A sequential one-pot protocol for the synthesis of dihydrobenzo[6,7]indolo- [3′,4′:3,4,5]azepino[2,1- a ]isoquinolines using a gold-silver combined catalyst 1

Article abstract of DOI:10.1055/s-0033-1338424

A sequential one-pot protocol for the synthesis of indole-based peri-annulated polyheterocycles using trifluoroacetic acid and a gold-silver combined catalyst system is described. The reaction is thought to proceed via an imine formation-cationic π-cycliz

Full text of DOI:10.1055/s-0033-1338424

PAPER
▌1553
paper
A Sequential One-Pot Protocol for the Synthesis of Dihydrobenzo[6,7]indolo-
[3′,4′:3,4,5]azepino[2,1-a]isoquinolines Using a Gold–Silver Combined
Catalyst1
Novel Hexacyclic Isoquinolinobenzazepinoindoles
Mohammad Saifuddin,a Srinivas Samala,a Deevi G. Venkata Krishna,b Bijoy Kundu*a,b,c
a
Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow 226001, India
Fax +91(522)2623405; E-mail: bijoy_kundu@yahoo.com; E-mail: b_kundu@cdri.res.in
b
Sophisticated Analytical and Instrumental Facility, CSIR-Central Drug Research Institute, Lucknow 226001, India
c
Academy of Scientific and Innovative Research, New Delhi, India
Received: 12.03.2013; Accepted after revision: 26.03.2013
either the benzazepine N–H or C-2 of the indole. Since
Abstract: A sequential one-pot protocol for the synthesis of indole-
both these cyclizations require the presence of a Brønsted
based peri-annulated polyheterocycles using trifluoroacetic acid
acid10 and a coinage metal (Au, Ag, Cu) derived Lewis
and a gold–silver combined catalyst system is described. The reac-
tion is thought to proceed via an imine formation–cationic π-cycli-
acid11 (for activating the imine and the alkyne respective-
zation–alkyne activation–intramolecular hydroamination sequence ly), the challenge remained to combine both sets of condi-
to yield novel dihydrobenzo[6,7]indolo[3′,4′:3,4,5]azepino[2,1-
a]isoquinolines in good yields.
tions in a one-pot format.
Initially, substrate 1a was treated with aldehyde 2a in the
Key words: polyheterocycles, alkyne, indole, annulation, Lewis
presence of trifluoroacetic acid (2%) and the combined
acid, regioselective
catalyst, chloro(triphenylphosphine)gold(I)–silver hexa-
fluoroantimonate (AuClPPh3–AgSbF6) in acetonitrile,
and the progress of the reaction was monitored by TLC
The search for one-pot reactions that facilitate the forma-
and HPLC. The reaction was complete in 20 minutes af-
tion of multiple bonds, either in one step, or in tandem,2 to
fording, after column chromatography, a new product in
access natural product inspired polyheterocycles with ar-
45% yield. The structure of this product was elucidated by
chitectural complexity, remains a major challenge for or-
a combination of homo- and heteronuclear two-dimen-
ganic chemists. In continuation of our studies on the
sional NMR experiments. Of the four possible structures,
design and development of one-pot procedures for the
the product was characterized as the peri-annulated in-
dole-based polyheterocycle, 9-(p-tolyl)-14b,16-dihydro-
syntheses3 of polyheterocycles by employing internal
alkyne-based reactants, we focused our attention on peri-
benzo[6,7]indolo[3′,4′:3,4,5]azepino[2,1-a]isoquinoline
annulated indole-based polyheterocycles.4 This frame-
(3a),12 arising from sequential cationic π-cyclization and
work is present in many natural products,5 and is associat-
regioselective intramolecular hydroamination (Scheme
ed with a broad range of activities.6 A detailed survey of
1).
the literature failed to reveal any reports on the one-pot
It is interesting to note that, as envisaged, our strategy
synthesis of natural product inspired peri-annulated in-
comprising the one-pot condensation of two bifunctional
dole-based polyheterocycles. Thus, the development of
reactants led to product 3a with a complex novel architec-
ture comprising a benzazepine ring annulated to an iso-
methods for the rapid, one-pot synthesis of these types of
compounds under mild conditions remains an area of sig-
quinoline moiety on one side, and an indole moiety on the
nificant interest.
other.
To synthesize the peri-annulated indole-based polyhetero-
Benzazepines and isoquinolines are important classes of
cycles, we proposed to carry out a one-pot condensation
compounds present in many natural products and in nu-
of two bifunctional reactants derived from an indole and
merous pharmaceutically active compounds.13 Figure 1
an internal alkyne. We envisaged that such a strategy
highlights selected HMBC, COSY and NOE correlations,
would trigger two sequential cyclizations in a single oper-
which helped establish the structure of 3a. This was fur-
ation, thereby enhancing the structural complexity of the
ther supported by performing restrained molecular dy-
final product. Accordingly, we commenced our studies by
namics calculations using Discover 3.0 software.
Distance restraints were derived on the basis of NOE in-
tensities.
condensing indole-based substrate 1a7 with 2-alkynyl
benzaldehyde 2a, in an effort to facilitate cationic π-cycli-
zation between C-3 of the indole and an iminium ion, fol-
lowed by an in situ intramolecular hydroamination8 or
carbocyclization9 reaction between the alkyne moiety and
Having developed a one-pot method for the synthesis of
peri-annulated indole-based polyheterocycles, we next
optimized the reaction conditions in order to improve the
yield of 3a; the results are summarized in Table 1. Since
the combination of the Brønsted acid and the gold–silver
complex furnished the final product via two consecutive
cyclizations in a poor yield (45%), we decided to add the
SYNTHESIS 2013, 45, 1553–1563
Advanced online publication: 08.05.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1338424; Art ID: SS-2013-T0203-OP
© Georg Thieme Verlag Stuttgart · New York

1554
M. Saifuddin et al.
PAPER
NH
O
N
N
H
N
H
3a
2a
+
cationic
cationic
5
π-cyclization and
π-cyclization and
hydroamination
carbocyclization
NH2
NH
N
H
N
1a
N
H
N
H
4
6
Scheme 1 Structures of the four regioisomeric products (3a, 4–6) that can potentially be obtained from the reaction of 1a and 2a
ene or N,N-dimethylformamide either failed to give the
desired product or produced polyheterocycle 3a in re-
duced yield (Table 1, entries 10–14). Performing the reac-
tion in the presence of either trifluoroacetic acid or the
gold–silver mixture alone failed to furnish the desired
product (Table 1, entries 8 and 9). Replacing silver hexa-
fluoroantimonate with silver triflate (AgOTf), and chlo-
ro(triphenylphosphine)gold(I) with other gold salts,
resulted in the formation of 3a in significantly lower
yields (Table 1, entries 15–20). Similarly, running the re-
actions in the presence of only a gold or silver salt fur-
nished 3a in poor yields or not at all (Table 1, entries 21–
25).
A plausible mechanism for the synthesis of dihydroben-
zo[6,7]indolo[3′,4′:3,4,5]azepino[2,1-a]isoquinoline 3 via
a sequential one-pot method is shown in Scheme 2. The
first step involves the condensation of amine 1 with alde-
hyde 2 to furnish an imine, followed by its activation un-
der acidic conditions to form iminium ion 8. The latter
triggers the formation of a C–C bond via a cationic π-(7-
endo-trig) cyclization followed by deprotonation leading
to benzazepine intermediate 7. Next, the alkyne moiety in
7 is activated by the gold complex to give intermediate 9,
the alkyne moiety of which undergoes regioselective at-
tack by the azepine nitrogen (instead of C-2) to form 10
via hydroamination. Finally, intermediate 10 undergoes
protodeauration to afford dihydrobenzo[6,7]indo-
lo[3′,4′:3,4,5]azepino[2,1-a]isoquinoline 3. Hence, this
two-component sequential reaction proceeds via a se-
quence involving iminium ion formation–cationic π-
cyclization–alkyne activation–intramolecular hydroami-
nation–protodeauration in a one-pot fashion.
