One-pot synthesis of polyhydropyrido[1,2-a]indoles and tetracyclic quinazolinones from 2-arylindoles using copper-mediated oxidative tandem reactions

Article abstract of DOI:10.1016/j.tet.2016.05.054

We developed facile one-pot methods for the transformation of 2-arylindoles to polyhydropyrido[1,2-a]indoles and tetracyclic quinazolinones. The copper-catalyzed oxidation of 2-arylindoles to C-acylimines followed by aza-Diels–Alder reactions or oxidative

Full text of DOI:10.1016/j.tet.2016.05.054

Accepted Manuscript
One-pot synthesis of polyhydropyrido[1,2-a]indoles and tetracyclic quinazolinones
from 2-arylindoles using copper-mediated oxidative tandem reactions
Mitsuaki Yamashita, Yukari Nishizono, Seiya Himekawa, Akira Iida
PII:
S0040-4020(16)30461-6
10.1016/j.tet.2016.05.054
TET 27781
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 25 March 2016
Revised Date: 16 May 2016
Accepted Date: 20 May 2016
Please cite this article as: Yamashita M, Nishizono Y, Himekawa S, Iida A, One-pot synthesis of
polyhydropyrido[1,2-a]indoles and tetracyclic quinazolinones from 2-arylindoles using copper-mediated
oxidative tandem reactions, Tetrahedron (2016), doi: 10.1016/j.tet.2016.05.054.
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Polyhydropyrido[1,2-a]indoles and
Tetracyclic Quinazolinones from
2-Arylindoles Using Copper-mediated
Oxidative Tandem Reactions
Mitsuaki Yamashita, Yukari Nishizono, Seiya Himekawa and Akira Iida

ACCEPTED MANUSCRIPT
One-pot synthesis of Polyhydropyrido[1,2-a]indoles and Tetracyclic
Quinazolinones from 2-Arylindoles Using Copper-mediated Oxidative Tandem
Reactions
a,*
a
a
a
Mitsuaki Yamashita , Yukari Nishizono , Seiya Himekawa and Akira Iida
a
School of Agriculture, Kindai University, Nakamachi, Nara 631-8505, Japan
Abstract
We developed facile one-pot methods for the transformation of 2-arylindoles to
polyhydropyrido[1,2-a]indoles and tetracyclic quinazolinones. The copper-catalyzed oxidation of
2-arylindoles to C-acylimines followed by aza-Diels-Alder reactions or oxidative ring-expansion
reactions afforded significant polycyclic heterocycles.
Keywords: Copper; Oxidation; aza-Diels-Alder; Rearrangement; Indoles
*
Corresponding author. Tel./fax: +81-742-43-1770; e-mail: yamash@nara.kindai.ac.jp (M.Y.).
1

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1
. Introduction
Copper-catalyzed reactions are one of the most important and attractive strategies in organic
ꢀ
synthesis due to their efficiency, good functional group tolerance, and economy. As part of our
ꢁ
work on one-pot catalysis, we recently reported the synthesis of 2-arylbenzoxazinones and
N-benzoyl anthranilic acids via copper-catalyzed tandem oxidative reactions of 2-arylindoles
ꢂ
(
Scheme 1a). In this paper, plausible intermediate 7a was proposed (Scheme 2a). To the best of our
knowledge, synthesis methods for the C-acylimine species involved drawbacks such as a complex
multistep procedure for the preparation of substrates, low reaction selectivity or yield, and the use of
ꢃ
an expensive palladium catalyst. Based on these reports and motivated by the interesting
ꢄ
reactivities of C-acylimine species, we decided to explore efficient methods to construct polycyclic
heterocycles via the acylimino species. Herein, we report the synthesis of
polyhydropyrido[1,2-a]indoles and tetracyclic quinazolinones from 2-arylindoles using a
combination of copper-mediated oxidative tandem reactions and aza-Diels-Alder reactions or
oxidative ring expansion reactions (Schemes 1b and 1c).
Preliminarily, we tested three reactions because we were unable to obtain 7a in previous work,
probably due to the fast conversion of 7a to 2a at high temperatures: (i) The reaction of
2
-phenylindole 1a with pyridine (2.0 equivalents) instead of Na CO proceeded even at room
2 3
temperature, giving 2-phenylbenzoxazinone 2a and N-benzoyl anthranilic acid 3a in 65% and 23%
2

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yields, respectively (Scheme 2b); (ii) the reaction of 2-phenylindolone 7a in the presence of CuCl
(
0.2 equivalents) and Na CO (2.0 equivalents) in DMSO at 80 °C for 12 h under an O atmosphere
2
3
2
resulted in 2-phenylbenzoxazinone 2a and N-benzoyl anthranilic acid 3a in 69% and 29% yields,
respectively (Scheme 2c); (iii) the reaction of 2-phenylindolone 7a in the presence of H O (3.0
2
2
equivalents) in DMSO at 80 °C for 21 h under O atmosphere resulted in N-benzoyl anthranilic acid
2
3a in <37% yield (Scheme 2d). These results indicate that 7a is an intermediate of the transformation
of 2-phenyl indole 1a to 2-phenylbenzoxazinone 2a.
Scheme 1. Copper-catalyzed oxidative reactions of 2-arylindoles
Scheme 2. Proposed mechanisms for the transformation of 1a to 3a
3

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O
Cu(I), O2
Ph
Ph
N
H
N
1a
7a
O
O
Cu(II)OOH
or H O
hydrolysis
OH
NH
Ph
2
2
O
(a)
Baeyer-Villiger
oxidation
N
Ph
2a
3a
O
2
0 mol % CuCl
O
O
N
2
equiv. pyridine
O
Ph
Ph
(b)
N
DMSO
rt, 12 h
1atm O2
N
H
Ph
1
a
a
7a, 65%
2a, 23%
O
O
20 mol % CuCl
O
2
equiv. Na CO
2
3
OH
O
(c)
Ph
Ph
N
DMSO
0 °C, 12 h
1atm O2
NHBz
N
Ph
8
7
2
a, 69%
3a, 29%
O
O
3
equiv. H O
2
2
OH
NHBz
(d)
N
DMSO
0 °C, 21 h
8
<
37%
7a
3a
2
. Results and Discussion
First, the results of our initial attempts to optimize the reaction conditions for the synthesis of a
unique type of tricyclic scaffold, polyhydropyrido[1,2-a]indoles 4, by an aza-Diels-Alder reaction are
shown in Table 1. Polyhydropyrido[1,2-a]indoles exist widely as key structures in several
ꢅ
ꢆ
ꢇ
biologically active materials such as cladoniamides, canthine-6-ones, and goniomitine. The
reaction of 1a in DMSO, which is a suitable solvent for the previously reported copper-catalyzed
3
oxidative reactions, at rt for 24 h with Danishefsky’s diene 8a resulted in a moderate conversion to
hydropyrido[1,2-a]indolone 4a in 59% yield (Table 1, entry 1). The use of other solvents (i.e.,
acetonitrile, dichloromethane, and acetone) for this reaction did not improve results compared to
4

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those obtained with DMSO (Table 1, entries 2–4). However, the yield of 4a was substantially
increased when the reaction was performed in benzene and toluene, demonstrating that toluene is the
best solvent for this aza-Diels-Alder reaction (Table 1, entries 5 and 6). We also examined the other
reaction conditions (e.g., temperature and number of equivalents of diene); however, there were no
further improvements in chemical yields (Table 1, entries 7 and 8). A combination of the
copper-catalyzed oxidative reactions and the aza-Diels-Alder reaction was then tested. Fortunately,
the reaction of 2-phenylindole 1a with CuCl (0.2 equivalents) and pyridine (2.0 equivalents) in
toluene gave hydropyrido[1,2-a]indolone 4a in moderate yield, while little improvement in the yield
of 4a was observed when the reaction was performed at 50 °C (Table 2, entries 1 and 2).
Unfortunately, neither 1.0 nor 4.0 equivalents of pyridine resulted in a higher yield (Table 2, entry 3).
No further improvement was obtained when 0.5 equivalents of CuCl was used (Table 2, entry 4).
These results suggest that the optimum number of equivalents of pyridine and CuCl are 2.0 and 0.2,
respectively.
a
Table 1. Optimization of reaction conditions for the aza-Diels-Alder reaction
5

