T. Boisse et al. / Tetrahedron 64 (2008) 7266–7272
7271
50.7 (CH3), 51.4 and 52 (CH3), 52.5 and 52.6 (CH3), 55.9 (CH3), 56
(CH2), 91.4 (CH2), 107.1 and 107.4 (C), 111.4 and 111.5 (CH), 114.4 and
114.6 (CH), 132.4 (CH), 146.8 (C), 149.4 (C), 154.2 (C), 155.2 (C), 166.6
Calcd for C15H14N2O3$3/2H2O: C 60.60, H 5.76, N 9.42; found: C
61.00, H 5.39, N 9.35.
(C); IR:
n
cmꢁ1 1697, 1666, 1544, 1518, 1446, 1388, 1281, 1258, 1237,
4.3.4. Dimethyl 6,7-dimethoxy-1H-pyrrolo[3,2-b]quinoline-1,3-
dicarboxylate 17d
1190. Anal. Calcd for C16H20N2O6: C 57.14, H 5.99, N 8.33; found: C
57.34, H 6.34, N 8.42.
Yellow oil; 95% yield; TLC Rf (AcOEt)¼0.3; 1H NMR (CDCl3,
200 MHz) d 3.91 (s, 3H, CH3), 3.99 (s, 3H, CH3), 4.00 (s, 3H, CH3), 4.03
4.2.5. Dimethyl 4-(1,3-benzodioxol-5-ylamino)-2,5-dihydro-1H-
pyrrole-1,3-dicarboxylate 11e
(s, 3H, CH3), 7.12 (s, 1H, ArH), 7.62 (s, 1H, ArH), 7.93 (s, 1H, ArH), 8.36
(s, 1H, ArH). Anal. Calcd for C16H16N2O4$3/2H2O: C 58.71, H 5.85, N
8.56; found: C 58.90, H 6.03, N 8.44.
Yellow foam; 69% yield; mp 156–158 ꢀC; TLC Rf (AcOEt)¼0.7; 1H
NMR 20 ꢀC (CDCl3, 200 MHz)
d 3.71, 3.73 (2s, 3H, COCH3), 3.75 (s,
3H, COCH3), 4.27–4.41 (m, 4H, CH2NCH2), 5.98, 5.99 (2s, 2H,
OCH2O), 6.49–6.59 (m, 2H, ArH), 6.71–6.79 (m, 1H, ArH), 8.91 (br s,
4.3.5. Dimethyl 8H-[1,3]dioxolo[4,5-g]pyrrolo[3,2-b]quinoline-6,8-
dicarboxylate 17e
1H, NH); 1H NMR 55 ꢀC (CDCl3, 200 MHz)
d
3.71 (s, 3H, COCH3), 3.74
Yellow oil; 87% yield; TLC Rf (AcOEt)¼0.3; 1H NMR (CDCl3,
(s, 3H, COCH3), 4.04–4.41 (m, 4H, CH2NCH2), 5.96 (2s, 2H, OCH2O),
6.52 (dd, J¼8.2, 2.5 Hz, 1H, NHCCHCH), 6.57 (d, J¼2.5 Hz, 1H,
NHCCHCO), 6.73 (d, J¼8.2 Hz, 1H, NHCCHCH), 8.89 (br s, 1H, NH);
200 MHz) d 6.11 (s, 2H, OCH2O), 7.14 (s, 1H, ArH), 7.61 (s, 1H, ArH),
7.9 (s, 1H, ArH), 8.17 (s, 1H, ArH); IR: n
cmꢁ1 1729, 1710, 1658, 1442,
1279, 1241, 1194. Anal. Calcd for C15H12N2O4: C 63.38, H 4.25, N
9.85; found: C 63.05, H 4.14, N 9.52.
13C NMR (CDCl3, 200 MHz)
d 48.9 and 49.3 (CH2), 49.7 and 49.8
(CH3), 50.4 and 51 (CH3), 51.5 and 51.6 (CH2), 90.5 and 90.7 (C),
100.6 (CH), 103.7 (CH2), 107.4 (CH), 115.1 (CH), 132.2 and 132.3 (C),
144.4 (C), 147.2 (C), 153 and 153.1 (C), 153.8 and 154.2 (C), 165.5 and
4.4. Dimethyl 4-[(2-formylphenyl)amino]-2,5-dihydro-1H-
pyrrole-1,3-dicarboxylate 21
165.6 (C); IR:
n
cmꢁ1 1729, 1710, 1658, 1442, 1279, 1241, 1194. Anal.
