer 2), 2.20 (dd, J = 15.8, 10.0 Hz, 1H, isomer 1), 2.09 (dd, J = 15.9, 5.5 Hz, 1H, isomer 1); 13C NMR (100 MHz, CDCl3, two diastereomers are reported together) δ 172.2, 172.0, 168.6, 168.5, 159.9, 159.3, 143.0, 141.9, 140.0, 139.2, 133.2, 132.9, 131.1, 130.8, 129.8, 129.3, 128.5, 128.5, 123.7, 123.5, 123.4, 122.7, 120.3, 114.3, 113.4, 112.9, 112.6, 66.4, 65.6, 55.3, 55.0, 52.0, 51.9, 43.1, 41.2, 35.1, 30.7, 28.8, 27.9; HRMS calcd for C20H22NO4+ 340.1543, observed 340.1559 [M+H]+
Methyl 3-(4-(dimethylamino)phenyl)-3-(2-methyl-3-oxoisoindolin-1-yl)propanoate (3af)
Prepared according to the general procedure (A) using 2-methylisoindolin-1-one 1a (0.1 mmol, 1.0 equiv.) and methyl (E)-3-(4-(dimethylamino)phenyl)acrylate 2f (3.0 equiv.). 25.0 mg, 71% yield, 3 h, d.r.=1:1, yellow solid; m.p. 137-145 °C; The dr value was determined by 1H NMR using the integral of methyl groups; The relative stereochemistry could not be assigned; 1H NMR (400 MHz, CDCl3, two diastereomers are reported together) δ 7.80 (d, J = 7.5 Hz, 1H), 7.72 (d, J = 7.4 Hz, 0.2H, isomer 2), 7.61 (d, J = 7.3 Hz, 0.2H, isomer 2), 7.55 (t, J = 7.5 Hz, 0.2H, isomer 2), 7.45 (d, J = 7.3 Hz, 0.2H,
67
isomer 2), 7.40 (t, J = 7.4 Hz, 1H), 7.32 (t, J = 7.4 Hz, 1H), 7.13 (d, J = 8.6 Hz, 2H), 6.76 (d, J = 8.7 Hz, 2H), 6.71 (d, J = 8.6 Hz, 0.3H, isomer 2), 6.67 (d, J = 7.6 Hz, 1H), 6.47 (d, J = 8.7 Hz, 0.3H, isomer 2), 4.67 (d, J = 3.7 Hz, 0.2H, isomer 2), 4.63 (d, J = 3.8 Hz, 1H, isomer 1), 4.18 (m, 0.2H, isomer 2), 4.04 (m, 1H, isomer 1), 3.63 (s, 0.5H, isomer 2), 3.56 (s, 3H, isomer 1), 3.25 (s, 3H, isomer 1), 3.03 (s, 0.5H, isomer 2), 2.98 (s, 6H, isomer 1), 2.85 (s, 1H, isomer 2), 2.52 (dd, J = 16.2, 1.9 Hz, 0.2H, isomer 2), 2.35 (dd, J = 16.2, 10.6 Hz, 0.2H, isomer 2), 2.23 (dd, J = 15.9, 9.9 Hz, 1H, isomer 1), 2.12 (dd, J = 15.9, 5.2 Hz, 1H, isomer 1); 13C NMR (100 MHz, CDCl3, two diastereomers are reported together) δ 172.5, 168.7, 149.8, 142.3, 132.9, 130.9, 130.7, 128.7, 128.3, 128.3, 125.5, 123.6, 123.6, 123.4, 122.7, 112.7, 112.2, 66.7, 65.9, 51.9, 51.8, 42.3, 40.5, 40.4, 40.3, 36.6, 35.3, 30.8, 28.8, 27.9, 25.6; HRMS calcd for C21H25N2O3+ 353.1860, observed 353.1861 [M+H]+
Methyl 3-(4-fluorophenyl)-3-(2-methyl-3-oxoisoindolin-1-yl)propanoate (3ag)
Prepared according to the general procedure (A) using 2-methylisoindolin-1-one 1a (0.1 mmol, 1.0 equiv.) and methyl (E)-3-(4-fluorophenyl)acrylate 2g (1.5 equiv.). 23.6 mg, 72% yield, 1 h, d.r. = 1.2:1, colorless oil; The dr value was determined by 1H NMR using the integral of methyl groups; The relative stereochemistry could not be assigned; 1H NMR (400 MHz, CDCl3, two diastereomers are reported together) δ 7.81 (d, J = 7.5 Hz, 1H), 7.70 (d, J = 7.5 Hz, 1H), 7.62 – 7.53 (m, 2H), 7.47 – 7.40 (m, 2H), 7.34 (t, J = 7.5 Hz, 1H), 7.23 (m, 2H), 7.10 (t, J = 8.5 Hz, 2H), 6.78 (d, J = 7.6 Hz, 4H), 6.60 (d, J = 7.6 Hz, 1H), 4.68 (d, J = 3.6 Hz, 1H, isomer 2), 4.64 (d, J = 3.7 Hz, 1H, isomer 1), 4.13 – 4.07 (m, 1H), 4.02 – 3.95 (m, 1H), 3.65 (s, 3H, isomer 2), 3.58 (s, 3H, isomer 1), 3.26 (s, 3H, isomer 1), 3.07 (s, 3H, isomer 2), 2.90 (m, 2H, isomer 2), 2.33 – 2.19 (m, 2H, isomer 1); 13C NMR (100 MHz, CDCl3, two diastereomers are reported together) δ 172.1, 171.8, 168.6, 168.3, 162.1, 161.9, 142.6, 141.8, 133.9, 133.9, 133.2, 132.9, 132.8, 132.8, 131.0 (d, J = 246.8 Hz), 129.7, 129.6, 129.3, 129.2, 128.6, 128.6, 123.8, 123.7, 123.1, 122.7, 115.8, 115.1, 66.3, 65.4, 52.0, 51.9, 42.3, 40.9, 35.6, 31.2, 28.6, 28.1; HRMS calcd for C19H19FNO3+ 328.1343, observed 328.1344 [M+H]+
Methyl 3-(3-bromophenyl)-3-(2-methyl-3-oxoisoindolin-1-yl)propanoate (3ah)
68
Prepared according to the general procedure (A) using 2-methylisoindolin-1-one 1a (0.1 mmol, 1.0 equiv.) and methyl (E)-3-(3-bromophenyl)acrylate 2h (1.5 equiv.). 14.8 mg, 38% yield, 1 h, d.r. = 4:1, yellow oil; The dr value was determined by 1H NMR using the integral of methyl groups; The relative stereochemistry could not be assigned; 1H NMR (400 MHz, CDCl3, two diastereomers are reported together) δ 7.82 (d, J = 7.5 Hz, 1H), 7.73 (d, J = 7.5 Hz, 0.25H, isomer 2), 7.59 (d, J = 6.3 Hz, 1H), 7.53 – 7.40 (m, 4H), 7.36 (t, J = 7.5 Hz, 1H), 7.30 (d, J = 7.8 Hz, 2H), 7.19 (d, J = 7.8 Hz, 1H), 7.04 – 6.94 (m, 1H), 6.78 (d, J = 7.8 Hz, 0.25H, isomer 2), 6.60 (d, J = 7.6 Hz, 1H), 4.70 (d, J = 3.6 Hz, 0.25H, isomer 2), 4.66 (d, J = 3.7 Hz, 1H, isomer 1), 4.10 (m, 1H, isomer 1), 4.03 – 3.91 (m, 0.25H, isomer 2), 3.66 (s, 1H, isomer 2), 3.59 (s, 3H, isomer 1), 3.25 (s, 3H, isomer 1), 3.05 (s, 1H, isomer 2), 2.95 – 2.57 (m, 0.5H, isomer 2), 2.23 (qd, J = 16.2, 7.5 Hz, 2H, isomer 1); 13C NMR (100 MHz, CDCl3, two diastereomers are reported together) δ 171.9, 171.7, 168.5, 168.4, 142.5, 141.6, 140.8, 139.8, 133.1, 132.8, 131.5, 131.2, 131.0, 130.9, 130.8, 130.6, 130.3, 129.8, 128.8, 128.7, 126.6, 126.4, 123.8, 123.7, 123.1, 123.0, 122.6, 122.3, 66.1, 65.4, 52.1, 52.0, 42.8, 41.2, 35.0, 30.6, 28.8, 28.0; HRMS calcd for C19H19BrNO3+ 388.0543, observed 388.0544 [M+H]+