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b
Yield (%)
Entry
Time (h)
Solvent
Diene 8a, equiv.
4
a
1
2
3
4
5
6
7
2
2
2
2
2
2
1
2
4
4
4
4
4
4
6
0
DMSO
acetonitrile
DCM
1.5
1.5
1.5
1.5
1.5
1.5
3.0
1.5
59
57
36
66
76
82
54
77
acetone
benzene
toluene
toluene
toluene
c
8
a
Substrate 7a (0.2 mmol) and diene 8a were stirred in solvent (1.0 mL) at rt under Ar. After the reaction was completed, 10% HCl (1.0
b
c
mL) was added. Isolated yield. Reaction at 50 °C.
Table 2. Optimization of reaction conditions for the synthesis of hydropyrido[1,2-a]indolone 4a from 2-arylindole
a
1
a
b
Yield (%)
Entry
CuCl, equiv.
Temp., degree
Pyridine, equiv.
4
a
1
2
3
4
5
0.2
0.2
0.2
0.2
0.5
rt
2.0
2.0
1.0
4.0
2.0
55
58
37
53
47
50
50
50
50
a
Substrate 1a (0.2 mmol), CuCl, diene (0.3 mmol), and pyridine were stirred in toluene (1.0 mL) under O (1 atm). After 24 h, 10%
2
b
HCl (1.0 mL) was added. Isolated yield.
Using the optimized conditions, we investigated other substrates to evaluate the developed methods,
and the results are shown in Figure 1. Our reaction proved to be a general methodology for the
6

ACCEPTED MANUSCRIPT
preparation of polyhydropyrido[1,2-a]indoles, and tolerated various functional groups. Notably, both
electron-donating and electron-withdrawing functional groups on the 2-aryl ring were tolerated under
the developed reaction conditions. The 2-arylindoles 1b–1h reacted smoothly to give the
corresponding polyhydropyrido[1,2-a]indoles 4ba–4ha in modest yields. On the other hand, the
reactions of 5-methyl-, methoxy-, fluoro-, chloro-, 6-methyl-, and 7-methyl- substituted indoles
1i–1n gave the corresponding products 4ia–4na in slightly lower yields compared to those of
4ba–4ha. The reactions of benz[g]indole 1o gave 4oa in good yield.
a,b
Figure 1. Reaction of various 2-arylindoles 1 under the optimized reaction conditions
7

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a
Substrate 1 (0.2 mmol), CuCl (0.04 mmol), diene 8a (0.3 mmol), and pyridine (0.4 mmol) were stirred in toluene
b
(
1.0 mL) at 50 °C under O (1 atm). After 24 h, 10% HCl (1.0 mL) was added. Isolated yields.
2
Quinazolinone derivatives are versatile building blocks in organic synthesis and medicinal
ꢈ
chemistry. In addition, they are widely found in various biological compounds and pharmaceutical
ꢀ
ꢉ
ꢀꢀ
ꢀꢁ
drugs,
such as rutaecarpine
and luotonin A.
Therefore, the development of efficient
ꢀ
ꢂ
methods to synthesize these compounds continues to be an active research area.
The results of
our initial attempts to optimize the reaction conditions are shown in Table 3. The reaction of 5a in
NMP at 80 °C for 24 h with 10 mol% of CuBr under O resulted in a low conversion to tetracyclic
2
quinazolinone 6a in 10% yield (Table 3, entry 1). Alternatively, the addition of 2 equivalents of
Na CO to the reaction mixture and an increase in the amount of CuBr improved the yield of 6a
2
3
(Table 3, entries 2 and 3). Meanwhile, the chemical yield was further improved when the reaction
was performed at 60 °C in DMSO instead of NMP (Table 3, entries 4 and 5). Unfortunately, reaction
at 40 °C did not result in a high yield, which suggests that the optimum reaction temperature is 60 °C
(Table 3, entry 6). Other copper catalysts, such as CuCl, were also tested, but produced similar
results to those with CuBr (Table 3, entry 7). The reaction with other bases (i.e., NaHCO and Et N)
3
3
produced results similar to those obtained with Na CO (Table 3, entries 8 and 9). The addition of
2
3
pyridine instead of Na CO provided the best result (Table 3, entry 10).
2
3
a
Table 3. Optimization of reaction conditions for the synthesis of tetracyclic quinazolinone 6a from indole 5a
8

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b
Yield (%)
Entry
1
Time (h)
Cu salt, equiv.
base
Solvent
temp. (°C)
6
a
24
3.0
3.0
24
24
24
24
24
24
24
CuBr (0.1)
CuBr (0.1)
CuBr (0.2)
CuBr (0.2)
CuBr (0.2)
CuCl (0.2)
CuBr (0.2)
CuBr (0.2)
CuBr (0.2)
CuBr (0.2)
none
NMP
NMP
80
80
80
60
60
60
40
60
60
10
45
54
59
65
66
51
61
62
71
2
3
4
5
6
7
8
9
Na CO
2
3
3
3
3
3
3
Na CO
NMP
2
Na CO
NMP
2
Na CO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
2
Na CO
2
Na CO
2
NaHCO3
Et N
3
10
pyridine
60
a
b
Substrate 5a (0.2 mmol), Cu salt, and base (0.4 mmol) were stirred in solvent (1.0 mL) under O (1 atm). Isolated yield.
2
9

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We then investigated other substrates to evaluate the developed methods; the results are shown in
Figure 2. The 5-chloro-, methoxy-, fluoro-, and 7-methoxy-substituted indoles 5b–5e reacted
smoothly to give the corresponding tetracyclic quinazolinones 6b–6e in 39%–56% yields,
demonstrating that our reaction tolerated some functional groups. Meanwhile, the reaction of 2-[2-
(aminomethyl)phenyl]indole 15a gave a lower yield of tetracyclic quinazolinone 16a, because of the
formation of unknown byproducts. These results indicate that the length of the aminoalkyl chain on
the 2-aryl group is crucial in the developed reactions.
Figure 2. Oxidation of 2-arylindoles 1 in the presence of CuBr for the synthesis of tetracyclic quinazolinones from
a,b
indoles
a
Substrate 1 (0.2 mmol), CuBr (0.04 mmol), and Na CO (0.4 mmol) were stirred in DMSO (1.0 mL) at 80 °C
2
3
b
under O (1 atm). Isolated yields.
2
1
0

ACCEPTED MANUSCRIPT
During our investigations, similar copper-catalyzed reactions of substituted 2-arylindoles to form
ꢀ
ꢃ
2-arylquinazolinones with amines or ammoniums were reported.
In this paper, Cui’s group
reported that the reaction of 2a with excess aqueous NH afforded only quinazolinone 10a (Scheme
3
3a). Contrary to their report, we observed that the reaction of 2a under the same reaction conditions
ꢀ
ꢄ
as Cui’s group gave only ring-opened amide 11a (Scheme 3b).
Moreover, the reaction of 7a
under the same reaction conditions afforded 10a and 11a in 63% and 4% yields, respectively. Thus, a
proposed mechanism on the basis of previous reports and our findings for the reaction is shown in
Scheme 4. Initially, the copper-catalyzed aerobic oxidation of 5a to 9a proceeded. The following
ꢀ
ꢅ
imine formation and Baeyer–Villiger-type oxidative reaction
of 12a, possibly mediated by a
ꢀ
ꢆ
Cu(II) hydroperoxo species or by a peroxide such as H O , gave 6a (Path A).
Usually, harsh
are needed to construct
quinazolinone motifs via benzoxazinone intermediates, while our reaction proceeded even at 40 °C
Table 3, entry 7) and formation of ring-opened amide was not observed. Thus, we suppose that the
2
2
ꢀ
ꢇ
ꢀꢈ
reaction conditions such as high temperature
or microwave irradiation
(
formation of benzoxazinone 14a and the subsequent intramolecular substitution reaction (Path B) is
unlikely in the developed reactions; however, the exact intermediates responsible for the
transformation of 9a to 6a remain unknown at this stage since intermediates 9a and 12a were not
isolated. Further studies are necessary to elucidate the detailed mechanism.
Scheme 3. Test reactions of 2a and 7a under the copper-catalyzed oxidative reaction conditions
1
1

