Synthesis of Novel Isoquinolino[5,4- ab ]phenanthridine Derivatives via Pictet-Spengler Reaction

Article abstract of DOI:10.1055/s-0037-1610670

The reaction of 5-amino-2-[2-(dimethylamino)ethyl]-6-phenyl-1 H -benzo[ de ]isoquinoline-1,3(2 H)-dione with a series of aldehydes in acidic media (phosphoric acid, trifluoromethanesulfonic acid, and trifluoroacetic acid) is described. This key step is ba

Full text of DOI:10.1055/s-0037-1610670

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
©
Georg Thieme Verlag Stuttgart · New York
2018, 50, A–F
paper
A
en
Synthesis
M.-C. Tsai et al.
Paper
Synthesis of Novel Isoquinolino[5,4-ab]phenanthridine Derivatives
via Pictet–Spengler Reaction
Min-Chen Tsai
N
N
Pei Yu Huang
O
O
O
Liang Sheng Syu
Tzenge-Lien Shih*
O
N
O
Pictet–Spengler reaction
O
N
O
4
steps
10 examples
17–61%
Department of Chemistry, Tamkang University,
Br
NH2
N
25137 Tamsui Dist., New Taipei City, Taiwan,
Republic of China
tlshih@mail.tku.edu.tw
Ar
Received: 11.09.2018
Accepted after revision: 16.10.2018
Published online: 21.11.2018
the other hand, we have recently reported the use of naph-
thalimide derivatives against murine melanoma.
12
DOI: 10.1055/s-0037-1610670; Art ID: ss-2018-h0604-op
We are interested in incorporating the above-men-
tioned compounds frameworks into a novel isoquinoli-
no[5,4-ab]phenanthridine-based motif (Scheme 1) in five
steps using 6-bromobenzo[de]isochromene-1,3-dione (1)
as starting material. The key steps involved a Suzuki–
Miyaura cross-coupling reaction between 4 and phenylbo-
ronic acid as well as Pictet–Spengler reaction (Scheme 2,
vide infra).
Abstract The reaction of 5-amino-2-[2-(dimethylamino)ethyl]-6-phe-
nyl-1H-benzo[de]isoquinoline-1,3(2H)-dione with a series of aldehydes
in acidic media (phosphoric acid, trifluoromethanesulfonic acid, and tri-
fluoroacetic acid) is described. This key step is based on the Pictet–
Spengler reaction to synthesize ten novel isoquinolino[5,4-ab]phenan-
thridine derivatives. The most effective acid is phosphoric acid and opti-
mized yields were obtained. The frameworks of target compounds are
unique and have never been reported.
Key words homophthalimide, isoquinoline-1,3-dione, naphthalim-
ide, phenanthridine, Pictet–Spengler reaction, Suzuki–Miyaura cross-
coupling reaction
Compounds possessing isoquinoline-1,3-dione (also
known as homophthalimide) framework present a wide va-
1
riety of biological activities. They have been reported as
selective inhibitors of tyrosyl DNA phosphodiesterase II
2
3
(
TDP2) and cyclin-dependent kinase. The extensive stud-
ies of inhibiting TDP2 are needed because TDP2 retarded
the efficacy of DNA-damage of anticancer drugs.
Phenanthridine-based derivatives were discovered in
natural products and chemists were interested in their
4
broad spectrum of biological activities. Owing to the im-
portance of phenanthridine derivatives, numerous synthe-
5
ses have been reported. The most common and key strate-
Scheme 1 Representative structures of isoquinoline-1,3-dione, naph-
thalimide, phenanthridine, and isoquinolino[5,4-ab]phenanthridine
gy employed for their syntheses was the Pictet–Spengler re-
6
action.
1
H-Benz[de]isoquinoline-1,3-dione
(naphthalimide)
7
derivatives show anticancer properties. The most promi-
nent drugs are mitonafide and amonafide. Furthermore,
naphthalimide derivatives were synthesized as dyes due to
their photostability. Their derivatives were also used as
sensors due to the intensive fluorescent properties. On
The synthesis of target molecules 7a–j is straightfor-
ward as described in Scheme 2. Nitration of the commer-
cially available 1 afforded 2. The nitro group of 2 was re-
8
8a,9
10
duced by SnCl dihydrate and the resulting 3 was converted
2
11
into imide 4. Compound 4 was coupled with phenylboronic
acid to afford amino compound 513 via Suzuki–Miyaura re-
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

B
Synthesis
M.-C. Tsai et al.
Paper
N
O
O
O
O
O
O
O
O
O
O
N
O
a
0%
b
c
6
70%
84%
NO2
NH2
NH2
Br
Br
Br
Br
1
2
3
4
N
N
N
O
N
O
O
N
O
O
N
O
d
e
8
0%
see text
NH2
NH
N
Ar
Ar
5
6a–j
7a–j
F
Cl
Br
F
Cl
Br
Ar =
7
a
7b
7c
7d
7e
7f
F
Cl
Br
OMe
7
g
7h
7i
7j
Scheme 2 Synthesis of isoquinolino[5,4-ab]phenanthridine derivatives 7a–j. Reagents and conditions: a) HNO , H SO , 60%; b) SnCl ·2H O/HCl, 70%; c)
3
2
4
2
2
NH CH CH N(Me) , EtOH, 84%; d) phenylboronic acid, PdCl /PPh , 80%; e) aldehydes, air oxygen, acid (see text).
