Concise synthesis and antiproliferative activity evaluation of ellipticine quinone and its analogs

Article abstract of DOI:10.1016/j.ejmech.2017.04.071

We developed a concise protocol for the synthesis of ellipticine quinone from the appropriate 3-iodoindole-2-carbaldehydes in four steps. The key step is the construction of carbazole-1,4-quinone through tandem Ring-Closing Metathesis (RCM) and dehydrogen

Full text of DOI:10.1016/j.ejmech.2017.04.071

Accepted Manuscript
Concise synthesis and antiproliferative activity evaluation of ellipticine quinone and its
analogs
Takashi Nishiyama, Noriyuki Hatae, Masataka Mizutani, Teruki Yoshimura, Tsuyoshi
Kitamura, Mana Miyano, Mami Fujii, Nanase Satsuki, Minoru Ishikura, Satoshi Hibino,
Tominari Choshi
PII:
S0223-5234(17)30345-8
10.1016/j.ejmech.2017.04.071
EJMECH 9422
DOI:
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 17 January 2017
Revised Date: 24 April 2017
Accepted Date: 25 April 2017
Please cite this article as: T. Nishiyama, N. Hatae, M. Mizutani, T. Yoshimura, T. Kitamura, M. Miyano,
M. Fujii, N. Satsuki, M. Ishikura, S. Hibino, T. Choshi, Concise synthesis and antiproliferative activity
evaluation of ellipticine quinone and its analogs, European Journal of Medicinal Chemistry (2017), doi:
10.1016/j.ejmech.2017.04.071.
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ACCEPTED MANUSCRIPT
Graphical Abstract

