Isoquinoline and Perimidine Derivatives
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 12 2011
1
1
.3 Hz), 8.04 (t), 8.52 (dd, J ) 7.7, 1.3 Hz), 8.60 (dd, J ) 8.3,
.3 Hz), 8.78 (dd, J ) 7.3, 1.3 Hz), 9.97 (s), 10.28 (s, CHO). 13
): δ 117.9 (CH), 125.3 (C), 127.6 (C), 128.0 (CH),
30.2 (CH), 130.4 (C), 130.6 (CH), 131.8 (CH), 133.7 (C), 134.6
C), 134.8 (C), 137.9 (2 × CH), 147.3 (C), 153.3 (C), 181.0 (C),
93.0 (CH). ESMS: m/z 294 (100%), 296 (37%) (both M + 1).
-F or m yl-7H-ben zo[e]p er im id in -7-on e (16g). This was
prepared as for 16a and recrystallized from toluene to give a
mL) was added 1,1′-carbonyldiimidazole (0.20 g, 1.2 mmol),
and the mixture was refluxed for 3 h. The solvent was removed
C
NMR (CDCl
1
(
1
3
at reduced pressure, and the residue was dissolved in CH
(20 mL), washed with 10% Na CO solution, warm water, and
dried (Na SO ). The solvent was evaporated to give the
2 2
Cl
2
3
2
4
intermediate imidazolide 18a as a pale-brown solid (0.23 g,
2
88%), mp 210-211 °C, which was used in the next step without
1
further purification. H NMR (CDCl
3
): δ 7.20 (s, ImH), 7.70
1
pale-yellow solid (89%), mp 237-238 °C. H NMR (CDCl
3
): δ
(t), 7.81 (t), 8.05 (t), 8.06 (s, ImH), 8.42-8.53 (m, 3 H), 8.79
(d), 8.97 (s), 9.15 (s, ImH). 13C NMR (CDCl
): δ 117.3 (CH),
7
1
1
.80 (t), 7.88 (t), 8.19 (t), 8.44 (d), 8.53 (d), 8.72 (d), 9.05 (d),
3
1
3
0.36 (s, CHO). C NMR (CDCl
3
): δ 120.2 (C), 126.4 (CH),
118.2 (CH), 124.2 (CH), 124.4 (C), 128.6 (CH), 130.5 (CH),
131.1 (CH), 131.4 (CH), 132.1 (CH), 133.0 (C), 134.1 (CH),
137.0 (CH), 140.0 (CH), 146.2 (C), 150.0 (C), 163.1 (C), 181.9
(C); 3 (C) were not observed.
28.2 (CH), 129.1 (C), 131.7 (CH), 131.8 (C), 133.4 (CH), 133.6
(C), 135.0 (CH), 136.0 (CH), 149.6 (C), 156.6 (C), 158.4 (C),
1
81.5 (C), 191.7 (C). ESMS: m/z 293 (M + 1).
P r ep a r a tion of 7-Oxo-7H-d iben z[f,ij]isoqu in olin e-2-
A solution of 18a (0.17 g, 0.52 mmol) in dry CH
was treated with a solution of N,N-dimethylethylenediamine
(55 mg, 0.62 mmol) in CH Cl (5 mL). The solution was stirred
at room temperature for 24 h, then washed with 10% Na CO
SO ). The solvent
2 2
Cl (15 mL)
ca r boxylic a cid (17a ). An Exa m p le of th e Gen er a l Oxid a -
tion of a n Ald eh yd e Gr ou p . A solution of sodium chlorite
2
2
(0.87 g) and sodium dihydrogen phosphate (0.87 g) in water
(8.7 mL) was added over 5 min to a mixture of aldehyde 16a
(0.26 g, 1 mmol) in tert-butyl alcohol (20 mL) and 2-methylbut-
2
3
solution, warm water (10 mL × 2), dried (Na
2
4
was removed to give 25 (0.15 g, 83%), brown solid, mp 143-
1
2
-ene (5 mL), and the resulting mixture was stirred at room
144 °C [toluene/light petroleum (bp 60-90 °C)]. H NMR
temperature for 4 h. Most of the organic solvent was evapo-
rated at reduced pressure, and water (15 mL) was added to
the residue. The precipitate that separated was collected by
(CDCl ): δ side chain + 7.63 (t), 7.76 (t), 7.91 (t), 8.38 (d), 8.41
3
13
(2 × d, 2 H), 8.49 (br s, NH), 8.63 (d), 8.97 (s). C NMR
(CDCl ): δ 37.4 (CH ), 45.4 (CH ), 58.2 (CH ), 114.5 (CH), 124.1
3
2
3
2
filtration, washed with water, and dried to give the acid as a
(C), 124.3 (CH), 128.3 (CH), 128.5 (C), 130.2 (CH), 130.5 (CH),
130.8 (CH), 131.9 (C), 133.6 (C), 133.9 (CH), 136.2 (C), 136.4
(CH), 146.0 (C), 150.9 (C), 164.1 (C), 182.2 (C). ESMS: m/z
346 (M + 1).