2
2
2
2
2
3
action. Pictet–Spengler reaction (PSR) was a powerful tool
in the syntheses of a variety of alkaloids. In order to study
the yields were all lower than those in phosphoric acid. On
the other hand, much longer reaction times (up to days)
were required and lower yields were obtained when triflu-
oroacetic acid (TFA) was used instead of PA.
6
whether the electron-withdrawing property will influence
the yields or not, the corresponding o-, m- and p-halo-sub-
stituted benzaldehydes were selected to react with amino
compound 5 via Pictet–Spengler reaction to afford 7a–i. In
addition, p-anisaldehyde, which has an electron-donating
group was used for comparison purpose (→ 7j). Three com-
Among the three selected acids in this study, phosphor-
ic acid is the best choice not only in yields but also in the
reaction time for Pictet–Spengler reaction. The electron-
withdrawing property on corresponding aldehydes did not
influence too much the yields of 7a–i in PA. These results
6b
mon acids, phosphoric acid (PA), trifluoromethanesulfon-
6
e
6c,d,g
6g
ic acid (TfOH), and trifluoroacetic acid (TFA)
were used
were quite consistent with the conclusion of report. How-
14
as solvents and surveyed, respectively. It is noteworthy to
mention that the formation of imines from 5 and aldehydes
followed by intramolecular electrophilic aromatic substitu-
tion afforded 6a–j, which were not isolated throughout the
reaction courses. The subsequent oxidation of 6a–j by air
oxygen led to target molecules 7a–j.
ever, the contrast result was while p-anisaldehyde was
used (→ 7j). The electron-donating group in aromatic ring
might retard the intermediate (an imine) to undergo intra-
molecular electrophilic substitution reaction even when
phosphoric acid was employed. The acids of TfOH and TFA
conditions afforded no reaction or very low yield in the syn-
thesis of 7j (Table 1, entry 10).
In conclusion, we have accomplished an efficient syn-
thesis of a series of novel isoquinolino[5,4-ab]phenanthri-
dine derivatives 7a–j in five steps from the commercially
available 1. This protocol provides a substrate scope that
electron-withdrawing property in benzaldehydes to pro-
vide higher yields. It is important to mention that more
equivalents of aldehydes (up to six equivalents) and using
phosphoric acid were essential to obtain the optimized
yields of target molecules.
When compound 5 and two equivalents of the corre-
sponding aldehydes were heated at 140–150 °C in phos-
phoric acid (PA) as solvent, the resulting target molecules
7a–j were obtained in moderate to lower yields (Table 1).
However, when six equivalents of aldehydes were used (see
experimental), all target molecules were formed in satisfac-
tory yields, except 7j (entry 10). The low yield of 7j was
consistent with the results of the less reactive aldehydes in
6c
PA reaction in the literature. When trifluormethanesul-
fonic acid (TfOH) was used as solvent and catalyst instead,
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

C
Synthesis
M.-C. Tsai et al.
Paper
Table 1 Optimized Yields of Pictet–Spengler Reaction with Respective to PA, TfOH, and TFA
Entry
PA
TfOH
TFA
Product
Time (h)
Yield (%)
Time (h)
Yield (%)
Time (d)
Yield (%)
1
2
3
4
5
6
7
8
9
10
51
47
49
57
51
49
61
58
61
17
10
10
10
22
8
18
3.5
4
11 (12)a
42
7a
7b
7c
7d
7e
7f
9.5
10
29
39
4
32
8.5
8.5
8.5
10
20 (61)a
38
4.5
3.5
3.5
4.5
4.5
4.5
4
37
28 (31)a
33 (39)a
28 (38)a
34 (36)a
14 (16)a
4 (7)a
10
8.5
10
22
22
43
32 (38)a
41
7g
7h
7i
9.5
8.5
8.5
24 (54)a
NR
10
7j
a
Yield in parentheses is for the recovery of 5.
1
H NMR (600 MHz, DMSO-d ): δ = 8.31 (d, J = 8.6 Hz, 1 H), 8.19 (d, J =
All chemicals were commercially available and used without further
6
purification, unless otherwise stated. The 1H and 13C NMR spectra
7.1 Hz, 1 H), 8.12 (s, 1 H), 7.83 (t, J = 8.5 Hz, 1 H), 6.42 (s, 2 H).
13
were recorded on a Bruker 600 MHz instrument. Chemical shifts
were reported in ppm and referenced to the residue of solvent:
C NMR (150 MHz, DMSO-d ): δ = 160.6, 160.4, 145.6, 131.8, 130.9,
6
128.9, 127.5, 123.4, 123.1, 119.3, 119.0, 107.4.
1
13
1
(
3
CDCl : 7.26 ppm for H; 77.0 ppm for C; DMSO: 2.49 ppm for H;
+
3
HRMS (ESI): m/z calcd for C12H BrNO [M + H] : 291.9609; found:
2
7
3
13
19
9.5 ppm for C). F NMR (376.3 MHz) spectra were recorded on a
91.9613.
Bruker AVIII 400 instrument. Melting points were determined on Far-
go MP-2D and are not corrected. IR spectra were recorded on a Ther-
mo Scientific Nicolet iS5 spectrophotometer. HRMS data were collect-
ed on a JMS-700 instrument.
