Concise synthesis of carbazole-1,4-quinones and evaluation of their antiproliferative activity against HCT-116 and HL-60 cells

Article abstract of DOI:10.1016/j.ejmech.2016.05.065

We report a convenient synthesis of carbazole-1,4-quinone alkaloid koeniginequinones A and B using a tandem ring-closing metathesis with the dehydrogenation reaction sequence under an O₂ atmosphere as an important step. Using this method, carbazole-1,4-quinones substituted at the 5-, 6-, 7-, and/or 8-positions have been synthesized. Moreover, 24 compounds, including koeniginequinones A and B, have been evaluated for their antiproliferative activity against HCT-116 and HL-60 cells, and the 6-nitro analog exhibited the most potent activity against both tumor cell types.

Full text of DOI:10.1016/j.ejmech.2016.05.065

Accepted Manuscript
Concise synthesis of carbazole-1,4-quinones and evaluation of their antiproliferative
activity against HCT-116 and HL-60 cells
Takashi Nishiyama, Noriyuki Hatae, Teruki Yoshimura, Sawa Takaki, Takumi Abe,
Minoru Ishikura, Satoshi Hibino, Tominari Choshi
PII:
S0223-5234(16)30473-1
10.1016/j.ejmech.2016.05.065
EJMECH 8657
DOI:
Reference:
To appear in: European Journal of Medicinal Chemistry
Received Date: 25 March 2016
Revised Date: 28 May 2016
Accepted Date: 30 May 2016
Please cite this article as: T. Nishiyama, N. Hatae, T. Yoshimura, S. Takaki, T. Abe, M. Ishikura, S.
Hibino, T. Choshi, Concise synthesis of carbazole-1,4-quinones and evaluation of their antiproliferative
activity against HCT-116 and HL-60 cells, European Journal of Medicinal Chemistry (2016), doi:
10.1016/j.ejmech.2016.05.065.
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ACCEPTED MANUSCRIPT
Graphical Abstract

ACCEPTED MANUSCRIPT
Concise Synthesis of Carbazole-1,4-quinones and Evaluation of Their Antiproliferative
Activity against HCT-116 and HL-60 Cells
a
b
b
a
b
Takashi Nishiyama , Noriyuki Hatae *, Teruki Yoshimura , Sawa Takaki , Takumi Abe , Minoru
b
a
a
Ishikura , Satoshi Hibino , and Tominari Choshi *
a
Graduate School of Pharmacy Pharmaceutical Sciences, Faculty of Pharmacy and
Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292, Japan
b
Faculty 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, koeniginequinone A, koeniginequinone B, antiproliferative
activity
Abstract: We report a convenient synthesis of carbazole-1,4-quinone alkaloid koeniginequinones A
and B using a tandem ring-closing metathesis with the dehydrogenation reaction sequence under an
O atmosphere as an important step. Using this method, carbazole-1,4-quinones substituted at the 5-,
2
6-, 7-, and/or 8-positions have been synthesized. Moreover, 24 compounds, including
koeniginequinones A and B, have been evaluated for their antiproliferative activity against HCT-116
and HL-60 cells, and the 6-nitro analog exhibited the most potent activity against both tumor cell
types.
1. Introduction
The carbazole-1,4-quinone alkaloid koeniginequinones A (1a) and B (1b) were isolated from
Murraya koenigii by Chowdhury et al. (Figure 1) who also reported the first total synthesis of these
compounds [1]. This was accomplished via Fremy’s salt oxidation of 1-hydroxycarbazoles, which
were obtained from 1-oxotetrahydrocarbazoles. Note that koeniginequinone A (1a) has been also
synthesized by construction of quinone moiety via either direct oxidation of
1-oxotetrahydrocarbazole with DDQ, which was reported by Kapil ’s group et al. [2a], and/or CAN,

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which was reported by Saha’s group et al. [2b], respectively. Recently, the McErlean’s group et al.
described the total synthesis of 1a using an in-water oxidation with an on-water conjugate addition
process, followed by palladium-mediated ring closure [2c]. Furthermore, the Knölker’s group et al.
achieved the total synthesis of both 1a and 1b based on using a palladium(II)-catalyzed oxidative
C–C bond formation of arylamino-1,4-benzoquinones [3]. We recently reported a one-pot synthesis
of the carbazole-1,4-quinone framework using a cyclocarbonylation reaction, followed by
desilylation and oxidation reactions [4] and completed the total synthesis of koeniginequinones A
(1a) and B (1b) from N-BOM-3-iodoindole-2-carbaldehyde 2 in four steps (Scheme 1) [5].
R1
R2
R1
R2
Me
I
I
a
CHO
N
N
OR3
BOM
BOM
3a,b : R =H
3
2
a,b
b
3
1
2
4a,b : R =TBS
a: R =H, R =OMe
1
2
b: R =R =OMe
O
O
R1
R2
Me
R1
R2
Me
c
d
N
N
O
H
O
BOM
5a,b
1a,b
Scheme 1. Synthesis of koeniginequinones A and B using
one-pot cyclocarbonylation. Reagents and conditions: (a)
propenylmagnesium bromide, THF, 0 °C; (b) TBSCl, iPr NEt,
2
CH Cl ; (c) tributyl(vinyl)tin, CO (1 atm), BHT, PdCl (dppf), DMF,
2
2
2
7
0 °C; (d) Na, liq.NH , −78 °C .
3
The quinone ring system is an important core in many drugs such as mitomycin and doxorubicin,
which are used clinically in cancer therapy [6]. Among the quinone-containing therapeutic agents,
the carbazolequinone alkaloids exhibit cardiotonic [7], antitumor [8], neuronal cell-protecting [9],
and antimalarial activities [10], in addition to other biological activities. Therefore, currently, these
compounds are the focus of intensive research. The biological activities of both synthetic and
natural carbazolequinones have been examined by numerous research groups.
We have been interested in the unique structure and pharmacological action of carbazolequinone
alkaloids and have achieved the total synthesis of several carbazolequinones (murrayaquinone A
[
11], carbazomycin G [12], carquinostatin A [13], carbazoquinocins [14], carbazomadurins [15],
and calothrixins [16]) using an allene-mediated electrocyclic reaction of the 6π-electron system as
our original method. Moreover, we have been searching for highly active compounds that are based
on these naturally occurring compounds and their derivatives [17]. Recently, we developed an
efficient synthetic method for the carbazole-1,4-quinone framework using a tandem ring-closing

ACCEPTED MANUSCRIPT
metathesis (RCM) and dehydrogenation reaction sequence and achieved the total synthesis of
murrayaquinone A [18, 11c].
Herein, we describe a facile total synthesis of koeniginequinones A (1a) and B (1b) by constructing
a carbazole-1,4-quinone core using a tandem RCM and dehydrogenation reaction sequence, starting
from the appropriate 3-acryloyl-2-propenylindoles. In addition, we report the synthesis of
carbazole-1,4-quinones substituted at the 5-, 6-, 7-, and/or 8-positions using this method. The
antiproliferative activity of these synthetic compounds, and several natural products, against
HCT-116 colon tumor cells and HL-60 promyelocytic leukemia cells were evaluated using the MTT
and WST-1 assays, respectively.
2. Results and Discussion
2.1. Chemistry
Our retrosynthetic strategy for synthesizing carbazole-1,4-quinones is illustrated in Scheme 2. In
our previous study [11c], the construction of carbazole-1,4-quinone from
-acryloyl-2-propenylindole 6 was accomplished using tandem RCM and dehydroxylation
1
3
reactions; furthermore, the indoles
6
could be derived from the appropriate
3-iodoindole-3-carbaldehydes 7.
To synthesize the carbazole-1,4-quinone alkaloid koeniginequinones A and B, we prepared two
N-BOM-3-iodoindole-2-carbaldehydes as starting materials [5]. Based on the sequence in Scheme 3,
a three-component Pd-catalyzed cross-coupling reaction [19] of the 3-iodoindoles 2a,b with
tributyl(isopropenyl)tin under a CO (1 atm) atmosphere was executed in DMF at 70 °C to afford
3-acryloylindoles 8a,b in 84% and 91% yields, respectively. Subsequently, the Grignard reaction of
the 3-acryloylindoles 8a,b with vinylmagnesium bromide resulted in the 2-allyl alcohols 9a,b in
39% and 30% yields, respectively. Subsequent treatment of the 2-allyl alcohols 9a,b with the
nd
Grubbs 2 generation catalyst in toluene at 70 °C under an O atmosphere afforded the desired
2

ACCEPTED MANUSCRIPT
N-BOM-koeniginequinones A (5a) and B (5b) in 82% and 60% yields, respectively. Note that the
deprotection of the BOM group of 5a,b has previously been reported using Birch reduction [5].
Thus, completing the formal synthesis of koeneginequinones A and B was possible; however,
improving the yield of the allyl alcohols 9a,b that were formed via the Grignard reaction was not
possible because of the steric hindrance of the BOM and 3-acryloyl groups.
O Me
R1
R2
R1
R2
I
a
CHO
CHO
N
N
R3
R3
3
3
2
2
7
7
a: R =BOM
8a: R =BOM (84%)
3
3
b: R =BOM
8b: R =BOM (91%)
10a: R =H (74%)
10b: R =H (78%)
3
3
a: R =H
1
2
a: R =H, R =OMe
3
3
b: R =H
1
2
b: R =R =OMe
O Me
O
R1
R2
R1
R2
Me
b
c
N
R3
N
R3
OH
O
3
3
9
9
6
6
a: R =BOM (39%)
b: R =BOM (30%)
a: R =H (85%)
b: R =H (63%)
5a: R =BOM (82%)
5b: R =BOM (60%)
1a: R =H (67%)
1b: R =H (79%)
3
3
3
3
3
3
Scheme 3. Synthesis of koeniginequinones A (1a) and B (1b).
Reagents and conditions: (a) tributyl(isopropenyl)tin, CO (1 atm),
BHT, PdCl (dppf), DMF, 70 °C; (b) vinylmagnesium bromide, THF,
2
2nd
0
°C; (c) Grubbs , under O , toluene, 70 °C.
2
Next, we attempted the total synthesis of koeniginequinones from 3-iodoindole-2-carbaldehydes
7a,b, which do not possess the BOM protecting group. As shown in Scheme 3, treating the
3-iodoindole-2-carbaldehydes 7a,b with tributyl(isopropenyl)tin and a Pd-catalyst under a CO (1
atm) atmosphere afforded the 3-acryloylindoles 10a,b in 74% and 78% yields, respectively.
Subsequently, the Grignard reaction of 10a,b with vinylmagnesium bromide afforded the 2-allyl
alcohols 6a,b in 85% and 63% yields, respectively. Finally, treating the 2-allyl alcohols 6a,b with
nd
Grubbs 2 generation catalyst in toluene at 70 °C under an O atmosphere afforded the
2
koeniginequinones A (1a) and B (1b) in 67% and 79% yields, respectively. Therefore, we
completed the total synthesis of koeniginequinones A and B from 3-iodoindole-2-carbaldehydes in
three steps and in 42% and 39% overall yields, respectively. The spectroscopic data of our synthetic
koeniginequinones A and B were identical to those of naturally occurring materials [1].
Based on the above results, we then attempted to synthesize new carbazole-1,4-quinones that
possess several substitutions on the benzene ring to prepare compounds, which display high
antiproliferative activity.

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As shown in Scheme 4 and Table 1, the indole-2-carboxylates 11 were purchased as commercial
reagents and/or synthesized according to reported procedures [20]. The reduction of the esters 11
with LiAlH afforded the alcohols 12 in 50%–99% yields. Subsequent oxidation of 12 with
4
activated MnO afforded the indole-2-carbaldehydes 13 in 28%–99% yields. Subsequently, the
2
treatment of the aldehydes 13 with I and KOH afforded the 3-iodoindoles 14 in 40%–87% yields.
2
We then prepared the important substrates 16 for synthesizing the carbazole-1,4-quinones (Scheme
5
and Table 2). The three-component Pd-catalyzed cross-coupling reaction of the 3-iodoindoles 14
with alkenyl tributyltin under a CO (1 atm) atmosphere was performed in DMF at 70 °C to provide
the 3-acryloylindoles 15 in 23%–90% yields. Subsequently, the Grignard reaction of the
3
-acryloylindoles 15 with vinylmagnesium bromide afforded the desired 2-allyl alcohols 16 in
6%–90% yields. Finally, we synthesized the carbazole-1,4-quinones 1, 17, and 18 in 53%–93%
3
yields using a tandem RCM and dehydrogenation reaction sequence from the alcohols 6 and 16
1
13
(
Table 3). The structures of the carbazole-1,4-quinones were supported by H and C NMR spectra
as well as the mass spectra.

