Synthesis of Indolo[2,1- a ]isoquinolines via Copper-Catalyzed C-C Coupling and Cyclization of 2-(2-Bromoaryl)-1 H -indoles with 1,3-Diketones

Article abstract of DOI:10.1055/s-0036-1591589

2-(2-Bromoaryl)-1 H -indoles are coupled and cyclized with 1,3-diketones by microwave irradiation in DMF in the presence of a catalytic amount of copper(I) iodide along with a base to afford the corresponding indolo[2,1- a ]isoquinolines in moderate to good yields.

Full text of DOI:10.1055/s-0036-1591589

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–G
paper
A
en
H. K. Lee et al.
Paper
Synthesis
Synthesis of Indolo[2,1-a]isoquinolines via Copper-Catalyzed
C–C Coupling and Cyclization of 2-(2-Bromoaryl)-1H-indoles with
1,3-Diketones
Ha Kyeong Leea
Pham Duy Quang Daoa
Young-su Kimb
R3
R2
R3
R2
O
R7
R4
CuI, K3PO4, DMF
R6
R5
N
R1
+
Chan Sik Cho*a
N
130 °C, 1 h
microwave irradiation
R1
H
O
R5
R4
Br
a Department of Applied Chemistry, Kyungpook National
University, 80 Daehakro, Bukgu, Daegu 41566, Republic
of Korea
cscho@knu.ac.kr
b School of Hotel Culinary, Kyungdong University, Sokcho
217-711, Republic of Korea
O
R6 R7
18 examples
yield up to 77%
Received: 23.03.2018
Accepted after revision: 23.04.2018
Published online: 12.06.2018
and 2-(2-bromoaryl)benzimidazoles are coupled and cy-
clized with 1,3-diketones in the presence of a copper cata-
lyst to give benzo[4,5]imidazo[1,2-a]pyridines and -iso-
quinolines.10
DOI: 10.1055/s-0036-1591589; Art ID: ss-2018-f0198-op
Abstract 2-(2-Bromoaryl)-1H-indoles are coupled and cyclized with
1,3-diketones by microwave irradiation in DMF in the presence of a cat-
alytic amount of copper(I) iodide along with a base to afford the corre-
sponding indolo[2,1-a]isoquinolines in moderate to good yields.
Isoquinoline
N
Indole
Key words copper, coupling, cyclization, heterocycles, fused-ring sys-
tems
Figure 1 Indolo[2,1-a]isoquinoline
It is known that indole-fused isoquinolines, indolo[2,1-
a]isoquinolines, and their reduced 5,6-dihydro analogues,
are used as biologically active pharmaceuticals as well as
solid-state fluorescent materials (Figure 1).1,2 Besides con-
ventional synthetic routes for indolo[2,1-a]isoquinoline
scaffold,1a,b,3 transition-metal-catalyzed versions also have
been attempted as alternative methods due to the wide
availability of substrates. It is reported that indoles undergo
hydroamination and cyclization with 2-bromoarylalkynes
in the presence of CuI along with benzotriazo-1-ylmethanol
as ligand to give indolo[2,1-a]isoquinolines.4 Such a similar
cyclization is also exemplified with 2-(2-ethynylphenyl)in-
dole catalyzed by platinum(II) chloride.5 Miura and Huang
have demonstrated that indolo[2,1-a]isoquinolines can be
synthesized by rhodium-catalyzed oxidative coupling and
cyclization of 2-arylindoles and aryltriazenes with alkynes
via C–H and N–H bond activations.2,6 Koning et al. have
shown that 2-bromo-3-methylindole reacts with 2-acetyl-
phenylboronic acid in the presence of a palladium catalyst
to give Suzuki–Miyaura coupling product, which triggers
subsequent cyclization and dehydration to afford indo-
lo[2,1-a]isoquinoline scaffold.7 During the course of our
continuing studies directed towards copper-catalyzed cou-
pling and cyclization reactions for the synthesis of N-fused
hybrid scaffolds,8,9 we have shown that 2-(2-bromovinyl)-
It is known that copper salts catalyze cross-coupling of
aryl and vinyl halides with activated methylene com-
pounds.10–14 Such an intrinsic copper-catalyzed coupling
and cyclization protocol using 1,3-diketones as building
blocks led us to search for a new synthetic method for N-
fused hybrid scaffolds.15 This report describes a new syn-
thetic method for indole-fused isoquinolines, indolo[2,1-
a]isoquinolines from 2-(2-bromoaryl)-1H-indoles and 1,3-
diketones via copper-catalyzed C–C coupling and cycliza-
tion under microwave irradiation conditions.
The results of several attempted coupling and cycliza-
tion of 2-(2-bromophenyl)-1H-indole (1a) with cyclohex-
ane-1,3-dione (2a) for the optimization of reaction condi-
tions are listed in Table 1. Treatment of 1a with equimolar
amount of 2a in DMF at 130 °C for 1 hour in the presence of
10 mol% of CuI along with K3PO4 under microwave irradia-
tion (100 W of initial power) afforded 7,8-dihydroindo-
lo[1,2-f]phenanthridin-5(6H)-one (3a) in 35% isolated yield
(Table 1, entry 1). The molar ratio of 2a to 1a affects the
yield of 3a with the yield increasing with an increase of the
molar ratio up to 2.0 (entries 1–3). The yield of 3a increases
on prolonging the reaction time up to 1 hour with complete
conversion of 1a, which was monitored until 1a had disap-
peared on TLC (entries 3 and 4). Lower reaction tempera-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

B
H. K. Lee et al.
Paper
Synthesis
ture resulted in a decreased yield of 3a (entry 5). The
amount of base is critical for the effective formation of 3a
(entry 6). No significant change of the yield of 3a was ob-
served with dilution of the reaction mixture (entry 7). The
reaction also proceeded in the presence of other inorganic
bases such as K2CO3, Cs2CO3, NaOt-Bu, and NaOAc, but the
yields of 3a were generally lower than that obtained in the
presence of K3PO4 (entries 8–11). We recently reported that
copper powder combined with microwave irradiation
shows an efficient catalytic activity for the synthesis of sev-
eral heterocycles by C–C or C–N bond coupling and cycliza-
tion protocol.11,16 However, such a combined system was re-
vealed to be ineffective for the present reaction (entry 12).