5
-Amino-6-bromo-2-[2-(dimethylamino)ethyl]-1H-benzo[de]iso-
quinoline-1,3(2H)-dione (4)
Compound 3 (0.629 g, 2.153 mmol) and N,N-dimethylenediamine
(
0.282 mL, 2.584 mmol) in anhyd EtOH (13 mL) were refluxed under
6
-Bromo-5-nitrobenzo[de]isochromene-1,3-dione (2)
N for 3 h. The mixture was filtered by suction and the resulting solid
was washed with cold EtOH to afford 4 as a yellow solid; yield: 0.668
g (84%); mp 194–196 °C; R = 0.32 (CH Cl /MeOH 7:3)
IR (KBr): 3425.0, 1699.0, 1654.6, 1616.1, 1427.1, 1340.3, 1160.9 cm–1
1
2
Compound 1 (0.50 g, 1.804 mmol) was dissolved in concd H SO (10
mL) and followed by the dropwise addition of concd HNO (0.15 mL,
2
4
3
f
2
2
3.609 mmol) at 0 °C and the mixture was stirred for 1 h. At the end of
.
the reaction time, the mixture was diluted with ice water and filtered
by suction. The resulting pale yellow solid was purified by flash col-
umn chromatography (230–400 mesh SiO , CH Cl /hexane 1:6) to af-
H NMR (600 MHz, CDCl ): δ = 8.34 (d, J = 7.1 Hz, 1 H), 8.25 (d, J = 8.3
3
Hz, 1 H), 8.00 (s, 1 H), 7.69 (t, J = 7.5 Hz, 1 H), 4.76 (s, 2 H), 4.30 (t, J =
6.7 Hz, 2 H), 2.67 (t, J = 6.7 Hz, 2 H), 2.36 (s, 6 H).
2
2
2
ford 2 as a white solid; yield: 0.351 g (60%); mp 233–236 °C.
1
3
IR (KBr): 1785.8, 1754.9, 1594.8, 1546.3, 1330.6, 1282.4, 1149.4,
C NMR (150 MHz, CDCl ): δ = 164.1, 163.7, 143.3, 131.8, 130.9,
3
–1
1035.6 cm
.
128.3, 127.7, 122.8, 122.7, 122.6, 121.3, 110.0, 57.1, 45.7 (2 ×), 38.2.
1
+
H NMR (600 MHz, CDCl ): δ = 8.92 (d, J = 8.6 Hz, 1 H), 8.84 (d, J = 7.3
HRMS (ESI): m/z calcd for C16H17BrN O [M + H] : 362.0504; found:
3
3
2
Hz, 1 H), 8.82 (s, 1 H), 8.10 (t, J = 7.5 Hz, 1 H).
362.0502.
13
C NMR (150 MHz, CDCl ): δ = 158.7, 158.2, 149.6, 136.4, 136.2,
3
1
31.8, 130.8, 130.6, 127.2, 123.9, 119.7, 119.6.
5-Amino-2-[2-(dimethylamino)ethyl]-6-phenyl-1H-benzo[de]iso-
quinoline-1,3(2H)-dione (5)
+
HRMS (EI): m/z calcd for C12H BrNO [M + H] : 321.9351; found:
5
5
To a solution of compound 4 (0.6608 g, 1.82 mmol), PdCl (0.0194 g,
321.9273.
2
0
.109 mmol), and PPh (0.0576 g, 0.219 mmol) in MeOH (15 mL) were
3
added KOH (0.205 g, 3.60 mmol) and phenylboronic acid (0.448 g,
.60 mmol) in MeOH (5 mL) under N , and the reaction mixture was
5
-Amino-6-bromobenzo[de]isochromene-1,3-dione (3)
3
2
Compound 2 (0.351 g, 1.089 mmol) was dissolved in AcOH (10 mL)
and followed by the addition of SnCl ·2H O (1.114 g, 4.359 mmol) in
concd HCl (0.5 mL) dropwise at 0 °C and stirred for 6 h. At the end of
reaction time, the mixture was filtered by suction and the resulting
solid was washed with ice water to afford 3 as a yellow solid; yield:
stirred for 9 h. At the end of reaction time, the mixture was filtered by
suction and the resulting solid was washed with cold MeOH. The solid
was purified by flash column chromatography (230–400 mesh SiO2,
CH Cl /MeOH 7:5) to afford 5 as a yellow solid; yield: 0.526 g (80%);
2
2
2
2
mp 174–175 °C; R = 0.3 (CH Cl /MeOH 7:5).
f
2
2
0.225 g (70%); mp 276.1–276.5 °C; R = 0.38 (CH Cl /hexane 6:1).
f 2 2
IR (KBr): 3452.0, 3363.2, 1699.0, 1650.8, 1610.3, 1415.5, 1384.6,
IR (KBr): 3475.1, 3372.9, 1772.3, 1731.8, 1618.0, 1563.0, 1423.2,
–1
1151.5 cm
.
–1
1284.4, 1153.2, 1027.9 cm .
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

D
Synthesis
M.-C. Tsai et al.
Paper
1
13
1
H NMR (600 MHz, CDCl ): δ = 8.32 (d, J = 6.8 Hz, 1 H), 8.13 (s, 1 H),
C NMR (150 MHz, CDCl ): δ = 164.5, 163.6, 160.1 ( J = 247.0 Hz),
3 C,F
3
3
7
7
4
.61 (d, J = 8.3 Hz, 1 H), 7.59 (t, J = 7.5 Hz, 2 H), 7.52 (t, J = 7.3 Hz, 1 H),
.48 (t, J = 7.9 Hz, 1 H), 7.35 (d, J = 7.1 Hz, 2 H), 4.34 (d, J = 6.6 Hz, 2 H),
.00 (s, 2 H), 2.66 (d, J = 6.6 Hz, 2 H), 2.36 (s, 6 H).