ACCEPTED MANUSCRIPT
Concise Synthesis and Antiproliferative Activity Evaluation of Ellipticine Quinone and its
Analogs
Takashi Nishiyamaa, Noriyuki Hataeb**, Masataka Mizutanib, Teruki Yoshimurab, Tsuyoshi
Kitamuraa, Mana Miyanoa, Mami Fujiia, Nanase Satsukia, Minoru Ishikurab, Satoshi Hibinoa, and
Tominari Choshia*
aGraduate School of Pharmacy Pharmaceutical Sciences, Faculty of Pharmacy and
Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, Japan
bFaculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu,
Hokkaido 061-0293, Japan
Corresponding author. E-mail address: choshi@fupharm.fukuyama-u.ac.jp (T. Choshi)
Keyword: carbazole-1,4-quinone, Ring-Closing Metathesis, pyrido[4,3-b]carbozole-5,11-quinone,
ellipticine quinone, antiproliferative activity
Abstract: We developed a concise protocol for the synthesis of ellipticine quinone from the
appropriate 3-iodoindole-2-carbaldehydes in four steps. The key step is the construction of
carbazole-1,4-quinone through tandem Ring-Closing Metathesis (RCM) and dehydrogenation under
oxygen atmosphere. Therefore, the ellipticine quinone analogs possessing substitution at the 8-
and/or 9-positions were synthesized using this method. In total, 14 compounds were evaluated for
antiproliferative activity against HCT-116 and HL-60 cell lines; 9-nitroellipticine quinone was
found to have superior activity compared to calothrixin B.
1. Introduction
Pyrido[4,3-b]carbazole alkaloid, an ellipticine, was isolated from the leaves of Ochrosia elliptica
Labill by Goodwin et al. in 1959 [1]. The alkaloid’s biological activity was suggested to primarily
occur through DNA intercalation and topoisomerase II inhibition [2]. In addition, ellipticine and its
derivatives have attracted broad interest in chemistry, biology, and pharmacology. Many synthetic
approaches to their formation has been investigated and summarized in the literature [3].
Ellipticine quinone (2) has been reported as a key intermediate in ellipticine synthesis by Gribble et
al. (Chart 1) [4]. Since then, 2 has been synthesized by many research groups [5] and revealed to
show antitumor activity by Bernardo et al. [6]. Moreover, the pentacyclic quinolino[4,3-b]carbazole
alkaloid and calothrixins A and B including the carbazole-1,4-quinone framework were isolated
from cyanobacteria Calothrix by Rickards et al. in 1999 [7]. These compounds have been reported
to exhibit antimalarial activity as well as activity against human HeLa cancer cells. In this way,
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heterocyclic quinones are currently the focus of intensive research because of their several
biological activities such as anticancer [6,8], neuronal cell-protecting [9], and antimalarial activities
[6,10].
We are interested in the unique structure and pharmacological action of carbazolequinone alkaloids.
To date, we have achieved the total synthesis of carbazolequonones (murrayaquinone A [11],
koeniginequinones [12], carbazomycin G [13], carquinostatin A [14], carbazoquinocins [15],
carbazomadurins [16], and calothrixins [17]) based on our original two methods of allene-mediated
electrocyclic reaction of a 6π-electron system [11a,b,13–17] or one-pot cyclocarbonylation,
desilylation, and oxidation reaction [11c,12]. Furthermore, we have been searching for stronger
biologically active compounds using these natural compounds and their derivatives. Recently, we
developed an efficient synthetic method for the carbazole-1,4-quinone framework from the
appropriate 3-acryloyl-2-propenylindoles using a tandem RCM [18] and dehydrogenation reaction,
and achieved the total synthesis of murrayaquinone A (7) (Scheme 1) [19]. In addition, we
evaluated the antiproliferative activity of these derivatives [20].
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Herein, we describe a concise total synthesis of ellipticine quinone based on the construction of a
carbazole-1,4-quinone using a tandem RCM and dehydrogenation reaction. In addition, we
synthesize its analogs that possess substitution in the 8- and/or 9-positions using this method and
aim at developing new drug candidates or lead compounds. We then evaluate the antiproliferative
activity of the new compounds and natural products against HCT-116 and HL-60 cell lines.
2. Results and Discussion
2.1. Chemistry
Our retrosynthetic strategy for ellipticine quinones is illustrated in Scheme 2. We envisioned that
the fused pyridine moiety of 2 could be constructed through a Pomeranz–Fritsch reaction [21]. The
carbazole-1,4-quinone framework of 2 was prepared from 3-acryloyl-2-propenylindole 8 using a
tandem RCM and dehydrogenation reaction as a key step. The 3-acryloyl-2-propenylindole 8 would
be provided by
a
three-component Pd-catalyzed cross-coupling reaction between
3-iodoindole-2-carbaldehyde (4), CO (1 atm), and alkenyl tributyltin 9, followed by a Grignard
reaction toward the formyl group.
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Initially, to obtain a required alkenyl tributyltin 9 (Scheme 3), treatment of aminoacetaldehyde
diethyl acetal with p-toluenesulfonyl chloride and Et3N afforded the p-toluenesulfonamide 10 [22]
in 76% yield, which was subjected to alkylation with propargyl bromide in the presence of K2CO3
to give the propargylamine 11 in 74% yield. Subsequently, 11 was subjected to Pd-catalyzed
hydrostannylation [23] with tributyltin hydride to afford the desired alkenyl tributyltin 9 in 97%
yield.
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The synthesis of ellipticine quinone was performed as outlined in Scheme 4. The three-component
Pd-catalyzed cross-coupling reaction [24] between 3-iodoindole-2-carbaldehyde (4) and alkenyl
tributyltin 9 under CO (1 atm) atmosphere was conducted in DMF at 70 °C to provide
3-acryloylindole 12 in 64% yield. Subsequently, the Grignard reaction of 12 with vinylmagnesium
bromide afforded the allyl alcohol 8. Treatment of 8 with Grubbs 2nd generation catalyst under
oxygen atmosphere in toluene at 70 °C for 2 h directly afforded the carbazole-1,4-quinone 13 in
66% yield. Finally, we investigated the construction of a fused pyridine moiety through a
Pomerantz–Fritsch reaction. Compound 13 was subjected to cyclization with 6 M HCl in
1,4-dioxane at 70 °C by conventional heating. The desired ellipticine quinone (2) was obtained in
35% yield. Next, according to Chern’s method [21f], we examined cyclization with 6 M HCl in
1,4-dioxane at 150 °C under microwave irradiation (in a sealed microwave tube). Under these
conditions, the yield improved and 2 was obtained in 67% yield. Furthermore, cyclization of 13
with 6 M HCl in 1,4-dioxane at 100 °C under microwave irradiation gave ellipticine quinone (2) as
the sole product in 90% yield. Thus, a concise synthesis of ellipticine quinone (2) was achieved
from 3-iodoindole-2-carbaldehyde (4) in 34.6% overall yield in four steps.
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Next, based on the above precedents, we attempted to synthesize new ellipticine quinone analogs
possessing several substitutions in the 8- and/or 9-positions to evaluate their in vitro
antiproliferative activity against HCT-116 and HL-60 cell lines.
As shown in Scheme 5 and Table 1, the starting material, indole-2-carbaldehyde 14, was
synthesized according to our reported procedure [20]. A three-component Pd-catalyzed
cross-coupling reaction of 3-iodoindole 14 and alkenyl tributyltin 9 under CO (1 atm) atmosphere
performed in DMF at 70 °C provided 3-acryloylindole 15 in 42%–66% yields. Subsequently, the
Grignard reaction of 15 with vinylmagnesium bromide gave the desired 2-allyl alcohol 16 in 53%–
70% yields. We synthesized the carbazole-1,4-quinone 17 in 52%–72% yields using a tandem RCM
and dehydrogenation reaction against 16. Finally, cyclization of the obtained carbazole-1,4-quinone
17 with HCl in 1,4-dioxane under microwave irradiation gave the ellipticine quinone 18 in 60%–
1
13
80% yields. The structures of these ellipticine quinone 18 are supported by the H, C NMR, and
mass spectra.
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Table 1. Yield of 15, 16, 17, and 18
Compd.
Yield (%)
16
R1
R2
No.
a
b
c
15
43
54
52
45
60
41
54
66
42
58
45
46
48
17
65
64
61
58
62
66
61
60
53
52
60
72
53
18
65
71
65
63
80
62
72
72
72
68
70
66
60
MeO
MeO
Me
Cl
MeO
H
57
63
56
60
66
64
65
60
53
56
64
72
53
H
H
d
e
F
H
NO2
CF3
H
H
f
H
g
h
i
MeO
Me
Cl
H
H
j
H
F
k
l
H
NO2
CF3
H
m
2.2. Antiproliferative studies
The HCT-116 and HL-60 cell viabilities treated with ellipticine quinone analogs were assessed by
the MTT [25] and WST-1 [26] method, respectively, and the data is shown in Table 2.
Antiproliferative activity by ellipticine quinone (2) has only been reported against the HeLa cell
line, showing an IC50 value of 0.15 µM [6]. Against HCT-116 and HL-60 cells, the IC50 values were
0.877 and 3.286 µM, respectively. Our previous report [8d] regarding the antiproliferative activity
against HCT-116 and HL-60 cells treated with calothrixin B and N-MOM calothrixin B that
included a pyrido[4,3-b]carbazole-5,11-quinone structure similar to ellipticine quinone also
exhibited weaker activity compared to that against HeLa cells in a report by Bernardo et al. [6].
Furthermore, all our synthetic pyrido[4,3-b]carbozole-5,11-quinone analogs, such as the current
ellipticine quinone analogs and previously reported calothrixin B analogs [8d], displayed weaker
activity against HL-60 cells than against HCT-116 cells.
Based on our previous report regarding the increasing effect of mono-MeO substitution on the
phenyl ring of murrayaquinone A on antiproliferative activity [20], mono-MeO ellipticine quinones
18b and 18h were predicted to show an increase in activity. Unlike mono-MeO murrayaquinone A,
the mono- and di-MeO analogs 18a, 18b, and 18h exhibited weaker activity compared to
unsubstituted ellipticine quinone 2. All our 8-monosubstituted analogs 18h–18m showed a decrease
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in antiproliferative activity compared to unsubstituted 2. For 9-monosubstituted analogs 18c–18g,
with the exception of 9-MeO analog 18b, the activity increased compared to the corresponding
8-monosubstituted analogs 18i–18m. Finally, we developed the 9-NO2 derivative 18f that showed
the most potent antiproliferative activity against HCT-116 and HL-60 cells with IC50 values of
0.187 and 1.350 µM, respectively. The values of 9-NO2 ellipticine quinone 18f were superior to
those of calothrixin B (3b), whose IC50 values are 0.32 µM against HCT-116 cells and over 10 µM
against HL-60 cells [8d]. Then, based on current antiproliferative activity against tumor cells, we
will be assessed to their selectivity index test using normal cells in the near future.
Table 2. Evaluation of Cell Growth Inhibitory activity against HCT-116 and HL-60 cell lines
O
1
R1
N2
10
11
9
3
R2
8
4
5
7
N
H
O
HCT-116
IC50 (µM)
0.877
3.721
5.430
0.849
1.380
1.127
0.187
1.641
3.137
5.795
4.066
1.600
1.254
4.619
0.159
HL-60
IC50 (µM)
3.286
7.487
>10
Compd. No.
R1
H
R2
H
MeO
H
2
MeO
MeO
Me
Cl
18a
18b
18c
18d
18e
18f
18g
18h
18i
H
4.268
3.881
4.500
1.350
5.084
9.005
>10
H
F
H
NO2
CF3
H
H
H
MeO
Me
Cl
H
H
>10
18j
18k
18l
H
F
4.500
4.429
>10
H
NO2
CF3
H
18m
Camptothecin
0.019
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3. Conclusion
In conclusion, we developed a concise protocol for the total synthesis of ellipticine quinone and
achieved the formal synthesis of ellipticine. Furthermore, we synthesized 13 analogs using our
protocol for evaluating their in vitro antiproliferative activity against HCT-116 and HL-60 cell lines.
The 9-monosubstituted analogs, with the exception of 9-MeO derivative 18b, were found to possess
good activity compared to the corresponding 8-monosubstituted compounds; notably, 9-NO2
ellipticine quinone 18f exhibited IC50 values 4.7-fold higher against HCT-116 cells and 2.4-fold
higher against HL-60 cells. This is the first report of an ellipticine quinone analog with higher IC50
values than calothrixin B (3b), which displayed extremely strong antiproliferative activity in natural
products with a carbazole-1,4-quinone structure. The current findings are considered to be
important for the development of antitumor carbazole-1,4-quinone analogs.
4. Experimental section
4.1. Chemistry
All non-aqueous reactions were carried out under an atmosphere of nitrogen in dried glassware
unless otherwise noted. Solvents were dried and distilled according to standard protocols.
Analytical thin-layer chromatography was performed with Silica gel 60PF254 (Merck). Silica gel
column chromatography was performed with Silica gel 60 (70–230 mesh, Canto Co. Lit.). All
melting points were determined on Yanagimoto micro melting point apparatus and are uncorrected.
Proton nuclear magnetic resonance (1H NMR) spectra were recorded on a JEOL AL-300 at 300
MHz. Chemical shifts are reported relative to Me4Si (δ 0.00). Multiplicity is indicated by one or
more of the following: s (singlet); d (doublet); t (triplet); q (quartet); m (multiplet); br (broad).
Carbon nuclear magnetic resonance (13C NMR) spectra were recorded on a JEOL AL-300 at 75
MHz. Chemical shifts are reported relative to CDCl3 (δ 77.0) and DMSO-d6 (δ 39.7). Infrared
spectra were recorded with ATR method using a Shimadzu FTIR-8000 spectrophotometer and
Technologies DuraScop. Low and High-resolution mass spectra were recorded on JEOL JMS-700
spectrometers by direct inlet system.
4.2. N-(2,2-Diethoxyethyl)-4-methylbenzenesulfonamide (10)
A mixture of aminoacetaldehyde diethyl acetal (10.0 g, 75 mmol), Et3N (21.0 mL, 150 mmol), and
p-toluenesulfonyl chloride (17.1 g, 90 mmol) in CH2Cl2 (80 mL) was stirred at rt for 1.5 h. After
water was added to the mixture, the mixture was extracted with CH2Cl2. The organic extract was
washed with water, 1 M HCl, 20% NaHCO3 and brine, dried over Na2SO4, and evaporated under
reduced pressure to give 10 (17.1 g, 79%) as white solid. mp 63–64 °C (EtOAc-hexane). IR (ATR)
ν = 3251 (NH), 1323 (SO2), 1122 (SO2) cm–1. 1H NMR (300 MHz, CDCl3) δ = 7.75 (d, J = 8.2 Hz,
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2H; ArH), 7.29 (d, J = 8.2 Hz, 2H; ArH), 5.13–5.18 (m, 1H; NH), 4.47 (t, J = 5.5 Hz, 1H; CH),
3.57–3.67 (m, 2H; OCH2), 3.40–3.50 (m, 2H; OCH2), 2.99–3.05 (m, 2H; CH2), 2.40 (s, 3H; CH3),
1.15 (t, J = 7.0 Hz, 6H; CH3 × 2). 13C NMR (75 MHz, CDCl3) δ = 143.1, 136.7, 129.4, 126.8, 100.4,
62.8, 45.2, 21.2, 14.9. MS m/z: 287 (M+, 5), 155 (25), 103 (100). HRMS (EI): calcd for
C13H21NO4S 287.1191; found 287.1123.
4.3. N-(2,2-Diethoxyethyl)-N-(2-propynyl)-4-methylbenzenesulfonamide (11)
A mixture of 10 (17.0 g, 59 mmol), 3-bromopropyne (7.0 g, 59 mmol), and K2CO3 (16.3 g, 118
mmol) in DMF (60 mL) was stirred at rt for 3 h. After water was added to the mixture, the mixture
was extracted with EtOAc. The organic extract was washed with water and brine, dried over
Na2SO4, and evaporated under reduced pressure to give 11 (16.1 g, 83%) as colorless crystals. mp
58–59 °C (EtOAc-hexane). IR (ATR) ν = 3275 (NH), 1335 (SO2), 1161 (SO2) cm–1. 1H NMR (300
MHz, CDCl3) δ = 7.75 (d, J = 8.3 Hz, 2H; ArH), 7.28 (d, J = 8.3 Hz, 2H; ArH), 4.69 (t, J = 5.6 Hz,
1H; CH), 4.29 (d, J = 2.4 Hz, 2H; CH2), 3.69–3.80 (m, 2H; OCH2), 3.52–3.62 (m, 2H; OCH2), 3.26
(d, J = 5.6 Hz, 2H; CH2), 2.42 (s, 3H; CH3), 1.99 (t, J= 2.4 Hz, 1H; CH), 1.22 (t, J= 7.0 Hz, 6H;
CH3 × 2). 13C NMR (75 MHz, CDCl3) δ = 143.5, 136.0, 129.4, 127.7, 102.7, 73.4, 63.4, 48.5, 38.3,
21.5, 15.3. MS m/z: 325 (M+, 2), 155 (17), 103 (100). HRMS (EI): calcd for C16H23NO4S 325.1348;
found 325.1348.
4.4. N-(2,2-Diethoxyethyl)-N-[2-(tributylstannyl)allyl]-4-methylbenzenesulfonamide (9)
A solution of tributyltin hydride (12.3 ml, 47 mmol) was added dropwise to a suspension of
propargylamine 11 (14 g, 43 mmol) and PdCl2(PPh3)2 (0.31 g, 0.43 mmol) in THF (50 mL) under
cooling with ice-water. After stirring at same temperature for 1 h, the mixture was evaporated in
vacuo. The residue was purified by column chromatography using EtOAc-hexane (1:9, v/v) as an
eluent to give the alkenyl tributyltin 9 (25.7 g, 97%). IR (ATR) ν =1342 (SO2), 1157 (SO2) cm–1. 1H
NMR (300 MHz, CDCl3) δ = 7.70 (d, J = 7.9 Hz, 2H; ArH), 7.26 (d, J = 7.9 Hz, 2H; ArH), 5.51 (d,
J = 1.8 Hz, 1H; =CH2), 5.18 (d, J = 1.8 Hz, 1H; =CH2), 4.54 (t, J = 5.3 Hz, 1H; CH), 4.21 (s, 2H;
CH2), 3.57–3.67 (m, 2H; OCH2), 3.34–3.44 (m, 2H; OCH2), 3.26 (d, J = 5.3 Hz, 2H; CH2), 2.41 (s,
3H; CH3), 1.42–1.50 (m, 6H; CH2CH2CH2), 1.27–1.37 (m, 6H; CH2CH2CH2), 1.22 (t, J= 7.0 Hz,
13
6H; CH3 × 2), 0.87–0.94 (m, 9H; CH3 × 3). C NMR (75 MHz, CDCl3) δ = 147.8, 142.9, 138.1,
129.4, 127.2, 125.7, 102.0, 63.1, 56.4, 49.0, 29.0, 27.3, 21.5, 15.3, 13.7, 9.3. MS m/z: 617 (M+, 3),
155 (30), 103 (100). HRMS (EI): calcd for C28H51NO4SSn 617.2561; found 617.2555.
4.5. N-(2,2-Diethoxyethyl)-N-{[2-(2-formylindol-3-yl)carbonyl]prop-2-en-1-yl}-
4-methylbenzenesulfonamide (12)
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Carbon monoxide was bubbled for 5 min to a mixture of the iodoindole 4 (500 mg, 1.85 mmol),
alkenyl tributyltin 9 (1.71 g, 2.77 mmol), BHT (448 mg, 2.04 mmol), and PdCl2(dppf) (75 mg,
0.093 mmol) in DMF (20 mL) at rt. The resulting mixture was stirred at 70 °C for 12 h under a CO
atmosphere. After cooling to an ambient temperature, 30% aq. KF solution (20 mL) was added to
the mixture and then the mixture was stirred at the same temperature for 1 h. The mixture was
quenched with water and then the mixture was extracted with EtOAc. The organic layer was
washed with brine, dried over Na2SO4, and evaporated in vacuo. The residue was purified by
column chromatography using EtOAc-hexane (2:8, v/v) as an eluent to give the 3-acryloylindole 12
(778 mg, 64%). mp 127–128 °C (EtOAc-hexane). IR (ATR) ν = 3302 (NH), 1658 (CO), 1616 (CO),
1334 (SO2), 1157 (SO2) cm–1. 1H NMR (300 MHz, CDCl3) δ = 10.08 (s, 1H; CHO), 9.49 (br s, 1H;
NH), 7.94 (d, J=8.1 Hz, 1H; ArH), 7.76 (d, J = 8.0 Hz, 2H; ArH), 7.40–7.51 (m, 2H; ArH), 7.24–
7.31 (m, 3H; ArH), 6.29 (s, 1H; =CH2), 6.08 (s, 1H; =CH2), 4.64 (t, J = 5.6 Hz, 1H; CH), 4.42 (s,
2H; CH2), 3.63–3.73 (m, 2H; OCH2), 3.43–3.53 (m, 2H; OCH2), 3.39 (d, J = 5.6 Hz, 2H; CH2),
2.41 (s, 3H; CH3), 1.16 (t, J = 6.9 Hz, 6H; CH3 × 2); 13C NMR (75 MHz, CDCl3) δ = 191.4, 183.3,
146.2, 143.6, 136.6, 136.3, 135.9, 129.8, 129.7, 127.5, 127.3, 126.6, 123.6, 123.1, 122.2, 112.4,
101.7, 63.0, 51.3, 49.6, 21.5, 15.3. MS m/z: 498 (M+, 1), 155 (23), 103 (100). HRMS (EI): calcd for
C26H30N2O6S 498.1825; found 498.1833.
4.6. N-(2,2-diethoxyethyl)-N-((2-(2-(1-hydroxyprop2-en-1-yl)indol-3-yl)carbonyl)prop-2-en-1-yl)-
4-methylbenzenesulfonamide (8)
A solution of vinylmagnesium bromide (1 M in THF, 3.2 mL, 3.2 mmol) was added dropwise to a
solution of 3-acryloylindole 12 (1.00 g, 0.23 mmol) in THF (30 mL) under cooling with ice-water.
After stirring at rt for 30 min, the reaction mixture was quenched with aqueous NH4Cl solution
(saturated), and then was extracted with EtOAc. The organic layer was washed with brine, dried
over Na2SO4, and evaporated in vacuo. The residue was purified by column chromatography using
EtOAc-hexane (1:9, v/v) as an eluent to give the allyl alcohol 8 (960 mg, 91%) as yellow oil. IR
(ATR) ν = 3336 (OH), 1608 (CO), 1330 (SO2), 1153 (SO2) cm–1. 1H NMR (300 MHz, CDCl3) δ =
9.19 (br s, 1H; NH), 7.79 (d, J = 7.9 Hz, 1H; ArH), 7.73 (d, J = 8.4 Hz, 2H; ArH), 7.36 (d, J = 7.9
Hz, 1H; ArH), 7.22 (d, J = 8.4 Hz, 2H; ArH), 7.12–7.20 (m, 2H; ArH), 6.13 (ddd, J = 17.1, 10.5,
5.0 Hz, 1H; CH=CH2), 6.02 (s, 1H; =CH2), 5.95 (s, 1H; =CH2), 5.64 (br s, 1H; CH), 5.50 (td, J =
17.1, 1.5 Hz, 1H; CH=CH2), 5.32 (td, J = 10.5, 1.5 Hz, 1H; CH=CH2), 4.69 (br s, 1H; OH), 4.65 (t,
J = 5.5 Hz, 1H; CH), 4.40 (s, 2H; CH2), 3.62–3.72 (m, 2H; OCH2), 3.42–3.51 (m, 2H; OCH2), 3.41
(d, J = 5.5 Hz, 2H; CH2), 2.37 (s, 3H; CH3), 1.15 (t, J = 7.2 Hz, 6H; CH3 × 2).13C NMR (75 MHz,
CDCl3) δ = 193.1, 147.5, 144.8, 143.4, 136.9, 136.1, 134.3, 129.6, 127.2, 126.9, 126.1, 123.0, 122.0,
121.3, 117.1, 112.8, 111.6, 101.7, 67.8, 63.0, 50.6, 49.6, 21.4, 15.2. MS m/z: 526 (M+, 2), 155 (24),
103 (100). HRMS (EI): calcd for C28H34N2O6S 526.2138; found 526.2142.
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4.7. N-(2,2-diethoxyethyl)-N-(1,4-dioxocarbazol-3-ylmethyl)-4-methylbenzenesulfonamide (13)
A suspension of the allyl alcohol 8 (100 mg, 0.19 mmol) and Grubbs2nd catalyst (17 mg, 0.02
mmol) in toluene (20 mL) was heated at 70 °C for 2 h under an O2 atmosphere. After cooling to an
ambient temperature, reaction solvent was evaporated in vacuo. The residue was purified by column
chromatography using EtOAc-hexane (3:7, v/v) as an eluent to give the carbazole-1,4-quinone 13
(62 mg, 66%) as red solid. mp 190–192 °C (EtOAc-hexane). IR (ATR) ν = 3181 (NH), 1643 (CO),
1
1612 (CO), 1342 (SO2), 1161 (SO2) cm–1. H NMR (300 MHz, CDCl3) δ = 9.51 (br s, 1H; NH),
8.16 (d, J = 7.6 Hz, 1H; ArH), 7.73 (d, J = 8.4 Hz, 2H; ArH), 7.52 (d, J = 7.6 Hz, 1H; ArH), 7.42 (t,
J = 7.6 Hz, 1H; ArH), 7.37 (t, J = 7.6 Hz, 1H; ArH), 7.29 (d, J = 8.4 Hz, 2H; ArH), 6.71 (t, J = 1.7
Hz, 1H; ArH), 4.62 (t, J = 5.0 Hz, 1H; CH), 4.42 (d, J = 1.7 Hz, 2H; CH2), 3.61–3.71 (m, 2H;
OCH2), 3.41–3.51 (m, 2H; OCH2), 3.36 (d, J = 5.0 Hz, 2H; CH2), 2.36 (s, 3H; CH3), 1.13 (t, J = 7.0
Hz, 6H; CH3 × 2). 13C NMR (75 MHz, CDCl3) δ = 182.7, 179.9, 146.7, 143.8, 137.1, 136.3, 135.2,
131.4, 129.8, 127.3, 127.2, 124.4, 124.0, 122.8, 116.8, 113.0, 101.9, 63.1, 52.3, 48.5, 21.4, 15.2.
MS m/z: 496 (M+, 2), 210 (4), 155 (15), 103 (100). HRMS (EI): calcd for C26H28N2O6S 496.1668;
found 496.1674.
4.8. ellipticine quinone (2)
A stirred solution of 13 (100 mg, 0.202 mmol) in dioxane/6 M HCl (3:2) (5 mL) under N2
atmosphere, was heated under microwave irradiation at 100 °C for 10 min. After cooling to an
ambient temperature, the pH of the reaction mixture was adjusted to 8 with Na2CO3 and extracted
with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and evaporated in vacuo.
The residue was purified by column chromatography using EtOAc-hexane (5:5, v/v) as an eluent to
give ellipticine quinone (2) (45 mg, 90%). mp 316–318 °C (EtOAc-hexane) (lit. [4] mp 317–320
1
ºC). IR (ATR) ν = 3078 (NH), 1662 (CO), 1651 (CO) cm–1. H NMR (300 MHz, DMSO-d6) δ =
13.2 (br s, 1H; NH), 9.24 (s, 1H; ArH), 9.06 (d, J = 4.8 Hz, 1H; ArH), 8.21 (d, J = 8.0 Hz, 1H;
ArH), 7.93 (d, J = 4.8 Hz, 1H; ArH), 7.61 (d, J = 8.0 Hz, 1H; ArH), 7.48 (t, J = 8.0 Hz, 1H; ArH),
7.39 (t, J = 8.0 Hz, 1H; ArH). 13C NMR (75 MHz, DMSO-d6) δ = 180.3, 176.9, 155.2, 147.4, 138.5,
138.4, 137.0, 128.1, 127.6, 124.4, 123.7, 122.5, 118.4, 117.5, 114.0. MS m/z: 248 (M+, 100). HRMS
(EI): calcd for C15H8N2O2 248.0586; found 248.0573.
4.9. Synthesis of 3-Acryloylindoles (15a–15m)
3-Acryloylindole 15a–15m were prepared according to a synthetic method for 12.
4.9.1. N-(2,2-diethoxyethyl)-N-{[2-(2-formyl-5,6-dimethoxyindol-3-yl)carbonyl]prop-2-en-1-yl}-
4-methylbenzenesulfonamide (15a)
12