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O
N
5 mol% CuBr
aqueous NH3
O
O
O
NH
Ph
NH2
NH
Ph
+
+
+
(a)
NMP
under O2
80 °C, 24 h
Ph
N
2a
10a: 99%
11a: 0%
O
5
mol% CuBr
aqueous NH3
2a
1
0a: 0%
11a: 99%
(b)
NMP
under O2
80 °C, 24 h
O
5
mol% CuBr
aqueous NH3
Ph
(c)
1
0a: 63%
11a: 4%
N
NMP
under O2
80 °C, 24 h
7a
Scheme 4. Proposed mechanisms for the transformation of 5a to 6a
RO O
oxidative
tandem
reactions
NH2
N
NH2
imine
formation
O
N
N
H
N
12a
9a
5a
Baeyer-Villiger
type oxidation
R = Cu(II) or H
Baeyer-Villiger
oxidation
O
N
RO
intramolecular
substitution
O
O
N
NH2
rearrangement
N
N
O
N
Path B
Path A
14a
6a
13
3. Conclusion
In conclusion, we demonstrated a facile access to polyhydropyrido[1,2-a]indoles and tetracyclic
quinazolinones from 2ꢊarylindoles via C-acylimine intermediates, generated in situ by using
copper-catalyzed oxidative reactions. Notably, the developed methods proceed under simple and
mild reaction conditions and tolerate some functional groups. Future applications of this strategy for
1
2

ACCEPTED MANUSCRIPT
the synthesis of biologically active compounds are still under investigation and will be reported in
due course.
4
4
. Experimental
.1. General Information: All melting points were taken on a Yanagimoto micromelting point
1
apparatus and were uncorrected. H-NMR spectra (400 MHz) were obtained in CDC1 , unless
3
otherwise noted. The chemical shift values are expressed in ppm relative to internal tetramethylsilane.
Abbreviations are as follows: s, singlet; d, doublet; t, triplet; m, multiplet; br, broad. Purification was
performed using silica gel column chromatography. All reagents including 1a and 8a were purchased
3
16
from chemical companies and used as received. Starting materials 1b–1o and 7a were prepared
according to a known literature procedure
.
4.2. General Procedure for the Synthesis of polyhydropyrido[1,2-a]indoles 4:
A mixture of compound 1 (0.20 mmol), CuCl (4.0 mg, 0.04 mmol) and pyridine (32 µg, 0.40 mmol)
in toluene (1.0 mL) was stirred at 50 °C under an oxygen atmosphere (1 atm). After 24 h, 10% HCl
(1.0 ml) was added, and the mixture was stirred for an additional 0.5 h. Then, the mixture was
extracted with EtOAc. The organic extracts were washed with H O and brine, dried over Na SO ,
2
2
4
and then concentrated. The crude product was chromatographed on silica gel.
4
.2.1. 9a-phenyl-9,9a-dihydropyrido[1,2-a]indole-8,10-dione (4aa): yield 58% (30 mg). white
1
solid. mp >216 °C dec. rf (hexane/EtOAc = 2/1) = 0.10. H-NMR: δ 2.89 (d, 1H, J‑= 16 Hz), 3.42
(
dd, 1H, J = 1.1, 16 Hz), 5.36 (dd, 1H, J = 1.1, 7.5 Hz), 7.14 (ddd, 1H, J = 0.3, 7.6, 7.6 Hz),
1
3
7
1
1
.29–7.39 (m, 6H), 7.70–7.74 (m, 2H), 7.83 (d, 1H, J = 7.5 Hz). C-NMR: δ 42.4, 71.2, 105.9,
10.0, 122.9, 123.2, 125.6, 126.4, 128.9, 129.2, 133.6, 137.7, 138.0, 152.2, 191.1, 197.0. IR (KBr):
+
719, 1654, 1598, 1575, 1475, 1334, 1282, 1228, 756. HRMS (ESI) m/z: [M+Na] calcd for
+
[
C H NO Na] , 298.0844; Found, 298.0844.
1
8
13
2
4
.2.2. 9a-(4-methylphenyl)-9,9a-dihydropyrido[1,2-a]indole-8,10-dione (4ba): yield 64% (37 mg).
1
white solid. mp 168–169 °C. rf (hexane/EtOAc = 2/1) = 0.15. H-NMR: δ 2.28 (s, 3H), 2.86 (d, 1H, J
=
16 Hz), 3.39 (dd, 1H, J = 1.2, 16 Hz), 5.36 (dd, 1H, J = 1.2, 7.7 Hz), 7.11–7.16 (m, 3H), 7.24–7.26
1
3
(m, 2H), 7.36 (d, 1H, J = 8.6 Hz), 7.70–7.74 (m, 2H), 7.81 (d, 1H, J = 7.7 Hz). C-NMR: δ 21.0,
4
1
2.2, 71.1, 105.8, 110.0, 122.9, 123.2, 125.5, 126.4, 129.9, 130.5, 137.7, 138.0, 138.9, 152.1, 191.3,
97.1. IR (KBr): 1714, 1651, 1598, 1573, 1508, 1475, 1419, 1334, 1282, 1228, 1197, 752. HRMS
+
+
(ESI) m/z: [M+Na] calcd for [C H NO Na] , 312.1000; Found, 312.1001.
19 15 2
1
3