Figure 1 Important HMBC, COSY and NOE correlations present in
3a and the energy minimized structure (1 ns restrained MD run)
two reagents sequentially. Accordingly, substrate 1a was
initially condensed with 2a in the presence of trifluoroace-
tic acid (2%) in dichloromethane at room temperature,
which was followed by the addition of the chloro(triphe-
nylphosphine)gold(I)–silver hexafluoroantimonate (15
mol%) catalytic system. The progress of the reaction, in
both steps, was monitored by HPLC and, pleasingly, the
two cyclizations were both found to be complete within
10 minutes giving the desired polyheterocycle 3a in 79%
isolated yield (Table 1, entry 1). Increasing or decreasing
the loading of the gold–silver bimetallic complex either
had no effect, or led to a reduction in the isolated yield of
3a (Table 1, entries 2–5). Similarly, increasing the con-
centration of the Brønsted acid, trifluoroacetic acid, from
2% to 5% and 10% had a detrimental effect on the yield
(Table 1, entries 5–7). Switching the solvent from dichlo-
romethane to water, acetonitrile, 1,2-dichloroethane, tolu-
Synthesis 2013, 45, 1553–1563
© Georg Thieme Verlag Stuttgart · New York

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Novel Hexacyclic Isoquinolinobenzazepinoindoles
1555
Table 1 Optimization of the Reaction Conditions for the One-Pot Synthesis of 3a in Sequential Formata
O
NH2
N
(i) cationic π-cyclization
(ii) hydroamination
NH
+
N
H
1a
N
H
3a
N
H
2a
7a
Entry
Sequential reaction conditions in one pot
Yield of 3a (%)d
(i) Cationic π-cyclizationb
(ii) Hydroaminationc
1
2
(i) 2% TFA, CH2Cl2, r.t.
(i) 2% TFA, CH2Cl2, r.t.
(i) 2% TFA, CH2Cl2, r.t.
(i) 2% TFA, CH2Cl2, r.t.
(i) 2% TFA, CH2Cl2, r.t.
(i) 5% TFA, CH2Cl2, r.t.
(i) 10% TFA, CH2Cl2, r.t.
2% TFA, CH2Cl2, r.t.
(ii) 15 mol% AuClPPh3–AgSbF6
(ii) 20 mol% AuClPPh3–AgSbF6
(ii) 5 mol% AuClPPh3–AgSbF6
(ii) 10 mol% AuClPPh3–AgSbF6
(ii) 2 mol% AuClPPh3–AgSbF6
(ii) 15 mol% AuClPPh3–AgSbF6
(ii) 15 mol% AuClPPh3–AgSbF6
79
75
3
51
4
57
5
43
6
73
7
61
8
NRe
NRe
NRe
53
9
15 mol% AuClPPh3–AgSbF6, CH2Cl2, r.t.
(i) 2% TFA, H2O, r.t.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
(ii) 15 mol% AuClPPh3–AgSbF6
(ii) 15 mol% AuClPPh3–AgSbF6
(ii) 15 mol% AuClPPh3–AgSbF6
(ii) 15 mol% AuClPPh3–AgSbF6
(ii) 15 mol% AuClPPh3–AgSbF6
(ii) 15 mol% AuClPPh3–AgOTf
(ii) 15 mol% AuCl3–AgSbF6
(ii) 15 mol% AuCl3–AgSbF6
(ii) 15 mol% AuCl3–AgSbF6
(ii) 15 mol% AuCl3–AgSbF6
(ii) 15 mol% AuCl3–AgSbF6
(ii) 15 mol% AuCl3
(i) 2% TFA, MeCN, r.t.
(i) 2% TFA, DCE, r.t.
65
(i) 2% TFA, toluene, r.t.
(i) 2% TFA, DMF, r.t.
37
15
(i) 2% TFA, CH2Cl2, r.t.
(i) 2% TFA, CH2Cl2, r.t.
(i) 15 mol% Yb(OTf)3, MeCN, r.t.
(i) 15 mol% Yb(OTf)3, MeCN, r.t.
(i) 15 mol% PTSA, MeCN, r.t.
(i) 15 mol% PTSA, CH2Cl2, r.t.
(i) 2% TFA, CH2Cl2, r.t.
(i) 2% TFA, CH2Cl2, r.t.
(i) 2% TFA, CH2Cl2, r.t.
(i) 2% TFA, CH2Cl2, r.t.
(i) 2% TFA, MeCN, r.t.
56
trace
10
15
45
59
25
(ii) 15 mol% AuClPPh3
10
(ii) 15 mol% AgSbF6
15
(ii) 15 mol% AgOTf
NRe
20
(ii) 15 mol% AuCl3
a All reactions were carried out on 1 mmol scale with amine/alkynyl aldehyde = 1:1.1, solvent (2.0 mL).
b Stirred for 10 min.
c Stirred for 10 min.
d Yield of isolated product.
e NR = no reaction.
© Georg Thieme Verlag Stuttgart · New York
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M. Saifuddin et al.
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R3
O
R1
2
R2
NH2
H+
H+
N
H
R2
+AuLn
1
R2
N
R1
AuLn
R1
R2
NH
R1
H+
H+
R3
N
R3
R2
N
H
N
H
9
10
R3
R1
N
H
8
H+
NH
+
R3
R2
N
H
R1
AgCl
N
H
7
AuCl(PPh3)
AgSbF6
R3
N
H
3
Scheme 2 A plausible mechanistic pathway for the synthesis of polyheterocycle 3
Next, we examined the efficacy of substrates 1b and 1c to this strategy by studying the effect of different substitu-
undergo this cationic π-cyclization and hydroamination ents on the 2-alkynyl aldehydes 2, which were formed by
under the optimized conditions. Although substrate 1b reactions of six alkynes with three different bromobenzal-
bearing a 4-methyl group on ring C (Table 2) reacted effi- dehydes, via Sonogashira coupling using a reported pro-
ciently to give the cyclized product, indole 1c possessing cedure.12 In all cases, the substrates underwent efficiently
a pyridine instead of an aryl ring (Table 2), failed to give the sequential cationic π-cyclization and hydroamination
the desired cyclized product. A careful analysis of the re- to furnish the corresponding products (26 in total), as sin-
action with substrate 1c revealed that the failure to obtain gle regioisomers in 61–79% isolated yields (Table 2). The
the desired product 3 was due to incomplete trifluoroace- electronic effects of the various substituents present on the
tic acid catalyzed cationic π-cyclization. This prompted us aromatic substrates 2a–m (R2 and R3) proved negligible
to replace trifluoroacetic acid with other Brønsted acids as both electron-donating and electron-withdrawing
for the cationic π-cyclization step, and of the different re- groups were tolerated. The use of aliphatic alkynes
agents employed, p-toluenesulfonic acid (15 mol%) in di- failed to furnish the desired dihydrobenzo[6,7]indo-
chloromethane furnished the cationic π-cyclized lo[3′,4′:3,4,5]azepino[2,1-a]isoquinolines.
intermediate (equivalent to 7 in Scheme 2) in 83% isolat-
ed yield. Encouraged by this finding, we evaluated the ef-
ficacy of p-toluenesulfonic acid in combination with the
gold–silver catalyst for the conversion of substrate 1c into
polyheterocycle 3z. Accordingly, substrate 1c was treated
with 2b in the presence of p-toluenesulfonic acid (15
In conclusion, we have developed a sequential, one-pot,
atom-economic method for the construction of the highly
substituted peri-annulated polyheterocycles dihydroben-
zo[6,7]indolo[3′,4′:3,4,5]azepino[2,1-a]isoquinolines in
good yields, via the trifluoroacetic acid–gold–silver cata-
lyzed sequential cationic π-cyclization and subsequent
mol%) in dichloromethane at room temperature for 10
hydroamination reaction. The salient feature of this strat-
minutes, which was followed by the addition of the gold–
egy involves the regioselective electrophilic 7-endo-trig
cationic π-cyclization followed by 6-endo-dig hydroami-
nation reactions.
silver (15 mol%) catalytic system. Pleasingly, the desired
product 3z was obtained in 71% isolated yield.