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Table 1. Yields of indole derivatives 12, 13, and 14.
1
1
12
13
14
No.
R
Yield (%) Yield (%) Yield (%)
a
b
c
5-MeO
72
68
70
71
54
76
96
80
50
71
65
87
83
76
77
81
99
70
44
60
81
40
63
90
76
79
98
62
98
78
84
99
28
67
63
40
51
83
62
72
86
80
74
56
48
85
56
54
87
61
85
4,5-diMeO
4,7-diMeO
4,6-diMeO
5,7-diMeO
5-Me
d
e
f
g
h
i
6-Me
5-Cl
6-Cl
j
5-NO
2
2
k
l
5-NO
5-CF
6-CF
5-F
3
m
n
o
p
q
3
6-F
4,5-fused benzene
5,6-fused benzene

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Table 2. Synthesis of 3-acryloylindoles 15 and 2-allylindoles 16
1
5
16
1
2
No.
R
R
Time (h) Yield (%) Time (h) Yield (%)
a
b
c
5-MeO
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
6
61
70
75
83
90
79
65
75
62
55
70
67
75
75
71
60
84
64
23
1
1
1
1
2
2
2
1
1
2
2
2
2
1
1
1
1
1
1
70
56
79
53
37
43
44
74
70
50
43
44
40
60
57
52
67
90
36
4,5-diMeO
4,7-diMeO
4,6-diMeO
5,7-diMeO
5-Me
13
13
13
13
7
d
e
f
g
h
i
6-Me
7
5-Cl
7
6-Cl
7
j
5-NO
2
2
13
13
13
13
13
13
13
13
13
1
k
l
5-NO
5-CF
6-CF
5-F
3
m
n
o
p
q
r
3
6-F
4,5-fused benzene
5,6-fused benzene
H
H
s

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2.2. Antiproliferative studies
The results of the antiproliferative studies are shown in Table 3. The IC50 values for the
antiproliferative activity of murrayaquinone A (17a) against HCT-116 and HL-60 cells were found
to be 3.716 and 3.022 µM (Entry 1 in Table 3), respectively, which was in good agreement with the
findings of a previous report [8b]. Koeniginequinone A (1a) has been reported to display moderate
antiproliferative activity against KB, SK-MEL-5, Colo-205, and HCT-8 tumor cells [8b]; however,
the IC values reported against these tumor cells were quite different when compared with our
5
0
findings of 0.992 and 1.751
M for HCT-116 and HL-60 cells, respectively (Entry 7 in Table 3).
This discrepancy could be the result of differences in the tumor cell types. Koeniginequinone B
(1b) was shown to be active against both tumor cell types, but its potency was diminished compared
with that of koeniginequinone A (1a). The reduction potential of chemical has been reviewed to
correlate with bioactive properties as a consequence of facile electron acceptance from biological
donors [21]. In contrast to this review, some of carbazole-1,4-quinone analogs like as N-MOM
calothrixin B and N-MOM ellipticine quinones, which are more easily reduced compared to the
corresponding N–H compounds, showed no direct correlation between their reduction potentials
and antiproliferative activity [8c]. Moreover, our studies of N-MOM murrayaquinone A 17b and
N-MOM carbazole-1,4-quinone 17d indicated that there could be no correlation between the
reduction potential and antiproliferative activity of a compound because of their decreased activity
compared with murrayaquinone A (17a) and carbazole-1,4-quinone (17c).
Based on the differences in the activity between koeniginequinone A (1a) and murrayaquinone A
(17a), we hypothesized that the substituents on the phenyl ring in carbazole-1,4-quinone might lead
to changes in the biological activities of the compounds. The monoMeO derivatives 1a and 18a
exhibited greater activity against both tumor cells than the diMeO derivatives 1b and 18b–e, with
the exception of the 5,8-diMeO derivative 18c against HL-60 cells. Furthermore, the sterically
hindered phenyl-fused derivatives 18p,q displayed weak activity against both tumor cell types.
These findings suggested that the mono-substituted derivatives might display higher
antiproliferative activity than the corresponding di-substituted derivatives. Therefore, the
mono-substituted derivatives 18f–o were synthesized and their antiproliferative activity was
assessed. The derivatives 1a, 18a, and 18f,g, which possessed MeO and Me groups as electron
donating groups (EDGs), exhibited increased activity against HCT-116 tumor cells compared to
unsubstituted 17a; however, only the MeO derivative 1a demonstrated better activity against HL-60
cells than compound 17a. Of the derivatives that contained EDGs, the 7-substituted derivatives 1a
and 18g exhibited more potent activity than the corresponding 6-substituted derivatives 18a and 18f.
However, with the exception of the 7-substituted derivative 18m, the derivatives 18j–l that
possessed NO and CF groups as electron withdrawing groups (EWGs) exhibited good activity
2
3
against both HCT-116 and HL-60 tumor cells. Note that the 6-NO derivative 18j demonstrated the
2

ACCEPTED MANUSCRIPT
most potent activity of all of the tested compounds. Of the derivatives that contained EWGs, the
6-substituted derivatives 18j and 18l were better than the corresponding 7-substituted derivatives
18k and 18m.
The halogenated derivatives 18h,i and 18n,o demonstrated increased activity against HCT-116
tumor cells compared to unsubstituted 17a. In contrast, the derivatives 18i (7-Cl) and 18n (6-F)
exhibited decreased activity against HL-60 cells compared to 17a.
Based on the antiproliferative activity data for all of the tested carbazole-1,4-quinones, several
generalizations may be made about the activity of these compounds against HCT-116 tumor cells.
Except in the case of the 7-CF derivative 18m, mono-substitution resulted in increased activity
3
against HCT-116 cells compared to un- or di-substituted analogs; however, there was no direct
correlation between the type of substituent and the biological activity. In addition, some preliminary
correlations between the substitution position and the antiproliferative activity against HCT-116
cells were observed; these can be summarized as follows: substitution at the C7-position resulted in
higher antiproliferative activity than substitution at C6-position among derivatives possessing single
EDG or halogen substituents. However, among derivatives bearing single EWGs, substitution at the
C6-position resulted in higher antiproliferative activity than substitution at C7-position. To better
understand the effect of the substitution position, EHOMO values were calculated for each
mono-substituent compound (see Supplementary data). With the aid of
B97X-D/6-31G(d)
calculations in Spartan 14 [22], the compounds that exhibited higher antiproliferative activity
against HCT-116 cells were found to have higher EHOMO values than those compounds that exhibit
low activity.

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Table 3. Synthesis of poly-substituted carbazole-1,4-quinones by tandem RCM reaction and
evaluation of antiproliferative activity against HCT-116 and HL-60 cells
Compd.
No.
Time Compd. Yield
IC (µM)
50
1
2
3
4
Entry
R
R
R
R
(min)
−
No.
(%) HCT-116 HL-60
1
2
3
4
5
6
7
8
9
16r
Me
Me
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
17a
70
−
3.716
6.494
0.763
1.311
>10
3.022
3.919
1.001
1.384
>10
a)
H
MOM
H
−
17b
16s
H
−
17c
53
−
a)
H
H
MOM
MOM
H
−
17d
17e
b)
H
H
−
−
16a
6a
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
6-MeO
7-MeO
6,7-diMeO
5,6-diMeO
5,8-diMeO
5,7-diMeO
6,8-diMeO
6-Me
60
30
30
10
30
30
30
30
30
30
30
30
30
30
30
30
30
20
18a
1a
80
67
79
82
78
78
92
93
80
74
70
67
72
74
77
78
72
60
1.597
0.992
4.094
>10
3.414
1.751
8.946
>10
H
6b
H
1b
16b
16c
16d
16e
16f
16g
16h
16i
H
18b
18c
18d
18e
18f
18g
18h
18i
1
0
1
H
1.842
>10
2.274
7.259
3.818
>10
1
H
12
13
14
15
16
17
18
19
20
21
22
23
H
3.602
2.033
1.005
2.208
0.895
0.569
1.370
0.921
>10
H
7-Me
H
6.928
1.283
>10
6-Cl
H
7-Cl
H
16j
16k
16l
6-NO2
7-NO2
6-CF3
H
18j
18k
18l
1.026
1.579
1.131
6.018
4.401
1.466
>10
H
H
16m
16n
16o
16p
7-CF3
H
18m
18n
18o
18p
6-F
H
2.701
1.000
>10
7-F
H
5,6-fused
benzene
6,7-fused
benzene
Camptothecin
H
2
4
16q
Me
H
H
20
18q
72
>10
5.269
0.159
0.019
a) 17b,d synthesized by the other method in ref.11c. b) 17e synthesized by the other method in
ref.4
.

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3. Conclusion
In summary, we achieved the total synthesis of the carbazole-1,4-quinone alkaloid
koeniginequinones A (1a) and B (1b) in three steps using our previously reported tandem RCM and
dehydrogenation reactions. Furthermore, 24 carbazole-1,4-quinones substituted at the 5-, 6-, 7-,
and/or 8-positions have been synthesized using this method. 24 compounds, including naturally
occurring compounds, have been evaluated for their antiproliferative activity against HCT-116 and
HL-60 cells. The mono-substituted derivatives were found to possess good antiproliferative activity
against both tumor cell types, and the 6-nitro derivative 18j exhibited IC values about 1.7-fold
50
higher against both HCT-116 and HL-60 cells compared with koeniginequinone A (1a). This is the
first report describing the development of synthetic carbazole-1,4-quinone derivatives that display
more potent antiproliferative activity than the corresponding naturally occurring alkaloids. Thus, the
findings of the present study suggest that the carbazole-1,4-quinone structure is an important
potential candidate for use in antitumor medicinal chemistry. The method reported here provides an
efficient synthesis of carbazole-1,4-quinones from 3-iodoindole-2-carbaldehydes using readily
available starting materials. Extension of this method to the synthesis of other biologically
interesting heterocyclic compounds is currently being investigated.
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.
1
Proton nuclear magnetic resonance ( H NMR) spectra were recorded on a JEOL AL-300 at 300
MHz. Chemical shifts are reported relative to Me Si (δ 0.00). Multiplicity is indicated by one or
4
more of the following: s (singlet); d (doublet); t (triplet); q (quartet); m (multiplet); br (broad).
1
3
Carbon nuclear magnetic resonance ( C NMR) spectra were recorded on a JEOL AL-300 at 75
MHz. Chemical shifts are reported relative to CDCl (δ 77.0) and DMSO-d (δ 39.7). Infrared
3
6
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.
4.2.1. N-(Benzyloxymethyl)-6-methoxy-3-(2-methylpropenoyl)indole-2-carbaldehyde (8a)
Carbon monoxide was bubbled for 5 min to a mixture of the iodoindole 2a (200 mg, 514 mmol),

ACCEPTED MANUSCRIPT
isopropenyltributyltin (315 mg, 617 mmol), BHT (210 mg, 617 mmol), and PdCl (dppf) (777 mg,
2
26 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 Na SO , and evaporated in vacuo. The residue was purified by
2
4
column chromatography using EtOAc-hexane (2:8, v/v) as an eluent to give the 3-acryloylindole 8a
–
1 1
(
330 mg, 84%). mp 66–67 ºC (EtOAc-hexane). IR (ATR) ν = 1662 (CO), 1616 (CO) cm . H NMR
(
300 MHz, CDCl ) δ = 9.94 (s, 1H; CHO), 7.63 (d, J = 9.6 Hz, 1H; ArH), 7.26–7.27 (m, 5H; ArH),
3
6
2
1
7
.90–6.93 (m, 2H; ArH), 6.15 (s, 2H; N-CH -O), 6.05 (s, 1H; =CH ), 5.79 (s, 1H; =CH ), 4.59 (s,
2 2 2
1
3
H; O-CH ), 3.87 (s, 3H; OCH ), 2.15 (s, 3H; CH ). C NMR (75 MHz, CDCl ) δ = 193.3, 182.7,
2
3
3
3
60.5, 147.0, 140.4, 137.3, 133.7, 129.9, 128.4, 128.4, 127.9, 127.7, 123.8, 120.2, 115.1, 93.0, 73.8,
+
0.6, 55.7, 17.7. MS m/z: 363 (M ). HRMS (EI): calcd for C H NO 363.1471; found 363.1452.
2
2
21
4
4.2.2. N-(Benzyloxymethyl)-5,6-dimethoxy-3-(2-methylpropenoyl)indole-2-carbaldehyde (8b)
3-Acryloylindole 8b was prepared according to a synthetic method for 8a.
–
1 1
Yield 91%. mp 75–76 ºC (EtOAc-hexane). IR (ATR) ν = 1658 (CO), 1619 (CO) cm . H NMR
300 MHz, CDCl ) δ = 9.92 (s, 1H; CHO), 7.22–7.32 (m, 5H; ArH), 7.14 (s, 1H; ArH), 6.93 (s, 1H;
(
3
ArH), 6.15 (s, 2H; N-CH -O), 6.04 (s, 1H; =CH ), 5.79 (s, 1H; =CH ), 4.56 (s, 2H; OCH ), 3.95 (s,
2
2
2
2
1
3
3
1
7
3
H; OCH ), 3.91 (s, 3H; OCH ), 2.16 (s, 3H; CH ). C NMR (75 MHz, CDCl ) δ = 193.5, 182.2,
3 3 3 3
51.9, 147.9, 147.4, 137.2, 134.7, 133.2, 129.6, 128.4, 127.9, 127.7, 127.4, 119.3, 102.1, 93.0, 74.0,
+
0.5, 56.3, 56.2, 17.7. MS m/z: 393 (M ). HRMS (EI): calcd for C H NO 393.1576; found
2
3
23
5
93.1597.
4.2.3. N-(Benzyloxymethyl)-2-(1-hydroxyprop-2-en-1-yl)-6-methoxy-3-(2-methylpropenoyl)indole
(9a)
A solution of vinylmagnesium bromide (1 M in THF, 0.35 mL, 0.35 mmol) was added dropwise to
a solution of 3-acryloylindole 8a (90 mg, 0.23 mmol) in THF (20 mL) under cooling with ice-water.
After stirring at rt for 4 h, the reaction mixture was quenched with aqueous NH Cl solution
4
(saturated), and then was extracted with EtOAc. The organic layer was washed with brine, dried
over Na SO , and evaporated in vacuo. The residue was purified by column chromatography using
2
4
EtOAc-hexane (1:9, v/v) as an eluent to give the allyl alcohol 9a (32 mg, 39%) as yellow oil. IR
–
1 1
(
ATR) ν = 3260 (OH), 1620 (CO) cm . H NMR (300 MHz, CDCl ) δ = 7.63 (d, J = 8.9 Hz, 1H;
3
ArH), 7.32–7.36 (m, 5H; ArH), 6.85 (dd, J = 8.9, 2.2 Hz, 1H; ArH), 6.81 (d, J = 2.2 Hz, 1H; ArH),
.12 (ddd, J =17.2, 10.6, 3.6 Hz, 1H; CH=CH ), 5.79 (s, 1H; =CH ), 5.71 (s, 1H; =CH ), 5.56–5.67
6
2
2
2
(
m, 4H; N-CH -O, CHOH), 5.28 (d, J = 17.2 Hz, 1H; CH=CH ), 5.13 (d, J = 10.6 Hz, 1H;
2
2

