Condensation reactions of indole with acetophenones affording mixtures of 3,3-(1-phenylethane-1,1-diyl)bis(1H-indoles) and 1,2,3,4-tetrahydro-3-(1H-indol-3-yl)-1-methyl-1,3-diphenylcyclopent[b]indoles

Article abstract of DOI:10.1080/00397911.2018.1460760

Condensation of indole 1a with eight acetophenones 8a–h in ethanolic HCl afforded the corresponding mixtures of condensation products: 3,3-(1-phenylethane-1,1-diyl)bis(1H-indoles) 11a–h (2:1 condensation of indole:acetophenone, –H₂O) and diaste

Full text of DOI:10.1080/00397911.2018.1460760

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Condensation reactions of indole with
acetophenones affording mixtures of 3,3-(1-
phenylethane-1,1-diyl)bis(1H-indoles) and
1,2,3,4-tetrahydro-3-(1H-indol-3-yl)-1-methyl-1,3-
diphenylcyclopent[b]indoles
Wayland E. Noland, Christopher D. Brown, Rodney D. DeKruif, Nicholas P.
Lanzatella, Siming M. Gao, Abigail E. Zabronsky & Kenneth J. Tritch
To cite this article: Wayland E. Noland, Christopher D. Brown, Rodney D. DeKruif, Nicholas
P. Lanzatella, Siming M. Gao, Abigail E. Zabronsky & Kenneth J. Tritch (2018): Condensation
reactions of indole with acetophenones affording mixtures of 3,3-(1-phenylethane-1,1-diyl)bis(1H-
indoles) and 1,2,3,4-tetrahydro-3-(1H-indol-3-yl)-1-methyl-1,3-diphenylcyclopent[b]indoles,
Synthetic Communications, DOI: 10.1080/00397911.2018.1460760
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SYNTHETIC COMMUNICATIONS
https://doi.org/10.1080/00397911.2018.1460760
Condensation reactions of indole with acetophenones
affording mixtures of 3,3-(1-phenylethane-1,1-diyl)bis(1H-
indoles) and 1,2,3,4-tetrahydro-3-(1H-indol-3-yl)-1-methyl-
1
,3-diphenylcyclopent[b]indoles
Wayland E. Noland , Christopher D. Brown, Rodney D. DeKruif,
Nicholas P. Lanzatella, Siming M. Gao, Abigail E. Zabronsky, and Kenneth J. Tritch
Department of Chemistry, University of Minnesota, Minneapolis, MN, USA
ABSTRACT
ARTICLE HISTORY
Condensation of indole 1a with eight acetophenones 8a–h in
ethanolic HCl afforded the corresponding mixtures of condensation
products: 3,3-(1-phenylethane-1,1-diyl)bis(1H-indoles) 11a–h (2:1
condensation of indole:acetophenone, –H O) and diastereomers of
2
substituted 1,2,3,4-tetrahydro-3-(1H-indol-3-yl)-1-methyl-1,3-diphenyl-
Received 18 January 2018
KEYWORDS
Acetophenones;
acid-catalyzed
condensation; bisindoles;
cyclopent[b]indoles 12a–h and 13a–h (2:2 condensation of indole:a-
cyclopent[b]indoles; indole
1
cetophenone, –2H
2
O). Each mixture was analyzed by H NMR. The
use of substituted electron-withdrawing acetophenones favored for-
mation of 2:1 condensation products, whereas the use of substituted
electron-donating acetophenones favored formation of 2:2 condensa-
tion products. Increased reaction temperature gave higher 2:2 con-
ꢀ
densation yields, but temperatures above 40 C were unfavorable,
giving complex, tarry mixtures.
GRAPHICAL ABSTRACT
R
R
R
O
Me
Me
Me
Me
+
HCl
NH
NH
N
H
NH
+
HN
R
+
HN
R
R
EtOH
N
H
1
a
8a-h
R = H, p-CH
3
,
p-NH
2
,
2
p-OCH
p-Br
3
,
m-OCH p-Cl, p-NO
3
,
,
11a-h
12a-h
13a-h
Introduction
The common presence of the indole structure in compounds of both biological and
[
1,2]
phamacotherapeutic significance
indoles.
has led to strong interest in the reactions of
[3–6]
Condensation of indole 1a with carbonyl compounds provides an array of
products, including synthetically useful 3-vinylindoles. As early as 1887, Emil Fischer
[7]
reported the heating of 2-methylindole 1b with benzaldehyde and zinc chloride catalyst to
0
[8]
produce 3,3 -(phenylmethylene)bis(2-methyl-1H-indole). This early example depicts an
CONTACT Wayland E. Noland
nolan001@umn.edu
Department of Chemistry, University of Minnesota,
Minneapolis, MN 55455, USA.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2018 Taylor & Francis

2
W. E. NOLAND ET AL.
ubiquitous class of 2:1 condensation products commonly formed from two equivalents of
1
acid.
a with aldehydes or ketones under relatively mildly acid conditions, notably with acetic
[9–12]
[13]
Bisindoles, often referred to as diindolylalkanes,
have been found to be
in addition to fungal
[14–17]
important natural products of terrestrial and marine origin
metabolites.
processes such as anticarcinogenic
[18]
Bisindoles have also shown a pronounced significance in various biological
[19,20]
[21,22]
[13]
and antibacterial
activity, among others.