After successfully optimizing the reaction conditions for
substrates 1a–c, we examined the scope and limitations of
Synthesis 2013, 45, 1553–1563
© Georg Thieme Verlag Stuttgart · New York

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Novel Hexacyclic Isoquinolinobenzazepinoindoles
1557
Table 2 Synthesis of Dihydrobenzo[6,7]indolo[3′,4′:3,4,5]azepino[2,1-a]isoquinolinesa
R2
N
R1
R2
R1
C
C
X
F
X
NH2
E
D
method A (for 1a, 1b)
method B (for 1c)
AuClPPh3/AgSbF6 (15 mol%)
O
+
7
D
R3
A
B
B
A
N
N
H
H
R3
2a–m
1a–c
3a–z
Entry
Indole
R1
X
Aldehyde
R2
R3
Product
Yield (%)
1
2
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
1b
1b
1c
1c
1c
1c
1c
H
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
N
N
N
N
N
2a
2b
2c
2d
2e
2f
4-MeC6H4
Ph
H
3a
3b
3c
3d
3e
3f
79
76
75
70
71
78
69
71
73
75
67
68
65
63
66
69
70
71
72
75
66
64
65
61
63
71
H
H
3
H
4-t-BuC6H4
4-MeOC6H4
2-O2NC6H4
cyclohexen-1-yl
Ph
H
4
H
H
5
H
H
6
H
H
7
H
2g
2h
2i
F
3g
3h
3i
8
H
4-MeC6H4
4-t-BuC6H4
cyclohexen-1-yl
Ph
F
9
H
F
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
H
2j
F
3j
H
2k
2l
OMe
OMe
H
3k
3l
H
cyclohexen-1-yl
Ph
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
H
2b
2a
2c
2f
3m
3n
3o
3p
3q
3r
3s
4-MeC6H4
4-t-BuC6H4
cyclohexen-1-yl
4-MeOC6H4
Ph
H
H
H
2d
2g
2i
H
F
4-t-BuC6H4
cyclohexen-1-yl
cyclohexen-1-yl
4-MeC6H4
cyclohexen-1-yl
4-t-BuC6H4
cyclohexen-1-yl
Ph
F
2j
F
3t
2l
OMe
F
3u
3v
3w
3x
3y
3z
2h
2j
H
F
H
2m
2l
OMe
OMe
H
H
H
2b
a Method A: TFA (2%), CH2Cl2. Method B: TsOH (15 mol%), CH2Cl2.
B-545 apparatus and are uncorrected. IR spectra were obtained us-
All reagents and solvents were purchased from commercial sources
and were used without purification. Column chromatography was
performed using silica gel 60 (Thomas Baker, 100–200 mesh) as the
stationary phase. All reactions were monitored by thin-layer chro-
matography (TLC) using Merck KGaA aluminium-backed TLC
silica gel 60 F254 plates. Melting points were determined on a Büchi
1
ing a Perkin-Elmer RX I FTIR spectrophotometer. H NMR (200
MHz, 300 MHz or 400 MHz) and 13C NMR (50 MHz, 75 MHz or
100 MHz) spectra were recorded using a Bruker Avance DRX-300
spectrometer. Chemical shifts (δ) are given in ppm relative to the re-
sidual signals of tetramethylsilane in CDCl3, or those of the deuter-
ated solvents (CDCl3 or DMSO-d6). Multiplicities are reported as
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1553–1563

1558
M. Saifuddin et al.
PAPER
follows: singlet (s), doublet (d), doublet of doublets (dd), doublet of
triplets (dt), triplet (t), quartet (q), multiplet (m). High-resolution
mass spectrometry was accomplished with a 3000 mass spectrome-
ter, using a Waters Agilent 6520-Q-TofMS/MS system and JEOL-
AccuTOF JMS-T100LC.
dryness under reduced pressure. The residue was purified by col-
umn chromatography (EtOAc–hexane) to afford products 3v–z.
9-(p-Tolyl)-14b,16-dihydrobenzo[6,7]indolo[3′,4′:3,4,5]azepi-
no[2,1-a]isoquinoline (3a)
Yield: 0.155 g (79%); yellow solid; mp 195–198 °C; Rf = 0.63
(EtOAc–hexane, 1:4).
Aldehydes 2a–m; Typical Procedure
IR (KBr): 3465, 3019, 2401, 1605 cm–1.
To a soln of 2-bromobenzaldehyde (10.8 mmol) and ethynylben-
zene (13.0 mmol) in Et3N (20 mL) was added CuI (0.10 mmol) un-
der an N2 atm. The reaction mixture was degassed with N2 for 15
min, followed by the addition of PdCl2(PPh3)2 (0.21 mmol) at r.t.
The resulting mixture was stirred at 80 °C for 2 h. After completion
of the reaction, the mixture was diluted with aq NH4Cl soln (20 mL)
and extracted with EtOAc (3 × 15 mL). The combined organic layer
was dried over anhyd Na2SO4 and concentrated under reduced pres-
sure. The residue was purified by column chromatography on silica
gel (EtOAc–hexane) to give the desired product 2b (1.91 g, 85%).
1H NMR (400 MHz, DMSO-d6): δ = 10.93 (d, J = 2.0 Hz, 1 H), 7.96
(dd, J1 = 8.0, J2 = 1.0 Hz, 1 H), 7.48 (d, J = 7.4 Hz, 1 H), 7.41 (d,
J = 7.8 Hz, 1 H), 7.32 (t, J = 7.7 Hz, 1 H), 7.25–7.17 (m, 3 H), 7.12–
7.08 (m, 2 H), 7.01 (td, J1 = 7.8, J2 = 1.3 Hz 1 H), 6.81–6.77 (m, 1
H), 6.78 (d, J = 8.2 Hz, 2 H), 6.70 (d, J = 8.1 Hz, 2 H), 6.40–6.39
(m, 1 H), 6.09 (s, 1 H), 5.44 (s, 1 H), 2.09 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 145.5, 143.2, 138.2, 137.1,
136.7, 134.9, 133.4, 130.2, 129.1, 128.5, 128.2, 127.7, 127.5, 127.1,
126.7, 126.3, 126.0, 125.1, 124.3, 123.1, 122.5, 122.4, 121.1, 118.7,
110.9, 99.6, 60.6, 20.5.
The characterization data for aldehydes 2a–m can be found in the
Supporting Information.
HRMS (ESI): m/z [M + H]+ calcd for C30H23N2: 411.1861; found:
411.1855.
3-[2-(p-Tolylethynyl)phenyl]-3,4-dihydro-1H-benzo[6,7]azepi-
no[3,4,5-cd]indole (7a); Typical Procedure
A soln of 1a (1 equiv) and aldehyde 2a (1.1 equiv) was treated with
a soln of TFA (2%) in >CH2Cl2 (5 mL). The mixture was stirred at
r.t. for 10 min. After completion of the reaction, aq NaHCO3 soln
(10 mL) was added to the mixture and the aq layer was extracted
with CH2Cl2 (3 × 5 mL). The combined organic layer was dried
over anhyd Na2SO4 and the solvent removed in vacuo. The crude
residue was purified by trituration with 5% Et2O in hexane to afford
pure compound 7a.
9-Phenyl-14b,16-dihydrobenzo[6,7]indolo[3′,4′:3,4,5]azepi-
no[2,1-a]isoquinoline (3b)
Yield: 0.144 g (76%); yellow solid; mp 175–178 °C; Rf = 0.64
(EtOAc–hexane, 1:4).
IR (KBr): 3433, 2963, 2054, 1615 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 10.99 (s, 1 H), 8.01 (d, J = 7.8
Hz, 1 H), 7.54 (d, J = 7.4 Hz, 1 H), 7.46 (d, J = 7.8 Hz, 1 H), 7.38
(d, J = 7.6 Hz, 1 H), 7.28–7.22 (m, 3 H), 7.18–7.13 (m, 2 H), 7.07–
6.99 (m, 4 H), 6.87–6.84 (m, 3 H), 6.45 (s, 1 H), 6.15 (s, 1 H), 5.52
(s, 1 H).
13C NMR (75 MHz, DMSO-d6): δ = 145.3, 143.2, 138.2, 137.8,
137.1, 133.3, 130.2, 129.1, 128.5, 127.8, 127.6, 127.4, 127.1, 126.8,
126.4, 126.0, 125.1, 124.5, 123.3, 122.5, 122.4, 121.2, 118.8, 111.0,
100.1, 60.6.
Yield: 0.179 g (91%); white solid; mp 145–147 °C, Rf = 0.51
(EtOAc–hexane, 1:4).