The reaction proceeded using other copper(I) salts such as
CuCl, CuBr, and Cu2O but the yield of 3a was lower than that
by the use of CuI (entries 13–15). CuO exhibited the same
catalytic activity as CuI (entry 16). Finally, lower yield was
observed under usual heating conditions (screw-capped vi-
al, 130 °C for 24 h) (entries 3 and 17). The best results in
terms of the yield of product 3a and complete conversion of
1a were achieved by using the set of reaction conditions
shown in entry 3 of Table 1.
After the reaction conditions had been established, vari-
ous 2-(2-bromoaryl)-1H-indoles 1 were subjected to the re-
action with 1,3-diketones 2 to investigate the scope of the
reaction and several representative results are summarized
in Table 2. The coupling and cyclization of 2-(2-bromoaryl)-
1H-indoles 1a and 1b with cyclic 1,3-diketones 2a–d af-
forded the corresponding indolo[2,1-a]isoquinolines 3a–g)
in 55–74% yields. Easily available 2-(2-bromoaryl)-1H-
indoles 1c–f having straight and branched alkyl chain and
phenyl at position 3 (R2) of indole moiety reacted with 2a to
give the corresponding indolo[2,1-a]isoquinolines 3h–k in
allowable yields irrespective of the identity of R2. From the
reaction of various 2-(2-bromoaryl)-1H-indoles 1g–k hav-
ing electron-donating and -withdrawing substituents (R1
and R3) on bromoaryl or indole moieties with 2a, the corre-
sponding indolo[2,1-a]isoquinolines 3l–p were also formed
in 49–75% yields.
Table 1 Optimization of Conditions for the Reaction of 1a with 2aa
O
Cu catalyst
N
+
N
base, DMF
H
O
microwave irradiation
Br
O
1a
2a
3a
Not shown in Table 2 are the reactions of 2-(2-bro-
moaryl)-1H-indoles having R1 (OMe) at para-position to Br
and R3 (Me, Cl) at ortho-position to N on indole moiety,
which did not proceed at all toward the coupling and cy-
clization; several unidentified products were formed. It ap-
pears that the position of substituents (R3) on the indole
moiety of 1 had significant impact on the product forma-
tion. Benzo-fused 2-(2-bromophenyl)-1H-indole 1l similar-
ly coupled and cyclized with 2a to give 9,10-dihydroben-
zo[i]indolo[1,2-f]phenanthridin-7(8H)-one (3q) in 58%
yield. Starting indole 1a coupled and regioselectively cy-
clized with 4,4-dimethylcyclohexane-1,3-dione (2e) to af-
ford 6,6-dimethyl-7,8-dihydroindolo[1,2-f]phenanthridin-
5(6H)-one (3r) in 77% yield. Similar treatment of 1a with
acyclic 1,3-diketone, 1,3-diphenylpropane-1,3-dione (2f)
under the employed conditions gave coupled and deacyla-
tive cyclized product 3s in only 18% yield.10 Slightly in-
creased yield (26%) of 3s was observed by the treatment of
two-fold amount of CuI under the employed conditions.
The reaction of 1a with 2-methylcyclohexane-1,3-dione
under the employed conditions did not proceed at all to-
ward coupled and cyclized product, with 2-phenylindole by
debromination of 1a being formed in 83% yield.
Entry
[2a]/[1a]
Cu catalyst
Base
K3PO4
Yield (%)b
1
2
1.0
1.5
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
CuI
35
63
74
60
19
17
67
35
41
48
32
29
64
59
68
74
50
CuI
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K2CO3
Cs2CO3
NaOt-Bu
NaOAc
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
3
CuI
4c
5d
6e
7f
CuI
CuI
CuI
CuI
8
CuI
9
CuI
10
11
12
13
14
15
16
17g
CuI
CuI
Cu powder
CuCl
CuBr
Cu2O
CuO
CuI
a Reaction conditions: 1a (0.3 mmol), Cu catalyst (0.03 mmol), base (0.6
mmol), and DMF (3 mL), 130 °C, 1 h, microwave irradiation (100 W of initial
power), unless otherwise stated.
Indole-fused isoquinolines 3a–c can be converted into
N-fused trinuclear hybrid scaffolds 4a–c by a one-pot pro-
cedure (Scheme 1). Sequential reduction of 3a–c to alcohols
with NaBH4 in MeOH, dehydration of the alcohols with
p-TsOH in benzene, and oxidation with DDQ in benzene af-
forded 4a–c in 60–73% yields.17
b Isolated yield.
c Reaction time: 30 min.
d Reaction temperature: 100 °C.
e Base (0.3 mmol).
f DMF (5 mL).
g Under usual heating (screw-capped vial, 130 °C for 24 h).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

C
H. K. Lee et al.
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Synthesis
Table 2 CuI-Calatyzed Synthesis of Indolo[2,1-a]isoquinolines 3 from
1 and 2a
1
2
3
Yield (%)
R3
R2
R3
+
R2
O
CuI, K3PO4
DMF
N
R7
R4
N
R1
R6
R5
N
H
N
130 °C, 1 h
microwave
irradiation
R1
Br
H
O
R5
R4
O
O
Br
R6 R7
1e
2a
2a
2a
2a
3j
72
66
59
49
2a R4 = R5 = R6 = R7 = H
1
3
2b R4 = R6 = R7 = H; R5 = Me
2c R4 = R6 = R7 = H; R5 = Ph
2d R4 = R5 = Me; R6 = R7 = H
2e R4 = R5 = H; R6 = R7 = Me
Ph
Ph
N
N
H
Br
1
2
3
Yield (%)
O
1f
3k
N
N
H
R5
N
Br
N
O
R4
H
Me
Me
Br
2a
2b
2c
2d
3a
3b
3c
3d
74
67
63
59
O
1a
1g
3l
F
N
F
N
N
H
N
H
Br
R5
O
Br
O
R4
1h
3m
3n
3o
2a
2c
2d
3e
3f
3g
64
55
72
Me
1b
Me
n-Bu
N
n-Bu
N
H
N
Br
N
H
O
Br
1i
2a
56
O
OMe
1c
2a
3h
51
OMe
5
N
5
N
H
N
N
H
Br
O
Br
O
1j
2a
54
1d
2a
3i
54
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

