2270 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 11
Carrigan et al.
solid (34% yield): mp 104-105 °C; 1H NMR (CDCl3) δ 8.70 (s,
1H), 8.26 (d, J ) 2.4 Hz, 1H), 8.20 (d, J ) 9.8 Hz, 1H), 7.45
(dd, J ) 2.4, 9.8 Hz, 1H), 4.15 (t, J ) 6.7 Hz, 2H), 4.07 (s, 3H),
4.03 (s, 3H), 3.66 (t, J ) 6.7 Hz, 2H), 1.88 (m, J ) 6.7 Hz, 2H),
1.63-1.43 (m, 8H); 13C NMR (CDCl3) δ 167.4, 166.6, 161.7,
146.1, 145.4, 134.1, 133.8, 129.6, 125.3, 124.2, 104.6, 69.5, 63.9,
(s, 2H); 13C NMR (DMSO-d6) δ 168.8, 167.5, 161.0, 151.3, 150.5,
138.0, 130.1, 129.6, 129.4, 128.5, 124.5, 122.4, 120.7, 110.9,
71.2; HRMS (FAB) m/z calcd for C18H13NO5 (M+) 323.0794,
found 323.0794; HPLC 99% (tR ) 7.1 min, 50:50; tR ) 3.8 min,
40:60).
6-(â-P h en yleth yloxy)qu in olin e-2,4-d ica r boxylic Acid
(1p ). 4-(â-Phenylethyloxy)aniline (2p ) was converted to dim-
ethyl 6-(â-phenylethyloxy)quinoline-2,4-dicarboxylate. Chro-
matography (hexanes/EtOAc, 4:1) afforded a white solid (34%
54.3, 33.7, 30.0, 26.9, 26.6; HRMS (ESI) m/z calcd for C19H22
-
NO5 (M + H) 362.1604, found 362.1602. Dimethyl 6-(6-
hydroxyhexyloxy)quinoline-2,4-dicarboxylate (4l) (20 mg, 0.05
mmol) was hydrolyzed to yield a beige solid (13 mg, 68%
yield): 1H NMR (DMSO-d6) δ 8.47 (s, 1H), 8.22 (d, J ) 2.6 Hz,
1H), 8.11 (d, J ) 9.0 Hz, 1H), 7.56 (dd, J ) 2.6, 9.0 Hz, 1H),
4.12 (t, J ) 6.4 Hz, 2H); 3.38 (t, J ) 6.4 Hz, 2H), 1.79 (m, J )
6.8 Hz, 2H), 1.46-1.34 (m, 6H); 13C NMR (DMSO-d6) δ 168.6,
167.4, 161.0, 145.7, 136.1, 133.7, 129.0, 125.0, 123.9, 105.7,
69.6, 62.1, 34.0, 30.0, 26.9, 26.8; HRMS (ESI) m/z calcd for
1
yield): mp 109-110 °C; H NMR (CDCl3) δ 8.70 (s, 1H), 8.28
(d, J ) 2.6 Hz, 1H), 8.21 (d, J ) 9.2 Hz, 1H), 7.46 (dd, J ) 2.6,
9.2 Hz, 1H), 7.33 (dd, J ) 1.2, 4.8 Hz, 2H), 7.32 (s, 2H), 7.25
(m, 1H), 4.37 (t, J ) 7.0 Hz, 2H), 4.07 (s, 3H), 4.02 (s, 3H),
3.18 (t, J ) 7.0 Hz, 2H); 13C NMR (CDCl3) δ 167.3, 166.6, 161.4,
146.2, 145.6, 138.9, 134.2, 133.8, 130.2, 129.6, 129.5, 127.7,
125.3, 124.2, 104.7, 70.2, 54.3, 53.8, 36.6. Anal. (C21H19NO5)
C, H, N. Dimethyl 6-(â-phenylethyloxy)quinoline-2,4-dicar-
boxylate (4p ) (25 mg, 0.07 mmol) was hydrolyzed to yield a
white solid (22 mg, 92% yield): 1H NMR (DMSO-d6) δ 8.49 (s,
1H), 8.28 (d, J ) 2.8 Hz, 1H), 8.13 (d, J ) 9.6 Hz, 1H), 7.57
(dd, J ) 2.8, 9.6 Hz, 1H), 7.38 (d, J ) 6.8 Hz, 2H), 7.33 (t, J )
6.8 Hz, 2H), 7.24 (t, J ) 6.8 Hz, 1H), 4.37 (t, J ) 6.8 Hz, 2H),
3.14 (t, J ) 6.8 Hz, 2H); 13C NMR (DMSO-d6) δ 168.6, 167.4,
160.7, 147.1, 145.8, 139.5, 136.1, 133.8, 130.6, 129.9, 128.9,
128.0, 124.9, 124.0, 105.9, 70.3, 36.1; HRMS (ESI) m/z calcd
for C19H16NO5 (M + H) 338.1029, found 338.1032; HPLC 96%
(tR ) 13.9 min, 50:50; tR ) 5.7 min, 40:60).