IR (KBr): 3475, 3020, 2401, 1606 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 11.00 (d, J = 1.8 Hz, 1 H), 7.88
(d, J = 7.0 Hz, 1 H), 7.63–7.60 (m, 1 H), 7.46 (d, J = 7.4 Hz, 1 H),
7.40–7.36 (m, 3 H), 7.31–7.26 (m, 3 H), 7.22 (d, J = 8.0 Hz, 2 H),
7.10–7.00 (m, 4 H), 6.75 (d, J = 1.9 Hz, 1 H), 6.00 (s, 1 H), 5.57 (d,
J = 2.1 Hz, 1 H), 2.34 (s, 3 H).
13C NMR (50 MHz, DMSO-d6): δ = 148.0, 145.2, 138.6, 136.6,
131.7, 131.1, 130.5, 129.3, 128.6, 128.4, 127.7, 127.4, 127.1, 125.6,
123.2, 121.8, 121.3, 120.8, 119.1, 118.4, 117.2, 110.0, 93.7, 87.3,
58.0, 20.9.
HRMS (ESI): m/z [M + H]+ calcd for C29H21N2: 397.1705; found:
397.1705.
9-[4-(tert-Butyl)phenyl]-14b,16-dihydrobenzo[6,7]indo-
lo[3′,4′:3,4,5]azepino[2,1-a]isoquinoline (3c)
Yield: 0.162 g (75%); yellow solid; mp 178–183 °C; Rf = 0.61
(EtOAc–hexane, 1:4).
HRMS (ESI): m/z [M + H]+ calcd for C30H23N2: 411.1861; found:
411.1855.
IR (KBr): 3439, 2993, 2021, 1655 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.93 (d, J = 7.0 Hz, 1 H), 7.86 (s,
1 H), 7.51 (d, J = 7.5 Hz, 1 H), 7.33 (t, J = 7.9 Hz, 1 H), 7.23–7.21
(m, 2 H), 7.16–7.13 (m, 1 H), 7.11–7.07 (m, 3 H), 6.97–6.94 (m, 3
H), 6.89–6.86 (m, 1 H), 6.81 (d, J = 8.3 Hz, 2 H), 6.36 (s, 1 H), 6.11
(s, 1 H), 5.52 (s, 1 H), 1.12 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 150.4, 146.1, 144.0, 138.4, 137.3,
135.2, 134.3, 131.4, 129.7, 128.8, 128.1, 127.9, 127.3, 127.1, 126.2,
125.9, 124.6, 124.4, 123.5, 123.2, 121.0, 119.9, 110.4, 100.1, 61.3,
34.5, 31.3.
Polyheterocycles 3a–u; General Procedure
To a stirred soln of substrate 1a,b (1 mmol) in CH2Cl2 (5 mL) was
added 2-alkynyl aldehyde 2a–k (1.2 mmol) and TFA (2%). The
mixture was allowed to stir under an N2 atm at r.t. for 10 min, fol-
lowed by the addition of the AuClPPh3–AgSbF6 (15 mol%) catalyst
system. The mixture was then stirred at r.t. for a further 10 min. The
progress of the reaction was monitored by TLC. After completion,
the mixture was quenched with aq NaHCO3 soln and the aq layer
was extracted with CH2Cl2 (3 × 20 mL). The combined organic lay-
er was dried over anhyd Na2SO4 and evaporated to dryness under
reduced pressure. The residue was purified by column chromatog-
raphy (EtOAc–hexane) to afford products 3a–u.
HRMS (ESI): m/z [M + H]+ calcd for C33H29N2: 453.2331; found:
453.2324.
9-(4-Methoxyphenyl)-14b,16-dihydrobenzo[6,7]indo-
lo[3′,4′:3,4,5]azepino[2,1-a]isoquinoline (3d)
Yield: 0.143 g (70%); yellow solid; mp 157–162 °C; Rf = 0.61
(EtOAc–hexane, 1:4).
Polyheterocycles 3v–z; General Procedure
To a stirred soln of substrate 1c (1 mmol) in CH2Cl2 (5 mL) was
added 2-alkynyl aldehyde 2b,h,j,l,m (1.2 mmol) and PTSA (15
mol%). The mixture was allowed to stir under an N2 atm at r.t. for
10 min, followed by the addition of the AuClPPh3–AgSbF6 (15
mol%) catalyst system. The mixture was then stirred at r.t. for a fur-
ther 10 min. The progress of the reaction was monitored by TLC.
After completion, the mixture was quenched with aq NaHCO3 soln
and the aq layer was extracted with CH2Cl2 (3 × 20 mL). The com-
bined organic layer was dried over anhyd Na2SO4 and evaporated to
IR (KBr): 3478, 3021, 2062, 1596 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 10.97 (d, J = 1.9 Hz, 1 H), 8.01
(d, J = 7.1 Hz, 1 H), 7.53 (d, J = 7.2 Hz, 1 H), 7.44 (d, J = 7.7 Hz, 1
H), 7.38–7.33 (m, 1 H), 7.29–7.20 (m, 3 H), 7.15–7.07 (m, 2 H),
7.04 (d, J = 1.1 Hz, 1 H), 6.84 (dd, J1 = 7.8, J2 = 1.0 Hz, 1 H), 6.78
Synthesis 2013, 45, 1553–1563
© Georg Thieme Verlag Stuttgart · New York

PAPER
Novel Hexacyclic Isoquinolinobenzazepinoindoles
1559
(d, J = 8.7 Hz, 2 H), 6.58 (d, J = 8.7 Hz, 2 H), 6.43 (s, 1 H), 6.12 (s,
1 H), 5.45 (s, 1 H), 3.62 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): δ = 158.5, 145.5, 142.9, 138.2,
137.1, 133.6, 130.1, 130.0, 129.2, 129.1, 128.5, 127.5, 127.0, 126.7,
126.3, 126.0, 125.1, 124.1, 123.0, 122.5, 122.4, 121.1, 118.8, 113.0,
110.9, 99.2, 60.6, 54.8.
13-Fluoro-9-(p-tolyl)-14b,16-dihydrobenzo[6,7]indo-
lo[3′,4′:3,4,5]azepino[2,1-a]isoquinoline (3h)
Yield: 0.146 g (71%); yellow solid; mp 172–174 °C; Rf = 0.59
(EtOAc–hexane, 1:4).
IR (KBr): 3472, 2998, 2058, 1598 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 11.02 (d, J = 1.90 Hz, 1 H),
8.00 (d, J = 7.3 Hz, 1 H), 7.52 (d, J = 7.3 Hz, 1 H), 7.45 (d, J = 7.7
Hz, 1 H), 7.38–7.33 (m, 1 H), 7.28–7.23 (m, 1 H), 7.19–7.08 (m, 3
H), 7.05–7.03 (m, 1 H), 6.85–6.81 (m, 3 H), 6.73 (d, J = 8.1 Hz, 2
H), 6.53 (s, 1 H), 6.16 (s, 1 H), 5.50 (s, 1 H), 2.12 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): δ = 161.4, 158.2, 145.3, 142.6,
138.2, 137.1, 136.7, 134.8, 130.2, 130.1, 129.2, 128.6, 128.5, 128.2,
127.7, 127.1, 126.4, 125.1, 124.6, 124.5, 122.5, 121.8, 121.0, 118.8,
114.4, 113.0, 112.7, 111.0, 98.8, 60.2, 20.5 (extra peaks are present
due to 13C–19F couplings).
HRMS (ESI): m/z [M + H]+ calcd for C30H23N2O: 427.1810; found:
427.1803.
9-(2-Nitrophenyl)-14b,16-dihydrobenzo[6,7]indo-
lo[3′,4′:3,4,5]azepino[2,1-a]isoquinoline (3e)
Yield: 0.150 g (71%); yellow solid; mp 190–192 °C; Rf = 0.63
(EtOAc–hexane, 1:4).
IR (KBr): 3500, 3012, 2054, 1610 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 11.04 (s, 1 H), 7.99 (d, J = 7.7
Hz, 1 H), 7.77 (d, J = 7.5 Hz, 1 H), 7.66–7.63 (m, 1 H), 7.53–7.46
(m, 3 H), 7.42–7.37 (m, 1 H), 7.34–7.22 (m, 5 H), 7.19–7.06 (m, 2
H), 7.03 (d, J = 7.2 Hz, 1 H), 6.37 (s, 1 H), 6.12 (s, 1 H), 5.22 (s, 1
H).
