Iron(II) chloride-1,1′-binaphthyl-2,2′-diamine (FeCl 2-BINAM) complex catalyzed domino synthesis of bisindolylmethanes from indoles and primary alcohols

Article abstract of DOI:10.1055/s-0033-1340052

Biologically important bisindolylmethanes are synthesized in a domino fashion by using an iron(II) chloride-(±)-1,1′-binaphthyl-2, 2′-diamine [FeCl₂-(±)-BINAM] complex as the catalyst. This method proceeds via oxidation of a primary alcohol into the corresponding aldehyde followed by nucleophilic addition of an indole in the presence of the catalyst. A reaction intermediate is synthesized separately and converted into the bisindolylmethane product under the same reaction conditions as support for the proposed mechanism. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1340052

See discussions, stats, and author profiles for this publication at: http://www.researchgate.net/publication/259840861
Iron(II) Chloride-1,1 '-Binaphthyl-2,2 '-
diamine (FeCl2-BINAM) Complex Catalyzed
Domino Synthesis of Bisindolylmethanes from
Indoles and Primary Alcohols
DATASET in CHEMINFORM · DECEMBER 2013
DOI: 10.1055/s-0033-1340052
CITATION
DOWNLOADS
VIEWS
1
144
114
5 AUTHORS, INCLUDING:
Dhandapani Ganapathy
Indian Institute of Technology Madras
9 PUBLICATIONS 30 CITATIONS
SEE PROFILE
Available from: Dhandapani Ganapathy
Retrieved on: 20 June 2015

PAPER
▌A
paper
Iron(II) Chloride–1,1′-Binaphthyl-2,2′-diamine (FeCl2–BINAM) Complex
Catalyzed Domino Synthesis of Bisindolylmethanes from Indoles and Primary
Alcohols
Domino Synthesis of Bisindolylmethanes
Sindhura Badigenchala, Dhandapani Ganapathy, Ankita Das, Rahul Singh, Govindasamy Sekar*
Department of Chemistry, Indian Institute of Technology Madras, Chennai, Tamil Nadu-600 036, India
Fax +91(44)22574202; E-mail: gsekar@iitm.ac.in
Received: 22.08.2013; Accepted after revision: 01.10.2013
substrates. Hence, there is a need for an efficient, econom-
Abstract: Biologically important bisindolylmethanes are synthe-
ic and ecofriendly catalyst for the synthesis of 1,1-bisin-
sized in a domino fashion by using an iron(II) chloride–(±)-1,1′-bi-
dolylmethanes starting from primary alcohols.
naphthyl-2,2′-diamine [FeCl2–(±)-BINAM] complex as the
catalyst. This method proceeds via oxidation of a primary alcohol
into the corresponding aldehyde followed by nucleophilic addition
of an indole in the presence of the catalyst. A reaction intermediate
ter.21 Unlike other metals, iron is involved as a key ele-
is synthesized separately and converted into the bisindolylmethane
product under the same reaction conditions as support for the pro-
Iron is an attractive alternative catalyst because of its
abundance, low price and environmentally benign charac-
ment in various biological systems, particularly in
oxidations. Due to its ability to undergo facile changes in
oxidation state and because of its distinct Lewis acid char-
acter, iron catalysts enable a broad range of synthetic
transformations such as oxidation, cross-coupling, alkyla-
tion and addition reactions.22 In continuation of our re-
search on environmentally friendly iron-catalyzed
reactions,23 herein, we report an efficient iron(II)
posed mechanism.
Key words: bisindolylmethanes, iron catalysts, alcohol oxidation,
domino reactions, BINAM ligand
1,1-Bisindolylmethanes and their derivatives are known
to have a broad spectrum of biological and pharmacolog-
ical activities.1 They are active against human breast can-
cer cells and are found to activate a specific estrogen
receptor.2 These compounds show growth inhibitory ac-
tivity toward lung cancer cells,3 inhibit bladder cancer
growth4 and have antimicrobial,5 antifungal,6
antibacterial7 and antitumor activities.8 In addition, 1,1-
bisindolylmethane derivatives are used as human dietary
supplements.9 The oxidized forms of 1,1-bisindolylmeth-
anes have been reported as chromogenic-sensing mole-
cules.10 As a result of their potential value in
pharmaceuticals and materials, the synthesis of this class
of compounds has attracted significant interest from syn-
thetic chemists.11 1,1-Bisindolylmethanes have been iso-
lated from metabolites of terrestrial and marine origin,12
and various protocols have been adopted for their synthe-
sis.13 Most of the common methods involve the addition
of indoles to aldehydes or ketones in the presence of a
Lewis acid,14 a Bronsted acid,15 transition metals,16 rare
earth catalysts17 or zeolites.18 However, many of these
methods suffer from the disadvantages of using stoichio-
metric amounts of acids, expensive metal catalysts and
easily oxidizable aldehyde precursors. There have been
very few reports in the literature on the synthesis of 1,1-
bisindolylmethanes from alcohols.19 Yokoyama et al. re-
ported the synthesis of 1,1-bisindolylmethanes from ben-
zyl alcohol using a palladium catalyst.20 Although, this
method worked well, the protocol utilized costly palladi-
um as the catalyst and was limited to benzylic alcohols as
chloride–(±)-1,1′-binaphthyl-2,2′-diamine
[FeCl2–(±)-
BINAM] complex catalyzed synthesis of 1,1-bisindolyl-
methanes from primary alcohols and indoles in a domino
fashion.24
In our preliminary studies, the synthesis was carried out
starting from ethanol via a domino alcohol oxidation in
the presence of the FeCl2–BINAM complex as the catalyst
and dicumyl peroxide (DCP), followed by condensation
of the resulting aldehyde with indole (1) in ethanol, at
120 °C. To our surprise, the bisindolyl product was
formed in 68% isolated yield after eight hours (Scheme 1).