ACCEPTED MANUSCRIPT
Yield 43%. mp 78–79 °C (EtOAc-hexane). IR (ATR) ν = 3332 (NH), 1666 (CO), 1628 (CO), 1342
(SO2), 1122 (SO2) cm–1. 1H NMR (300 MHz, CDCl3) δ = 10.48 (br s, 1H; NH), 10.00 (s, 1H; CHO),
7.76 (d, J = 7.5 Hz, 2H; ArH), 7.43 (s, 1H; ArH), 7.30 (d, J = 7.5 Hz, 2H; ArH), 6.94 (s, 1H; ArH),
6.31 (s, 1H, =CH2), 6.09 (s, 1H, =CH2), 4.61 (t, J = 5.1 Hz, 1H; CH), 4.41 (s, 2H; CH2), 3.97 (s,
3H; OCH3), 3.93 (s, 3H; OCH3), 3.62–3.72 (m, 2H; OCH2), 3.42–3.49 (m, 2H; OCH2), 3.40 (d, J =
5.1 Hz, 2H; CH2), 2.42 (s, 3H; CH3), 1.14 (t, J = 6.9 Hz, 6H; CH3 × 2). 13C NMR (75 MHz, CDCl3)
δ = 191.9, 182.4, 151.8, 148.0, 146.6, 143.7, 136.4, 135.1, 132.3, 129.7, 128.9, 127.3, 122.3, 120.5,
102.9, 101.4, 93.4, 62.9, 56.3, 56.2, 51.4, 49.8, 21.5, 15.1. MS m/z: 558 (M+, 2), 403 (10), 155 (14),
103 (100). HRMS (EI): calcd for C28H34N2O8S 558.2036; found 558.2023.
4.9.2. N-(2,2-diethoxyethyl)-N-{[2-(2-formyl-5-methoxyindol-3-yl)carbonyl]prop-2-en-1-yl}-
4-methylbenzenesulfonamide (15b)
Yield 54%. mp 121–122 °C (EtOAc-hexane). IR (ATR) ν = 3294 (NH), 1651 (CO), 1612 (CO),
1342 (SO2), 1134 (SO2) cm–1. 1H NMR (300 MHz, CDCl3) δ = 10.06 (s, 1H; CHO), 9.41 (br s, 1H;
NH), 7.75 (d, J = 8.4 Hz, 2H; ArH), 7.45 (d, J = 2.6 Hz, 1H; ArH), 7.37 (d, J = 9.2 Hz, 1H; ArH),
7.30 (d, J = 8.4 Hz, 2H; ArH), 7.09 (dd, J = 9.2, 2.6 Hz, 1H; ArH), 6.29 (s, 1H; =CH2), 6.06 (s, 1H;
=CH2), 4.61 (t, J = 5.3 Hz, 1H; CH), 4.40 (s, 2H; CH2), 3.86 (s, 3H; OCH3), 3.61–3.69 (m, 2H;
OCH2), 3.42–3.50 (m, 2H; OCH2), 3.39 (d, J = 5.3 Hz, 2H; CH2), 2.41 (s, 3H; CH3), 1.15 (t, J = 7.0
Hz, 6H; CH3 × 2). 13C NMR (75 MHz, CDCl3) δ = 182.8, 179.6, 157.7, 146.6, 143.8, 136.3, 135.2,
132.3, 131.6, 129.8, 127.3, 125.1, 119.0, 116.5, 114.0, 102.3, 102.0, 63.2, 55.7, 52.2, 48.4, 21.4,
15.2. MS m/z: 528 (M+, 1), 373 (14), 155 (6), 103 (100). HRMS (EI): calcd for C27H32N2O7S
528.1930; found 528.1943.
4.9.3. N-(2,2-diethoxyethyl)-N-{[2-(2-formyl-5-methylindol-3-yl)carbonyl]prop-2-en-1-yl}-
4-methylbenzenesulfonamide (15c)
Yield 52%. mp 104–105 °C (EtOAc-hexane). IR (ATR) ν = 3294 (NH), 1654 (CO), 1616 (CO),
1331 (SO2), 1153 (SO2) cm–1. 1H NMR (300 MHz, CDCl3) δ = 10.04 (s, 1H; CHO), 9.39 (br s, 1H;
NH), 7.74–7.77 (m, 3H; ArH), 7.37 (d, J = 8.3 Hz, 1H; ArH), 7.24–7.30 (m 3H; ArH), 6.27 (s, 1H;
=CH2), 6.07 (s, 1H; =CH2), 4.64 (t, J = 5.5 Hz, 1H; CH), 4.42 (s, 2H; CH2), 3.63–3.73 (m, 2H;
OCH2), 3.42–3.53 (m, 2H; OCH2), 3.39 (d, J = 5.5 Hz, 2H; CH2), 2.45 (s, 3H; CH3), 2.41 (s, 3H;
CH3), 1.16 (t, J = 7.1 Hz, 6H; CH3 × 2). 13C NMR (75 MHz, CDCl3) δ = 191.5, 183.2, 146.4, 143.6,
136.6, 136.3, 134.4, 132.8, 129.7, 129.6, 129.5, 127.3, 126.9, 122.6, 121.6, 112.1, 101.6, 62.9, 51.3,
49.6, 21.6, 21.5, 15.3. MS m/z: 512 (M+, 1), 357 (14), 155 (7), 103 (100). HRMS (EI): calcd for
C27H32N2O6S 512.1981; found 512.1996.
4.9.4. N-(2,2-diethoxyethyl)-N-{[2-(5-chloro-2-formylindol-3-yl)carbonyl]prop-2-en-1-yl}-
13

ACCEPTED MANUSCRIPT
4-methylbenzenesulfonamide (15d)
Yield 45%. mp 123–125 °C (EtOAc-hexane). IR (ATR) ν = 3278 (NH), 1658 (CO), 1635 (CO),
1369 (SO2), 1149 (SO2) cm–1. 1H NMR (300 MHz, CDCl3) δ = 10.10 (s, 1H; CHO), 9.58 (br s, 1H;
NH), 7.95 (s, 1H; ArH), 7.76 (d, J = 8.2 Hz, 2H; ArH), 7.43 (d, J = 8.8 Hz, 1H; ArH), 7.38 (d, J =
8.8 Hz, 1H; ArH), 7.30 (d, J = 8.2 Hz, 2H; ArH), 6.28 (s, 1H; =CH2), 6.04 (s, 1H; =CH2), 4.66 (t, J
= 5.2 Hz, 1H; CH), 4.41 (s, 2H; CH2), 3.63–3.73 (m, 2H; OCH2), 3.42–3.53 (m, 2H; OCH2), 3.40 (d,
13
J = 5.2 Hz, 2H; CH2), 2.41 (s, 3H; CH3), 1.17 (t, J = 7.1 Hz, 6H; CH3 × 2). C NMR (75 MHz,
CDCl3) δ = 190.8, 183.3, 146.5, 143.7, 137.1, 136.5, 134.2, 129.9, 129.8, 129.0, 128.2, 127.5, 127.3,
122.8, 121.2, 113.7, 101.6, 62.9, 51.4, 49.6, 21.5, 15.3. MS m/z: 534 (M++2, 1), 532 (M+, 3), 377
(12), 155 (16), 103 (100). HRMS (EI): calcd for C26H29ClN2O6S 532.1435; found 532.1421.
4.9.5. N-(2,2-diethoxyethyl)-N-{[2-(5-fluoro-2-formylindol-3-yl)carbonyl]prop-2-en-1-yl}-
4-methylbenzenesulfonamide (15e)
Yield 60%. mp 142–143 °C (EtOAc-hexane). IR (ATR) ν = 3301 (NH), 1651 (CO), 1616 (CO),
1342 (SO2), 1146 (SO2) cm–1. 1H NMR (300 MHz, CDCl3) δ = 10.10 (s, 1H; CHO), 9.58 (br s, 1H;
NH), 7.75 (d, J = 8.4 Hz, 2H; ArH), 7.62 (dd, J = 9.1, 2.6 Hz, 1H; ArH), 7.44 (dd, J = 9.1, 4.2 Hz,
1H; ArH), 7.31 (d, J = 8.4 Hz, 2H; ArH), 7.16–7.23 (m, 1H; ArH), 6.27 (s, 1H; =CH2), 6.04 (s, 1H;
=CH2), 4.65 (t, J = 5.2 Hz, 1H; CH), 4.40 (s, 2H; CH2), 3.64–3.74 (m, 2H; OCH2), 3.44–3.54 (m,
2H; OCH2), 3.39 (d, J = 5.2 Hz, 2H; CH2), 2.41 (s, 3H; CH3), 1.17 (t, J = 6.6 Hz, 6H; CH3 × 2). 13C
NMR (75 MHz, CDCl3) δ = 191.4, 183.9, 159.2 (d, JC–F = 240.6 Hz), 146.7, 144.1, 137.5, 136.4,
132.6, 129.7, 129.4, 127.2, 126.9, 121.8, 117.4 (d, JC–F = 27.4 Hz), 113.7 (d, JC–F = 10.0 Hz), 108.1
(d, JC–F = 24.9 Hz), 101.6, 63.4, 51.8, 50.4, 21.9, 15.6. MS m/z: 516 (M+, 1), 361 (23), 155 (8), 103
(100). HRMS (EI): calcd for C26H29FN2O6S 516.1730; found 516.1718.
4.9.6. N-(2,2-diethoxyethyl)-N-{[2-(2-formyl-5-nitroindol-3-yl)carbonyl]prop-2-en-1-yl}-
4-methylbenzenesulfonamide (15f)
Yield 41%. mp 125–126 °C (EtOAc-hexane). IR (ATR) ν = 3274 (NH), 1654 (CO), 1616 (CO),
1535 (NO2), 1352 (SO2), 1338 (NO2), 1153 (SO2) cm–1. 1H NMR (300 MHz, CDCl3) δ = 10.18 (s,
1H; CHO), 9.99 (br s, 1H; NH), 8.94 (d, J = 2.2 Hz, 1H; ArH), 8.30 (dd, J = 9.0, 2.2 Hz, 1H; ArH),
7.77 (d, J = 8.5 Hz, 2H; ArH), 7.59 (d, J = 9.0 Hz, 1H; ArH), 7.32 (d, J = 8.5 Hz, 2H; ArH), 6.37 (s,
1H; =CH2), 6.05 (s, 1H; =CH2), 4.66 (t, J = 5.3 Hz, 1H; CH), 4.41 (s, 2H; CH2), 3.65–3.75 (m, 2H;
OCH2), 3.45–3.55 (m, 2H; OCH2), 3.41 (d, J = 5.3 Hz, 2H; CH), 2.42 (s, 3H; CH3), 1.16 (t, J = 7.1
Hz, 6H; CH3 × 2). 13C NMR (75 MHz, CDCl3) δ = 190.1, 183.2, 147.2, 144.0, 143.8, 138.4, 138.2,
136.1, 130.2, 129.8, 127.3, 125.9, 123.1, 122.4, 120.9, 113.0, 101.6, 62.9, 51.4, 49.6, 21.5, 15.3.
MS m/z: 543 (M+, 2), 387 (18), 155 (10), 103 (100). HRMS (EI): calcd for C26H29N3O8S 543.1675;
found 543.1687.
14