ACCEPTED MANUSCRIPT
4
.2.3. 9a-(4-methoxyphenyl)-9,9a-dihydropyrido[1,2-a]indole-8,10-dione (4ca): yield 59% (36
1
mg). white solid. mp 134–135 °C. rf (hexane/EtOAc = 2/1) = 0.2. H-NMR: δ 2.85 (d, 1H, J = 16
Hz), 3.36 (dd, 1H, J = 1.1, 16 Hz), 3.75 (s, 3H), 5.37 (dd, 1H, J = 1.1, 7.6 Hz), 6.83 (m, 2H), 7.14
(
dd, 1H, J = 7.5, 7.5 Hz) 7.26–7.30 (m, 2H,), 7.36 (d, 1H, J = 7.9 Hz), 7.70–7.74 (m, 2H), 7.80 (d,
1
3
1
1
1
3
H, J = 7.6 Hz). C-NMR: δ: 42.2, 55.3, 70.8, 105.8, 110.0, 114.6, 122.9, 123.2, 125.4, 126.4,
26.9, 137.7, 137.9, 152.1, 160.0, 191.3, 197.2. IR (KBr): 1716, 1653, 1598, 1573, 1508, 1475,
+
+
334, 1255, 1230, 752. HRMS (ESI) m/z: [M+Na] calcd for [C H NO Na] , 328.0950; Found,
19
15
3
28.0958.
4
.2.4. 9a-(4-fluorophenyl)-9,9a-dihydropyrido[1,2-a]indole-8,10-dione (4da): yield 52% (30 mg).
1
white solid. mp 149–151 °C. rf (hexane/EtOAc = 2/1) = 0.20. H-NMR: δ 2.88 (d, 1H, J = 16 Hz),
3
7
1
1
1
.34 (dd, 1H, J = 1.2, 16 Hz), 5.39 (dd, 1H, J = 1.2, 7.6 Hz), 6.99–7.04 (m, 2H), 7.14–7.18 (m, 1H),
1
3
.34–7.39 (m, 3H) 7.71–7.76 (m, 2H), 7.82 (d, 1H, J = 7.6 Hz). C-NMR: δ 42.4, 70.6, 106.0, 110.1,
16.3 (d, J = 21.9 Hz), 122.7, 123.4, 126.5, 127.6 (d, J = 8.1 Hz), 129.4 (d, J = 2.9 Hz), 137.9, 138.1,
52.1, 163.1 (d, J = 148.9 Hz), 191.0, 196.8. IR (KBr): 1719, 1654, 1598, 1575, 1475, 1334, 1282,
+
+
228, 756. HRMS (ESI) m/z: [M+Na] calcd for [C H FNO Na] , 316.0750; Found, 316.0731.
18
12
2
4
.2.5. 9a-(4-chlorophenyl)-9,9a-dihydropyrido[1,2-a]indole-8,10-dione (4ea): yield 47% (29 mg).
1
white solid. mp 129–130 °C. rf (hexane/EtOAc = 2/1) = 0.05. H-NMR: δ 2.88 (d, 1H, J = 16 Hz),
3
7
1
1
3
.34 (dd, 1H, J = 1.1, 16 Hz), 5.39 (dd, 1H, J = 1.1, 7.5 Hz), 7.14–7.18 (m, 1H), 7.28–7.38 (m, 5H),
1
3
.72–7.76 (m, 2H), 7.82 (d, 1H, J = 7.5 Hz). C-NMR: δ 42.4, 70.7, 106.1, 110.1, 122.7, 123.5,
26.5, 127.1, 129.4, 132.3, 135.1, 138.0, 138.0, 152.1, 190.8, 196.6. IR (KBr): 1718, 1654, 1647,
+
+
598, 1575, 1475, 1327, 1128, 1070, 754. HRMS (ESI) m/z: [M+Na] calcd for [C H ClNO Na] ,
18
12
2
32.0454; Found, 332.0461.
4
.2.6. 9a-(4-(trifluoromethyl)phenyl)-9,9a-dihydropyrido[1,2-a]indole-8,10-dione (4fa): yield
1
4
3% (29 mg). white solid. mp 137–138 °C. rf (hexane/EtOAc = 1/1) = 0.13. H-NMR: δ 2.93 (d, 1H,
J = 16 Hz), 3.38 (dd, 1H, J= 1.1, 16 Hz), 5.40 (dd, 1H, J = 1.1, 7.6 Hz), 7.16–7.19 (m, 1H), 7.40 (d,
1
H, J = 8.3 Hz), 7.54 (d, 2H, J = 8.4 Hz), 7.59 (d, 2H, J = 8.4 Hz), 7.73–7.78 (m, 2H), 7.86 (d, 1H, J
1
3
=
7.6 Hz). C-NMR: δ 42.6, 70.9, 106.2, 110.2, 122.6, 123.6, 123.7 (q, J = 272.4 Hz), 126.1 (q, J =
4
.3 Hz), 126.2, 126.5, 131.1 (d, J = 34.2 Hz), 137.9, 138.1, 138.1, 152.2, 190.5, 196.2. IR (KBr):
+
1
716, 1563, 1598, 1575, 1485, 1327, 1282, 1228, 1168, 1126, 1070, 754. HRMS (ESI) m/z: [M+Na]
+
calcd for [C H F NO Na] , 366.0718; Found, 366.0712.
19
12
3
2
4
.2.7. 9a-(2-fluorophenyl)-9,9a-dihydropyrido[1,2-a]indole-8,10-dione (4ga): yield 48% (28 mg).
1
white solid. mp 182–183 °C. rf (hexane/EtOAc = 2/1) = 0.2. H-NMR: δ 2.83 (d, 1H, J = 16.4 Hz),
3
7
.54 (dd, 1H, J = 1.1, 16.4 Hz), 5.39 (dd, 1H, J = 0.6, 7.5 Hz), 7.0 (ddd, 1H, J = 1.3, 8.2, 12.3 Hz)
1
3
.09–7.19 (m, 2H), 7.29–7.37 (m, 3H), 7.71–7.75 (m, 2H), 7.78 (d, 1H, J = 7.5 Hz). C-NMR: δ
1
4

ACCEPTED MANUSCRIPT
40.8 (d, J = 3.3 Hz), 69.7 (d, J = 3.0 Hz), 106.1, 110.2, 117.2 (d, J = 22.9 Hz), 121.5 (d, J = 12.0
Hz), 123.2 (d, J = 2.9 Hz), 123.3, 124.5 (d, J = 3.7 Hz), 126.0, 129.0 (d, J = 3.7 Hz), 131.1 (d, J =
8
.9 Hz), 137.7, 138.7, 152.4, 161.1 (d, J = 251.4 Hz), 191.6, 196.6. IR (KBr): 1718, 1653, 1600,
+
1
575, 1475, 1456, 1334, 1303, 1287, 1272, 1230, 753. HRMS (ESI) m/z: [M+H] calcd for
+
[
C H FNO ] , 294.0930; Found, 294.0936.
1
8
13
2
4
.2.8. 9a-(2-naphthalenyl)-9,9a-dihydropyrido[1,2-a]indole-8,10-dione (4ha): yield 49% (32 mg).
1
white solid. mp 239–240 °C. rf (hexane/EtOAc = 2/1) = 0.15. H-NMR: δ 2.96 (d, 1H, J‑= 16.2 Hz),
3
7
1
1
3
.55 (d, 1H, J = 16.2 Hz), 5.38 (d, 1H, J = 7.4 Hz), 7.15 (dd, 1H, J = 7.4, 7.4 Hz), 7.42–7.48 (m, 4H),
1
3
.73–7.81 (m, 6H), 7.89 (d, 1H, J = 7.4 Hz). C-NMR: δ 42.3, 71.3, 106.0, 110.1, 122.7, 122.9,
23.3, 125.4, 126.5. 126.6, 126.8, 127.6, 128.2, 129.3, 130.9, 133.1, 133.2, 137.8, 138.1. IR (KBr):
+
+
718, 1653, 1600, 1575, 1475, 1334, 754. HRMS (ESI) m/z: [M+H] calcd for [C H NO ] ,
22
16
2
26.1181; Found, 326.1190.
4
.2.9. 2-methyl-9a-phenyl-9,9a-dihydropyrido[1,2-a]indole-8,10-dione (4ia): yield 38% (22 mg).
1
white solid. mp 205–206 °C. rf (hexane/EtOAc = 2/1) = 0.05. H-NMR: δ 2.37 (s, 3H), 2.87 (d, 1H, J
=
16 Hz), 3.39 (dd, 1H, J = 1.0, 16 Hz), 5.34 (d, 1H, J = 1.0, 7.4 Hz), 7.26–7.38 (m, 6H), 7.28–7.55
1
3
(m, 2H), 7.81 (d, 1H, J = 7.4 Hz). C-NMR: δ 20.8, 42.3, 71.3, 105.2, 109.8, 123.1, 125.6, 125.9,
1
28.8, 129.1, 133.4, 133.7, 138.2, 138.9, 150.4, 191.1, 197.0. IR (KBr): 1718, 1653, 1618, 1595,
+
+
1
575, 1494, 1332, 1282, 734. HRMS (ESI) m/z: [M+Na] calcd for [C H NO Na] , 312.1000;
19 15 2
Found, 312.0994.
4
.2.10. 2-methoxy-9a-phenyl-9,9a-dihydropyrido[1,2-a]indole-8,10-dione (4ja): yield 38% (23
1
mg). white solid. mp 212–213 °C. rf (hexane/EtOAc = 2/1) = 0.05. H-NMR: δ 2.88 (d, 1H, J = 16
Hz), 3.39 (d, 1H, J = 16 Hz), 5.32 (d, 1H, J = 7.4 Hz), 7.13 (d, 1H, J = 2.3 Hz), 7.28–7.39 (m, 7H),
1
3
7
1
1
3
.77 (d, 1H, J = 7.4 Hz) C-NMR: δ 42.3, 56.0, 71.6, 104.7, 106.6, 111.3, 123.7, 125.6, 127.5,
28.9, 129.2, 133.7, 138.3, 147.0, 156.2, 190.9, 197.1. IR (KBr): 1716, 1653, 1647, 1597, 1575,
+
+
492, 1327, 1278. HRMS (ESI) m/z: [M+Na] calcd for [C H NO Na] , 328.0950; Found,
19
15
3
28.0943.
4
.2.11. 2-fluoro-9a-phenyl-9,9a-dihydropyrido[1,2-a]indole-8,10-dione (4ka): yield 17% (10 mg).
1
white solid. mp 150–151 °C. rf (hexane/EtOAc = 2/1) = 0.15. H-NMR: δ 2.90 (d, 1H, J = 16 Hz),
3
.40 (dd, 1H, J = 1.0, 16 Hz), 5.37 (d, 1H, J = 1.0, 7.5 Hz), 7.31–7.44 (m, 7H), 7.45 (ddd, 1H, J =
1
3
2
.7, 8.8. 8.8 Hz), 7.78 (d, 1H, J = 7.5 Hz). C-NMR: δ 42.4, 71.9, 105.9, 111.2 (d, J = 7.8 Hz), 111.8
(d, J = 23.3 Hz), 124.0 (d, J = 7.8 Hz), 125.5 (d, J = 25.6 Hz), 125.5, 129.0, 129.2, 133.2, 137.9,
1
1
48.6, 158.6 (d, J = 247 Hz), 190.6, 196.3 (d, J = 3.0 Hz). IR (KBr): 1718, 1654, 1647, 1577, 1489,
+
+
336, 1263. HRMS (ESI) m/z: [M+Na] calcd for [C H FNO Na] , 316.0750; Found, 316.0756.
1
8
12
2
1
5