Methyl 3-(2-bromophenyl)-3-(2-methyl-3-oxoisoindolin-1-yl)propanoate (3ai)
Prepared according to the general procedure (A) using 2-methylisoindolin-1-one 1a (0.1 mmol, 1.0 equiv.) and methyl 3-(2-bromophenyl)acrylate 2i (1.5 equiv.). 34.9 mg, 90% yield, 1 h, d.r. = 4:1, yellow oil; The dr value was determined by 1H NMR using the integral of methyl groups; The relative stereochemistry could not be assigned; 1H NMR (400 MHz, CDCl3, two diastereomers are reported together) δ 7.84 (t, J = 7.7 Hz, 1H), 7.80 – 7.69 (m, 1H), 7.71 – 7.57 (m, 1H), 7.55 – 7.30 (m, 4H), 7.27 – 7.19 (m, 1H), 7.16 (m, 1H), 7.11 – 7.06 (m, 0.25H, isomer 2), 6.64 (d, J = 7.6 Hz, 1H), 4.95 (d, J = 2.4 Hz, 0.25H, isomer 2), 4.86 (d, J = 3.4 Hz, 1H, isomer 1), 4.52 (m, 1H, isomer 1), 4.49 – 4.44 (m, 0.25H, isomer 2), 3.55 (s, 3H, isomer 1), 3.49 (s, 1H, isomer 2), 3.32 (s, 3H, isomer 1), 2.82 (s, 1H, isomer 2), 2.76 (dd, J = 16.3, 10.2 Hz, 0.25H, isomer 2), 2.26 – 2.22 (m, 0.25H, isomer 2), 2.20 (m, 2H,
69
isomer 1); 13C NMR (100 MHz, CDCl3, two diastereomers are reported together) δ 171.7, 171.6, 169.5, 168.5, 144.0, 141.8, 138.5, 137.3, 133.9, 133.9, 133.2, 132.6, 131.8, 130.7, 129.4, 129.1, 129.0, 128.7, 128.6, 128.1, 127.5, 127.5, 125.6, 125.3, 123.7, 123.6, 123.4, 122.5, 64.8, 62.8, 52.0, 51.9, 43.7, 40.4, 31.9, 30.6, 30.4, 27.6; HRMS calcd for C19H19BrNO3+ 388.0543, observed 388.0543 [M+H]+
Methyl 3-(4-acetylphenyl)-3-(2-methyl-3-oxoisoindolin-1-yl)propanoate (3aj)
Prepared according to the General Procedure (A) using 2-methylisoindolin-1-one 1a (0.1 mmol, 1.0 equiv.) and methyl (E)-3-(4-acetylphenyl)acrylate 2j (1.5 equiv.). 21.1 mg, 60% yield, 1 h, d.r. = 5:1, colorless oil; The dr value was determined by 1H NMR using the integral of methyl groups; The relative stereochemistry could not be assigned; 1H NMR (400 MHz, CDCl3, two diastereomers are reported together) δ 8.00 (d, J = 8.0 Hz, 2H), 7.81 (d, J = 7.5 Hz, 1H), 7.70 (d, J = 7.8 Hz, 0.4H, isomer 2), 7.66 – 7.53 (m, 0.4H, isomer 2), 7.50 – 7.29 (m, 4.6H), 6.94 (d, J = 8.0 Hz, 0.2H, isomer 2), 6.57 (d, J = 7.6 Hz, 1H), 4.74 (d, J = 3.3 Hz, 0.2H, isomer 2), 4.70 (d, J = 3.4 Hz, 1H, isomer 1), 4.18 (m, 1H, isomer 1), 4.09 (m, 0.2H, isomer 2), 3.66 (s, 0.6H, isomer 2), 3.59 (s, 3H, isomer 1), 3.28 (s, 3H, isomer 1), 3.07 (s, 0.6H, isomer 2), 3.02 – 2.82 (m, 0.4H, isomer 2), 2.64 (s, 3H, isomer 1), 2.51 (s, 0.6H, isomer 2), 2.31 (qd, J = 16.3, 7.6 Hz, 2H, isomer 1); 13C NMR (100 MHz, CDCl3, two diastereomers are reported together) δ 197.5, 171.9, 168.5, 143.8, 141.6, 136.4, 132.8, 131.2, 131.0, 128.8, 128.7, 128.4, 128.2, 128.0, 123.9, 123.8, 123.0, 122.6, 66.0, 65.4, 52.1, 52.0, 43.0, 41.7, 35.0, 30.8, 28.7, 28.1, 26.6, 26.5; HRMS calcd for C21H22NO4+ 352.1543, observed 352.1547 [M+H]+
Methyl 4-(3-methoxy-1-(2-methyl-3-oxoisoindolin-1-yl)-3-oxopropyl)benzoate (3ak)
Prepared according to the general procedure (A) using 2-methylisoindolin-1-one 1a (0.1 mmol, 1.0 equiv.) and methyl (E)-4-(3-methoxy-3-oxoprop-1-en-1-yl)benzoate 2k (3.0 equiv.). 15.8 mg, 43%
70
yield, 1 h, d.r. = 2.4:1, yellow oil; The dr value was determined by 1H NMR using the integral of methyl groups; The relative stereochemistry could not be assigned; 1H NMR (400 MHz, CDCl3, two diastereomers are reported together) δ 8.08 (d, J = 7.8 Hz, 2H, isomer 1), 7.81 (d, J = 7.7 Hz, 1.6H, isomer 1 and 2), 7.69 (d, J = 7.6 Hz, 0.3H, isomer 2), 7.58 (m, 0.6H, isomer 2), 7.42 (t, J = 8.0 Hz, 1.6H, isomer 1 and 2), 7.34 (m, 3H), 6.93 (d, J = 7.9 Hz, 0.3H, isomer 2), 6.53 (d, J = 7.6 Hz, 1H, isomer 1), 4.73 (m, 0.3H, isomer 2), 4.70 (d, J = 3.7 Hz, 1H, isomer 1), 4.19 (d, J = 5.1 Hz, 1H, isomer 1), 4.07 (m, 0.3H, isomer 2), 3.94 (s, 3H, isomer 1), 3.85 (s, 0.9H, isomer 2), 3.64 (s, 0.9H, isomer 2), 3.58 (s, 3H, isomer 1), 3.27 (s, 3H, isomer 1), 3.05 (s, 0.9H, isomer 2), 2.97 (m, 0.3H, isomer 2), 2.92 – 2.78 (m, 0.3H, isomer 2), 2.29 (m, 2H, isomer 1); 13C NMR (100 MHz, CDCl3, two diastereomers are reported together) δ 171.9, 171.7, 168.5, 168.3, 166.6, 166.5, 143.6, 142.7, 142.5, 141.6, 133.0, 132.8, 131.2, 131.0, 130.0, 129.5, 129.5, 129.3, 128.7, 128.7, 128.2, 127.8, 123.8, 123.7, 123.0, 122.6, 66.0, 65.4, 52.2, 52.2, 52.0, 52.0, 43.0, 41.6, 34.9, 30.7, 28.7, 28.0; HRMS calcd for C21H22NO5+ 368.1492, observed 368.1496 [M+H]+
Methyl 3-(4-(dimethylcarbamoyl)phenyl)-3-(2-methyl-3-oxoisoindolin-1-yl)propanoate (3al)
Prepared according to the general procedure (A) using 2-methylisoindolin-1-one 1a (0.1 mmol, 1.0 equiv.) and methyl (E)-3-(4-(dimethylcarbamoyl)phenyl)acrylate 2l (1.5 equiv.). 26.6 mg, 70% yield, 1 h, d.r. = 1.1:1; The dr value was determined by 1H NMR using the integral of methyl groups; The relative stereochemistry could not be assigned.