ACCEPTED MANUSCRIPT
4.9.7. N-(2,2-diethoxyethyl)-N-{[2-(2-formyl-5-trifluoromethylindol-3-yl)carbonyl]prop-2-en-1-yl}-
4-methylbenzenesulfonamide (15g)
Yield 54%. mp 134–135 °C (EtOAc-hexane). IR (ATR) ν = 3286 (NH), 1651 (CO), 1635 (CO),
1
1327 (SO2), 1153 (SO2) cm–1. H NMR (300 MHz, CDCl3) δ = 10.14 (s, 1H; CHO), 9.83 (br s,
1H; NH), 8.31 (s, 1H; ArH), 7.75 (d, J = 8.4 Hz, 2H; ArH), 7.64 (d, J = 8.8 Hz, 1H; ArH), 7.59 (d, J
= 8.8 Hz, 1H; ArH), 7.30 (d, J = 8.4 Hz, 2H; ArH), 6.33 (s, 1H; =CH2), 6.04 (s, 1H; =CH2), 4.65 (t,
J = 5.5 Hz, 1H; CH), 4.41 (s, 2H; CH2), 3.63–3.73 (m, 2H; OCH2), 3.43–3.53 (m, 2H; OCH2), 3.39
(d, J = 5.5 Hz, 2H; CH2), 2.41 (s, 3H; CH3), 1.16 (t, J = 7.2 Hz, 6H; CH3 × 2). 13C NMR (75 MHz,
CDCl3) δ = 190.8, 183.5, 146.9, 143.8, 137.4, 137.2, 136.3, 130.0, 129.8, 127.3, 125.8, 125.4 (q, JC–
F = 32.5 Hz), 124.4 (q, JC–F = 272.8 Hz), 123.9 (q, JC–F = 3.1 Hz), 122.4, 121.4 (q, JC–F = 5.1 Hz),
113.4, 101.5, 62.8, 51.3, 49.6, 21.4, 15.2. MS m/z: 566 (M+, 1), 366 (14), 155 (13), 103 (100).
HRMS (EI): calcd for C27H29F3N2O6S 566.1698; found 566.1678.
4.9.8. N-(2,2-diethoxyethyl)-N-{[2-(2-formyl-6-methoxyindol-3-yl)carbonyl]prop-2-en-1-yl}-
4-methylbenzenesulfonamide (15h)
Yield 66%. mp 116–117 °C (EtOAc-hexane). IR (ATR) ν = 3294 (NH), 1651 (CO), 1639 (CO),
1342 (SO2), 1134 (SO2) cm–1. 1H NMR (300 MHz, CDCl3) δ = 9.97 (s, 1H; CHO), 9.42 (br s, 1H;
NH), 7.74–7.80 (m, 3H; ArH), 7.30 (d, J = 8.2 Hz, 2H; ArH), 6.92 (dd, J = 9.0, 2.3 Hz, 1H; ArH),
6.84 (d, J = 2.3 Hz, 1H; ArH), 6.28 (s, 1H; =CH2), 6.07 (s, 1H; =CH2), 4.63 (t, J = 5.6 Hz. 1H; CH),
4.40 (s, 2H; CH2), 3.88 (s, 3H; OCH3), 3.64–3.74 (m, 2H; OCH2), 3.44–3.54 (m, 2H; OCH2), 3.38
(d, J = 5.6 Hz, 2H; CH2), 2.41 (s, 3H; CH3), 1.16 (t, J = 6.9 Hz, 6H; CH3 × 2). 13C NMR (75 MHz,
CDCl3) δ = 191.4, 182.5, 160.3, 146.2, 143.6, 137.4, 136.6, 135.6, 129.8, 129.7, 127.3, 124.5, 122.7,
121.0, 115.0, 101.6, 93.5, 63.0, 55.6, 51.3, 49.6, 21.5, 15.2. MS m/z: 528 (M+, 2), 373 (17), 155 (15),
103 (100). HRMS (EI): calcd for C27H32N2O7S 528.1930; found 528.1942.
4.9.9. N-(2,2-diethoxyethyl)-N-{[2-(2-formyl-6-methylindol-3-yl)carbonyl]prop-2-en-1-yl}-
4-methylbenzenesulfonamide (15i)
Yield 42%. mp 115–116 °C (EtOAc-hexane). IR (ATR) ν = 3302 (NH), 1655 (CO), 1620 (CO),
1331 (SO2), 1153 (SO2) cm–1. 1H NMR (300 MHz, CDCl3) δ = 10.04 (s, 1H; CHO), 9.55 (br s, 1H;
NH), 7.75–7.81 (m, 3H; ArH), 7.26–7.31 (m, 3H; ArH), 7.09 (d, J = 8.3 Hz, 1H; ArH), 6.27 (s, 1H;
=CH2), 6.07 (s, 1H; =CH2), 4.64 (t, J = 5.3 Hz, 1H; CH), 4.42 (s, 2H; CH2), 3.63–3.73 (m, 2H;
OCH2), 3.42–3.52 (m, 2H; OCH2), 3.40 (d, J = 5.3 Hz, 2H; CH2), 2.49 (s, 3H; CH3), 2.41 (s, 3H;
CH3), 1.16 (t, J = 6.8 Hz, 6H; CH3 × 2). 13C NMR (75 MHz, CDCl3) δ = 191.5, 183.4, 146.1, 143.6,
138.2, 136.7, 136.6, 135.9, 129.7, 129.6, 127.3, 125.3, 124.5, 123.0, 122.4, 112.1, 101.6, 63.0, 51.2,
15

ACCEPTED MANUSCRIPT
49.6, 22.0, 21.5, 15.2. MS m/z: 512 (M+, 2), 357 (7), 155 (11), 103 (100). HRMS (EI): calcd for
C27H32N2O6S 512.1981; found 512.1986.
4.9.10. N-(2,2-diethoxyethyl)-N-{[2-(6-chloro-2-formylindol-3-yl)carbonyl]prop-2-en-1-yl}-
4-methylbenzenesulfonamide (15j)
Yield 58%. mp 131–132 °C (EtOAc-hexane). IR (ATR) ν = 3278 (NH), 1651 (CO), 1635 (CO),
1327 (SO2), 1149 (SO2) cm–1. 1H NMR (300 MHz, CDCl3) δ = 10.08 (s, 1H; CHO), 9.73 (br s, 1H;
NH), 7.88 (d, J = 9.0 Hz, 1H; ArH), 7.76 (d, J = 7.8 Hz, 2H; ArH), 7.50 (s, 1H; ArH), 7.31 (d, J =
7.8 Hz, 2H; ArH), 7.22 (d, J = 9.0 Hz, 1H; ArH), 6.32 (s, 1H; =CH2), 6.05 (s, 1H; =CH2), 4.63 (t, J
= 5.5 Hz, 1H; CH), 4.40 (s, 2H; CH2), 3.63–3.73 (m, 2H; OCH2), 3.42–3.52 (m, 2H; OCH2), 3.38 (d,
13
J = 5.5 Hz, 2H; CH), 2.42 (s, 3H; CH3), 1.16 (t, J = 7.2 Hz, 6H; CH3 × 2). C NMR (75 MHz,
CDCl3) δ = 191.0, 183.2, 146.4, 143.7, 136.7, 136.4, 136.2, 133.6, 129.8, 129.7, 127.3, 125.1, 124.6,
124.2, 122.1, 112.3, 101.6, 63.0, 51.4, 49.6, 21.5, 15.2. MS m/z: 534 (M++ 2, 1), 532 (M+, 3), 377
(4), 155 (13), 103 (100). HRMS (EI): calcd for C26H29ClN2O6S 532.1435; found: 532.1447.
4.9.11. N-(2,2-diethoxyethyl)-N-{[2-(6-fluoro-2-formylindol-3-yl)carbonyl]prop-2-en-1-yl}-
4-methylbenzenesulfonamide (15k)
Yield 45%. mp 126–127 °C (EtOAc-hexane). IR (ATR) ν = 3302 (NH), 1651 (CO), 1616 (CO),
1342 (SO2), 1146 (SO2) cm–1. 1H NMR (300 MHz, CDCl3) δ = 10.05 (s, 1H; CHO), 9.77 (br s, 1H;
NH), 7.89-7.94 (m, 1H; ArH), 7.76 (d, J = 8.2 Hz, 2H; ArH), 7.31 (d, J = 8.2 Hz, 2H; ArH), 7.18
(dd, J = 8.9, 2.1 Hz, 1H; ArH), 7.18 (dt, J = 9.1, 2.1 Hz, 1H; ArH), 6.32 (s, 1H, =CH2), 6.06 (s, 1H;
=CH2), 4.63 (t, J = 5.4 Hz, 1H; =CH2), 4.40 (s, 2H; CH2), 3.63–3.73 (m, 2H; OCH2), 3.42–3.52 (m,
2H; OCH2), 3.39 (d, J = 5.4 Hz, 2H; CH2), 2.42 (s, 3H; CH3), 1.16 (t, J = 7.0 Hz, 6H; CH3 × 2). 13C
NMR (75 MHz, CDCl3) δ = 191.1, 183.0, 163.5 (d, JC–F = 246.9 Hz), 146.5, 143.7, 136.9 (d, JC–F
=
3.9 Hz), 136.4 (d, JC–F = 5.0 Hz), 136.3, 129.8, 129.7, 127.3, 125.2 (d, JC–F = 10.7 Hz), 123.2, 122.3,
112.9 (d, JC–F = 24.9 Hz), 101.6, 98.3 (d, JC–F = 26.5 Hz), 63.0, 51.4, 49.6, 21.5, 15.2. MS m/z: 516
(M+, 1), 361 (22), 155 (8), 103 (100). HRMS (EI): calcd for C26H29FN2O6S 516.1730; found
516.1736.
4.9.12. N-(2,2-diethoxyethyl)-N-{[2-(2-formyl-6-nitroindol-3-yl)carbonyl]prop-2-en-1-yl}-
4-methylbenzenesulfonamide (15l)
Yield 46%. mp 135–136 °C (EtOAc-hexane). IR (ATR) ν = 3278 (NH), 1655 (CO), 1620 (CO),
1543 (NO2), 1348 (SO2), 1338 (NO2), 1153 (SO2) cm–1. 1H NMR (300 MHz, CDCl3) δ = 10.15 (s,
1H; CHO), 9.81 (br s, 1H; NH), 8.08 (d, J = 8.1 Hz, 1H; ArH), 7.79 (s, 1H; ArH), 7.75 (d, J = 8.4
Hz, 2H; ArH), 7.47 (d, J = 8.1 Hz, 1H; ArH), 7.30 (d, J = 8.4 Hz, 2H; ArH), 6.35 (s, 1H, =CH2),
6.05 (s, 1H; =CH2), 4.64 (t, J = 5.2 Hz, 1H; CH), 4.40 (s, 2H; CH2), 3.63–3.71 (m, 2H; OCH2),
16

ACCEPTED MANUSCRIPT
3.42–3.49 (m, 2H; OCH2), 3.39 (d, J = 5.2 Hz, 2H; CH2), 2.42 (s, 3H; CH3), 1.16 (t, J = 6.8 Hz, 6H;
13
CH3 × 2). C NMR (75 MHz, CDCl3) δ =190.1, 183.0, 147.2, 144.1, 148.3, 138.4, 138.1, 136.2,
130.2, 129.8, 127.4, 125.9, 123.0, 122.4, 120.9, 113.0, 101.6, 62.9, 51.4, 49.6, 21.5, 15.3. MS m/z:
543 (M+, 1), 387 (10), 155 (8), 103 (100). HRMS (EI): Calcd for C26H29N3O8S 543.1675; found
543.1693.
4.9.13.
N-(2,2-diethoxyethyl)-N-{[2-(2-formyl-6-trifluoromethylindol-3-yl)carbonyl]prop-2-en-1-yl}-
4-methylbenzenesulfonamide (15m)
Yield 48%. mp 130-132 °C (EtOAc-hexane). IR (ATR) ν = 3290 (NH), 1651 (CO), 1635 (CO),
1330 (SO2), 1153 (SO2) cm–1. 1H NMR (300 MHz, CDCl3) δ = 10.15 (s, 1H; CHO), 9.73 (br s, 1H;
NH), 8.09 (d, J = 8.7 Hz, 1H; ArH), 7.79 (s, 1H; ArH), 7.76 (d, J = 7.9 Hz, 2H; ArH), 7.49 (d, J =
8.7 Hz, 1H; ArH), 7.23 (d, J = 7.9 Hz, 2H; ArH), 6.35 (s, 1H; =CH2), 6.05 (s, 1H; =CH2), 4.63 (t, J
= 5.3 Hz, 1H; CH), 4.40 (s, 2H; CH2), 3.63–3.73 (m, 2H; OCH2), 3.42–3.52 (m, 2H; OCH2), 3.39 (d,
13
J = 5.3 Hz, 2H; CH), 2.42 (s, 3H; CH3), 1.15 (t, J = 7.2 Hz, 6H; CH3 × 2). C NMR (75 MHz,
CDCl3) δ = 190.8, 183.3, 146.5, 143.8, 138.0, 136.4, 134.6, 129.9, 129.8, 128.9 (q, JC–F = 37.9 Hz),
127.5 (q, JC–F = 271.1 Hz), 127.3, 127.1, 124.5, 121.6, 119.4 (q, JC–F = 3.6 Hz), 110.2 (q, JC–F = 5.5
Hz), 101.6, 63.0, 51.5, 49.6, 21.5, 15.2. MS m/z: 566 (M+, 1), 387 (12), 155 (9), 103 (100). HRMS
(EI): calcd for C27H29F3N2O6S 566.1698; found 566.1688.
4.10. Synthesis of 3-Acryloyl-2-allylindoles (16a–16m)
3-Acryloyl-2-allylindole 16a–16m were prepared according to a synthetic method for 8.
4.10.1. N-(2,2-diethoxyethyl)-N-((2-(2-(1-hydroxyprop2-en-1-yl)-5,6-dimethoxyindol-3-yl)carbonyl)
prop-2-en-1-yl)-4-methylbenzenesulfonamide (16a)
1
Yield 57%. IR (ATR) ν = 3332 (OH), 1601 (CO), 1338 (SO2), 1119 (SO2) cm–1. H NMR (300
MHz, CDCl3) δ = 9.05 (br s, 1H; NH), 7.73 (d, J = 8.2 Hz, 2H; ArH), 7.47 (s, 1H; ArH), 7.26 (d, J
= 8.2 Hz, 2H; ArH), 6.84 (s, 1H; ArH), 6.13 (ddd, J = 17.0, 10.0, 5.0 Hz, 1H; CH=CH2), 6.10 (s,
1H; =CH2), 5.97 (s, 1H; =CH2), 5.60 (d, J = 5.0 Hz, 1H; CH), 5.50 (d, J = 17.0 Hz, 1H; CH=CH2),
5.32 (d, J = 10.0 Hz, 1H; CH=CH2), 4.62–4.84 (m, 1H; OH), 4.59 (t, J = 5.8 Hz, 1H; CH), 4.35 (s,
2H; CH2), 3.91 (s, 3H; OCH3), 3.87 (s, 3H; OCH3), 3.59–3.68 (m, 2H; OCH2), 3.39–3.47 (m, 2H;
13
OCH2), 3.39 (d, J = 5.8 Hz, 2H; CH2), 2.39 (s, 3H; CH3), 1.12 (t, J = 7.5 Hz, 6H; CH3 × 2). C
NMR (75 MHz, CDCl3) δ = 193.3, 147.5, 146.4, 145.6, 145.3, 143.5, 136.6, 136.2, 129.6, 128.5,
127.2, 125.2, 120.2, 117.0, 113.3, 103.2, 101.3, 94.3, 67.7, 62.8, 56.4, 56.1, 50.9, 50.1, 21.4, 15.2.
MS m/z: 586 (M+, 2), 155 (29), 103 (100). HRMS (EI): calcd for C30H38N2O8S 586.2349; found
586.2336.
17

