LETTER
Guo, Y.; Guo, J.; Pease, L. J.; Li, J.; Marcotte, P. A.; Glaser,
Synthesis of Alkyl Indole-2-Carboxylates
131
solid; mp 65–67 °C. IR (Nujol): 749, 1250, 1675, 3326 cm–1.
1H NMR (400 MHz, CDCl3): δ = 0.88 (t, J = 6.8 Hz, 3 H),
1.07–1.43 (m, 12 H), 1.62–1.73 (m, 2 H), 3.06–3.14 (m,
2 H), 3.95 (s, 3 H), 7.11–7.16 (m, 1 H), 7.28–7.40 (m, 2 H),
7.69 (dd, J = 0.9, 9.0 Hz, 1 H), 8.75 (br s, 1 H). 13C NMR
(100 MHz, CDCl3): δ = 14.4, 22.9, 24.9, 29.6, 29.8, 29.9,
30.0, 31.3, 32.2, 51.9, 111.9, 120.1, 121.2, 123.0, 125.8,
126.0, 128.2, 136.2, 163.1. MS (EI, 70 eV): m/z (%) = 301
[M]+, 242, 188 (100), 156, 128. Anal. Calcd for C19H27NO2
(301.42): C, 75.71; H, 9.03; N, 4.65. Found: C, 75.74; H,
9.05; N, 4.64.
K. B.; Tapang, P.; Albert, D. H.; Richardson, P. L.;
Davidsen, S. K.; Michaelides, M. R. Bioorg. Med. Chem.
2003, 13, 1897.
(11) (a) Japp, F. R.; Klingemann, F. Ber. Dtsch. Chem. Ges.
1887, 20, 2942. (b) Delfourne, E.; Roubin, C.; Bastide, J.
J. Org. Chem. 2000, 65, 5476. (c) Meyer, M. D.; Kruse, L. I.
J. Org. Chem. 1984, 49, 3195.
(12) (a) Knittel, D. Synthesis 1985, 186. (b) Hemetsberger, H.;
Knittel, D. Monatsh. Chem. 1972, 103, 194. (c) Venable, J.
D.; Cai, H.; Chai, W.; Dvorak, C. A.; Grice, C. A.;
Jablonowski, J. A.; Shah, C. R.; Kwok, A. K.; Ly, K. S.; Pio,
B.; Wei, J.; Desai, P. J.; Jiang, W.; Nguyen, S.; Ling, P.;
Wilson, S. J.; Dunford, P. J.; Thurmond, R. L.; Lovenberg,
T. W.; Karlsson, L.; Carruthers, N. I.; Edwards, J. P. J. Med.
Chem. 2005, 48, 8289.
Ethyl 3-(4-Cyanobutyl)-1H-indole-2-carboxylate (5e):
White solid; mp 115–117 °C. IR (Nujol): 752, 1021, 1250,
1697, 2248, 3374 cm–1. 1H NMR (400 MHz, CDCl3): δ =
1.44 (t, J = 7.3 Hz, 3 H), 1.67–1.78 (m, 2 H), 1.81–1.92 (m,
2 H), 2.36 (t, J = 6.8 Hz, 2 H), 3.17 (t, J = 7.3 Hz, 2 H), 4.43
(q, J = 7.3 Hz, 2 H), 7.12–7.18 (m, 1 H), 7.29–7.42 (m, 2 H),
7.66 (d, J = 8.1 Hz, 1 H), 8.81 (br s, 1 H). 13C NMR (100
MHz, CDCl3): δ = 14.7, 17.3, 23.9, 25.3, 29.9, 61.1, 112.1,
120.0, 120.5, 120.8, 123.5, 124.0, 125.9, 128.0, 136.1,
162.4. MS (EI, 70 eV): m/z (%) = 270 [M]+, 224, 202, 197,
156 (100), 128, 101, 77, 29. Anal. Calcd for C16H18N2O2
(270.33): C, 71.09; H, 6.71; N, 10.36. Found: C, 71.06; H,
6.70; N, 10.40.
