Hydrated ferric sulfate-catalyzed reactions of indole with aldehydes, ketones, cyclic ketones, and chromanones: Synthesis of bisindoles and trisindoles

Article abstract of DOI:10.1016/j.tet.2017.05.061

Hydrated ferric sulfate [Fe₂(SO₄)₃·xH₂O] has been found to be an efficient catalyst for condensation of bisindoles or trisindoles with aliphatic or aryl aldehydes and ketones including methyl and ethyl-alkyl ketones, methyl aryl ketones, cyclic ketones, and 4-chromanones in 19–96% yields. Trisindoles and 2,2'-alkylidenebisindoles were obtained from indole-3-carbaldehydes or 3-methylindole in 72–84% yields. A total of 43 substrates was employed, giving 33 bisindoles, 3 trisindoles, and one 2:2 product; seventeen of these are new. The best results were obtained from heating ethanolic suspensions, with Fe₂(SO₄)₃·xH₂O loaded at 60 mg per mmol of electrophiles. The reaction times were typically 1–4 h, while hindered electrophiles required 8–24 h. These conditions were strong enough to promote 2:1 condensation of indole with substrates without forming higher-order byproducts, with few exceptions. This strategy features tolerance by the catalyst of a wide range of functional groups, readily available starting materials, simple operation, mild reaction conditions, and is environmentally friendly.

Full text of DOI:10.1016/j.tet.2017.05.061

Accepted Manuscript
Hydrated ferric sulfate-catalyzed reactions of indole with aldehydes, ketones, cyclic
ketones, and chromanones: Synthesis of bisindoles and trisindoles
Wayland E. Noland, Honnaiah Vijay Kumar, Grant C. Flick, Cole L. Aspros, Jong
Hyeon Yoon, Andre C. Wilt, Nasim Dehkordi, Sheng Thao, Andrew K. Schneerer,
Siming Gao, Kenneth J. Tritch
PII:
S0040-4020(17)30547-1
10.1016/j.tet.2017.05.061
TET 28727
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 17 April 2017
Revised Date: 10 May 2017
Accepted Date: 16 May 2017
Please cite this article as: Noland WE, Kumar HV, Flick GC, Aspros CL, Yoon JH, Wilt AC, Dehkordi
N, Thao S, Schneerer AK, Gao S, Tritch KJ, Hydrated ferric sulfate-catalyzed reactions of indole
with aldehydes, ketones, cyclic ketones, and chromanones: Synthesis of bisindoles and trisindoles,
Tetrahedron (2017), doi: 10.1016/j.tet.2017.05.061.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Hydrated Ferric Sulfate-Catalyzed Reactions of Indole
with Aldehydes, Ketones, Cyclic Ketones, and Chromanones:
Synthesis of Bisindoles and Trisindoles
Wayland E. Noland*, Honnaiah Vijay Kumar, Grant C. Flick, Cole L. Aspros,
Jong Hyeon Yoon, Andre C. Wilt, Nasim Dehkordi, Sheng Thao,
Andrew K. Schneerer, Siming Gao, and Kenneth J. Tritch
Department of Chemistry, University of Minnesota
2
07 Pleasant St. SE, Minneapolis, Minnesota, 55455, USA
E-mail: nolan001@umn.edu
1

ACCEPTED MANUSCRIPT
2 4 3 2
ABSTRACT: Hydrated ferric sulfate [Fe (SO ) •xH O] has been found to be an efficient catalyst
for condensation of bisindoles or trisindoles with aliphatic or aryl aldehydes and ketones
including methyl and ethyl-alkyl ketones, methyl aryl ketones, cyclic ketones, and 4-
chromanones in 19–96% yields. Trisindoles and 2,2'-alkylidenebisindoles were obtained from
indole-3-carbaldehydes or 3-methylindole in 72–84% yields. A total of 43 substrates was
employed, giving 33 bisindoles, 3 trisindoles, and one 2:2 product; seventeen of these are new.
2 4 3 2
The best results were obtained from heating ethanolic suspensions, with Fe (SO ) •xH O loaded
at 60 mg per mmol of electrophiles. The reaction times were typically 1–4 h, while hindered
electrophiles required 8–24 h. These conditions were strong enough to promote 2:1 condensation
of indole with substrates without forming higher-order byproducts, with few exceptions. This
strategy features tolerance by the catalyst of a wide range of functional groups, readily available
starting materials, simple operation, mild reaction conditions, and is environmentally friendly.
Keywords: Ferric sulfate, Bisindole, Trisindole, Chromanone, Cyclic ketone, Aldehyde
2

ACCEPTED MANUSCRIPT
1
. Introduction
The development of syntheses of bisindoles also called alkylidenebisindol, or
bisindolylmethanes is of interest because of their structural simplicity and pharmacological
1
activities. 3,3'-Bisindoles and their derivatives are found as metabolites of a wide range of
2
3
4
eukaryotes, notably cruciferous plants. Several coumarin and benzofuran bisindole derivatives
have demonstrated antihyperlipidemic activity, and methanetriyltris(heteroaryl) compounds have
5
demonstrated useful electrochemical properties. Most studies have targeted 3,3'-bisindole
6
derivatives, but the less explored 2,2'-bisindoles have also shown anticancer potential.
Bisindoles were originally obtained as precipitates from solutions of indoles and aryl
7
aldehydes in glacial acetic acid. However, acetic acid can be ineffective when a starting material
is more sterically hindered than α-unbranched methyl ketones or aldehydes, which frequently
8
leads to slow conversion or poor selectivity. Recently, increasingly diverse syntheses of
9
10
bisindoles have been reported. Catalysts include Lewis-acidic halides , ionic liquids,
1
1
12
13
14
surfactants, adsorbent-sulfuric acids, chiral Bronsted acids and montmorillonite clay.
It is desirable to maintain the simplicity of a catalyst like acetic acid while expanding the
scope of obtainable bisindoles. Increasing the temperature or acidity to promote condensation
with less reactive substrates is a straightforward strategy; however, this can favor the formation
of higher-order products and dimerization of the indole. Examples include the 2:2 condensation
1
5
of indole with methyl ketones in ethanolic HCl, and products of 2:2 (–2H O) or higher-order
2
16
17
condensation, sometimes accompanied by autoxidation, in the presence of H SO4 or BF3.
2
Although higher-order products are interesting, their presence can complicate the process of
bisindole isolation.
3

ACCEPTED MANUSCRIPT
Several iron(III) catalysts have shown promise. Hydrates of ferric chlorides and nitrates
1
8
19
in ionic liquids as well as silica-coated Fe O nanoparticles have shown good selectivity for
2
3
2
:1 (–H O) condensation of indole with aldehydes. Ferric dodecyl sulfate has shown broader
2
reactivity, catalyzing 2:1 (–H O) condensation of indoles with acetophenones and
2
2
0
cyclohexanones in good yields.
In the present work, hydrated ferric sulfate [Fe (SO ) •xH O], was employed as a
2
4 3
2
2 4 3 2
simplified form of ferric dodecyl sulfate. Other reports have shown Fe (SO ) •xH O to promote
2
1
22
23
tetrahydropyranylations, glycosylations
and O-acylations, as well as syntheses of
2
4
25
tetrahydroquinolines
and pyrazole-4-carbodithioates.
Previous studies concluded that
18
Fe (SO ) was unsuccessful in promoting bisindole formation in ionic liquids. To the best of
2
4 3
our knowledge, this report presents the first detailed investigation of ferric sulfate-promoted
bisindole syntheses from aldehydes, alkyl ketones, including ethyl ketones, cyclic ketones, and
chromanones.
2
. Results and Discussion
We began our investigation using indole and benzaldehyde as model substrates. Initially,
the one-pot reaction was carried out in the presence of indole (1a, 2 mmol), benzaldehyde (2a, 1
mmol), and hydrated ferric sulfate (20 mg) in ethanol (5 mL) at room temperature for 15 h. The
desired product, bisindole 3a, was isolated in 64% yield (Table 1, entry 2). The structure of 3a
1
13
was confirmed by H and C NMR, and MS analyses. When the experiment was repeated in the
absence of Fe (SO ) •xH O or other catalysts, no 3a was observed (Table 1, entry 1). Increasing
2
4 3
2
the amount of Fe (SO ) •xH O to 60 mg gave up to yield of 93% (Table 1, entry 4); but yields
2
4 3
2
diminished drastically with higher catalyst loads (Table 1, entries 5 and 6).
4