ACCEPTED MANUSCRIPT
4
.2.12. 2-chloro-9a-phenyl-9,9a-dihydropyrido[1,2-a]indole-8,10-dione (4la): yield 26% (16 mg).
1
white solid. mp >220 °C dec. rf (hexane/EtOAc = 2/1) = 0.15. H-NMR: δ 2.89 (d, 1H, J =16 Hz),
3
1
1
1
.41 (d, 1H, J = 1.0, 16 Hz), 5.39 (d, 1H, J =7.5 Hz), 7.30–7.36 (m, 6H), 7.65–7.68 (m, 2H), 7.78 (d,
1
3
H, J = 7.5 Hz). C-NMR: δ 42.4, 71.8, 106.5, 111.2, 124.1, 125.5, 125.9, 128.8, 129.1, 129.3,
33.1, 137.6, 137.6, 150.5, 190.7, 195.8. IR (KBr): 1724, 1670, 1653, 1647, 1593, 1571, 1477, 1336,
+
+
282, 1228. HRMS (ESI) m/z: [M+Na] calcd for [C H ClNO Na] , 332.0454; Found, 332.0454.
1
8
12
2
4
.2.13. 3-methyl-9a-phenyl-9,9a-dihydropyrido[1,2-a]indole-8,10-dione (4ma): yield 40% (23
1
mg). white solid. mp 242–243 °C. rf (hexane/EtOAc = 2/1) = 0.05. H-NMR: δ 2.52 (s, 3H), 2.87 (d,
1
7
4
1
H, J = 15.9 Hz), 3.40 (dd, 1H, J = 0.8, 15.9 Hz), 5.35 (d, 1H, J = 7.5 Hz), 7.00 (d, 1H, J = 8.0 Hz),
13
.17 (s,1H), 7.28–7.38 (m, 5H), 7.60 (d, 1H, J = 8.0 Hz), 7.80 (d, 1H, J = 7.5 Hz). C-NMR: δ 22.8,
2.4, 71.4, 105.7, 110.2, 120.6, 124.8, 125.6, 126.1, 128.8, 129.1, 133.9, 138.0, 149.8, 152.6, 191.2,
+
96.4. IR (KBr): 1707, 1651, 1612, 1597, 1570, 1465, 1340, 1325. HRMS (ESI) m/z: [M+H] calcd
+
for [C H NO ] , 290.1181; Found, 290.1178.
19
16
2
4
.2.14. 3-methyl-9a-phenyl-9,9a-dihydropyrido[1,2-a]indole-8,10-dione (4na): yield 35% (20
1
mg). white solid. mp 197–198 °C. rf (hexane/EtOAc = 2/1) = 0.10. H-NMR: δ 2.73 (s, 3H), 2.91 (d,
1
7
1
1
1
2
H, J = 16.3 Hz), 3.41 (d, 1H, J = 16.3 Hz), 5.35 (d, 1H, J = 7.6 Hz), 7.07 (d, 1H, J = 7.7 Hz),
.29–7.34 (m, 3H), 7.38–7.41 (m, 2H), 7.48 (d, 1H, J = 7.3 Hz), 7.61 (d, 1H, J = 7.7 Hz), 8.16 (d,
1
3
H, J = 7.6 Hz). C-NMR: δ 20.8, 42.3, 71.8, 105.7, 122.7, 123.6, 124.0, 124.1, 125.5, 128.8, 129.1,
33.7, 140.7, 140.9, 150.7, 190.7, 197.5. IR (KBr): 1718, 1650, 1593, 1492, 1470, 1446, 1437, 1413,
+
+
329, 1281, 1247, 1226, 954, 786, 756, 705. HRMS (ESI) m/z: [M+H] calcd for [C H NO ] ,
19
16
2
90.1181; Found, 290.1182.
4
.2.15. 7a-phenyl-7a,8-dihydrobenzo[g]pyrido[1,2-a]indole-7,9-dione (4oa): yield 66% (43 mg).
1
white solid. mp 243–244 °C. rf (hexane/EtOAc = 2/1) = 0.15. H-NMR: δ 3.00 (d, 1H, J = 16.3 Hz),
3
1
1
1
1
6
.49 (d, 1H, J = 16.3 Hz), 5.45 (d, 1H, J = 7.7 Hz), 7.29–7.33 (m, 3H), 7.48–7.50 (m, 2H), 7.58 (d,
H, J = 8.4 Hz), 7.67 (d, 1H, J = 8.4 Hz), 7.73–7.77 (m, 2H), 8.01 (dd, 1H, J = 1.8, 8.2 Hz), 8.44 (d,
1
3
H, J = 7.9 Hz), 8.58 (d, 1H, J = 7.7 Hz). C-NMR: δ 43.0, 72.6, 106.6, 120.2, 120.7, 121.4, 123.7,
25.3, 125.4, 127.8, 128.9, 129.2, 130.2, 130.4, 139.5, 140.9, 152.0, 190.9, 197.3. IR (KBr): 1706,
684, 1654, 1623, 1590, 1564, 1526, 1459, 1442, 1381, 1330, 1292, 1265, 1241, 1107, 798, 756,
+
+
94. HRMS (ESI) m/z: [M+H] calcd for [C H NO ] , 290.1181; Found, 290.1182.
19
16
2
4
4
.3. Procedure for the Synthesis of Substrate amine 5 and 15:
.3.1. tert-butyl (2-(1H-indol-2-yl)phenethyl)carbamate: To
a
solution of tert-butyl
(9.3 g, 28
(343 mg, 0.42 mmol) and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
ꢁ
ꢉ
(2-bromophenethyl)carbamate
(2.1 g, 7.0 mmol) in DMF (10.0 mL) were added CsCO3
mmol), PdCl
2
(dppf)·CH
2
Cl
2
1
6