It is noteworthy that the reaction did not proceed without
the iron catalyst.
FeCl2 (5 mol%)
( )-BINAM (10 mol%)
DCP (3.5 equiv)
EtOH, 120 °C, 68%
N
N
N
H
H
H
1
2
Scheme 1 Synthesis of bisindolylmethane 2 from indole
In order to improve the reaction efficiency, several
BINAM-derived and other ligands were screened, but
none of them provided a better yield compared to BINAM
(L1) (Figure 1). When the reaction was carried out with
iron(II) chloride, but without a ligand, only a 27% yield of
the product was obtained.
SYNTHESIS 2013, 45, 000A–000I
Advanced online publication: 04.11.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1340052; Art ID: SS-2013-M0582-OP
© Georg Thieme Verlag Stuttgart · New York

B
S. Badigenchala et al.
PAPER
Table 1 Screening of Metal Salts for the Synthesis of 2
metal salt (5 mol%)
( )-BINAM (5 mol%)
DCP (3.5 equiv)
NHCH3
NHCH3
NH2
NH2
NHCH2Ph
NHCH2Ph
EtOH, 120 °C
N
N
N
H
L1
8 h, 68%
L2
10 h, 58%
L3
9 h, 61%
H
H
1
2
NH2
NH2
N
OH
Entry
Metal salt
Time (h)
Yield (%)a
1
FeCl2
6
68
40
15
0
N
OH
L6
12 h, 20%
2
Fe(OAc)2
FeSO4
16
16
24
20
15
12
12
12
24
12
24
16
8
L4
12 h, 60%
L5
12 h, 20%
3
H2N
NH2
4
FeCl3
N
N
N
N
5
FeBr3
0
L7
6 h, 30%
L8
6 h, 40%
L9
12 h, 46%
6
Fe(ClO4)2
CuCl2
0
7
14
42
45
25
20
20
38
50b
75c
69d
70e
N
N
8
Cu(OAc)2
Cu(OTf)2
CuI
N
N
N
N
9
OH
HO
L11
12 h, nr
L10
8 h, 36%
10
11
12
13
14
15
16
17
Co(OAc)2
Ni(OAc)2
Zn(OAc)2
L12
8 h, 46%
Figure 1 Ligand screening for the domino synthesis of 2
FeCl2
FeCl2
6
To optimize the conditions in terms of the yield, we
screened several other metal salts in combination with
BINAM (L1) as the ligand in this domino reaction (Table
1). Although copper, cobalt and zinc salts catalyzed the
reaction, none of them provided better yields than iron(II)
chloride. It was found that when a higher oxidation state
iron catalyst (Fe3+) was used, no product formation was
observed. The best result was obtained with iron(II) chlo-
ride (5 mol%), which gave bisindolylmethane 2 in 75%
yield after six hours. The results are summarized in Table 1.
FeCl2
FeCl2
8
12
a Yield of isolated product.
b FeCl2 (2.5 mol%).
c FeCl2 (5 mol%) and L1 (10 mol%).
d FeCl2 (10 mol%) and L1 (10 mol%).
e FeCl2 (10 mol%) and L1 (20 mol%).
Next, different types of oxidizing agents were examined.
Oxidants including hydrogen peroxide (H2O2), tert-butyl
hydroperoxide (t-BuOOH) and benzoyl peroxide were
less effective for the formation of product 2 when com-
pared with dicumyl peroxide (DCP). The reaction was
also attempted with 2,2,6,6-tetramethylpiperidine 1-oxyl
(TEMPO) and molecular oxygen as the oxidant, however,
there was no product formation. The number of equiva-
lents of dicumyl peroxide used was important with 3.5
equivalents giving the best result.
Since the temperature plays a major role in catalyst effi-
ciency, the reaction was examined at different tempera-
tures. When the temperature was lowered to 80 °C, the
yield of product 2 (76%) remained almost the same (Table
2, entry 9). However, when the temperature was reduced
to 60 °C, the yield decreased to 62% (Table 2, entry 10).