ACCEPTED MANUSCRIPT
CH=CH ), 4.56 (d, J = 11.7 Hz, 1H; OCH ), 4.50 (d, J = 11.7 Hz, 1H; OCH ), 3.81 (s, 3H; OCH ),
2
2
2
3
1
3
2
.12 (s, 3H; CH ). C NMR (75 MHz, CDCl ) δ = 191.1, 157.1, 146.6, 146.2, 137.5, 137.4, 136.6,
3 3
128.6, 128.2, 127.9, 125.0, 122.1, 120.7, 115.2, 114.9, 112.0, 93.8, 72.1, 70.0, 67.0, 55.6, 18.3. MS
+
m/z: 391 (M ). HRMS (EI): calcd for C H NO 391.1784; found 391.1796.
2
4
25
4
4.2.4.
N-(Benzyloxymethyl)-2-(1-hydroxyprop-2-en-1-yl)-5,6-dimethoxy-3-(2-methylpropenoyl)indole (9b)
Allyl alcohol 9b was prepared according to a synthetic method for 9a.
–
1 1
Yield 30%. IR (ATR) ν = 3262 (OH), 1633 (CO) cm . H NMR (300 MHz, CDCl ) δ = 7.29–7.39
3
(m, 5H; ArH), 7.24 (s, 1H; ArH), 6.77 (s, 1H; ArH), 6.10 (ddd, J = 17.2, 10.3, 4.1 Hz, 1H;
CH=CH ), 5.53–5.81 (m, 6H; =CH , N-CH -O, CHOH), 5.28 (d, J = 17.0 Hz, 1H; CH=CH ), 6.14
2
2
2
2
(
d, J = 10.3 Hz, 1H; CH=CH ), 4.55 (d, J = 12.4 Hz, 1H; OCH ), 4.47 (d, J = 12.4 Hz, 1H; OCH ),
2 2 2
1
3
3
1
1
4
.89 (s, 3H; OCH ), 3.86 (s, 3H; OCH ), 2.14 (s, 3H; CH ). C NMR (75 MHz, CDCl ) δ = 184.5,
3 3 3 3
80.1, 151.1, 149.4, 146.2, 137.0, 134.5, 133.4, 132.1, 128.4, 128.0, 127.9, 127.8, 118.2, 117.5,
+
02.3, 93.7, 73.8, 70.8, 56.3, 56.2 15.5. MS m/z: 421 (M ). HRMS (EI): calcd for C H NO
2
5
27
5
21.1889; found 421.1877.
4.2.5. N-(Benzyloxymethyl)-6-methoxy-3-methylcarbazole-1,4-quinone (5a)
2
nd
A suspension of the allyl alcohol 9a (53 mg, 0.15 mmol) and Grubbs catalyst (13 mg, 0.015 mml)
in toluene (20 mL) was heated at 70 ºC for 5 min under an O atmosphere. After cooling to an
2
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 N-BOM-koeniginequinone
5a (40 mg, 82%) as red solid. mp 117–118 ºC (EtOAc-hexane). IR (ATR) ν = 1639 (CO), 1624
–
1 1
(
CO) cm . H NMR (300 MHz, CDCl ) δ = 8.13 (d, J = 8.8 Hz, 1H; ArH), 7.20–7.28 (m, 5H; ArH),
3
7.02 (dd, J = 8.8, 2.2 Hz, 1H; ArH), 6.96 (d, J = 2.2 Hz, 1H; ArH), 6.42 (q, J = 1.6 Hz, 1H; ArH),
13
6
.11 (s, 2H; N-CH -O), 4.57 (s, 2H; OCH ), 3.87 (s, 3H; OCH ), 2.13 (d, J = 1.6 Hz, 3H; CH ). C
2
2
3
3
NMR (75 MHz, CDCl ) δ = 184.3, 180.6, 160.1, 146.4, 140.6, 137.1, 133.0, 132.9, 128.4, 127.9,
3
+
1
27.7, 123.9, 118.6, 118.0, 116.1, 93.8, 73.6, 70.8, 55.7, 15.5. MS m/z: 361 (M ). HRMS (EI): calcd
for C H NO 361.1314; found 361.1299.
2
2
19
4
4
.2.6. N-(Benzyloxymethyl)-6,7-dimethoxy-3-methylcarbazole-1,4-quinone (5b)
Carbazole-14,-quinone 5b was prepared according to a synthetic method for 5a.
Yield 60%. mp 143–145 ºC (EtOAc-hexane). IR (ATR) ν = 1635 (CO), 1612 (CO) cm . H NMR
300 MHz, CDCl ) δ = 7.64 (s, 1H; ArH), 7.20–7.30 (m, 5H; ArH), 6.95 (s, 1H; ArH), 6.42 (q, J =
–
1 1
(
3
1
.6 Hz, 1H; ArH), 6.12 (s, 2H; N-CH -O), 4.55 (s, 2H; OCH ), 4.00 (s, 3H; OCH ), 3.94 (s, 3H;
2 2 3
13
OCH ), 2.13 (d, J = 1.6 Hz, 3H; CH ). C NMR (75 MHz, CDCl ) δ = 184.5, 180.1, 151.1, 149.4,
3
3
3

ACCEPTED MANUSCRIPT
1
5
46.2, 137.0, 134.5, 133.4, 132.1, 128.4, 128.0, 127.9, 127.8, 118.2, 117.5, 102.3, 93.7, 73.8, 70.8,
+
6.3, 15.5. MS m/z: 391 (M ). HRMS (EI): calcd for C H NO 391.1420; found 391.1446.
2
3
21
5
4.2.7. 6-Methoxy-3-(2-methylpropenoyl)indole-2-carbaldehyde (10a)
3-Acryloylindole 10a was prepared according to a synthetic method for 8a
–
1 1
Yield 74%. mp 126–128 ºC (EtOAc-hexane). IR (ATR) ν = 3273 (NH), 1620 (CO) cm . H NMR
(
300 MHz, CDCl ) δ = 9.99 (s, 1H; CHO), 9.43 (br s, 1H; NH), 7.78 (d, J = 9.2 Hz, 1H; ArH), 6.91
3
(
dd, J = 9.2, 2.3 Hz, 1H; ArH), 6.85 (d, J = 2.3 Hz, 1H; ArH), 6.03 (s, 1H; =CH ), 5.85 (s, 1H;
2
1
3
=
CH ), 3.89 (s, 3H; OCH ), 2.17 (s, 3H; CH ). C NMR (75 MHz, CDCl ) δ = 192.8, 182.3, 160.3,
2 3 3 3
+
1
47.1, 137.5, 135.3, 128.6, 124.3, 123.5, 121.1, 114.8, 93.4, 55.6, 18.0. MS m/z: 243 (M ). HRMS
(
EI): calcd for C H NO 243.0895; found 243.0907.
1
4
13
3
4.2.8. 5,6-Dimethoxy-3-(2-methylpropenoyl)indole-2-carbaldehyde (10b)
3-Acryloylindole 10b was prepared according to a synthetic method for 8a.
–
1 1
Yield 78%. mp 182–183 ºC (EtOAc-hexane). IR (ATR) ν = 3297 (NH), 1620 (CO) cm . H NMR
300 MHz, CDCl ) δ = 9.96 (s, 1H; CHO), 9.64 (br s, 1H; NH), 7.32 (s, 1H; ArH), 6.88 (s, 1H;
(
3
ArH), 6.01 (s, 1H; =CH ), 5.85 (s, 1H; =CH ), 3.97 (s, 3H; OCH ), 3.93 (s, 3H; OCH ), 2.19 (s, 3H;
2
2
3
3
13
CH ). C NMR (75 MHz, CDCl ) δ = 192.9, 181.6, 151.8, 147.9, 147.8, 134.8, 131.9, 128.1, 122.6,
3
3
+
1
20.4, 102.6, 93.4, 56.2, 18.2. MS m/z: 273 (M ). HRMS (EI): calcd for C H NO 273.1001;
15 15 4
found 273.1011.
4.2.9. 2-(1-Hydroxyprop-2-en-1-yl)-6-methoxy-3-(2-methylpropenoyl)indole (6a)
3-Acryloyl-2-allylindole 6a was prepared according to a synthetic method for 9a.
–
1 1
Yield 85%. IR (ATR) ν = 3494 (OH), 1624 (CO) cm . H NMR (300 MHz, CDCl ) δ = 9.38 (br s,
3
1H; NH), 7.66 (d, J = 9.5 Hz, 1H; ArH), 6.79–6.82 (m, 2H; ArH), 6.12 (ddd, J = 17.3, 10.3, 5.3 Hz,
1
H; CH=CH ), 5.75 (s, 1H; =CH ), 5.69 (s, 1H; =CH ), 5.48–5.69 (m, 1H, CH), 5.45 (d, J = 17.3
2
2
2
13
Hz, 1H; CH=CH ), 5.27 (m, 2H; OH, CH=CH ), 3.79 (s, 3H; OCH ), 2.11 (s, 3H; CH ). C NMR
2
2
3
3
(
75 MHz, CDCl ) δ = 195.5, 156.7, 146.3, 146.1, 136.1, 135.3, 123.8, 121.9, 121.1, 116.9, 112.9,
3
+
1
11.7, 94.8, 68.1, 55.6, 18.5. MS m/z: 271 (M ). HRMS (EI): calcd for C H NO 271.1208; found
1
6
17
3
271.1194.
4.2.10 2-(1-Hydroxyprop-2-en-1-yl)-5,6-dimethoxy-3-(2-methylpropenoyl)indole (6b)
3-Acryloyl-2-allylindole 6b was prepared according to a synthetic method for 9a.
–
1 1
Yield 63%. IR (ATR) ν = 3298 (OH), 1597 (CO) cm . H NMR (300 MHz, CDCl ) δ = 8.81 (br s,
3
1
H; NH), 7.29 (s, 1H; ArH), 6.86 (s, 1H; ArH), 6.16 (ddd, J = 17.2, 10.4, 5.3 Hz, 1H; CH=CH2),
.77 (s, 1H; =CH ), 5.74 (s, 1H; =CH ), 5.60 (br s, 1H; CH), 5.65 (td, J = 17.2, 1.4 Hz, 1H;
5
2
2

