The Journal of Organic Chemistry
ARTICLE
(CDCl3, 125 MHz) 161.7, 159.5, 159.0, 138.9, 135.3, 131.8, 130.8,
129.4, 124.9, 121.9, 121.7, 121.6, 115.3, 113.8, 112.9, 112.5, 61.0, 55.1,
29.0, 14.0; ESI-MS m/z 377.3 [M þ H]þ; HR-MS (ESI) calcd for
C22H21N2O4þ [M þ H] þ requires 377.1496, found 377.1500.
Ethyl 5,8-dimethyl-4-oxo-3-phenyl-4,5-dihydro-1H-pyrrolo[3,2-c]-
Diethyl 3-butyl-5-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]-
quinolin-2-ylphosphonate (6n): 1H NMR (CDCl3, 400 MHz) δ
11.57 (s, 1H), 8.40 (d, J = 7.6 Hz, 1H), 7.50 (t, J = 7.6 Hz, 1H), 7.41
(d, J = 8.0 Hz, 1H), 7.24 (t, J = 7.2 Hz, 1H), 4.20ꢀ4.26 (m, 4H), 3.76
(s, 3H), 3.07 (t, J = 8.0 Hz, 2H), 1.69ꢀ1.79 (m, 2H), 1.48ꢀ1.55 (m,
2H), 1.35 (t, J = 7.2 Hz, 6H), 0.98 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3,
125 MHz) δ 160.3, 138.6, 137.4, 137.3, 135.0, 134.9, 128.7, 122.4, 121.5,
118.4, 116.6, 115.1, 114.0, 113.8, 62.5, 62.5, 33.8, 28.9, 25.6, 23.2, 16.3,
16.2, 14.0; ESI-MS m/z 391.3 [M þ H]þ; HR-MS (ESI) calcd for
C20H28N2O4Pþ [M þ H] þ requires 391.1781, found 391.1781.
3-Butyl-5-methyl-2-tosyl-1H-pyrrolo[3,2-c]quinolin-4(5H)-one (6o):
1H NMR (CDCl3, 400 MHz) δ 9.75 (s, 1H), 7.85ꢀ7.88 (m, 3H),
7.51ꢀ7.55 (m, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.26ꢀ7.32 (m, 3H), 3.71
(s, 3H), 3.07 (t, J = 7.2 Hz, 2H), 2.41 (s, 3H), 1.38ꢀ1.43 (m, 4H), 0.89
(t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 125 MHz) 159.6, 144.5, 139.0,
138.9, 135.4, 131.6, 130.0, 129.7, 127.4, 127.1, 122.0, 121.3, 115.4, 114.2,
112.6, 32.9, 29.0, 24.7, 23.1, 21.6, 13.9; ESI-MS m/z 409.3 [M þ H]þ;
HR-MS (ESI) calcd for C23H25N2O3Sþ [M þ H] þ requires 409.1580,
found 409.1574.
General Procedure for the Two-Step Synthesis of Pyrrolo-
[3, 2-c]quinolin-4-ones through Ugi-4-CR and Copper-
Catalyzed Reactions. 2-Iodoaniline 7 (0.5 mmol) and benzaldehyde
9 (0.5 mmol) were mixed together in MeOH (5 mL) and stirred for
30 min. Then acid 8 (0.5 mmol) and, after 15 min, isocyanide 10
(0.5 mmol) were added. The mixture was stirred for 24 h. After removal
of the solvent, cesium carbonate (325 mg, 1.0 mmol, 2.0 equiv), copper
iodide (10 mg, 0.05 mmol, 10% equiv), ethyl isocyanoacetate 2a
(0.56 mmol, 1.2 equiv), and DMF (1 mL) were added to Ugi adduct
11 in the flask. The mixture was stirred at 130 °C for 10 min. After being
cooled to room temperature, the reaction mixture was diluted with brine
and extracted with ethyl acetate. The combined organic phase was
washed with brine, dried over MgSO4, and evaporated in vacuum. The
residues were purified by column chromatography on silica gel to give
the desired products as white solids.
1
quinoline-2-carboxylate (6g): H NMR (CDCl3, 400 MHz) δ 9.93
(s, 1H), 7.70 (s, 1H), 7.48ꢀ7.50 (m, 2H), 7.30ꢀ7.40 (m, 5H), 4.22 (q,
J = 7.2 Hz, 2H), 3.67 (s, 3H), 2.47 (s, 3H), 1.11 (t, J = 7.2 Hz, 3H); 13C
NMR (CDCl3, 125 MHz) δ 161.6, 159.3, 136.9, 135.1, 132.9, 131.4,
130.9, 130.6, 130.5, 127.3, 126.9, 122.0, 121.3, 115.3, 113.9, 112.6, 60.9,
28.9, 20.7, 13.8; ESI-MS m/z 361.1 [M þ H]þ; HR-MS (ESI) calcd for
C22H21N2O3þ [M þ H] þ requires 361.1547, found 361.1549.