D
H. K. Lee et al.
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Synthesis
1
2
3
Yield (%)
[1] NaBH4, MeOH/THF, rt, 1 h
Cl
N
N
Cl
[2] p-TsOH, benzene, reflux, 1 h
[3] DDQ, benzene, 50 °C, 24 h
N
R
O
R
N
H
4a R = H (72%)
3a R = H
4b R = Me (73%)
4c R = Ph (60%)
3b R = Me
3c R = Ph
Br
O
Scheme 1 One-pot reduction–dehydration–oxidation of 3 to 4
1k
2a
3p
75
As to the reaction pathway, this seems to proceed via an
initial formation of C–C coupled intermediate 5 by copper-
catalyzed C–C coupling between 1a and 2 (Scheme 2). It is
reported that aryl and vinyl halides are found to couple
with 1,3-dicarbonyl compounds in the presence of a copper
salt to give 2-aryl- and 2-vinyl-1,3-dicarbonyl intermedi-
ates or products.10–14 This is followed by cyclocondensation
(cyclic 1,3-diketone) to give 3a or deacylative cycloconden-
sation (acyclic 1,3-diketone) to give 3s.10,13a,18
N
N
H
Br
O
1l
2a
3q
58
N
In summary, we have shown that 2-(2-bromoaryl)-1H-
indoles react with 1,3-diketones by microwave irradiation
in the presence of copper(I) iodide and K3PO4 to give in-
dole-fused isoquinolines and indolo[2,1-a]isoquinolines via
coupling and cyclization process. The present reaction pro-
vides a new method for the synthesis of such scaffolds. Fur-
ther attempts on the syntheses of N-fused hybrid scaffolds
using copper-catalyzed coupling and cyclization reaction
are underway.
O
1a
1a
2e
3r
3s
77
N
Ph
2f
26b
a Reaction conditions: 1 (0.3 mmol), 2 (0.6 mmol), CuI (0.03 mmol), K3PO4
(0.6 mmol), DMF (3 mL), 130 °C, 1 h, microwave irradiation (100 W of ini-
tial power), unless otherwise stated.
1H (500 MHz) and 13C NMR (125 MHz) spectra were recorded on a
Bruker Avance III 500 spectrometer using TMS as an internal stan-
dard. Melting points were determined on a Standford Research Inc.
MPA100 automated melting point apparatus. High-resolution mass
b CuI used: 0.06 mmol.
O
O
CuI, K3PO4
DMF
N
H
COR
+
N
R
R
H
Br
COR
1a
2
5
(CH2)3
N
N
R–R =
OH
– H2O
cyclic 1,3-diketone
O
O
3a
5
R–R = Ph
N
H
N
N
OH
Ph
acyclic 1,3-diketone
– H2O
Ph
3s
O
Ph
Scheme 2 Reaction pathway
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

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H. K. Lee et al.
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Synthesis
data were recorded using electronic ionization (HRMS-EI, magnetic
sector-electric sector double focusing mass analyzer) at the Korea
Basic Science Center, Daegu, Korea. All microwave reactions (CEM,
Discover LabMate) were carried out in sealed tube (5 mL) and mainte-
nance of the reaction temperature was monitored by an external in-
frared sensor. The isolation of pure products was carried out via TLC
(silica gel 60 GF254, Merck). The starting 2-(2-bromoaryl)-1H-indoles
were prepared from the corresponding bromoketones and arylhydra-
zines according to literature procedures.19 Commercially available or-
ganic and inorganic compounds were used without further purifica-
tion.
HRMS (EI): m/z [M+] calcd for C26H19NO: 361.1467; found: 361.1468.
7,7-Dimethyl-7,8-dihydroindolo[1,2-f]phenanthridin-5(6H)-one
(3d)
Yellow solid; yield: 55 mg (59%); mp 228–229 °C (hexane).
1H NMR (500 MHz, CDCl3): δ =1.22 (s, 6 H), 2.60 (s, 2 H), 3.44 (s, 2 H),
7.20 (s, 1 H), 7.30–7.33 (m. 1 H), 7.39–7.42 (m, 1 H), 7.44–7.47 (m, 1
H), 7.49–7.52 (m, 1 H), 7.79 (d, J = 7.8 Hz, 1 H), 8.06 (d, J = 8.2 Hz, 2 H),
9.25–9.27 (m, 1 H).
13C NMR (125 MHz, CDCl3): δ = 28.54, 32.32, 44.14, 52.32, 96.90,
112.36, 116.39, 121.05, 121.57, 122.98, 123.35, 124.46, 125.70,
126.75, 127.20, 128.34, 131.48, 133.51, 136.37, 149.00, 197.75.
Indolo[2,1-a]isoquinolines 3; General Procedure
HRMS (EI): m/z [M+] calcd for C22H19NO: 313.1467; found: 313.1468.
A 5 mL microwave reaction tube was charged with 2-(2-bromoaryl)-
1H-indole 1 (0.3 mmol), 1,3-diketone 2 (0.6 mmol), K3PO4 (0.127 g,
0.6 mmol), CuI (0.006 g, 0.03 mmol), and DMF (3 mL). After stirring at
r.t. for 5 min, the reaction mixture was heated at 130 °C for 1 h under
microwave irradiation at 100 W of initial power. The mixture was
then cooled to r.t., and filtered through a short silica gel column
(CH2Cl2–MeOH) to remove inorganic salts. Evaporation of the solvent
gave a crude mixture that was purified by TLC [silica gel 60 GF254
(Merck), CH2Cl2–MeOH] to give 3.