ACCEPTED MANUSCRIPT
CH=CH ), 5.38 (td, J = 10.4, 1.4 Hz, 1H; CH=CH ), 4.68 (br s, 1H; OH), 3.89 (s, 3H; OCH ), 3.88
2
2
3
1
3
(
s, 3H; OCH ), 2.14 (s, 3H; CH ). C NMR (75 MHz, CDCl ) δ = 195.1, 147.6, 146.3, 146.3, 145.3,
3 3 3
+
1
36.1, 128.6, 123.5, 120.1, 117.3, 113.3, 103.2, 94.5, 67.8, 56.3, 56.1, 18.6. MS m/z: 301 (M ).
HRMS (EI): calcd for C H NO 301.1314; found 301.1304.
1
7
19
4
4.2.11. Koniginequinone A (1a)
1
Koniginequinone A (1a) was prepared according to a synthetic method for 5a. H NMR spectrum
data of synthetic 1a by CDCl were identical with those of natural 1a [1]. However, the spectrum
3
data of our synthetic 1a was measured again in DMSO-d , because its solubility was lower against
6
CDCl3.
Yield 67%. mp 241–242 ºC (EtOAc-hexane) (lit. [1] mp 241 ºC). IR (ATR) ν = 3221 (NH), 1651
–
1 1
(
CO), 1631 (CO) cm . H NMR (300 MHz, CDCl ) δ = 9.00 (br s, 1H; NH), 8.09 (d, J = 8.9 Hz,
3
1
1
1
H; ArH), 7.00 (dd, J = 8.9, 2.2 Hz, 1H; ArH), 6.86 (d, J = 2.2 Hz, 1H; ArH), 6.46 (q, J = 1.7 Hz,
1
H; ArH), 3.88 (s, 3H; OCH ), 2.15 (d, J = 1.7 Hz, 3H; CH ). H NMR (300 MHz, DMSO-d ) δ =
3
3
6
2.63 (br s, 1H; NH), 7.90 (d, J = 8.9 Hz, 1H; ArH), 6.96 (dd, J = 8.9, 2.2 Hz, 1H; ArH), 6.92 (d, J
=
2.2 Hz, 1H; ArH), 6.56 (q, J = 1.6 Hz, 1H; ArH), 3.82 (s, 3H; OCH ), 2.04 (d, J = 1.6 Hz, 3H;
3
13
CH ). C NMR (75 MHz, DMSO-d ) δ = 183.3, 179.4, 158.7, 147.1, 138.8, 135.0, 131.6, 122.4,
3
6
+
1
17.7, 115.9, 115.1, 95.0, 55.3, 15.5. MS m/z: 241 (M ). HRMS (EI): calcd for C H NO
14 11 3
241.0739; found 241.0721.
4.2.12. Koniginequinone B (1b)
1
Koniginequinone B (1b) was prepared according to a synthetic method for 5b. H NMR spectrum
data of synthetic 1b by CDCl were identical with those of natural 1b [1]. However, the spectrum
3
data of our synthetic 1b was measured again in DMSO-d , because its solubility was lower against
6
CDCl3.
Yield 79%. mp 245–246 ºC (EtOAc-hexane) (lit. [1] mp 246–247 ºC). IR (ATR) ν = 3286 (NH),
–
1 1
1
631 (CO), 1619 (CO) cm . H NMR (300 MHz, CDCl ) δ = 8.88 (br s, 1H; NH), 7.59 (s, 1H;
3
ArH), 6.86 (s, 1H; ArH), 6.46 (1H, q, J = 1.4 Hz; ArH), 3.99 (s, 3H; OCH ), 3.96 (s, 3H; OCH ),
3
3
1
2
1
.15 (d, J = 1.4 Hz, 3H; CH ). H NMR (300 MHz, DMSO-d ) δ = 12.60 (br s, 1H; NH), 7.40 (s,
3 6
H; ArH), 6.92 (s, 1H; ArH), 6.54 (q, J = 1.6 Hz, 1H; ArH), 3.83 (s, 6H; OCH × 2), 2.04 (d, J = 1.6
3
13
Hz, 3H; CH ). C NMR (75 MHz, DMSO-d ) δ = 183.3, 178.8, 150.2, 148.5, 147.0, 134.0, 132.8,
3
6
+
1
31.9, 117.1, 115.8, 101.3, 95.2, 79.1, 55.6, 15.4. MS m/z: 271 (M ). HRMS (EI): calcd for
C H NO 271.0845; found 271.0873.
15
13
4
4.3. General procedure for the synthesis of indol-2-ylmethanol (12a–12q)
A solution of indole-2-carboxylate 11 (1 mmol) in THF (10 mL) was added dropwise to a

ACCEPTED MANUSCRIPT
suspension of LiAlH (0.8 mmol) in THF (20 mL) under cooling with ice-water. After stirring at rt
4
for 5 h, the reaction mixture was quenched with water, and then was filtrated through a Celite pad.
The filtrate was extracted with EtOAc. The organic layer was washed with brine, dried over Na SO ,
2
4
and evaporated in vacuo. The residue was purified by column chromatography using EtOAc-hexane
as an eluent to give the alcohol 12.
4.3.1. 5-Methoxyindol-2-ylmethanol (12a)
–1 1
Yield 72%. mp 67–69 ºC (EtOAc-hexane). IR (ATR) ν = 3194 (OH) cm . H NMR (300 MHz,
CDCl ) δ = 8.24 (br s, 1H; NH), 7.24 (d, J = 8.8 Hz, 1H; ArH), 7.04 (d, J = 2.5 Hz, 1H; ArH), 6.77
3
(
dd, J = 8.8, 2.5 Hz, 1H; ArH), 6.34 (s, 1H; ArH), 4.81 (s, 2H; CH ), 3.84 (s, 3H; OCH ), 1.79 (br s,
2 3
1
3
1
H; OH). C NMR (75 MHz, CDCl ) δ = 154.2, 138.3, 131.4, 128.5, 112.3, 111.6, 102.4, 100.3,
3
+
5
8.8, 55.8. MS m/z: 177 (M ). HRMS (EI): calcd for C H NO 177.0790; found 177.0810.
1
0
11
2
4.3.2. 4,5-Dimethoxyindol-2-ylmethanol (12b)
–1 1
Yield 68%. mp 76–78 ºC (EtOAc-hexane). IR (ATR) ν = 3289 (OH) cm . H NMR (300 MHz,
CDCl ) δ = 8.34 (br s, 1H; NH), 6.98 (d, J = 8.9 Hz, 1H; ArH), 6.90 (d, J = 8.9 Hz, 1H; ArH), 6.47
3
1
3
(
s, 1H; ArH), 4.77 (s, 2H; CH ), 4.03 (s, 3H; OCH ), 3.89 (s, 3H; OCH ), 2.14 (br s, 1H; OH). C
2 3 3
NMR (75 MHz, CDCl ) δ = 144.6, 141.7, 138.2, 133.7, 122.4, 111.5, 105.8, 97.7, 60.7, 58.6, 58.2.
3
+
MS m/z: 207 (M ). HRMS (EI): calcd for C H NO 207.0895; found 207.0877.
11
13
3
4.3.3. 4,7-Dimethoxyindol-2-ylmethanol (12c)
–1 1
Yield 70%. mp 78–80 ºC (EtOAc-hexane). IR (ATR) ν = 3228 (OH) cm . H NMR (300 MHz,
CDCl ) δ = 8.73 (br s, 1H; NH), 6.50 (d, J = 8.3 Hz, 1H; ArH), 6.48 (d, J = 2.4 Hz, 1H; ArH), 6.37
3
(
d, J = 8.3 Hz, 1H; ArH), 4.76 (d, J = 5.0 Hz, 2H; ArH), 3.90 (s, 3H; OCH ), 3.89 (s, 3H; OCH ),
3 3
1
3
2
9
2
.06 (br s, 1H; OH). C NMR (75 MHz, CDCl ) δ = 147.6, 140.9, 136.1, 128.0, 120.0, 101.8, 98.9,
3
+
8.4, 58.6, 55.7, 55.7. MS m/z: 207 (M ). HRMS (EI): calcd for C H NO 207.0895; found
11
13
3
07.0890.
4.3.4. 4,6-Dimethoxyindol-2-ylmethanol (12d)
–1 1
Yield 71%. mp 74–76 ºC (EtOAc-hexane). IR (ATR) ν = 3298 (OH) cm . H NMR (300 MHz,
CDCl ) δ = 8.31 (br s, 1H; NH), 6.40 (d, J = 1.6 Hz, 1H; ArH), 6.26–6.43 (m, 1H; ArH), 6.20 (d, J
3
=
1.6 Hz, 1H; ArH), 4.68 (s, 2H; CH ), 3.88 (s, 3H; OCH ), 3.80 (s, 3H; OCH ), 2.29 (br s, 1H;
2 3 3
1
3
OH). C NMR (75 MHz, CDCl ) δ = 157.6, 153.6, 137.8, 134.6, 112.9, 98.1, 91.7, 86.8, 58.5, 55.6,
3
+
5
5.3. MS m/z: 207 (M ). HRMS (EI): calcd for C H NO 207.0895; found 207.0903.
11
13
3
4.3.5. 5,7-Dimethoxyindol-2-ylmethanol (12e)

ACCEPTED MANUSCRIPT
–1 1
Yield 54%. mp 68–69 ºC (EtOAc-hexane). IR (ATR) ν = 3290 (OH) cm . H NMR (300 MHz,
CDCl ) δ = 8.63 (br s, 1H; NH), 6.61 (d, J = 2.2 Hz, 1H; ArH), 6.33 (d, J = 2.2 Hz, 1H; ArH), 6.28
3
(
d, J = 2.2 Hz, 1H; ArH), 4.72 (s, 2H; CH ), 3.88 (s, 3H; OCH ), 3.82 (s, 3H; OCH ), 2.25 (br s,
2 3 3
1
3
1
5
H; OH). C NMR (75 MHz, CDCl ) δ = 154.9, 146.3, 137.5, 128.6, 122.1, 100.8, 94.2, 93.7, 58.6,
3
+
5.8, 55.3. MS m/z: 207 (M ). HRMS (EI): calcd for C H NO 207.0895; found 207.0913.
11
13
3
4.3.6. 5-Methylindol-2-ylmethanol (12f)
–1 1
Yield 76%. mp 82–84 ºC (EtOAc-hexane). IR (ATR) ν = 3278 (OH) cm . H NMR (300 MHz,
CDCl ) δ = 8.24 (br s, 1H; NH), 7.36 (s, 1H; ArH), 7.22 (d, J = 8.3 H, 1H; ArH), 7.00 (d, J = 8.3 Hz,
3
1
1
5
H; ArH), 6.32 (s, 1H; ArH), 4.78 (d, J = 5.8 Hz, 2H; CH ), 2.43 (s, 3H; OCH ), 1.89 (t, J = 5.8 Hz,
2 3
1
3
H; OH). C NMR (75 MHz, CDCl ) δ = 137.6, 134.6, 129.1, 128.2, 123.7, 120.2, 110.6, 100.1,
3
+
8.6, 21.4. MS m/z: 161 (M ). HRMS (EI): calcd for C H NO 161.0841; found 161.0833.
1
0
11
4.3.7. 6-Methylindol-2-ylmethanol (12g)
–1 1
Yield 96%. mp 74–76 ºC (EtOAc-hexane). IR (ATR) ν = 3263 (OH) cm . H NMR (300 MHz,
CDCl ) δ = 8.22 (br s, 1H; NH), 7.45 (d, J = 8.1 Hz, 1H; ArH), 7.08 (s, 1H; ArH), 6.93 (d, J = 8.1
3
1
3
Hz, 1H; ArH), 6.34 (s, 1H; ArH), 4.75 (s, 2H; CH ), 2.44 (s, 3H; OCH ), 2.04 (br s, 1H; OH). C
2
3
NMR (300 MHz, CDCl ) δ = 136.9, 136.8, 132.0, 125.6, 121.7, 120.2, 111.0, 100.5, 58.4, 21.7. MS
3
+
m/z: 161 (M ). HRMS (EI): calcd for C H NO 161.0841; found 161.0825.
1
0
11
4.3.8. 5-Chloroindol-2-ylmethanol (12h)
–
1 1
Yield 80%. mp 110–111 ºC (EtOAc-hexane). IR (ATR) ν = 3305 (OH) cm . H NMR (300 MHz,
CDCl ) δ = 8.41 (br s, 1H; NH), 7.54 (s, 1H; ArH), 7.24–7.28 (m, 1H; ArH), 7.13 (dd, J = 8.6, 2.0
3
1
3
Hz, 1H; ArH), 6.34 (s, 1H; ArH), 4.84 (d, J = 5.3 Hz, 2H; CH ), 1.86 (br s, 1H; OH). C NMR (75
2
+
MHz, CDCl ) δ = 139.0, 134.6, 129.2, 125.5, 122.4, 120.0, 111.9, 100.0, 58.6. MS m/z: 181 (M ),
3
+
1
83 (M +2). HRMS (EI): calcd for C H ClNO 181.0294; found 181. 0288.
9
8
4.3.9. 6-Chloroindol-2-ylmethanol (12i)
–
1 1
Yield 50%. mp 108–109 ºC (EtOAc-hexane). IR (ATR) ν = 3386 (NH), 3294 (OH) cm . H NMR
300 MHz, CDCl ) δ = 8.37 (br s, 1H; NH 7.46 (d, J = 8.3 Hz, 1H; ArH), 7.34 (d, J = 1.8 Hz, 1H;
(
3
ArH), 7.07 (dd, J = 8.3, 1.8 Hz, 1H; ArH), 6.37 (s, 1H; ArH), 4.83 (s, 2H; CH ), 1.83 (br s, 1H; OH).
2
1
3
C NMR (75 MHz, CDCl ) δ = 138.2, 136.7, 127.9, 126.6, 121.4, 120.6, 110.9, 100.5, 58.6. MS
3
+
+
m/z: 181 (M ), 183 (M +2). HRMS (EI): calcd for C H ClNO 181.0294; found 181.0279.
9
8
4.3.10. 5-Nitroindol-2-ylmethanol (12j)
Yield 71%. mp 125–127 ºC (EtOAc-hexane). IR (ATR) ν = 3197 (OH), 1518 (NO ), 1362 (NO )
2
2