From the optimization studies the best catalytic system
was found to be: iron(II) chloride (5 mol%), 1,1′-binaph-
thyl-2,2′-diamine (L1) (10 mol%), dicumyl peroxide (3.5
Synthesis 2013, 45, A–I
© Georg Thieme Verlag Stuttgart · New York

PAPER
Domino Synthesis of Bisindolylmethanes
C
Table 2 Screening of Oxidants for the Synthesis of 2
equiv), 80 °C. The substrate scope of this methodology
was evaluated using the optimized reaction conditions and
the results are summarized in Table 3. Notably, indole re-
acted with ethanol to give the important natural product,
vibrindole A (2) (Table 3, entry 1). For substituted in-
doles, it was found that the presence of an electron-releas-
ing group on the nitrogen atom resulted in a good yield of
the corresponding product (Table 3, entry 2). However,
electron-withdrawing groups on the indole nitrogen atom,
such as tosyl, completely inhibited the reaction (Table 3,
entry 8), whilst an electron-withdrawing group on the
benzene ring reduced the yield (Table 3, entry 5).
FeCl2 (5 mol%)
( )-BINAM (10 mol%)
oxidant
EtOH, temp
N
N
N
H
H
H
1
2
Entry
Oxidant
Temp (°C)
Time (h)
Yield (%)a
1
DCP
120
120
120
120
120
120
120
100
80
6
75
0
2
H2O2
16
16
18
40
48
18
10
6
3
t-BuOOH
(PhCO2)2
TEMPO
DCP
0
Increasing the length of the aliphatic chain of the alcohol
led to reduced yields; when the alkyl chain was more than
three carbon atoms long, the reaction did not take place.
In the case of benzyl alcohol the reaction required a longer
time than aliphatic alcohols (Table 3, entries 11–14).
4
trace
0b
5
6
0c
7
DCP
55d
72
76
62
0
8
DCP
9
DCP
10
11
DCP
60
12
24
DCP
r.t.
a Yield of isolated product.
b O2 was used as a co-oxidant.
c TEMPO (1.0 equiv) was added.
d DCP (2.0 equiv).
Table 3 Iron-Catalyzed Domino Synthesis of Bisindolylmethanes from Indoles and Alcohols
R2
R2
R2
FeCl2 (5 mol%)
( )-BINAM (10 mol%)
DCP (3.5 equiv)
R3
R3
OH
N
R1
80 °C
N
R1
N
R1
Entry
1
Indole
Alcohol
Product
Time (h)
Yield (%)
6
76a
OH
OH
OH
N
N
N
N
N
H
H
Me
Et
H
2
3
4
2
3
6
80
62
N
N
Me
Me
24
N
N
Et
Et
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, A–I

D
S. Badigenchala et al.
PAPER
Table 3 Iron-Catalyzed Domino Synthesis of Bisindolylmethanes from Indoles and Alcohols (continued)
R2
R2
R2
FeCl2 (5 mol%)
( )-BINAM (10 mol%)
DCP (3.5 equiv)
R3
R3
OH
N
R1
80 °C
N
R1
N
R1
Entry
Indole
Alcohol
Product
Time (h)
Yield (%)
MeO
OMe
MeO
4
12
70
OH
N
N
N
H
H
H
5
Br
Br
Br
5
6
OH
36
15
63
63
N
N
N
Me
Me
Me
6
MeO
OMe
MeO
OH
N
N
N
H
H
H
7
N
N
N
7
OH
48
54
MeO
OMe
OMe
8
8
9
OH
24
10
0
N
N
Ts
N
Ts
Ts
9
OH
85
N
N
N
H
H
H
10
11
10
OH
36
62
N
N
N
Me
Me
Me
Synthesis 2013, 45, A–I
© Georg Thieme Verlag Stuttgart · New York

PAPER
Domino Synthesis of Bisindolylmethanes
E
Table 3 Iron-Catalyzed Domino Synthesis of Bisindolylmethanes from Indoles and Alcohols (continued)
R2
R2
R2
FeCl2 (5 mol%)
( )-BINAM (10 mol%)
DCP (3.5 equiv)
R3
R3
OH
N
R1
80 °C
N
R1
N
R1
Entry
11
Indole
Alcohol
Product
Time (h)
Yield (%)
OH
OH
OH
OH
36
60b,c
N
N
N
H
H
H
12
12
13
14
48
48
36
62b,c
58b,c
59b,c
N
N
N
Me
Me
Me
13
MeO
OMe
MeO
N
H
N
N
H
H
14
Br
Br
Br
N
N
N
H
H
H
15
a Yield of isolated product.
b tert-Butyl hydroperoxide was used as the oxidant.
c tert-Butyl alcohol (2 mL) was used as the solvent.
The reaction was completely suppressed by adding one of indole, which is directed by the lone pair of electrons
equivalent of TEMPO (with respect to FeCl2), a radical on the nitrogen of the indole.
trapping agent, to the reaction mixture. These results indi-
cate that a radical intermediate is most likely involved in
Based on these observations, a plausible mechanism for
the domino synthesis of bisindolylmethanes, using 2 as an
the initial steps of the domino transformation. This ex-
example, is suggested (Scheme 2). Two catalytic cycles
plains the observed fact that aliphatic alcohols are more
are proposed in the mechanism. In the first cycle, the pri-
reactive than benzyl alcohol, since benzylic radicals are
mary alcohol 16 is oxidized by iron(II) chloride and dicu-
myl peroxide to give the corresponding aldehyde 19
through the radical intermediates 17 and 18. In the second
cycle, nucleophilic addition of indole (1) to the iron(II)
chloride activated aldehyde 19 (which is formed in first
the cycle) affords secondary alcohol 20a (see Scheme 3).