ACCEPTED MANUSCRIPT
4.10.2.
N-(2,2-diethoxyethyl)-N-((2-(2-(1-hydroxyprop2-en-1-yl)-5-methoxyindol-3-yl)carbonyl)
prop-2-en-1-yl)-4-methylbenzenesulfonamide (16b)
1
Yield 63%. IR (ATR) ν = 3373 (OH), 1620 (CO), 1338 (SO2), 1153 (SO2) cm–1. H NMR (300
MHz, CDCl3) δ = 9.03 (br s, 1H; NH), 7.73 (d, J = 8.0 Hz, 2H; ArH), 7.43 (d, J = 1.5 Hz, 1H; ArH),
7.22–7.26 (m, 3H; ArH), 6.85 (dd, J = 8.2, 1.5 Hz, 1H; ArH), 6.13 (ddd, J = 17.3, 10.5, 5.1 Hz, 1H;
CH=CH2), 6.07 (s, 1H; =CH2), 5.97 (s, 1H; =CH2), 5.59–5.62 (m, 1H; CH), 5.52 (d, J = 17.3 Hz,
1H; CH=CH2), 5.34 (d, J = 10.5 Hz, 1H; CH=CH2), 4.68–4.86 (m, 1H; OH), 4.60 (t, J = 5.6 Hz,
1H; CH), 4.36 (s, 2H; CH2), 3.83 (s, 3H; OCH3), 3.60–3.70 (m, 2H; =CH2), 3.42–3.49 (m, 2H;
=CH2), 3.40 (d, J= 5.6 Hz, 2H; CH2), 2.38 (s, 3H; CH3), 1.13 (t, J= 7.5 Hz, 6H; CH3 × 2). 13C NMR
(75 MHz, CDCl3) δ = 193.3, 155.7, 147.7, 145.1, 143.5, 136.7, 136.0, 129.6, 129.1, 127.9, 127.3,
125.3, 117.3, 113.5, 113.1, 112.3, 103.3, 101.4, 67.8, 62.9, 55.9, 50.8, 50.0, 21.5, 15.2. MS m/z: 556
(M+, 3), 401 (6), 155 (14), 103 (100). HRMS (EI): calcd for C29H36N2O7S 556.2243; found
556.2258.
4.10.3. N-(2,2-diethoxyethyl)-N-((2-(2-(1-hydroxyprop2-en-1-yl)-5-methylindol-3-yl)carbonyl)prop-
2-en-1-yl)-4-methylbenzenesulfonamide (16c)
1
Yield 56%. IR (ATR) ν = 3324 (OH), 1608 (CO), 1639 (CO), 1338 (SO2), 1157 (SO2) cm–1. H
NMR (300 MHz, CDCl3) δ = 9.53 (br s, 1H; NH), 7.72 (d, J = 8.9 Hz, 2H; ArH), 7.62 (s, 1H; ArH),
7.19–7.24 (m, 3H; ArH), 6.99 (d, J = 8.3 Hz, 1H; ArH), 6.08 (ddd, J = 15.2, 11.0, 4.8 Hz, 1H;
CH=CH2), 5.99 (s, 1H; =CH2), 5.92 (s, 1H; =CH2), 5.60–5.63 (m, 1H; CH), 5.42 (d, J = 15.2 Hz,
1H; CH=CH2), 5.22 (d, J = 11.0 Hz, 1H; CH=CH2), 5.06–5.12 (m, 1H; OH), 4.65 (t, J = 5.3 Hz,
1H; CH), 4.40 (s, 2H; CH2), 3.61–3.71 (m, 2H; OCH2), 3.41–3.50 (m, 2H; OCH2), 3.40 (d, J = 5.3
Hz, 2H; CH2), 2.40 (s, 3H; CH3), 2.34 (s, 3H; CH3), 1.14 (t, J = 6.7 Hz, 6H; CH3 × 2). 13C NMR (75
MHz, CDCl3) δ = 193.2, 147.5, 144.8, 143.4, 136.8, 136.0, 132.6, 131.4, 129.6, 129.5, 127.2, 125.9,
124.6, 120.9, 117.1, 112.5, 111.3, 101.4, 67.8, 62.9, 50.5, 49.7, 21.6, 21.4, 15.2 MS m/z: 540 (M+,
2), 385 (10), 155 (17), 103 (100). HRMS (EI): calcd for C29H36N2O6S 540.2294; found 540.2286.
4.10.4. N-(2,2-diethoxyethyl)-N-((2-(2-(5-chloro-1-hydroxyprop2-en-1-yl)indol-3-yl)carbonyl)prop-
2-en-1-yl)-4-methylbenzenesulfonamide (16d)
1
Yield 60%. IR (ATR) ν = 3345 (OH), 1616 (CO), 1338 (SO2), 1153 (SO2) cm–1. H NMR (300
MHz, CDCl3) δ = 9.17 (br s, 1H; NH), 7.77 (d, J = 2.0 Hz, 1H; ArH), 7.73 (d, J = 8.2 Hz, 2H; ArH),
7.28 (d, J = 8.5 Hz, 1H; ArH), 7.25 (d, J = 8.2 Hz, 2H; ArH), 7.16 (dd, J = 8.5, 2.0 Hz, 1H; ArH),
6.12 (ddd, J = 17.0, 10.5, 5.0 Hz, 1H; CH=CH2), 5.99 (s, 1H; =CH2), 5.91 (s, 1H; =CH2), 5.58–5.66
(m, 1H; CH), 5.52 (d, J = 17.0 Hz, 1H; CH=CH2), 5.34 (d, J = 10.5 Hz, 1H; CH=CH2), 4.65 (t, J =
5.8 Hz, 1H; CH), 4.38 (s, 2H; CH2), 3.63–3.73 (m, 2H; OCH2), 3.45–3.53 (m, 2H; OCH2), 3.39 (d,
18

ACCEPTED MANUSCRIPT
13
J = 5.8 Hz, 2H; CH2), 2.37 (s, 3H; CH3), 1.16 (t, J = 7.5 Hz, 6H; CH3 × 2). C NMR (75 MHz,
CDCl3) δ = 192.6, 148.3, 144.9, 143.5, 136.8, 135.9, 132.7, 129.7, 128.0, 127.8, 127.2, 126.4, 123.6,
120.8, 117.4, 112.6, 101.6, 67.5, 62.9, 62.8, 50.6, 49.7, 21.4, 15.2. MS m/z: 562 (M++2, 1), 560 (M+,
2), 405 (1), 155 (10), 103 (100). HRMS (EI): calcd for C28H33ClN2O6S 560.1748; found 560.1762.
4.10.5. N-(2,2-diethoxyethyl)-N-((2-(2-(5-fluoro-1-hydroxyprop2-en-1-yl)indol-3-yl)carbonyl)prop-
2-en-1-yl)-4-methylbenzenesulfonamide (16e)
1
Yield 66%. IR (ATR) ν = 3733 (OH), 1612 (CO), 1338 (SO2), 1153 (SO2) cm–1. H NMR (300
MHz, CDCl3) δ = 9.89 (br s, 1H; NH), 7.72 (d, J = 8.2 Hz, 2H; ArH), 7.42 (dd, J = 10.3, 2.3 Hz,
1H; ArH), 7.26–7.31 (m, 1H; ArH), 7.26 (d, J = 8.2 Hz, 2H; ArH), 6.95 (dt, J = 8.9, 2.3 Hz, 1H;
ArH), 6.07 (ddd, J = 16.0, 10.8, 5.4 Hz, 1H; CH=CH2), 5.93 (s, 1H; =CH2), 5.86 (s, 1H; =CH2),
5.66–5.68 (m, 1H; CH), 5.40 (d, J = 16.0 Hz, 1H; CH=CH2), 5.19 (d, J = 10.8 Hz, 1H; CH=CH2),
5.06–5.12 (m, 1H; OH), 4.66 (t, J = 5.4 Hz, 1H; CH), 4.40 (s, 2H; CH2), 3.62–3.72 (m, 2H; OCH2),
3.43–3.51 (m, 2H; OCH2), 3.41 (d, J = 5.4 Hz, 2H; CH2), 2.36 (s, 3H; CH3), 1.14 (t, J = 6.3 Hz, 6H;
13
CH3 × 2). C NMR (75 MHz, CDCl3) δ = 192.7, 159.4 (d, JC–F = 239.0 Hz), 148.8, 144.7, 143.6,
136.8, 135.7, 130.7, 129.7, 127.5, 127.2, 126.1, 117.5, 113.1 (d, JC–F = 5.6 Hz), 112.4 (d, JC–F = 10.0
Hz), 111.6 (d, JC–F = 26.2 Hz), 106.7 (d, JC–F = 25.1 Hz), 101.7, 67.6, 63.0, 50.7, 49.7, 21.5, 15.2
MS m/z: 544 (M+, 1), 389 (7), 155 (22), 103 (100). HRMS (EI): calcd for C28H33FN2O6S 544.2043;
found 544.2056.
4.10.6. N-(2,2-diethoxyethyl)-N-((2-(2-(1-hydroxyprop2-en-1-yl)-5-nitroindol-3-yl)carbonyl)prop-
2-en-1-yl)-4-methylbenzenesulfonamide (16f)
Yield 64%. IR (ATR) ν = 3237 (OH), 1619 (CO), 1523 (NO2), 1348 (SO2), 1334 (NO2), 1153
1
(SO2) cm–1. H NMR (300 MHz, CDCl3) δ = 9.68 (br s, 1H; NH), 8.70 (d, J = 1.5 Hz, 1H; ArH),
8.06 (dd, J = 8.5, 1.5 Hz, 1H; ArH), 7.74 (d, J = 8.3 Hz, 2H; ArH), 7.43 (d, J = 8.5 Hz, 1H; ArH),
7.25 (d, J = 8.3 Hz, 2H; ArH), 6.10 (ddd, J = 17.0, 10.3, 5.0 Hz, 1H; CH=CH2), 6.05 (s, 1H; =CH2),
5.88 (s, 1H; =CH2), 5.78–5.81 (m, 1H; CH), 5.52 (d, J = 17.0 Hz, 1H; CH=CH2), 5.32 (d, J = 10.3
Hz, 1H; CH=CH2), 4.65 (t, J = 5.5 Hz, 1H; CH), 4.40 (s, 2H; CH2), 4.25 (br s, 1H; OH), 3.63–3.73
(m, 2H; OCH2), 3.45–3.53 (m, 2H; OCH2), 3.44 (d, J = 5.5 Hz, 2H; CH2), 2.37 (s, 3H; CH3), 1.15 (t,
J = 7.5 Hz, 6H; CH3 × 2). 13C NMR (75 MHz, CDCl3) δ = 192.0, 149.9, 145.4, 143.6, 143.1, 137.3,
136.5, 135.9, 129.7, 127.3, 126.9, 126.4, 118.5, 118.1, 117.4, 113.9, 111.8, 101.6, 67.4, 62.9, 50.5,
49.7, 21.4, 15.2. MS m/z: 571 (M+, 2), 416 (5), 155 (57), 103 (100). HRMS (EI): calcd for
C28H33N3O8S 571.1988; found 571.1982.
4.10.7.
N-(2,2-diethoxyethyl)-N-((2-(2-(1-hydroxyprop2-en-1-yl)-5-trifluoromethylindol-3-yl)
carbonyl)prop-2-en-1-yl)-4-methylbenzenesulfonamide (16g)
19

ACCEPTED MANUSCRIPT
1
Yield 65%. IR (ATR) ν = 3270 (OH), 1651 (CO), 1326 (SO2), 1111 (SO2) cm–1. H NMR (300
MHz, CDCl3) δ = 9.08 (br s, 1H; NH), 8.13 (s, 1H; ArH), 7.71 (d, J = 7.9 Hz, 2H; ArH), 7.45–
7.46 (m 2H; ArH), 7.22 (d, J = 7.9 Hz, 2H; ArH), 6.15 (ddd, J = 17.1, 10.2, 4.8 Hz, 1H; CH=CH2),
6.07 (s, 1H; =CH2), 5.93 (s, 1H; =CH2), 5.75–5.78 (m, 1H; CH), 5.58 (d, J = 17.1 Hz, 1H;
CH=CH2), 5.39 (d, J = 10.2 Hz, 1H; CH=CH2), 4.65 (t, J = 5.5 Hz, 1H; CH), 4.39 (d, J = 4.8 Hz,
2H; CH2), 4.04 (br s, 1H; OH), 3.62–3.72 (m, 2H; OCH2), 3.44–3.52 (m, 2H; OCH2), 3.39 (d, J =
5.5 Hz, 2H; CH2), 2.35 (s, 3H; CH3), 1.15 (t, J = 7.2 Hz, 6H; CH3 × 2). 13C NMR (75 MHz, CDCl3)
δ = 192.0, 147.8, 144.9, 143.0, 136.3, 135.4, 135.2, 129.2, 126.8, 126.3, 126.0, 125.9 (q, JC–F
=
32.2 Hz), 124.6 (q, JC–F = 271.4 Hz), 124.1, 119.6 (q, JC–F = 3.6 Hz), 118.7 (q, JC–F = 3.6 Hz), 117.1,
111.5, 101.2, 66.9, 62.4, 50.1, 49.2, 21.0, 15.2. MS m/z: 594 (M+, 1), 439 (7), 155 (25), 103 (100).
HRMS (EI): calcd for C29H33F3N2O6S 594.2011; found 594.2023.
4.10.8.
N-(2,2-diethoxyethyl)-N-((2-(2-(1-hydroxyprop2-en-1-yl)-6-methoxyindol-3-yl)carbonyl)
prop-2-en-1-yl)-4-methylbenzenesulfonamide (16h)
1
Yield 60%. IR (ATR) ν = 3232 (OH), 1620 (CO), 1338 (SO2), 1157 (SO2) cm–1. H NMR (300
MHz, CDCl3) δ = 8.86 (br s, 1H), 7.66–7.73 (d, J = 8.1 Hz, 2H; ArH), 7.67 (d, J = 8.6 Hz, 1H;
ArH), 7.23–7.26 (m, 2H; ArH), 6.80–6.84 (m, 2H; ArH), 6.13 (ddd, J = 16.9, 10.7, 5.1 Hz, 1H;
CH=CH2), 6.03 (s, 1H; =CH2), 5.96 (s, 1H; =CH2), 5.58-5.62 (m, 1H; CH), 5.54 (d, J = 16.9 Hz,
1H; CH=CH2), 5.35 (d, J = 10.7 Hz, 1H; CH=CH2), 4.64 (t, J = 5.1 Hz, 1H; CH), 4.54–4.57 (m,
1H; OH), 4.36 (s, 2H; CH2), 3.82 (s, 3H; OCH3), 3.64–3.82 (m, 2H; OCH2), 3.43–3.49 (m, 2H;
OCH2), 3.40 (d, J = 5.1 Hz, 2H; CH2), 2.38 (s, 3H CH3), 1.14 (t, J= 7.5 Hz, 6H; CH3 × 2). 13C NMR
(75 MHz, CDCl3) δ = 192.9, 156.6, 146.7, 144.7, 143.4, 136.7, 136.2, 135.3, 129.6, 127.1, 125.8,
121.9, 120.9, 116.7, 112.6, 111.7, 101.5, 94.8, 67.9, 63.0, 55.4, 50.6, 49.6, 21.4, 15.2. MS m/z: 556
(M+, 2), 401 (5), 155 (10), 103 (100). HRMS (EI): calcd for C29H36N2O7S 556.2243; found
556.2248.
4.10.9.
N-(2,2-diethoxyethyl)-N-((2-(2-(1-hydroxyprop2-en-1-yl)-6-methylindol-3-yl)carbonyl)
prop-2-en-1-yl)-4-methylbenzenesulfonamide (16i)
Yield 53%. IR (ATR) ν = 3294 (OH), 1612 (CO), 1338 (SO2), 1157 (SO2) cm–1. 1H NMR (CDCl3)
δ = 8.67 (br s, 1H; NH), 7.73 (d, J = 8.6 Hz, 2H; ArH), 7.68 (d, J = 8.3 Hz, 1H; ArH), 7.25 (d, J =
8.6 Hz, 2H; ArH), 7.15 (s, 1H; ArH), 7.00 (d, J = 8.3 Hz, 1H; ArH), 6.15 (ddd, J = 17.2, 10.4, 5.0
Hz, 1H; CH=CH2), 6.04 (s, 1H; =CH2), 5.97 (s, 1H; =CH2), 5.59–5.61 (m, 1H; CH), 5.56 (d, J =
17.2 Hz, 1H; CH=CH2), 5.39 (d, J = 10.4 Hz, 1H; CH=CH2), 4.65 (t, J = 5.5 Hz, 1H; CH), 4.39–
4.42 (m, 1H; OH), 4.39 (s, 2H; CH2), 3.62–3.70 (m, 2H; OCH2), 3.43–3.52 (m, 2H; OCH2), 3.40 (d,
J = 5.5 Hz, 2H; CH2), 2.44 (s, 3H; CH3), 2.38 (s, 3H; CH3), 1.16 (t, J = 7.2 Hz, 6H; CH3 × 2). 13C
NMR (75 MHz, CDCl3) δ = 193.0, 147.0, 144.8, 143.4, 136.9, 136.1, 134.7, 133.0, 129.6, 127.2,
20