ACCEPTED MANUSCRIPT
yl)-1H-Indole (2.6 g, 10.7 mmol). The reaction mixture was heated to 50 °C for 3 h under Ar. The
reaction was cooled down, EtOAc and a saturated aqueous solution of NH Cl were added and the
4
mixture was stirred for 30 min. After extracting with EtOAc, the organic extracts were washed with
H O and brine, dried over Na SO , and then concentrated. The crude product was chromatographed
2
2
4
1
on silica gel. yield 88% (2.1 g). pale yellow oil. rf (hexane/EtOAc = 15/1) = 0.20. H-NMR: δ 1.43
s, 9H), 2.93 (t, 2H, J = 7.9 Hz), 3.30 (dt, 2H, J = 7.9, 6.7 Hz), 4.80 (s, 1H), 6.61 (s, 1H), 7.12 (ddd,
(
1
7
1
2
H, J = 7.5, 7.5, 1.1 Hz), 7.20 (ddd, 1H, J = 7.6, 7.6, 1.2Hz), 7.26–7.32 (m, 3H), 7.51–7.62 (m, 2H),
1
3
.64 (d, 1H, J = 7.8 Hz), 9.66 (s, 1H). C-NMR δ 28.6, 34.3, 42.4, 79.8, 102.6, 111.6, 119.9, 120.4,
21.9, 126.8, 128.2, 128.7, 130.5, 130.7, 133.2, 136.5, 137.1, 137.8, 156.8. IR (KBr): 3404, 3319,
+
978, 1689, 1508, 1365, 1296, 1273, 1251, 1168, 750. HRMS (ESI) m/z: [M+Na] calcd for
+
[
C H N O Na] , 359.1735; Found, 359.1717.
2
1
24
2
2
2-(2-(1H-indol-2-yl)phenyl)ethanamine
(5a):
To
a
solution
of
tert-butyl
(
2-(1H-indol-2-yl)phenethyl)carbamate (1.42 g, 4.23 mmol) in CH
2
Cl (30 mL) was added
2
trifluoroacetic acid (0.40 mL, 5.00 mmol) at 0 °C, and then, the mixture was stirred at rt for 4 h.
After the solvent was evaporated, the residue was dissolved in EtOAc, washed with saturated
NaHCO , H O and brine, dried over Na SO , and then concentrated. Recrystallization from EtOH
3
2
2
4
1
afforded the titled compound. yield 54% (537 mg). colorless plates. mp 138–139 °C. H-NMR: δ
1
7
7
1
3
2
.76 (brs, 2H), 3.20 (t, 2H, J = 6.4 Hz), 2.95 (t, 1H, J = 6.4 Hz), 6.57 (s, 1H), 7.08 (ddd, 1H J= 7.5,
.5, 1.0 Hz), 7.16 (ddd, 1H, J = 7.5, 7.5, 1.2Hz), 7.26–7.38 (m, 3H), 7.42 (dd, 1H, J = 8.1, 0.9 Hz),
1
3
.57 (dd, 1H, J = 7.6, 1.3 Hz), 7.65 (d, 1H, J = 7.8 Hz), 12.2 (s, 1H). C-NMR: δ 34.3, 42.3, 101.3,
11.2, 119.3, 120.3, 121.3, 126.6, 128.2, 128.8, 130.1, 130.7, 134.6, 136.5, 137.0, 138.8. IR (KBr):
+
+
057, 2862, 1560, 1541, 1477, 1448, 1298, 750. HRMS (ESI) m/z: [M+H] calcd for [C H N ] ,
1
6
17
2
37.1392; Found, 237.1402.
.3.2. 2-(2-(5-chloro-1H-indol-2-yl)phenyl)ethan-1-amine (5b): Starting from tert-butyl
4
(2-bromobenzyl)carbamate and 5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole,
this compound was prepared according to the procedure for the synthesis of 5a. white solid. mp
1
5
8–59 °C. H-NMR: δ 2.89 (t, 2H, J = 5.8 Hz), 3.19 (m, 2H), 6.49 (s, 1H), 7.08 (dd, 1H, J = 2.0, 8.9
1
3
Hz), 7.19–7.40 (m, 4H), 7.55 (d, 1H, J = 7.5 Hz), 7.59 (d, 1H, J = 1.7 Hz), 12.7 (s, 1H).
C-NMR:
δ 34.7, 42.4, 100.8, 112.4, 119.5, 121.4, 124.8, 126.7, 128.4, 129.9, 130.2, 130.7, 134.2, 134.9,
1
37.1, 140.5. IR (KBr): 3115, 3010, 2927, 1577, 1473, 1444, 1317, 1215, 1058, 916, 867, 796, 759.
+
+
HRMS (ESI) m/z: [M+H] calcd for [C H ClN ] , 271.1002; Found, 271.1001.
1
6
15
2
tert-butyl (2-(5-chloro-1H-indol-2-yl)phenethyl)carbamate: white solid. mp 117–118 °C. rf
1
(
hexane/acetone = 4/1) = 0.30. H-NMR: δ 1.44 (s, 9H), 2.91 (t, 2H, J = 8.1 Hz), 3.28 (td, 2H, J =
8
7
3
1
.1, 7.2 Hz), 4.90 (brs, 1H), 6.52 (s, 1H), 7.13 (dd, 1H, J = 8.5, 1.9 Hz), 7.14–7.22 (m, 1H),
1
3
.22–7.30 (m, 2H), 7.45 (d, 1H, J = 8.5 Hz), 7.50–7.61 (m, 2H), 10.1 (brs, 1H). C-NMR: δ 28.5,
4.5, 42.6, 80.1, 102.1, 112.6, 119.5, 122.0, 125.3, 126.9, 128.3, 129.5, 130.6, 130.7, 132.5, 135.5,
35.9, 139.2, 157.0. IR (KBr): 3421, 3302, 2978, 2933, 1685, 1508, 1490, 1465, 1458, 1446, 1365,
1
7