Isomer 1yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 7.5 Hz, 1H), 7.47 (d, J = 8.0 Hz, 2H), 7.42 (t, J = 7.5 Hz, 1H), 7.35 – 7.29 (m, 3H), 6.61 (d, J = 7.6 Hz, 1H), 4.68 (d, J = 3.6 Hz, 1H), 4.14 (m, 1H), 3.58 (s, 3H), 3.26 (s, 3H), 3.13 (s, 3H), 3.01 (s, 3H), 2.31 (dd, J = 16.2, 9.8 Hz, 1H), 2.21 (dd, J = 16.2, 5.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 172.0, 171.2, 168.7, 141.7, 140.1, 135.3, 132.7, 131.1, 128.7, 128.2, 127.7, 123.7, 123.2, 66.2, 52.0, 41.4, 30.7, 29.7, 28.1; HRMS calcd for C22H25N2O4+ 381.1809, observed 381.1813 [M+H]+
Isomer 2yellow oil; 1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 7.6 Hz, 1H), 7.62 – 7.53 (m, 2H), 7.43 (t, J = 7.4 Hz, 1H), 7.17 (d, J = 7.9 Hz, 2H), 6.88 (d, J = 7.9 Hz, 2H), 4.71 (d, J = 3.5 Hz, 1H), 4.06 – 4.00 (m, 1H), 3.64 (s, 3H), 3.06 (s, 3H), 3.04 (s, 3H), 2.94 (dd, J = 16.1, 8.8 Hz, 1H), 2.87 – 2.78 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 171.8, 171.0, 168.3, 142.7, 139.0, 135.3, 133.1, 131.2, 128.6, 127.8,
71
127.0, 123.7, 122.7, 65.5, 52.1, 42.8, 39.5, 35.0, 28.8; HRMS calcd for C22H25N2O4+ 381.1809, observed 381.1815 [M+H]+
Methyl 3-(2-methyl-3-oxoisoindolin-1-yl)-3-(naphthalen-1-yl)propanoate (3am)
Prepared according to the general procedure (A) using 2-methylisoindolin-1-one 1a (0.1 mmol, 1.0 equiv.) and methyl (E)-3-(naphthalen-1-yl) 2m (1.5 equiv.). 26.9 mg, 75% yield, d.r. = 99:1, 1 h, clear oil; The relative stereochemistry could not be assigned; 1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 8.6 Hz, 1H), 7.98 (d, J = 8.1 Hz, 1H), 7.91 (d, J = 8.2 Hz, 1H), 7.84 (d, J = 7.5 Hz, 1H), 7.68 (ddd, J = 8.4, 6.8, 1.4 Hz, 1H), 7.60 – 7.49 (m, 2H), 7.41 (d, J = 7.5 Hz, 1H), 7.31 – 7.26 (m, 2H), 6.41 (d, J = 7.6 Hz, 1H), 4.97 (m, 1H), 4.85 (m, 1H), 3.54 (s, 3H), 3.45 (s, 3H), 2.42 – 2.27 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 172.2, 168.6, 141.9, 134.3, 133.8, 133.0, 131.4, 130.7, 129.6, 128.7, 128.5, 126.9, 126.0, 125.0, 124.9, 123.8, 123.6, 122.1, 63.9, 51.9, 36.6, 30.9, 27.8; HRMS calcd for C23H22NO3+ 360.1594, observed 360.1598 [M+H]+
Methyl 3-(2-methyl-3-oxoisoindolin-1-yl)-3-(pyridin-3-yl)propanoate (3an)
Prepared according to the general procedure (A) using 2-methylisoindolin-1-one 1a (0.1 mmol, 1.0 equiv.) and methyl (E)-3-(pyridin-3-yl)acrylate 2n (1.5 equiv.). 17 mg, 55% yield, 2 h, d.r.=1.2:1, yellow oil; The dr value was determined by 1H NMR using the integral of methyl groups; The relative stereochemistry could not be assigned; 1H NMR (400 MHz, CDCl3, two diastereomers are reported together) δ 8.60 – 8.52 (m, 1H), 8.36 (m, 1H), 8.18 – 8.13 (m, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.70 (d, J
= 7.6 Hz, 1H), 7.60 (m, 3H), 7.46 (m, 2H), 7.35 (m, 1H), 6.99 (m, 2H), 4.72 (d, J = 3.4 Hz, 1H, isomer 1), 4.68 (d, J = 3.3 Hz, 1H, isomer 2), 4.16 – 4.11 (m, 0.6 H, isomer 2), 4.02 (dt, J = 7.7, 3.9 Hz, 1H, isomer 1), 3.68 (s, 3H, isomer 1), 3.60 (s, 2H, isomer 2), 3.28 (s, 2H, isomer 2), 3.12 (s, 3H, isomer 1),
72
2.99 (m, 2H, isomer 1), 2.38 – 2.34 (m, 1.2H, isomer 2).13C NMR (100 MHz, CDCl3, two diastereomers are reported together) δ 171.7, 171.5, 168.5, 168.1, 149.8, 149.3, 149.0, 148.9, 142.1, 141.6, 135.6, 135.1, 133.8, 133.1, 132.7, 132.7, 131.3, 131.2, 128.9, 128.8, 124.0, 123.8, 123.5, 123.0, 122.8, 122.7, 65.9, 64.9, 52.2, 52.1, 40.7, 39.9, 35.4, 31.0, 28.5, 28.4; HRMS calcd for C18H19N2O3+ 311.1390, observed 311.1393 [M+H]+
Methyl 3-(furan-2-yl)-3-(2-methyl-3-oxoisoindolin-1-yl)propanoate (3ao)
Prepared according to the general procedure (A) using 2-methylisoindolin-1-one 1a (0.1 mmol, 1.0 equiv.) and methyl (E)-3-(furan-2-yl)acrylate 2o (1.5 equiv.). 18.3 mg, 61% yield, 1 h, d.r. = 1.6:1, yellow oil; The dr value was determined by 1H NMR using the integral of methyl groups; The relative stereochemistry could not be assigned; 1H NMR (400 MHz, CDCl3, two diastereomers are reported together) δ 7.84 – 7.76 (m, 1.6H), 7.57 – 7.46 (m, 2.8H), 7.46 – 7.39 (m, 1H), 7.36 (t, J = 7.5 Hz, 1H), 7.30 (s, 0.6H, isomer 2), 6.51 (d, J = 7.5 Hz, 1H), 6.42 (m, 1H), 6.24 (m, 0.6H, isomer 2), 6.15 (d, J = 3.3 Hz, 1H, isomer 1), 5.95 (d, J = 3.3 Hz, 0.6H, isomer 2), 4.92 (d, J = 3.7 Hz, 1H, isomer 1), 4.89 (m, 0.6H, isomer 2), 4.16 (m, 1H, isomer 1), 4.09 (m, 0.6H, isomer 2), 3.61 (s, 3H, isomer 1), 3.60 (s, 1.8H, isomer 2), 3.21 (s, 3H, isomer 1), 2.90 (s, 1.8H, isomer 2), 2.71 (dd, J = 16.2, 9.4 Hz, 0.6H, isomer 2), 2.29 (dd, J = 16.2, 5.1 Hz, 0.6H, isomer 2), 2.12 – 1.96 (m, 2H, isomer 1); 13C NMR (100 MHz, CDCl3, two diastereomers are reported together) δ 172.0, 171.9, 168.8, 168.7, 152.9, 152.7, 142.7, 142.1, 141.7, 141.6, 132.9, 132.8, 131.4, 131.2, 128.6, 128.5, 123.6, 123.5, 122.9, 122.3, 110.7, 110.5, 107.3, 106.7, 64.0, 63.2, 52.0, 52.0, 37.8, 35.8, 31.8, 30.0, 28.4, 27.7; HRMS calcd for C17H18NO4+ 300.1230, observed 300.1230 [M+H]+
Methyl 3-(2-methyl-3-oxoisoindolin-1-yl)-3-(thiophen-2-yl)propanoate (3ap)
73
Prepared according to the general procedure (A) using 2-methylisoindolin-1-one 1a (0.1 mmol, 1.0 equiv.) and methyl (E)-3-(thiophen-2-yl)acrylate 2p (1.5 equiv.). 23.8 mg, 76% yield, 1 h, d.r. = 1.2:1;
The dr value was determined by 1H NMR using the integral of methyl groups; The relative stereochemistry could not be assigned.