1
yellow solid (0.24 g, 87%), mp 224-225 °C (from CHCl
3
). H
NMR (CDCl
3
): δ 7.73 (t), 7.86 (t), 8.07 (t), 8.48-8.54 (m, 3 H),
13
8
1
.82 (d), 9.05 (s). C NMR (CDCl
3
): δ 114.8 (CH), 124.5 (CH),
24.9 (C), 128.7 (CH), 128.8 (C), 131.2 (CH), 131.6 (CH), 131.8
For microanalysis, a sample was converted to the monoper-
(
1
CH), 132.1 (C), 133.0 (C), 134.3 (CH), 136.0 (CH), 138.1 (C),
45.4 (C), 146.9 (C), 163.9 (C), 181.9 (C). ESMS: m/z 276 (M
19 3 2 4
chloratesalt,mp252-253°C(from EtOH).Anal.(C21H N O .HClO )
C, H, N.
+
1).
The following imidazolides and amides were made in a
similar manner.
The following acids were prepared in similar manner.
8
-Ch lor o-7-oxo-7H-d iben z[f,ij]isoqu in olin e-2-ca r boxy-
N-[2-(Dim eth yla m in o)eth yl]-2-m eth yl-7-oxo-7H-d iben -
z[f,ij]isoqu in olin e-4-ca r boxa m id e (30). The intermediate
lic Acid (17e). This was prepared from 16e, with dioxane as
solvent and a reaction time of 16 h. The final aqueous solution
was acidified with concentrated HCl, and the precipitate that
formed was filtered off, washed with water, and dried at 80
C to give 17e as an orange solid (98%), mp 245-247 °C. H
imidazolide 18b was a brown-red solid (85%), mp 163-165 °C.
1
H NMR (CDCl
3
3
): δ 2.71 (s, 3 H, CH ), 7.11 (s, ImH), 7.48 (s,
ImH), 7.69 (t), 7.75 (s, ImH), 7.81 (t), 8.05 (d), 8.09 (s), 8.34
(d), 8.50 (d), 8.67(d). C NMR (CDCl
1
13
°
3
3
): δ 25.9 (CH ), 117.1
NMR: δ 7.76-7.82 (m, 2 H), 8.10 (t, 8.50-8.53 (m, 2 H), 8.69
d), 8.92 (s). ESMS: m/z 310 (100%), 312 (42%) (both M + 1).
1-Ch lor o-7-oxo-7H-d iben z[f,ij]isoqu in olin e-2-ca r box-
(CH), 118.4 (CH), 122.1 (C), 123.6 (CH), 127.2 (CH), 128.7
(CH), 129.0 (CH), 130.6 (C), 130.9 (2 × CH), 131.9 (C), 133.5
(C), 134.1 (CH), 134.9 (C), 137.3 (C), 138.3 (CH), 144.7 (C),
161.8 (C), 165.6 (C), 181.9 (C).
(
1
ylic Acid (17f). This was prepared from 16f, as for 17e, as a
brown solid (99%), mp 230-231 °C (some sublimation at >196
Reaction of 18b as above gave 30 (63%); brick-red, mp 207-
1
1
°
C). H NMR: δ 7.72 (t), 8.01 (d), 8.11 (t), 8.36 (d), 8.56-8.62
208 °C [benzene/light petroleum (bp 60-90 °C)]. H NMR
1
3
(
m, 2 H), 9.94 (s). C NMR: δ 120.5 (CH), 123.4 (C), 126.6 (C),
(CDCl
3
3
): δ side chain + 2.86 (s, 3 H, CH ), 7.63 (t), 7.75 (t),
1
1
27.5 (CH), 129.5 (C), 130.5 (CH), 130.7 (CH), 131.1 (CH),
32.3 (C), 133.1 (C), 134.1 (C), 137.7 (CH), 137.9 (CH), 146.2
8.01 (s), 8.25 (d), 8.43 (d), 8.62 (d), 8.94 (d), 11.63 (br s, NH).
1
3
C NMR (CDCl
3
): δ 25.4 (CH
3 2 3
), 37.7 (CH ), 45.2 (CH ), 57.9
(
3
C), 149.6 (C), 165.9 (C), 179.8 (C). ESMS: m/z 310 (100%),
12 (40%) (both M + 1).
-Oxo-7H-ben zo[e]p er im id in e-2-ca r boxylic Acid (17g).