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Table 1. Results of catalyst and solvent screening for the model reaction of indole (2 mmol) with
benzaldehyde (1 mmol).
b
Entry
Catalyst
Catalyst load
Solvent
Temp.
ºC
Time
h
Yield
%
c
1
2
3
4
5
6
7
8
9
none
0
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeOH
DCM
EA
reflux
rt
24
15
1
0
Fe (SO ) •xH O
20 mg/mmol
40 mg/mmol
60 mg/mmol
80 mg/mmol
100 mg/mmol
15 mol%
64
86
93
57
52
6
2
4 3
2
Fe (SO ) •xH O
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
2
4 3
2
Fe (SO ) •xH O
1
2
4 3
2
Fe (SO ) •xH O
1
2
4 3
2
Fe
2
(SO
Fe
CH COOH
4
)
3
•xH
2
O
2
2
O
3
24
3
3
15 mol%
53
67
45
32
12
75
52
50
46
45
78
Sc(OTf)3
15 mol%
10
3
1
0
1
CF COOH
15 mol%
3
1
HCl
15 mol%
2
1
1
1
1
1
1
1
2
3
4
5
6
7
8
FeCl3
15 mol%
15
24
24
24
24
24
24
Fe (SO ) •xH O
60 mg/mmol
60 mg/mmol
60 mg/mmol
60 mg/mmol
60 mg/mmol
2
2
2
4 3
2
2
2
Fe
Fe
(SO
4
4
)
3
3
•xH
•xH
O
O
(SO
)
Fe (SO ) •xH O
THF
2
4 3
2
Fe (SO ) •xH O
CHCl3
2
4 3
2
Fe (SO ) •xH O
60 mg/mmol
1:1 H O:EtOH
2
4 3
2
2
a
b
c
Based on electrophile. Isolated yields of bisindole 3a. No reaction was observed.
5

ACCEPTED MANUSCRIPT
Various alternative catalysts were then investigated at 15 mol% loading, which roughly
corresponds to the amount of ferric sulfate present in entry 4. Acetic acid, iron (III) oxide, and
scandium (III) triflate showed good selectivity for 2:1 (–H O) condensation, but slow conversion
2
(Table 1, entries 7–9). Trifluoroacetic acid, hydrochloric acid, and iron (III) chloride showed
conversion rates comparable to Fe (SO ) •xH O, but numerous byproducts were observed by
2
4 3
2
TLC and NMR analyses (Table 1, entries 10–12). Having found ferric sulfate to be the best
catalyst, we turned to the effect of the solvent (Table 1, entries 13–17). Ethanol provided
superior yields of the 2:1 product. Following the optimization experiments, and experimentation
with solvent volume at larger scales, the standard condition was established as 5 mmol of
substrate, 10 mmol of indole, and 300 mg of Fe (SO ) •xH O, suspended in 25 mL of refluxing
2
4 3
2
ethanol.
During the course of these reactions we observed that the initial yellow color of the
suspension changed to dark red, providing a clue to the mechanistic pathway of this reaction.
When the model experiment was carried out in the absence of indole, this color change was still
observed, suggesting that coordination between the benzaldehyde carbonyl and iron (III) may be
responsible. Further evidence was deduced from the observed decrease in reaction rates with
greater amounts of ferric sulfate (Table 1, entries 5 and 6). These results led us to believe that
oligomeric iron-carbonyl aggregation obstructs the attack of indole on the iron-bound substrate.
It was considered that the diminished yields were due to some interference by excess water from
the hydrated catalyst. However, substituting 1:1 H O:EtOH for EtOH only modestly decreased
2
the rate of formation of bisindole 3a (Table 1, entry 18).
Assuming the initial formation of an iron (III) complex, the remaining steps are assumed
to follow the generally accepted pathway for acid-catalyzed 2:1 (–H
2
O) condensation of indole
6

ACCEPTED MANUSCRIPT
1
a
with carbonyl compounds (Scheme 1). The mechanism of formation of 2,2'-alkylidene
bisindoles from 3-substituted indoles likely proceeds through quaternization of the indole 3-
9
b
position, followed by a Plancher rearrangement.
indole
–
cat.
1O
1
a
–
cat.
R
R2
H
O+
O
b
R R2
1
R R2
1
–
NH+
a
cat.
OH
c
cat. = Fe (SO ) •xH O
2
4 3
2
1
2
R R
H O
2
e
NH
H
NH+
d
R R2
1
R1
R2
1a
–
cat.
OH
N
N
N+
H
H
H
Scheme 1. The proposed reaction mechanism is: (a) Coordination of the carbonyl O atom with an
Fe atom, with color change; (b) Nucleophilic attack by an indole-3-C atom at the carbonyl C
atom; (c) Elimination of hydrated ferric sulfate hydroxide; (d) Nucleophilic attack by a second
indole-3-C atom at the carbonyl C atom; (e) Proton transfer and elimination of water.
The reusability of ferric sulfate was examined in the reaction of indole with benzaldehyde
under optimized conditions. The catalysts could be recovered and reused several times. Ferric
sulfate was recovered by filtration following the synthesis of a batch of bisindole 3a. The
recovered ferric sulfate was used iteratively and recovered for use in four consecutive batches.
Upon initial reuse, the yield of 3a dropped from 93 to 79%. The decline in yield slowed
7

ACCEPTED MANUSCRIPT
thereafter, with 72% yield obtained from the fourth reuse. Thus, reused ferric sulfate retains
roughly 80% of its efficacy. With the optimized reaction conditions in hand, we then examined
the scope of the reaction for the construction of various bisindoles.
A series of substituted benzaldehydes readily underwent 2:1 condensation with 1a, giving
bisindoles 3b–i. No other products were observed to form appreciably. Some expected trends
were observed regarding the nature of the substituents. Aromatic aldehydes having electron-
donating groups (Table 2, entries 2,3, and 5–7) react slightly slower than those with electron-
withdrawing groups (Table 2, entries 8 and 9). The reaction was tolerant toward sterically
hindered 2,6-disubstituted benzaldehydes (Table 2, entries 2 and 7), although the reaction rate
was somewhat reduced. Vanillin performed anomalously well among electron-rich examples,
nearly matching the results obtained from plain benzaldehyde (Table 2, entry 4). This could be a
result of the hydroxy and methoxy O atoms engaging in bidentate coordination with the catalyst.
Table 2. Preparation of aldehyde-derived bisindoles 3a–k.
8

ACCEPTED MANUSCRIPT
Entry Aldehyde
R
Bisindole
Temp.
ºC
Time
h
Yield
%
a
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
Ph
3a
3b
3c
3d
3e
3f
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
rt
1
6
93
78
82
90
81
80
76
89
88
96
62
2,6-di-ClC H3
6
2-HOC H4
4
6
4-HO–3-MeOC H3
1
6
4-MeC
6
H
4
4
4-MeOC
6
H
4
3
2g
2h
2i
2,6-di-MeOC H3
6
3g
3h
3i
3
2-O NC H
2
2
6
4
4
4-O
2
NC
H
6
H
2
b
1
0
1
2
3
2j
3j
10
12
12
12
c
1
1
1
2k
2l
Pr
3k
3l
50
c
d
C H
5
50
0
11
c
d
2m
C H
7
15
3m
50
0
a
b
c
d
Isolated yield. As ethanolic ethoxymethanol. 25 mL of EtOH was used. No single product was isolable.
Alkyl aldehydes proved to be challenging substrates. Minimal progress was observed
when paraformaldehyde powder was used, indicating that these conditions were too mild to
promote efficient in situ monomerization of polyaldehydes. Conversely, these conditions were
too harsh for monomeric alkyl aldehydes. A suspension of Fe (SO ) •xH O and 1a in refluxing
2
4 3
2
ethanolic ethoxymethanol rapidly gave a dark, complex reaction mixture; similar results were
obtained from aldehydes 2k–m. Reducing the reaction temperature to rt gave bisindole 3j as the
only product observable by TLC (Table 2, entry 10). Aldehydes 2k–m performed best when the
solvent volume was increased from 10 to 25 mL and the temperature was maintained at 50 ºC
(Table 2, entries 11–13). However, 2k–m each gave several co-products that were observable by
1
TLC and H NMR analysis. Bisindole 3k was readily isolable by column chromatography.
9

ACCEPTED MANUSCRIPT
f
Decreasing difference in the R values of the products of a given reaction was observed with
increasing chain length. Thus, the mixtures obtained from 2l and 2m could not be resolved.
The scope was extended to various methyl and ethyl ketones. Ketones required longer
reaction times, probably because of the hindered carbonyl group relative to aldehydes. Methyl
ketones performed well, including highly-hindered pinacolone (4d, Table 3, entry 4), for which
no indole condensates are previously reported, and heteroaryl 4g and 4h (Table 3, entries 7 and
2
6
8
), both of which are reported to have biologically active derivatives. The performance of ethyl
ketones 4e and 4i shows that bisindoles derived from longer-chain dialkyl ketones are probably
accessible via Fe (SO •xH O, albeit at modest yields, whereas ethyl-aryl analogs require
2
4
)
3
2
stronger conditions (Table 3, entries 5 and 9). As expected, the required reaction times were
longer than with aldehydes. The standard method was efficient for aryl ketones and 4d (Table 3,
entries 4 and 6–9). As with butyraldehyde, lowering the reaction temperature and concentration
greatly improved the selectivity for 2:1 (–H O) condensation with the less-hindered alkyl ketones
2
(Table 3, entries 1–3 and 5). Ketone 4c demonstrates the compatibility of this method with
hydroxylalkyl substrates (Table 3, entry 3).
Table 3. Preparation of ketone-derived bisindoles 5a–h.
1
2
R R
1a
O
Fe (SO ) •xH O
2
4 3
2
R R2
1
N
N
H
H
EtOH
4a–i
5
a–h
10