13C NMR (75 MHz, DMSO-d6): δ = 144.2, 138.8, 138.3, 137.1,
133.9, 132.8, 131.2, 131.0, 130.4, 129.7, 129.0, 128.7, 127.6, 127.5,
127.3, 125.9, 124.9, 123.6, 123.2, 122.5, 122.2, 121.5, 118.8, 111.2,
99.5, 60.3.
HRMS (ESI): m/z [M + H]+ calcd for C30H22FN2: 429.1767; found:
429.1758.
9-[4-(tert-Butyl)phenyl]-13-fluoro-14b,16-dihydrobenzo[6,7]in-
dolo[3′,4′:3,4,5]azepino[2,1-a]isoquinoline (3i)
Yield: 0.164 g (73%); yellow solid; mp 139–142 °C; Rf = 0.60
(EtOAc–hexane, 1:4).
IR (KBr): 3454, 3025, 2148, 1602 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 11.01 (s, 1 H), 8.02 (d, J = 7.6
Hz, 1 H), 7.60–7.53 (m, 1 H), 7.45 (d, J = 7.8 Hz, 1 H), 7.39–7.34
(m, 1 H), 7.26 (t, J = 7.1 Hz, 1 H), 7.13–7.11 (m, 3 H), 7.07–7.01
(m, 3 H), 6.87 (d, J = 7.7 Hz, 1 H), 6.80 (d, J = 7.8 Hz, 2 H), 6.53
(s, 1 H), 6.16 (s, 1 H), 5.53 (s, 1 H), 1.13 (s, 9 H).
13C NMR (75 MHz, DMSO-d6): δ = 161.4, 158.3, 149.9, 145.4,
142.3, 138.1, 137.1, 134.7, 130.2, 130.1, 129.1, 128.6, 128.5, 127.4,
127.1, 126.4, 125.1, 124.6, 124.5, 124.4, 122.5, 121.8, 121.0, 118.9,
114.4, 114.1, 113.0, 112.7, 110.9, 99.2, 60.3, 34.0, 30.8 (extra peaks
are present due to 13C–19F couplings).
HRMS (ESI): m/z [M + H]+ calcd for C29H20N3O2: 442.1556; found:
442.1542.
9-(Cyclohex-1-en-1-yl)-14b,16-dihydrobenzo[6,7]indo-
lo[3′,4′:3,4,5]azepino[2,1-a]isoquinoline (3f)
Yield: 0.150 g (78%); yellow solid; mp 145–148 °C; Rf = 0.63
(EtOAc–hexane, 1:4).
IR (KBr): 3438, 2992, 2042, 1696 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 10.89 (d, J = 1.8 Hz, 1 H), 8.03
(d, J = 6.9 Hz, 1 H), 7.45 (d, J = 7.4 Hz, 1 H), 7.41–7.35 (m, 2 H),
7.31–7.26 (m, 2 H), 7.24–7.21 (m, 1 H), 7.19–7.16 (m, 1 H), 7.13–
7.11 (m, 1 H), 7.09–7.07 (m, 1 H), 7.05–7.01 (m, 1 H), 6.34 (s, 1 H),
5.98 (s, 1 H), 5.67 (s, 1 H), 5.31 (s, 1 H), 1.29–1.23 (m, 2 H), 1.16–
1.11 (m, 6 H).
13C NMR (75 MHz, DMSO-d6): δ = 146.1, 145.2, 137.8, 137.0,
135.3, 133.5, 130.2, 129.1, 128.3, 127.7, 127.4, 126.7, 126.6, 126.5,
125.8, 125.2, 123.8, 122.8, 122.3, 122.2, 121.0, 118.5, 110.6, 96.9,
60.2, 26.4, 24.7, 21.8, 21.3.
HRMS (ESI): m/z [M + H]+ calcd for C33H28FN2: 471.2237; found:
471.2228.
9-(Cyclohex-1-en-1-yl)-13-fluoro-14b,16-dihydrobenzo[6,7]in-
dolo[3′,4′:3,4,5]azepino[2,1-a]isoquinoline (3j)
Yield: 0.150 g (75%); yellow solid; mp 135–137 °C; Rf = 0.55
(EtOAc–hexane, 1:4).
IR (KBr): 3434, 2963, 2132, 1686 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 10.93 (s, 1 H), 8.03 (d, J = 7.5
Hz, 1 H), 7.44 (d, J = 7.4 Hz, 1 H), 7.41–7.35 (m, 2 H), 7.30–7.24
(m, 2 H), 7.11–7.04 (m, 4 H), 6.43 (s, 1 H), 6.02 (s, 1 H), 5.65 (s, 1
H), 5.33 (s, 1 H), 1.81 (s, 2 H), 1.26–1.11 (m, 6 H).
13C NMR (75 MHz, DMSO-d6): δ = 161.1, 157.9, 145.52, 145.50,
145.1, 137.8, 137.0, 135.2, 130.2, 129.1, 128.5, 128.4, 128.3, 127.7,
126.8, 126.5, 125.1, 124.2, 124.1, 122.3, 121.7, 120.9, 118.6, 114.2,
113.9, 112.9, 112.6, 110.7, 96.1, 59.9, 26.4, 24.6, 21.8, 21.3 (extra
peaks are present due to 13C–19F couplings).
HRMS (ESI): m/z [M + H]+ calcd for C29H25N2: 401.2018; found:
401.2006.
13-Fluoro-9-phenyl-14b,16-dihydrobenzo[6,7]indo-
lo[3′,4′:3,4,5]azepino[2,1-a]isoquinoline (3g)
Yield: 0.137 g (69%); yellow solid; mp 165–166 °C; Rf = 0.62
(EtOAc–hexane, 1:4).
IR (KBr): 3480, 3033, 2454, 1609 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 11.03 (d, J = 1.9 Hz, 1 H), 8.00
(d, J = 7.2 Hz, 1 H), 7.53 (d, J = 7.5 Hz, 1 H), 7.45 (d, J = 7.7 Hz, 1
H), 7.37 (d, J = 7.7 Hz, 1 H), 7.28–7.22 (m, 1 H), 7.18–7.11 (m, 4
H), 7.05–7.01 (m, 3 H), 6.86–6.82 (m, 3 H), 6.54 (s, 1 H), 6.20–6.18
(m, 1 H), 5.54 (s, 1 H).
13C NMR (75 MHz, DMSO-d6): δ = 161.5, 158.3, 145.2, 144.1,
142.6, 139.1, 138.2, 137.6, 137.1, 130.1, 130.0, 129.9, 129.2, 128.7,
128.6, 128.5, 127.7, 127.6, 127.5, 127.1, 126.4, 125.1, 124.8, 124.7,
124.6, 122.5, 121.8, 121.1, 118.8, 114.4, 114.1, 113.1, 112.8, 111.0,
99.2, 60.2 (extra peaks are present due to 13C–19F couplings).
HRMS (ESI): m/z [M + H]+ calcd for C29H24FN2: 419.1924; found:
419.1916.
13-Methoxy-9-phenyl-14b,16-dihydrobenzo[6,7]indo-
lo[3′,4′:3,4,5]azepino[2,1-a]isoquinoline (3k)
Yield: 0.137 g (67%); yellow solid; mp 141–145 °C; Rf = 0.50
(EtOAc–hexane, 1:4).
IR (KBr): 3502, 3012, 2111, 1625 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.94–7.90 (m, 2 H), 7.49 (d, J =
7.2 Hz, 1 H), 7.36–7.34 (m, 1 H), 7.30 (d, J = 9.6 Hz, 1 H), 7.24 (d,
J = 9.0 Hz, 1 H), 7.17–7.12 (m, 1 H), 7.05 (d, J = 8.3 Hz, 1 H), 6.97–
6.91 (m, 4 H), 6.88–6.87 (m, 2 H), 6.85–6.84 (m, 1 H), 6.73 (d, J =
2.3 Hz, 1 H), 6.49 (s, 1 H), 6.14 (s, 1 H), 5.53 (s, 1 H), 3.79 (s, 3 H).
HRMS (ESI): m/z [M + H]+ calcd for C29H20FN2: 415.1611; found:
415.1590.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1553–1563

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M. Saifuddin et al.