Ethyl 8-methoxy-5-methyl-4-oxo-3-phenyl-4,5-dihydro-1H-pyrrolo-
1
[3,2-c]quinoline-2-carboxylate (6h): H NMR (CDCl3, 400 MHz) δ
10.65 (s, 1H), 7.59 (d, J = 4.2 Hz, 1H), 7.49 (d, J = 7.2 Hz, 2H),
7.23ꢀ7.27 (m, 3H), 7.14ꢀ7.18 (m, 1H), 7.08 (dd, J = 8.0, 2.4 Hz, 1H),
4.17 (q, J = 7.2 Hz, 2H), 3.82 (s, 3H), 3.67 (s, 3H), 1.01 (t, J = 7.2 Hz,
3H); 13C NMR (CDCl3, 125 MHz) δ 161.8, 159.2, 154.6, 135.4,
133.2, 133.0, 130.8, 130.5, 127.0, 126.8, 122.4, 117.1, 116.5, 113.9,
113.7, 105.0, 60.9, 55.7, 29.0, 13.6; ESI-MS m/z 377.2 [M þ H]þ; HR-
MS (ESI) calcd for C22H21N2O4þ [M þ H] þ requires 377.1496, found
377.1495.
Ethyl 3,5-dimethyl-4-oxo-8-(trifluoromethyl)-4,5-dihydro-1H-pyrrolo-
1
[3,2-c]quinoline-2-carboxylate (6i): H NMR (CDCl3, 400 MHz) δ
10.12 (s, 1H), 8.20 (s, 1H), 7.72 (d, J =8.4 Hz, 1H), 7.49 (d, J =8.8 Hz,
1H), 4.42 (q, J =7.2 Hz, 2H), 3.75 (s, 3H), 2.71 (br s, 3H), 1.41(t,
J = 7.2 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 162.5, 160.3, 140.7,
134.4, 128.4, 125.3, 124.0, 123.0, 122.7, 119.1, 115.7, 114.7, 113.0, 61.3,
29.1, 14.2, 11.1; ESI-MS m/z 353.1 [M þ H]þ; HR-MS (ESI) calcd for
C17H16F3N2O3þ [M þ H]þ requires 353.1108, found 353.1110.
Ethyl 8-cyano-3,5-dimethyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]-
quinoline-2-carboxylate (6j): 1H NMR (DMSO-d6, 400 MHz) δ 12.62
(s, 1H), 8.95 (s, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 8.8 Hz, 1H),
4.36 (q, J = 7.2 Hz, 2H), 3.60 (s, 3H), 2.65 (s, 3H), 1.37 (t, J = 7.2 Hz,
3H); 13C NMR (125 MHz, DMSO-d6) δ 160.8, 159.2, 140.7, 133.5,
131.4, 127.3, 126.4, 122.8, 118.8, 116.5, 113.6, 113.4, 103.7, 60.3, 28.7,
14.3, 10.9; ESI-MS m/z 310.3 [M þ H]þ; HR-MS (ESI) calcd for
C17H16N3O3þ [M þ H]þ requires 310.1186, found 310.1194.
Ethyl 5-(2-(tert-butylamino)-2-oxo-1-p-tolylethyl)-4-oxo-3-phenyl-
4,5-dihydro-1H-pyrrolo[3,2-c]quinoline-2-carboxylate (12a): 1H
NMR (CDCl3, 400 MHz) δ 11.80 (br s, 1H), 8.06 (d, J = 7.2 Hz,
1H), 7.46 (d, J = 5.2 Hz, 2H), 7.26ꢀ7.31 (m, 5H), 7.08ꢀ7.12 (m,
3H), 7.01ꢀ7.04(m, 1H), 6.92 (br s, 1H), 6.37 (br s, 1H), 5.66 (s, 1H),
4.25 (q, J = 7.2 Hz, 2H), 2.30 (s, 3H), 1.42 (s, 9H), 1.20 (t, J = 7.2 Hz,
3H); 13C NMR (125 MHz, CDCl3) δ 169.8, 161.4, 159.8, 138.2,
137.8, 136.1, 132.4, 132.0, 131.6, 130.3, 129.6, 128.5, 128.0, 127.0,
126.2, 122.7, 122.5, 122.1, 113.5, 113.1, 60.3, 52.0, 28.4, 21.1, 14.1;
Ethyl 3,5-dimethyl-8-nitro-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]-
quinoline-2-carboxylate (6k): 1H NMR (DMSO-d6, 400 MHz)
δ 12.88 (s, 1H), 9.45 (s, 1H), 8.23 (d, J = 8.8 Hz, 1H), 7.59 (d,
J =8.8 Hz, 1H), 4.35 (q, J =7.2 Hz, 2H), 3.59 (s, 3H), 2.61 (s, 3H), 1.38
(t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 125 MHz) δ 161.6, 160.1, 142.7,
141.8, 133.5, 128.4, 123.8, 117.2, 115.7, 115.1, 112.9, 61.3, 29.4,
14.4, 11.1; ESI-MS m/z 330.2 [M þ H]þ; HR-MS (ESI) calcd for
C16H16N3O5þ [M þ H]þ requires 330.1084, found 330.1090.