C
17H20NO6 (M + H) 334.1291, found 334.1287; HPLC 98% (tR
) 4.4 min, 50:50; tR ) 2.4 min, 40:60).
6-P h en oxyqu in olin e-2,4-d ica r boxylic Acid (1m ). 4-Ami-
nobiphenyl ether (2m ) (400 mg, 2.16 mmol) was converted to
dimethyl 6-phenoxyquinoline-2,4-dicarboxylate. Chromatog-
raphy (hexanes/EtOAc, 4:1) yielded a white solid (168 mg, 23%
1
yield): mp 124-125 °C; H NMR (CDCl3) δ 8.68 (s, 1H), 8.31
(d, J ) 8.4 Hz, 1H), 8.30 (s, 1H), 7.57 (d, J ) 8.4 Hz, 1H), 7.43
(t, J ) 7.6 Hz, 2H), 7.23 (t, J ) 7.6 Hz, 1H), 7.13 (d, J ) 7.6
Hz, 2H); 13C NMR (CDCl3) δ166.9, 166.4, 160.4, 156.5, 146.8,
146.6, 135.4, 134.3, 131.2, 128.9, 125.9, 124.9, 124.2, 121.3,
117.3, 111.2, 54.4, 53.8; TLC Rf 0.21 (hexanes/EtOAc, 3:1).
Anal. (C19H15NO5) C, H, N. Dimethyl 6-phenoxyquinoline-2,4-
dicarboxylate (4m ) (35 mg, 0.104 mmol) was hydrolyzed to
yield a white solid (26 mg, 76% yield): 1H NMR (DMSO-d6) δ
8.48 (s, 1H), 8.26 (d, J ) 9.4 Hz, 1H), 8.24 (d, J ) 3.4 Hz, 1H),
7.69 (dd, J ) 3.4, 9.4 Hz, 1H), 7.49 (t, 8.1 Hz, 2H), 7.27 (t, J )
8.1 Hz, 1H), 7.21 (d, J ) 8.1 Hz, 2H); 13C NMR (DMSO-d6) δ
168.2, 167.3, 159.8, 156.6, 148.3, 146.4, 136.8, 134.5, 131.9,
128.5, 126.5, 125.3, 123.9, 121.6, 111.3; HRMS (ESI) m/z calcd
for C17H12NO5 (M + H) 310.0715, found 310.0718; HPLC 97%
(tR ) 8.5 min, 50:50; tR ) 3.9 min, 40:60).