14-Methyl-7,8-dihydroindolo[1,2-f]phenanthridin-5(6H)-one (3e)
Yellow solid; yield: 57 mg (64%); mp 157–158 °C (hexane).
1H NMR (500 MHz, CDCl3): δ = 2.12–2.17 (m, 2 H), 2.55 (s, 3 H), 2.64–
2.66 (m, 2 H), 3.36 (t, J = 6.1 Hz, 2 H), 7.26–7.29 (m, 1 H), 7.38–7.42
(m, 2 H), 7.43–7.46 (m, 1 H), 7.70 (d, J = 7.9 Hz, 1 H), 7.90 (d, J = 8.6 Hz,
1 H), 8.07 (d, J = 7.7 Hz, 1 H), 9.19–9.20 (m, 1 H).
13C NMR (125 MHz, CDCl3): δ = 11.69, 21.35, 30.65, 38.68, 107.69,
112.87, 116.11, 118.64, 121.80, 122.74, 124.15, 126.12, 126.39,
126.57, 126.74, 127.21, 130.78, 132.00, 132.50, 151.10, 197.12.
Except for known 3s,4 all new products were characterized spectro-
scopically.
HRMS (EI): m/z [M+] calcd for C21H17NO: 299.1310; found: 299.1313.
7,8-Dihydroindolo[1,2-f]phenanthridin-5(6H)-one (3a)
Yellow solid; yield: 63 mg (74%); mp 161–163 °C (hexane).
14-Methyl-7-phenyl-7,8-dihydroindolo[1,2-f]phenanthridin-
5(6H)-one (3f)
1H NMR (500 MHz, CDCl3): δ = 2.23–2.28 (m, 2 H), 2.71–2.73 (m, 2 H),
3.57 (t, J = 6.2 Hz, 2 H), 7.16 (s, 1 H), 7.28–7.31 (m, 1 H), 7.37–7.40 (m,
1 H), 7.42–7.45 (m, 1 H), 7.47–7.51 (m, 1 H), 7.77 (d, J = 7.4 Hz, 1 H),
8.01–8.05 (m, 2 H), 9.20–9.22 (m, 1 H).
13C NMR (125 MHz, CDCl3): δ = 21.55, 30.74, 38.98, 97.12, 113.64,
116.35, 121.21, 121.81, 123.17, 123.53, 124.64, 126.14, 127.06,
127.36, 128.48, 131.64, 133.68, 136.33, 151.07, 197.69.
Yellow solid; yield: 62 mg (55%); mp 166–168 °C (hexane).
1H NMR (500 MHz, CDCl3): δ = 2.59 (s, 3H), 2.90–2.92 (m, 2 H), 3.32–
3.46 (m, 2 H), 3.78–3.82 (m, 1 H), 7.22–7.25 (m, 1 H), 7.33–7.36 (m, 3
H) , 7.38–7.49 (m, 5 H), 7.72–7.74 (m, 1 H), 7.81 (d, J = 8.6 Hz, 1 H),
8.11–8.13 (m, 1 H), 9.27–9.29 (m, 1 H).
13C NMR (125 MHz, CDCl3): δ = 11.75, 38.42, 39.42, 45.23, 107.95,
112.57, 116.17, 118.72, 122.01, 122.92, 124.21, 126.17, 126.35,
126.58, 126.78, 126.87, 127.35, 129.03, 130.86, 131.94, 132.57,
142.50, 150.23, 196.40.
HRMS (EI): m/z [M+] calcd for C20H15NO: 285.1154; found: 285.1155.
7-Methyl-7,8-dihydroindolo[1,2-f]phenanthridin-5(6H)-one (3b)
Yellow solid; yield: 60 mg (67%); mp 158–160 °C (hexane).
HRMS (EI): m/z [M+] calcd for C27H21NO: 375.1623; found: 375.1625.
1H NMR (500 MHz, CDCl3): δ = 1.28 (d, J = 6.2 Hz, 3 H), 2.36–2.48 (m, 2
H), 2.73–2.76 (m, 1 H), 3.08–3.13 (m, 1 H), 3.70–3.74 (m, 1 H), 7.16 (s,
1 H), 7.29–7.32 (m, 1 H), 7.38–7.41 (m, 1 H), 7.42–7.45 (m, 1 H), 7.47–
7.50 (m, 1 H), 7.77 (dd, J = 7.8, 0.4 Hz, 1 H), 8.01–8.05 (m, 2 H), 9.22
(dd, J = 8.3, 1.0 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 21.22, 28.72, 38.51, 46.82, 96.89,
113.05, 116.20, 121.01, 121.58, 122.96, 123.33, 124.41, 125.87,
126.74, 127.16, 128.29, 131.44, 133.46, 136.16, 150.26, 197.64.
7,7,14-Trimethyl-7,8-dihydroindolo[1,2-f]phenanthridin-5(6H)-
one (3g)
Yellow solid; yield: 71 mg (72%); mp 70–73 °C (hexane).
1H NMR (500 MHz, CDCl3): δ = 1.16 (s, 6 H), 2.55 (s, 2 H), 2.65 (s, 3 H),
3.31 (s, 2 H), 7.31–7.34 (m, 1 H), 7.41–7.50 (m, 3 H), 7.75–7.77 (m, 1
H), 7.96 (d, J = 8.6 Hz, 1 H), 8.17–8.19 (m, 1 H), 9.27–9.28 (m, 1 H).
13C NMR (125 MHz, CDCl3): δ = 11.85, 28.49, 32.37, 44.33, 52.28,
107.71, 111.86, 116.41, 118.76, 121.82, 122.84, 124.18, 126.27,
126.38, 126.53, 126.68, 127.36, 131.15, 132.11, 132.67, 149.20,
197.44.