The secondary alcohol is further activated by iron(II)
stabilized by resonance effects. When a secondary alcohol
was subjected to the optimized conditions there was no re-
action at all. These observations prove that the first step
involves oxidation of the alcohol into an aldehyde. More
importantly, there was no product formation at all when
the strongly electron-deficient indole, N-tosylindole was
used. The second step might involve nucleophilic attack
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, A–I

F
S. Badigenchala et al.
PAPER
Ph
H
O
O
Cl
Ph
N
+
••
Cl
O
O-FeCl
O-FeCl
OH
16
1
H
Fe(II)
H
••
••
Ph
OH
19
H
N
FeCl2
N
N
HCl
H
H
20
O
Fe(III)
Fe(III)
O
H2O
Ph
+
N
OH
17
H
18
H
N
N
N
N
H
H
H
H
2
Scheme 2 A plausible mechanism for the domino synthesis of bisindolylmethanes
All reactions were carried out in screw-cap pressure tubes under N2.
All the solvents used for the reactions were obtained from Merck,
India and were dried according to standard procedures. EtOH was
purchased from Changshu Yangyuan Chemical, China, and dried
over 4 Å molecular sieves. Reactions were monitored by thin-layer
chromatography (TLC) using Merck silica gel 60 F254 precoated
plates (0.25 mm), and samples were made visual by UV fluores-
cence. Silica gel (particle size: 100–200 mesh) was purchased from
SRL India and was used for column chromatography using appro-
priate mixtures of hexanes–EtOAc as the eluent. FeCl2 was ob-
tained from Sigma-Aldrich Company. Other chemicals were
purchased: indole from Spectrochem Pvt. Ltd., Mumbai, India
(AR), dicumyl peroxide from Acros Organics, and 1,1′-binaphthyl-
2,2′-diamine (BINAM) ligand L1 was purchased from GERCHEM
chemicals, Hyderabad, India. Reaction temperatures were con-
trolled using a Varivolt temperature modulator. Melting points were
obtained using a Toshniwal melting point apparatus and are uncor-
rected. FTIR spectra were recorded on a Nicolet 6700 spectrometer
chloride and undergoes a second addition of indole to give
the bisindolylmethane 2. We anticipated that the reaction
proceeded through the secondary alcohol 20a of the inter-
mediate 20, and we thus carried out a control experiment
to understand the mechanism. The intermediate 20a was
synthesized by the reduction of 3-acetylindole using sodi-
um borohydride,25 and then subjected to our standard con-
ditions for the preparation of bisindolylmethanes. As
expected, the reaction took place smoothly and afforded
an 80% isolated yield of compound 2 (Scheme 3). The in-
stability of the intermediate 20a explains the adverse ef-
fect of high temperature on this reaction.26
N
1
and absorptions are reported in wavenumbers (cm–1). H and 13C
FeCl2 (5 mol%)
( )-BINAM (10 mol%)
H
NMR spectra were recorded on Bruker 400 or 500 MHz instru-
ments. 1H NMR spectra are reported relative to Me4Si (δ 0.0) or re-
sidual CHCl3 (δ 7.26). 13C NMR are reported relative to CDCl3 (δ
77.16). High-resolution mass spectra (HRMS) were recorded on Q-
Tof Micro mass spectrometer.
1
DCP (3.5 equiv)
+
N
80 °C, 80%
N
HO
H
H
2
3,3′-(Ethane-1,1-diyl)bis(1H-indole) (2);27 Typical Procedure
An oven-dried, screw-cap pressure tube containing a magnetic stir
bar was charged with FeCl2 (3.2 mg, 0.025 mmol), 1,1′-binaphthyl-
2,2′-diamine (BINAM) (14.2 mg, 0.05 mmol), dicumyl peroxide
(DCP) (473.2 mg, 1.75 mmol) and indole (1) (58.6 mg, 0.5 mmol).
The pressure tube was evacuated and back-filled with N2. Anhy-
drous EtOH (2 mL) was added and the mixture was stirred at 80 °C
for 6 h. After the complete disappearance of indole (the progress of
the reaction was monitored by TLC), the mixture was allowed to
cool to r.t. and the EtOH was evaporated under reduced pressure us-
ing a rotary evaporator. Next, H2O (15 mL) was added, and the
product was extracted with EtOAc (3 × 10 mL) and dried over an-
hydrous Na2SO4. The solvent was evaporated and the residue puri-
fied by column chromatography on silica gel (EtOAc–hexane,
12:88) to afford pure product 2.
N
H
20a
Scheme 3 Synthesis of bisindolylmethane 2 from indole and the sec-
ondary alcohol 20a
In summary, an efficient, cost-effective, and environmen-
tally friendly iron-catalyzed domino synthesis of bisin-
dolylmethanes and their derivatives from indoles and
primary alcohols has been reported. A plausible mecha-
nism has been proposed for this domino process. In sup-
port of the mechanism, one of the postulated reaction
intermediates was independently synthesized and con-
verted into the corresponding bisindolylmethane under
the same reaction conditions.
Yield: 49.8 mg (76%); light yellow solid; mp 148 °C (Lit.27 158–
160 °C); Rf = 0.39 (20% EtOAc in hexane).