PAPER
13C NMR (75 MHz, CDCl3): δ = 157.5, 146.2, 142.2, 138.3, 137.4,
131.6, 131.5, 129.7, 128.9, 128.8, 128.6, 128.4, 127.6, 127.3, 127.2,
126.1, 126.0, 124.8, 123.9, 123.2, 120.7, 119.9, 116.3, 113.4, 112.2,
110.4, 100.2, 61.3, 55.6.
HRMS (ESI): m/z [M + H]+ calcd for C30H23N2O: 427.1810; found:
427.1794.
Hz, 2 H), 6.69 (s, 2 H), 6.28 (s, 1 H), 6.00 (s, 1 H), 5.41 (s, 1 H),
2.23 (s, 3 H), 1.04 (s, 9 H).
13C NMR (75 MHz, DMSO-d6): δ = 150.3, 144.2, 143.7, 138.1,
137.3, 135.6, 135.3, 134.4, 131.6, 129.4, 129.3, 128.2, 128.1, 127.8,
127.1, 126.2, 124.6, 124.2, 124.1, 123.4, 123.1, 121.0, 119.7, 110.3,
99.8, 61.4, 34.5, 31.3, 21.3.
HRMS (ESI): m/z [M + H]+ calcd for C34H31N2: 467.2487; found:
467.2472.
9-(Cyclohex-1-en-1-yl)-13-methoxy-14b,16-dihydroben-
zo[6,7]indolo[3′,4′:3,4,5]azepino[2,1-a]isoquinoline (3l)
Yield: 0.140 g (68%); yellow solid; mp 130–135 °C; Rf = 0.52
(EtOAc–hexane, 1:4).
9-(Cyclohex-1-en-1-yl)-5-methyl-14b,16-dihydrobenzo[6,7]in-
dolo[3′,4′:3,4,5]azepino[2,1-a]isoquinoline (3p)
Yield: 0.128 g (69%); yellow solid; mp 180–183 °C; Rf = 0.60
(EtOAc–hexane, 1:4).
IR (KBr): 3460, 3021, 2102, 1593 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 10.87 (s, 1 H), 8.02 (d, J = 7.6
Hz, 1 H), 7.61 (m, 1 H), 7.42 (d, J = 7.4 Hz, 1 H), 7.37–7.34 (m, 2
H), 7.28–7.25 (m, 2 H), 7.06 (d, J = 7.6 Hz, 1 H), 6.97 (d, J = 8.7
Hz, 1 H), 6.81 (s, 1 H), 6.42 (s, 1 H), 5.98 (s, 1 H), 5.63 (s, 1 H),
5.31 (s, 1 H), 3.76 (s, 3 H), 1.81 (s, 2 H), 1.26–1.23 (m, 6 H).
13C NMR (75 MHz, DMSO-d6): δ = 156.6, 145.7, 143.9, 137.6,
137.0, 135.4, 130.3, 129.0, 128.3, 128.2, 127.1, 126.7, 126.4, 126.2,
125.3, 123.9, 122.2, 120.7, 118.5, 113.0, 111.7, 110.6, 97.0, 60.3,
55.1, 26.4, 24.7, 21.9, 21.4.
IR (KBr): 3434, 2863, 2132, 1696 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 10.87 (s, 1 H), 7.84 (s, 1 H),
7.45 (d, J = 7.6 Hz, 1 H), 7.35 (d, J = 7.8 Hz, 1 H), 7.27 (d, J = 7.7
Hz, 1 H), 7.23–7.19 (m, 1 H), 7.15–7.08 (m, 3 H), 7.05–7.03 (m, 1
H), 6.99 (d, J = 8.0 Hz, 1 H), 6.31 (s, 1 H), 5.93 (s, 1 H), 5.68 (s, 1
H), 5.27 (s, 1 H), 2.44 (s, 3 H), 1.85 (s, 2 H), 1.28–1.27 (m, 6 H).
13C NMR (50 MHz, DMSO-d6): δ = 146.3, 142.9, 137.5, 137.0,
135.5, 133.6, 130.3, 128.8, 127.5, 127.4, 126.6, 125.8, 125.2, 123.6,
122.7, 122.4, 122.2, 120.9, 118.4, 110.5, 96.5, 60.3, 26.4, 24.7,
21.9, 21.4, 20.8.
HRMS (ESI): m/z [M + H]+ calcd for C30H27N2O: 431.2123; found:
431.2118.
HRMS (ESI): m/z [M + H]+ calcd for C30H27N2: 415.2174; found:
415.2163.
5-Methyl-9-phenyl-14b,16-dihydrobenzo[6,7]indo-
lo[3′,4′:3,4,5]azepino[2,1-a]isoquinoline (3m)
Yield: 0.120 g (65%); yellow solid; mp 185–190 °C; Rf = 0.55
(EtOAc–hexane, 1:4).
9-(4-Methoxyphenyl)-5-methyl-14b,16-dihydrobenzo[6,7]indo-
lo[3′,4′:3,4,5]azepino[2,1-a]isoquinoline (3q)
Yield: 0.138 g (70%); reddish oil; Rf = 0.52 (EtOAc–hexane, 1:4).
IR (KBr): 3509, 3025, 2132, 1609 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 10.97 (d, J = 1.6 Hz, 1 H), 7.81
(s, 1 H), 7.54 (d, J = 7.3 Hz, 1 H), 7.44 (d, J = 7.8 Hz, 1 H), 7.38–
7.33 (m, 1 H), 7.29–7.20 (m, 2 H), 7.17–7.09 (m, 2 H), 7.07–6.99
(m, 3 H), 6.86–6.84 (m, 3 H), 6.74 (d, J = 7.9 Hz, 1 H), 6.43 (s, 1
H), 6.10 (s, 1 H), 5.48 (s, 1 H), 2.33 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): δ = 143.3, 142.9, 137.9, 137.8,
137.1, 135.4, 133.4, 130.2, 128.9, 128.8, 127.8, 127.6, 127.5, 127.4,
126.7, 126.0, 125.1, 124.3, 123.2, 122.5, 122.4, 121.1, 118.7, 110.9,
99.7, 60.7, 20.6.
IR (neat): 3472, 3015, 2401, 1605 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.06 (s, 1 H), 7.83 (d, J = 8.7 Hz,
2 H), 7.51 (d, J = 8.3 Hz, 2 H), 7.13 (d, J = 8.0 Hz, 2 H), 7.08 (d, J =
6.0 Hz, 3 H), 6.88 (d, J = 8.8 Hz, 2 H), 6.81 (s, 1 H), 6.79–6.77 (m,
2 H), 6.50 (s, 1 H), 6.10 (d, J = 1.2 Hz, 1 H), 5.45 (s, 1 H), 3.85 (s,
3 H), 2.04 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): δ = 158.9, 144.1, 143.6, 139.4,
137.7, 136.3, 136.0, 133.6, 132.8, 132.3, 131.8, 129.8, 129.5, 128.2,
127.8, 127.1, 126.7, 126.2, 123.6, 123.3, 123.1, 121.0, 119.7, 113.1,
110.4, 98.9, 61.3, 55.5, 20.9.
HRMS (ESI): m/z [M + H]+ calcd for C30H23N2: 411.1861; found:
411.1851.
HRMS (ESI): m/z [M + H]+ calcd for C31H25N2O: 441.1967; found:
441.1954.
5-Methyl-9-(p-tolyl)-14b,16-dihydrobenzo[6,7]indo-
lo[3′,4′:3,4,5]azepino[2,1-a]isoquinoline (3n)
13-Fluoro-5-methyl-9-phenyl-14b,16-dihydrobenzo[6,7]indo-
lo[3′,4′:3,4,5]azepino[2,1-a]isoquinoline (3r)
Yield: 0.136 g (71%); yellow solid; mp 177–180 °C; Rf = 0.52
(EtOAc–hexane, 1:4).
Yield: 0.120 g (63%); reddish oil; Rf = 0.56 (EtOAc–hexane, 1:4).
