1.7.2 EXPERIMENTAL PROCEDURES AND SPECTROSCOPIC DATA
1.7.2.1 Experimental Procedures and Spectroscopic Data for the Synthesis of Tetralone Substrates
Isopropyl 1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (56b). A solution of methyl ester 5216 (0.75 g, 3.7 mmol, 1 equiv), Bu2SnO (0.091 g, 0.37 mmol, 0.1 equiv), and IPA (15 mL) was heated under reflux for 72 h then concentrated onto silica and purified by silica gel flash column chromatography (3% Et2O/hexanes) to give isopropyl ester 56b (1:1 mixture of enol/keto isomers) as a colorless oil (0.62 g, 72% yield): 1H NMR (400 MHz, CDCl3) δ 12.56 (s, 0.5H), 8.05 (ddd, J = 7.8, 1.5, 0.6 Hz, 0.5H), 7.81 – 7.77 (m, 0.5H), 7.49 (td, J = 7.8, 1.5 Hz, 0.5H), 7.35 – 7.23 (m, 2H), 7.20 – 7.14 (m, 0.5H), 5.14 (dp, J = 17.1, 6.2 Hz, 1H), 3.56 (dd, J = 10.5, 4.7 Hz, 0.5H), 3.13 – 2.93 (m, 1H), 2.81 (dd, J = 8.6, 6.9 Hz, 1H), 2.60 – 2.52 (m, 1H), 2.53 – 2.43 (m, 0.5H), 2.35 (ddt, J = 13.5, 5.7, 4.7 Hz, 0.5H), 1.32 (d, J = 6.3 Hz, 3H), 1.28 (dd, J = 6.3, 2.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 193.6, 172.5, 170.0, 165.0, 143.8, 139.5, 133.9, 132.0, 130.5, 130.3, 128.9, 127.8, 127.5, 127.0, 126.7, 124.4, 97.5, 69.0, 68.2, 54.9, 27.9, 27.8, 26.5, 22.2 (2C), 21.9, 21.9, 20.7; IR (Neat Film, NaCl) 3070, 3027, 2980, 2937, 2847, 1736, 1687, 1644, 1618, 1571, 1454, 1384, 1322, 121, 1214, 1106, 1084, 949, 831, 770, 744 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C14H17O3 [M+H]+: 233.1172, found 233.1174.
O O O
2-(Trimethylsilyl)ethyl 1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (56c). A solution of LiHMDS (1.83 g, 10.9 mmol, 2 equiv) in THF (20 mL) was added dropwise to a solution of 1-tetralone (0.804 g, 5.50 mmol, 1 equiv) in THF (20 mL) via cannula at –78 °C. After 1.5 h at –78 °C, a solution of 2-(trimethylsilyl)ethyl 1H-imidazole-1- carboxylate (1.39 g, 6.55 mmol, 1.2 equiv) in THF (5 mL) was then added. The resulting reaction mixture was allowed to warm to ambient temperature and stirred for 18 h. The reaction was quenched with the addition of saturated NH4Cl aqueous solution (40 mL) and the aqueous layer was then extracted with Et2O (3 x 50 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by CombiFlash EZ Prep (12 g silica, 1à5% Et2O/hexanes, 30 min) to provide ester 56c (3:1 mixture of enol/keto isomers) as a colorless oil (0.40 g, 25%): 1H NMR (400 MHz, CDCl3) δ 12.57 (s, 0.75H), 8.08 (dd, J
= 7.8, 1.4 Hz, 0.25H), 7.83 (dd, J = 7.8, 1.4 Hz, 0.75H), 7.52 (td, J = 7.8, 1.4 Hz, 0.25H), 7.39 – 7.24 (m, 2H), 7.23 – 7.16 (m, 0.75H), 4.41 – 4.14 (m, 2H), 3.61 (dd, J = 10.3, 4.7 Hz, 0.25H), 3.14 – 2.97 (m, 0.5H), 2.83 (dd, J = 8.9, 6.6 Hz, 1.5H), 2.64 – 2.57 (m, 1.5H), 2.56 – 2.47 (m, 0.25H), 2.38 (m, 0.25H), 1.24 – 0.99 (m, 2H), 0.10 (s, 9H); 13C NMR (101 MHz, CDCl3) δ 193.4, 173.1, 170.5, 165.1, 155.5, 143.8, 139.5, 134.0, 131.9, 131.0, 130.2, 128.9, 127.9, 127.5, 127.0, 126.7, 124.4, 97.2, 66.2, 63.8, 62.9, 54.8, 27.9, 27.8, 26.5, 20.7, 17.7, 17.5, 17.5, –1.3, –1.39, –1.41; IR (Neat Film, NaCl) 3071, 3028, 2954, 2898, 2846, 1739, 1689, 1644, 1620, 1571, 1454, 1394, 1355, 1325, 1270, 1212,
O O O
TMS
1175, 1133, 1084, 859, 837, 769 cm-1; HRMS (FAB+) m/z calc’d for C16H23O3Si [M+H]+: 291.1417, found 291.1421.