157.7, 142.6, 135.1, 133.4, 132.2, 131.9, 131.4 ( J = 7.9 Hz), 131.3,
130.2, 128.8, 128.6 ( J = 20.0 Hz), 127.9, 127.8, 127.4 ( J = 7.3 Hz),
C,F C,F
126.6, 126.5, 126.5, 124.8 ( J = 8.0 Hz), 123.4, 123.0, 57.0, 45.8 (2 ×),
C,F
2
3
3
C,F
1
3
38.4.
C NMR (150 MHz, CDCl ): δ = 164.6, 164.2, 142.4, 135.2, 130.6,
3
19
1
30.3, 129.6, 128.5, 127.2, 127.0, 125.8, 122.7, 122.4, 122.0, 57.0, 45.8
F NMR (376.3 MHz, CDCl ): δ = –113.2.
3
(
2 ×), 38.2.
+
HRMS (ESI): m/z calcd for C29H23FN O [M + H] : 464.1774; found:
464.1775.
3
2
+
HRMS (ESI): m/z calcd for C22H22N O [M + H] : 360.1712; found:
3
2
360.1707.
9-(2-Chlorophenyl)-5-[2-(dimethylamino)ethyl]-4H-isoquinoli-
Pictet–Spengler Reactions To Form 7a; Typical Reactions
no[5,4-ab]phenanthridine-4,6(5H)-dione (7b)
Reaction in Phosphoric Acid (PA): To a stirred solution of compound 5
Prepared following the Typical Procedure 1 (PA). Purification by flash
column chromatography (230–400 mesh SiO , CH Cl /MeOH 23:0.1 to
(0.0506 g, 0.1407 mmol) in phosphoric acid (0.9 mL) was added 2-fluo-
2
2
2
robenzaldehyde (0.0299 mL, 0.2821mmol). The mixture was heated
at 140–150 °C for 2 h and the remaining 4 equiv of the corresponding
aldehyde were added in intervals of 2 equiv every 2 h. At the end of
the reaction, the mixture was poured into ice water and aq 14.2 N
KOH was added until pH 10. The mixture was filtered by suction and
15:0.1) afforded 7b as a pale-yellow solid; mp 144–146 °C; R = 0.37
f
(CH Cl /MeOH 1:0.1).
2
2
IR (KBr): 1702.8, 1660.4, 1600.6, 1436.7, 1384.6, 1357.6, 1241.9,
–1
1056.8 cm
.
1
H NMR (600 MHz, CDCl ): δ = 9.37 (d, J = 8.4 Hz, 1 H), 9.30 (s, 1 H),
3
the solid was washed with H O to afford a yellow-green solid.
2
9
7
7
.06 (d, J = 8.4 Hz, 1 H), 8.74 (d, J = 7.3 Hz, 1 H), 7.99 (d, J = 6.8 Hz, 1 H),
.97 (d, J = 7.6 Hz, 1 H), 7.91 (d, J = 8.2 Hz, 1 H), 7.77 (t, J = 7.7 Hz, 1 H),
.66 (t, J = 4.9 Hz, 1 H), 7.60 (t, J = 4.2 Hz, 1 H), 7.54–7.52 (m, 2 H), 4.41
Reaction in Trifluoromethanesulfonic Acid (TfOH): To a solution of
compound 5 (0.0307 g, 0.0854 mmol) in TfOH (1 mL) was added 2-
fluorobenzaldehyde (0.0181 mL, 0.1708 mmol) in a sealed tube. The
mixture was heated at 140–150 °C and the remaining 4 equiv of the
corresponding aldehyde were added in 2 equiv in every 2 h interval.
After the addition was completed, the mixture was heated for further
(t, J = 6.6 Hz, 2 H), 2.76 (t, J = 6.6 Hz, 2 H), 2.40 (s, 6 H).
13
C NMR (150 MHz, CDCl ): δ = 164.4, 163.6, 160.4, 142.5, 137.7,
3
135.1, 133.4, 133.3, 132.2, 131.3, 129.9, 128.7, 128.5, 127.9, 127.7,
127.5, 127.4, 127.3, 124.8, 123.3, 123.0, 56.8, 45.7 (2 ×), 38.2.
4
h. At the end of reaction time, the mixture was cooled in an ice bath
+
and aq KOH was added to the mixture until basic. The mixture was
filtered by suction and the solid was washed with water to afford a
black solid. The solid was purified by flash column chromatography
HRMS (ESI): m/z calcd for C29
H
23ClN
3
O
2
[M + H] : 480.1479; found:
480.1481.
(
230–400 mesh SiO , CH Cl /MeOH 23:0.3 to 15:0.3) to afford 7a as a
9-(2-Bromophenyl)-5-[2-(dimethylamino)ethyl]-4H-isoquinoli-
no[5,4-ab]phenanthridine-4,6(5H)-dione (7c)
2
2
2
pale-yellow solid; yield: 0.0073 g (18%).