IR (neat): 3413, 3053, 2969, 2871, 1456, 1417, 1340, 1221, 1092,
1012, 746, 585 cm–1.
Synthesis 2013, 45, A–I
© Georg Thieme Verlag Stuttgart · New York

PAPER
Domino Synthesis of Bisindolylmethanes
G
1H NMR (400 MHz, CDCl3): δ = 1.83 (d, J = 7.2 Hz, 3 H), 4.70 (q,
J = 7.2 Hz, 1 H), 6.89 (d, J = 2.4 Hz, 2 H), 7.08 (td, J = 8, 0.8 Hz, 2
H), 7.20 (td, J = 8.0, 0.8 Hz, 2 H), 7.34 (d, J = 8 Hz, 2 H), 7.61 (d,
J = 8.4 Hz, 2 H), 7.80 (br s, 2 H).
1H NMR (400 MHz, CDCl3): δ = 1.79 (d, J = 7.2 Hz, 3 H), 3.77 (s,
6 H), 4.57 (q, J = 6.8 Hz, 1 H), 6.83 (d, J = 9.2 Hz, 2 H), 6.92 (s, 2
H), 7.01 (s, 2 H), 7.23 (s, 2 H), 7.81 (s, 2 H).
13C NMR (100 MHz, CDCl3): δ = 21.6, 28.2, 56.0, 101.9, 111.7,
111.8, 121.3, 122.2, 127.4, 132.0, 153.6.
13C NMR (100 MHz, CDCl3): δ = 21.9, 28.3, 111.2, 119.1, 119.9,
121.3, 121.8, 121.9, 127.0, 136.8.
HRMS (ESI, +): m/z [M + Na]+ calcd for C18H16N2Na: 283.1211;
found: 283.1220.
3,3′-(Ethane-1,1-diyl)bis[1-(4-methoxyphenyl)-1H-indole] (8)
Yield: 63.7 mg (54%); brown solid; mp 89 °C; Rf = 0.46 (10%
EtOAc in hexane).
IR (KBr): 3049, 2925, 2838, 1607, 1457, 1370, 1246, 834, 743 cm–1.
3,3′-(Ethane-1,1-diyl)bis(1-methyl-1H-indole) (3)
Yield: 58.4 mg (80%); colorless oil; Rf = 0.77 (20% EtOAc in
hexane).
IR (neat): 2925, 1612, 1469, 739 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.71 (d, J = 7.0 Hz, 3 H), 3.63 (s,
6 H), 4.59 (q, J = 7.1 Hz, 1 H), 6.71 (s, 2 H), 6.96 (t, J = 7.0 Hz, 2
H), 7.12 (td, J = 7.0, 1.1 Hz, 2 H), 7.20 (t, J = 8.2 Hz, 2 H), 7.51 (d,
J = 8 Hz, 2 H).
1H NMR (500 MHz, CDCl3): δ = 1.80 (d, J = 7.5 Hz, 3 H), 3.77 (s,
6 H), 4.69 (q, J = 7 Hz, 1 H), 6.91 (d, J = 8.5 Hz, 4 H), 7.02 (m, 4
H), 7.11 (t, J = 7 Hz, 2 H), 7.29 (d, J = 9 Hz, 4 H), 7.37 (d, J = 8.5
Hz, 2 H), 7.59 (d, J = 8 Hz, 2 H).
13C NMR (125 MHz, CDCl3): δ = 22.0, 28.2, 55.7, 110.5, 114.7,
119.5, 120.0, 121.9, 122.2, 125.6, 125.9, 128.1, 133.2, 136.9, 158.0.
HRMS (ESI, +): m/z [M + Na]+ calcd for C32H28N2O2Na: 495.2048;
found: 495.2068.
13C NMR (125 MHz, CDCl3): δ = 22.5, 28.3, 32.9, 109.4, 118.7,
120.1, 120.6, 121.6, 126.3, 127.6, 137.6.
HRMS (ESI, +): m/z [M + H]+ calcd for C20H21N2: 289.1705; found:
289.1714.
3,3′-(Propane-1,1-diyl)bis(1H-indole) (10)29
Yield: 58.2 mg (85%); colorless oil; Rf = 0.45 (20% EtOAc in
hexane).
1H NMR (500 MHz, CDCl3): δ = 0.93 (t, J = 7.4 Hz, 3 H), 2.16
(quin, J = 7.4 Hz, 2 H), 4.29 (t, J = 7.4 Hz, 1 H), 6.87 (d, J = 2.2 Hz,
2 H), 6.95 (t, J = 7.1 Hz, 2 H), 7.06 (t, J = 7.6 Hz, 2 H), 7.22 (d, J =
8.1 Hz, 2 H), 7.51 (d, J = 8 Hz, 2 H), 7.75 (s, 2 H).
13C NMR (125 MHz, CDCl3): δ = 13.2, 28.8, 36.0, 111.1, 119.1,
119.8, 120.4, 121.5, 121.8, 127.3, 136.7.
3,3′-(Ethane-1,1-diyl)bis(1-ethyl-1H-indole) (4)
Yield: 49.7 mg (62%); pale brown solid; mp 101 °C; Rf = 0.54 (5%
EtOAc in hexane).