ACCEPTED MANUSCRIPT
1
2
Entry Ketone
R
R
Bisindole Temp.
ºC
Time
h
Yield
%
a
b
1
2
3
4
5
6
7
8
9
4a
4b
4c
4d
4e
4f
Me
Me
Me
Me
Et
Me
5a
5b
5c
5d
5e
5f
50
50
50
6
72
83
74
32
64
89
84
86
b
b
2-PhEt
3-HOPr
t-Bu
Et
10
10
10
24
15
15
15
24
reflux
b
50
Me
Me
Me
Et
Ph
reflux
reflux
reflux
reflux
4g
4h
2-furanyl 5g
2-thienyl 5h
c
4i
Ph
5i
nr
a
b
c
Isolated yield. 25 mL of EtOH was used. No reaction was observed.
Synthetic screenings with cyclic ketones beyond C5–7 are not commonly reported in the
literature. To the best of our knowledge, the only reported screening of C4–12 cyclic ketones
2
7
condensing with indole was a Diels-Alder reaction study conducted in ethanolic HCl. In the
present work, we investigated the same scope of cyclic ketones, in the absence of good
dienophiles (Table 4).
Table 4. Preparation of cyclic ketone-derived bisindoles 7a–e,h,i.
n–3 = 4–12
1
a
O
NH
Fe (SO ) •xH O
2
4 3
2
N
n–3 = 4–12
a–i
H
6
EtOH
7
a–e,h,i
11

ACCEPTED MANUSCRIPT
Entry Ketone Ring size (n) Bisindole
Temp
ºC
Time
h
Yield
%
a
b
1
2
3
4
5
6
7
8
9
6a
6b
6c
6d
6e
6f
4
5
7a
7b
7c
7d
7e
7f
50
18
24
12
24
24
24
24
24
24
70
43
92
35
20
b
50
b
6
50
7
reflux
reflux
reflux
reflux
reflux
reflux
8
c
9
nr
c
6g
6h
6i
10
11
12
7g
7h
7i
nr
10
15
a
b
c
Isolated yield. 25 mL of EtOH was used. No reaction was observed.
C4–6 ketones 6a–c reacted readily with indole by the standard method, but performed best
at rt with additional EtOH (Table 4, entries 1–3). The larger examples reacted much more
slowly, but with the bisindoles as the only observed products (Table 4, entries 4–9). The
anomalously low bisindole yield from 6b is apparently due to an unusually narrow activation
2
8
window between 2:1 and 2:2 condensations, behavior that has also been observed with 6b in
ongoing research in our laboratories with indole, cyclic ketones, and various Brønsted acids.
Derivatives of 4-chromanones have been reported to exhibit a wide range of biological
2
9
30
effects. Several examples have been developed into potassium channel openers. The carbonyl
group in 4-chromanones is in a steric and electronic environment similar to a hybrid of 4f (Table
3
, entry 6) and 6c (Table 4, entry 3). Thus, it seemed likely that 4-chromanone-derived
bisindoles could be synthesized using Fe (SO •xH O. The only reported synthesis of 4-
chromanone-derived bisindoles features indole condensing at a pendant aldehyde C atom.
2
4
)
3
2
3
1
12

ACCEPTED MANUSCRIPT
3
2
4
-Chromanones 8a–f were prepared in 2 steps from 4-substituted phenols (Table 5), and
1
13
33
were identified by comparing m.p., H and C NMR, and MS data with the literature. Initially,
-phenoxypropanoic acid intermediates were prepared by a Williamson ether synthesis, by the
3
NaOH-promoted reaction of substituted phenols with 3-chloropropanoic acid (step 1).
Substituted chromanones (8a–f), were then produced by Friedel-Crafts acylation utilizing
polyphosphoric acid (PPA, step 2). Finally, chromanone-derived bisindole analogs (9a–f) were
prepared using ferric sulfate (Table 5). Yields generally decreased with increasing electron-
2 4 3 2
donating or releasing strength of the chromanone-6-substituent. Fe (SO ) •xH O performed
better than other common acids. Refluxing acetic acid failed to affect appreciable conversion.
When toluene-4-sulfonic or hydrochloric acids were used, the bisindole yields ranged from 0–
7
%. The product mixtures were complex and tarry, possibly a consequence of chromanone ring
opening between the 1- and 2-positions.
Table 5. Preparation of chromanone-derived bisindoles 9a–f via chromanones 8a–f
O
O
OH
1
. NaOH, H O,
reflux
1a
2
R
O
Cl
HO
Fe (SO ) •xH O
2 4 3 2
+
NH
O
HN
R
2
. PPA
EtOH
R
8a–f
reflux, 15 h
9a–f
13

ACCEPTED MANUSCRIPT
a
Entry
1
Chromanone
R
H
Yield %
Bisindole Yield
b
%
8a
88
9a
43
2
3
4
5
6
8b
8c
8d
8e
8f
Br
76
73
71
59
67
9b
9c
9d
9e
9f
35
37
38
29
24
Cl
Me
OMe
NO
2
3
,3',3''-(Ethane-1,1,1-triyl)trisindole (trisindolylethane) has been isolated as a B. flavum
2
a
metabolite. Symmetrical trisindoles have been synthetically prepared by the 3:1 condensation
3
4
of indoles with orthoformate analogs. Symmetrical or mixed trisindoles have been reported via
3
5
2
:1 condensation of indoles with indole-3-carbaldehydes using acetic acid, montmorillonite
1
4b
36
clay, or poly(N-chlorosulfonamides). The latter two have also been used to prepare 2,2'-
3
7
bisindoles from 3-methylindole, as hassilicotungstic acid, and ionic liquids with microwave
3
8
activation.
In the present study, Fe (SO ) •xH O was found to be sufficiently active to give
2
4 3
2
trisindoles and 2,2'-bisindoles (Table 6). Product 11b is both a trisindole and a 2,2'-bisindole, and
demonstrates that Fe (SO •xH O can promote the condensation of 3-alkylindoles with
2
4
)
3
2
heteroaryl aldehydes (Table 6, entry 6). Although good results were obtained with heteroaryl
ketones 4g and 4h (Table 3, entries 7 and 8), ferric sulfate was found to be too mild for the
preparation of ketone-derived trisindoles 10c or 10d (Table 6, entries 3 and 4). Among the
reported methods, only microwave-activated conditions allow shorter reaction times than
Fe (SO ) •xH O.
2
4 3
2
14

ACCEPTED MANUSCRIPT
Table 6. Preparation of trisindoles 10a,b and 11b, and 2-indolyl products 11a,b.
R2
Me
Ar
R3
NH
R1
R1
R3
Ar
N
H
Fe (SO ) •xH O
NH
2
4 3
2
N
or
1
a–c
H
HN
R1
0a,b
Me
+
EtOH
reflux
O
1
11a,b
Ar R3
2
a,m,n
or 4j,k
1
2
3
Entry Indole
R
R
Substrate
R
Ar
3-indolyl
Time Product
h
Yield
%
a
1
2
3
4
1a
1b
1a
1a
1c
H
Me
H
H
H
H
H
2m
2n
4j
H
H
2
1
10a
10b
10c
10d
84
76
3-(2-Me–indolyl)
2-indolyl
b
Me
Me
15
15
nr
b
H
4k
3-indolyl
nr
5
6
H
H
Me
Me
2a
H
H
Ph
4
4
11a
11b
82
72
1c
2m
3-indolyl
a
b
Isolated yield. No reaction was observed.
1
5
Indole with 2,2-dimethoxypropane gave 12a as the major product (Figure 1). The co-
1
products observed from cyclic ketones 6b and 6c had H NMR signals that matched previously
2
8
39
reported 2:2 products 12b and 13a, respectively.
15