In 1913, Scholtz reported the condensation of 1a or 1-methylindole 1b with acetone 2
[23]
and other ketones in ethanolic hydrochloric acid.
In addition to a corresponding 2:1
–
H O bisindole product, a 2:2–2H O product was obtained from 1b with 2, which was
2
2
the incorrectly given cyclobutane structure 3b (Scheme 1). Two 2:2 –2H O condensation
2
products were obtained from 1a with 2; these were subsequently given structures 4a and
[
24–26]
[27,28]
5a by Bergman et al.
and our group
decades later. Additionally, compound
5b was determined to be the correct structure of 3b. Further studies by Banerji et al.
examined higher order condensation products from similar reactions of 1a and ketones
[
29–32]
in the presence of boron trifluoride diethyl etherate.
Products of type 6a were not
obtained from any methyl ketones; however, the corresponding analog of 6a is obtained
[
33]
from 2:2 condensation of 1a with cyclohexanone.
With this precedent of condensations of indoles with methyl ketones,
was directed to reactions with 1a and substituted acetophenones to find which types of
[
27,28,34,35]
focus
2
:1 or 2:2 products would form. There are numerous examples of reactions with indole
[
36–40]
and acetophenones
to 4a in the literature;
and a few examples of cyclopent[b]indoles structures similar
[
41–43]
however, examples of 2:2 condensation products of
indole with acetophenones are scarce. Black et al. reported that 9 is the product of
condensation of 4,6-dimethoxy-1-methlyindole 7 with acetophenone 8a, although no
[
44]
characterization data are given (Scheme 2).
Ferrer et al. reported a diastereomeric
mixture of analogs of 9 from a gold-catalyzed reaction of 1a with 3,5-bis(trifluorome-
[
45]
thylphenylacetylene).
acetophenones 8a–h in the presence of hydrochloric acid, producing mixtures of 2:1 and
:2 condensation products similar in structure to 4a and 9.
Here, we present condensation reactions of 1a with substituted
2
Scheme 1. 2:2 Condensation products of 1a, b with 2 in ethanolic HCl.
Scheme 2. Work of Black et al.: Reaction of 7 with 8a in ethanolic HCl.

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SYNTHETIC COMMUNICATIONS
3
Experimental
General information
Melting points were measured with a Mel-Temp apparatus, and were not corrected or
calibrated. R values were obtained using SiO in 1:2 EtOAc:hexane. Infrared spectra
f
2
TM
TM TM
1
were collected on a Thermo Fisher Scientific
NMR and C NMR spectra were recorded on an AV-500 Bruker Avance III HD, HD-
00 Bruker Avance III HD, or AM-400 Bruker Avance III HD spectrometers at ambient
Nicolet
iS 5 spectrophotometer. H
1
3
5
temperature and are referenced to the solvent. Mass spectra were recorded on a Bruker
Biotof II instrument using poly(ethylene glycol) as an internal calibrant, or on an
Agilent 7890B gas chromatograph using an Agilent DB-5MS 250 lm capillary column
with an Agilent 7200 GC/QTOF-MS detector calibrated with external perfluorotributyl-
amine. Reagents and solvents were used as purchased.
General procedures
ꢀ
Method A: Reactions of indole with acetophenones in ethanolic HCl at 20 C
Indole 1a (0.234 g, 2.00 mmol, 1 Eq.), naphthalene 10 (0.064 g, 0.50 mmol, 0.25 Eq.), and
acetophenone 8a–h (3.00 mmol, 1.5 Eq.) were dissolved in ethanol (10 mL).
Concentrated hydrochloric acid (1 mL) was added dropwise at room temperature. The
ꢀ
resulting solution was stirred at 20 C for 5 d. The reaction mixture was neutralized
using sat. sodium bicarbonate (25 mL) and the organic layer was extracted with
dichloromethane (4 ꢁ 25 mL). The combined organic extracts were dried with magne-
sium sulfate, filtered, and excess solvent was removed with a rotary evaporator. The
1
resulting mixtures were analyzed using H NMR spectroscopy, with naphthalene as the
internal integration standard. The crude mixture was dry-loaded onto silica gel and the
products were purified by column chromatography or MPLC using EtOAc:hexane as
the eluent.
ꢀ
Method B: Reaction of indole with acetophenones in ethanolic HCl at 40 C
ꢀ
This procedure is identical with Method A, except reactions were stirred at 40 C for
3
d before neutralization.