5,7-Dim eth oxyqu in olin e-2,4-dicar boxylic Acid (1q). 3,5-
Dimethoxyaniline (2q) was converted to dimethyl 5,7-dimethoxy-
quinoline-2,4-dicarboxylate. Chromatography (hexanes/EtOAc,
2:1) yielded a bright yellow product (17% yield): mp 133-136
1
°C; H NMR (CDCl3) δ 7.92 (s, 1H), 7.25 (d, J ) 2.2 Hz, 1H),
6.63 (d, J ) 2.2 Hz, 1H), 4.04 (s, 3H), 3.97 (s, 3H), 3.92 (s,
3H), 3.91 (s, 3H); 13C NMR (CDCl3) δ 170.3, 166.3, 163.2, 156.0,
151.5, 149.0, 139.9, 117.4, 114.3, 102.7, 102.5, 57.7, 57.0, 54.3,
53.8. Anal. (C15H15NO6) C, H, N. Dimethyl 5,7-dimethox-
yquinoline-2,4-dicarboxylate (4q) (50 mg, 0.16 mmol) was
hydrolyzed to yield a bright yellow solid (23 mg, 48% yield):
1H NMR (DMSO-d6) δ 7.65 (s, 1H), 7.12 (d, J ) 2.4 Hz, 1H),
6.78 (d, J ) 2.4 Hz, 1H), 3.90 (s, 3H), 3.86 (s, 3H); 13C NMR
(DMSO-d6) δ 171.3, 167.6, 163.1, 156.8, 152.3, 151.0, 142.6,
116.7, 113.1, 102.4, 58.0, 57.2; HRMS (FAB) m/z calcd for
6-Ben zyloxyqu in olin e-2,4-dicar boxylic Acid (1n ). 4-Ben-
zyloxyaniline (2n ) (694 mg, 3.47 mmol) was converted to
dimethyl 6-benzyloxyquinoline-2,4-dicarboxylate. Chromatog-
raphy (hexanes/EtOAc, 3: 1) afforded a light yellow solid (14%
C
13H11NO6 (M+) 277.0586, found 277.0576; HPLC 96% (tR
3.8 min, 50:50; tR ) 2.5 min, 40:60).
)
1
yield): mp 184-186 °C dec; H NMR (CDCl3) δ 8.70 (s, 1H),
8.39 (d, J ) 2.8 Hz, 1H), 8.23 (d, J ) 8.8 Hz, 1H), 7.54-7.49
(m, 3H), 7.41 (t, J ) 6.8 Hz, 2H), 7.35 (d, J ) 6.8 Hz, 1H), 5.2
(s, 2H), 4.07 (s, 3H), 4.03 (s, 3H); 13C NMR (CDCl3) δ 166.2,
165.5, 160.2, 145.2, 144.7, 135.9, 133.4, 132.8, 128.7, 128.4,
128.7, 127.9, 127.5, 124.2, 123.2, 104.2, 70.5, 53.2, 52.7; HRMS
(FAB) m/z calcd for C20H17NO5 (M+) 351.1107, found 351.1103.
Dimethyl 6-benzyloxyquinoline-2,4-dicarboxylate (4n ) (25 mg,
0.0712 mmol) was hydrolyzed to yield light yellow needles (24
5,8-Dim eth oxyqu in olin e-2,4-d ica r boxylic Acid (1r ). 2,5-
Dimethoxyaniline (2r ) was converted to dimethyl 5,8-dimethoxy-
quinoline-2,4-dicarboxylate. Chromatography (hexanes/EtOAc,
3:1) afforded a dark brown solid (15% yield): mp 186-187 °C;
1H NMR (CDCl3) δ 8.16 (s, 1H), 7.06 (d, J ) 8.8 Hz, 1H), 6.98
(d, J ) 8.8 Hz, 1H), 4.06 (s, 6H), 4.02 (s, 3H), 3.94 (s, 3H); 13
C
NMR (CDCl3) δ 170.1, 166.3, 151.4, 148.6, 147.6, 141.2, 140.1,
1
mg, 96% yield): mp 184-186 °C dec; H NMR (DMSO-d6) δ
120.2, 119.3, 109.6, 109.2, 58.0, 57.3, 54.3, 53.9. Anal. (C15H15
-
8.70 (d, J ) 9.6 Hz, 1H), 8.30 (s, 1H), 7.67 (d, J ) 2.6 Hz, 1H),
7.55 (dd, J ) 2.6, 9.6 Hz, 1H), 7.51 (d, J ) 6.8 Hz, 1H), 7.42-
7.33 (m, Ar-H, 5H), 5.33 (s, 2H); 13C NMR (DMSO-d6) δ 168.6,
167.4, 161.1, 151.5, 150.4, 138.2, 137.9, 130.1, 129.6, 129.3,
129.2, 128.3, 124.8, 122.4, 120.9, 111.1, 71.2; HRMS (FAB) m/z
calcd for C18H13NO5 (M+) 323.0794, found 323.0790; HPLC 97%
(tR ) 2.3 min, 50:50; tR ) 4.3 min, 70:30).