HRMS (EI): m/z [M+] calcd for C21H17NO: 299.1310; found: 299.1312.
7-Phenyl-7,8-dihydroindolo[1,2-f]phenanthridin-5(6H)-one (3c)
Yellow solid; yield: 68 mg (63%); mp 242–244 °C (hexane).
HRMS (EI): m/z [M+] calcd for C23H21NO: 327.1623; found: 327.1624.
1H NMR (500 MHz, CDCl3): δ = 2.96–3.06 (m, 2 H), 3.53–3.63 (m, 2 H),
4.00–4.03 (m, 1 H), 7.23–7.26 (m, 2 H), 7.35–7.40 (m, 4 H), 7.44–7.55
(m, 4 H), 7.79 (d, J = 7.8 Hz, 1 H), 7.95 (d, J = 8.7 Hz, 1 H), 8.07–8.09 (m,
1 H), 9.28 (d, J = 8.1 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 38.44, 39.43, 45.30, 97.15, 113.23,
116.18, 121.08, 121.80, 123.04, 123.49, 124.53, 125.81, 126.83,
126.87, 127.39, 127.48, 128.42, 129.12, 131.47, 133.44, 136.22,
142.39, 150.01, 196.75.
14-Butyl-7,8-dihydroindolo[1,2-f]phenanthridin-5(6H)-one (3h)
Yellow solid; yield: 52 mg (51%); mp 124–127 °C (hexane).
1H NMR (500 MHz, CDCl3): δ = 1.01 (t, J = 7.4 Hz, 3 H), 1.51–1.59 (m, 2
H), 1.73–1.80 (m, 2 H), 2.22–2.27 (m, 2 H), 2.71–2.74 (m, 2 H), 3.19–
3.23 (m, 2 H), 3.60 (t, J = 6.1 Hz, 2 H), 7.31–7.34 (m, 1 H), 7.42 (t, J = 7.4
Hz, 1 H), 7.46–7.51 (m, 2 H), 7.80 (d, J = 7.7 Hz, 1 H), 8.06 (d, J = 8.6 Hz,
1 H), 8.19–8.21 (m, 1 H), 9.21–9.24 (m, 1 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

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13C NMR (125 MHz, CDCl3): δ = 14.05, 21.58, 23.10, 25.33, 31.05,
31.31, 38.78, 113.17, 113.47, 116.16, 118.85, 122.01, 122.91, 123.88,
126.01, 126.66, 126.87, 126.91, 127.43, 130.56, 132.27, 132.48,
151.18, 197.10.
2-Fluoro-7,8-dihydroindolo[1,2-f]phenanthridin-5(6H)-one (3m)
Yellow solid; yield: 45 mg (49%); mp 177–178 °C (hexane).
1H NMR (500 MHz, CDCl3): δ = 2.29–2.34 (m, 2 H), 2.75–2.78 (m, 2 H),
3.59–3.61 (m, 2 H), 7.15 (s, 1 H), 7.27–7.31 (m, 1 H), 7.37–7.40 (m, 1
H), 7.41–7.45 (m, 1 H), 7.47–7.50 (m, 1 H), 7.60–7.64 (m, 2 H), 9.45
(dd, J = 10.4, 4.4 Hz, 1 H).
HRMS (EI): m/z [M+] calcd for C24H23NO: 341.1780; found: 341.1781.
14-Heptyl-7,8-dihydroindolo[1,2-f]phenanthridin-5(6H)-one (3i)
13C NMR (125 MHz, CDCl3): δ = 21.34, 30.52, 38.77, 96.91, 113.36 (d,
J = 19.8 Hz), 116.11 (d, J = 8.6 Hz), 121.01, 121.52 (d, J = 19.8 Hz),
122.94 (d, J = 8.6 Hz), 123.33, 124.44, 125.94, 126.86, 127.16, 128.27,
131.42 (d, J = 3.0 Hz), 133.48, 136.13, 158.91 (d, J = 233.6 Hz), 197.50.
Yellow solid; yield: 62 mg (54%); mp 88–89 °C (hexane).
1H NMR (500 MHz, CDCl3): δ = 0.89 (t, J = 6.9 Hz, 3 H), 1.27–1.35 (m, 4
H), 1.35–1.42 (m, 2 H), 1.48–4.54 (m, 2 H), 1.72–7.78 (m, 2 H), 2.19–
2.24 (m, 2 H), 2.69–2.72 (m, 2 H), 3.14–.3.17 (m, 2 H), 3.55 (t, J = 6.1
Hz, 2 H), 7.29–7.32 (m, 1 H), 7.41 (t, J = 7.4 Hz, 1 H), 7.44–7.49 (m, 2
H), 7.78 (d, J = 7.8 Hz, 1 H), 8.02 (d, J = 8.6 Hz, 1 H), 8.14–8.16 (m, 1 H),
9.20–9.23 (m, 1 H).
13C NMR (125 MHz, CDCl3): δ = 14.12, 21.52, 22.69, 25.57, 29.08,
29.19, 29.96, 30.97, 31.86, 38.73, 113.08, 113.48, 116.16, 118.79,
121.97, 122.87, 123.84, 125.94, 126.59, 126.83, 126.85, 127.37,
130.45, 132.21, 132.40, 151.21, 197.13.
HRMS (EI): m/z [M+] calcd for C20H14FNO: 303.1059; found: 303.1058.
12-Methyl-7,8-dihydroindolo[1,2-f]phenanthridin-5(6H)-one (3n)
Yellow solid; yield: 50 mg (56%); mp 167–170 °C (hexane).
1H NMR (500 MHz, CDCl3): δ = 2.24–2.29 (m, 2 H), 2.52 (s, 3 H), 2.71–
2.74 (m, 2 H), 3.58 (t, J = 6.2 Hz, 2 H), 7.09–7.11 (m, 1 H), 7.13 (s, 1 H),
7.42–7.45 (m, 1 H), 7.47–7.50 (m, 1 H), 7.54–7.55 (m, 1 H), 7.92 (t, J =
8.8 Hz, 1 H), 8.03–8.05 (m, 1 H), 9.21–9.23 (m, 1 H).
13C NMR (125 MHz, CDCl3): δ = 21.26, 21.36, 30.39, 38.75, 96.55,
113.04, 115.76, 120.65, 122.88, 123.21, 124.40, 125.95, 126.80,
127.01, 128.12, 131.73, 131.77, 132.98, 136.18, 150.85, 197.44.