Isomer 1 white solid, m.p. 102-105 °C; 1H NMR (400 MHz, CDCl3) δ 7.81 (d, J = 7.5 Hz, 1H), 7.43 (t, J = 7.4 Hz, 1H), 7.39 – 7.30 (m, 2H), 7.03 (m, 1H), 6.88 (m, 1H), 6.63 (d, J = 7.6 Hz, 1H), 4.78 (d, J = 3.6 Hz, 1H), 4.34 (dt, J = 9.1, 4.5 Hz, 1H), 3.63 (s, 3H), 3.25 (s, 3H), 2.33 – 2.17 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 171.9, 168.7, 142.3, 141.7, 132.8, 131.1, 128.7, 127.1, 125.0, 124.8, 123.5, 123.1, 66.4, 52.1, 37.7, 32.8, 28.1; HRMS calcd for C17H18NO3S+ 316.1002, observed 316.1002 [M+H]+ Isomer 2 white solid, m.p. 135-137 °C; 1H NMR (400 MHz, CDCl3) δ 7.77 – 7.70 (m, 1H), 7.61 – 7.52 (m, 2H), 7.49 – 7.42 (m, 1H), 7.02 (m, 1H), 6.75 (m, 1H), 6.58 – 6.53 (m, 1H), 4.73 (d, J = 3.4 Hz, 1H), 4.35 – 4.27 (m, 1H), 3.69 (s, 3H), 3.10 (s, 3H), 3.02 – 2.81 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 171.6, 168.5, 142.2, 140.1, 133.4, 131.2, 128.7, 126.4, 125.3, 124.5, 123.7, 122.8, 65.3, 52.1, 38.7, 36.9, 28.2; HRMS calcd for C17H18NO3S+ 316.1002, observed 316.1005 [M+H]+
Methyl 3-(1-methyl-1H-indol-3-yl)-3-(2-methyl-3-oxoisoindolin-1-yl)propanoate (3aq)
Prepared according to the general procedure (A) using 2-methylisoindolin-1-one 1a (0.1 mmol, 1.0 equiv.) and methyl (E)-3-(1-methyl-1H-indol-3-yl)acrylate 2q (1.5 equiv.). 19.2 mg, 53% yield, 1 h, d.r.
= 2:1, yellow oil; The dr value was determined by 1H NMR using the integral of methyl groups; The relative stereochemistry could not be assigned; 1H NMR (400 MHz, CDCl3, two diastereomers are reported together) δ 7.82 (d, J = 7.5 Hz, 1.4H), 7.73 (d, J = 7.8 Hz, 1.4H), 7.65 – 7.60 (m, 0.8H), 7.51 (t, J = 7.5 Hz, 0.4H, isomer 2), 7.43 – 7.37 (m, 2H), 7.31 (q, J = 7.4 Hz, 2H), 7.25 – 7.17 (m, 1.8H), 7.11 (t, J = 7.4 Hz, 0.4H, isomer 2), 6.88 (s, 1H, isomer 1), 6.65 (d, J = 7.6 Hz, 1H), 6.24 (s, 0.4H, isomer 2), 4.97 – 4.93 (m, 1.4H, isomer 1 and 2), 4.42 (m, 1.4H, isomer 1 and 2), 3.84 (s, 3H, isomer 1), 3.61 (s, 1.2H, isomer 2), 3.58 (s, 1.2H, isomer 2), 3.56 (s, 3H, isomer 1), 3.38 (s, 3H, isomer 1), 2.90 (s, 1.2H, isomer 2), 2.82 (dd, J = 15.5, 9.4 Hz, 0.4H, isomer 2), 2.58 (dd, J = 15.5, 5.9 Hz, 0.4H, isomer 2), 2.19 – 2.13 (m, 2H, isomer 1); 13C NMR (100 MHz, CDCl3, two diastereomers are reported together) δ 172.5, 172.4, 168.7, 143.8, 142.4, 137.6, 136.9, 133.0, 131.3, 130.6, 128.5, 128.3, 127.1, 126.8, 126.6, 126.0, 123.6, 123.5, 123.3, 122.7, 122.4, 121.9, 119.4, 119.2, 118.6, 118.4, 112.3, 111.9, 109.8, 109.6,
74
64.6, 63.9, 51.9, 35.5, 35.5, 33.6, 33.1, 32.8, 31.6, 29.7, 29.0, 27.9; HRMS calcd for C22H23N2O3+
363.1703, observed 363.1705 [M+H]+
Methyl 3-(benzo[b]thiophen-3-yl)-3-(2-methyl-3-oxoisoindolin-1-yl)propanoate (3ar)
Prepared according to the general procedure (A) using 2-methylisoindolin-1-one 1a (0.1 mmol, 1.0 equiv.) and methyl (E)-3-(benzo[b]thiophen-3-yl)acrylate 2r (1.5 equiv.). 33.6 mg, 92% yield, 1 h, d.r.