IR (KBr): 2929, 2869, 1607, 1547, 1462, 1394, 1334, 931, 819 cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.33 (t, J = 7 Hz, 6 H), 1.72 (d,
J = 7 Hz, 3 H), 4.02 (dq, J = 7.0, 1.5 Hz, 4 H), 4.59 (q, J = 7.5 Hz,
1 H), 6.77 (s, 2 H), 6.95 (t, J = 7 Hz, 2 H), 7.10 (t, J = 7.5 Hz, 2 H),
7.23 (d, J = 8.5 Hz, 2 H), 7.50 (d, J = 8 Hz, 2 H).
3,3′-(Propane-1,1-diyl)bis(1-methyl-1H-indole) (11)
Yield: 46.5 mg (62%); dark red solid; Rf = 0.56 (10% EtOAc in
hexane).
13C NMR (125 MHz, CDCl3): δ = 15.5, 22.2, 28.2, 40.8, 109.2,
IR (KBr): 2923, 1607, 1465, 1370, 1086, 747 cm–1.
118.3, 120.0, 121.1, 124.3, 125.6, 127.9, 136.3.
HRMS (ESI, +): m/z [M + K]+ calcd for C22H24N2K: 355.1577;
found: 355.1589.
1H NMR (500 MHz, CDCl3): δ = 0.93 (t, J = 7.5 Hz, 3 H), 2.14 (q,
J = 7.5 Hz, 2 H), 3.64 (s, 6 H), 4.29 (t, J = 7.0 Hz, 1 H), 6.77 (s, 2
H), 6.94–6.97 (m, 2 H), 7.09–7.12 (m, 2 H), 7.18 (s, 2 H), 7.53 (d,
J = 8 Hz, 2 H).
3,3′-(Propane-1,1-diyl)bis(5-methoxy-1H-indole) (5)
Yield: 58.2 mg (70%); brown solid; mp 121 °C; Rf = 0.41 (30%
EtOAc in hexane).
13C NMR (125 MHz, CDCl3): δ = 13.3, 29.4, 32.8, 35.9, 109.2,
118.5, 119.1, 119.9, 121.3, 126.4, 127.7, 137.4.
HRMS (ESI, +): m/z [M + Na]+ calcd for C21H22N2Na: 325.1681;
IR (KBr): 3409, 2924, 2853, 1617, 1452, 1309, 1089, 878, 800, 760
cm–1.
found: 325.1696.
1H NMR (400 MHz, CDCl3): δ = 1.02 (t, J = 7.2 Hz, 3 H), 2.23
(quin, J = 7.2 Hz, 2 H), 3.77 (s, 6 H), 4.27 (t, J = 7.2 Hz, 1 H), 6.81
(dd, J = 8, 2 Hz, 2 H), 6.99 (d, J = 1.6 Hz, 2 H), 7.03 (d, J = 2 Hz, 2
H), 7.22 (d, J = 8 Hz, 2 H), 7.81 (br s, 2 H).
13C NMR (100 MHz, CDCl3): δ = 13.3, 28.2, 55.7, 56.0, 102.1,
111.7, 118.8, 122.4, 128.3, 128.4, 144.6, 158.0.
3,3′-(Phenylmethane-1,1-diyl)bis(1H-indole) (12)30
Yield: 48.3 mg (60%); pink solid; mp 139 °C (Lit.30 141–142 °C);
Rf = 0.49 (20% EtOAc in hexane).
IR (KBr): 3409, 2924, 2853, 1605, 1455, 1198, 744 cm–1.
1H NMR (400 MHz, CDCl3): δ = 5.80 (s, 1 H), 6.55 (d, J = 1.6 Hz,
2 H), 6.92 (t, J = 7.2 Hz, 2 H), 7.06–7.14 (m, 3 H), 7.19 (t, J = 7.2
Hz, 2 H), 7.25–7.27 (m, 4 H), 7.31 (d, J = 8 Hz, 2 H), 7.79 (s, 2 H).
3,3′-(Ethane-1,1-diyl)bis(5-bromo-1-methyl-1H-indole) (6)28
Yield: 65.8 mg (63%); brown solid; mp 112 °C; Rf = 0.41 (10%
EtOAc in hexane).
13C NMR (100 MHz, CDCl3): δ = 40.2, 111.0, 119.2, 119.9, 121.9,
IR (neat): 3114, 2968, 2821, 1611, 1535, 1420, 1366, 907, 866, 790
cm–1.
1H NMR (500 MHz, CDCl3): δ = 1.66 (d, J = 7.0 Hz, 3 H), 3.62 (s,
6 H), 4.44 (q, J = 7.0 Hz, 1 H), 6.69 (s, 2 H), 7.07 (d, J = 8.5 Hz, 2
H), 7.19 (dd, J = 8.5, 2.0 Hz, 2 H), 7.57 (d, J = 2 Hz, 2 H).
13C NMR (125 MHz, CDCl3): δ = 22.1, 28.0, 32.9, 110.8, 112.2,
119.6, 122.3, 124.4, 127.3, 128.9, 136.2.
123.6, 126.1, 127.1, 128.2, 128.7, 133.7, 136.7, 144.0.