ACCEPTED MANUSCRIPT
–
1 1
cm . H NMR (300 MHz, DMSO-d ) δ = 11.81 (br s, 1H; NH), 8.50 (d, J =2.3 Hz, 1H; ArH), 7.96
6
(dd, J = 8.8, 2.3 Hz, 1H; ArH), 7.49 (d, J = 8.8 Hz, 1H; ArH), 6.57 (s, 1H; ArH), 5.46 (t, J = 5.5 Hz,
1
3
1
1
1
H; OH), 4.66 (d, J = 5.5 Hz, 2H; CH ). C NMR (75 MHz, DMSO-d ) δ = 144.4, 140.5, 139.5,
2 6
+
27.3, 116.8, 116.2, 111.4, 100.8, 56.7. MS m/z: 192 (M ). HRMS (EI): calcd for C H N O
3
9
8
2
92.0535; found 192.0552.
4.3.11. 6-Nitroindol-2-ylmethanol (12k)
Yield 65%. mp 121–123 ºC (EtOAc-hexane). IR (ATR) ν = 3194 (OH), 1585 (NO ), 1304 (NO )
2
2
–
1 1
cm . H NMR (300 MHz, DMSO-d ) δ = 11.85 (br s, 1H; NH), 8.27 (d, J =2.6 Hz, 1H; ArH), 7.86
6
(dd, J =8.8, 2.6 Hz, 1H; ArH), 7.63 (d, J = 8.8 Hz, 1H; ArH), 6.50 (s, 1H; ArH), 5.56 (t, J = 6.0 Hz,
1
3
1
1
1
H; OH), 4.70 (d, J = 6.0 Hz, 2H; CH ). C NMR (75 MHz, DMSO-d ) δ = 147.8, 141.3, 134.4,
2 6
+
33.2, 119.6, 114.2, 107.7, 99.3, 56.8. MS m/z: 192 (M ). HRMS (EI): calcd for C H N O
3
9
8
2
92.0535; found 192.0543.
4.3.12. 5-Trifluoromethylindol-2-ylmethanol (12l)
–1 1
Yield 87%. mp 96–98 ºC (EtOAc-hexane). IR (ATR) ν = 3217 (OH) cm . H NMR (300 MHz,
CDCl ) δ = 8.60 (br s, 1H; NH), 7.87 (s, 1H; ArH), 7.41 (m, 2H; ArH), 6.48 (s, 1H; ArH), 4.88 (s,
3
1
3
2
H; CH ), 1.88 (br s, 1H; OH). C NMR (75 MHz, CDCl ) δ = 139.3, 137.5, 127.5, 123.8 (q, J
2 3 C–F
=
271.2 Hz), 122.4 (q, JC–F = 32.2 Hz), 118.8 (q, JC–F = 3.7 Hz), 118.3 (q, JC–F = 3.7 Hz), 111.1,
+
1
01.0, 58.6. MS m/z: 215 (M ). HRMS (EI): calcd for C H F NO 215.0558; found 215.0546.
1
0
8 3
4.3.13. 6-Trifluoromethylindol-2-ylmethanol (12m)
–1 1
Yield 83%. mp 100–101 ºC (EtOAc-hexane). IR (ATR) ν = 3290 (OH) cm . H NMR (300 MHz,
CDCl ) δ = 8.71 (br s, 1H; NH), 7.63 (d, J = 8.3 Hz, 1H; ArH), 7.61 (s, 1H; ArH), 7.33 (d, J = 8.3
3
1
3
Hz, 1H; ArH), 6.44 (s, 1H; ArH), 4.87 (s, 2H; CH ), 2.13 (br s, 1H; OH). C NMR (75 MHz,
2
CDCl ) δ = 140.2, 135.1, 130.5, 124.1 (q, J = 32.5 Hz), 121.6 (q, JC–F = 271.2 Hz), 120.9, 116.7
3
C–F
+
(
q, JC–F = 3.7 Hz), 105.5 (q, JC–F = 5.0 Hz), 100.4, 58.6. MS m/z: 215 (M ). HRMS (EI): calcd for
C H F NO 215.0558; found 215.0568.
10
8 3
4.3.14. 5-Fluoroindol-2-ylmethanol (12n)
–
1 1
Yield 76%. mp 113–115 ºC (EtOAc-hexane). IR (ATR) ν = 3390 (OH) cm . H NMR (300 MHz,
CDCl ) δ = 8.41 (br s, 1H; NH), 7.13-7.25 (m, 2H; ArH), 6.85–6.95 (m, 1H; ArH), 6.34 (s, 1H;
3
1
3
ArH), 4.75 (s, 2H; CH ), 2.12 (br s, 1H; OH). C NMR (75 MHz, CDCl ) δ = 158.0 (d, J =
C–F
2
3
234.2 Hz), 139.2, 132.8, 128.4 (d, JC–F = 11.1 Hz), 111.5 (d, JC–F = 10.0 Hz), 110.5 (d, JC–F = 26.2
+
Hz), 105.4 (d, JC–F = 23.7 Hz), 100.5 (d, JC–F = 4.8 Hz), 58.6. MS m/z: 165 (M ). HRMS (EI): calcd
for C H FNO 165.0590; found 165.0610.
9
8

ACCEPTED MANUSCRIPT
4.3.15. 6-Fluoroindol-2-ylmethanol (12o)
–
1 1
Yield 77%. mp 119–120 ºC (EtOAc-hexane). IR (ATR) ν = 3310 (OH) cm . H NMR (300 MHz,
CDCl ) δ = 8.45 (br s, 1H; NH), 7.47 (dd, J = 8.7, 5.5 Hz, 1H; ArH), 6.97-7.01 (m, 1H; ArH), 6.86
3
1
3
(
ddd, J = 8.7, 2.3, 0.9 Hz, 1H; ArH), 6.36 (s, 1H; ArH), 4.77 (s, 2H; CH ), 2.11 (br s, 1H; OH). C
2
NMR (75 MHz, CDCl ) δ = 159.9 (d, J = 238.2 Hz), 137.8 (d, JC–F = 3.7 Hz), 136.3 (d, JC–F
=
3
C–F
12.6 Hz), 124.5, 121.3 (d, JC–F = 10.0 Hz), 108.7 (d, JC–F = 24.8 Hz), 100.6 (d, JC–F = 2.7 Hz), 97.3
+
(
d, JC–F = 26.2 Hz), 58.6. MS m/z: 165 (M ). HRMS (EI): calcd for C H FNO 165.0590; found
9
8
165.0601.
4.3.16. Benzo[e]indol-2-ylmethanol (12p)
–
1 1
Yield 81%. mp 118–119 ºC (EtOAc-hexane). IR (ATR) ν = 3263 (OH) cm . H NMR (300 MHz,
CDCl ) δ = 8.70 (br s, 1H; NH), 8.17 (d, J = 8.2 Hz, 1H; ArH), 7.79 (d, J = 8.2 Hz, 1H; ArH),
3
7
1
1
.51–7.59 (m, 2H; ArH), 7.47 (d, J = 8.7 Hz, 1H; ArH), 7.41 (dt, J = 8.2, 1.1 Hz, 1H; ArH), 6.93 (s,
1
3
H; ArH), 4.89 (s, 2H; CH ), 1.68 (br s, 1H; OH). C NMR (75 MHz, CDCl ) δ = 135.6, 132.7,
2
3
+
29.1, 128.6, 128.1, 125.8, 123.3, 123.2, 122.9, 122.8, 112.6, 100.0, 58.8. MS m/z: 197 (M ).
HRMS (EI): calcd C H NO 197.0841; found 197.0841.
1
3
11
4.3.17. Benzo[f]indol-2-ylmethanol (12q)
–1 1
Yield 99%. mp 123–125 ºC (EtOAc-hexane). IR (ATR) ν = 3236 (OH) cm . H NMR (300 MHz,
CDCl ) δ = 9.25 (br s, 1H; NH), 7.98 (d, J = 8.1 Hz, 1H; ArH), 7.92 (d, J = 8.1 Hz, 1H; ArH), 7.65
3
(d, J = 8.6 Hz, 1H; ArH), 7.48–7.54 (m, 2H; ArH), 7.39–7.45 (m, 1H; ArH), 6.54 (d, J = 2.2 Hz,
1
3
1
1
H; ArH), 4.90 (s, 2H; CH ), 1.97 (br s, 1H; OH). C NMR (75 MHz, CDCl ) δ = 135.5, 131.1,
2 3
+
30.5, 128.9, 125.5, 123.9, 123.9, 121.6, 120.8, 120.6, 119.4, 102.4, 58.8. MS m/z: 197 (M ).
HRMS (EI): calcd for C H NO 197.0841; found 197.0857.
1
3
11
4.4. General procedure for the synthesis of indole-2-carbaldehyde (13a–13q)
A suspension of the alcohol 12 (1 mmol) and active MnO (10 mmol) in DMF (30 mL) was stirred
2
at rt for 12 h. The reaction mixture was filtrated through a Celite pad. The filtrate was evaporated in
vacuo. The residue was purified by column chromatography using EtOAc-hexane as an eluent to
give the indole-2-carbaldehyde 13.
4.4.1. 5-Methoxyindole-2-carbaldehyde (13a)
–
1 1
Yield 70%. mp 178–179 ºC (EtOAc-hexane). IR (ATR) ν = 3188 (NH), 1639 (CO) cm . H NMR
(
300 MHz, CDCl ) δ = 9.80 (s, 1H; CHO), 9.25 (br s, 1H; NH), 7.36 (d, J = 8.8 Hz, 1H; ArH), 7.19
3
(d, J = 2.2 Hz, 1H; ArH), 7.11 (s, 1H; ArH), 7.08 (dd, J = 8.8, 2.2 Hz, 1H; ArH), 3.86 (s, 3H; OCH3).

ACCEPTED MANUSCRIPT
1
3
C NMR (75 MHz, CDCl ) δ = 181.9, 155.1, 136.3, 133.6, 127.7, 119.4, 114.3, 113.5, 102.8, 55.7.
3
+
MS m/z: 175 (M ). HRMS (EI): calcd for C H NO 175.0633; found 175.0656.
1
0
9
2
4.4.2. 4,5-Dimethoxyindole-2-carbaldehyde (13b)
–
1 1
Yield 44%. mp 142–144 ºC (EtOAc-hexane). IR (ATR) ν = 3186 (NH), 1662 (CO) cm . H NMR
(
300 MHz, CDCl ) δ = 9.80 (s, 1H; CHO), 9.02 (br s, 1H; NH), 7.36–7.37 (m, 1H; ArH), 7.17 (d, J
3
13
=
9.0 Hz, 1H; ArH), 7.09 (d, J = 9.0 Hz, 1H; ArH), 4.10 (s, 3H; OCH ), 3.91 (s, 3H; OCH ). C
3 3
NMR (75 MHz, CDCl ) δ = 182.1, 144.7, 143.3, 136.2, 135.3, 122.4, 118.3, 112.4, 107.2, 60.9,
3
+
5
8.4. MS m/z: 205 (M ). HRMS (EI): calcd for C H NO 205.0739; found 205.0756.
11
11
3
4.4.3. 4,7-Dimethoxyindole-2-carbaldehyde (13c)
–
1 1
Yield 60%. mp 137–138 ºC (EtOAc-hexane). IR (ATR) ν = 3313 (NH), 1670 (CO) cm . H NMR
(
300 MHz, CDCl ) δ = 9.78 (s, 1H; CHO), 9.23 (br s, 1H; NH), 7.33 (m, 1H; ArH), 6.66 (d, J = 8.2
3
13
Hz, 1H; ArH), 6.36 (d, J = 8.2 Hz, 1H; ArH), 3.92 (s, 3H; OCH ), 3.91 (s, 3H; OCH ). C NMR
3
3
(
CDCl ) δ = 181.5, 149.0, 141.1, 134.9, 130.3, 120.2, 112.6, 106.2, 99.0, 55.8, 55.5. MS m/z: 205
3
+
(
M ). HRMS (EI): calcd for C H NO 205.0739; found 205.0744.
11
11
3
4.4.4. 4,6-Dimethoxyindole-2-carbaldehyde (13d)
–
1 1
Yield 81%. mp 148–149 ºC (EtOAc-hexane). IR (ATR) ν = 3282 (NH), 1639 (CO) cm . H NMR
300 MHz, CDCl ) δ = 9.80 (s, 1H; CHO), 8.91 (br s, 1H; NH), 7.36 (dd, J = 2.2, 0.9 Hz, 1H; ArH),
(
3
7
.16 (d, J = 8.8 Hz, 1H; ArH), 7.09 (d, J = 8.8, 0.9 Hz, 1H; ArH), 4.10 (s, 3H; OCH ), 3.91 (s, 3H;
3
1
3
OCH ). C NMR (75 MHz, CDCl ) δ = 182.0, 144.7, 143.3, 136.2, 135.3, 122.4, 118.3, 112.4,
3
3
+
1
07.1, 60.9, 58.4. MS m/z: 205 (M ). HRMS (EI): calcd for C H NO 205.0739; found 205.0714.
11 11 3
4.4.5. 5,7-Dimethoxyindole-2-carbaldehyde (13e)
–
1 1
Yield 40%. mp 143–146 ºC (EtOAc-hexane). IR (ATR) ν = 3321 (NH), 1651 (CO) cm . H NMR
(
300 MHz, CDCl ) δ = 9.78 (s, 1H; CHO), 9.11 (br s, 1H; NH), 7.14 (d, J = 2.1 Hz, 1H; ArH), 6.67
3
(
d, J = 1.7 Hz, 1H; ArH), 6.48 (d, J = 2.1 Hz, 1H; ArH), 3.93 (s, 3H; OCH ), 3.84 (s, 3H; OCH ).
3
3
1
3
C NMR (75 MHz, CDCl ) δ = 181.6, 155.8, 147.2, 135.7, 127.8, 125.3, 114.1, 99.1, 93.9, 55.7,
3
+
5
5.6. MS m/z: 205 (M ). HRMS (EI): calcd for C H NO : 205.0739; found 205.0727.
11
11
3
4.4.6. 5-Methylindole-2-carbaldehyde (13f)
–
1 1
Yield 63%. mp 123–125 ºC (EtOAc-hexane). IR (ATR) ν = 3233 (NH), 1641 (CO) cm . H NMR
(
300 MHz, CDCl ) δ = 9.82 (s, 1H; CHO), 9.21 (br s, 1H; NH), 7.51 (d, J = 0.7 Hz, 1H; ArH), 7.36
3
(d, J = 8.5 Hz, 1H; ArH), 7.23 (dd, J = 8.5, 1.6 Hz, 1H; ArH), 7.19 (dd, J = 1.6, 0.7 Hz, 1H; ArH),
1
3
2
.45 (s, 3H; CH ). C NMR (75 MHz, CDCl ) δ = 182.0, 136.4, 136.0, 130.6, 129.4, 127.6, 122.5,
3
3