Reaction in Trifluoroacetic Acid (TFA): To a solution of compound 5
Purification by flash column chromatography (230–400 mesh SiO2,
(0.0507 g, 0.1410 mmol) in TFA (1 mL) was added 2-fluorobenzalde-
CH Cl /MeOH 26:0.1 to 15:0.1) afforded 7c as a pale-yellow solid; mp
2
2
hyde (0.0299 mL, 0.2821 mmol) in a sealed tube. The mixture was
heated at 140–150 °C and the remaining 4 equiv of the corresponding
aldehyde were added in two equiv in every 2 h interval. After the ad-
dition was completed, the mixture was heated for further 3.5 d. At the
end of reaction time, the mixture was cooled in in ice bath and aq
KOH was added to the mixture until basic. The mixture was extracted
with CH Cl and the combined organic layers were dried (MgSO ). The
183–184 °C; R = 0.37 (CH Cl /MeOH 1:0.1).
IR (KBr): 1702.8, 1656.6, 1600.6, 1384.6, 1348.0, 1243.9, 1025.9 cm–1
f 2 2
.
1
H NMR (600 MHz, CDCl ): δ = 9.32 (d, J = 8.5 Hz, 1 H), 9.23 (s, 1 H),
3
9.04 (d, J = 8.3 Hz, 1 H), 8.73 (dd, J = 7.1 Hz, 1 H), 8.28 (d, J = 8.3 Hz, 1
H), 7.99 (d, J = 7.3 Hz, 1 H), 7.96 (d, J = 8.7 Hz, 1 H), 7.81–7.76 (m, 5 H),
4.39 (d, J = 6.6 Hz, 2 H), 2.72 (d, J = 6.6 Hz, 2 H), 2.38 (s, 6 H).
2
2
4
13C NMR (150 MHz, CDCl
): δ = 164.4, 163.6, 160.6, 142.3, 137.5,
resulting mixture was purified by flash column chromatography
230–400 mesh SiO , CH Cl /MeOH 23:0.3 to 15:0.3) to afford 7a as a
3
(
135.0, 133.2, 132.9, 131.9, 131.7, 131.2, 130.1, 128.7, 128.4, 127.8,
127.7, 127.4, 127.0, 124.2, 124.0, 123.3, 123.1, 57.0, 45.8 (2 ×), 38.4.
2
2
2
pale-yellow solid; yield: 0.0075 g (11%) (12% based on the recovery of
).
5
+
HRMS (ESI): m/z calcd for C29H23BrN O [M + H] : 524.0974; found:
3
2
Yields for products 7a–j are reported in Table 1 for the three typical
524.0974.
procedures.
9-(3-Fluorophenyl)-5-[2-(dimethylamino)ethyl]-4H-isoquinoli-
9-(2-Fluorophenyl)-5-[2-(dimethylamino)ethyl]-4H-isoquinoli-
no[5,4-ab]phenanthridine-4,6(5H)-dione (7d)
no[5,4-ab]phenanthridine-4,6(5H)-dione (7a)
Purification by flash column chromatography (230–400 mesh SiO2,
The solid was purified by flash column chromatography (230–400
CH
(CH
2
Cl
Cl
2
/MeOH 20:0.5) afforded 7d as a pale-yellow solid; R
/MeOH 1:0.1); mp 236–238 °C.
2
f
= 0.45
mesh SiO , CH Cl /MeOH 23:0.1 to 10:0.1) to afford 7a as a pale-yel-
2
2
2
2
low solid; mp 215–216 °C; R = 0.37 (CH Cl /MeOH 1:0.1).
IR (KBr): 1700.9, 1658.5, 1616.1, 1384.6, 1357.6, 1241.9 cm–1
IR (KBr): 1699.0, 1656.6, 1616.1, 1440.6, 1384.6, 1357.6, 1025.9 cm–1
f
2
2
.
.
1
H NMR (600 MHz, CDCl ): δ = 9.34 (d, J = 8.3 Hz, 1 H), 9.26 (s, 1 H),
3
1
H NMR (600 MHz, CDCl ): δ = 9.37 (d, J = 8.2 Hz, 1 H), 9.30 (s, 1 H),
9.06 (d, J = 8.5 Hz, 1 H), 8.74 (d, J = 7.2 Hz, 1 H), 8.32 (d, J = 8.3 Hz, 1 H),
8.00 (d, J = 7.5 Hz, 1 H), 7.98 (d, J = 8.8 Hz, 1 H), 7.81 (d, J = 7.3 Hz, 1 H),
7.66 (d, J = 7.4 Hz, 1 H), 7.62–7.57 (m, 2 H), 7.29 (t, J = 8.0 Hz, 1 H),
4.40 (t, J = 6.6 Hz, 2 H), 2.73 (t, J = 6.6 Hz, 2 H), 2.38 (s, 6 H).
3
9.07 (d, J = 8.5 Hz, 1 H), 8.75 (d, J = 7.1 Hz, 1 H), 8.08 (d, J = 5.5 Hz, 1 H),
8.00–7.96 (m, 2 H), 7.80 (t, J = 7.4 Hz, 2 H), 7.60–7.58 (m, 1 H), 7.44 (t,
J = 7.1 Hz, 1 H), 7.30 (t, J = 9.0 Hz, 1 H), 4.40 (t, J = 6.6 Hz, 2 H), 2.73 (t,
J = 6.6 Hz, 2 H), 2.38 (s, 6 H).
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

E
Synthesis
M.-C. Tsai et al.