Method C: Reactions of indole with acetophenones in refluxing acetic acid
Indole 1a (1.171 g, 10.00 mmol, 1 Eq.) and acetophenone 8a–h (12.00 mmol, 1.2 Eq.)
were dissolved in AcOH (1 mL) and then refluxed overnight. The reaction mixture was
neutralized using sat. sodium bicarbonate (10 mL) and the organic layer was extracted
with dichloromethane (4 ꢁ 25 mL). The combined organic extracts were dried with
magnesium sulfate, filtered, and excess solvent was removed with a rotary evaporator.
The crude mixture was dry-loaded onto silica gel and purified by column chromatog-
raphy using EtOAc:hexane as the eluent, giving products 11a–h.
0
[46]
3
,3 -(1-phenylethane-1,1-diyl)bis(1H-indole) (11a)
was prepared by Method A
1
from 8a (361 mg) as a white crystalline powder; 130 mg, 37% (calcd by H NMR); mp

4
W. E. NOLAND ET AL.
ꢀ
ꢀ
ꢂ1
1
1
18–120 C (lit. 113–117 C); R ¼ 0.37; IR (KBr, cm ): 3412, 3053, 2977, 2936, 1490,
f
1
457, 1414, 1371, 1338, 1245, 1100, 1070, 1026, 1011, 742, 702; H NMR (500 MHz,
CD Cl ): d 8.011 (brs, 2H), 7.421–7.397 (m, 2H), 7.361 (d, J ¼ 8.2 Hz, 2H), 7.281–7.253
2
2
(
7
m, 4H), 7.227–7.193 (m, 1H), 7.111 (ddd, J ¼ 8.2, 7.0, 1.1 Hz, 2H), 6.894 (ddd, J ¼ 8.1,
13
.1, 1.1 Hz, 2H), 6.702 (d, J ¼ 2.5 Hz, 2H), 2.350 (s, 3H); C NMR (126 MHz, CD Cl ):
2
2
d 148.7, 137.7, 128.6, 128.3, 127.0, 126.4, 125.0, 123.9, 122.3, 122.0, 119.3, 111.8, 44.2,
2
þ
9.3; HRMS (ESI) m/z: [M þ Na] Calcd for C H N 359.1519; Found 359.1518.
24
20 2
rac-(1R,3S)-1,2,3,4-tetrahydro-3-(1H-indol-3-yl)-1-methyl-1,3-bis(4-methylphenyl)-
H-cyclopent[b]indole (12b) was prepared by Method A from 8b (402 mg) as an
1
1
ꢀ
off-white crystalline solid; 126 mg, 26% (calcd by H NMR); mp 168.5–172 C; R ¼ 0.39;
f
ꢂ1
IR (KBr, cm ): 3411, 3052, 3021, 2960, 2922, 2865, 1622, 1511, 1456, 1414, 1371, 1288,
1
1
243, 1187, 1097, 1068, 818, 743; H NMR (500 MHz, CD Cl ): d 8.125 (brs, 1H), 7.985
2
2
(
7
brs, 1H), 7.393 (d, J ¼ 8.2 Hz, 2H), 7.319 (d, J ¼ 8.1 Hz, 1H), 7.285 (d, J ¼ 8.2 Hz, 2H),
.168–7.043 (m, 8H), 6.966–6.939 (m, 4H), 3.554 (d, J ¼ 13.3 Hz, 1H), 3.434 (d,
13
J ¼ 13.4 Hz, 1H), 2.296 (s, 3H), 2.238 (s, 3H), 1.754 (s, 3H); C NMR (126 MHz,
CD Cl ): d 147.9, 147.6, 144.3, 141.8, 137.9, 136.2 135.6, 129.3, 129.2, 127.8, 126.8,
2
2
1
6
26.7, 125.0, 124.8, 123.3, 123.1, 122.6, 121.7, 121.1, 120.2, 120.0, 119.7, 112.5, 112.0,
þ
5.1, 51.7, 47.6, 30.1, 21.2, 21.1; HRMS (EI) m/z: [M] Calcd for C H N 466.2404;
34
30 2
Found 466.2413.