ACCEPTED MANUSCRIPT
R2
R1
R1 R R3 R4
2
R3
1
2a
12b
2c
Me Me H
Me
R4
N
H
NH
(CH )
(CH )
2 3
2 4
12
1
Pr H Et
H
1
2
H R R
N
1
3a
3b
(
CH2)5 (CH2)5
N
3
4
R R H
1
H
H H
H
13
Figure 1. 2:2 Condensation (–2H O) reaction of indole with 2,2-dimethoxypropane
2
These findings shed light on the mixtures obtained from alkyl aldehydes and low-hindrance
1
ketones; some of the H NMR signals were consistent with analogs of 12b or 12c. The complex
1
6,40
mixture obtained from 2j probably included symmetrical components related to 13b.
However, only 12a was isolated and characterized in the present study. The extent to which the
use of Fe (SO •xH O can be optimized to favor 2:2 condensations has not been explored.
. Conclusion
The present work is the first reported screening of hydrated ferric sulfate-catalyzed
2
4
)
3
2
3
condensations of indole with ketones and aldehydes. Bisindoles are the major products obtained
from most of the attempted substrates, from ethanolic suspensions at 50 ºC or reflux. 2:2
Products may be isolable from some aldehydes or relatively unhindered ketones. Hydrated ferric
sulfate performs comparably to other catalysts with aryl aldehydes, and better than acetic or
hydrochloric acids with methyl and ethyl ketones, cyclic ketones, and 4-chromanones. The scope
of known bisindoles has been expanded to include those derived from methyl furanyl and methyl
thienyl ketones, C4,7,8,11, and C cyclic ketones, and 4-chromanones. For bisindole syntheses,
12
alkyl aldehydes are likely to perform better with milder catalysts, whereas ethyl aryl ketones,
16

ACCEPTED MANUSCRIPT
methyl indolyl ketones, and hindered cyclic ketones might perform better under stronger
conditions. For chromanone-derived bisindoles, promising preliminary antioxidant activity
results have been obtained from 2,2-diphenyl-1-picrylhydrazyl (DPPH) free-radical scavenging
assays. The initial results of antitumor testing performed by the National Institutes of Health
were also promising, and further investigation is in progress on both fronts. Additional
exploration of the reactions of indole with cyclic ketones and the potential antioxidant or
antitumor applications for 4-chromanone-derived bisindoles is also underway in our laboratories.
4
. Experimental section
4
.1.General Information
Hydrated ferric sulfate was purchased from Sigma-Aldrich Co. LLC, cat. no. 307718, and was
4
1
32
used on a dry mass basis. Cyclononanone 6f and cyclodecanone 6g, and 4-chromanones 8a–f
were prepared according to the literature. Other reagents were used as purchased. Column
chromatography was performed using 40–75 µm silica gel with 60 Å pores, using mixtures of
ethyl acetate (EA) & hexane (typically a gradient from 1:19 to 1:2, v/v). Melting points were
obtained from samples in open 1.5 mm glass capillaries, and are uncalibrated. Product samples
were dried using an Abderhalden apparatus (4 h, up to 110 ºC, 0.05 mm Hg), heated to no closer
than 30 ºC from the melting point of the sample. TLC analyses were performed on plastic-
1
3
backed plates pre-coated with 0.2 mm of silica gel with UV254 indicator. C NMR spectra are
proton-decoupled. Mass spectra were collected on a gas chromatograph coupled to a Q-TOF
detector (EI), or an ESI-TOF instrument.
4
.2. General procedure for the synthesis of bisindoles and trisindoles
Indole (1.17 g, 10 mmol), substrate (5 mmol), Fe (SO •xH O (300 mg), and EtOH (10 mL)
were combined in a round-bottomed flask. The resulting mixture was refluxed for the indicated
2
4
)
3
2
17

ACCEPTED MANUSCRIPT
time. The EtOH was removed at reduced pressure. The resulting residue was extracted into EA,
washed with water, dried with MgSO , and then filtered. The product was then purified by
4
column chromatography.
4
2
4
1
1
6
2
1
.2.1. 3,3'-Phenylmethylenebisindole (3a). Benzaldehyde (0.5 mL), 1 h, giving a red powder;
–
1
.47 g, 93%; mp 92 °C (lit. 86–87 °C); R = 0.43 (1:2 EA:hexane); IR (neat, cm ) 3412, 3056,
f
1
455, 1417, 1337, 1093, 1010; H NMR (500 MHz, CD
2
Cl
2
) δ 7.94 (brs, 2H), 7.40–7.35 (m,
H), 7.32 (t, J = 7.3 Hz, 2H), 7.27–7.22 (m, 1H), 7.18 (t, J = 7.5 Hz, 2H), 7.01 (t, J = 7.5 Hz,
1
3
H), 6.66 (s, 2H), 5.91 (s, 1H); C NMR (126 MHz, CD Cl ) δ 144.9, 137.2, 129.1, 128.7,
2
2
+
27.5, 126.7, 124.0, 122.4, 120.1, 120.0, 119.7, 111.7, 40.7; HRMS (EI-TOF) m/z: [M] Calcd
for C H N 322.1465; Found 322.1472.
2
3
18
2
4
3
4
.2.2. 3,3'-(2,6-Dichlorophenyl)methylenebisindole (3b). 2,6-Dichlorobenzaldehyde (880 mg),
6
h, giving a yellow powder; 1.53 g, 78%; mp 91–94 °C (lit. 108 °C); R = 0.68 (1:1 EA:hexane);
f
–
1
1
IR (neat, cm ) 3414, 3058, 1456, 1434, 1419, 1124; H NMR (500 MHz, CD
2
2
Cl ) δ 8.05 (brs,
2
H), 7.38–7.34 (m, 6H), 7.19–7.16 (m, 3H), 7.01 (t, J = 7.5 Hz, 2H), 6.86–6.85 (m, 2H), 6.82 (s,
1
3
1
H); C NMR (126 MHz, CD Cl ) δ 139.1, 136.9, 136.7, 130.3, 128.8, 127.6, 125.0, 122.3,
2 2
+
1
19.9, 119.8, 115.6, 111.7, 37.7; HRMS (EI-TOF) m/z: [M] Calcd for C H Cl N 390.0685;
23 16 2 2
Found 390.0705.
4
4
4
1
3
4
.2.3. 2-(Diindol-3-yl)methylphenol (3c). Salicylaldehyde (0.55 mL), 4 h, giving a red powder;
–
1
f
.39 g, 82%; mp 100 °C (lit. 102–104 °C); R = 0.40 (1:1 EA:hexane); IR (neat, cm ) 3411,
1
055, 2978, 1455, 1338, 1092; H NMR (500 MHz, CD Cl ) δ 8.14 (brs, 2H), 7.40–7.37 (m,
2
2
1
3
H), 7.19–7.16 (m, 4H), 7.00 (t, J = 6.1, 2H), 6.88–6.79 (m, 4H), 6.044 (s, 1H); 5.35 (s, 1H); C
NMR (126 MHz, CD Cl ) δ 154.9, 137.5, 130.4, 129.9, 128.4, 127.4, 124.1, 122.8, 121.1, 120.1,
2
2
18

ACCEPTED MANUSCRIPT
+
1
19.9, 117.8, 116.9, 111.8, 35.8; HRMS (EI-TOF) m/z: [M] Calcd for C23
H
18
N
2
O 338.1414;
Found 338.1415.
.2.4. 4-(Diindol-3-yl)methyl-2-methoxyphenol (3d). Vanillin (760 mg), 1 h, giving a tan
powder; 1.65 g, 90%; mp 120–122 °C (lit. 110–112 °C); R = 0.21 (1:2 EA:hexane); IR (neat,
4
4
4
f
–
1
1
cm ) 3411, 3054, 2849, 1509, 1215, 1122, 1032; H NMR (500 MHz, CD Cl ) δ 8.05 (brs, 2H),
2
2
7
5
1
.40–7.36 (m, 4H), 7.15 (t, J = 7.6 Hz, 2H), 7.00–6.94 (m, 3H), 6.81 (s, 2H), 6.70–6.69 (m, 2H),
1
3
2 2
.82 (s, 1H), 5.61 (brs, 1H), 3.78 (s, 3H); C NMR (126 MHz, CD Cl ) δ 147.1, 144.5, 137.3,
36.9, 127.5, 124.0, 122.4, 121.6, 120.3, 120.1, 119.6, 114.3, 112.0, 111.6, 56.4, 40.4;HRMS
+
(
EI-TOF) m/z: [M] Calcd for C H N O 368.1519; Found 368.1520.
2
4
20
2
2
4
4
4
.2.5. 3,3'-(4-Methylphenyl)methylenebisindole (3e). 4-Methylbenzaldehyde (0.60 mL), 4 h,
giving a red powder; 1.36 g, 81%; mp 95–98 °C (lit. 98–100 °C); R = 0.52 (1:2 EA:hexane); IR
f
–
1
1
(
neat, cm ) 3413, 3053, 2921, 1455, 1092, 777; H NMR (500 MHz, CD
2
Cl
2
) δ 7.91 (brs, 2H),
7
4
.41 (d, J = 7.9 Hz, 2H), 7.35 (d, J = 8.2 Hz, 2H), 7.28 (d, J = 7.9 Hz, 2H), 7.19–7.14 (m,
1
3
H),7.02 (t, J = 7.5 Hz, 2H), 6.66 (s, 2H), 5.88 (s, 1H),2.37 (s, 3H); C NMR (126 MHz,
CD Cl ) δ 141.8, 137.2, 136.2, 129.4, 129.0, 127.5, 124.0, 122.4, 120.2, 119.6, 111.7, 40.3, 21.3;
2
2
+
HRMS (EI-TOF) m/z: [M] Calcd for C H N 336.1621; Found 336.1644.
2
4
20
2
4
7
4
.2.6. 3,3'-(4-Methoxyphenyl)methylenebisindole (3f). 4-Methoxybenzaldehyde (680 mg), 3 h,
giving a tan powder; 1.41 g, 80%; mp 179–181 °C (lit. 188–190 °C); R = 0.63 (1:1 EA:hexane);
f
–
1
1
IR (neat, cm ) 3415, 2835, 1509, 1456, 1243, 1092, 850; H NMR (500 MHz, CD
2 2
Cl ) δ 8.08
(brs, 2H), 7.38–7.35 (m, 4H), 7.26 (d, J = 8.6 Hz, 2H), 7.13 (t, J = 7.6 Hz, 2H), 6.97 (t, J = 7.6
1
3
Hz, 2H), 6.83 (d, J = 8.5 Hz, 2H), 6.71 (s, 2H), 5.83 (s, 1H), 3.77 (s, 3H); C NMR (126 MHz,
CD Cl ) δ 158.6, 137.3, 136.9, 130.0, 127.5, 123.9, 122.4, 120.4, 120.2, 119.6, 114.0, 111.6,
2
2
+
5
5.7, 39.9; HRMS (EI-TOF) m/z: [M] Calcd for C H N O 352.1570; Found 352.1582.
24 20 2
19