ACCEPTED MANUSCRIPT
126.0, 124.7, 123.7, 121.0, 117.0, 112.8, 111.5, 101.6, 67.8, 63.0, 50.6, 49.6, 21.5, 21.4, 15.2. MS
m/z: 540 (M+, 1), 385 (7), 155 (10), 103 (100). HRMS (EI): calcd for C29H36N2O6S 540.2294; found
540.2286.
4.10.10.
N-(2,2-diethoxyethyl)-N-((2-(2-(6-chloro-1-hydroxyprop-2-en-1-yl)indol-3-yl)carbonyl)
prop-2-en-1-yl)-4-methylbenzenesulfonamide (16j)
Yield 56%. IR (ATR) ν = 3294 (OH), 1612 (CO), 1328 (SO2), 1154 (SO2) cm–1. 1H NMR (300
MHz, CDCl3) δ = 9.75 (br s, 1H; NH), 7.71 (d, J = 8.4 Hz, 2H; ArH), 7.67 (d, J = 8.9 Hz, 1H;
ArH), 7.30 (d, J = 1.9 Hz, 1H; ArH), 7.24 (d, J = 8.4 Hz, 2H; ArH), 7.06 (dd, J = 8.9, 1.9 Hz, 1H;
ArH), 6.08 (ddd, J = 17.2, 10.5, 5.3 Hz, 1H; CH=CH2), 6.01 (s, 1H; =CH2), 5.88 (s, 1H; =CH2),
5.57–5.68 (m, 1H; CH), 5.42 (d, J = 17.2 Hz, 1H; CH=CH2), 5.22 (d, J = 10.5 Hz, 1H; CH=CH2),
4.91–4.95 (m, 1H; OH), 4.62 (t, J = 5.0 Hz, 1H; CH), 4.38 (s, 2H; CH2), 3.61–3.71 (m, 2H; OCH2),
3.42–3.50 (m, 2H; OCH2), 3.39 (d, J= 5.0 Hz, 2H; CH2), 2.37 (s, 3H; CH3), 1.14 (t, J = 7.5 Hz, 6H;
CH3 × 2). 13C NMR (75 MHz, CDCl3) δ = 192.8, 148.2, 144.8, 143.6, 136.6, 136.1, 134.8, 129.6,
128.6, 127.1, 126.1, 125.4, 122.4, 122.1, 116.9, 112.4, 111.6, 101.5, 67.8, 63.0, 50.7, 49.7, 21.4,
15.2. MS m/z: 562 (M++2, 1), 560 (M+, 2), 405 (3), 155 (10), 103 (100). HRMS (EI): calcd for
C28H33ClN2O6S 560.1748; found 560.1753.
4.10.11.
N-(2,2-diethoxyethyl)-N-((2-(2-(6-fluoro-1-hydroxyprop-2-en-1-yl)indol-3-yl)carbonyl)
prop-2-en-1-yl)-4-methylbenzenesulfonamide (16k)
1
Yield 64%. IR (ATR) ν = 3734 (OH), 1620 (CO), 1338 (SO2), 1153 (SO2) cm–1. H NMR (300
MHz, CDCl3) δ = 9.40 (br s, 1H; NH), 7.71–7.74 (m, 3H; ArH), 7.24 (d, J = 8.5 Hz, 2H; ArH),
7.03 (dd, J = 9.0, 2.2 Hz, 1H; ArH), 6.89 (dt, J = 9.0, 2.2 Hz, 1H; ArH), 6.09 (ddd, J = 16.8, 10.7,
5.2 Hz, 1H; CH=CH2), 6.04 (s, 1H; =CH2), 5.91 (s, 1H; =CH2), 5.64–5.66 (m, 1H; CH), 5.47 (d, J =
16.8 Hz, 1H; CH=CH2), 5.27 (d, J = 10.7 Hz, 1H; CH=CH2), 4.71 (br s, 1H; OH), 4.65 (t, J = 5.5
Hz, 1H; CH), 4.39 (s, 2H; CH2), 3.62–3.70 (m, 2H; OCH2), 3.44–3.52 (m, 2H; OCH2), 3.40 (d, J =
5.5 Hz, 2H; CH2), 2.35 (s, 3H; CH3), 1.16 (t, J = 7.2 Hz, 6H; CH3 × 2). 13C NMR (75 MHz, CDCl3)
δ = 192.8, 159.7 (d, JC–F = 243.8 Hz), 148.2, 144.7, 143.5, 136.4, 136.2 (d, JC–F = 4.8 Hz), 134.6 (d,
JC–F = 11.2 Hz), 129.5, 127.0, 125.7, 123.2, 122.0 (d, JC–F = 9.7 Hz), 116.5, 112.1, 110.2 (d, JC–F
=
24.3 Hz), 101.4, 97.9 (d, JC–F = 27.4 Hz), 67.9, 62.9, 50.6, 49.6, 21.2 15.0. MS m/z: 544 (M+, 3),
389 (4), 155 (40), 103 (100). HRMS (EI): calcd for C28H33FN2O6S 544.2043; found 544.2048.
4.10.12.
N-(2,2-diethoxyethyl)-N-((2-(2-(1-hydroxyprop-2-en-1-yl)-6-nitroindol-3-yl)carbonyl)
prop-2-en-1-yl)-4-methylbenzenesulfonamide (16l)
Yield 72%. IR (ATR) ν = 3733 (OH), 1620 (CO), 1523 (NO2), 1348 (SO2), 1334 (NO2), 1153
(SO2) cm–1. 1H NMR (300 MHz, CDCl3) δ = 8.98 (br s, 1H; NH), 7.71–7.74 (m, 3H; ArH), 7.36 (d,
21

ACCEPTED MANUSCRIPT
J = 1.8 Hz, 1H; ArH), 7.25 (d, J = 8.2 Hz, 2H; ArH), 7.13 (dd, J = 8.6, 1.8Hz, 1H; ArH), 6.12 (ddd,
J = 16.5, 10.3, 5.1 Hz, 1H; CH=CH2), 6.06 (s, 1H; =CH2), 5.94 (s, 1H; =CH2), 5.64–5.66 (m, 1H;
CH), 5.55 (d, J = 16.5 Hz, 1H; CH=CH2), 5.37 (d, J = 10.3 Hz, 1H; CH=CH2), 4.63 (t, J = 5.3 Hz,
1H; CH), 4.37 (s, 2H; CH2), 4.26 (br s, 1H; OH), 3.62–3.69 (m, 2H; OCH2), 3.44–3.49 (m, 2H;
13
OCH2), 3.38 (d, J = 5.3 Hz, 2H; CH2), 2.39 (s, 3H; CH3), 1.15 (t, J = 6.9 Hz, 6H; CH3 × 2). C
NMR (75 MHz, CDCl3) δ = 192.1, 149.8, 145.3, 143.6, 143.1, 137.3, 136.5, 135.9, 129.7, 127.3,
126.9, 126.4, 118.5, 118.1, 117.4, 113.9, 111.8, 101.5, 67.4, 62.9, 50.5, 49.7, 21.4, 15.2. MS m/z:
571 (M+, 1), 416 (1), 155 (30), 103 (100). HRMS (EI): calcd for C28H33N3O8S 571.1988; found
571.1998.
4.10.13.
N-(2,2-diethoxyethyl)-N-((2-(2-(1-hydroxyprop2-en-1-yl)-6-trifluoromethylindol-3-yl)
carbonyl)prop-2-en-1-yl)-4-methylbenzenesulfonamide (16m)
1
Yield 53%. IR (ATR) ν = 3116 (OH), 1635 (CO), 1331 (SO2), 1115 (SO2) cm–1. H NMR (300
MHz, CDCl3) δ = 9.60 (br s, 1H; NH), 7.85 (d, J = 8.5 Hz, 1H; ArH), 7.72 (d, J = 8.3 Hz, 2H;
ArH), 7.64 (s, 1H; ArH), 7.36 (d, J = 8.5 Hz, 1H; ArH), 7.25 (d, J = 8.3 Hz, 2H; ArH), 6.11 (ddd, J
= 17.0, 10.4, 4.8 Hz, 1H; CH=CH2), 6.07 (s, 1H; =CH2), 5.91 (s, 1H; =CH2), 5.57–5.73 (m, 1H;
CH), 5.49 (d, J = 17.0 Hz, 1H; CH=CH2), 5.30 (d, J = 10.4 Hz, 1H; CH=CH2), 4.63 (t, J = 5.2 Hz,
1H; CH), 4.58 (br s, 1H; OH), 4.39 (s, 2H; CH2), 3.62–3.72 (m, 2H; OCH2), 3.43–3.51 (m, 2H;
13
OCH2), 3.40 (d, J = 5.2 Hz, 2H, CH2), 2.38 (s, 3H; CH3), 1.15 (t, J = 7.2 Hz, 6H; CH3 × 2). C
NMR (75 MHz, CDCl3) δ = 192.7, 149.5, 145.0, 143.6, 136.6, 135.8, 133.2, 129.7, 129.2, 127.2,
126.7, 125.1 (q, JC–F = 32.9 Hz), 124.4 (q, JC–F = 272.5 Hz), 121.8, 118.5 (q, JC–F = 5.0 Hz), 117.4,
112.8, 109.1 (q, JC–F = 5.0 Hz), 101.6, 67.6, 63.1, 50.8, 49.7, 21.5, 15.2. MS m/z: 594 (M+, 1), 439
(5), 155 (32), 103 (100). HRMS (EI): calcd for C29H33F3N2O6S 594.2011; found 594.2032.
4.11. Synthesis of Carbazole-1,4-quinones (17a–17m)
Carbazole-1,4-quinones 17a–17m were prepared according to a synthetic method for 13.
4.11.1. N-(2,2-diethoxyethyl)-N-(6,7-dimethoxyl-1,4-dioxocarbazol-3-ylmethyl)-4-
methylbenzenesulfonamide (17a)
Yield 65%. mp 210–212 °C (EtOAc-hexane). IR (ATR) ν = 3263 (NH), 1627 (CO), 1601 (CO),
1
1350 (SO2), 1161 (SO2) cm–1. H NMR (300 MHz, CDCl3) δ = 10.05 (br s, 1H; NH), 7.72 (d, J =
8.2 Hz, 2H; ArH), 7.46 (s, 1H; ArH), 7.28 (d, J = 8.2 Hz, 2H; ArH), 6.93 (s, 1H; ArH), 6.66 (t, J =
1.8 Hz, 1H; ArH), 4.61 (t, J = 5.5 Hz, 1H; CH), 4.39 (d, J =1.8 Hz 2H; CH2), 3.98 (s, 3H; OCH3),
3.97 (s, 3H; OCH3), 3.60–3.71 (m, 2H; OCH2), 3.43–3.51 (m, 2H; OCH2), 3.36 (d, J = 5.5 Hz, 2H;
CH2), 2.38 (s, 3H; CH3), 1.13 (t, J = 7.2 Hz, 6H; CH3 × 2). 13C NMR (75 MHz, CDCl3) δ = 183.1,
178.9, 155.1, 149.1, 145.7, 143.8, 136.2, 133.5, 133.0, 132.1, 129.8, 127.3, 117.9, 117.1, 101.9,
22