= 2.6:1, yellow oil; The dr value was determined by 1H NMR using the integral of methyl groups; The relative stereochemistry could not be assigned; 1H NMR (400 MHz, CDCl3, two diastereomers are reported together) δ 8.02 – 7.92 (m, 3H), 7.90 – 7.82 (m, 2H), 7.76 (d, J = 7.6 Hz, 0.4H, isomer 2), 7.65 (d, J = 1.2 Hz, 0.4H, isomer 2), 7.56 – 7.32 (m, 6H), 7.19 (s, 1H, isomer 1), 6.79 (s, 0.4H, isomer 2), 6.60 (d, J = 7.6 Hz, 1H), 4.98 (d, J = 2.9 Hz, 0.4H, isomer 2), 4.86 (d, J = 3.4 Hz, 1H, isomer 1), 4.52 (tt, J = 6.4, 3.9 Hz, 2H, isomer 1), 4.48 – 4.43 (m, 0.4H, isomer 2), 3.57 (s, 3H, isomer 1), 3.55 (s, 1.2H, isomer 2), 3.40 (s, 3H, isomer 1), 2.88 (dd, J = 15.9, 9.7 Hz, 0.4H, isomer 2), 2.84 (s, 1.2H, isomer 2), 2.48 (dd, J = 15.9, 5.4 Hz, 0.4H, isomer 2), 2.33 – 2.19 (m, 2H, isomer 1); 13C NMR (100 MHz, CDCl3, two diastereomers are reported together) δ 172.0, 171.9, 169.0, 168.6, 143.5, 141.8, 140.9, 140.6, 137.9, 137.7, 133.8, 133.4, 133.1, 132.9, 131.7, 130.9, 128.9, 128.6, 125.0, 124.8, 124.6, 124.3, 123.8, 123.7, 123.5, 123.4, 123.4, 123.3, 122.9, 122.5, 121.2, 121.1, 64.2, 62.9, 52.0, 52.0, 37.8, 35.7, 33.9, 31.3, 29.6, 27.8; HRMS calcd for C21H20NO3S+ 366.1158, observed 366.1157 [M+H]+
Ethyl 3-(2-methyl-3-oxoisoindolin-1-yl)butanoate (3as)
Prepared according to the general procedure (A) using 2-methylisoindolin-1-one 1a (0.1 mmol, 1.0 equiv.) and ethyl (E)-but-2-enoate 2s (3.0 equiv.). 17.8 mg, 68% yield, 1 h, d.r. = 1:1, clear oil; The dr value was determined by 1H NMR using the integral of methyl groups; The relative stereochemistry could not be assigned; 1H NMR (400 MHz, CDCl3, two diastereomers are reported together) δ 7.85 (d, J = 7.3 Hz, 2H), 7.48 (m, 6H), 4.45 (d, J = 3.1 Hz, 1H), 4.40 (d, J = 2.9 Hz, 1H), 4.19 (q, J = 7.2 Hz,
75
2H), 4.09 (q, J = 7.2 Hz, 2H), 3.14 (s, 6H), 2.90 – 2.77 (m, 2H), 2.58 (dd, J = 15.6, 6.7 Hz, 1H), 2.48 (dd, J = 15.6, 8.4 Hz, 1H), 2.00 (dd, J = 15.6, 4.7 Hz, 1H), 1.75 – 1.65 (m, 1H), 1.29 (t, J = 7.2 Hz, 3H), 1.21 (t, J = 6.7 Hz, 6H), 0.58 (d, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3, two diastereomers are reported together) δ 172.4, 172.1, 168.6, 168.5, 143.0, 142.5, 133.4, 133.0, 131.2, 131.0, 128.4, 128.3, 123.7, 122.8, 65.8, 64.9, 60.8, 60.6, 37.9, 35.5, 31.6, 31.3, 28.1, 27.8, 16.4, 14.2, 14.1, 13.2; HRMS calcd for C15H20NO3+ 262.1438, observed 262.1441 [M+H]+
Methyl 3-(2-methyl-3-oxoisoindolin-1-yl)-5-phenylpentanoate (3at)
Prepared according to the general procedure (A) using 2-methylisoindolin-1-one 1a (0.1 mmol, 1.0 equiv.) and methyl (E)-5-phenylpent-2-enoate 2t (3.0 equiv.). 13.3 mg, 40% yield, 1 h, d.r.=1.2:1, yellow oil; The dr value was determined by 1H NMR using the integral of methyl groups; The relative stereochemistry could not be assigned; 1H NMR (400 MHz, CDCl3, two diastereomers are reported together) δ 7.84 (t, J = 7.5 Hz, 2H), 7.52 – 7.41 (m, 6H), 7.33 (m, 2H), 7.24 – 7.15 (m, 4H), 7.07 (d, J
= 7.5 Hz, 2H), 4.52 (s, 1H, isomer 1), 4.48 (s, 0.8H, isomer 2), 3.72 (s, 2.5H, isomer 2), 3.61 (s, 3H, isomer 1), 3.06 (s, 3H, isomer 1), 2.97 (s, 2.5H, isomer 2), 2.80 (m, 3H), 2.71 – 2.57 (m, 3H), 2.54 – 2.46 (m, 2H), 1.97 (m, 2H), 1.84 (m, 2H); 13C NMR (100 MHz, CDCl3, two diastereomers are reported together) δ 172.9, 172.8, 168.7, 168.6, 143.0, 142.7, 141.0, 140.9, 133.3, 133.2, 131.2, 131.2, 128.6, 128.5, 128.4, 128.3, 128.3, 126.3, 126.2, 123.8, 123.7, 122.7, 122.6, 63.9, 63.9, 51.9, 51.8, 35.9, 35.5, 35.4, 33.8, 33.8, 33.4, 33.2, 30.5, 27.9, 27.8; HRMS calcd for C21H24NO3+ 338.1751, observed 338.1748 [M+H]+
Methyl 3-cyclohexyl-3-(2-methyl-3-oxoisoindolin-1-yl)propanoate (3au)
Prepared according to the general procedure (A) using 2-methylisoindolin-1-one 1a (0.1 mmol, 1.0 equiv.) and methyl 3-cyclohexylacrylate 2u (3.0 equiv.). 14.5 mg, 46% yield, 1 h, d.r.=2.6:1, yellow
76
solid; m.p. 104-106 °C; The dr value was determined by 1H NMR using the integral of methyl groups;
The relative stereochemistry could not be assigned; 1H NMR (400 MHz, CDCl3, two diastereomers are reported together) δ 7.87 – 7.82 (m, 1.2H, isomer 2), 7.53 – 7.42 (m, 4H), 7.38 (d, J = 7.3 Hz, 1H), 4.71 (d, J = 3.1 Hz, 1H, isomer 1), 4.62 (d, J = 2.6 Hz, 0.4H, isomer 2), 3.62 (s, 1.2H, isomer 2), 3.57 (s, 3H, isomer 1), 3.14 (s, 1.2H, isomer 2), 3.10 (s, 3H, isomer 1), 2.57 (m, 1.4H), 2.40 (m, 0.4H, isomer 2), 2.29 – 2.22 (m, 1.4H), 1.88 (m, 1H), 1.83 – 1.53 (m, 9H), 1.41 – 0.94 (m, 8H); 13C NMR (100 MHz, CDCl3, two diastereomers are reported together) δ 173.6, 173.5, 168.7, 144.2, 142.7, 133.6, 132.8, 131.1, 128.4, 128.2, 123.7, 123.5, 122.9, 122.8, 62.6, 62.0, 51.8, 51.8, 42.7, 41.1, 40.0, 37.4, 32.5, 32.1, 31.9, 31.5, 31.5, 30.3, 28.6, 27.6, 26.4, 26.3, 26.2, 26.2, 26.1, 26.1; HRMS calcd for C19H26NO3+ 316.1907, observed 316.1909 [M+H]+