3,3′-(Phenylmethane-1,1-diyl)bis(1-methyl-1H-indole) (13)27
Yield: 54.2 mg (59%); dark red solid; mp 163 °C; Rf = 0.43 (10%
EtOAc in hexane).
IR (KBr): 3020, 2927, 1607, 1547, 1472, 1366, 744, 700 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.66 (s, 6 H), 5.87 (s, 1 H), 6.52
(d, J = 0.8 Hz, 2 H), 6.96–7.00 (m, 2 H), 7.16–7.21 (m, 3 H), 7.24–
7.29 (m, 4 H), 7.33–7.35 (m, 2 H), 7.38 (d, J = 7.6 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 32.8, 40.2, 109.2, 118.4, 118.8,
120.2, 121.5, 126.1, 127.6, 128.3, 128.4, 128.8, 137.5, 144.6.
HRMS (ESI, +): m/z [M + Na]+ calcd for C25H22N2Na: 373.1681;
3,3′-(Ethane-1,1-diyl)bis(5-methoxy-1H-indole) (7)28
Yield: 50.6 mg (63%); brown sticky solid; Rf = 0.43 (30% EtOAc in
hexane).
IR (KBr): 3412, 2954, 2830, 1619, 1479, 1361, 1212, 805, 739 cm–1.
found: 373.1696.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, A–I

H
S. Badigenchala et al.
PAPER
3,3′-(Phenylmethane-1,1-diyl)bis(5-methoxy-1H-indole) (14)28
Yield: 55.4 mg (58%); red solid; mp 198 °C; Rf = 0.56 (30% EtOAc
in hexane).
IR (KBr): 3004, 2934, 1619, 1586, 1484, 1448, 1208, 1028, 799 cm–1.
1H NMR (500 MHz, CDCl3): δ = 3.61 (s, 6 H), 5.69 (s, 1 H), 7.11–
7.22 (m, 7 H), 7.27 (d, J = 7.2 Hz, 2 H), 7.39 (t, J = 7.6 Hz, 2 H),
7.76 (s, 2 H), 8.04 (d, J = 7.6 Hz, 2 H).
13C NMR (125 MHz, CDCl3): δ = 40.4, 56.0, 102.2, 111.8, 112.0,
119.5, 124.6, 126.2, 128.3, 128.6, 128.9, 130.3, 132.0, 133.8.
HRMS (ESI, +): m/z [M + Na]+ calcd for C25H22N2O2Na: 405.1579;
found: 405.1566.
(10) He, X.; Hu, S.; Liu, K.; Guo, Y.; Xu, J.; Shao, S. Org. Lett.
2006, 8, 333.
(11) (a) Jafarpour, M.; Rezaeifard, A.; Golshani, T.
J. Heterocycl. Chem. 2009, 46, 535. (b) Gong, H.; Xie, Z.
Youji Huaxue 2012, 32, 1195.
(12) (a) Osawa, T.; Namiki, M. Tetrahedron Lett. 1983, 24, 4719.
(b) Porter, J. K.; Bacon, C. W.; Robbins, J. D.;
Himmelsbach, D. S.; Higman, H. C. J. Agric. Food Chem.
1977, 25, 88.
(13) Deb, M. L.; Bhuyan, P. J. Tetrahedron Lett. 2006, 47, 1441.
(14) (a) Wang, Y. M.; Wen, Z.; Chen, X. M.; Du, D.-M.;
Matsuura, T.; Meng, J. B. J. Heterocycl. Chem. 1998, 35,
313. (b) Chatterjee, A.; Manna, S.; Banerji, J.; Pascard, C.;
Prange, T.; Shoolery, J. N. J. Chem. Soc., Perkin Trans. 1
1980, 553.
(15) (a) Kokare, N. D.; Sangshetti, J. N.; Shinde, D. B. Chin.
Chem. Lett. 2008, 19, 1186. (b) Singh, P.; Singh, D.;
Samant, S. Synth. Commun. 2005, 35, 2133.
(16) (a) Young, P. C.; Hadfield, M. S.; Arrowsmith, L.;
MacLeod, K. M.; Mudd, R. J.; Jordan-Hore, J. A.; Lee, A.-
L. Org. Lett. 2012, 14, 898. (b) Yang, J.; Wang, Z.; Pan, F.;
Li, Y.; Bao, W. Org. Biomol. Chem. 2010, 8, 2975. (c) Xia,
D.; Wang, Y.; Du, Z.; Zheng, Q. Y.; Wang, C. Org. Lett.
2012, 14, 588. (d) Guo, X.; Pan, S.; Liu, J.; Li, Z. J. Org.
Chem. 2009, 74, 8848.
3,3′-(Phenylmethane-1,1-diyl)bis(5-bromo-1H-indole) (15)31
Yield: 59.1 mg (59%); dark red solid; mp 223 °C; Rf = 0.55 (30%
EtOAc in hexane).
IR (KBr): 3416, 3068, 2927, 2859, 1592, 1558, 1449, 976, 775 cm–1.
1H NMR (500 MHz, CDCl3): δ = 5.75 (s, 1 H), 6.65 (d, J = 1.5 Hz,
2 H), 7.23–7.24 (m, 4 H), 7.26 (s, 2 H), 7.29–7.30 (m, 4 H), 7.47 (d,
J = 0.5 Hz, 2 H), 7.99 (s, 2 H).