Paper
1
3
1
13
1
C NMR (150 MHz, CDCl ): δ = 164.4, 163.6, 162.8 ( J = 246.0 Hz),
C NMR (150 MHz, CDCl ): δ = 164.4, 163.6, 163.5 ( J = 246.0 Hz),
3 C,F
3
C,F
3
3
3
1
1
1
1
60.4, 142.3, 140.7 ( J = 7.4 Hz), 140.7 ( J = 7.4 Hz), 135.0, 133.2,
32.9, 131.2, 130.2 ( J = 8.1 Hz), 13.1, 128.7, 128.6, 128.4, 127.8,
27.7, 127.4, 127.0, 125.8, 124.3, 123.4, 123.1, 117.1 ( J = 22.0 Hz),
16.3 ( J = 22.0 Hz), 57.0, 45.8 (2 ×), 38.4.
160.7, 142.3, 134.9, 134.7, 133.2, 132.9, 132.0 ( J = 8.0 Hz, 2 ×),
131.2, 130.1, 128.8, 128.6, 128.4, 127.7, 127.6, 127.4, 127.1, 124.1,
123.3, 123.0, 115.8 ( J = 21.0 Hz, 2 ×), 56.9, 45.8 (2 ×), 38.3.
C,F
C,F
C,F
3
C,F
2
2
C,F
C,F
2
C,F
19
F NMR (376.3 MHz, CDCl ): δ = –111.7.
3
19
F NMR (376.3 MHz, CDCl ): δ = –112.3.
+
3
HRMS (ESI): m/z calcd for C29H23FN O [M + H] : 464.1774; found:
464.1773.
3
2
+
HRMS (ESI): m/z calcd for C29H23FN O [M + H] : 464.1774; found:
3
2
464.1775.
9-(4-Chlorophenyl)-5-[2-(dimethylamino)ethyl]-4H-isoquinoli-
9-(3-Chlorophenyl)-5-[2-(dimethylamino)ethyl]-4H-isoquinoli-
no[5,4-ab]phenanthridine-4,6(5H)-dione (7h)
no[5,4-ab]phenanthridine-4,6(5H)-dione (7e)
Purification by flash column chromatography (230–400 mesh SiO2,
Purification by flash column chromatography (230–400 mesh SiO2,
CH Cl /MeOH 20:0.5) afforded 7h as a pale-yellow solid; mp 236–239
2
2
CH Cl /MeOH 22:0.3) afforded 7e as a pale-yellow solid; mp 236–238
°C; R = 0.37 (CH Cl /MeOH 1:0.1).
2
2
f 2 2
°
C; R = 0.45 (CH Cl /MeOH 1:0.1).
f 2 2
IR (KBr): 1702.8, 1660.4, 1600.6, 1384.6, 1357.6, 1241.0, 1091.0,
IR (KBr): 1699.0, 1654.6, 1598.7, 1432.9, 1357.6, 1079.9, 1025.0 cm–1
.
1016.0 cm
–1
.
1
1
H NMR (600 MHz, CDCl ): δ = 9.33 (d, J = 8.4 Hz, 1 H), 9.25 (s, 1 H),
H NMR (600 MHz, CDCl ): δ = 9.37 (d, J = 8.4 Hz, 1 H), 9.30 (s, 1 H),
3
3
9
.05 (d, J = 8.4 Hz, 1 H), 8.74 (d, J = 7.3 Hz, 1 H), 8.29 (d, J = 8.2 Hz, 1 H),
9.06 (d, J = 8.5 Hz, 1 H), 8.74 (d, J = 7.3 Hz, 1 H), 7.99 (d, J = 6.8 Hz, 1 H),
7.97 (d, J = 7.6 Hz, 1 H), 7.91 (d, J = 8.2 Hz, 1 H), 7.77 (t, J = 7.7 Hz, 1 H),
7.66 (t, J = 4.9 Hz, 1 H), 7.60 (t, J = 4.2 Hz, 1 H), 7.54–7.52 (m, 2 H), 4.41
(t, J = 6.6 Hz, 2 H), 2.76 (t, J = 6.6 Hz, 2 H), 2.40 (s, 6 H).
13
8.01–7.96 (m, 2 H), 7.88 (s, 1 H), 7.81 (t, J = 7.4 Hz, 1 H), 7.76 (d, J = 6.4
Hz, 1 H), 7.57–7.55 (m, 2 H), 4.39 (t, J = 6.6 Hz, 2 H), 2.72 (t, J = 6.6 Hz,
2
H), 2.38 (s, 6 H).
13
C NMR (150 MHz, CDCl ) δ = 164.4, 163.6, 160.3, 142.3, 140.4, 134.9,
C NMR (150 MHz, CDCl ): δ = 164.4, 163.6, 160.4, 142.5, 137.7,
3
3
1
34.7, 133.2, 132.9, 131.3, 130.2, 130.1, 129.9, 129.5, 128.8, 128.7,
135.1, 133.4, 133.3, 132.2, 131.3, 129.9, 128.7, 128.5, 127.9, 127.7,
127.5, 127.4, 127.3, 124.8, 123.3, 123.0, 56.8, 45.6 (2 ×), 38.2.
128.4, 128.2, 127.7, 127.4, 127.0, 124.3, 123.4, 123.1, 57.0, 45.8, 38.4.
+
+
HRMS (ESI): m/z calcd for C29H23ClN O [M + H] : 480.1479; found:
HRMS (ESI): m/z calcd for C29H23ClN O [M + H] : 480.1479; found:
3
2
3
2
480.1476.
480.1478.