rac-(1R,3R)-1,2,3,4-tetrahydro-3-(1H-indol-3-yl)-1-methyl-1,3-bis(4-aminophenyl)-
H-cyclopent[b]indole (13c) was prepared according to Method A from 8c (406 mg) as
1
1
ꢀ
a red crystalline solid; 37.5 mg, 7.5% (calcd by H NMR); mp 190–193 C; R ¼ 0.38; IR
f
ꢂ1
(
KBr, cm ): 3411, 3335, 3213, 3052, 2958, 2921, 2862, 1620, 1512, 1449, 1290, 1244,
183, 1103, 1043, 829, 744; H NMR (400 MHz, (CD ) SO): d 10.870 (s, 1H), 10.709 (s,
1
1
1
7
6
3 2
H), 7.321 (d, J ¼ 8.0 Hz, 1H), 7.260 (d, J ¼ 8.1 Hz, 1H), 7.203 (d, J ¼ 7.8 Hz, 1H),
.070–6.896 (m, 8H), 6.733 (ddd, J ¼ 8.0, 1.2, 1.0 Hz, 1H), 6.593 (d, J ¼ 2.5 Hz, 1H),
.497 (d, J ¼ 8.6 Hz, 2H), 6.437 (d, J ¼ 8.5 Hz, 2H), 4.892 (s, 2H), 4.767 (s, 2H), 3.302 (d,
1
3
J ¼ 13.1 Hz, 1H), 3.254 (d, J ¼ 13.1 Hz, 1H), 1.564 (s, 3H); C NMR (126 MHz, CD Cl ):
2
2
d 147.6, 145.5, 144.8, 141.6, 140.9, 138.2, 137.6, 128.8, 127.7, 126.7, 125.3, 124.8, 123.5,
1
4
22.4, 122.2, 121.4, 120.9, 120.1, 119.8, 119.6, 115.32, 115.26, 112.5, 111.9, 66.0, 51.5,
þ
7.1, 29.8; HRMS (ESI) m/z: [M þ Na] Calcd for C H N 491.2206; Found 491.2201.
32
28 4
Results and discussion
Indole 1a (1 Eq.) reacted with eight acetophenones 8a–h (1.5 Eq.) in a solution of
ethanol and hydrochloric acid. A small quantity of naphthalene 10 was added as an
ꢀ
internal NMR standard. The resulting mixtures were stirred at 20 C for 5 days, or
ꢀ
4
0 C for 3 days. The organics were extracted, neutralized, concentrated, and then
separated by column chromatography. Yields of the corresponding 2:1 condensation
products, 3,3-(1-phenylethane-1,1-diyl)bis(1H-indoles) (11a–h), and 2:2 condensation
products, diastereomers of 1,2,3,4-tetrahydro-3-(1H-indol-3-yl)-1-methyl-1,3-diphenylcy-
clopent[b]indoles (12a–h, syn; 13a–h, anti), are listed in Table 1.
þ
Compared to 8a, the ketones with electron-withdrawing groups, 8c (as R ¼ NH ),
3
and 8f–h, gave higher 2:1 and lower 2:2 condensation yields. Conversely, the electron-
rich ketones, 8b, 8d, and 8e favored 2:2 condensation. Increasing the temperature from
ꢀ
2
0 to 40 C gave higher yields of the 2:2 products, and lower 2:1 yields. The reaction

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SYNTHETIC COMMUNICATIONS
5
Table 1. Condensation products from the reaction of 1a with acetophenone 8a–h in ethanolic HCl.
ꢀ
a
a
a
b
c
Entry Acetophenone Temp ( C)
#
Yield (11a–h, %)
#
Yield (12a–h, %)
#
Yield (13a–h, %) Sum (%) dr
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
a
8a, R ¼ H
20
40
20
40
20
40
20
40
20
40
20
40
20
40
20
40
1
11a
37
7
12a
19
23
26
20
2.2
4
17
23
41
34
11
26
1.9
5.9
11
27
13aꢃ
16
24
26
26
7.5
4.5
14
25
19
34
13
25
9.5
21
13
25
35
47
52
46
9.7
8.5
31
48
60
68
24
51
55:46
49:51
50:50
43:57
23:77
47:53
55:45
48:52
68:32
50:50
46:54
51:49
8b, R ¼ p-CH
3
11b
11c
11d
11e
11f
14
4.2
78
16
28
13
14
4.4
55
24
67
61
53
38
12b
12cꢃ
12d
12e
12f
13b
13c
8c, R ¼ p-NH
2
8d, R ¼ p-OCH
3
13dꢃ
13eꢃ
13f
8e, R ¼ m-OCH
8f, R ¼ p-Cl
3
0
1
2
3
4
5
6
8g, R ¼ p-NO
8h, R ¼ p-Br
2
11g
11h
12g
12h
13gꢃ
13h
11.4 17:83
26.9 22:78
24
52
46:54
52:48
Yields were calculated by H NMR.
b
c
1
Summed yield of 12a–h and 13a–h from each mixture (calcd by H NMR).
Diastereomeric ratio (dr) of 2:2 condensation products 12a–h:13a–h.
ꢃ
Product could not be purely isolated as a single epimer by preparative liquid chromatography.
time was shortened from 5 to 3 days; however, the increased rate of 2:2 product forma-
tion came at the cost of lower total yield and formation of dark, tarry by-products. At
either temperature, the diastereomeric ratios (dr) of 2:2 products were fairly close to
5
0:50 for most substrates, except the strongly electron-withdrawing acetophenones 8c
and 8g. Increasing the reaction temperature tended to push the dr closer to 50:50.