ACCEPTED MANUSCRIPT
1
d
4
.2.7. 3,3'-(2,6-Dimethoxyphenyl)methylenebisindole (3g). 2,6-Dimethoxybenzaldehyde (830
mg), 3 h, giving an orange powder; 1.45 g, 76%; mp 188–190 °C (lit. 170–172 ºC); R = 0.21
f
–
1
1
(
1:2 EA:hexane); IR (neat, cm ) 3411, 3056, 2836, 1509, 1456, 1244, 1030, 794; H NMR (500
MHz, CD Cl ) δ 8.09 (brs, 2H), 7.39–7.36 (m, 4H), 7.14 (t, J = 7.6 Hz, 2H), 6.99–6.96 (m, 3H),
2
2
6
3
1
.85–6.83 (m, 1H), 6.80–6.78 (m, 1H), 6.72–6.71 (m, 2H), 5.83 (s, 1H), 3.80 (s, 3H), 3.73 (s,
1
3
H); C NMR (126 MHz, CD
2
Cl
2
) δ149.5, 148.1, 137.4, 137.3, 127.5, 124.0, 122.4, 120.9,
+
20.3, 120.1, 119.6, 113.0, 111.7, 111.6, 56.29, 56.23, 40.3; HRMS (EI-TOF) m/z: [M] Calcd
for C H N O 382.1676; Found 382.1684.
2
5
22
2
2
4
5
4
.2.8. 3,3'-(2-Nitrophenyl)methylenebisindole (3h). 2-Nitrobenzaldehyde (760 mg), 2 h, giving
brown crystals; 1.63 g, 89%; mp 118–122 °C (lit. 111–112 °C); R = 0.24 (1:2 EA:hexane); IR
f
–
1
1
(
neat, cm ) 3413, 3055, 1521, 1456, 1352, 1095; H NMR (500 MHz, CD
2
2
Cl ) δ 8.08 (brs, 2H),
7
6
1
.84 (d, J = 7.9 Hz, 1H), 7.45–7.34 (m, 7H), 7.16 (t, J = 7.6 Hz, 2H) 6.99 (t, J = 7.6 Hz, 2H),
1
3
2 2
.67–6.66 (m, 2H), 6.61 (s, 1H); C NMR (126 MHz, CD Cl ) δ 150.3, 138.5, 137.2, 132.9,
31.5, 127.9, 127.2, 124.9, 124.4, 122.7, 120.0, 119.9, 118.1, 111.8, 35.3; HRMS (EI-TOF) m/z:
+
[
M] Calcd for C H N O 367.1315; Found 367.1319.
2
3
17
3
2
4
5
4
.2.9. 3,3'-(4-Nitrophenyl)methylenebisindole (3i). 4-Nitrobenzaldehyde (760 mg), 2 h, giving
an orange powder; 1.61 g, 88%; mp 241 °C (lit. 235–237 °C); R = 0.4 (1:2 EA:hexane); IR
f
–
1
1
(
neat, cm ) 3412, 3055, 2850, 1515, 1456, 1343; H NMR (500 MHz, CD
2
2
Cl ) δ 8.17 (brs, 2H),
8
7
.13 (d, J = 8.2 Hz, 2H), 7.53 (d, J = 7.9 Hz, 2H), 7.40 (d, J = 8.2 Hz, 2H), 7.33 (d, J = 7.9, 2H),
1
3
.17 (t, J = 7.6, 2H), 6.99 (t, J = 7.3, 2H), 6.74 (s, 2H), 6.01 (s, 1H); C NMR (126 MHz,
CD Cl ) δ 152.6, 147.1, 137.3, 130.0, 127.2, 124.2, 124.1, 122.7, 120.0, 119.9, 118.5, 111.8,
2
2
+
4
0.7; HRMS (EI-TOF) m/z: [M] Calcd for C H N O 367.1315; Found 367.1326.
23 17 3 2
20

ACCEPTED MANUSCRIPT
4
.2.10a. Ethanolicethoxymethanol. A slow stream of argon was passed through a boiling flask
containing paraformaldehyde powder (5 g), through a sparging tube, and into EtOH (50 mL).
The paraformaldehyde was heated with a flame until most of the powder had vaporized. Before
removing the flame or exhaustion of powder, the argon flow was increased to prevent the
backflow of EtOH into the boiler. The ethanolic solution was diluted with additional EtOH until
1
the ethoxymethanol concentration was approximately 0.5 M, as indicated by H NMR
spectroscopy (1:33 EtOCH
.2.10b. 3,3'-Methylenebisindole (3j). Ethanolic ethoxymethanol (0.5 M, 10 mL) was used in
place of substrate and EtOH, 10 h at rt, giving a white powder; 1.18 g, 96%; mp 162–165 °C (lit.
2 2 3
OH:EtOH molar ratio; EtOCH OH δ 4.78 ppm in CDCl ).
4
6
4
–
1
1
1
2
2
67–169 °C); R = 0.33 (1:2 EA:hexane); IR (KBr, cm ) 3397, 3059, 2890, 2855, 2832, 1619,
f
1
488, 1455, 1427, 1340, 1220, 1090, 1034, 1007, 741; H NMR (300 MHz, CD Cl ) δ 8.05 (brs,
2
2
H), 7.58 (dq, J = 7.9, 0.9 Hz, 2H), 7.36 (dt, J = 8.1, 1.0 Hz, 2H), 7.15 (ddd, J = 8.1, 7.0, 1.2 Hz,
1
3
H), 7.04 (ddd, J = 8.0, 7.0, 1.1 Hz, 2H), 7.00 (dt, J = 2.2, 1.0 Hz, 2H), 4.24 (s, 2H); C NMR
(
126 MHz, CD Cl ) δ 137.0, 128.1, 122.7, 122.3, 119.6, 116.1, 111.6, 21.7; HRMS (EI-TOF)
2
2
+
14 2
m/z: [M] Calcd for C17H N 246.1151; Found 246.1144.
4
7
4
.2.11. 3,3'-(Butane-1,1-diyl)bisindole (3k). Butyraldehyde (0.45 mL), EtOH (25 mL), 12 h at
5
0 ºC, giving tan needles; 895 mg, 62%;mp 153–155 °C (lit. 154–156 °C); R = 0.63 (1:2
f
–
1
1
EA:hexane); IR (NaCl, cm ) 3412, 3054, 2954, 2928, 2868, 1455, 740; H NMR (400 MHz,
CD Cl ) δ 8.03 (brs, 2H), 7.55 (dd, J = 8.0, 1.0 Hz, 2H), 7.34 (d, J = 8.2, 2H), 7.12 (ddd, J = 8.2,
2
2
7
7
.0, 1.2 Hz, 2H), 7.08 (dd, J = 2.4, 0.8 Hz, 2H), 6.99 (ddd, J = 8.0, 7.0, 1.0 Hz, 2H), 4.48 (t, J =
.5 Hz, 1H), 2.21 (q, J = 7.6 Hz, 2H), 1.43 (dq, J = 14.9, 7.4 Hz, 2H), 0.97 (t, J = 7.4 Hz, 3H);
1
3
C NMR (100 MHz, CD
2
Cl
2
) δ 137.1, 127.7, 122.2, 121.9, 120.9, 120.0, 119.4, 111.6, 38.4,
+
3
4.2, 21.9, 14.5; HRMS (EI-TOF) m/z: [M] Calcd for C20
H
20
N
2
288.1621; Found 288.1649.
21