IR (neat): 3468, 2952, 2121, 1646 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 10.96 (d, J = 1.8 Hz, 1 H), 7.80
(s, 1 H), 7.52 (d, J = 7.1 Hz, 1 H), 7.44–7.37 (m, 2 H), 7.35–7.32
(m, 1 H), 7.30–7.29 (m, 1 H), 7.20–7.16 (m, 2 H), 7.14–7.11 (m, 2
H), 6.84 (d, J = 8.1 Hz, 2 H), 6.73 (d, J = 8.2 Hz, 2 H), 6.41 (s, 1 H),
6.08 (s, 1 H), 5.43 (s, 1 H), 2.34 (s, 3 H), 2.14 (s, 3 H).
13C NMR (50 MHz, DMSO-d6): δ = 143.3, 143.0, 137.9, 137.1,
136.7, 135.3, 133.5, 131.7, 130.3, 128.9, 128.2, 127.7, 126.7, 125.9,
125.1, 124.1, 123.0, 122.5, 121.1, 118.6, 110.8, 99.2, 60.7, 20.6,
20.5.
IR (KBr): 3473, 2998, 2512, 1512 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 11.01 (s, 1 H), 7.80 (s, 1 H),
7.53 (d, J = 7.3 Hz, 1 H), 7.44 (d, J = 7.8 Hz, 1 H), 7.35 (t, J = 7.6
Hz, 1 H), 7.19–7.11 (m, 3 H), 7.08–6.99 (m, 3 H), 6.87–6.82 (m, 3
H), 6.74 (d, J = 7.9 Hz, 1 H), 6.52 (s, 1 H), 6.13 (s, 1 H), 5.50 (s, 1
H), 2.33 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): δ = 161.5, 158.3, 142.8, 142.7,
137.9, 137.7, 137.1, 135.5, 130.2, 130.1, 130.0, 128.9, 128.6, 128.5,
127.8, 127.6, 127.4, 125.0, 124.6, 124.5, 122.5, 121.8, 121.0, 118.7,
114.4, 114.1, 113.0, 112.7, 110.9, 98.9, 60.3, 20.6 (extra peaks are
present due to 13C–19F couplings).
HRMS (ESI): m/z [M + H]+ calcd for C31H25N2: 425.2018; found:
425.2007.
9-[4-(tert-Butyl)phenyl]-5-methyl-14b,16-dihydrobenzo[6,7]in-
dolo[3′,4′:3,4,5]azepino[2,1-a]isoquinoline (3o)
Yield: 0.138 g (66%); reddish oil; Rf = 0.57 (EtOAc–hexane, 1:4).
HRMS (ESI): m/z [M + H]+ calcd for C30H22FN2: 429.1767; found:
429.1750.
IR (neat): 3452, 3028, 2502, 1582 cm–1.
9-[4-(tert-Butyl)phenyl]-13-fluoro-5-methyl-14b,16-dihydro-
benzo[6,7]indolo[3′,4′:3,4,5]azepino[2,1-a]isoquinoline (3s)
Yield: 0.156 g (72%); white solid; mp 195–198 °C; Rf = 0.59
(EtOAc–hexane, 1:4).
1H NMR (300 MHz, CDCl3): δ = 7.75 (s, 1 H), 7.64 (s, 1 H), 7.42
(t, J = 7.5 Hz, 2 H), 7.24 (t, J = 7.8 Hz, 1 H), 7.14 (d, J = 7.3 Hz, 2
H), 6.99–6.98 (m, 2 H), 6.88 (d, J = 8.1 Hz, 2 H), 6.73 (d, J = 8.2
IR (KBr): 3509, 3120, 2509, 1612 cm–1.
Synthesis 2013, 45, 1553–1563
© Georg Thieme Verlag Stuttgart · New York

PAPER
Novel Hexacyclic Isoquinolinobenzazepinoindoles
1561
1H NMR (300 MHz, CDCl3): δ = 7.84 (s, 1 H), 7.72 (s, 1 H), 7.52
(d, J = 7.5 Hz, 1 H), 7.35 (t, J = 7.9 Hz, 1 H), 7.27–7.23 (m, 1 H),
7.05–7.00 (m, 1 H), 6.98–6.93 (m, 3 H), 6.87–6.78 (m, 5 H), 6.43
(s, 1 H), 6.07 (s, 1 H), 5.47 (s, 1 H), 2.32 (s, 3 H), 1.03 (s, 9 H).
13C NMR (75 MHz, CDCl3): δ = 162.2, 158.9, 150.4, 143.6, 143.5,
138.0, 137.4, 135.7, 135.1, 131.6, 130.7, 129.4, 128.7, 128.6, 128.3,
128.0, 125.9, 124.6, 124.5, 123.5, 123.3, 120.7, 119.9, 114.8, 114.5,
113.1, 112.8, 110.4, 99.0, 61.3, 34.5, 31.3, 21.3 (extra peaks are
present due to 13C–19F couplings).
9-(Cyclohex-1-en-1-yl)-13-fluoro-14b,16-dihydroindo-
lo[3′,4′:3,4,5]pyrido[2′,3′:6,7]azepino[2,1-a]isoquinoline (3w)
Yield: 0.130 g (65%); yellow solid; mp 135–137 °C; Rf = 0.52
(EtOAc–hexane, 1:4).
IR (KBr): 3534, 2963, 2532, 1526 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 11.06–11.01 (m, 1 H), 8.66–
8.61 (m, 1 H), 8.17–8.07 (m, 1 H), 7.92–7.90 (m, 1 H), 7.48–7.46
(m, 1 H), 7.33–7.30 (m, 2 H), 7.18–7.15 (m, 1 H), 7.10–7.08 (m, 2
H), 6.51–6.48 (m, 1 H), 6.08–6.04 (m, 2 H), 5.67–5.64 (m, 1 H),
1.82 (s, 2 H), 1.26–1.14 (m, 6 H).
HRMS (ESI): m/z [M + H]+ calcd for C34H30FN2: 485.2393; found:
13C NMR (75 MHz, DMSO-d6): δ = 161.3, 158.2, 146.7, 145.2,
140.9, 137.0, 136.6, 134.7, 133.8, 133.7, 132.2, 129.8, 129.7, 129.5,
128.5, 127.4, 121.9, 121.3, 121.2, 120.0, 114.1, 113.0, 111.9, 97.6,
59.7, 36.5, 24.7, 21.7, 21.2 (extra peaks are present due to 13C–19F
couplings).
HRMS (ESI): m/z [M + H]+ calcd for C28H23FN3: 420.1876; found:
420.1868.
485.2380.
9-(Cyclohex-1-en-1-yl)-13-fluoro-5-methyl-14b,16-dihydroben-
zo[6,7]indolo[3′,4′:3,4,5]azepino[2,1-a]isoquinoline (3t)
Yield: 0.145 g (75%); reddish oil; Rf = 0.59 (EtOAc–hexane, 1:4).
IR (neat): 3502, 2902, 2502, 1580 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 10.86 (s, 1 H), 7.80 (s, 1 H),
7.41 (d, J = 7.4 Hz, 1 H), 7.31 (d, J = 7.9 Hz, 1 H), 7.23 (d, J = 7.6
Hz, 2 H), 7.00 (d, J = 8.0 Hz, 3 H), 6.94 (d, J = 7.9 Hz, 1 H), 6.36
(s, 1 H), 5.92 (s, 1 H), 5.62 (s, 1 H), 5.25 (s, 1 H), 2.40 (s, 3 H), 2.40
(s, 2 H), 1.98 (s, 3 H), 1.79 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 161.9, 158.7, 146.8, 143.3, 139.4,
137.9, 137.3, 136.0, 135.9, 131.5, 129.4, 129.3, 128.6, 127.9, 125.8,
124.3, 124.2, 123.4, 123.1, 120.6, 119.6, 114.6, 114.3, 114.2, 113.0,
112.7, 110.1, 95.7, 60.5, 27.0, 25.4, 22.8, 22.5, 21.4 (extra peaks are
present due to 13C–19F couplings).
9-[4-(tert-Butyl)phenyl]-13-methoxy-14b,16-dihydroindo-
lo[3′,4′:3,4,5]pyrido[2′,3′:6,7]azepino[2,1-a]isoquinoline (3x)
Yield: 0.140 g (61%); yellow solid; mp 129–133 °C; Rf = 0.48
(EtOAc–hexane, 1:4).