Overall, the syn isomer 12 was slightly preferred, except for products derived from 8c
and 8g, which showed a strong preference for the anti isomer 13. Reaction temperatures
ꢀ
1
above 40 C gave tarry mixtures.
In the H NMR spectra of product mixtures, bisindoles 11a–h can be easily identified
by the presence of two signals: a 2H strong doublet between 6.72 and 6.67 ppm, with a
coupling constant of roughly 2 Hz, representing the indol-2-yl protons, and a 3H singlet
between 2.39 and 2.24 ppm, representing the methyl group. The 2:2 products 12a–h and
13a–h can be identified by three key signals: two 1H doublets between 3.75 and
3
.15 ppm, representing the diastereotopic CH protons, and a 3H singlet between 1.85
2
and 1.70 ppm representing the methyl group. The epimers were distinguished by
Nuclear Overhauser Effect (NOE) experiments (Fig. 1a). The methylene (H , H ; H ,
a
b
w
H ), indol-2-yl (H ; H ), and methanetriyl (H ; H ) protons were individually irradiated.
x
c
y
d
z
The NOE enhancements showed that for all epimeric mixtures, the “outer” pair of
methylene doublets near 3.5 ppm corresponded to the anti isomer 13a–h, and the
“inner” pair of doublets corresponded to the syn isomer 12a–h (Fig. 1b).

6
W. E. NOLAND ET AL.
Figure 1. (a) Selected NOE enhancements of the methylene protons in 12a and 13a; (b) The “outer”
1
1
3a and “inner” 12a pairs of methylene doublets in a H NMR spectrum containing both epimers.
The mechanistic routes to 2:1 products 11a–h and 2:2 products 12a–h and 13a–h are
hypothesized to be similar to those described by Bergman et al. for the condensation of
[26]
indole 1a with acetone (Scheme 3).
Acid-promoted nucleophilic attack of the 3-position
of 1a at the carbonyl C atom of 8a, followed by dehydration, gives intermediate 14. Attack
of a second molecule of 1a leads to bisindole 11a. Alternatively, proton loss from 14 gives
15, which can add to another molecule of 14, giving 16. Cyclization of 16 and loss of a
proton gives 12a or 13a, depending on which face of the indolenium system in 16 was
facing the neutral indole unit during cyclization. The phenyl ring in acetophenones 8a–h
prevents the formation of tetrahydrocarbazoles of type 5a (Scheme 1).
[9–12]
Refluxing acetic acid (AcOH), commonly used to form bisindoles,
an alternate reaction condition (Table 2). No 2:2 products were observed. Except for
1e, the bisindole yields were lower in AcOH than ethanolic HCl. However, the AcOH
was tried as
1
reaction mixtures were less complicated, so purification of the 2:1 products was easily
accomplished by column chromatography. As was the case from HCl, the highest yields
were obtained from electron-deficient ketones 8f–h. The electron-rich ketones 8d, e
performed moderately well, with electron neutral 8a, b performing poorly. The bisindole
11a–h yields in Tables 1 and 2 do not correlate well with the substituent effects on rate
constants in an acetophenone reduction study performed by Cs u~ r o€ s and coworkers with
[
47]
triisopropyl aluminate,
suggesting that different rate-determining factors apply to the
electrophilicity of acetophenones in the presence of Brønsted acids. The biggest outlier
was 8c in AcOH, from which no products were obtained, consistent with the amino
group not being appreciably protonated.
Conclusion
Bisindoles 11a–h and two epimers of 2:2 condensation products 12a–h and 13a–h were
obtained from indole 1a and acetophenones 8a–h in ethanolic HCl. All three product
types were obtained from each ketone, and these mixtures were difficult to separate by
preparative chromatography. No other isomers of 2:2 condensation were observed.
Electron-deficient acetophenones favored formation of 2:1 condensation structures, while

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SYNTHETIC COMMUNICATIONS
7

8
W. E. NOLAND ET AL.
Table 2. Reaction of 1a with 8a–h in refluxing acetic acid.
a
Entry
Acetophenone
#
Yield (%)
1
2
3
4
5
6
7
8
a
8a, R ¼ H
11a
11b
11c
11d
11e
11f
6
2.6
8b, R ¼ p-CH
3
ꢃ
8c, R ¼ p-NH
2
nr
20
38
46
37
48
8d, R ¼ p-OCH
3
8e, R ¼ m-OCH
8f, R ¼ p-Cl
3
8g, R ¼ p-NO
2
11g
11h
8h, R ¼ p-Br
Yields of 11a–h are reported after purification by column chromatography.
ꢃ
No reaction was observed, returning only starting materials.
electron-rich acetophenones favored 2:2 condensation. Increasing the reaction tempera-
ꢀ
ture from 20 to 40 C gave higher 2:2 condensation yields and decreased the reaction
time, but higher temperatures gave poor results. The syn 12a–h and anti 13a–h epimers
1
can be distinguished based on the chemical shifts of the H NMR signals generated by
the cyclopentyl methylene protons. Replacing ethanolic HCl with refluxing acetic acid
gave only bisindoles 11a–h, and at lower yields than in HCl, however, these mixtures
were easily separated by column chromatography.