Methyl 3-(2-methyl-3-oxoisoindolin-1-yl)-5-phenylpent-4-enoate (3av)
Prepared according to the General Procedure (A) using 2-methylisoindolin-1-one 1a (0.1 mmol, 1.0 equiv.) and methyl (2E,4E)-5-phenylpenta-2,4-dienoate 2v (3.0 equiv.). 17.4 mg, 48% yield, 2 h, d.r. = 2.6:1, yellow oil; The dr value was determined by 1H NMR using the integral of methyl groups; The relative stereochemistry could not be assigned; 1H NMR (400 MHz, CDCl3, two diastereomers are reported together) δ 7.85 (d, J = 6.7 Hz, 2H), 7.58 – 7.50 (m, 3H), 7.48 (m, 3H), 7.42 (d, J = 7.5 Hz, 2H), 7.36 (t, J = 7.5 Hz, 2H), 7.30 (d, J = 7.4 Hz, 1H), 7.23 – 7.18 (m, 3H), 7.14 (d, J = 7.5 Hz, 2H), 6.62 (d, J = 16.0 Hz, 1H), 6.48 (d, J = 15.8 Hz, 1H), 6.33 (dd, J = 16.0, 7.1 Hz, 1H), 5.61 (dd, J = 15.8, 8.4 Hz, 1H), 4.59 (dd, J = 7.3, 3.3 Hz, 2H), 3.68 (s, 3H), 3.66 – 3.63 (m, 1H), 3.61 (s, 3H), 3.57 (d, J = 3.5 Hz, 1H), 3.20 (d, J = 6.6 Hz, 6H), 2.70 – 2.52 (m, 2H), 2.00 (qd, J = 15.6, 7.0 Hz, 2H); 13C NMR (100 MHz, CDCl3, two diastereomers are reported together) δ 172.3, 172.0, 168.6, 168.4, 142.4, 142.4, 136.5, 133.4, 133.1, 131.3, 131.2, 128.7, 128.6, 128.6, 128.5, 128.0, 127.7, 127.7, 126.3, 126.3, 126.0, 123.8, 123.8, 122.9, 122.6, 65.1, 64.9, 52.0, 51.9, 41.1, 39.8, 35.3, 32.3, 28.6, 27.8; HRMS calcd for C21H22NO3+ 336.1594, observed 336.1595 [M+H]+
2-Methyl-3-(3-oxo-3-phenyl-1-(p-tolyl)propyl)isoindolin-1-one (3aw)
77
Prepared according to the general procedure (A) using 2-methylisoindolin-1-one 1a (0.1 mmol, 1.0 equiv.) and (E)-1-phenyl-3-(p-tolyl)prop-2-en-1-one 2w (1.5 equiv.). 26.2 mg, 71% yield, 1 h, d.r. = 1.3:1, yellow solid, m.p. 105-110 °C;The dr value was determined by 1H NMR using the integral of methyl groups; The relative stereochemistry could not be assigned; 1H NMR (400 MHz, CDCl3, two diastereomers are reported together) δ 7.93 (d, J = 7.3 Hz, 2H), 7.83 (d, J = 7.5 Hz, 0.8H, isomer 2), 7.75 – 7.70 (m, 3H), 7.62 – 7.32 (m, 11H), 7.20 – 7.11 (m, 3H), 6.92 (d, J = 7.9 Hz, 2H), 6.81 (d, J = 8.1 Hz, 2H), 6.66 (d, J = 7.6 Hz, 0.8H, isomer 2), 4.84 (d, J = 3.4 Hz, 1H, isomer 1), 4.74 (d, J = 3.8 Hz, 0.8H, isomer 2), 4.40 (m, 0.8H, isomer 2), 4.26 (m, 1H, isomer 1), 3.63 (dd, J = 17.7, 8.0 Hz, 1H, isomer 1), 3.27 (m, 0.8H, isomer 2), 3.24 (s, 2.4H, isomer 2), 3.06 (m, 0.8H, isomer 2), 3.04 (s, 3H, isomer 1), 2.69 (dd, J = 17.7, 4.1 Hz, 1H, isomer 1), 2.35 (s, 2.4H, isomer 2), 2.21 (s, 3H, isomer 1);
13C NMR (100 MHz, CDCl3, two diastereomers are reported together) δ 197.7, 168.7, 143.5, 142.6, 137.0, 136.8, 136.7, 136.6, 135.6, 135.3, 133.4, 133.3, 133.2, 132.9, 131.1, 130.9, 129.5, 129.0, 128.7, 128.6, 128.4, 128.4, 128.0, 128.0, 127.9, 127.7, 123.7, 123.6, 123.5, 122.6, 66.5, 66.0, 41.5, 39.7, 38.3, 34.0, 29.0, 28.0, 21.0, 20.9; HRMS calcd for C25H24NO2+ 370.1802, observed 370.1809 [M+H]+
2-Methyl-3-(3-oxo-1-phenylbutyl)isoindolin-1-one (3ax)
Prepared according to the general procedure (A) using 2-methylisoindolin-1-one 1a (0.1 mmol, 1.0 equiv.) and methyl (E)-4-phenylbut-3-en-2-one 2x (3.0 equiv.). 19.9 mg, 68% yield, 1 h, d.r.=1:1, yellow solid; m.p. 93-97 °C; The dr value was determined by 1H NMR using the integral of methyl groups; The relative stereochemistry could not be assigned; 1H NMR (400 MHz, CDCl3, two diastereomers are reported together) δ 7.83 (d, J = 7.5 Hz, 1H), 7.72 (d, J = 7.5 Hz, 0.6H, isomer 2), 7.56 (d, J = 3.3 Hz, 1H), 7.43 – 7.38 (m, 3H), 7.32 (t, J = 7.4 Hz, 2H), 7.23 (d, J = 7.5 Hz, 2H), 7.14 – 7.12 (m, 1H), 6.91 – 6.86 (m, 1H), 6.55 (d, J = 7.6 Hz, 1H), 4.72 (d, J = 3.3 Hz, 0.3H, isomer 2), 4.66 (d, J = 3.8 Hz, 1H, isomer 1), 4.22 (m, 1H, isomer 1), 4.12 – 4.02 (m, 0.3H, isomer 2), 3.22 (s, 3H, isomer 1), δ 3.11 (dd,
78
J = 17.5, 8.6 Hz, 0.3H, isomer 2), 3.01 (s, 1H, isomer 2), 2.75 (dd, J = 17.5, 5.7 Hz, 0.3H, isomer 2), 2.48 (dd, J = 17.6, 9.8 Hz, 1H, isomer 1), 2.17 (dd, J = 17.6, 4.3 Hz, 1H, isomer 1), 2.11 (s, 1H, isomer 2), 2.04 (s, 3H, isomer 1). 13C NMR (100 MHz, CDCl3, two diastereomers are reported together) 206.0, 168.6, 168.6, 143.3, 142.3, 138.6, 138.1, 133.1, 132.9, 131.1, 130.8, 128.8, 128.5, 128.3, 128.2, 127.8, 127.7, 127.5, 127.3, 123.7, 123.5, 123.4, 122.5, 66.4, 66.1, 43.3, 41.9, 40.0, 39.1, 30.6, 30.6, 29.0, 27.9;
HRMS calcd for C19H20NO2+ 294.1489, observed 294.1490 [M+H]+