Ethyl 6-(dimethylamino)-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (56e).
To a suspension of NaH (0.98 g, 29 mmol, 3.7 equiv, 60 wt %) in THF (10 mL) was added diethyl carbonate (1.9 mL, 16 mmol, 2 equiv). The reaction mixture was brought to reflux at which point a solution of 6-(dimethylamino)-3,4-dihydronaphthalene-1(2H)-one (1.5 g, 7.9 mmol, 1 equiv) in THF (10 mL) was added dropwise via addition funnel over 15 min. The reaction mixture was heated to reflux for an additional 18 h then allowed to cool to ambient temperature, whereupon it was quenched with conc. AcOH (10 mL) and diluted with Et2O (30 mL). The organic layer was washed with brine (5 x 10 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by CombiFlash EZ Prep (12 g silica, 10à20% EtOAc/hexanes, 30 min) to provide dimethylamine 56e (keto isomer) as a tan solid (1.36 g, 66%): 1H NMR (400 MHz, CDCl3) δ 7.95 (d, J = 9.0 Hz, 1H), 6.60 (dd, J = 9.0, 2.6 Hz, 1H), 6.36 (d, J = 2.6 Hz, 1H), 4.32 – 4.12 (m, 2H), 3.52 (dd, J = 10.2, 4.7 Hz, 1H), 3.06 (s, 6H), 2.99 – 2.83 (m, 2H), 2.44 (m, 1H), 2.29 (m, 1H), 1.29 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 191.4, 171.2, 153.8, 145.9, 130.1, 128.5, 120.8, 110.6, 109.3, 61.2, 54.5, 40.2, 28.6, 26.8, 14.4; IR (Neat Film, NaCl) 2935, 1735, 1660, 1593, 1521, 1449, 1372, 1308, 1197, 1121, 1084, 923 cm-1; HRMS (FAB+) m/z calc’d for C15H20NO3 [M+H]+: 262.1443, found 262.1473.
O
OEt O
Me2N
Ethyl 7-nitro-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (56g). A solution of LiHMDS (1.8 g, 11 mmol, 2.1 equiv) in THF (20 mL) was added dropwise to a solution of 7-nitro-3,4-dihydronaphthalene-1(2H)-one (1.0 g, 5.2 mmol, 1 equiv) in THF (20 mL) via cannula at –78 °C. The reaction was stirred for 1.5 h at –78 °C, whereupon ethyl cyanoformate (0.61 g, 6.2 mmol, 1.2 equiv) was added. The resulting reaction mixture was allowed to warm to ambient temperature and was stirred for 18 h. The reaction was quenched with the addition of saturated NH4Cl aqueous solution (40 mL) and the aqueous layer was then extracted with Et2O (3 x 50 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by silica gel flash column chromatography (8%
EtOAc/hexanes) to provide nitroarene 56g (enol isomer) as a colorless solid (114 mg, 8%): 1H NMR (400 MHz, CDCl3) δ 12.45 (s, 1H), 8.65 (d, J = 2.4 Hz, 1H), 8.20 (dd, J = 8.3, 2.4 Hz, 1H), 7.37 (dt, J = 8.3, 1.0 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 2.95 (t, J = 7.8 Hz, 2H), 2.66 (dd, J = 8.8, 6.9 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 172.4, 162.5, 147.3, 146.3, 131.6, 128.5, 125.0, 119.6, 98.9, 61.2, 28.0, 20.2, 14.4; IR (Neat Film, NaCl) 2996, 2962, 2907, 2858, 1755, 1648, 1514, 1401, 1344, 1270, 1252, 1216, 1068, 1027, 907, 806, 745 cm-1; HRMS (FAB+) m/z calc’d for C13H14NO5
[M+H]+: 264.0872, found 264.0871. Please note that a minor amount of keto isomer is present in the spectra, which does not impact the characterization.