ACCEPTED MANUSCRIPT
+
1
14.3, 112.0, 21.4. MS m/z: 159 (M ). HRMS (EI): calcd for C H NO: 159.0684; found 159.0671.
10 9
4.4.7. 6-Methylindole-2-carbaldehyde (13g)
–
1 1
Yield 90%. mp 133–137 ºC (EtOAc-hexane). IR (ATR) ν = 3178 (NH), 1643 (CO) cm . H NMR
(
300 MHz, CDCl ) δ = 9.79 (s, 1H; CHO), 9.06 (br s, 1H; NH), 7.62 (dd, J = 8.4, 2.4 Hz, 1H; ArH),
3
13
7
.23–7.26 (m, 2H; ArH), 7.02 (d, J = 8.4 Hz, 1H; ArH), 2.48 (s, 3H; CH ). C NMR (75 MHz,
3
+
CDCl ) δ = 182.0, 138.9, 137.9, 135.6, 125.2, 123.4, 122.9, 115.4, 112.1, 22.1. MS m/z: 159 (M ).
3
HRMS (EI): calcd for C H NO 159.0684; found 159.0669.
1
0
9
4
.4.8. 5-Chloroindole-2-carbaldehyde (13h)
Yield 76%. mp 139–142 ºC (EtOAc-hexane). IR (ATR) ν = 3290 (NH), 1655 (CO) cm . H NMR
300 MHz, DMSO-d ) δ = 9.85 (s, 1H; CHO), 9.12 (br s, 1H; NH), 7.73 (d, J = 9.0 Hz, 1H; ArH),
–
1 1
(
6
7.40 (d, J = 8.8 Hz, 1H; ArH), 7.36 (dd, J = 8.8, 1.9 Hz, 1H; ArH), 7.21 (d, J = 1.9 Hz, 1H; ArH).
1
3
C NMR (75 MHz, DMSO-d ) δ = 183.3, 137.4, 136.7, 127.7, 126.4, 124.9, 122.0, 114.6, 113.2.
6
+
+
MS m/z: 179 (M ), 181 (M +2). HRMS (EI): calcd for C H ClNO 179.0138; found 179.0125.
9
6
4.4.9. 6-Chloroindole-2-carbaldehyde (13i)
–
1 1
Yield 79%. mp 144–147 ºC (EtOAc-hexane). IR (ATR) ν = 3205 (NH), 1635 (CO) cm . H NMR
(300 MHz, CDCl ) δ = 9.84 (s, 1H; CHO), 9.16 (br s, 1H; NH), 7.67 (d, J=8.5 Hz, 1H; ArH), 7.47
3
1
3
(
s, 1H; ArH), 7.25–7.26 (m, 1H; ArH), 7.16 (dd, J=8.5, 1.7 Hz, 1H; ArH). C NMR (75 MHz,
+
CDCl ) δ = 182.0, 138.3, 136.5, 133.3, 125.8, 124.4, 122.4, 114.7, 112.3. MS m/z: 179 (M ), 181
3
+
(
M +2). HRMS (EI): calcd for C H ClNO 179.0138; found 179.0149.
9
6
4.4.10. 5-Nitroindole-2-carbaldehyde (13j)
Yield 98%. mp 162–164 ºC (EtOAc-hexane). IR (ATR) ν = 3316 (NH), 1678 (CO), 1521 (NO2),
–1 1
1
338 (NO ) cm . H NMR (300 MHz, DMSO-d ) δ = 12.66 (br s, 1H; NH), 9.96 (s, 1H; CHO),
2 6
8.84 (s, 1H; ArH), 8.19 (dd, J = 9.0 Hz, 1H; ArH), 7.69 (s, 1H; ArH), 7.62 (d, J = 9.0 Hz, 1H; ArH).
1
3
C NMR (75 MHz, DMSO-d ) δ = 183.8, 141.7, 140.8, 139.0, 126.0, 120.8, 120.7, 116.0, 113.6.
6
+
MS m/z: 190 (M ). HRMS (EI): calcd for C H N O 190.0378; found 190.0362.
9
6
2
3
4.4.11. 6-Nitroindole-2-carbaldehyde (13k)
Yield 62%. mp 155–157 ºC (EtOAc-hexane). IR (ATR) ν = 3305 (NH), 1651(CO), 1508 (NO2),
–
1 1
1
8
1
338 (NO ) cm . H NMR (300 MHz, DMSO-d ) δ = 12.66 (br s, 1H; NH), 10.00 (s, 1H; CHO),
2 6
1
3
.33 (s, 1H; ArH), 7.92-8.01 (m, 2H; ArH), 7.56 (s, 1H; ArH). C NMR (75 MHz, DMSO-d ) δ =
6
+
83.9, 145.2, 140.3, 136.4, 131.1, 124.0, 114.9, 113.0, 109.5. MS m/z: 190 (M ). HRMS (EI): calcd
for C H N O 190.0378; found 190.0374.
9
6
2
3

ACCEPTED MANUSCRIPT
4.4.12. 5-Trifluoromethylindole-2-carbaldehyde (13l)
–1
1
Yield 98%. mp 132–135 ºC. IR (ATR) ν = 3282 (NH), 1651 (CO) cm . H NMR (300 MHz,
CDCl ) δ = 9.92 (s, 1H; CHO), 9.55 (br s, 1H; NH), 8.08 (s, 1H; ArH), 7.56–7.64 (m, 2H; ArH),
3
1
3
7
.37 (s, 1H; ArH). C NMR (75 MHz, CDCl ) δ = 182.3, 138.9, 137.1, 124.7 (q, J = 271.5 Hz),
3 C–F
126.5, 123.8 (q, JC–F = 32.5 Hz), 123.7 (q, JC–F = 2.5 Hz), 121.4 (q, JC–F = 3.9 Hz), 115.1, 113.1. MS
+
m/z: 213 (M ). HRMS (EI): calcd for C H F NO 213.0401; found 213.0411.
1
0
6 3
4.4.13. 6-Trifluoromethylindole-2-carbaldehyde (13m)
–
1 1
Yield 78%. mp 138–140 ºC (EtOAc-hexane). IR (ATR) ν = 3294 (NH), 1666 (CO) cm . H NMR
(300 MHz, CDCl ) δ = 9.92 (s, 1H; CHO), 9.22 (br s, 1H; NH), 7.87 (d, J = 8.7 Hz, 1H; ArH), 7.76
3
1
3
(
s, 1H; ArH), 7.42 (d, J= 8.7 Hz, 1H; ArH), 7.33 (s, 1H; ArH). C NMR (75 MHz, CDCl ) δ =
3
182.6, 137.6, 136.8, 129.2, 128.9 (q, JC–F = 32.4 Hz), 124.4 (q, JC–F = 272.6 Hz), 124.1, 117.6 (q,
+
JC–F = 3.7 Hz), 114.3, 110.4 (q, JC–F = 4.7 Hz). MS m/z: 213 (M ). HRMS (EI): calcd for
C H F NO 213.0401; found 213.0423.
10
6 3
4.4.14. 5-Fluorolindole-2-carbaldehyde (13n)
–
1 1
Yield 84%. mp 122–123 ºC (EtOAc-hexane). IR (ATR) ν = 3302 (NH), 1670 (CO) cm . H NMR
(300 MHz, CDCl ) δ = 9.85 (s, 1H; CHO), 9.36 (br s, 1H; NH), 7.36–7.44 (m, 2H; ArH), 7.24–7.25
3
1
3
(
m, 1H; ArH), 7.17 (dt, J = 9.2, 2.5 Hz, 1H; ArH). C NMR (75 MHz, CDCl ) δ = 182.2, 158.3 (d,
3
JC–F = 237.8 Hz), 137.1, 134.6, 127.5 (d, JC–F = 10.0 Hz), 116.6 (d, JC–F = 27.3 Hz), 114.4 (d, JC–F
=
+
5
.0 Hz), 113.5 (d, JC–F = 8.9 Hz), 107.5 (d, JC–F = 22.4 Hz). MS m/z: 163 (M ). HRMS (EI): calcd
for C H FNO 163.0433; found 163.0412.
9
6
4.4.15. 6-Fluorolindole-2-carbaldehyde (13o)
–1
1
Yield 99%. mp 132–135 ºC. IR (ATR) ν = 3298 (NH), 1651 (CO) cm . H NMR (300 MHz,
CDCl ) δ = 9.81 (s, 1H; CHO), 9.50 (br s, 1H; NH), 7.70 (dd, J = 8.9, 5.4 Hz, 1H; ArH), 7.26–7.28
3
1
3
(
m, 1H; ArH), 7.14 (dd, J = 9.4, 2.2 Hz, 1H; ArH), 6.96 (dt, J = 9.4, 2.2 Hz, 1H; ArH). C NMR
75 MHz, CDCl ) δ = 181.7, 162.9 (d, JC–F = 245.4 Hz), 138.4, (d, JC–F = 12.6 Hz), 136.7 (d, JC–F
(
=
3
3.9 Hz), 124.9, 124.4 (d, JC–F = 57.0 Hz), 115.1, 111.2 (d, JC–F = 26.2 Hz), 98.3 (d, JC–F = 26.5 Hz).
+
MS m/z: 163 (M ). HRMS (EI): calcd for C H FNO 163.0433; found 163.0439.
9
6
4.4.16. Benzo[e]indole-2-carbaldehyde (13p)
–
1 1
Yield 28%. mp 163–165 ºC (EtOAc-hexane). IR (ATR) ν = 3313 (NH), 1639 (CO) cm . H NMR
(
300 MHz, CDCl ) δ = 9.86 (s, 1H; CHO), 9.43 (br s, 1H; NH), 8.26 (d, J = 8.2 Hz, 1H; ArH), 7.91
3
(d, J = 8.2 Hz, 1H; ArH), 7.77–7.80 (m, 2H; ArH), 7.63 (dt, J = 7.0, 1.2 Hz, 1H; ArH), 7.47–7.53

ACCEPTED MANUSCRIPT
1
3
(
m, 2H; ArH). C NMR (75 MHz, CDCl ) δ = 181.0, 135.7, 134.5, 130.3, 129.4, 129.3, 129.0,
3
+
1
27.5, 127.3, 124.8, 122.8, 113.4, 113.1. MS m/z: 195 (M ). HRMS (EI): calcd for C H NO
1
3
9
195.0684; found 195.0692.
4.4.17. Benzo[f]indole-2-carbaldehyde (13q)
–
1 1
Yield 67%. mp 158–160 ºC (EtOAc-hexane). IR (ATR) ν = 3298 (NH), 1651 (CO) cm . H NMR
300 MHz, CDCl ) δ = 10.44 (br s, 1H; NH), 9.87 (s, 1H; CHO), 8.27 (d, J = 7.6, 1.3 Hz, 1H; ArH),
(
3
7.90–7.93 (m, 1H; ArH), 7.68 (d, J = 8.7 Hz, 1H; ArH), 7.53-7.64 (m, 3H; ArH), 7.39 (d, J = 2.2 Hz,
1
3
1
H; ArH). C NMR (75 MHz, CDCl ) δ = 181.4, 134.9, 134.7, 132.9, 128.9, 126.6, 126.4, 123.9,
3
+
1
22.7, 121.9, 121.3, 121.2, 116.3. MS m/z: 195 (M ). HRMS (EI): calcd for C H NO 195.0684;
1
3
9
found 195.0682.
4.5. General procedure for the synthesis of 3-iodoindole-2-carbaldehyde (14a–14q)
A solution of indole-2-carbaldehyde (6.6 mmol) in DMF (10 mL) was added to a suspension of
powdered KOH (23.8 mmol) in DMF (10 mL) under cooling with ice-water, and then stirred at
same temperature for 30 min. A solution of I (6.6 mmol) in DMF (30 mL) was added dropwise to
2
the reaction mixture under cooling with ice-water. After stirring at rt for 4 h, the mixture was poured
into a solution of 28% NH OH (100 mL) and NaHSO (9.6 mmol) in water (1.5 L). The precipitates
4
3
were separated by filtration to give the 3-iodoindole.
4.5.1. 3-Iodo-5-methoxyindole-2-carbaldehyde (14a)
–
1 1
Yield 63%. mp 174–177 ºC (EtOAc-hexane). IR (ATR) ν = 3209 (NH), 1793 (CO) cm . H NMR
(
300 MHz, DMSO-d ) δ = 12.31 (br s, 1H; NH), 9.76 (s, 1H; CHO), 7.39 (d, J = 8.9 Hz, 1H; ArH),
6
1
3
7
.07 (dd, J = 8.9, 2.4 Hz, 1H; ArH), 6.87 (d, J = 2.4 Hz, 1H; ArH), 3.84 (s, 3H; OCH ). C NMR
3
(
75 MHz, DMSO-d ) δ = 182.7, 155.0, 133.9, 133.3, 130.3, 119.7, 114.7, 101.6, 71.6, 55.4. MS m/z:
6
+
3
01 (M ). HRMS (EI): calcd for C H INO 300.9600; found 300.9616.
1
0
8
2
4.5.2. 3-Iodo-4,5-dimethoxylindole-2-carbaldehyde (14b)
–
1 1
Yield 40%. mp 167–170 ºC (EtOAc-hexane). IR (ATR) ν = 3290 (NH), 1778 (CO) cm . H NMR
(
300 MHz, DMSO-d ) δ
12.32 (br s, 1H; NH), 9.81 (s, 1H; CHO), 7.33 (d, J = 9.1 Hz, 1H; ArH),
6
13
7
.24 (d, J = 9.1 Hz, 1H; ArH), 3.92 (s, 3H; OCH ), 3.89 (s, 3H; OCH ). C NMR (75 MHz,
3 3
DMSO-d ) δ = 183.5, 145.6, 142.6, 134.8, 134.2, 122.8, 117.8, 108.8, 65.6, 61.3, 57.7. MS m/z: 331
6
+
(
M ). HRMS (EI): calcd for C H INO 330.9705; found 330.9727.
11
10
3
4.5.3. 3-Iodo-4,7-dimethoxylindole-2-carbaldehyde (14c)
–
1 1
Yield 51%. mp 160–163 ºC (EtOAc-hexane). IR (ATR) ν = 3259 (NH), 1666 (CO) cm . H NMR