N,N-Dimethyl-3-(2-methyl-3-oxoisoindolin-1-yl)-3-phenylpropanamide (3ay)
Prepared according to the general procedure (A) using 2-methylisoindolin-1-one 1a (0.1 mmol, 1.0 equiv.) and N,N-dimethylcinnamamide 2y (1.5 equiv.). 21.1 mg, 74% yield, 1 h, d.r. = 1.5:1, colorless oil; The dr value was determined by 1H NMR using the integral of methyl groups; The relative stereochemistry could not be assigned; 1H NMR (400 MHz, CDCl3, two diastereomers are reported together) δ 7.79 (d, J = 7.6 Hz, 0.7H, isomer 2), 7.69 (d, J = 7.5 Hz, 1H), 7.59 – 7.50 (m, 2H), 7.44 – 7.26 (m, 4.6H), 7.22 (d, J = 7.3 Hz, 1.4H), 7.11 – 7.06 (m, 3H), 6.84 – 6.80 (m, 2H), 6.62 (d, J = 7.6 Hz, 0.7H, isomer 2), 4.88 (d, J = 3.6 Hz, 1H, isomer 1), 4.72 (d, J = 3.8 Hz, 0.7H, isomer 2), 4.34 (m, 1H, isomer 1), 4.15 (m, 0.7H, isomer 2), 3.25 (s, 2H, isomer 2), 3.05 (s, 3H, isomer 1), 2.99 (s, 3H, isomer 1), 2.91 (s, 3H, isomer 1), 2.86 (s, 2H, isomer 2), 2.85 – 2.93 (m, 1H, isomer 1), 2.76 (s, 2H, isomer 2), 2.72 – 2.79 (m, 1H, isomer1), 2.33 (dd, J = 16.3, 8.7 Hz, 0.7H, isomer 2), 2.12 (dd, J = 16.3, 5.1 Hz, 0.7H, isomer 2); 13C NMR (100 MHz, CDCl3, two diastereomers are reported together) δ 170.4, 170.2, 168.6, 168.5, 143.5, 142.7, 139.4, 138.6, 133.3, 132.9, 130.9, 130.8, 128.7, 128.7, 128.3, 128.3, 128.2, 128.2, 128.1, 128.1, 127.8, 127.8, 127.2, 127.1, 123.6, 123.5, 123.4, 122.7, 66.6, 65.6, 42.8, 41.2, 37.2, 37.0, 35.6, 35.6, 33.6, 28.8, 28.7, 28.2; HRMS calcd for C20H23N2O2+ 323.1754, observed 323.1752 [M+H]+
3-(2-Methyl-3-oxoisoindolin-1-yl)-3-phenylpropanenitrile (3az)
79
Prepared according to the general procedure (A) using 2-methylisoindolin-1-one 1a (0.1 mmol, 1.0 equiv.) and cinnamonitrile 2z (3.0 equiv.). 20.7 mg, 75% yield, 1 h, d.r. = 1:1, yellow solid, m.p. 78- 84 °C; The dr value was determined by 1H NMR using the integral of methyl groups; The relative stereochemistry could not be assigned; 1H NMR (400 MHz, CDCl3, two diastereomers are reported together) δ 7.82 (d, J = 7.5 Hz, 1H), 7.76 (d, J = 7.5 Hz, 1H), 7.60 (t, J = 7.4 Hz, 1H), 7.56 – 7.38 (m, 6H), 7.33 (dd, J = 23.8, 7.5 Hz, 3H), 7.25 – 7.19 (m, 3H), 6.94 (dd, J = 6.3, 2.7 Hz, 2H), 6.57 (d, J = 7.6 Hz, 0.8H, isomer 2), 4.86 (d, J = 3.7 Hz, 1H, isomer 1), 4.75 (d, J = 3.9 Hz, 1H, isomer 2), 3.92 (m, 0.8H, isomer 2), 3.79 (ddd, J = 8.9, 7.2, 3.7 Hz, 1H, isomer 1), 3.28 (s, 2.4H, isomer 2), 2.97 (s, 3H, isomer 1), 2.87 (dd, J = 17.1, 8.9 Hz, 1H, isomer 1), 2.69 (dd, J = 17.1, 7.2 Hz, 1H, isomer 1), 2.37 – 2.20 (m, 1.6H, isomer 2); 13C NMR (100 MHz, CDCl3, two diastereomers are reported together) δ 168.6, 168.3, 142.2, 140.6, 135.8, 132.9, 132.7, 131.6, 131.2, 129.2, 129.1, 129.1, 128.8, 128.4, 128.3, 128.0, 127.5, 124.1, 123.9, 123.4, 122.3, 117.9, 117.9, 110.0, 65.9, 65.3, 44.2, 42.0, 29.3, 28.1, 18.5, 14.7;
HRMS calcd for C18H17N2O+ 277.1335, observed 277.1337 [M+H]+
Diethyl 2-(2-methyl-3-oxoisoindolin-1-yl)-2-phenylethyl)phosphonate (3aaa)
Prepared according to the general procedure (A) using 2-methylisoindolin-1-one 1a (0.1 mmol, 1.0 equiv.) and diethyl (E)-styrylphosphonate 2aa (1.5 equiv.). 24.0 mg, 62% yield, 1 h, d.r. = 1.5:1, clear oil; The dr value was determined by 1H NMR using the integral of methyl groups; The relative stereochemistry could not be assigned; 1H NMR (400 MHz, CDCl3, two diastereomers are reported together) δ 7.77 (d, J = 7.4 Hz, 1H), 7.65 (m, 2H), 7.54 (t, J = 7.5 Hz, 1H), 7.45 – 7.34 (m, 4H), 7.29 (m, 3H), 7.09 – 6.98 (m, 4H), 6.72 (t, J = 6.0 Hz, 3H), 4.80 (d, J = 3.9 Hz, 1H, isomer 1), 4.63 (t, J = 3.4 Hz, 0.8H, isomer 2), 4.04 – 3.66 (m, 10H, isomer 1 and 2), 3.28 (s, 2.4H, isomer 2), 3.11 (s, 3H, isomer 1), 2.45 – 2.36 (m, 2H), 1.78 (m, 1H), 1.58 (m, 1H), 1.23 (t, J = 7.0 Hz, 3H), 1.13 (t, J = 7.1 Hz, 6H), 1.05 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3, two diastereomers are reported together) δ 168.6, 168.2, 142.7, 141.7, 137.6, 137.5, 137.0, 136.9, 133.4, 133.0, 130.9, 130.8, 129.5, 128.8, 128.50, 128.46, 128.0, 127.9, 127.6, 127.5, 123.7, 123.54, 123.48, 122.9, 67.2, 67.0, 66.0, 65.9, 61.9, 61.8, 61.71, 61.66, 61.59, 61.53, 61.47, 41.42, 41.39, 40.24, 40.22, 28.9, 28.4, 28.0, 27.5, 22.8, 21.4, 16.32, 16.28, 16.26, 16.21, 16.19, 16.17, 16.13, 16.11; HRMS calcd for C21H27NO4P+ 388.1672, observed 388.1671 [M+H]+
80
2-Methyl-3-(1-phenyl-2-(phenylsulfonyl)ethyl)isoindolin-1-one (3aab)