ACCEPTED MANUSCRIPT
101.8, 94.6, 63.1, 56.2, 56.1, 52.1, 48.3, 21.4, 15.2. MS m/z: 556 (M+, 3), 270 (10), 155 (40), 103
(100). HRMS (EI): calcd for C28H32N2O8S 556.1879; found 556.1887.
4.11.2. N-(2,2-diethoxyethyl)-N-(6-methoxy-1,4-dioxocarbazol-3-ylmethyl)-4-
methylbenzenesulfonamide (17b)
Yield 64%. mp 186–188 °C (EtOAc-hexane). IR (ATR) ν = 3244 (NH), 1635 (CO), 1608 (CO),
1342 (SO2), 1165 (SO2) cm–1. 1H NMR (300 MHz, CDCl3) δ = 9.54 (br s, 1H; NH), 7.73 (d, J = 8.5
Hz, 2H; ArH), 7.54 (d, J = 2.0 Hz, 1H; ArH), 7.41 (d, J = 8.2 Hz, 1H; ArH), 7.29 (d, J = 8.5 Hz,
2H; ArH), 7.05 (dd, J = 8.2, 2.0 Hz, 1H; ArH), 6.67 (t, J = 2.0 Hz, 1H; ArH), 4.62 (t, J = 5.5 Hz,
1H; CH), 4.42 (d, J = 2.0 Hz, 2H; CH2), 3.89 (s, 3H; OCH3), 3.61–3.71 (m, 2H; OCH2), 3.43–3.51
(m, 2H; OCH2), 3.35 (d, J = 5.5 Hz, 2H; CH2), 2.37 (s, 3H; CH3), 1.14 (t, J = 7.2 Hz, 6H; CH3 × 2).
13C NMR (75 MHz, CDCl3) δ = 182.8, 179.6, 157.7, 146.6, 143.8, 136.3, 135.2, 132.3, 131.6, 129.8,
127.3, 125.1, 119.0, 116.5, 114.0, 102.3, 102.0, 63.2, 55.7, 52.2, 48.4, 21.4, 15.2. MS m/z: 526 (M+,
1), 240 (7), 155 (19), 103 (100). HRMS (EI): calcd for C27H30N2O7S 526.1774; found 526.1782.
4.11.3. N-(2,2-diethoxyethyl)-N-(6-methyl-1,4-dioxocarbazol-3-ylmethyl)-4-
methylbenzenesulfonamide (17c)
Yield 61%. mp 151–153 °C (EtOAc-hexane). IR (ATR) ν = 3217 (NH), 1651 (CO), 1647 (CO),
1
1338 (SO2), 1161 (SO2) cm–1. H NMR (300 MHz, CDCl3) δ = 9.92 (br s, 1H; NH), 7.92 (s, 1H;
ArH), 7.74 (d, J = 8.1 Hz, 2H; ArH), 7.44 (d, J = 8.4 Hz, 1H; ArH), 7.29 (d, J = 8.1 Hz, 2H; ArH),
7.23 (d, J = 8.4 Hz, 1H; ArH), 6.69 (t, J = 1.8 Hz, 1H; ArH), 4.62 (t, J = 5.4 Hz, 1H; CH), 4.42 (d, J
= 1.8 Hz, 2H; CH2), 3.61–3.71 (m, 2H; OCH2), 3.41–3.51 (m, 2H; OCH2), 3.37 (d, J = 5.4 Hz, 2H;
CH2), 2.48 (s, 3H, CH3), 2.36 (s, 3H; CH3), 1.14 (t, J = 7.2 Hz, 6H; CH3 × 2). 13C NMR (75 MHz,
CDCl3) δ = 182.8, 180.0, 146.7, 143.8, 136.2, 135.7, 135.1, 134.4, 131.5, 129.8, 129.1, 127.3, 124.3,
122.1, 116.3, 122.8, 101.9, 101.8, 63.1, 52.2, 48.5, 21.4, 15.3. MS m/z: 510 (M+, 6), 224 (5), 155
(10), 103 (100). HRMS (EI): calcd for C27H30N2O6S 510.1825; found 510.1849.
4.11.4. N-(2,2-diethoxyethyl)-N-(6-chloro-1,4-dioxocarbazol-3-ylmethyl)-4-
methylbenzenesulfonamide (17d)
Yield 58%. mp 183–184 °C (EtOAc-hexane). IR (ATR) ν = 3286 (NH), 1662 (CO), 1648 (CO),
1338 (SO2), 1157 (SO2) cm–1. 1H NMR (300 MHz, CDCl3) δ = 9.72 (br s, 1H; NH), 8.14 (d, J = 1.8
Hz, 1H; ArH), 7.74 (d, J = 8.3 Hz, 2H; ArH), 7.46 (d, J = 8.9 Hz, 1H; ArH), 7.37 (dd, J = 8.9, 1.8
Hz, 1H; ArH), 7.30 (d, J = 8.3 Hz, 2H; ArH), 6.76 (t, J = 2.0 Hz, 1H; ArH), 4.60 (t, J = 5.6 Hz, 1H;
CH), 4.41 (d, J = 2.0 Hz, 2H; CH2), 3.61–3.71 (m, 2H; OCH2), 3.40–3.50 (m, 2H; OCH2), 3.35 (d, J
= 5.6 Hz, 2H; CH2), 2.39 (s, 3H, CH3), 1.13 (t, J = 7.7 Hz, 6H; CH3 × 2). 13C NMR (75 MHz,
CDCl3) δ = 182.3, 179.8, 147.1, 143.9, 136.1, 136.0, 135.4, 131.6, 130.4, 129.9, 127.8, 127.3, 124.8,
23

ACCEPTED MANUSCRIPT
122.2, 116.2, 114.2, 101.8, 63.1, 52.2, 48.5, 21.5, 15.2. MS m/z: 532 (M++2, 1), 530 (M+, 4), 244
(9), 155 (23), 103 (100). HRMS (EI): calcd for C26H27ClN2O6S 530.1278; found 530.1296.
4.11.5. N-(2,2-diethoxyethyl)-N-(6-fluoro-1,4-dioxocarbazol-3-ylmethyl)-4-
methylbenzenesulfonamide (17e)
Yield 62%. mp 199–200 °C (EtOAc-hexane). IR (ATR) ν = 3236 (NH), 1639 (CO), 1628 (CO),
1338 (SO2), 1157 (SO2) cm–1. H NMR (300 MHz, CDCl3) δ = 9.35 (br s, 1H; NH), 7.81 (dd, J = 8.8,
2.5 Hz, 1H; ArH), 7.73 (d, J = 8.5 Hz, 2H; ArH), 7.47 (dd, J = 9.1, 4.3 Hz, 1H; ArH), 7.30 (d, J =
8.5 Hz, 2H; ArH), 7.18 (dt, J = 9.1, 2.5 Hz, 1H; ArH), 6.75 (t, J = 2.1 Hz, 1H; ArH), 4.60 (t, J = 5.0
Hz, 1H; CH), 4.41 (d, J = 2.1 Hz, 2H; CH2), 3.61–3.70 (m, 2H; OCH2), 3.40–3.50 (m, 2H; OCH2),
3.34 (d, J = 5.0 Hz, 2H; CH2), 2.38 (s, 3H; CH3), 1.13 (t, J = 7.1 Hz, 6H; CH3 × 2). 13C NMR (75
MHz, CDCl3) δ = 182.4, 179.6, 158.8, 147.0, 143.9, 136.4, 136.2, 133.5, 131.5, 129.9, 127.3, 124.6
(d, JC–F = 11.1 Hz), 116.3 (d, JC–F = 27.7 Hz), 114.1 (d, JC–F = 10.1 Hz), 107.7 (d, JC–F = 26.5 Hz),
101.9, 63.2, 52.3, 48.5, 21.5, 15.2. MS m/z: 514 (M+, 3), 228 (6), 155 (14), 103 (100). HRMS (EI):
calcd for C26H27FN2O6S 514.1574; found 514.1566.
4.11.6. N-(2,2-diethoxyethyl)-N-(6-nitro-1,4-dioxocarbazol-3-ylmethyl)-4-
methylbenzenesulfonamide (17f)
Yield 66%. mp 113–115 °C (EtOAc-hexane). IR (ATR) ν = 3236 (NH), 1643 (CO), 1624 (CO),
1543 (NO2), 1342 (SO2), 1323 (NO2), 1157 (SO2) cm–1. 1H NMR (300 MHz, CDCl3) δ = 10.47 (br
s, 1H, NH), 9.00 (d, J = 1.5 Hz, 1H; ArH), 8.29 (dd, J = 8.4, 1.5 Hz, 1H; ArH), 7.79 (d, J = 8.8 Hz,
2H; ArH), 7.67 (d, J = 8.4 Hz, 1H; ArH), 7.36 (d, J = 8.8 Hz, 2H; ArH), 6.88 (t, J = 2.0 Hz, 1H;
ArH), 4.61 (t, J = 5.4 Hz, 1H; CH), 4.41 (d, J = 2.0 Hz, 2H; CH2), 3.61–3.71 (m, 2H; OCH2), 3.40–
3.48 (m, 2H; OCH2), 3.36 (d, J = 5.4 Hz, 2H; CH2), 2.43 (s, 3H, CH3), 1.12 (t, J = 7.5 Hz, 6H, CH3
× 2). 13C NMR (75 MHz, CDCl3) δ =181.9, 179.6, 147.4, 144.9, 144.2, 139.6, 137.8, 135.7, 131.6,
130.0, 127.3, 123.1, 122.1, 119.6, 117.9, 113.7, 101.6, 63.1, 52.2, 48.4, 21.5, 15.2. MS m/z: 541
(M+, 2), 255 (9), 155 (56), 103 (100). HRMS (EI): calcd for C26H27N3O8S 541.1519; found
541.1531.
4.11.7. N-(2,2-diethoxyethyl)-N-(1,4-dioxo-6-trifluoromethylcarbazol-3-ylmethyl)-
4-methylbenzenesulfonamide (17g)
Yield 61%. mp 102–104 °C (EtOAc-hexane). IR (ATR) ν = 3251 (NH), 1666 (CO), 1643 (CO),
1
1346 (SO2), 1119 (SO2) cm–1. H NMR (300 MHz, CDCl3) δ = 9.74 (br s, 1H; NH), 8.48 (s, 1H;
ArH), 7.74 (d, J = 8.3 Hz, 2H; ArH), 7.56–7.68 (m, 2H; ArH), 7.31 (d, J = 8.3 Hz, 2H; ArH), 6.81
(t, J = 2.0 Hz, 1H; ArH), 4.61 (t, J = 5.4 Hz, 1H; CH), 4.42 (d, J = 2.0 Hz, 2H; CH2), 3.61–3.71 (m,
2H; OCH2), 3.40–3.51 (m, 2H; OCH2), 3.35 (d, J = 5.4 Hz, 2H; CH2), 2.39 (s, 3H; CH3), 1.13 (t, J =
24

ACCEPTED MANUSCRIPT
13
7.2 Hz, 6H; CH3 × 2). C NMR (75 MHz, CDCl3) δ = 182.4, 179.7, 147.1, 144.0, 138.1, 136.6,
135.9, 131.6, 129.9, 127.3, 128.6 (q, JC–F = 31.1 Hz), 126.9, 126.2, 124.6 (q, JC–F = 276.2 Hz), 123.8
(q, JC–F = 3.1 Hz), 123.2, 120.8 (q, JC–F = 4.6 Hz), 117.1, 63.1, 52.3, 48.5, 21.5, 15.2 MS m/z: 564
(M+, 7), 278 (13), 155 (44), 103 (100). HRMS (EI): calcd for C27H27F3N2O6S 564.1542; found
564.1536.
4.11.8. N-(2,2-diethoxyethyl)-N-(7-methoxy-1,4-dioxocarbazol-3-ylmethyl)-4-
methylbenzenesulfonamide (17h)
Yield 60%. mp 101–103 °C (EtOAc-hexane). IR (ATR) ν = 3232 (NH), 1639 (CO), 1624 (CO),
1346 (SO2), 1157 (SO2) cm–1. 1H NMR (300 MHz, CDCl3) δ = 9.18 (br s, 1H; NH), 8.02 (d, J = 8.5
Hz, 1H; ArH), 7.72 (d, J = 8.5 Hz, 2H; ArH), 7.28 (d, J = 8.5 Hz, 2H; ArH), 6.99 (dd, J = 8.5, 2.0
Hz, 1H; ArH), 6.87 (d, J = 2.0 Hz, 1H; ArH), 6.64 (t, J = 2.0 Hz, 1H; ArH), 4.61 (t, J = 5.5 Hz, 1H;
CH), 4.39 (d, J = 2.0 Hz, 2H; CH2), 3.89 (s, 3H; OCH3), 3.61–3.71 (m, 2H; OCH2), 3.41–3.51 (m,
2H; OCH2), 3.34 (d, J = 5.5 Hz, 2H; CH2), 2.37 (s, 3H; CH3), 1.13 (t, J = 6.8 Hz, 6H; CH3 × 2). 13C
NMR (75 MHz, CDCl3) δ = 183.0, 179.3, 160.0, 145.9, 143.8, 138.7, 136.2, 134.4, 131.6, 129.8,
127.3, 123.5, 118.3, 117.3, 115.8, 101.9, 94.5, 63.1, 55.6, 52.2, 48.4, 21.4, 15.2. MS m/z: 526 (M+,
3), 240 (6), 155 (20), 103 (100). HRMS (EI): calcd for C27H30N2O7S 526.1774; found 526.1778.
4.11.9. N-(2,2-diethoxyethyl)-N-(7-methyl-1,4-dioxocarbazol-3-ylmethyl)-4-
methylbenzenesulfonamide (17i)
Yield 53%. mp 107–108 °C (EtOAc-hexane). IR (ATR) ν = 3228 (NH), 1647 (CO), 1631 (CO),
1338 (SO2), 1161 (SO2) cm–1. 1H NMR (300 MHz, CDCl3) δ = 9.40 (br s, 1H; NH), 8.02 (d, J = 8.7
Hz, 1H; ArH), 7.72 (d, J = 8.1 Hz, 2H; ArH), 7.26–7.30 (m, 3H; ArH), 7.17 (dd, J = 8.7, 1.2 Hz,
1H; ArH), 6.68 (t, J = 1.9 Hz, 1H; ArH), 4.61 (t, J = 5.2 Hz, 1H; CH), 4.41 (d, J = 2.0 Hz, 2H; CH2),
3.61–3.71 (m, 2H; OCH2), 3.41–3.48 (m, 2H; CH2), 3.35 (d, J = 5.2 Hz. 2H; CH2), 2.50 (s, 3H;
CH3), 2.36 (s, 3H; CH3), 1.13 (t, J = 7.0 Hz, 6H; CH3 × 2). 13C NMR (75 MHz, CDCl3) δ = 182.8,
179.9, 146.4, 143.8, 137.8, 136.2, 134.8, 131.5, 129.8, 127.4, 127.3, 126.5, 122.3, 121.9, 116.9,
112.7, 101.9, 63.1, 52.2, 48.4, 22.0, 21.4, 15.2. MS m/z: 510 (M+, 3), 224 (2), 155 (17), 103 (100).
HRMS (EI): calcd for C27H30N2O6S 510.1825; found 510.1833.
4.11.10. N-(2,2-diethoxyethyl)-N-(7-chloro-1,4-dioxocarbazol-3-ylmethyl)-4-
methylbenzenesulfonamide (17j)
Yield 52%. mp 139–140 °C (EtOAc-hexane). IR (ATR) ν = 3290 (NH), 1647 (CO), 1620 (CO),
1338 (SO2), 1157 (SO2) cm–1. 1H NMR (300 MHz, CDCl3) δ = 9.74 (br s, 1H; NH), 8.06 (d, J = 8.9
Hz, 1H; ArH), 7.74 (d, J = 8.2 Hz, 2H; ArH), 7.55 (s, 1H; ArH), 7.27–7.33 (m, 3H; ArH), 6.75 (t, J
= 1.9 Hz, 1H; ArH), 4.62 (t, J = 5.8 Hz, 1H; CH), 4.41 (d, J = 1.9 Hz, 2H; CH2), 3.62–3.72 (m, 2H;
25