Acknowledgment
[
48]
A large portion of this work is from the MS thesis of Rodney D. DeKruif.
Funding
The authors thank the Wayland E. Noland Research Fellowship Fund at the University of
Minnesota Foundation for generous financial support of this project.
ORCID
Wayland E. Noland
http://orcid.org/0000-0001-8183-0767
References
[
1] Gul, W.; Hamann, M. Indole Alkaloid Marine Natural Products: An Established Source of
Cancer Drug Leads with Considerable Promise for the Control of Parasitic, Neurological
and Other Diseases. Life Sci. 2005, 78, 442–453.
[
2] Pindur, U.; Lemster, T. Advances in Marine Natural Products of the Indole and Annelated
Indole Series: Chemical and Biological Aspects. Curr. Med. Chem. 2001, 8, 1681–1698.

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9
[
[
[
3] Sundberg, R. J.; Katritzky, A. R.; Meth-Cohn, O.; Rees, C. S. Indoles; Academic Press:
London, 1996.
4] Gribble, G. W. Recent Developments in Indole Ring Synthesis: Methodology and
Applications. J. Chem. Soc., Perkin Trans. 1. 2000, 7, 1045–1075.
5] He, L.; Chang, H.-X.; Chou, T.-C.; Savaraj, N.; Cheng, C. C. Design of Antineoplastic
Agents Based on the ‘2-Phenylnaphthalenetype’ Structural Pattern/Synthesis and Biological
Activity Studies of 11H-Indolo[3.2-c]Quinoline Derivatives. Eur. J. Med. Chem. 2003, 38,
101–107.
[
6] Kuo, C.-C.; Hsieh, H.-P.; Pan, W.-Y.; Chen, C.-P.; Liou, J.-P.; Lee, S.-J.; Chang, Y.-L.;
Chen, L.-T.; Chen, C.-T.; Chang, J.-Y. BPR0L075, a Novel Synthetic Indole Compound
with Antimitotic Activity in Human Cancer Cells, Exerts Effective Antitumoral Activity in
Vivo. Cancer Res. 2004, 64, 4621–4628.
[
7] Noland, W. E.; Wahlstrom, M. J.; Konkel, M. J.; Brigham, M. E.; Trowbridge, A. G.;
Konkel, L. M. C.; Gourneau, R. P.; Scholten, C. A.; Lee, N. H.; Condoluci, J. J.; et al.
In Situ Vinylindole Synthesis. Diels-Alder Reactions with Maleimides to Give
Tetrahydrocarbazoles. J. Heterocycl. Chem. 1993, 30, 81–91.
[
[
8] Fischer, E. Ueber das Methylketol. Liebigs. Ann. Chem. 1887, 242, 372–383.
9] El Sayed, M. T.; Ahmed, K. M.; Mahmoud, K.; Hilgeroth, A. Synthesis, Cytostatic
Evaluation and Structure Activity Relationships of Novel Bis-Indolylmethanes and Their
Corresponding Tetrahydroindolocarbazoles. Eur. J. Med. Chem. 2015, 90, 845–859.
[
[
[
10] Gray, A. P.; Archer, W. L. The Pyridylethylation of Indole and Related Reactions. J. Am.
Chem. Soc. 1957, 79, 3554–3559.
11] Kamal, A.; Qureshi, A. A. Syntheses of Some Substituted Di-Indolyl-Methanes in Aqueous
Medium at Room Temperature. Tetrahedron. 1963, 19, 513–520.
12] Singh, H.; Singh, K. Carbon Transfer Reactions with Heterocycles-IV: Synthetic
Equivalence of Perhydrooxazines with Carbonyl Compounds. A Facile Synthesis of
Streptindole and Analogues. Tetrahedron. 1988, 44, 5897–5904.
[13] Chakrabarty, M.; Basak, R.; Harigaya, Y. A Sojourn in the Synthesis and Bioactivity of
Diindolylalkanes. Heterocycles. 2001, 55, 2431–2447, and references cited therein.
[14] Fahy, E.; Potts, B. C. M.; Faulkner, D. J.; Smith, K. 6-Bromotryptamine Derivatives from
the Gulf of California Tunicate Didemnum candidum. J. Nat. Prod. 1991, 54, 564–569.
[15] Bell, R.; Carmeli, S.; Sar, N. Vibrindole A, a Metabolite of the Marine Bacterium, Vibrio
parahaemolyticus, Isolated from the Toxic Mucus of the Boxfish Ostracion cubicus. J. Nat.
Prod. 1994, 57, 1587–1590.
[
16] Bifulco, G.; Bruno, I.; Riccio, R.; Lavayre, J.; Bourdy, G. Further Brominated Bis- and
Tris-Indole Alkaloids from the Deep-Water New Caledonian Marine Sponge Orina Sp. J.