Calcd for C15H16N2O6: C 56.25, H 5.04, N 8.75; found: C 56.29, H
5.26, N 8.39.
A stirred mixture of ketone 12 (3 g, 15 mM), aniline 20 (2.5 g,
15 mM), pyrrolidine (1 g, 15 mM), and methanesulfonic acid (0.5 g,
5.2 mM) in chloroform (120 mL) and methanol (120 mL) was
refluxed for 24 h while drying the solvent by condensing it in
a Soxhlet-type apparatus containing 3 Å molecular sieves (150 g).
Solvents were evaporated, then dichloromethane (300 mL) and
water (300 mL) were added. The organic phase was extracted with
slightly (HCl) acidified water (100 mL), then twice with water
(100 mL), and the combined aqueous phases were extracted with
dichloromethane (50 mL). The residue obtained upon evaporation
was analyzed by NMR then utilized directly for the next reaction.
Yellow powder; 85% yield; TLC Rf (AcOEt)¼0.7; 1H NMR (CDCl3,
4.3. General procedure for the synthesis of pyrrolo[3,2-
b]quinolines 17a–e
A
stirred mixture of enaminoester 11 (0.5 mmol), tBuOK
(145 mg, 0.5 mmol), and Bredereck’s reagent (632 mg, 3 mmol) was
heated at 110 ꢀC for 6 h (N2). Dichloromethane (20 mL) and HCl 5%
solution (10 mL) were added to the residue obtained upon evapo-
ration, and then aqueous NaHCO3 was added until neutralization.
The aqueous phase was extracted with dichloromethane
(2ꢂ100 mL). The organic phase was dried (MgSO4). The residue
obtained upon evaporation was purified by HPLC on SiO2 (heptane/
EtOAc, 100/0%–0/100%) to give the corresponding pyrroloquinoline.
200 MHz)
d 3.76, 3.77 (2s, 3H, COCH3), 3.80 (s, 3H, COCH3), 4.04–
4.30 (m, 4H, CH2NCH2), 6.57–6.89 (m, 1H, ArH), 7.16–7.65 (m, 3H,
ArH), 9.87, 9.96 (2s, 1H, CHO).
4.3.1. Dimethyl 1H-pyrrolo[3,2-b]quinoline-1,3-dicarboxylate 17a
Yellow oil; 68% yield; TLC Rf (AcOEt)¼0.3; 1H NMR (CDCl3,
4.5. Ethyl 2,3-[(4-fluorophenyl)amino]but-2-enoate 23
200 MHz)
d
3.94 (s, 3H, CO2CH3), 4.01 (s, 3H NCH3), 7.5 (t, J¼7.5 Hz,
A solution of fluoroaniline (11.1 g, 100 mmol) and ethyl acetoa-
cetate (13 g, 100 mmol) in toluene (80 mL) was refluxed for 3 h
while drying the solvent by Dean–Stark device. Solvent was evap-
orated and the residue was dissolved in 40 mL of dichloromethane/
heptane mixture (50/50) then was taken to ꢁ40 ꢀC. The precipitate
was removed by filtration and the product 23 was obtained upon
evaporation; Yellow oil; 75% yield; TLC Rf (ether/heptane 50/
1H, ArH), 7.68 (t, J¼7.5 Hz, 1H, ArH), 7.93 (d, J¼8.4, 1H, ArH), 8.07 (s,
1H, ArH), 8.34 (d, J¼9.2 Hz, 1H, ArH); IR:
n
cmꢁ1 1752, 1685, 1647,
1528, 1306, 1257, 1201. Anal. Calcd for C14H12N2O2$H2O: C 65.11, H
5.46, N 10.85; found: C 65.17, H 5.69, N 11.02.