Prepared according to the general procedure (A) using 2-methylisoindolin-1-one 1a (0.1 mmol, 1.0 equiv.) and (E)-(2-(phenylsulfonyl)vinyl)benzene 2ab (1.5 equiv.). 29.4 mg, 75% yield, 1 h, d.r. = 1.2:1, clear oil; The dr value was determined by 1H NMR using the integral of methyl groups; The relative stereochemistry could not be assigned; 1H NMR (400 MHz, CDCl3, two diastereomers are reported together) δ 7.80 – 7.74 (m, 3H), 7.71 – 7.60 (m, 4H), 7.54 (m, 3H), 7.46 – 7.31 (m, 7H), 7.25 (m, 2H), 7.14 – 7.10 (m, 2H), 7.02 (t, J = 7.3 Hz, 0.8H, isomer 2), 6.94 (t, J = 7.5 Hz, 2H, isomer 1), 6.72 (d, J
= 7.6 Hz, 0.8H, isomer 2), 6.57 (d, J = 7.6 Hz, 2H, isomer 1), 4.99 (d, J = 3.7 Hz, 1H, isomer 1), 4.66 (d, J = 3.6 Hz, 0.8H, isomer 2), 4.17 (m, 0.8H, isomer 2), 4.09 (m, 1H, isomer 1), 3.73 – 3.67 (m, 2H, isomer 1), 3.25 (dd, J = 14.9, 10.6 Hz, 0.8H, isomer 2), 3.20 (s, 2.4H, isomer 2), 3.09 (s, 3H, isomer 1), 2.84 (dd, J = 14.8, 2.3 Hz, 0.8H, isomer 2); 13C NMR (100 MHz, CDCl3, two diastereomers are reported together) δ 168.4, 168.2, 142.1, 141.2, 139.3, 139.2, 135.3, 134.8, 133.8, 133.7, 133.3, 132.7, 131.2, 131.1, 129.3, 129.1, 128.8, 128.8, 128.7, 128.5, 128.2, 128.0, 127.9, 127.9, 127.8, 127.8, 123.8, 123.8, 123.4, 122.7, 66.3, 65.0, 57.2, 52.5, 41.8, 40.6, 28.6, 27.9; HRMS calcd for C23H22NO3S+ 392.1315, observed 392.1317 [M+H]+
N,N-Diethyl-2-(2-methyl-3-oxoisoindolin-1-yl)-2-phenylethane-1-sulfonamide (3aac)
Prepared according to the general procedure (A) using 2-methylisoindolin-1-one 1a (0.1 mmol, 1.0 equiv.) and (E)-N,N-diethyl-3-phenylprop-2-ene-1-sulfonamide 2ac (1.5 equiv.). 27.4 mg, 71% yield, 1 h, d.r. = 1.1:1, yellow oil; The dr value was determined by 1H NMR using the integral of methyl groups;
The relative stereochemistry could not be assigned; 1H NMR (400 MHz, CDCl3, two diastereomers are reported together) δ 7.81 – 7.74 (m, 0.7H, isomer 2), 7.71 (d, J = 7.6 Hz, 1H), 7.66 (d, J = 7.5 Hz, 1H), 7.58 (t, J = 7.5 Hz, 1H), 7.49 – 7.30 (m, 5H), 7.27 – 7.24 (m, 1H), 7.16 – 7.01 (m, 3H), 6.83 (d, J = 7.3 Hz, 0.7H, isomer 2), 6.68 (dd, J = 7.5, 1.7 Hz, 2H), 5.06 (d, J = 3.8 Hz, 1H, isomer 1), 4.76 (d, J = 3.6
81
Hz, 0.7H, isomer 2), 4.17 (m, 0.7H, isomer 2), 4.06 (m, 1H, isomer 1), 3.57 (dd, J = 14.2, 7.9 Hz, 1H, isomer 1), 3.46 (dd, J = 14.2, 6.3 Hz, 1H, isomer 1), 3.35 (s, 2H, isomer 2), 3.23 (m, 2H), 3.16 (s, 3H, isomer 1), 3.15 – 2.94 (m, 6H), 2.74 (dd, J = 14.5, 3.1 Hz, 0.7H, isomer 2), 1.16 (t, J = 7.1 Hz, 6H, isomer 1), 1.07 (t, J = 7.1 Hz, 4.2H, isomer 2); 13C NMR (100 MHz, CDCl3, two diastereomers are reported together) δ 168.5, 168.2, 142.4, 141.7, 136.3, 135.7, 133.4, 132.7, 131.0, 128.7, 128.7, 128.6, 128.5, 128.2, 128.0, 127.9, 127.9, 123.8, 123.7, 123.4, 123.0, 66.1, 64.5, 53.2, 48.4, 42.4, 42.2, 41.8, 41.6, 28.4, 28.4, 14.7, 14.6; HRMS calcd for C21H27N2O3S+ 387.1737, observed 387.1737 [M+H]+
Methyl 3-((8R,9S,13S,14S)-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H- cyclopenta[a]phenanthren-3-yl)-3-(2-methyl-3-oxoisoindolin-1-yl)propanoate (3aad)
Prepared according to the general procedure (A) using 2-methylisoindolin-1-one 1a (0.1 mmol, 1.0 equiv.) and methyl (E)-3-((8R,9S,13S,14S)-13-methyl 17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro- 6H-cyclopenta[a]phenanthren-3-yl)acrylate 2d (1.5 equiv.). 32.5 mg, 67% yield, 1 h, d.r. = 1:1, colorless oil; The dr value was determined by 1H NMR using the integral of methyl groups; The relative stereochemistry could not be assigned; 1H NMR (400 MHz, CDCl3, two diastereomers are reported together) δ 7.82 (d, J = 7.5 Hz, 1H), 7.73 (d, J = 7.5 Hz, 1H), 7.65 (d, J = 7.6 Hz, 1H), 7.57 (t, J = 7.4 Hz, 1H), 7.49 – 7.39 (m, 2H), 7.37 – 7.29 (m, 2H), 7.01 (t, J = 10.0 Hz, 3H), 6.71 – 6.52 (m, 3H), 4.71 (d, J = 3.6 Hz, 1H, isomer 1), 4.65 (d, J = 3.6 Hz, 1H, isomer 2), 4.10 – 4.03 (m, 1H, isomer 2), 3.94 (m, 1H, isomer 1), 3.66 (s, 3H, isomer 1), 3.58 (s, 3H, isomer 2), 3.26 (s, 3H, isomer 2), 3.03 (s, 3H, isomer 1), 2.96 – 2.84 (m, 3H), 2.81 – 2.60 (m, 3H), 2.53 – 2.44 (m, 2H), 2.36 – 1.89 (m, 15H), 1.71 – 1.39 (m, 15H), 0.95 (s, 3H, isomer 2), 0.89 (s, 3H, isomer 1); 13C NMR (100 MHz, CDCl3, two diastereomers are reported together) δ 220.8, 220.7, 172.4, 172.2, 168.5, 168.5, 143.1, 142.0, 139.0, 138.8, 136.9, 136.2, 135.6, 134.9, 134.9, 133.3, 132.9, 131.0, 130.7, 129.0, 128.9, 128.5, 128.4, 125.7, 125.2, 125.1, 125.0, 123.6, 123.4, 122.8, 66.5, 65.6, 52.0, 51.9, 50.5, 50.5, 48.0, 47.9, 44.3, 44.1, 42.7, 40.7, 40.6, 38.1, 37.8, 35.8, 35.3, 31.5, 30.6, 29.5, 29.2, 28.7, 27.9, 26.5, 26.4, 25.7, 25.6, 25.5, 25.4, 21.6, 13.9, 13.8; HRMS calcd for C31H36NO4+ 486.2639, observed 486.2640 [M+H]+
Methyl 2-((1S,2R,3S)-1-benzyl-2'-methyl-3'-oxo-1,3-dihydrospiro[indene-2,1'-isoindolin]-3- yl)acetate (3aae)