IR (KBr): 3502, 3012, 2205, 1598 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 11.02 (s, 1 H), 8.46 (s, 1 H),
8.11 (d, J = 6.7 Hz, 1 H), 7.51–7.48 (m, 2 H), 7.40 (s, 1 H), 7.18–
7.10 (m, 2 H), 7.03–7.01 (m, 3 H), 6.90 (s, 2 H), 6.74–6.72 (m, 1 H),
6.56 (s, 1 H), 6.13 (s, 1 H), 5.62 (s, 1 H), 3.79 (s, 3 H), 1.12 (s, 9 H).
HRMS (ESI): m/z [M + H]+ calcd for C30H26FN2: 433.2080; found:
13C NMR (75 MHz, DMSO-d6): δ = 157.2, 149.7, 146.2, 141.8,
140.4, 137.1, 136.4, 134.5, 133.8, 133.6, 132.2, 129.9, 129.7, 129.5,
128.5, 127.3, 124.5, 122.0, 121.8, 121.5, 121.2, 120.2, 113.3, 111.9,
101.8, 60.0, 55.1, 34.0, 30.8.
HRMS (ESI): m/z [M + H]+ calcd for C33H30N3O: 484.2389; found:
484.2384.
433.2072.
9-(Cyclohex-1-en-1-yl)-13-methoxy-5-methyl-14b,16-dihydro-
benzo[6,7]indolo[3′,4′:3,4,5]azepino[2,1-a]isoquinoline (3u)
Yield: 0.132 g (66%); reddish oil; Rf = 0.63 (EtOAc–hexane, 1:4).
IR (neat): 3433, 2969, 2135, 1656 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.96 (s, 1 H), 7.74 (s, 1 H), 7.42
(d, J = 6.9 Hz, 1 H), 7.28 (s, 1 H), 7.22 (d, J = 5.4 Hz, 1 H), 7.00 (s,
2 H), 6.96 (d, J = 8.6 Hz, 1 H), 6.77 (d, J = 8.3 Hz, 1 H), 6.66 (s, 1
H), 6.41 (s, 1 H), 5.95 (s, 1 H), 5.68 (s, 1 H), 5.33 (s, 1 H), 3.77 (s,
3 H), 2.42 (s, 3 H), 2.03–2.00 (m, 5 H), 1.83 (m, 3 H).
9-(Cyclohex-1-en-1-yl)-13-methoxy-14b,16-dihydroindo-
lo[3′,4′:3,4,5]pyrido[2′,3′:6,7]azepino[2,1-a]isoquinoline (3y)
Yield: 0.129 g (63%); reddish oil; Rf = 0.50 (EtOAc–hexane, 1:4).
IR (neat): 3472, 2993, 2522, 1626 cm–1.
13C NMR (75 MHz, CDCl3): δ = 156.9, 145.5, 143.8, 139.4, 137.3,
136.1, 129.4, 129.2, 128.5, 128.0, 127.8, 126.0, 124.2, 123.8, 123.6,
122.9, 120.6, 119.5, 114.2, 113.3, 112.0, 110.0, 96.3, 61.1, 55.6,
27.0, 25.5, 22.6, 21.4.
1H NMR (300 MHz, DMSO-d6): δ = 10.95 (d, J = 1.9 Hz, 1 H),
8.60–8.58 (m, 1 H), 8.07 (d, J = 7.4 Hz, 1 H), 7.46–7.41 (m, 2 H),
7.32–7.26 (m, 2 H), 7.02 (d, J = 8.0 Hz, 1 H), 6.88–6.85 (m, 2 H),
6.47 (s, 1 H), 6.00 (s, 1 H), 5.65 (s, 1 H), 5.42 (s, 1 H), 3.77 (s, 3 H),
1.83 (s, 2 H), 1.27 (s, 6 H).
HRMS (ESI): m/z [M + H]+ calcd for C31H29N2O: 445.2280; found:
13C NMR (75 MHz, DMSO-d6): δ = 156.9, 146.3, 143.5, 141.4,
140.2, 139.0, 134.9, 134.1, 129.9, 128.6, 127.9, 126.1, 124.1, 123.1,
122.6, 121.2, 115.6, 113.2, 111.9, 111.8, 98.6, 59.7, 55.1, 26.5,
24.7, 21.8, 21.3.
445.2267.
13-Fluoro-9-(p-tolyl)-14b,16-dihydroindolo[3′,4′:3,4,5]pyri-
do[2′,3′:6,7]azepino[2,1-a]isoquinoline (3v)
Yield: 0.131 g (64%); yellow solid; mp 130–133 °C; Rf = 0.49
(EtOAc–hexane, 1:4).
HRMS (ESI): m/z [M + H]+ calcd for C29H26N3O: 432.2076; found:
432.2066.
IR (KBr): 3424, 2763, 2522, 1626 cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.48 (d, J = 3.1 Hz, 1 H), 8.33 (s,
1 H), 8.17 (d, J = 7.1 Hz, 1 H), 7.69 (d, J = 8.1 Hz, 1 H), 7.53 (s, 4
H), 7.49 (s, 6 H), 6.22 (s, 1 H), 6.01 (s, 1 H), 5.56 (s, 1 H), 2.39 (s,
3 H).
13C NMR (100 MHz, DMSO-d6): δ = 161.3, 159.1, 155.4, 152.6,
147.6, 147.5, 146.6, 141.3, 140.5, 138.6, 138.1, 137.8, 133.9, 133.7,
132.3, 132.2, 130.9, 129.7, 129.6, 129.2, 128.6, 128.4, 124.8, 122.4,
122.3, 122.1, 120.3, 119.7, 112.7, 112.2, 100.3, 59.5, 20.9 (extra
peaks are present due to 13C–19F couplings).
9-Phenyl-14b,16-dihydroindolo[3′,4′:3,4,5]pyrido[2′,3′:6,7]aze-
pino[2,1-a]isoquinoline (3z)
Yield: 0.134 g (71%); yellow solid; mp 185–188 °C; Rf = 0.51
(EtOAc–hexane, 1:4).
IR (KBr): 3473, 3020, 2401, 1605 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 11.05 (s, 1 H), 8.45 (d, J = 3.7
Hz, 1 H), 8.12 (d, J = 7.4 Hz, 1 H), 7.66–7.61 (m, 2 H), 7.51 (d, J =
7.9 Hz, 1 H), 7.41–7.36 (m, 1 H), 7.28–7.25 (m, 1 H), 7.21–7.19 (m,
3 H), 7.06–7.03 (m, 3 H), 6.79 (d, J = 6.9 Hz, 2 H), 6.48 (s, 1 H),
6.16 (s, 1 H), 5.62 (s, 1 H).
HRMS (ESI): m/z [M + H]+ calcd for C29H21FN3: 430.1720; found:
13C NMR (100 MHz, DMSO-d6): δ = 154.6, 146.5, 142.9, 141.3,
137.3, 137.1, 136.7, 133.8, 133.7, 133.0, 129.8, 129.7, 129.5, 127.8,
127.0, 126.1, 125.5, 123.5, 122.1, 121.9, 121.6, 120.3, 112.2, 101.6,
59.8.
430.1714.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1553–1563

1562
M. Saifuddin et al.
PAPER
V. S. P.; Sprague, S.; Schilling, J. K.; Kingston, D. G. I.
HRMS (ESI): m/z [M + H]+ calcd for C28H20N3: 398.1657; found:
398.1667.
J. Nat. Prod. 2003, 66, 528. (f) Zhao, Z.; Wolkenberg, S. E.;
Lu, M.; Munshi, V.; Moyer, G.; Feng, M.; Carella, A. V.;
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McGaughey, G. B.; Miller, M. D.; Lindsley, C. W.;
Hartman, G. D.; Vacca, J. P.; Williams, T. M. Bioorg. Med.
Chem. Lett. 2008, 18, 554. (g) Scribner, A.; Moore, J. A. III;
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Acknowledgment
M.S. and S.S. are thankful to the CSIR, New Delhi, India for fellow-
ships. The authors would also like to thank SAIF, CDRI, India for
providing analytical data.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
nnfomartit
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