Nat. Prod. 1995, 58, 1254–1260.
[17] Garbe, T. R.; Kobayashi, M.; Shimizu, N.; Takesue, N.; Ozawa, M.; Yukawa, H. Indolyl
Carboxylic Acids by Condensation of Indoles with a-Keto Acids. J. Nat. Prod. 2000, 63,
596–598.
[18] Porter, J. K.; Bacon, C. W.; Robbins, J. D.; Himmelsbach, D. S.; Higman, H. C. Indole
Alkaloids from Balansia epichlo €e (Weese). J. Agric. Food Chem. 1977, 25, 88–93.
[
19] Hong, C.; Firestone, G. L.; Bjeldanes, L. F. Bcl-2 Family-Mediated Apoptotic Effects of
0
3,3 -Diindolylmethane (DIM) in Human Breast Cancer Cells. Biochem. Pharmacol. 2002,
6
3, 1085–1097.
0
[
20] Rahimia, M; Huanga, K.-L.; Tang, C. K. 3,3 -Diindolylmethane (DIM) Inhibits the Growth
and Invasion of Drug-Resistant Human Cancer Cells Expressing EGFR Mutants. Cancer
Lett. 2010, 295, 59–68.
[
[
21] Osawa, T.; Namiki, M. Structure Elucidation of Streptindole, a Novel Genotoxic
Metabolite Isolated from Intestinal Bacteria. Tetrahedron Lett. 1983, 24, 4719–4722.
22] Opperman, T. J.; Kwasny, S. M.; Li, J. B.; Lewis, M. A.; Aiello, D.; Williams, J. D.;
Peet, N. P.; Moir, D. T.; Bowlin, T. L.; Long, E. C. DNA Targeting as a Likely Mechanism
Underlying the Antibacterial Activity of Synthetic Bis-Indole Antibiotics. Antimicrob.
Agents Chemother. 2016, 60, 7067–7076.

1
0
W. E. NOLAND ET AL.
€
[
[
[
23] Scholtz, M. Uber die Einwirkung aliphatischer Ketone auf Indol und seine Homologen
and u€ ber polymere Indole. Ber. Dtsch. Chem. Ges. 1913, 46, 1082–1089.
24] Bergman, J.; H o€ gberg, S.; Lindstr o€ m, J.-O. Macrocyclic Condensation Products of Indole
and Simple Aldehydes. Tetrahedron. 1970, 26, 3347–3352.
25] Bergman, J. Condensation of Indole and Formaldehyde in the Presence of Air and
Sensitizers: A Facile Synthesis of Indolo [3.2-b] Carbazole. Tetrahedron. 1970, 26,
3353–3355.
[
[
[
26] Bergman, J.; Norrby, P.-O.; Tilstam, U.; Venemalm, L. Structure Elucidation of Some
Products Obtained by Acid-Catalyzed Condensation of Indole with Acetone. Tetrahedron.
1
989, 45, 5549–5564.
27] Noland, W. E.; Richards, C. G.; Desai, D. S.; Venkiteswaran, M. R. Cyclizative
Condensations. III. Indole and 1-Methylindole with Methyl Ketones. J. Org. Chem. 1961,
26, 4254–4262.
28] Noland, W. E.; Venkiteswaran, M. R. Cyclizative Condensations. IV. 3,3’-
Alkylidenebisindoles from Methyl Ketones and Their Conversion to Indolo[2,3-b]
Carbazoles. J. Org. Chem. 1961, 26, 4263–4269.
[
[
[
29] Banerji, J.; Chatterjee, A.; Manna, S.; Pascard, C.; Prange, T.; Shoolery, J. N. Lewis Acid
Induced Electrophilic Substitution of Indole: Part 3. Heterocycles. 1981, 15, 325–326.
30] Banerji, J.; Mustafi, R.; Shoolery, J. N. Lewis Acid Induced Electrophilic Substitution of
Indoles: Part 6. Heterocycles. 1982, 20, 1355–1362.
31] Banerji, J.; Saha, R.; Manna, A. P.; Shoolery, J. N.; Prange, T.; Pascard, C. Electrophilic
Substitution of Indoles. Part IV Addition & Annulation Reactions with Mesityl Oxide.
Indian J. Chem. 1982, 21B, 83–87.
[
32] Banerji, J.; Saha, M.; Kanrar, S.; Chakrabarti, R.; Grover, N. J. Lewis Acid-Catalyzed
Electrophilic Substitution of Indoles: Part XIII – Reaction of Indole with Phorone. Indian
J. Chem. 1993, 32B, 730–732.
0 0
33] Guzei, I. A.; Spencer, L. C.; Codner, E.; Boehm, J. M. 5 ,11 -Dihydrodispiro[Cyclohexane-
[
0
0
00
1
,6 -Indolo[3,2-b]Carbazole-12 ,1 -Cyclohexane]. Acta Crystallogr. Sect. E. 2012, 68, o1–o2.