ACCEPTED MANUSCRIPT
+
+
1
313, 1274, 1251, 1166, 759. HRMS (ESI) m/z: [M+Na] calcd for [C H ClN O Na] , 393.1346;
2
1
23
2
2
Found, 393.1335.
4.3.2. 2-(2-(5-methoxy-1H-indol-2-yl)phenyl)ethan-1-amine (5b): Starting from tert-butyl
(2-bromobenzyl)carbamate and 5-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-
indole, this compound was prepared according to the procedure for the synthesis of 5a. pale yellow
1
oil. H-NMR: δ 1.73 (s, 1H), 2.90 (t, 2H, J = 6.0 Hz), 3.14 (t, 2H, J = 6.0 Hz), 3.85 (s, 3H), 6.49 (s,
1
H), 6.82 (dd, 1H, J = 2.4, 8.7 Hz), 7.10 (d, 1H, J = 2.4 Hz), 7.26–7.31 (m, 4H), 7.54 (m, 1H), 12.0
1
3
(s, 1H). C-NMR: δ 34.7, 42.4, 100.8, 112.4, 119.5, 121.4, 124.8, 126.7, 128.4, 129.9, 130.2, 130.7,
1
1
34.2, 134.9, 137.1, 140.5. IR (KBr): 3378, 2938, 1623, 1588, 1492, 1480, 1450, 1215, 1146, 1115,
+
+
031, 797, 759. HRMS (ESI) m/z: [M+H] calcd for [C H N O] , 267.1497; Found, 267.1493.
17
19
2
tert-butyl (2-(5-methoxy -1H-indol-2-yl)phenethyl)carbamate: white solid. mp 128–129 °C. rf
1
(
hexane/acetone = 10/1) = 0.35. H-NMR: δ 1.45 (s, 9H), 2.94 (t, 2H, J = 8.3 Hz), 3.28–3.33 (m,
2
7
5
1
H), 3.85 (s, 3H), 4.84 (s, 1H), 6.52 (s, 1H), 6.86 (dd, 1H, J = 2.4, 8.8 Hz), 7.09 (d, 1H, J = 2.4 Hz),
1
3
.19–7.28 (m, 3H), 7.42 (d, 1H, J = 8.2 Hz), 7.54 (s, 1H), 9.63 (s, 1H). C-NMR: δ 28.5, 34.4, 42.5,
5.9, 79.9, 101.9, 102.4, 112.2, 112.2, 126.8, 128.0, 128.8, 130.4, 130.6, 132.3, 133.1, 136.1, 138.4,
54.2, 156.7. IR (KBr): 3415, 3322, 2977, 1690, 1509, 1452, 1215, 1166, 759. HRMS (ESI) m/z:
+
+
[
M+H] calcd for [C H N O ] , 367.2022; Found, 367.2032.
22 27 2 3
4.3.3. 2-(2-(5-fluoro-1H-indol-2-yl)phenyl)ethan-1-amine (5c): Starting from tert-butyl
(2-bromobenzyl)carbamate and 5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole,
this compound was prepared according to the procedure for the synthesis of 5a. pale yellow oil.
1
H-NMR: δ 1.73 (s, 1H), 2.90 (t, 2H, J = 6.0 Hz), 3.14 (t, 2H, J = 6.0 Hz), 3.85 (s, 3H), 6.49 (s, 1H),
6
1
1
7
.82 (dd, 1H, J = 2.4, 8.7 Hz), 7.10 (d, 1H, J = 2.4 Hz), 7.26–7.31 (m, 4H), 7.54 (m, 1H), 12.0 (s,
1
3
H). C-NMR: δ 34.7, 42.4, 100.8, 112.4, 119.5, 121.4, 124.8, 126.7, 128.4, 129.9, 130.2, 130.7,
34.2, 134.9, 137.1, 140.5. IR (KBr): 3380, 2946, 2867, 1587, 1327, 1202, 1130, 1108, 953, 854,
+
+
92, 759. HRMS (ESI) m/z: [M+H] calcd for [C H FN ] , 255.1298; Found, 255.1286.
16
16
2
tert-butyl (2-(5-fluoro-1H-indol-2-yl)phenethyl)carbamate: white solid. mp 130–131 °C. rf
1
(
hexane/acetone = 10/1) = 0.40. H-NMR: δ 1.45 (s, 9H), 2.92 (t, 2H, J = 7.6 Hz), 3.26–3.30 (m,
2
1
2
1
1
H), 4.87 (s, 1H), 6.55 (s, 1H), 6.90–6.95 (m, 1H), 7.18–7.29 (m, 4H), 7.45–7.55 (m, 2H), 9.96 (s,
1
3
H). C-NMR: δ 28.5, 34.4, 42.6, 80.1, 102.6 (d, J = 4.5 Hz), 104.8 (d, J = 23.3 Hz), 110.1 (d, J =
6.3 Hz), 112.2 (d, J = 8.6 Hz), 126.9, 128.3, 128.7 (d, J = 10.1 Hz), 130.5, 130.7, 132.7, 133.7,
36.0, 139.5, 156.9, 158.1 (d, J = 230 Hz). IR (KBr): 3421, 3302, 2978, 2933, 1685, 1508, 1490,
+
465, 1458, 1446, 1365, 1313, 1274, 1251, 1166, 759. HRMS (ESI) m/z: [M+H] calcd for
+
[
C H FN O ] , 355.1822; Found, 355.1830.
2
1
24
2
2
4.3.4. 2-(2-(7-methoxy-1H-indol-2-yl)phenyl)ethan-1-amine (5e): Starting from tert-butyl
(2-bromobenzyl)carbamate and 7-methoxy-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-
indole, this compound was prepared according to the procedure for the synthesis of 5a. white solid.
1
8

ACCEPTED MANUSCRIPT
1
mp 141–142 °C. H-NMR: δ 2.85–3.35 (m, 4H), 3.95 (s, 3H), 6.54 (s, 1H), 6.61 (d, 1H, J = 7.8 Hz),
7
.00 (dd, 1H, J = 7.9, 7.9 Hz), 7.19–7.36 (m, 4H), 7.55 (d, 1H, J = 7.6 Hz), 12.33 (s, 1H).
1
3
C-NMR: δ 35.4, 42.6, 55.5, 101.4, 101.6, 113.2, 119.6, 126.5, 127.2, 128.1, 130.2, 130.2, 130.7,
+
1
34.6, 137.6, 138.5, 146.4. IR (KBr): 3016, 1251, 1215, 1097, 754. HRMS (ESI) m/z: [M+H] calcd
+
for [C H N O] , 267.1497; Found, 267.1500.
17
19
2
tert-butyl
(2-(7-methoxy-1H-indol-2-yl)phenethyl)carbamate:
pale
yellow
oil.
rf
1
(
hexane/acetone = 4/1) = 0.30. H-NMR: δ 1.36 (s, 9H), 2.92 (t, 2H, J = 7.3 Hz), 3.17–3.31 (m, 2H),
3
.90 (s, 3H), 4.52 (s, 1H), 6.50 (s, 1H), 6.63 (d, 1H, J = 7.7 Hz), 7.03 (dd, 1H, J = 7.7, 7.7 Hz),
1
3
7
.19–7.32 (m, 4H), 7.39 (d, 1H, J = 7.2 Hz), 8.77(s, 1H). C-NMR: δ 28.4, 33.7, 41.5, 55.3, 79.2,
01.9, 103.0, 113.2, 120.4, 126.6, 126.8, 128.4, 130.3, 130.2, 130.4, 133.3, 136.9, 137.6, 146.0,
55.9. IR (KBr): 3408, 3348, 2976, 2933, 1693, 1627, 1583, 1504, 1483, 1446, 1394, 1365, 1328,
1
1
+
+
1
311, 1257, 1168, 1097, 1056, 758. HRMS (ESI) m/z: [M+H] calcd for [C H N O ] , 367.2022;
22 27 2 3
Found, 367.2021.
4
.3.5.
(2-(1H-indol-2-yl)phenyl)methanamine
(15a):
Starting
from
tert-butyl
ꢁ
ꢀ
(2-bromobenzyl)carbamate
and 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole, this
compound was prepared according to the procedure for the synthesis of 5a. white solid. mp
1
9
1–92 °C. H-NMR: δ 1.78 (brs, 2H), 3.88 (s, 2H), 6.70 (s, 1H), 7.05–7.13 (m, 1H), 7.13–7.32 (m,
1
H), 7.23–7.28 (m, 2H), 7.31–7.38 (m, 1H), 7.41 (d, 1H, J = 8.1 Hz), 7.66 (d, 1H, J = 7.6 Hz), 7.74
1
3
(d, 1H, J = 7.7 Hz), 12.67 (s, 1H). C-NMR: δ 46.2, 100.6, 111.4, 119.4, 120.4, 121.5, 127.6, 128.4,
1
28.7, 130.2, 131.2, 134.4, 136.7, 136.8, 139.2. IR (KBr): 3057, 1450. 1300, 750. HRMS (ESI) m/z:
+
+
[
M+Na] calcd for [C H N Na] , 245.1055; Found, 245.1055.
15 14 2
tert-butyl (2-(1H-indol-2-yl)benzyl)carbamate: white solid. mp 106–108 °C. rf (hexane/acetone =
1
2
/1) = 0.50. H-NMR δ 1.44 (s, 9H), 4.35 (d, 2H, J = 6.3 Hz), 5.14 (s, 1H), 6.56 (s, 1H), 7.11 (ddd,
1
H, J = 1.0, 7.5, 7.5 Hz), 7.18 (ddd, 1H, J = 1.0, 7.6, 7.6 Hz), 7.27–7.38 (m, 3H), 7.40 (d, 1H, J = 7.9
1
3
Hz), 7.45–7.52 (m, 1H), 7.62 (d, 1H, J = 7.8 Hz), 10.0 (s, 1H). C-NMR: δ 28.4, 42.6, 80.2, 102.4,
11.3, 119.8, 120.4, 121.9, 127.6, 128.3, 128.7, 129.3, 130.4, 132.6, 136.5, 136.7, 137.2, 156.5. IR
KBr): 3406, 2978, 1685, 1654, 1508, 1490, 1456, 1365, 1296, 1247, 1166, 750. HRMS (ESI) m/z:
1
(
[
+
+
M+Na] calcd for [C H N O Na] , 345.1579; Found, 345.1551.
20
22
2
2
4.4. General Procedure for the Synthesis of Tetracyclic Quinazolinones 6 and 16:
A mixture of compound 1 (0.20 mmol), CuBr (6.3 mg, 0.04 mmol) and pyridine (32 µL, 0.40 mmol)
in DMSO (1.0 mL) was stirred at 60 °C under an oxygen atmosphere (1 atm). After 24 h, the mixture
was quenched with H O and extracted with EtOAc. The organic extracts were washed with H O and
2
2
brine, dried over Na SO , and then concentrated. The crude product was chromatographed on silica
2
4
gel.
1
9