4.3.2. Dimethyl 7-methyl-1H-pyrrolo[3,2-b]quinoline-1,3-
dicarboxylate 17b
50)¼0.4; 1H NMR (CDCl3, 200 MHz)
1.28 (t, J¼7.1 Hz, 3H, CH2CH3),
d
Yellow oil; 82% yield; TLC Rf (AcOEt)¼0.3; 1H NMR (CDCl3,
1.92 (s, 3H, CH3), 2.24 (br s, 1H, NH), 4.15 (q, J¼7.1 Hz, 2H, CH2CH3),
4.69 (s, 1H, COCH), 6.95–7.12 (m, 4H, ArH); 13C NMR (CDCl3,
200 MHz) d 2.55 (s, 3H, CH3), 3.9 (s, 3H, CO2CH3), 3.99 (s, 3H, NCH3),
7.5 (dd, J¼8.7, 2.2 Hz, 1H, ArH), 7.65 (br s, 1H, ArH), 7.93 (s, 1H, ArH),
50 MHz)
and 86.0 (CH), 115.1–116.47 (m, 2CH), 126.2–127.2 (m, 2CH), 135.1
cmꢁ1
d 14.4 and 14.5 (CH3), 20.1 and 20.9 (CH3), 58.7 (CH2), 85.5
8.21 (d, J¼2.2 Hz, 1H, ArH), 8.23 (s, 1H, ArH); IR:
n
cmꢁ1 1710, 1680,
1543, 1377, 1335, 1236; LC–MS (APCIþ) m/z 255 (MHþ). Anal. Calcd
for C15H14N2O2: C 70.85, H 5.55, N 11.02; found: C 70.76, H 5.59, N
11.19.
and 135.2 (C), 159.1 (C), 160.2 (d, J¼244.1 Hz, C), 170.4; IR:
n
1649, 1613, 1509, 1271, 1230, 1154. Anal. Calcd for C12H14FNO2: C
64.56, H 6.32, N 6.27; found: C 64.46, H 6.58, N 6.33.
4.3.3. Dimethyl 7-methoxy-1H-pyrrolo[3,2-b]quinoline-1,3-
dicarboxylate 17c
References and notes
Yellow powder; 58% yield; TLC Rf (AcOEt)¼0.3; mp 175–177 ꢀC;
1. Zhu, J.; Wong, H.; Zhang, Z.; Yin, Z.; Meanwell, N.; Kadow, J.; Wang, T. Tetra-
hedron Lett. 2006, 47, 5653.
2. Moureau, F.; Wouters, J.; Depas, M.; Vercauteren, D.; Durant, F.; Ducrey, F.;
Koenig, J.; Jarreau, F. Eur. J. Med. Chem. 1995, 30, 823.
3. Mardenborough, L.; Zhu, X.; Fan, P.; Jacob, M.; Khan, S.; Walkerb, L.; Ablor-
deppey, S. Bioorg. Med. Chem. 2005, 13, 3955.
4. Snyder, S.; Vosburg, D.; Jarvis, M.; Markgraf, J. Tetrahedron 2000, 56, 5329.
5. (a) Parrick, J.; Wilcox, R. J. Chem. Soc., Perkin Trans. 1 1976, 2121; (b) Khan, H.;
Rocha, J. Heterocycles 1977, 6, 1927; (c) Szmuszkovicz, J.; Baczynskyj, L.;
Chidester, C.; Duchamp, D. J. Org. Chem. 1976, 41, 1743.
1H NMR (300 MHz, DMSO-d6)
d 3.87 (s, 3H, CO2CH3), 3.92 (s, 3H,
OCH3), 3.99 (s, 3H, NCH3), 7.49 (dd, J¼9, 2.7 Hz, 1H, ArH), 7.51 (s, 1H,
ArH), 8.21 (d, J¼9 Hz, 1H, ArH), 8.7 (s, 1H, ArH), 8.79 (s, 1H, ArH); 13
C
NMR (CDCl3, 50 MHz)
d 34.2 (CH3), 51.5 (CH3), 56 (CH3), 103.3 (C),
106 (CH), 114.6 (CH), 123.2 (CH), 125.7 (CH), 127.7 (C), 131.6 (C), 138
(C), 142 (C), 146.2 (CH), 156.8 (C), 163.3 (C); IR:
cmꢁ1 1710, 1380,
1368, 1332, 1235, 1206, 1112; LC–MS (APCIþ) m/z 271 (MHþ). Anal.
n