[34] Noland, W. E.; Venkiteswaran, M. R.; Richards, C. G. Cyclizative Condensations. I.
2
4
-Methylindole with Acetone and Methyl Ethyl Ketone. J. Org. Chem. 1961, 26,
241–4248.
[35] Noland, W. E.; Venkiteswaran, M. R.; Lovald, R. A. Cyclizative Condensations. II. 2-
Methylindole with Methyl Ketones. J. Org. Chem. 1961, 26, 4249–4254.
[
36] Zhu, Y.-P.; Liu, M.-C.; Jia, F.-C.; Yuan, J.-J.; Gao, Q.-H.; Lian, M.; Wu, A.-X. Metal-Free
3
sp C-H Bond Dual-(Het)arylation: I -Promoted Domino Process to Construct 2,2-
2
Bisindolyl-1-Arylethanones. Org. Lett. 2012, 14, 3392–3395.
37] Tabatabaeian, K.; Mamaghani, M.; Mahmoodi, N.; Khorshidi, A. Efficient Ru -Catalyzed
III
[
[
[
Condensation of Indoles and Aldehydes or Ketones. Can. J. Chem. 2006, 84, 1541–1545.
38] Li, J.-T.; Sun, S.-F. Synthesis of Diindolylmethanes (DIMs) Catalyzed by Silicotungstic
Acid by Grinding Method. E- J. Chem. 2010, 7, 922–926.
39] Kumar, G. S.; Kumar, A. S.; Swetha, A.; Babu, B. M.; Meshram, H. M. An Unexpected
C-C Bond Cleavage of Acetophenones: Synthesis of Bis(Heteroaryl)Arylmethanes and
Triarylmethanes via SeO /Lanthanide Chloride Catalyzed Friedel–Crafts Arylation. Synlett.
2
2
016, 27, 631–639.
[
40] Zolfigol, M. A.; Salehi, P.; Shiri, M. An Efficient Procedure for the Preparation of Mono,
and Di-Bis-Indolylmethanes Catalyzed by Molibdatophosphoric Acid. Phosphorus, Sulfur
Silicon Relat. Elem. 2004, 179, 2273–2277.
[41] Eitel, M.; Pindur, U. Reactions of 2-Vinylindoles with Carbodienophiles: Synthetic and
Mechanistic Aspects. J. Org. Chem. 1990, 55, 5368–5374.
[
42] Schollmeyer, D.; Fischer, G.; Pindur, U. Dimeric 3-Vinylindoles as Potential
Antitumor Active Compounds: 1,1,3,4-Tetramethyl-3-(1-Methyl-1H-Indol-3-yl)-1,2,3,4-
Tetrahydrocyclopenta[b]Indole and 1,1,3-Trimethyl-4-Phenylsulfonyl-3-(1-Phenylsulfonyl-
1H-Indol-3-yl)-1,2,3,4-Tetrahydrocyclopenta[b]Indole. Acta Cryst. 1995, C51, 2572–2575.

V
R
SYNTHETIC COMMUNICATIONS
11
[43] Xu, B.; Guo, Z.-L.; Jin, W.-Y.; Wang, Z.-P.; Peng, Y.-G.; Guo, Q.-X. Multistep One-Pot
Synthesis of Enantioenriched Polysubstituted Cyclopent[b]indoles. Angew. Chem. Int. Ed.
2
012, 51, 1059–1062.
[
[
[
[
44] Black, D. C.; Craig, D. C.; Kumar, N. Acid-Catalyzed Reactions of Activated Indoles with
Methyl Ketones. Tetrahedron Lett. 1991, 32, 1587–1590.
45] Ferrer, C.; Amijs, C. H. M.; Echavarren, A. Intra- and Intermolecular Reactions of Indoles
with Alkynes Catalyzed by Gold. M. Chem. Eur. J. 2007, 13, 1358–1373.
46] Luo, C.; Yang, H.; Mao, R.; Lu, C.; Cheng, G. An Efficient Au(I) Catalyst for Double
Hydroarylation of Alkynes with Heteroarenes. New J. Chem. 2015, 39, 3417–3423.
ꢀ
47] Cs u~ r o€ s, Z.; K ꢀa lm ꢀa n, V.; Lengyel-M ꢀe z ꢀa ros, A.; Petr oꢀ , J. Study of the Correlation between
Structure and Reducibility of Acetophenone Derivatives: I. The Validity of the Hammett
Equation in the Meerwein-Ponndorf-Verley Reduction of Acetophenone Derivatives.
Period. Polytech., Chem. Eng. 1968, 12, 161–179.
[48] DeKruif, R. D. Condensation Reactions of Indole with Acetophenones: Substituent Effects
and Reaction Conditions. MS Thesis, University of Minnesota, 1982.