ACCEPTED MANUSCRIPT
4
8
4
.2.12. 3,3'-(Propane-2,2-diyl)bisindole (5a). Acetone (0.35 mL), EtOH (25 mL), 6 h at 50 ºC,
giving a tan powder; 939 mg, 72%; mp 156–157 °C (lit. 160–162 °C); R = 0.38 (1:2
f
–
1
1
EA:hexane); IR (KBr, cm ) 3408, 3392, 3047, 2961, 2931, 2866, 1622, 1242, 744; H NMR
(
500 MHz, CD Cl ) δ 8.05 (brs, 2H), 7.33 (dd, J = 8.1, 1.0 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H),
2 2
7
1
1
4
.19 (d, J = 2.6 Hz, 2H), 7.05 (ddd, J = 7.2, 7.1, 0.9 Hz, 2H), 6.82 (ddd, J = 8.0, 7.2, 1.0 Hz, 2H),
1
3
.91 (s, 6H); C NMR (126 MHz, CD Cl ) δ 137.6, 126.8, 125.8, 121.8, 121.2, 120.9, 119.0,
2
2
+
11.6, 35.1, 30.3; HRMS (EI-TOF) m/z: [M] Calcd for C19
.2.13.3,3'-(4-Phenylbutane-2,2-diyl)bisindole (5b). 4-Phenylbutan-2-one (0.75 mL), EtOH (25
= 0.56 (1:2 EA:hexane);
IR (neat, cm ) 3414, 3056, 2946, 2872, 1456, 1013; H NMR (500 MHz, CD Cl ) δ 8.10 (brs,
18 2
H N 274.1465; Found 274.1475.
mL), 10 h at 50 ºC, giving a white powder; 1.51 g, 83%; mp 145 °C; R
f
–
1
1
2
2
2
1
3
1
3
8
4
H), 7.34 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 7.9 Hz, 2H), 7.23–7.22 (m, 4H), 7.14 (t, J = 7.3 Hz,
H), 7.08–7.04 (m, 4H), 6.82 (t, J = 7.5 Hz, 2H), 2.69–2.66 (m, 2H), 2.49–2.45 (m, 2H), 1.93 (s,
1
3
H); C NMR (126 MHz, CD
2
Cl
2
) δ 143.9, 137.6, 129.0, 128.7, 126.9, 125.9, 124.4, 121.9,
+
21.7, 121.2, 119.1, 111.6, 43.3, 38.8, 31.7, 27.2; HRMS (EI-TOF) m/z: [M] Calcd for C26
H
24
N
2
64.1934; Found 364.1923. Anal. Calcd for C26
5.58; H, 6.91; N, 7.75.
24 2
H N : C, 85.68; H, 6.64; N, 7.69. Found: C,
.2.14. 4,4-Di(indol-3-yl)pentan-1-ol (5c). 5-Hydroxypentan-2-one(0.50 mL),EtOH (25 mL), 10
h at 50 ºC, giving a white powder; 1.16 g, 74%; mp 159–162 °C; R = 0.30 (1:2 EA:hexane); IR
f
–
1
1
(
neat, cm ) 3412, 3054, 2946, 2875, 1457, 1337, 1101, 1013; H NMR (500 MHz, DMSO-d6) δ
1
7
1
1
0.74 (brs, 2H), 7.26–7.23 (m, 4H), 7.10 (d, J = 7.9 Hz, 2H), 6.88 (t, J = 7.5 Hz, 2H) 6.30 (t, J =
.5 Hz, 2H), 4.29 (t, J = 5.2 Hz, 1H), 3.31 (q, J = 6.6 Hz, 2H), 2.28–2.25 (m, 2H), 1.72 (s, 3H),
13
.25 (ddd, J = 11.5, 9.8, 5.7 Hz, 2H); C NMR (126 MHz, CD
2
Cl
2
) δ 151.4, 140.5, 137.2, 135.8,
+
34.7, 134.6, 131.9, 125.7, 76.1, 51.7, 50.9, 42.5, 41.5; HRMS (EI-TOF) m/z: [M] Calcd for
22

ACCEPTED MANUSCRIPT
C
21
H
22
N
2
O 318.1727; Found 318.1714; Anal. Calcd for C21
Found: C, 79.11; H, 6.92; N, 8.65.
.2.15. 3,3'-(3,3-Dimethylbutane-2,2-diyl)bisindole (5d). Pinacolone (0.65 mL), 10 h, giving a
22 2
H N O: C, 79.21; H, 6.96; N, 8.80.
4
–
1
beige powder; 514 mg, 32%; mp 248–250°C; R = 0.59 (1:2 EA:hexane); IR (neat, cm ) 3411,
f
1
3
056, 2981, 2955, 2922, 1456, 1105, 1014; H NMR (500 MHz, CD Cl ) δ 8.15 (brs, 2H), 7.31
2
2
(d, J = 2.4 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H), 6.94 (t, J = 7.5 Hz, 2H) 6.81 (d, J = 8.2 Hz, 2H),
1
3
6
1
.61 (t, J = 7.5 Hz, 2H), 1.91 (s, 3H), 1.26 (s, 9H); C NMR (126 MHz, CD
2
Cl
2
) δ 136.6, 128.8,
+
23.3, 122.8, 122.5, 121.3, 118.7, 111.1, 46.3, 38.8, 28.4, 25.3; HRMS (EI-TOF) m/z: [M] Calcd
for C H N 316.1934; Found 316.1914; Anal. Calcd for C H N : C, 83.50; H, 7.64; N, 8.85.
2
2
24
2
22 24
2
Found: C, 83.18; H, 7.66; N, 8.64.
4
9
4
.2.16. 3,3'-(Pentane-3,3-diyl)bisindole (5e). 3-Pentanone (0.55 mL), EtOH (25 mL), 24 h at
5
0 ºC, giving a white powder; 965 mg 64%; mp 125–127 °C (lit. 129–130 °C); R = 0.27 (1:2
f
–
1
1
EA:hexane); IR (KBr, cm ) 3414, 3053, 2960, 2924, 2852, 1457, 1335, 1101, 742; H NMR
(
400 MHz, CD Cl ) δ 8.15 (s, 2H), 7.30 (dt, J = 8.2, 0.9 Hz, 2H), 7.28 (d, J = 2.4 Hz, 2H), 7.11
2 2
(dq, J = 8.0, 0.9 Hz, 2H), 6.98 (ddd, J = 8.2, 7.0, 1.2 Hz, 2H), 6.69 (ddd, J = 8.1, 7.0, 1.1 Hz,
1
3
2
1
H), 2.29 (q, J = 7.4 Hz, 4H), 0.67 (t, J = 7.4 Hz, 6H); C NMR (100 MHz, CD Cl ) δ 137.6,
2 2
+
27.1, 123.2, 122.5, 121.8, 121.2, 118.8, 111.4, 30.3, 27.9, 8.4; HRMS (EI-TOF) m/z: [M] Calcd
for C H N 302.1778; Found 302.1787.
2
1
22
2
4
8
4
.2.17. 3,3'-(1-Phenylethane-1,1-diyl)bisindole (5f). Acetophenone (0.60 mL), 15 h, giving a
beige powder; 1.50 g, 89%; mp 153–156 °C (lit. 165–166 ºC); R = 0.37 (1:2 EA:hexane); IR
f
–
1
(
KBr, cm ) 3420, 3366, 3122, 3052, 2974, 2936, 1617, 1490, 1456, 1415, 1338, 1246, 1101,
1
1
010, 744; H NMR (500 MHz, CD Cl ) δ 8.01 (brs, 2H), 7.42–7.39 (m, 2H), 7.36 (d, J = 8.2
2
2
Hz, 2H), 7.27–7.25 (m, 4H), 7.21 (tdd, J = 7.2, 2.2, 1.4 Hz, 1H), 7.11 (ddd, J = 8.2, 7.0, 1.1 Hz,
23