(CH ), 116.9 (CH), 121.9 (C), 123.5 (CH), 127.7 (CH), 128.4
2
(CH), 130.0 (C), 130.7 (CH), 131.7 (C), 133.0 (CH), 133.3 (C),
133.5 (C), 133.7 (CH), 135.7 (C), 144.8 (C), 159.2 (C), 164.8
(C), 182.1 (C). ESMS: m/z 360(M + 1). Anal. (C22H N O ) C,
21 3 2
H, N.
7
This was prepared from 16g, as for 17a except that dioxane
was used as the solvent, and was obtained as a yellow solid
1
(
8
1
0.25 g, 90%), mp 266-267 °C. H NMR: δ 7.88 (t), 7.98 (t),
N-[2-(Dim eth yla m in o)eth yl]-2-m eth yl-7-oxo-7H-d iben -
z[f,ij]isoqu in olin e-8-ca r boxa m id e (31). The intermediate
.25-8.31 (m, 2 H), 8.49 (d), 8.56 (d), 8.84 (d). 13C NMR: δ
19.2 (C), 125.7 (CH), 127.6 (CH), 128.5 (C), 130.4 (CH), 133.3
1
imidazolide 18c was a dark solid (83%), mp >310 °C. H NMR
(CH), 134.1 (C), 134.8 (CH), 135.5 (CH), 149.0 (C), 156.0 (C),
(CDCl
3
3
): δ 2.90 (s, 3 H, CH ), 7.09 (s, ImH), 7.46 (s, ImH),
1
57.1 (C), 165.6 (C), 181.2 (C). ESMS: m/z 277 (M + 1).
P r ep a r a tion of 7-Oxo-7H-d iben z[f,ij]isoqu in olin e-2,8-
7.64 (d), 7.77(s, ImH), 7.88-7.95 (m, 2 H), 8.14 (s), 8.36 (d),
8.46 (d), 8.57 (d).
d ica r boxylic Acid (17c). A mixture of 13c (2.32 g, 8.0 mmol)
and SeO (4.0 g) in dry dioxane (100 mL) was heated to reflux,
Reaction of 18c was as above but in THF with reflux for 3
days. The solvent was removed, and the residue was dissolved
2
with stirring, for 4 h, then filtered while hot, and the filtrate
was evaporated to dryness at reduced pressure. The residue
was extracted with 5% NaOH, and the extract was acidified
with concentrated HCl. The precipitate that formed was
collected by filtration, washed with water, and dried at 80 °C
in CH
2 2
Cl and treated as above to give 31 (67%); brick-red
solid, mp 174-176 °C [benzene/light petroleum (bp 60-90 °C)].
1
H NMR (CDCl
s, NH), 7.54 (d), 7.73 (t), 7.87 (t), 8.02 (s), 8.30 (d), 8.32 (d),
8.52 (d). 13C NMR (CDCl
): δ 25.8 (CH3), 37.4 (CH ), 45.0
(CH ), 57.5 (CH ), 117.9 (CH), 121.5 (C), 124.4 (CH), 128.5 (C),
3
): δ side chain + 2.85 (s, 3 H, CH
3
), 6.38 (br
3
2
1
to give 17c as a brown solid (2.12 g, 83%), mp >316 °C. H
3
2
NMR: δ 7.68 (1H, d, J ) 7.3 Hz), 7.95 (1 H, t, J ) 7.3 Hz),
128.6 (CH), 129.2 (C), 130.0 (2 × CH), 133.0 (CH), 134.3 (C),
8
7
.16 (1 H, t, J ) 7.6 Hz), 8.58-8.64(2 H, m), 8.84 (1 H, d, J )
.7 Hz), 9.04 (1 H, s, H-1). ESMS: m/z 320 (M + 1).
134.7 (C), 135.3 (CH), 139.9 (C), 147.3 (C), 160.1 (C), 171.1
(C), 181.8 (C). ESMS: m/z 360 (M + 1). Anal. (C22
O) C, H, N.
N-[2-(Dim eth yla m in o)eth yl]-2-m eth yl-7-oxo-7H-d iben -
21 3 2
H N O ‚
P r ep a r a tion of N-[2-(Dim eth yla m in o)eth yl]-7-oxo-7H-
d iben z[f,ij]isoqu in olin -2-ca r boxa m id e (25). An Exa m p le
H
2
of th e Gen er a l Meth od for Am id e F or m a tion (Sch em e
z[f,ij]isoqu in olin e-11-ca r boxa m id e (32). The intermediate
imidazolide 18d was prepared in dioxane (4 h reflux) and
6
). To a solution of acid 17a (0.22 g, 0.8 mmol) in dry THF (15