9
-(3-Bromophenyl)-5-[2-(dimethylamino)ethyl]-4H-isoquinoli-
9-(4-Bromophenyl)-5-[2-(dimethylamino)ethyl]-4H-isoquinoli-
no[5,4-ab]phenanthridine-4,6(5H)-dione (7i)
no[5,4-ab]phenanthridine-4,6(5H)-dione (7f)
Purification by flash column chromatography (230–400 mesh SiO2,
Purification by flash column chromatography (230–400 mesh SiO2,
CH Cl /MeOH 25:0.3 to 20:0.3) afforded 7f as a pale-yellow solid; mp
CH Cl /MeOH 25:0.5) afforded 7i as a pale-yellow solid; mp 251–252
2
2
2
2
2
38–242 °C; R = 0.45 (CH Cl /MeOH 1:0.1).
°C; R = 0.37 (CH Cl /MeOH 1:0.1).
f
2
2
f 2 2
IR (KBr): 1700.9, 1658.5, 1600.6, 1434.8, 1355.7, 1241.9, 1155.0 cm–1
.
IR (KBr): 1702.8, 1658.5, 1618.0, 1436.7, 1384.6, 1346.1, 1241.9,
1089.0, 1024.0 cm .
–1
1
H NMR (600 MHz, CDCl ): δ = 9.33 (d, J = 8.3 Hz, 1 H), 9.25 (s, 1 H),
3
1
9
1
7
.06 (d, J = 8.5 Hz, 1 H), 8.74 (dd, J = 7.4, 1.4 Hz, 1 H), 8.29 (d, J = 8.3 Hz,
H), 8.03 (t, J =1.7 Hz, 1 H), 8.02–7.97 (m, 2 H), 7.84–7.80 (m, 2 H),
.74–7.70 (m, 1 H), 7.50 (t, J = 7.9 Hz, 1 H), 4.40 (t, J = 7.2 Hz, 2 H), 2.72
H NMR (600 MHz, CDCl ): δ = 9.37 (d, J = 8.5 Hz, 1 H), 9.29 (s, 1 H),
3
9.07 (d, J = 8.5 Hz, 1 H), 8.74 (d, J = 7.4 Hz, 1 H), 8.07–7.96 (m, 2 H),
7.89 (d, J = 7.5 Hz, 1 H), 7.79 (d, J = 7.2 Hz, 1 H), 7.76 (d, J = 7.7 Hz, 1 H),
7.63 (dd, J = 7.4, 1.7 Hz, 1 H), 7.57 (td, J = 7.5, 0.9 Hz, 1 H), 7.45 (td, J =
7.7, 1.7 Hz, 1 H), 4.39 (t, J = 7.2 Hz, 2 H), 2.71 (t, J = 7.2 Hz, 2 H), 2.37 (s,
(t, J = 7.2 Hz, 2 H), 2.38 (s, 6 H).
13
C NMR (150 MHz, CDCl ) δ = 164.4, 163.6, 160.2, 142.3, 140.7, 134.9,
3
6
H).
133.2, 132.9, 132.8, 132.4, 131.3, 130.2, 130.0, 128.8, 128.7, 128.4,
13
127.8, 127.7, 127.5, 127.0, 124.3, 123.1, 122.8, 57.0, 45.8 (2 ×), 38.4.
C NMR (150 MHz, CDCl ): δ = 164.4, 163.6, 161.5, 142.4, 139.6,
3
+
135.0, 133.4, 133.1, 132.2, 131.3, 131.2, 130.6, 130.2, 128.7, 128.5,
HRMS (ESI): m/z calcd for C29H23BrN O [M + H] : 524.0974; found:
3
2
127.8, 127.7, 127.5, 127.4, 124.8, 123.3, 123.0, 122.8, 56.9, 45.8 (2 ×),
524.0974.
38.3.
+
HRMS (ESI): m/z calcd for C29H23BrN O [M + H] : 524.0974; found:
9
-(4-Fluorophenyl)-5-[2-(dimethylamino)ethyl]-4H-isoquinoli-
3
2
524.0969.
no[5,4-ab]phenanthridine-4,6(5H)-dione (7g)
Purification by flash column chromatography (230–400 mesh SiO2,
9
-(4-Methoxyphenyl)-5-[2-(dimethylamino)ethyl]-4H-isoquinoli-
CH Cl /MeOH 16:0.5) afforded 7g as a pale-yellow solid; mp 241–245
2
2
no[5,4-ab]phenanthridine-4,6(5H)-dione (7j)
°
C; R = 0.37 (CH Cl /MeOH 1:0.1).
f 2 2
Purification by flash column chromatography (230–400 mesh SiO2,
IR (KBr): 1702.8, 1658.5, 1602.6, 1384.6, 1355.7, 1240.0, 1159.0,
–1
CH Cl /MeOH 21.5:0.5) afforded 7j as a yellow solid; mp 170–172 °C;
2 2
1024.0 cm .
R = 0.5 (CH Cl /MeOH 1:0.1).
f
2
2
1
H NMR (600 MHz, CDCl ): δ = 9.31 (d, J = 8.3 Hz, 1 H), 9.23 (s, 1 H),
3
IR (KBr): 1700.9, 1658.5, 1602.6, 1384.6, 1357.6, 1243.0, 1025.0 cm–1
.