þ
ESI-MS m/z 536.3 [M þ H]þ; HR-MS (ESI) calcd for C33H34N3O4
[M þ H]þ requires 536.2544, found 536.2543.
Ethyl 5-(2-(tert-butylamino)-2-oxo-1-p-tolylethyl)-4-oxo-3-propyl-
4,5-dihydro-1H-pyrrolo[3,2-c]quinoline-2-carboxylate (12b): 1H
NMR (CDCl3, 400 MHz) δ 7.84 (d, J = 7.2 Hz, 1H), 7.33 (d,
J = 7.2 Hz, 2H), 7.18 (d, J = 7.2 Hz, 2H), 7.07ꢀ7.11 (m, 1H), 6.98ꢀ
7.02 (m, 1H), 6.90 (br s, 1H), 6.28 (br s, 1H), 5.77 (s, 1H), 4.35ꢀ4.49
(m, 2H), 3.11 (m, 1H), 2.81 (m, 1H), 2.34 (s, 3H), 1.43ꢀ1.62 (m,
14H), 0.93 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 169.4,
161.9, 160.5, 138.2, 137.8, 135.9, 133.3, 132.3, 129.7, 128.2, 127.7,
122.7, 122.0, 121.9, 115.5, 113.8, 113.5, 60.2, 51.9, 28.5, 27.2, 24.4,
21.0, 14.5, 14.1; ESI-MS m/z 502.3 [M þ H]þ; HR-MS (ESI) calcd
for C30H35N3O4Naþ [M þ Na]þ requires 524.2520, found 524.2512
Ethyl 5-(2-(cyclohexylamino)-2-oxo-1-p-tolylethyl)-4-oxo-3-pro-
pyl-4,5-dihydro-1H-pyrrolo[3,2-c]quinoline-2-carboxylate (12c): 1H
NMR (CDCl3, 400 MHz) δ 11.45 (br s, 1H), 7.82 (d, J = 7.2 Hz,
1H), 7.32 (d, J = 7.6 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 7.10 (t, J = 7.6 Hz,
1H), 7.03 (t, J = 7.2 Hz, 1H), 6.97 (br s, 1H), 6.43 (s, 1H), 5.83 (d, J = 8.0
Hz, 1H), 4.34ꢀ4.49 (m, 2H), 3.91ꢀ3.99 (m, 1H), 3.13 (m, 2H), 2.84
(m, 1H), 2.33 (s, 3H), 2.15 (d, J = 10.8 Hz, 1H), 1.85 (d, J = 10.0 Hz,
1H), 1.72(d, J = 13.2 Hz, 1H), 1.53ꢀ1.62 (m, 3H), 1.46 (t, J = 7.2 Hz,
tert-Butyl 3-butyl-5-methyl-4-oxo-4,5-dihydro-1H-pyrrolo[3,2-c]-
quinoline-2-carboxylate (6l): 1H NMR (CDCl3, 400 MHz) δ 9.66 (s,
1H), 7.79 (d, J = 7.6 Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H), 7.38 (d, J = 8.4 Hz,
1H), 7.21ꢀ7.27(m, 1H), 3.73 (s, 3H), 3.28 (t, J = 8.0 Hz, 2H),
1.61ꢀ1.68 (m, 11H), 1.43ꢀ1.50 (m, 2H), 0.94 (t, J = 7.6 Hz, 3H);
13C NMR (CDCl3, 125 MHz) 161.9, 160.3, 138.6, 135.1, 132.4, 128.9,
123.1, 121.7, 121.4, 115.1, 113.7, 113.1, 82.0, 33.7, 28.8, 28.4, 28.3, 28.3,
28.2, 25.3, 23.0, 14.2; ESI-MS m/z 355.4 [M þ H]þ; HR-MS (ESI)
calcd for C21H27N2O3þ [M þ H] þ requires 355.2016, found 355.2021.
3-Butyl-5-methyl-2-phenyl-1H-pyrrolo[3,2-c]quinolin-4(5H)-one
(6m): 1H NMR (CDCl3, 400 MHz) δ 9.15 (s, 1H), 7.85 (d, J = 8.0 Hz,
1H), 7.53 (d, J = 7.2 Hz, 2H), 7.39ꢀ7.47 (m, 3H), 7.32 (t, J = 7.2 Hz,
2H), 7.23ꢀ7.26 (m, 1H), 3.74 (s, 3H), 3.02 (t, J = 8.0 Hz, 2H),
1.74ꢀ1.78 (m, 2H), 1.37ꢀ1.43 (m, 2H), 0.89 (t, J = 7.2 Hz, 3H); 13C
NMR (CDCl3, 125 MHz) 160.5, 137.7, 133.7, 132.6, 132.1, 128.8, 127.9,
127.6, 127.4, 121.7, 121.6, 120.1, 115.2, 114.2, 113.8, 34.1, 28.9, 24.8,
22.9, 13.9; ESI-MS m/z 331.4 [M þ H]þ; HR-MS (ESI) calcd for
C22H23N2Oþ [M þ H]þ requires 331.1805, found 331.1804.
5351
dx.doi.org/10.1021/jo2006939 |J. Org. Chem. 2011, 76, 5346–5353