HRMS (EI): m/z [M+] calcd for C27H29NO: 383.2249; found: 383.2248.
14-Isopropyl-7,8-dihydroindolo[1,2-f]phenanthridin-5(6H)-one
(3j)
HRMS (EI): m/z [M+] calcd for C21H17NO: 299.1310; found: 299.1313.
Yellow solid; yield: 71 mg (72%); mp 153–154 °C (hexane).
1H NMR (500 MHz, CDCl3): δ = 1.63 (d, J = 7.1 Hz, 6 H), 2.20–2.26 (m, 2
H), 2.68–2.71 (m, 2 H), 3.57 (t, J = 6.1 Hz, 2 H), 4.08 (sept, J = 7.1 Hz, 1
H), 7.27–7.30 (m, 1 H), 7.35–7.38 (m, 1 H), 7.42–7.49 (m, 2 H), 8.02–
8.05 (m, 2 H), 8.11 (dd, J = 1.4, 7.9 Hz, 1 H), 9.12–9.14 (m. 1 H).
13C NMR (125 MHz, CDCl3): δ = 21.66, 22.19, 26.68, 30.89, 38.70,
113.03, 116.52, 119.46, 121.26, 121.71, 122.50, 124.78, 125.62,
126.54, 126.56, 127.45, 127.68, 130.49, 130.82, 133.23, 150.92,
196.91.
12-Methoxy-7,8-dihydroindolo[1,2-f]phenanthridin-5(6H)-one
(3o)
Yellow solid; yield: 51 mg (54%); mp 119–121 °C (hexane).
1H NMR (500 MHz, CDCl3): δ = 2.23–2.28 (m, 2 H), 2.71–2.73 (m, 2 H),
3.56–3.59 (m, 2 H), 3.82 (s, 3 H), 6.93 (dd, J =8.9, 2.8 Hz, 1 H), 7.00 (d,
J = 2.8 Hz, 1 H), 7.13 (s, 1 H), 7.28–7.31 (m, 1 H), 7.42 (d, J = 8.9 Hz, 1
H), 7.47–7.51 (m, 1 H), 7.77 (d, J = 7.5 Hz, 1 H), 9.20–9.22 (m, 1 H).
13C NMR (125 MHz, CDCl3): δ = 18.73, 22.35, 30.75, 55.77, 97.30,
103.57, 113.55, 115.49, 121.26, 121.42, 122.13, 123.71, 127.12,
127.25, 129.52, 131.44, 133.64, 136.04, 158.45, 170.14, 199.26.
HRMS (EI): m/z [M+] calcd for C23H21NO: 327.1623; found: 327.1624.
14-Phenyl-7,8-dihydroindolo[1,2-f]phenanthridin-5(6H)-one (3k)
HRMS (EI): m/z [M+] calcd for C21H17NO2: 315.1259; found: 315.1256.
Yellow solid; yield: 72 mg (66%); mp 227–229 °C (hexane).
1H NMR (500 MHz, CDCl3): δ = 2.23–2.28 (m, 2 H), 2.71–2.73 (m, 2 H),
3.56–3.58 (m, 2 H), 7.27–7.31 (m, 1 H), 7.37–7.40 (m, 1 H), 7.41–7.45
(m, 1 H), 7.47–7.51 (m, 1 H), 7.54–7.56 (m, 2 H), 7.68–7.73 (m, 3 H),
7.77 (d, J = 7.5 Hz, 1 H), 8.01–8.05 (m, 2 H), 9.20–9.21 (m, 1 H).
13C NMR (125 MHz, CDCl3): δ = 21.03, 30.22, 38.46, 110.21, 113.25,
116.19, 121.10, 121.82, 123.05, 123.51, 124.54, 125.83, 126.85,
126.89, 127.40, 127.49, 128.44, 129.13, 131.49, 133.45, 136.24,
142.41, 150.03, 196.77.
12-Chloro-7,8-dihydroindolo[1,2-f]phenanthridin-5(6H)-one (3p)
Yellow solid; yield: 72 mg (75%); mp 203–206 °C (hexane).
1H NMR (500 MHz, CDCl3): δ = 2.29–2.34 (m, 2 H), 2.75–2.78 (m, 2 H),
3.60 (t, J = 6.1 Hz, 2 H), 7.16 (s, 1 H), 7.24–7.26 (m, 1 H), 7.47–7.50 (m,
1 H), 7.52–7.56 (m, 1 H), 7.74 (d, J = 2.2 Hz, 1 H), 7.99 (d, J = 9.1 Hz, 1
H), 8.06–8.08 (m, 1 H), 9.22–9.23 (m, 1 H).
13C NMR (125 MHz, CDCl3): δ = 21.33, 30.49, 38.76, 96.22, 113.91,
117.00, 120.20, 121.66, 123.15, 124.16, 126.03, 126.99, 127.42,
128.76, 129.12, 131.80, 132.60, 137.45, 150.16, 197.42.
HRMS (EI): m/z [M+] calcd for C26H19NO: 361.1467; found: 361.1469.
HRMS (EI): m/z [M+] calcd for C20H14ClNO: 319.0764; found:
319.0761.
3-Methyl-7,8-dihydroindolo[1,2-f]phenanthridin-5(6H)-one (3l)
Yellow solid; yield: 53 mg (59%); mp 161–163 °C (hexane).