ACCEPTED MANUSCRIPT
(
300 MHz, DMSO-d ) δ = 12.15 (br s, 1H; NH), 9.48 (s, 1H; CHO), 6.77 (d, J = 8.4 Hz, 1H; ArH),
6
13
6
.38 (d, J = 8.4 Hz, 1H; ArH), 3.90 (s, 3H; OCH ), 3.50 (s, 3H; OCH ). C NMR (75 MHz,
3 3
DMSO-d ) δ = 181.8, 149.2, 141.3, 133.3, 129.2, 119.3, 117.4, 105.9, 99.6, 55.8, 55.1. MS m/z: 331
6
+
(
M ). HRMS (EI): calcd for C H INO 330.9705; found 330.9703.
11
10
3
4.5.4. 3-Iodo-4,6-dimethoxylindole-2-carbaldehyde (14d)
–
1 1
Yield 83%. mp 166–170 ºC (EtOAc-hexane). IR (ATR) ν = 3271 (NH), 1612 (CO) cm . H NMR
(
300 MHz, DMSO-d ) δ = 12.14 (br s, 1H; NH), 9.57 (s, 1H; CHO), 6.42 (d, J = 2.0 Hz, 1H; ArH),
6
13
6
.20 (d, J = 2.0 Hz, 1H; ArH), 3.84 (s, 3H; OCH ), 3.77 (s, 3H; OCH ). C NMR (75 MHz,
3 3
DMSO-d ) δ = 181.8, 160.8, 155.6, 140.7, 132.4, 114.2, 93.6, 86.5, 68.6, 55.4, 55.4. MS m/z: 331
6
+
(
M ). HRMS (EI): calcd for C H INO 330.9705; found 330.9711.
11
10
3
4.5.5. 3-Iodo-5,7-dimethoxylindole-2-carbaldehyde (14e)
–
1 1
Yield 62%. mp 154–157 ºC (EtOAc-hexane). IR (ATR) ν = 3367 (NH), 1628 (CO) cm . H NMR
(
300 MHz, CDCl ) δ = 9.77 (s, 1H; CHO), 9.33 (br s, 1H; NH), 6.50 (d, J = 2.0 Hz, 1H; ArH), 6.48
3
1
3
(
d, J = 2.0 Hz, 1H; ArH), 3.93 (s, 3H; OCH ), 3.89 (s, 3H; OCH ). C NMR (75 MHz, CDCl ) δ =
3 3 3
+
1
82.4, 156.5, 147.2, 133.2, 131.3, 124.6, 100.1, 93.7, 71.6, 55.8, 55.8. MS m/z: 331 (M ). HRMS
(
EI): calcd for C H INO 330.9705; found 330.9729.
11 10 3
4.5.6. 3-Iodo-5-methylindole-2-carbaldehyde (14f)
–
1 1
Yield 72%. mp 169–171 ºC (EtOAc-hexane). IR (ATR) ν = 3294 (NH), 1647 (CO) cm . H NMR
(
300 MHz, DMSO-d ) δ = 12.30 (br s, 1H; NH), 9.77 (s, 1H; CHO), 7.36 (d, J = 8.3 Hz, 1H; ArH),
6
1
3
7
.28 (s, 1H; ArH), 7.24 (d, J = 8.3 Hz, 1H; ArH), 2.42 (s, 3H; CH ). C NMR (75 MHz, DMSO-d )
3
6
+
δ = 182.9, 136.5, 133.7, 130.6, 130.1, 129.7, 121.5, 113.2, 72.1, 21.0. MS m/z: 285 (M ). HRMS
(
EI): calcd for C H INO 284.9651; found 284.9663.
10 8
4.5.7. 3-Iodo-6-methylindole-2-carbaldehyde (14g)
–
1 1
Yield 86%. mp 154–157 ºC (EtOAc-hexane). IR (ATR) ν = 3275 (NH), 1643 (CO) cm . H NMR
(
300 MHz, DMSO-d ) δ = 9.78 (s, 1H; CHO), 9.10 (br s, 1H; NH), 7.47 (d, J = 8.3 Hz, 1H; ArH),
6
13
7
.19–7.23 (m, 1H; ArH), 7.09 (d, J = 8.0 Hz, 1H; ArH), 2.50 (s, 3H; CH ). C NMR (75 MHz,
3
+
DMSO-d ) δ = 182.8, 139.3, 137.9, 133.2, 128.8, 124.4, 123.0, 112.2, 73.2, 22.1. MS m/z: 285 (M ).
6
HRMS (EI): calcd for C H INO 284.9651; found 284.9653.
1
0
8
4
.5.8. 5-Chloro-3-iodoindole-2-carbaldehyde (14h)
Yield 80%. mp 132–135 ºC (EtOAc-hexane). IR (ATR) ν = 3275 (NH), 1643 (CO) cm . H NMR
300 MHz, DMSO-d ) δ = 12.58 (br s, 1H; NH), 9.81 (s, 1H; CHO), 7.46-7.52 (m, 2H; ArH),
–
1 1
(
6

ACCEPTED MANUSCRIPT
1
3
7
1
3
.39–7.43 (m, 1H; ArH). C NMR (75 MHz, DMSO-d ) δ = 183.2, 136.4, 135.0, 131.0, 127.7,
6
+
+
26.1, 121.4, 115.4, 71.3. MS m/z: 304 (M ), 306 (M +2). HRMS (EI): calcd for C H ClINO
9
5
04.9104; found 304.9126.
4.5.9. 6-Chloro-3-iodoindole-2-carbaldehyde (14i)
–
1 1
Yield 74%. mp 137–139 ºC (EtOAc-hexane). IR (ATR) ν = 3267 (NH), 1651 (CO) cm . H NMR
1
3
(
300 MHz, DMSO-d ) δ = 12.58 (br s, 1H; NH), 9.80 (s, 1H; CHO), 7.36–7.52 (m, 3H; ArH). C
6
NMR (75 MHz, DMSO-d ) δ = 183.3, 136.4, 135.0, 131.0, 127.7, 126.1, 121.4, 115.4, 71.3. MS
6
+
+
m/z: 304 (M ), 306 (M +2). HRMS (EI): calcd for C H ClNO 304.9104; found 304.9116.
9
5
4.5.10. 3-Iodo-5-nitroindole-2-carbaldehyde (14j)
Yield 56%. mp 171–173 ºC (EtOAc-hexane). IR (ATR) ν = 3310 (NH), 1687 (CO), 1561 (NO2),
–1 1
1
357 (NO ) cm . H NMR (300 MHz, DMSO-d ) δ = 13.05 (br s, 1H; NH), 9.85 (s, 1H; CHO),
2 6
8.40 (d, J = 1.7 Hz, 1H; ArH), 8.23 (dd, J = 9.1, 1.7 Hz, 1H; ArH), 7.22 (d, J = 9.1 Hz, 1H; ArH).
1
3
C NMR (75 MHz, DMSO-d ) δ = 183.6, 142.3, 140.7, 137.0, 129.4, 121.9, 119.7, 114.5, 74.8. MS
6
+
m/z: 316 (M ). HRMS (EI): calcd for C H IN O 315.9345; found 315.9369
9
5
2
3
4.5.11. 3-Iodo-6-nitroindole-2-carbaldehyde (14k)
Yield 48%. mp 184–186 ºC (EtOAc-hexane). IR (ATR) ν = 3359 (NH), 1658 (CO), 1508 (NO2),
–
1 1
1
7
1
331 (NO ) cm . H NMR (300 MHz, DMSO-d ) δ = 12.51 (br s, 1H; NH), 9.80 (s, 1H; CHO),
2
6
1
3
.50 (dd, J = 8.9, 4.6 Hz, 1H; ArH), 7.23–7.33 (m, 2H; ArH). C NMR (75 MHz, DMSO-d ) δ =
6
+
83.2, 159.5, 156.4, 134.7, 130.4, 116.9, 115.3, 106.8, 71.6. MS m/z: 316 (M ). HRMS (EI): calcd
for C H IN O 315.9345; found 315.9349.
9
5
2
3
4.5.12. 3-Iodo-5-trifluromethylindole-2-carbaldehyde (14l)
–
1 1
Yield 85%. mp 176–178 ºC (EtOAc-hexane). IR (ATR) ν = 3286 (NH), 1651 (CO) cm . H NMR
1
3
(
300 MHz, DMSO-d ) δ = 12.79 (br s, 1H; NH), 9.83 (s, 1H; CHO), 7.64–7.80 (m, 3H; ArH). C
6
NMR (75 MHz, DMSO-d ) δ = 183.5, 139.3, 135.7, 129.3, 124.6 (q, J = 270.9 Hz), 123.4 (q,
6
C–F
+
JC–F = 2.5 Hz), 122.2 (q, JC–F = 31.5 Hz), 120.3 (q, JC–F = 3.9 Hz), 114.8, 73.2. MS m/z: 339 (M ).
HRMS (EI): calcd for C H F INO 338.9368; found 338.9376.
1
0
5 3
4.5.13. 3-Iodo-6-trifluromethylindole-2-carbaldehyde (14m)
–
1 1
Yield 56%. mp 168–170 ºC (EtOAc-hexane). IR (ATR) ν = 3278 (NH), 1658 (CO) cm . H NMR
(300 MHz, DMSO-d ) δ = 12.83 (br s, 1H; NH), 9.87 (s, 1H; CHO), 7.75–7.78 (m, 2H; ArH), 7.49
6
1
3
(
d, J = 8.6 Hz, 1H; ArH). C NMR (75 MHz, DMSO-d ) δ = 183.7, 136.6, 136.1, 132.3, 127.2 (q,
6
JC–F = 31.6 Hz), 124.4 (q, JC–F = 271.9 Hz), 124.1, 117.3 (q, JC–F = 3.6 Hz), 110.9 (q, JC–F = 4.8 Hz),