ACCEPTED MANUSCRIPT
OCH2), 3.41–3.51 (m, 2H; OCH2), 3.35 (d, J = 5.8 Hz, 2H; CH2), 2.39 (s, 3H; CH3), 1.14 (t, J = 7.7
Hz, 6H; CH3 × 2). 13C NMR (75 MHz, CDCl3) δ = 182.5, 179.8, 146.8, 144.0, 137.6, 136.0, 135.6,
133.2, 131.5, 129.9, 127.4, 125.3, 1238, 122.4, 116.7, 113.0, 101.7, 63.2, 52.2, 48.5, 21.5, 15.2. MS
m/z: 532 (M++2, 2), 530 (M+, 4), 244 (3), 155 (10), 103 (100). HRMS (EI): calcd for
C26H27ClN2O6S 530.1278; found 530.1263.
4.11.11. N-(2,2-diethoxyethyl)-N-(7-fluoro-1,4-dioxocarbazol-3-ylmethyl)-4-
methylbenzenesulfonamide (17k)
Yield 60%. mp 130–131 °C (EtOAc-hexane). IR (ATR) ν = 3236 (NH), 1639 (CO), 1628 (CO),
1338 (SO2), 1157 (SO2) cm–1. H NMR (300 MHz, CDCl3) δ = 9.91 (br s, 1H; NH), 8.07–8.11 (m,
1H; ArH), 7.74 (d, J = 7.6 Hz, 2H; ArH), 7.31 (d, J = 7.6 Hz, 2H; ArH), 7.21–7.23 (m, 1H; ArH),
7.11 (t, J = 8.8 Hz, 1H; ArH), 6.72 (t, J = 1.8 Hz, 1H; ArH), 4.62 (t, J = 4.9 Hz, 1H; CH), 4.41 (d, J
= 1.8 Hz, 2H; CH2), 3.62–3.71 (m, 2H; OCH2), 3.43–3.51 (m, 2H; OCH2), 3.34 (d, J = 5.0 Hz, 2H;
CH2), 2.38 (s, 3H; CH3), 1.13 (t, J = 7.1 Hz, 6H; CH3 × 2). 13C NMR (75 MHz, CDCl3) δ = 182.6,
179.7, 162.1 (d, JC–F = 246.0 Hz), 146.6, 143.9, 137.8 (d, JC–F = 12.6 Hz), 136.0, 135.6 (d, JC–F
=
2.8 Hz), 131.4, 129.9, 127.3, 124.0 (d, JC–F = 9.7 Hz), 120.4, 116.8, 113.8 (d, JC–F = 25.9 Hz), 101.8,
99.4 (d, JC–F = 26.0 Hz), 63.2, 52.2, 48.4, 21.4, 15.2. MS m/z: 514 (M+, 2), 228 (8), 155 (22), 103
(100). HRMS (EI): calcd for C26H27FN2O6S 514.1574; found 514.1568.
4.11.12. N-(2,2-diethoxyethyl)-N-(7-nitro-1,4-dioxocarbazol-3-ylmethyl)-4-
methylbenzenesulfonamide (17l)
Yield 72%. mp 168–171 °C (EtOAc-hexane). IR (ATR) ν = 3236 (NH), 1643 (CO), 1624 (CO),
1543 (NO2), 1346 (SO2), 1335 (NO2), 1161 (SO2) cm–1. 1H NMR (300 MHz, CDCl3) δ = 9.44 (br s,
1H; NH), 8.12 (dd, J = 8.7, 5.3 Hz, 1H; ArH), 7.72 (d, J = 8.2 Hz, 2H; ArH), 7.28 (d, J = 8.2 Hz,
2H; ArH), 7.08–7.19 (m, 2H; ArH), 6.70 (t, J = 1.8 Hz, 1H; ArH), 4.61 (t, J = 5.1 Hz, 1H; CH),
4.41 (d, J = 1.8 Hz;, 2H; CH2), 3.61–3.69 (m, 2H; OCH2), 3.43–3.51 (m, 2H; OCH2), 3.34 (d, J =
5.1 Hz, 2H; CH2), 2.38 (s, 3H; CH3), 1.13 (t, J = 7.3 Hz, 6H; CH3 × 2). 13C NMR (75 MHz, CDCl3)
δ = 182.5, 179.8, 146.8, 144.0, 137.6, 136.0, 135.6, 133.2, 131.5, 129.9, 127.4, 125.3, 123.8, 122.4,
116.7, 113.0, 101.7, 63.2, 52.2, 48.4, 21.5, 15.2. MS m/z: 541 (M+, 5), 255 (8), 155 (36), 103 (100).
HRMS (EI): calcd for C26H27N3O8S 541.1519; found 541.1526.
4.11.13. N-(2,2-diethoxyethyl)-N-(1,4-dioxo-7-trifluoromethylcarbazol-3-ylmethyl)-
4-methylbenzenesulfonamide (17m)
Yield 53%. mp 108–109 °C (EtOAc-hexane). IR (ATR) ν = 3255 (NH), 1666 (CO), 1647 (CO),
1335 (SO2), 1153 (SO2) cm–1. 1H NMR (300 MHz, CDCl3) δ = 9.85 (br s, 1H; NH), 8.28 (d, J = 9.0
Hz, 1H; ArH), 7.82 (s, 1H; ArH), 7.75 (d, J = 8.3 Hz, 2H; ArH), 7.57 (d, J = 9.0 Hz, 1H; ArH), 7.31
26

ACCEPTED MANUSCRIPT
(d, J = 8.3 Hz, 2H; ArH), 6.81 (t, J = 2.0 Hz, 1H; ArH), 4.61 (t, J = 5.4 Hz, 1H; CH), 4.42 (d, J =
2.0 Hz, 2H; CH2), 3.61–3.71 (m, 2H; OCH2), 3.41–3.49 (m, 2H; OCH2), 3.34 (d, J = 5.4 Hz, 2H;
CH2), 2.39 (s, 3H; CH3), 1.13 (t, J = 6.9 Hz, 6H; CH3 × 2). 13C NMR (75 MHz, CDCl3) δ = 182.4,
179.7, 147.3, 144.0, 137.1, 136.0, 135.9, 131.6, 129.9, 128.5 (q, JC–F = 31.8 Hz), 127.3, 126.0,
123.6 (q, JC–F = 274.8 Hz), 120.8, 120.7 (q, JC–F = 3.7 Hz), 116.0, 110.3 (q, JC–F = 3.9 Hz), 101.4,
62.7, 51.9, 48.1, 21.0, 13.7. MS m/z: 564 (M+, 3), 278 (2), 155 (17), 103 (100). HRMS (EI): calcd
for C27H27F3N2O6S 564.1542; found 564.1548.
4.12. Synthesis of Ellipticine quinones (18a–18m)
Ellipticine quinones 18a–18m were prepared according to a synthetic method for 2.
4.12.1. 8,9-dimethoxyellipticine quinone (18a)
Yield 65%. mp 310–312 °C (EtOAc-hexane). IR (ATR) ν = 3097 (NH), 1666 (CO), 1650 (CO) cm–
1. 1H NMR (300 MHz, DMSO-d6) δ = 13.05 (br s, 1H; NH), 9.21 (s, 1H; ArH), 9.04 (d, J = 4.7 Hz,
1H; ArH), 7.90 (d, J = 4.7 Hz, 1H; ArH), 7.54 (s, 1H; ArH), 6.96 (s, 1H; ArH), 3.88 (s, 3H; OCH3),
13
3.87 (s, 3H; OCH3). C NMR (75 MHz, DMSO-d6) δ = 180.1, 176.5, 157.3, 155.1, 147.4, 138.6,
136.7, 133.9, 126.7, 124.7, 122.9, 119.1, 118.4, 115.2, 102.1, 55.5 (× 2). MS m/z: 308 (M+, 100),
247 (52). HRMS (EI): calcd for C17H12N2O4 308.0797; found 308.0788.
4.12.2. 9-methoxyellipticine quinone (18b)
Yield 71%. mp 323–325 °C (EtOAc-hexane). IR (ATR) ν = 3012 (NH), 1666 (CO), 1631 (CO) cm–
1. 1H NMR (300 MHz, DMSO-d6) δ = 13.17 (br s, 1H; NH), 9.23 (s, 1H; ArH), 9.04 (d, J = 5.0 Hz,
1H; ArH), 7.91 (d, J = 5.0 Hz, 1H; ArH), 7.59 (d, J = 2.6 Hz, 1H; ArH), 7.51 (d, J = 8.6 Hz, 1H;
ArH), 7.11 (dd, J = 8.6, 2.6 Hz, 1H; ArH), 3.85 (s, 3H; OCH3). 13C NMR (75 MHz, DMSO-d6) δ =
180.1, 176.4, 157.2, 155.0, 147.4, 138.6, 136.7, 133.9, 126.6, 125.4, 124.7, 119.1, 118.4, 115.2,
102.1, 55.4. MS m/z: 278 (M+, 100), 263 (57), 247 (66). HRMS (EI): calcd for C16H10N2O3
278.0691; found 278.0672.
4.12.3. 9-methylellipticine quinone (18c)
Yield 65%. mp 317–319 °C (EtOAc-hexane). IR (ATR) ν = 3059 (NH), 1666 (CO), 1651 (CO) cm–
1. 1H NMR (300 MHz, DMSO-d6) δ = 13.10 (br s, 1H; NH), 9.21 (s, 1H; ArH), 9.04 (d, J = 4.8 Hz,
1H; ArH), 7.95 (s, 1H; ArH), 7.89 (d, J = 4.8 Hz, 1H; ArH), 7.46 (d, J = 8.9 Hz, 1H; ArH), 7.27 (d,
13
J = 8.9 Hz, 1H; ArH), 2.44 (s, 3H; CH3). C NMR (75 MHz, DMSO-d6) δ = 180.3, 176.8, 155.1,
147.4, 138.5, 137.1, 136.9, 133.9, 129.5, 126.6, 124.1, 121.7, 118.4, 117.0, 113.7, 21.4. MS m/z:
262 (M+, 100). HRMS (EI): calcd for C16H10N2O2 262.0742; found 262.0751.
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ACCEPTED MANUSCRIPT
4.12.4. 9-chloroellipticine quinone (18d)
Yield 63%. mp 325–328 °C (EtOAc-hexane). IR (ATR) ν = 3081 (NH), 1651 (CO), 1639 (CO) cm–
1. 1H NMR (300 MHz, DMSO-d6) δ = 13.40 (br s, 1H; NH), 9.23 (s, 1H; ArH), 9.06 (d, J=4.8 Hz,
1H; ArH), 8.11 (d, J=2.0 Hz, 1H; ArH), 7.92 (d, J=4.8 Hz, 1H; ArH), 7.60 (d, J=8.9 Hz, 1H; ArH),
7.47 (dd, J=8.9, 2.0 Hz, 1H; ArH). 13C NMR (75 MHz, DMSO-d6) δ = 180.0, 176.8, 155.2, 147.4,
138.3, 137.9, 136.8, 128.9, 127.6, 126.3, 124.5, 121.2, 118.4, 116.7, 115.8. MS m/z: 284 (M++2, 33),
282 (M+, 100), 247 (5). HRMS (EI): calcd for C15H7ClN2O2 282.0196; found 282.0183.
4.12.5. 9-fluoroellipticine quinone (18e)
1
Yield 80%. mp 320–323 °C (EtOAc). IR (ATR) ν = 3033 (NH), 1670 (CO), 1651 (CO) cm–1. H
NMR (300 MHz, DMSO-d6) δ = 13.39 (br s, 1H; NH), 9.22 (s, 1H; ArH), 9.05 (d, J = 4.7 Hz, 1H;
ArH), 8.10 (d, J = 2.0 Hz, 1H; ArH), 7.90 (d, J = 4.7 Hz, 1H; ArH), 7.58 (d, J = 9.0 Hz, 1H; ArH),
13
7.47 (dd, J = 9.0, 2.0 Hz). C NMR (75 MHz, DMSO-d6) δ = 180.5, 176.7, 160.4, 155.5, 147.6,
139.3, 138.6, 138.0, 126.6, 124.9, 124.6 (d, JC–F =10.4 Hz), 120.7, 118.7 (d, JC–F = 25.4 Hz), 113.9
(d, JC–F = 20.8 Hz), 99.9 (d, JC–F = 25.3 Hz). MS m/z: 266 (M+, 100), 247 (10). HRMS (EI): calcd
for C15H7FN2O2 266.0492; found 266.0486.
4.12.6. 9-nitroellipticine quinone (18f)
1
Yield 62%. mp 322–325 °C (EtOAc). IR (ATR) ν = 3077 (NH), 1656 (CO), 1648 (CO) cm–1. H
NMR (300 MHz, DMSO-d6) δ = 13.41 (br s, 1H; NH), 9.24 (s, 1H; ArH), 9.08 (d, J = 4.5 Hz, 1H;
ArH), 8.12 (d, J = 1.9 Hz, 1H; ArH), 7.93 (d, J = 4.5 Hz, 1H; ArH), 7.59 (d, J = 8.8 Hz, 1H; ArH),
13
7.47 (dd, J = 8.8, 1.9 Hz). C NMR (75 MHz, DMSO-d6) δ = 180.0, 176.8, 155.2, 147.4, 138.3,
137.9, 136.8, 128.8, 127.6, 126.3, 124.4, 121.2, 118.4, 116.7, 115.7. MS m/z: 293 (M+, 100), 247
(4). HRMS (EI): calcd for C15H7N3O4 293.0437; found 293.0449.
4.12.7. 9-trifluoromethylellipticine quinone (18g)
Yield 72%. mp 310–313 °C (EtOAc-hexane). IR (ATR) ν = 3051 (NH), 1674 (CO), 1651 (CO) cm–
1. H NMR (300 MHz, DMSO-d6) δ = 13.63 (br s, 1H; NH), 9.28 (s, 1H; ArH), 9.10 (d, J = 4.9 Hz,
1H; ArH), 8.48 (s, 1H; ArH), 7.96 (d, J = 5.2 Hz, 1H; ArH), 7.76-7.83 (m, 2H; ArH). 13C NMR (75
MHz, DMSO-d6) δ = 180.2, 177.0, 155.4, 147.4, 139.7, 138.8, 138.3, 126.3, 125.0 (q, JC–F = 31.9
Hz), 124.8 (q, JC–F = 271.4 Hz), 123.5 (q, JC–F = 3.9 Hz), 122.8, 119.7 (q, JC–F = 3.9 Hz), 118.5,
117.7, 115.2. MS m/z: 316 (M+, 100), 247 (23). HRMS (EI): calcd for C16H7F3N2O2 316.0460;
found 316.0472.
4.12.8. 8-methoxyellipticine quinone (18h)
28