O
OEt O O2N
Ethyl 6-bromo-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (56h). A solution of LiHMDS (1.8 g, 11 mmol, 2.1 equiv) in THF (20 mL) was added dropwise to a solution of 6-bromo-3,4-dihydronaphthalene-1(2H)-one16 (1.2 g, 5.2 mmol, 1 equiv) in THF (20 mL) via cannula at –78 °C. The reaction was stirred for 1.5 h at –78 °C, whereupon ethyl cyanoformate (0.61 g, 6.2 mmol, 1.2 equiv) was added. The resulting reaction mixture was allowed to warm to ambient temperature and was stirred for 18 h.
The reaction was quenched with the addition of saturated NH4Cl aqueous solution (40 mL) and the aqueous layer was then extracted with Et2O (3 x 50 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by CombiFlash EZ Prep (12 g silica, 5à20% EtOAc/hexanes, 30 min) to provide bromide 56h (4:1 mixture of enol/keto isomers) as a tan solid (0.63 g, 41%): 1H NMR (400 MHz, CDCl3) δ 12.44 (s, 0.8H), 7.90 (d, J = 8.3 Hz, 0.2H), 7.64 (d, J = 8.3 Hz, 0.8H), 7.46 – 7.38 (m, 1.2H), 7.33 (dd, J = 2.0, 1.0 Hz, 0.8H), 4.27 (p, J = 7.0 Hz, 2H), 3.58 (dd, J = 10.0, 4.7 Hz, 0.2H), 3.09 – 2.90 (m, 0.4H), 2.78 (dd, J = 8.9, 6.7 Hz, 1.6H), 2.62 – 2.52 (m, 1.6H), 2.53 – 2.27 (m, 0.4H), 1.34 (t, J = 7.1 Hz, 2.4H), 1.29 (t, J = 7.1 Hz, 0.6H); 13C NMR (101 MHz, CDCl3) δ 192.5, 172.7, 170.0, 164.2, 145.4, 141.4, 131.8, 130.7, 130.6, 130.0 129.9, 129.6, 129.3, 129.1, 126.0, 124.9, 97.4, 61.6, 60.8, 54.4, 27.7, 27.5, 26.3, 20.5, 14.4, 14.3; IR (Neat Film, NaCl) 2979, 2958, 2902, 2848, 1740, 1689, 1645, 1616, 1588, 1558, 1479, 1406, 1377, 1267, 1214, 1195, 1096, 1025, 845, 829, 758 cm-1; HRMS (FAB+) m/z calc’d for C13H14BrO3 [M+H]+: 297.0126, found 297.0134.
O
OEt O
Br
2-Acetyl-3,4-dihydronaphthalen-1(2H)-one (56k). To a suspension of NaH (0.49 g, 21 mmol, 2 equiv, 60 wt %) in EtOAc (2 mL) cooled to 0 °C, a solution of 1-tetralone (1.5 g, 10 mmol, 1 equiv) in toluene (0.5 mL) was added dropwise. After H2 evolution ceased, the resulting solution was heated to 40 °C for 3 h. The reaction mixture was then allowed to cool to ambient temperature, whereupon it was quenched with MeOH (5 mL), poured onto H2O (20 mL), neutralized with conc. HCl, and extracted with CH2Cl2 (3 x 30 mL).
The combined organic extracts were washed with brine (30 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude residue was purified by silica gel flash column chromatography (10% EtOAc/hexanes) to give ketone 56k (enol isomer) as a pale yellow solid (0.51 g, 26%): 1H NMR (400 MHz, CDCl3) δ 7.94 (dd, J = 7.7, 1.4 Hz, 1H), 7.40 (td, J = 7.7, 1.4 Hz, 1H), 7.36 – 7.29 (m, 1H), 7.20 (dq, J = 7.7, 0.7 Hz, 1H), 2.87 (dd, J = 8.5, 6.3 Hz, 2H), 2.68 – 2.59 (m, 2H), 2.24 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 194.0, 177.0, 140.9, 132.0, 131.2, 127.7, 127.0, 126.0, 106.1, 28.4, 24.1, 22.9;
IR (Neat Film, NaCl) 3061, 2940, 2893, 2838, 1598, 1567, 1414, 1354, 1294, 1213, 1156, 1079, 1033, 974, 902, 788, 737, 548 cm-1; HRMS (MM: ESI-APCI+) m/z calc’d for C12H13O2 [M+H]+: 189.0910, found 189.0908. Please note that the exchangeable enol proton was not observed in the 1H NMR spectrum.
O O