1H NMR (500 MHz, CDCl3): δ = 2.04–2.09 (m, 2 H), 2.46 (s, 3 H), 2.55–
2.58 (m, 2 H), 3.27–3.29 (m, 2 H), 7.02 (s, 1 H), 7.18–7.21 (m, 1 H),
7.29–7.33 (m, 2 H), 7.34–7.38 (m, 1 H), 7.81 (d, J = 8.6 Hz, 1 H), 7.99
(d, J = 7.7 Hz, 1 H), 9.12 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 21.31, 22.61, 30.61, 38.63, 97.65,
112.83, 116.06, 118.60, 121.76, 122.70, 124.11, 126.35, 126.52,
126.70, 127.17, 129.47, 130.74, 131.96, 132.46, 151.06, 197.08.
9,10-Dihydrobenzo[i]indolo[1,2-f]phenanthridin-7(8H)-one (3q)
Yellow solid; yield: 58 mg (58%); mp 210–211 °C (hexane).
1H NMR (500 MHz, CDCl3): δ = 2.23–2.28 (m, 2 H), 2.71–2.73 (m, 2 H),
3.56–3.59 (m, 2 H), 7.16 (s, 1 H), 7.28–7.31 (m, 1 H), 7.37–7.40 (m, 1
H), 7.42–7.45 (m, 1 H), 7.47–7.51 (m, 1 H), 7.90–7.92 (m, 1 H), 8.15–
8.23 (m, 3 H), 9.20–9.22 (m, 1 H), 9.80 (d, J = 8.3 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 21.34, 30.53, 38.77, 96.92, 113.44,
116.15, 117.01, 117.61, 122.98, 123.33, 124.44, 125.95, 126.33,
126.52, 126.86, 127.16, 128.28, 129.57, 130.14, 131.44, 133.49,
136.13, 150.88, 197.50.
HRMS (EI): m/z [M+] calcd for C22H17NO: 299.1310; found: 299.1311.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

G
H. K. Lee et al.
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Synthesis
HRMS (EI): m/z [M+] calcd for C24H17NO: 335.1310; found: 335.1312.
Supporting Information
Supporting information for this article is available online at
6,6-Dimethyl-7,8-dihydroindolo[1,2-f]phenanthridin-5(6H)-one
(3r)
https://doi.org/10.1055/s-0036-1591589.
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Yellow solid; yield: 72 mg (77%); mp 152–154 °C (hexane).
1H NMR (500 MHz, CDCl3): δ = 1.33 (s, 6 H), 2.17 (t, J = 6.3 Hz, 2 H),
3.70 (t, J = 6.3 Hz, 2 H), 7.30–7.33 (m, 2 H), 7.39–7.42 (m, 1 H), 7.47–
7.51 (m, 2 H), 7.82 (d, J = 7.8 Hz, 1 H), 8.12–8.14 (m, 1 H), 8.18 (d, J =
8.6 Hz, 1 H), 9.14–9.16 (m, 1 H).
13C NMR (125 MHz, CDCl3): δ = 24.81, 27.14, 34.47, 41.31, 96.76,
116.16, 121.06, 121.61, 123.08, 123.28, 124.86, 126.35, 127.00,
127.17, 128.24, 129.01, 131.48, 133.55, 136.28, 148.93, 202.64.
References
(1) (a) Ambros, R.; von Angerer, S.; Wiegrebe, W. Arch. Pharm.
(Weinheim) 1988, 321, 481. (b) Ambros, R.; von Angerer, S.;
Wiegrebe, W. Arch. Pharm. (Weinheim) 1988, 321, 743.
(c) Ambros, R.; Schneider, M. R. von Angerer S. J. Med. Chem.
1990, 33, 153. (d) Goldbrunner, M.; Loidl, G.; Polossek, T.;
Mannschreck, A.; von Angerer, E. J. Med. Chem. 1997, 40, 3524.
(2) Morimoto, K.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2010, 12,
2068.
HRMS (EI): m/z [M+] calcd for C22H19NO: 313.1467; found: 313.1465.
Indolo[1,2-f]phenanthridines 4; General Procedure
(3) (a) Harley-Mason, J. J. Chem. Soc. 1953, 1465. (b) Kametani, T.;
Ogasawara, K. J. Chem. Soc. C 1967, 2208. (c) Boente, J. M.;
Castedo, L.; Rodriguez de Lera, A.; Saá, J. M.; Suau, R.; Vidal, M.
C. Tetrahedron Lett. 1983, 24, 2295. (d) Orito, K.; Harada, R.;
Uchiito, S.; Tokuda, M. Org. Lett. 2000, 2, 1799. (e) Kraus, G. A.;
Beasley, J. Tetrahedron Lett. 2013, 54, 5597.
(4) Verma, A. K.; Kesharwani, T.; Singh, J.; Tandon, V.; Larock, R. C.
Angew. Chem. Int. Ed. 2009, 48, 1138.
(5) Mamane, V.; Hannen, P.; Fürstner, A. Chem. Eur. J. 2004, 10,
4556.
A 25 mL round-bottomed flask was charged with 3 (0.2 mmol), NaBH4
(0.045 g, 1.2 mmol), and THF–MeOH (5 mL, 1:4). The reaction mix-
ture was stirred at r.t. for 1 h. After removing the solvent under re-
duced pressure followed by the addition of p-TsOH·H2O (0.006 g, 0.03
mmol) in benzene (5 mL) to the crude alcohol, the reaction mixture
was heated to 90 °C for 1 h. After cooling to 50 °C, DDQ (0.050 g, 0.22
mmol) was added and the mixture was stirred for 24 h. Removal of
the solvent under reduced pressure left a crude mixture that was sep-
arated by TLC (CH2Cl2) to give the desired product 4.
(6) Sun, H.; Wang, C.; Yang, Y.-F.; Chen, P.; Wu, Y. D.; Zhang, X.;
Huang, Y. J. Org. Chem. 2014, 79, 11863.
Compound 4a is known.20
(7) (a) de Koning, C. B.; Michael, J. P.; Pathak, R.; van Otterlo, W. A.
L. Tetrahedron Lett. 2004, 45, 1117. (b) Lötter, A. N. C.; Pathak, R.;
Sello, T. S.; Fernandes, M. A.; van Otterlo, W. A. L.; de Koning, C.