Cyclopentyl 3-Ethyl-5-methyl-1H-indole-2-carboxylate
(5f): White solid; mp 113–115 °C. IR (Nujol): 783, 799,
1255, 1679, 3314 cm–1. 1H NMR (400 MHz, CDCl3): δ =
1.26 (t, J = 7.7 Hz, 3 H), 1.58–2.06 (m, 8 H), 2.45 (s, 3 H),
3.06 (q, J = 7.7 Hz, 2 H), 5.44–5.50 (m, 1 H), 7.14 (dd, J =
1.3, 8.5 Hz, 1 H), 7.24–7.28 (m, 1 H), 7.45 (s, 1 H), 8.61 (br
s, 1 H). 13C NMR (100 MHz, CDCl3): δ = 15.8, 18.4, 21.8,
24.0, 33.2, 77.8, 111.6, 120.2, 123.5, 126.1, 127.6, 128.1,
129.4, 134.5, 162.7. MS (EI, 70 eV): m/z = 271 [M]+, 203,
188, 186, 185 (100), 170, 142, 115, 41 Anal Calcd. for
C17H21NO2 (271.35): C, 75.25; H, 7.80; N, 5.16. Found: C,
75.29; H, 7.82; N, 5.13.
Ethyl 5-Methyl-3-phenethyl-1H-indole-2-carboxylate
(5g): White solid; mp 132–134 °C. IR (Nujol): 755, 779,
798, 1601, 1678, 3309 cm–1. 1H NMR (400 MHz, CDCl3):
δ = 1.44 (t, J = 7.3 Hz, 3 H), 2.47 (s, 3 H), 2.91–2.99 (m,
2 H), 3.34–3.41 (m, 2 H), 4.41 (q, J = 7.3 Hz, 2 H), 7.13–
7.33 (m, 7 H), 7.41 (s, 1 H), 8.75 (br s, 1 H). 13C NMR (100
MHz, CDCl3): δ = 14.8, 21.8, 27.4, 37.6, 60.9, 111.7, 120.2,
123.6, 123.8, 126.1, 127.7, 128.2, 128.5, 128.8, 129.6,
134.5, 142.6, 162.7. MS (EI, 70 eV): m/z (%) = 307 [M]+,
216 (100), 170, 142, 115, 91, 65, 39, 29. Anal. Calcd for
C20H21NO2 (307.39): C, 78.15; H, 6.89; N, 4.56. Found: C,
78.19; H, 6.91; N, 4.53.
(13) The 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) bound to
polystyrene (3 mmol/g) was purchased from Sigma–Aldrich
(01961-5G-F) and used directly without any manipulation.
(14) Synthesis of Indoles 5; General Procedure: o-
Bromoaniline 1 (0.5 mmol) and β-nitroacrylate 2 (0.5 mmol)
were stirred at 70 °C for 24 h, then MeCN (3 mL) and TBD
(1 mmol, 333 mg) were added and the resulting solution was
stirred at r.t. for 5 h. Finally, after TBD filtration (washing
with EtOAc) and solvent evaporation, the crude material 4
was dissolved in DMF (4 mL), treated with Pd2(dba)3 (32
mg, 0.034 mmol), P(o-Tol)3 (42 mg, 0.138 mmol), Et3N
(0.96 mL, 6.9 mmol), and heated at 110 °C for 12 h. After
cooling, the reaction was quenched with 2 M HCl (10 mL),
extracted with Et2O (3 × 30 mL) and the organic extracts
were dried over Na2SO4. After filtration and solvent
evaporation at reduced pressure, the crude indole 5 was
purified by flash chromatography (hexane–EtOAc).
Ethyl 3-Ethyl-1H-indole-2-carboxylate (5a): White solid;
mp 91–93 °C. IR (Nujol): 747, 1257, 1673, 3329 cm–1. 1H
NMR (400 MHz, CDCl3): δ = 1.29 (t, J = 7.7 Hz, 3 H), 1.44
(t, J = 7.3 Hz, 3 H), 3.14 (q, J = 7.7 Hz, 2 H), 4.43 (q, J =
7.3 Hz, 2 H), 7.14 (t, J = 7.7 Hz, 1 H), 7.32 (t, J = 8.1 Hz,
1 H), 7.38 (d, J = 7.7 Hz, 1 H), 7.70 (d, J = 8.1 Hz, 1 H), 8.78
(br s, 1 H). 13C NMR (100 MHz, CDCl3): δ = 14.7, 15.7,
18.3, 60.9, 111.9, 120.1, 121.0, 123.0, 125.7, 127.1, 127.9,
136.2, 162.7. MS (EI, 70 eV): m/z (%) = 217 (100) [M]+,
202, 188, 171, 170, 156, 143, 128, 115, 101, 89, 77, 63, 51,
39, 29. Anal. Calcd for C13H15NO2 (217.26): C, 71.87; H,
6.96; N, 6.45. Found: C, 71.91; H, 7.00; N, 6.41.