ACCEPTED MANUSCRIPT
+
7
1.9. MS m/z: 339 (M ). HRMS (EI): calcd for C H F INO 338.9368; found 338.9348.
10 5 3
4.5.14. 5-Fluoro-3-iodoindole-2-carbaldehyde (14n)
–
1 1
Yield 54%. mp 148–149 ºC (EtOAc-hexane). IR (ATR) ν = 3297 (NH), 1639 (CO) cm . H NMR
(
300 MHz, DMSO-d ) δ = 12.50 (br s, 1H; NH), 9.78 (s, 1H; CHO), 7.46–7.50 (m, 1H; ArH),
6
1
3
7
1
1
2
.22–7.30 (m, 2H; ArH). C NMR (75 MHz, DMSO-d ) δ = 183.2, 159.5 (d, J
= 235.3 Hz),
6
C–F
35.0 (d, JC–F = 37.7 Hz), 130.3 (d, JC–F = 9.5 Hz), 121.8, 116.8 (d, JC–F = 27.6 Hz), 115.3 (d, JC–F
=
+
0.0 Hz), 106.5 (d, JC–F = 26.5 Hz), 71.6. MS m/z: 289 (M ). HRMS (EI): calcd for C H FINO
9
5
88.9400; found 288.9411.
4.5.15. 6-Fluoro-3-iodoindole-2-carbaldehyde (14o)
–
1 1
Yield 87%. mp 140–142 ºC (EtOAc-hexane). IR (ATR) ν = 3286 (NH), 1651 (CO) cm . H NMR
(
300 MHz, CDCl ) δ = 9.77 (s, 1H; CHO), 9.60 (br s, 1H; NH), 7.57 (dd, J = 9.0, 5.4 Hz, 1H; ArH),
3
1
3
7
1
9
.12 (d, J = 9.0 Hz, 1H; ArH), 6.99–7.05 (m, 1H; ArH). C NMR (75 MHz, CDCl ) δ = 182.6,
3
65.2, 137.6 (d, JC–F = 13.4 Hz), 134.4 (d, JC–F = 3.4 Hz), 127.4, 125.1 (d, JC–F = 11.2 Hz), 98.7,
+
8.3, 72.9. MS m/z: 289 (M ); HRMS (EI): calcd for C H FINO 288.9400; found 288.9411.
9
5
4.5.16. 3-Iodobenzo[e]indole-2-carbaldehyde (14p)
–
1 1
Yield 61%. mp 170–172 ºC (EtOAc-hexane). IR (ATR) ν = 3244 (NH), 1627 (CO) cm . H NMR
300 MHz, DMSO-d ) δ = 12.94 (br s, 1H; NH), 9.84 (s, 1H; CHO), 9.41 (d, J = 8.6 Hz, 1H; ArH),
(
6
8
7
1
.01 (d, J = 7.9 Hz, 1H; ArH), 7.86 (d, J = 8.6 Hz, 1H; ArH), 7.72 (t, J = 7.9 Hz, 1H; ArH),
1
3
.52–7.61 (m, 2H; ArH). C NMR (75 MHz, DMSO-d ) δ = 182.7, 136.5, 132.5, 129.8, 129.5,
6
+
29.1, 128.8, 126.5, 124.8, 120.6, 120.4, 114.1, 70.0. MS m/z: 321 (M ). HRMS (EI): calcd for
C H INO 320.9651; found 320.9667.
13
8
4.5.17. 3-Iodobenzo[f]indole-2-carbaldehyde (14q)
–
1 1
Yield 85%. mp 161–162 ºC (EtOAc-hexane). IR (ATR) ν = 3267 (NH), 1612 (CO) cm . H NMR
(
300 MHz, DMSO-d ) δ = 13.34 (br s, 1H; NH), 9.79 (s, 1H; CHO), 8.75 (d, J = 7.9 Hz, 1H; ArH),
6
1
3
7
.97 (d, J = 7.9 Hz, 1H; ArH), 7.5–7.64 (m, 3H; ArH), 7.47 (d, J = 8.7 Hz, 1H; ArH). C NMR (75
MHz, DMSO-d ) δ = 182.0, 134.8, 132.8, 132.8, 128.8, 126.8, 126.6, 126.6, 123.1, 122.5, 122.0,
6
+
1
20.6, 74.9. MS m/z: 321 (M ). HRMS (EI): calcd for C H INO 320.9651; found 320.9651.
1
3
8
4.6. General procedure for the synthesis of 3-Acryloylindole-2-carbaldehyde (15a–15s)
Carbon monoxide was bubbled for 5 min to a mixture of the iodoindole 14 (514 mmol),
isopropenyltributyltin (617 mmol), BHT (617 mmol), and PdCl (dppf) (26 mmol) in DMF (20 mL)
2
at rt. The resulting mixture was stirred at 70 °C for 12 h under a CO atmosphere. After cooling to an

ACCEPTED MANUSCRIPT
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 Na SO ,
2
4
and evaporated in vacuo. The residue was purified by column chromatography using EtOAc-hexane
as an eluent to give the 3-acryloylindole 15.
4.6.1. 5-Methoxy-3-(2-methylpropenoyl)indole-2-carbaldehyde (15a)
–
1
Yield 61%. mp 152–153 ºC (EtOAc-hexane). IR (ATR) ν = 3305 (NH), 1655 (CO), 1620 (CO) cm .
1
H NMR (300 MHz, CDCl ) δ = 10.07 (s, 1H; CHO), 9.62 (br s, 1H, NH), 7.38 (d, J = 9.0 Hz, 1H;
3
ArH), 7.35 (d, J = 2.4 Hz, 1H; ArH), 7.10 (dd, J = 9.0, 2.4 Hz, 1H; ArH), 6.01 (s, 1H; =CH ), 5.84
2
1
3
(
s, 1H; =CH ), 3.85 (s, 3H; OCH ), 2.19 (s, 3H; CH ). C NMR (75 MHz, CDCl ) δ = 192.9, 182.8,
2 3 3 3
+
1
56.3, 147.7, 136.3, 131.5, 127.9, 127.5, 122.0, 119.7, 113.5, 102.9, 55.7, 18.2. MS m/z: 243 (M ).
HRMS (EI): calcd for C H NO 243.0895; found 243.0908.
1
4
13
3
4.6.2. 4,5-Dimethoxy-3-(2-methylpropenoyl)indole-2-carbaldehyde (15b)
–
1
Yield 70%. mp 166–168 ºC (EtOAc-hexane). IR (ATR) ν = 3263 (NH), 1658 (CO), 1647 (CO) cm .
1
H NMR (300 MHz, CDCl ) δ = 9.75 (s, 1H; CHO), 9.30 (br s, 1H; NH), 7.19 (d, J = 8.9 Hz, 1H;
3
ArH), 7.13 (d, J = 8.9 Hz, 1H; ArH), 5.96 (s, 1H; =CH ), 5.63 (s, 1H; =CH ), 3.89 (s, 3H; OCH ),
2
2
3
1
3
3
.86 (s, 3H; OCH ), 2.15 (s, 3H; CH ). C NMR (75 MHz, CDCl ) δ = 194.8, 181.8, 146.9, 146.3,
3 3 3
+
1
43.0, 134.4, 133.1, 129.1, 124.6, 122.2, 118.5, 107.6, 60.5, 58.0, 17.5. MS m/z: 273 (M ). HRMS
(
EI): calcd for C H NO 273.1001; found 273.1019.
15 15 4
4.6.3. 4,7-Dimethoxy-3-(2-methylpropenoyl)indole-2-carbaldehyde (15c)
–
1
Yield 75%. mp 157–158 ºC (EtOAc-hexane). IR (ATR) ν = 3263 (NH), 1646 (CO), 1620 (CO) cm .
1
H NMR (300 MHz, CDCl ) δ = 9.73 (s, 1H; CHO), 9.37 (br s, 1H; NH), 6.69 (d, J = 8.5 Hz, 1H;
3
ArH), 6.39 (d, J = 8.5 Hz, 1H; ArH), 5.91 (s, 1H; =CH ), 5.57 (s, 1H; =CH ), 3.93 (s, 3H; OCH ),
2
2
3
1
3
3
.79 (s, 3H; OCH ), 2.12 (s, 3H; CH ). C NMR (75 MHz, CDCl ) δ = 194.6, 181.2, 148.7, 147.0,
3 3 3
+
1
46.9, 140.8, 133.1, 128.7, 125.4, 118.6, 106.5, 100.5, 55.8, 55.7, 17.5. MS m/z: 273 (M ). HRMS
(
EI): calcd for C H NO 273.1001; found 273.1008.
15 15 4
4.6.4. 4,6-Dimethoxy-3-(2-methylpropenoyl)indole-2-carbaldehyde (15d)
–
1
Yield 83%. mp 149–151 ºC (EtOAc-hexane). IR (ATR) ν = 3263 (NH), 1658 (CO), 1647 (CO) cm .
1
H NMR (300 MHz, CDCl ) δ = 9.60 (s, 1H; CHO), 9.13 (br s, 1H; NH), 6.42 (d, J = 1.8 Hz, 1H;
3
ArH), 6.19 (d, J = 1.8 Hz, 1H; ArH), 5.91 (s, 1H; =CH ), 5.60 (s, 1H; =CH ), 3.86 (s, 3H; OCH ),
2
2
3
1
3
3
.81 (s, 3H; OCH ), 2.11 (s, 3H; CH ). C NMR (75 MHz, CDCl ) δ = 194.8, 180.4, 162.2, 155.5,
3 3 3
+
1
46.9, 138.7, 132.6, 128.9, 126.4, 112.9, 94.3, 86.0, 55.7, 55.4, 17.2. MS m/z: 273 (M ). HRMS

ACCEPTED MANUSCRIPT
(
EI): calcd for C H NO 273.1001; found 273.1022.
15 15 4
4.6.5. 5,7-Dimethoxy-3-(2-methylpropenoyl)indole-2-carbaldehyde (15e)
–
1
Yield 90%. mp 155–157 ºC (EtOAc-hexane). IR (ATR) ν = 3263 (NH), 1662 (CO), 1647 (CO) cm .
1
H NMR (300 MHz, CDCl ) δ = 10.04 (s, 1H; CHO), 9.49 (br s, 1H; NH), 6.90 (d, J = 1.8 Hz, 1H;
3
ArH), 6.49 (d, J = 1.8 Hz, 1H; ArH), 5.98 (s, 1H; =CH ), 5.83 (s, 1H; =CH ), 3.95 (s, 3H; OCH ),
2
2
3
1
3
3
.84 (s, 3H; OCH ), 2.18 (s, 3H; CH ). C NMR (75 MHz, CDCl ) δ = 193.0, 182.5, 157.2, 147.4,
3 3 3
+
1
47.0, 135.7, 127.8, 127.7, 123.4, 122.0, 99.3, 94.0, 55.8, 55.7, 18.1. MS m/z: 273 (M ). HRMS
(
EI): calcd for C H NO 273.1001; found 273.1003
15 15 4
4.6.6. 5-Methyl-3-(2-methylpropenoyl)indole-2-carbaldehyde (15f)
–
1
Yield 79%. mp 137–139 ºC (EtOAc-hexane). IR (ATR) ν = 3294 (NH), 1651 (CO), 1620 (CO) cm .
1
H NMR (300 MHz, CDCl ) δ = 10.07 (s, 1H; CHO), 9.45 (br s, 1H; NH), 7.37 (d, J = 8.6 Hz, 1H;
3
ArH), 7.24–7.26 (m, 2H; ArH), 6.02 (s, 1H; =CH ), 5.85 (s, 1H; =CH ), 2.45 (s, 3H; OCH ), 2.19 (s,
2
2
3
1
3
3
1
2
H; CH ). C NMR (75 MHz, CDCl ) δ = 193.1, 183.3, 147.2, 136.0, 134.8, 132.5, 129.6, 128.4,
3
3
+
26.9, 122.6, 122.4, 112.3, 21.6, 18.0. MS m/z: 227 (M ). HRMS (EI): calcd for C H NO
1
4
13
2
27.0946; found 227.0962.
4.6.7. 6-Methyl-3-(2-methylpropenoyl)indole-2-carbaldehyde (15g)
–
1
Yield 65%. mp 124–126 ºC (EtOAc-hexane). IR (ATR) ν = 3298 (NH), 1651 (CO), 1619 (CO) cm .
1
H NMR (300 MHz, CDCl ) δ = 10.06 (s, 1H; CHO), 9.42 (br s, 1H; NH), 7.79 (d, J = 8.3 Hz, 1H;
3
ArH), 7.13–7.33 (m, 1H; ArH), 7.09 (dd, J = 8.3, 1.2 Hz, 1H; ArH), 6.02 (s, 1H; =CH ), 5.84 (s,
2
1
3
1
1
H; =CH ), 2.49 (s, 3H; CH ), 2.18 (s, 3H; CH ). C NMR (75 MHz, CDCl ) δ = 192.9, 183.0,
2 3 3 3
+
47.1, 138.2, 136.6, 135.7, 128.3, 125.1, 124.7, 123.1, 123.0, 112.0, 22.0, 18.0. MS m/z: 227 (M ).
HRMS (EI): calcd for C H NO 227.0946; found 227.0924.
1
4
13
2
4.6.8. 5-Chloro-3-(2-methylpropenoyl)indole-2-carbaldehyde (15h)
–
1
Yield 75%. mp 142–144 ºC (EtOAc-hexane). IR (ATR) ν = 3290 (NH), 1658 (CO), 1631 (CO) cm .
1
H NMR (300 MHz, CDCl ) δ = 10.10 (s, 1H; CHO), 9.64 (br s, 1H; NH), 7.90 (d, J = 1.9 Hz, 1H;
3
ArH), 7.44 (dd, J = 8.9, 0.6 Hz, 1H; ArH), 7.38 (dd, J = 8.9, 1.9 Hz, 1H; ArH), 6.06 (s, 1H; =CH2),
1
3
5
.84 (s, 1H; =CH ), 2.19 (s, 3H; CH ). C NMR (75 MHz, CDCl ) δ = 192.2, 183.0, 147.1, 136.9,
2 3 3
+
+
1
34.3, 128.8, 128.6, 128.1, 127.5, 122.6, 122.1, 113.7, 18.0. MS m/z: 247 (M ), 249 (M +2). HRMS
(
EI): calcd for C H ClNO 247.0400; found 247.0382.
13 10 2
4.6.9. 6-Chloro-3-(2-methylpropenoyl)indole-2-carbaldehyde (15i)
–
1
Yield 62%. mp 149–151 ºC (EtOAc-hexane). IR (ATR) ν = 3278 (NH), 1651 (CO), 1612 (CO) cm .