B. Tetrahedron 2007, 63, 2263.
(8) (a) Dao, P. D. Q.; Lee, H. K.; Sohn, H.-S.; Yoon, N. S.; Cho, C. S. ACS
Omega 2017, 2, 2953. (b) Ho, S. L.; Dao, P. D. Q.; Cho, C. S. Synlett
2017, 28, 1811.
2-Methylindolo[1,2-f]phenanthridine (4b)
Yellow solid; yield: 41 mg (73%); mp 173–175 °C (hexane).
1H NMR (500 MHz, CDCl3): δ = 2.35 (s, 3 H), 7.19 (s, 1 H), 7.31–7.34
(m, 1 H), 7.39–7.43 (m, 2 H), 7.44–7.47 (m, 1 H), 7.49–7.53 (m, 1 H),
7.76 (d, J = 7.8 Hz, 1 H), 7.79–7.80 (m, 1 H), 7.88 (dd, J = 7.9, 1.2 Hz, 1
H), 8.04–8.07 (m, 2 H), 8.44–8.46 (m, 1 H).
(9) (a) For palladium-catalyzed synthesis of N-fused hybrid scaf-
folds, see: Yoo, J. M.; Ho, S. L.; Cho, C. S. Synlett 2016, 27, 1383.
(b) Yang, B. W.; Ho, S. L.; Lim, H.-J.; Cho, C. S. J. Organomet. Chem.
2016, 806, 83.
(10) Yang, B. W.; Dao, P. D. Q.; Yoon, N. S.; Cho, C. S. J. Organomet.
Chem. 2017, 851, 136.
13C NMR (125 MHz, CDCl3): δ = 38.65, 94.33, 115.32, 115.51, 115.68,
120.51, 120.67, 121.79, 121.84, 122.92, 123.52, 124.55, 125.43,
126.58, 127.52, 127.81, 128.08, 130.08, 132.86, 135.93, 136.81.
HRMS (EI): m/z [M+] calcd for C21H15N: 281.1204; found: 281.1205.
2-Phenylindolo[1,2-f]phenanthridine (4c)
(11) Ho, S. L.; Cho, C. S.; Sohn, H.-S. Synthesis 2015, 47, 216.
(12) Xie, X.; Cai, G.; Ma, D. Org. Lett. 2005, 7, 4693.
(13) (a) Fan, X.; He, Y.; Cui, L.; Guo, S.; Wang, J.; Zhang, X. Eur. J. Org.
Chem. 2012, 673. (b) Kavala, V.; Wang, C.-C.; Barange, D. K.; Kuo,
C.-W.; Lei, P.-O.; Yao, C.-F. J. Org. Chem. 2012, 77, 5022.
(14) (a) Cai, S.; Wang, F.; Xi, C. J. Org. Chem. 2012, 77, 2331. (b) Yip, S.
F.; Cheung, H. Y.; Zhou, Z.; Kwong, F. Y. Org. Lett. 2007, 9, 3469.
(c) Wang, F.; Liu, H.; Fu, H.; Jiang, Y.; Zhao, Y. Org. Lett. 2009, 11,
2469. (d) Kálai, T.; Bognár, B.; Zsolnai, D.; Berente, Z.; Hideg, K.
Synthesis 2012, 44, 3655. (e) Malakar, C. C.; Schmidt, D.; Conrad,
J.; Beifuss, U. Org. Lett. 2011, 13, 1972.
Yellow solid; yield: 41 mg (60%); mp 140–142 °C (hexane).
1H NMR (500 MHz, CDCl3): δ = 7.25 (s, 1 H), 7.26–7.29 (m, 1 H), 7.38–
7.43 (m, 4 H), 7.46–7.52 (m, 3 H), 7.54–7.57 (m, 2 H), 7.81 (d, J = 7.8
Hz, 1 H), 7.92 (d, J = 8.8 Hz, 1 H), 7.98 (d, J = 8.7 Hz, 1 H), 8.03–8.05 (m,
1 H), 8.09–8.11 (m, 1 H), 8.61 (d, J = 8.1 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 97.18, 113.26, 115.07, 116.21, 119.47,
120.79, 121.11, 121.83, 123.07, 123.52, 124.56, 125.84, 126.87,
126.90, 127.42, 127.51, 128.45, 129.15, 130.82, 131.50, 133.47,
136.26, 139.72, 142.42.
HRMS (EI): m/z [M+] calcd for C26H17N: 343.1361; found: 343.1362.
(15) Nishibayashi, Y.; Yoshikawa, M.; Inada, Y.; Hidai, M.; Uemura, S.
J. Org. Chem. 2004, 69, 3408.
(16) (a) Jiao, Y.; Cho, C. S. Appl. Organomet. Chem. 2015, 29, 372.
(b) Ho, S. L.; Cho, C. S. Synlett 2013, 24, 2705.
(17) Utermoehlen, C. M.; Singh, M.; Lehr, R. E. J. Org. Chem. 1987, 52,
5574.
(18) Zeevaart, J. G.; Parkinsown, C. J.; de Koning, C. B. Tetrahedron
Lett. 2004, 45, 4261.
(19) (a) Xie, R.; Ling, Y.; Fu, H. Chem. Commun. 2012, 48, 12210.
(b) Bhunia, S. K.; Polley, A.; Natarajan, R.; Jana, R. Chem. Eur. J.
2015, 21, 16786.
Funding Information
This research was supported by Basic Science Research Program
through the National Research Foundation of Korea (NRF) funded by
the Ministry of Education (2017R1D1A1B03028226). P.D.Q.D. thanks
Y. M. Park, Internal Medicine of Geoje Medical Center (Gyeongnam,
Republic of Korea) for partial financial support during his stay in the
Republic of Korea.
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(20) Xie, C.; Zhang, Y.; Huang, Z.; Xu, P. J. Org. Chem. 2007, 72, 5431.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G