ACCEPTED MANUSCRIPT
1
3
2
H), 6.89 (ddd, J = 8.1, 7.0, 1.0 Hz, 2H), 6.70 (d, J = 2.6 Hz, 2H), 2.35 (s, 3H); C NMR (126
MHz, CD Cl ) δ 148.7, 137.7, 128.6, 128.2, 127.0, 126.4, 124.9, 123.8, 122.3, 122.0, 119.3,
2
2
+
1
11.7, 44.2, 29.3; HRMS (EI-TOF) m/z: [M] Calcd for C H N 336.1621; Found 336.1646.
24 20 2
4
.2.18. 3,3'-[1-(Furan-2-yl)ethane-1,1-diyl]bisindole (5g). 2-Acetylfuran (0.50 mL), 15 h, giving
–
1
a tan powder; 1.37 g, 84%; mp 154 °C; R = 0.36 (1:2 EA:hexane); IR (neat, cm ) 3412, 3054,
f
1
2
978, 1456, 1417, 1338, 1101, 1012; H NMR (500 MHz, CD
2
Cl
2
)δ 8.10 (brs, 2H), 7.36–7.35
(m, 3H), 7.28 (d, J = 7.9 Hz, 2H), 7.09 (t, J = 7.5 Hz, 2H), 6.89–6.86 (m, 4H), 6.33 (s, 1H), 6.09
1
3
(
d, J = 2.8 Hz, 1H), 2.26 (s, 3H); C NMR (126 MHz, CD Cl ) δ 161.6, 141.4, 137.4, 126.7,
2 2
1
23.0, 122.7, 122.0, 121.7, 119.4, 111.7, 110.4, 106.3, 40.7, 27.5; HRMS (EI-TOF) m/z:
+
[
M] Calcd for C H N O 326.1414; Found 326.1422; Anal. Calcd for C H N O: C, 80.96; H,
2
2
18
2
22 18
2
5
.56; N, 8.58. Found: C, 80.67; H, 5.80; N, 8.59.
.2.19. 3,3'-[1-(Thien-2-yl)ethane-1,1-diyl]bisindole (5h). 2-Acetylthiophene (0.55 mL), 15 h,
4
–
1
giving a white powder; 1.48 g, 86%; mp 94–96 °C; R
f
= 0.45 (1:2 EA:hexane); IR (neat, cm )
1
3
8
412, 3057, 2996, 2969, 1456, 1415, 1337, 1100, 1012, 846; H NMR (500 MHz, CD Cl ) δ
2
2
.10 (brs, 2H), 7.36 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H), 7.17 (t, J = 3.2 Hz, 1H), 7.10 (t,
J = 7.3 Hz, 2H), 6.92 (d, J = 3.3 Hz, 2H), 6.88 (t, J = 7.3 Hz, 2H), 6.85 (d, J = 2.3 Hz, 2H), 2.39
1
3
(
s, 3H); C NMR (126 MHz, CD Cl ) δ 155.1, 137.6, 126.7, 126.5, 125.3, 124.9, 123.9, 123.4,
2 2
+
1
3
7
4
22.1, 122.0, 119.4, 111.8, 42.3, 30.8; HRMS (EI-TOF) m/z: [M] Calcd for C H N S
22 18 2
42.1185; Found 342.1157; Anal. Calcd for C22
18 2
H N S: C, 77.16; H, 5.30; N, 8.18. Found: C,
7.08; H, 5.29; N, 8.11.
.3.1. 3,3'-(Cyclobutane-1,1-diyl)bisindole (7a).Cyclobutanone (0.35 mL), EtOH (25 mL), 18 h
at 50 ºC, the resulting yellow oil was dissolved in DCM (3 mL), and then filtered through a
column of silica gel (50 cm H × 1 cm D). The desired fraction was concentrated at reduced
24

ACCEPTED MANUSCRIPT
pressure, and then dried at reduced pressure (24 h, 83 ºC, 0.05 mm Hg), giving a white,
amorphous solid; 998 mg (98.6 wt% 7a, 984 mg; 1.4 wt% DCM, 14 mg), 70%; mp 101–107 °C;
–
1
R = 0.37 (1:2 EA:hexane); IR (KBr, cm ) 3411, 3053, 2978, 2940, 2861, 1617, 1484, 1455,
f
1
1
8
416, 1334, 1242, 1098, 1012, 741; H NMR (500 MHz, CD Cl ) δ 7.98 (brs, 2H), 7.52 (dd, J =
2
2
.0, 1.0 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 2.6 Hz, 2H), 7.13 (ddd, J = 8.2, 7.0, 1.2
Hz, 2H), 6.97 (ddd, J = 8.1, 7.0, 1.1 Hz, 2H), 2.89 (t, J = 7.6 Hz, 4H), 2.21 (p, J = 7.6 Hz, 2H);
1
3
C NMR (126 MHz, CD
2
Cl
2
) δ 137.7, 126.8, 124.3, 122.1, 121.5, 120.9, 119.1, 111.7, 41.4,
+
3
4.8, 18.0; HRMS (EI-TOF) m/z: [M] Calcd for C20
H
18
N
2
286.1465; Found 286.1460; Anal.
Calcd for [C20
.63. No condition was found by which additional DCM could be removed without resulting in
decomposition of the sample.
.3.2. 3,3'-(Cyclopentane-1,1-diyl)bisindole (9b). Cyclopentanone(0.45 mL), EtOH (25 mL), 24
h at 50 ºC, giving a white powder; 643 mg, 43%; mp 164–167 °C (lit. 116–119 °C); R = 0.38
18 2 2 2
H N • 0.048 CH Cl ]: C, 82.90; H, 6.28; N, 9.64. Found: C, 82.91; H, 6.28; N,
9
4
9
4
f
–
1
(
1:2 EA:hexane); IR (KBr, cm ) 3440, 3419, 3060, 2960, 2872, 1622, 1474, 1453, 1417, 1342,
1
1
7
242, 1106, 1012, 740; H NMR (500 MHz, CD
2
Cl
2
) δ 8.06 (brs, 2H), 7.40 (d, J = 8.1 Hz, 2H),
.30 (dd, J = 8.2, 1.0 Hz, 2H), 7.22 (d, J = 2.5 Hz, 2H), 7.02 (ddd, J = 8.1, 7.6, 1.1 Hz, 2H), 6.83
1
3
(
ddt, J = 8.1, 7.9, 1.0 Hz, 2H), 2.49–2.44 (m, 4H), 1.85–1.80 (m, 4H); C NMR (126 MHz,
CD Cl ) δ 137.7, 127.1, 123.7, 121.9, 121.4, 121.2, 119.0, 111.6, 46.5, 39.1, 24.2; HRMS (EI-
2
2
+
TOF) m/z: [M] Calcd for C H N 300.1621; Found 300.1614; Anal. Calcd for C H N : C,
21
20
2
21 20
2
8
3.96; H, 6.71; N, 9.33. Found: C, 83.79; H, 6.60; N, 9.29.
5
0
4
.3.3. 3,3'-(Cyclohexane-1,1-diyl)bisindole (7c). Cyclohexanone (0.50 mL), EtOH (25 mL), 12
= 0.39 (1:2
EA:hexane); IR (KBr, cm ) 3452, 3408, 3139, 3051, 2932, 2854, 1615, 1484, 1455, 1414, 1336,
h at 50 ºC, giving a white powder; 1.40 g, 92%; mp 164–168 °C, (lit. 119–120 °C); R
f
–
1
25

ACCEPTED MANUSCRIPT
1
1
8
243, 1101, 1014, 992, 817, 742; H NMR (500 MHz, CD
2
Cl
2
) δ 8.08 (brs, 2H), 7.43 (dd, J =
.2, 1.0 Hz, 2H), 7.30 (d, J = 8.2 Hz, 2H), 7.24 (d, J = 2.5 Hz, 2H), 7.02 (ddd, J = 8.1, 7.0, 1.1
Hz, 2H), 6.83 (ddd, J = 8.1, 7.0, 1.0 Hz, 2H), 2.53–2.51 (m, 4H), 1.71–1.66 (p, J = 5.9 Hz, 4H),
1
3
1
1
.62–1.57 (m, 2H); C NMR (126 MHz, CD Cl ) δ 137.5, 126.8, 124.1, 122.4, 121.7, 121.5,
2 2
+
18.9, 111.6, 39.7, 37.6, 27.4, 23.6; HRMS (EI-TOF) m/z: [M] Calcd for C H N 314.1778;
22
22
2
Found 314.1783; Anal. Calcd for C H N : C, 84.04; H, 7.05; N, 8.91. Found: C, 84.05; H,
2
2
22
2
7
.05; N, 8.81.
.3.4. 3,3'-(Cycloheptane-1,1-diyl)bisindole (7d).Cycloheptanone (0.60 mL), 24 h, giving a white
4
–
1
powder; 569 mg, 35%; mp 176–178 °C; R
f
= 0.40 (1:2 EA:hexane); IR (KBr, cm ) 3414, 3054,
1
2
924, 2853, 1616, 1484, 1456, 1415, 1338, 1243, 1101, 1013, 952, 742; H NMR (500 MHz,
CD Cl ) δ 8.09 (brs, 2H), 7.32 (d, J = 2.5 Hz, 2H), 7.30 (d, J = 8.2 Hz, 2H), 7.17 (d, J = 8.1 Hz,
2
2
2
H), 6.99 (ddd, J = 8.1, 7.1, 1.1 Hz, 2H), 6.73 (dd, J = 8.1, 7.1 Hz, 2H), 2.54–2.52 (m, 4H),
1
3
1
.68–1.61 (m, 8H); C NMR (126 MHz, CD Cl ) δ 137.7, 127.1, 125.5, 121.8, 121.5, 121.3,
2 2
+
1
18.9, 111.5, 42.5, 39.5, 31.2, 23.6; HRMS (EI-TOF) m/z: [M] Calcd for C H N 328.1934;
23 24 2
24 2
Found 328.1931; Anal. Calcd for C23H N : C, 84.11; H, 7.37; N, 8.53. Found: C, 84.02; H,
7
.39; N, 8.58.
.3.5. 3,3'-(Cyclooctane-1,1-diyl)bisindole (7e). Cyclooctanone (630 mg), 24 h, giving a tan
4
–
1
powder; 345 mg, 20%; mp 190–192 °C; R = 0.42 (1:2 EA:hexane); IR (KBr, cm ) 3404, 3383,
f
1
3
311, 3083, 3054, 2920, 2849, 1616, 1475, 1456, 1416, 1338, 1243, 1101, 1013, 804, 744; H
NMR (500 MHz, CD Cl ) δ 8.14 (brs, 2H), 7.38 (d, J = 2.5 Hz, 2H), 7.30 (d, J = 8.2 Hz, 2H),
2
2
7
.07 (dd, J = 8.1, 1.0 Hz, 2H), 6.97 (ddd, J = 8.2, 7.0, 1.1 Hz, 2H), 6.67 (ddd, J = 8.0, 7.0, 1.0
1
3
Hz, 2H), 2.51–2.49 (m, 4H), 1.71–1.62 (m, 6H), 1.40 (pd, J = 5.7, 1.9 Hz 4H); C NMR (126
MHz, CD Cl ) δ 137.6, 126.9, 124.2, 122.0, 121.8, 121.0, 118.8, 111.5, 42.4, 33.2, 29.4, 26.0,
2
2
26