NO6) C, H, N. Dimethyl 5,8-dimethoxyquinoline-2,4-dicarboxy-
late (4r ) (50 mg, 0.16 mmol) was hydrolyzed to yield a yellow
solid (33 mg, 69% yield): 1H NMR (DMSO-d6) δ 7.87 (s, 1H),
7.16 (d, J ) 8.8 Hz, 1H), 7.02 (d, J ) 8.8 Hz, 1H), 3.92 (s, 3H),
3.80 (s, 3H); 13C NMR (DMSO-d6) δ 171.2, 167.6, 151.2, 151.0,
149.1, 142.4, 140.8, 119.4, 118.1, 110.6, 109.8, 58.1, 57.4;
HRMS (ESI) m/z calcd for C13H11NO6 (M + H) 278.0665, found
278.0665; HPLC 99% (tR ) 2.1 min, 60:40; tR ) 1.5 min, 40:
60).
7-Ben zyloxyqu in olin e-2,4-dicar boxylic Acid (1o). 3-Ben-
zyloxyaniline (2o) was converted to dimethyl 7-benzylox-
yquinoline-2,4-dicarboxylate. Chromatography (hexanes/EtOAc,
6,7-Dim eth oxyqu in olin e-2,4-d ica r boxylic Acid (1s). 3,4-
Dimethoxyaniline (2s) was converted to dimethyl 6,7-dimethoxy-
quinoline-2,4-dicarboxylate, which was triturated with EtOAc
to yield a dark green-brown solid (26% yield): mp 186-188
1
3:1) afforded a light yellow solid (26%): mp 184-186 °C; H
NMR (CDCl3) δ 8.70 (s, 1H), 8.39 (d, J ) 3.0 Hz, 1H), 8.23 (d,
J ) 8.8 Hz, 1H), 7.53 (dd, J ) 3.0, 8.8 Hz, 1H), 7.49 (d, J )
6.8 Hz, 1H), 7.42-7.34 (m, 4H), 5.23 (s, 2H), 4.07 (s, 3H), 4.03
(s, 3H); 13C NMR (CDCl3) δ 166.2, 165.5, 160.2, 145.2, 144.7,
135.9, 133.2, 132.8, 128.7, 128.4, 127.9, 127.4, 124.2, 123.2,
104.2, 70.5, 53.2, 52.7. Anal. (C20H17NO5) C, H, N. Dimethyl
7-benzyloxyquinoline-2,4-dicarboxylate (4o) (25 mg, 0.07 mmol)
was hydrolyzed to yield a gold-colored solid (24 mg, 96%
yield): mp 149-150 °C; 1H NMR (DMSO-d6) δ 8.69 (d, J )
9.2 Hz, 1H), 8.24 (s, 1H), 7.64 (d, J ) 2.8 Hz, 1H), 7.53-7.50
(m, 3H), 7.40 (t, J ) 7.0 Hz, 2H), 7.33 (t, J ) 7.0 Hz, 1H), 5.32
1
°C; H NMR (CDCl3) δ 8.61 (s, 1H), 8.32 (s, 1H), 7.63 (s, 1H),
4.06 (br, 6H), 4.02 (s, 3H), 4.02 (s, 3H); 13C NMR (CDCl3) δ
166.4, 165.6, 153.2, 146.4, 144.7, 132.6, 123.6, 121.2, 109.1,
103.0, 56.4, 56.3, 53.2, 52.7. Anal. (C15H15NO6) C, H, N.
Dimethyl 6,7-dimethoxyquinoline-2,4-dicarboxylate (4s) (50
mg, 0.16 mmol) was hydrolyzed to yield bright yellow needles
(32 mg, 70% yield): 1H NMR (DMSO-d6) δ 8.36 (s, 1H), 8.22
(s, 1H), 7.56(s, 1H), 3.96 (s, 3H), 3.93 (s, 3H); 13C NMR (DMSO-
d6) δ 167.8, 166.5, 153.3, 152.7, 146.2, 146.0, 134.4, 122.8,