Ethyl 3-Methyl-1H-indole-2-carboxylate (5b): Pale-
orange solid; mp 128–130 °C. IR (Nujol): 744, 780, 1257,
1683, 3326 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.45 (t,
J = 7.3 Hz, 3 H), 2.63 (s, 3 H), 4.44 (q, J = 7.3 Hz, 2 H),
7.08–7.44 (m, 3 H), 7.68 (d, J = 8.1 Hz, 1 H), 8.73 (br s,
1 H). 13C NMR (100 MHz, CDCl3): δ = 10.1, 14.7, 60.9,
111.8, 120.1, 120.4, 121.0, 123.6, 125.8, 128.8, 136.0,
162.9. MS (EI, 70 eV): m/z (%) = 203 [M]+, 174, 157 (100),
129, 102, 77, 51, 29. Anal. Calcd for C12H13NO2 (203.24): C,
70.92; H, 6.45; N, 6.89. Found: C, 70.98; H, 6.48; N, 6.86.
Propyl 3-Methyl-1H-indole-2-carboxylate (5c): Pale-
yellow solid; mp 102–105 °C. IR (Nujol): 744, 780, 1242,
1682, 3328 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.06 (t,
J = 7.3 Hz, 3 H), 1.77–1.89 (m, 2 H), 2.62 (s, 3 H), 4.33 (t, J
= 6.8 Hz, 2 H), 7.14 (t, J = 7.3 Hz, 1 H), 7.29–7.40 (m, 2 H),
7.67 (d, J = 8.1 Hz, 1 H), 8.70 (br s, 1 H). 13C NMR (100
MHz, CDCl3): δ = 10.2, 10.9, 22.4, 66.6, 111.8, 120.1,
120.3, 121.0, 123.7, 125.8, 128.8, 136.1, 163.1. MS (EI, 70
eV): m/z (%) = 217 [M]+, 174, 157 (100), 129, 102, 77, 51,
41, 29. Anal. Calcd for C13H15NO2 (217.26): C, 71.87; H,
6.96; N, 6.45. Found: C, 71.84; H, 6.93; N, 6.47.
Ethyl 5-Methoxy-3-[(2-phenyl-1,3-dioxolan-2-
yl)methyl]-1H-indole-2-carboxylate (5h): White solid; mp
144–146 °C. IR (Nujol): 752, 762, 779, 1022, 1258, 1539,
1668, 3326 cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.37 (t,
J = 7.3 Hz, 3 H), 3.68–3.85 (m, 9 H), 4.27 (q, J = 7.3 Hz,
2 H), 6.96 (dd, J = 2.5, 8.5 Hz, 1 H), 7.11 (d, J = 2.5 Hz,
1 H), 7.22–7.30 (m, 4 H), 7.36–7.42 (m, 2 H), 8.72 (br s,
1 H). 13C NMR (100 MHz, CDCl3): δ = 14.6, 36.5, 55.9,
60.8, 64.9, 102.9, 110.7, 112.4, 117.0, 117.7, 125.8, 126.2,
127.9, 129.5, 131.2, 142.9, 154.4, 162.5. MS (EI, 70 eV):
m/z (%) = 381 [M]+, 232, 186, 149 (100), 105, 77. Anal.
Calcd for C22H23NO5 (381.42): C, 69.28; H, 6.08; N, 3.67.
Found: C, 69.32; H, 6.10; N, 3.66.
Ethyl 3-(3-Acetoxypropyl)-5-methoxy-1H-indole-2-
carboxylate (5i): Pale-yellow solid; mp 74–76 °C. IR
(Nujol): 782, 1220, 1674, 1732, 3327 cm–1. 1H NMR (400
MHz, CDCl3): δ = 1.42 (t, J = 7.3 Hz, 3 H), 1.97–2.07 (m,
2 H), 2.05 (s, 3 H), 3.11–3.18 (m, 2 H), 3.87 (s, 3 H), 4.12 (t,
J = 6.8 Hz, 2 H), 4.41 (q, J = 7.3 Hz, 2 H), 6.97–7.04 (m,
Methyl 3-Nonyl-1H-indole-2-carboxylate (5d): White
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 128–132