9
.03 (d, J = 8.3 Hz, 1 H), 8.72 (d, J = 7.3 Hz, 1 H), 8.29 (d, J = 8.2 Hz, 1 H),
.99 (d, J = 8.3 Hz, 1 H), 7.97 (d, J = 7.5 Hz, 1 H), 7.89 (d, J = 5.5 Hz, 1 H),
.88 (d, J = 5.5 Hz, 1 H), 7.80 (t, J = 7.7 Hz, 1 H), 7.31 (t, J = 8.5 Hz, 2 H),
.39 (t, J = 6.6 Hz, 2 H), 2.72 (t, J = 6.6 Hz, 2 H), 2.38 (s, 6 H).
1
7
7
4
H NMR (600 MHz, CDCl ): δ = 9.31 (d, J = 8.5 Hz, 1 H), 9.25 (s, 1 H),
3
9.01 (d, J = 8.4 Hz, 1 H), 8.71 (dd, J = 7.3, 0.8 Hz, 1 H), 8.38 (d, J = 8.2 Hz,
1 H), 7.97–7.94 (m, 2 H), 7.87 (dd, J = 6.7, 1.9 Hz, 2 H), 7.78 (t, J = 7.1
Hz, 1 H), 7.15 (d, J = 8.6 Hz, 2 H), 4.40 (t, J = 7.2 Hz, 2 H), 3.94 (s, 3 H),
2.73 (t, J = 7.2 Hz, 2 H), 2.39 (s, 6 H).
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F

F
Synthesis
M.-C. Tsai et al.
Paper
1
3
C NMR (150 MHz, CDCl ): δ = 164.5, 163.7, 161.5, 160.8, 142.4,
Org. Lett. 2015, 17, 2692. (g) Li, J.; Wang, H.; Sun, J.; Yang, Y.; Liu,
L. Org. Biomol. Chem. 2014, 12, 7904. (h) Chu, W.; Chepetan, A.;
Zhou, D.; Shoghi, K. I.; Xu, J.; Dugan, L. L.; Gropler, R. J.; Mintun,
M. A.; Mach, R. H. Org. Biomol. Chem. 2014, 12, 4421. (i) Bao, X.;
Yao, W.; Zhu, O.; Xu, Y. Eur. J. Org. Chem. 2014, 7443. (j) Deb, I.;
Yoshikai, N. Org. Lett. 2013, 15, 4254. (k) Budén, M. E.; Dorn, V.
B.; Gamba, M.; Pierini, A. B.; Rossi, R. A. J. Org. Chem. 2010, 75,
3
1
1
35.1, 133.1, 133.0, 131.6, 131.0, 129.9, 129.2, 128.5, 127.6, 127.3,
27.2, 123.9, 123.3, 122.8, 114.2, 56.9, 55.0, 45.7 (2 ×), 38.3.
+
HRMS (ESI): m/z calcd for C30H26N O [M + H] : 476.1974; found:
4
3
3
76.1972.
2
8
206. (l) Budén, M. E.; Rossi, R. A. Tetrahedron Lett. 2007, 48,
739. (m) Hanaoka, M.; Yamagishi, H.; Mukai, C. Chem. Pharm.
Funding Information
Bull. 1985, 33, 1763.
The work was supported by the Ministry of Science and Technology
(
6) For reviews and selected syntheses, see: (a) Heravi, M. M.;
Zadsirjan, V.; Malmir, M. Molecules 2018, 23, 943. (b) Qi, L.;
Hou, H.; Ling, F.; Zhong, W. Org. Biomol. Chem. 2018, 16, 566.
(MOST 104-2113-M-032-002) in Taiwan.
M
i
n
i
stry of
S
c
i
e
n
c
e
a
n
d
T
e
c
h
n
o
l
o
g
y
(M
O
S
T
1
0
4-2
1
1
3-M -0
3
2-0
0
2)
(
c) Kulakov, I. V.; Shatsauskas, A. L.; Matsukevich, M. V.;
Acknowledgment
Palamarchuk, I. V.; Seilkhanov, T. M.; Gatilov, Y. V.; Fisyuk, A. S.
Synthesis 2017, 49, 3700. (d) Schulze, M.; Philipp, M.; Waigel,
W.; Schmidt, D.; Würthner, F. J. Org. Chem. 2016, 81, 8394.
We thank the precision instruments center of the National Taiwan
Normal University for HRMS measurements.
(e) Chrzanowska, M.; Grajewska, A.; Rozwadowska, M. D. Chem.
Rev. 2016, 116, 12369. (f) Zhang, X.; Xu, X.; Yu, L.; Zhao, Q. Tetra-
hedron Lett. 2014, 55, 2280. (g) Youn, S. W.; Bihn, J. H. Tetrahe-
dron Lett. 2009, 50, 4598. (h) Stöckigt, J.; Antonchick, A. P.; Wu,
F.; Waldmann, H. Angew. Chem. Int. Ed. 2011, 50, 8538. (i) Cox, E.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610670. Spectra of the new com-
D.; Cook, J. M.
Chem. Rev. 1995, 95, 1797.
7) (a) Al-Salahi, R.; Alswaidan, I.; Marzouk, M. Int. J. Mol. Sci. 2014,
5, 22483. (b) Mukherjee, A.; Dutta, S.; Shanmugavel, M.;
pounds are included.
S
u
p
p
orit
n
g Inform ati
o
n
S
u
p
p
orti
n
g Inform ati
o
n
(
1
Mondhe, D. M.; Sharma, P. R.; Singh, S. K.; Saxena, A. K.; Sanyal,
U. J. Exp. Clin. Cancer Res. 2010, 29, 175. (c) Yang, P.; Yang, Q.;
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©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–F