ACCEPTED MANUSCRIPT
+
2
3.0; HRMS (EI-TOF) m/z: [M] Calcd for C24
26
H N
2
342.2091; Found 342.2094; Anal. Calcd for
C H N : C, 84.17; H, 7.65; N, 8.18. Found: C, 84.19; H, 7.67; N, 8.19.
24
26
2
4
.3.6. 3,3'-(Cycloundecane-1,1-diyl)bisindole (7h). Cycloundecanone (0.95 mL), 24 h, giving a
–
1
white powder; 201 mg, 10%; mp 197–198 °C; R = 0.45 (1:2 EA:hexane); IR (KBr, cm ) 3417,
f
1
3
051, 2928, 2858, 1617, 1475, 1456, 1415, 1337, 1243, 1100, 1013, 741; H NMR (500 MHz,
CD Cl ) δ 8.12 (brs, 2H), 7.32 (d, J = 2.5 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H), 7.13 (dd, J = 8.1, 1.0
2
2
Hz, 2H), 6.97 (ddd, J = 8.1, 6.9, 1.1 Hz, 2H), 6.69 (ddd, J = 8.1, 7.0, 1.0 Hz, 2H), 2.41 (t, J = 7.6
1
3
Hz, 4H), 1.63–1.54 (m, 4H), 1.52–1.44 (m, 4H), 1.39 (p, J = 6.1 Hz, 4H), 1.17–1.08 (m, 4H); C
NMR (126 MHz, CD
2
Cl
2
) δ 137.5, 127.0, 123.9, 121.8, 121.7, 120.9, 118.8, 111.4, 41.9, 33.4,
+
2
3
7
4
7.7, 27.1, 26.5, 22.2; HRMS (EI-TOF) m/z: [M] Calcd for C H N 384.2560; Found
2
7
32
2
84.2561; Anal. Calcd for C H N : C, 84.33; H, 8.39; N, 7.28. Found: C, 84.27; H, 8.38; N,
27
32
2
.22.
.3.7. 3,3'-(Cyclododecane-1,1-diyl)bisindole (7i). Cyclododecanone(920 mg), 24 h, giving
colorless block-shaped crystals; 300 mg, 15%; mp 210–213 °C; R = 0.46 (1:2 EA:hexane); IR
f
–
1
1
(
KBr, cm ) 3438, 3395, 3045, 2934, 2859, 1617, 1482, 1470, 1338, 1101, 1009, 746; H NMR
500 MHz, CD Cl ) δ 8.12 (brs, 2H), 7.30 (d, J = 6.9 Hz, 2H), 7.29 (d, J = 2.2 Hz, 2H), 7.16 (d, J
8.1 Hz, 2H), 6.99 (ddd, J = 8.1, 6.9, 1.1 Hz, 2H), 6.71 (ddd, J = 8.1, 6.9, 1.0 Hz, 2H), 2.31 (dd,
(
2
2
=
1
3
J = 9.1, 7.2 Hz, 4H), 1.49–1.38 (m, 10H), 1.34–1.28 (m, 4H), 1.14–0.85 (m, 4H); C NMR (126
MHz, CD Cl ) δ 137.5, 127.1, 124.0, 121.8, 121.6, 120.9, 118.8, 111.4, 40.9, 32.4, 27.1, 26.9,
2
2
+
2
3.0, 22.8, 20.1; HRMS (EI-TOF) m/z: [M] Calcd for C H N 398.2717; Found 398.2722;
28 34 2
Anal. Calcd for C H N : C, 84.37; H, 8.60; N, 7.03. Found: C, 84.38; H, 8.54; N, 7.02.
2
8
34
2
27

ACCEPTED MANUSCRIPT
4
.4. Synthesis of 4-chromanone-derived bisindoles (9a–f). The general method was performed at
4
0% scale, in EtOH (5 mL), refluxed for 15 h: Indole (470 mg, 4 mmol), substrate (2 mmol),
Fe (SO ) •xH O (120 mg).
2
4 3
2
4
3
2
2
2
.4.1. 3,3'-(Chromane-4,4-diyl)bisindole (9a). Chroman-4-one(300 mg), giving a white powder;
–
1
10 mg, 43%; mp 163–165°C; R = 0.45 (1:2 EA:hexane); IR (KBr, cm ) 3394, 3045, 2974,
f
1
884, 1484, 1259, 748; H NMR (500 MHz, DMSO-d ) δ 10.88 (brs, 2H), 7.38 (d, J = 7.9 Hz,
6
H), 7.11–7.09 (m, 3H), 7.02 (t, J = 7.3 Hz, 2H), 6.87 (t, J = 6.1 Hz, 2H), 6.80 (t, J = 7.3 Hz,
1
3
H), 6.68–6.64 (m, 3H), 3.98 (t, J = 5.0 Hz, 2H), 2.86 (t, J = 5.0 Hz, 2H); C NMR (126 MHz,
DMSO-d
6
) δ 153.8, 137.3, 130.2, 129.0, 127.5, 125.5, 125.1, 121.1, 120.7, 120.6, 119.5, 118.2,
+
1
3
7
4
16.3, 118.8, 62.9, 39.9, 33.3; HRMS (EI-TOF) m/z: [M] Calcd for C H N O 364.1570; Found
2
5
20
2
64.1579; Anal.Calcd for C H N O: C, 82.39; H, 5.53; N, 7.69. Found: C, 82.15; H, 5.74; N,
2
5
20
2
.67.
.4.2. 3,3'-(6-Βromochromane-4,4-diyl)bisindole (9b). 6-Bromochroman-4-one (450 mg), giving
–
1
a beige powder; 304 mg, 35%; mp 298–301°C; R = 0.40 (1:2 EA:hexane); IR (KBr, cm ) 3403,
f
1
3
2
369, 3045, 2982, 2883, 1479, 1457, 1232, 748; H NMR (500 MHz, DMSO-d
6
) δ 10.93 (brs,
H), 7.38 (d, J = 7.9 Hz, 2H), 7.28 (dd, J = 8.7, 2.6 Hz, 1H), 7.07–7.01 (m, 4H), 6.95 (d, J = 2.4
Hz, 1H), 6.86 (d, J = 8.5 Hz, 1H), 6.81 (ddd, J = 8.0, 7.0, 1.0 Hz, 2H), 6.66 (d, J = 2.1 Hz, 2H),
1
3
3
1
3
.98 (t, J = 4.9 Hz, 2H), 2.83 (t, J = 4.9 Hz, 2H); C NMR (126 MHz, DMSO-d ) δ 153.2,
6
37.3, 132.0, 131.5, 130.4, 125.5, 124.9, 120.9, 120.3, 118.9, 118.4, 112.0, 110.8, 63.2, 40.0,
+
2.7; HRMS (EI-TOF) m/z: [M] Calcd for C H BrN O 442.0675; Found 442.0672; Anal.
2
5
19
2
Calcd for C H BrN O: C, 67.73; H, 4.32; N, 6.32; Br, 18.02. Found: C, 67.46; H, 4.22; N,
2
5
19
2
6
.27; Br, 18.12.
28