ACCEPTED MANUSCRIPT
ꢁ
ꢁ
4
.4.1. 5H-isoquinolino[1,2-b]quinazolin-8(6H)-one (6a):
yield 71% (35 mg). white solid. rf
1
(
hexane/EtOAc = 5/1) = 0.20. H-NMR δ 8.48 (d, 1H, J‑= 7.9 Hz), 8.31 (d, 1H, J = 7.9 Hz),
7
.72–7.77 (m, 2H), 7.40–7.48 (3H, m), 7.27 (d, 1H, J = 7.4 Hz), 4.41 (t, 2H, J = 6.4 Hz), 3.09 (t, 2H,
1
3
J = 6.4 Hz).
C-NMR: δ 27.4, 39.5, 120.7, 126.46, 126.8, 127.4, 127.5, 127.9, 129.5, 131.6, 134.1,
136.9, 147.7, 149.3, 161.6.
2
2
4
.4.2. 10-chloro-5,6-dihydro-8H-isoquinolino[1,2-b]quinazolin-8-one (6b): yield 39% (22 mg).
1
white solid. rf (hexane/EtOAc = 4/1) = 0.35. H-NMR: δ 8.45 (d, 1H, J = 7.8 Hz), 8.26 (d, 1H, J =
2
1
1
.3 Hz), 7.63–7.73 (m, 2H), 7.49 (dd, 1H, J = 7.3, 1.5 Hz), 7.43 (dd, 1H, J = 1.5, 7.6 Hz), 7.28 (dd,
1
3
H, J = 7.3, 0.5 Hz), 4.28 (t, 2H, J = 6.5 Hz), 3.11 (t, 2H, J = 6.4 Hz,). C-NMR: δ 26.2, 39.4, 121.5,
25.2, 127.2, 127.4, 127.8, 128.8, 129.5, 130.6, 131.9, 134.5, 137.8, 146.0, 149.8, 159.7.
4
.4.3. 10-methoxy-5,6-dihydro-8H-isoquinolino[1,2-b]quinazolin-8-one (6c): yield 54% (28 mg).
1
white solid. mp 172–173 °C. rf (hexane/EtOAc = 2/1) = 0.40. H-NMR: δ 3.10 (t, 2H, J = 6.4 Hz),
3
.93 (s, 3H), 4.42 (t, 2H, J = 6.4 Hz), 7.28 (d, 2H, J = 7.7 Hz), 7.35 (dd, 1H, J = 2.8, 8.8 Hz),
.40–7.47 (m, 2H), 7.67 (d, 1H, J = 2.9 Hz), 7.70 (d, 1H, J = 8.8 Hz), 8.44 (d, 1H, J = 7.7 Hz).
C-NMR: δ 27.5, 39.8, 55.9, 106.2, 121.5, 124.7, 127.5, 127.6, 127.7, 129.3, 129.7, 131.3, 136.7,
42.5, 147.4, 158.3, 161.5. IR (KBr): 1662, 1616, 1558, 1490, 1472, 1442, 1419, 1386, 1362, 1324,
7
1
3
1
1
+
264, 1220, 1144, 1108, 1092, 1031, 867, 832, 779, 739, 706. HRMS (ESI) m/z: [M+H] calcd for
+
[
C H N O ] , 279.1134; Found, 279.1125.
1
7
15
2
2
4
.4.4. 10-fluoro-5,6-dihydro-8H-isoquinolino[1,2-b]quinazolin-8-one (6d): yield 52% (27 mg).
1
white solid. mp 211–212 °C. rf (hexane/EtOAc = 2/1) = 0.40. H-NMR: δ 3.10 (t, 2H, J = 6.4 Hz),
4
.41 (t, 2H, J = 6.4 Hz), 7.28 (d, 2H, J = 7.4 Hz), 7.41–7.50 (m, 3H), 7.77 (dd, 1H, J = 4.9, 8.9 Hz),
1
3
7
.93 (dd, 1H, J = 2.9, 8.5 Hz), 8.45 (d, 1H, J = 7.6 Hz). C-NMR: δ 27.4, 39.8, 111.7 (d, J = 23.4
Hz), 121.9 (d, J = 8.5 Hz), 123.0 (d, J = 24.1 Hz), 127.6, 127.7, 127.9, 129.4, 123.0 (d, J = 8.0 Hz),
1
1
7
31.8, 136.9, 144.5, 148.8 (d, J = 2.1 Hz), 160.8 (d, J = 248 Hz), 161.1 (d, J = 3.4 Hz). IR (KBr):
669, 1654, 1592, 1565, 1491, 1484, 1471, 1394, 1347, 1329, 1253, 1137, 895, 849, 784, 771, 736,
+
+
06, 685. HRMS (ESI) m/z: [M+H] calcd for [C H FN O] , 267.0934; Found, 267.0934.
16
12
2
2
2
4
.4.5. 12-methoxy-5,6-dihydro-8H-isoquinolino[1,2-b]quinazolin-8-one (6e): yield 56% (31 mg).
1
white solid. rf (hexane/EtOAc = 2/1) = 0.35. H-NMR: δ: 8.55 (dd, 1H, J = 1.7, 7.5 Hz), 7.91 (dd, 1H,
J = 1.3, 8.0 Hz), 7.49–7.40 (m, 3H), 7.29–7.26 (m, 1H), 7.20 (dd, 1H, J = 1.2, 8.0 Hz), 4.42 (t, 2H, J
1
3
=
6.9 Hz), 4.05 (s, 3H ), 3.10 (t, 2H, J = 6.9 Hz,). C-NMR: δ 27.6, 39.9, 56.6, 114.3, 118.5, 122.1,
126.9, 127.5, 127.8, 128.5, 129.8, 131.8, 136.9, 138.7, 148.9, 154.9, 161.7.
ꢁ
ꢂ
4
.4.6. isoindolo[1,2-b]quinazolin-10(12H)-one (16a):
yield 12% (5.6 mg). white solid. rf
1
(
hexane/EtOAc = 1/1) = 0.30. H-NMR: δ 8.36 (dd, 1H, J = 8.0, 1.0 Hz), 8.16 (d, 1H, J = 7.6 Hz),
2
0

ACCEPTED MANUSCRIPT
1
3
7
.80 (m, 2H), 7.63 (m, 2H), 7.58 (m, 1H), 7.49 (m, 1H), 5.16 (s, 2H). C-NMR: δ 49.9, 120.7, 123.5,
123.6, 126.5, 126.6, 127.5, 129.0, 132.4, 132.8, 134.4, 139.7, 149.6, 155.0, 160.8.
2
1

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ꢀꢄ
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