13C NMR (125 MHz, CDCl3): δ = 40.0, 112.7, 112.8, 119.2, 122.4,
124.9, 125.1, 126.7, 128.6, 128.7, 128.8, 135.5, 143.1.
HRMS (ESI, +): m/z [M + H]+ calcd for C23H17N2Br2: 478.9758;
found: 478.9743.
(17) (a) Chen, D.; Yu, L.; Wang, P. G. Tetrahedron Lett. 1996,
37, 4467. (b) Sun, W. Y.; Sun, Y.; Tang, Y. C.; Hu, J. Q.
Synlett 1993, 337. (c) Wang, L.; Han, J.; Tian, H.; Sheng, J.;
Fan, Z.; Tang, X. Synlett 2005, 337. (d) Mi, X.; Luo, S.; He,
J.; Cheng, J. P. Tetrahedron Lett. 2004, 45, 4567.
(18) Karthik, M.; Magesh, C. J.; Perumal, P. T.; Palanichamy,
M.; Arabindoo, B.; Murugesan, V. Appl. Catal., A 2005,
286, 137.
Acknowledgment
We thank CSIR [Project No. 01/(2378)/10/EMR-II], DST New
Delhi for financial support. B.S. thanks UGC, New Delhi for a JRF,
D.G. thanks CSIR New Delhi for an SRF, and A.D. thanks IIT-M for
infrastructure.
(19) (a) Suda, K.; Takanami, T. Chem. Lett. 1994, 10, 1915.
(b) Khosropour, A. R.; Mohammadpoor-Baltork, I.;
Khodaei, M. M.; Ghanbary, P. Z. Naturforsch., B: Chem.
Sci. 2007, 62, 537. (c) Zanardi, A.; Corberan, R.; Mata, J. A.;
Peris, E. Organometallics 2008, 27, 3570.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
(20) Hikawa, H.; Yokoyama, Y. RSC Adv. 2013, 3, 1061.
(21) Bolm, C.; Legros, J.; Le, P. J.; Zani, L. Chem. Rev. 2004,
104, 6217.
(22) (a) Gopalaiah, K. Chem. Rev. 2013, 113, 3248. (b) Chen, Q.
Y.; He, Y. B.; Yang, Z. Y. J. Fluorine Chem. 1986, 34, 255.
(c) Sherry, B. D.; Furstner, A. Chem. Commun. 2009, 7116.
(d) Takeuchi, M.; Shimakoshi, H.; Kano, K.
References
(1) (a) Mahboobi, S.; Teller, S.; Pongratz, H.; Hufsky, H.;
Sellmer, A.; Botzki, A.; Uecker, A.; Beckers, T.; Baasner,
S.; Schaechtele, C.; Ueberall, F.; Kassack, M. U.; Dove, S.;
Boehmer, F. D. J. Med. Chem. 2002, 45, 1002.
(b) Samsoniya, S. A.; Lomtatidze, Z. S.; Ovsyannikova, N.
N.; Suvorov, N. N. Khim. Farm. Zh. 1987, 21, 827. (c) Shiri,
M.; Zolfigol, M. A.; Kruger, H. G.; Tanbakouchian, Z.
Chem. Rev. 2010, 110, 2250.
Organometallics 1994, 13, 1208. (e) Zhang, L.; Peng, D.;
Leng, X.; Huang, Z. Angew. Chem. Int. Ed. 2013, 52, 3676.
(f) Wei, Y.; Ding, H.; Lin, S.; Liang, F. Org. Lett. 2011, 13,
1674. (g) Niu, T.; Huang, L.; Wu, T.; Zhang, Y. Org.
Biomol. Chem. 2011, 9, 273. (h) De H, J.; Abbaspour, T. K.;
Maes, B. U. W. Angew. Chem. Int. Ed. 2012, 51, 2745.
(i) Enthaler, S. ChemCatChem 2011, 3, 1929. (j) Liu, W.;
Liu, J.; Ogawa, D.; Nishihara, Y.; Guo, X.; Li, Z. Org. Lett.
2011, 13, 6272. (k) Agrawal, T.; Cook, S. P. Org. Lett. 2013,
15, 96. (l) Kuzmina, O. M.; Steib, A. K.; Flubacher, D.;
Knochel, P. Org. Lett. 2012, 14, 4818. (m) Singh, P. P.;
Aithagani, S. K.; Yadav, M.; Singh, V. P.; Vishwakarma, R.
A. J. Org. Chem. 2013, 78, 2639.
(2) (a) Safe, S.; Papineni, S.; Chintharlapalli, S. Cancer Lett.
2008, 269, 326. (b) Vanderlaag, K.; Su, Y.; Frankel, A. E.;
Burghardt, R. C.; Barhoumi, R.; Chadalapaka, G.; Jutooru,
I.; Safe, S. BMC Cancer 2010, 10, 669.
(3) Ichite, N.; Chougule, M. B.; Jackson, T.; Fulzele, S. V.; Safe,
S.; Singh, M. Clin. Cancer Res. 2009, 15, 543.
(4) Inamoto, T.; Papineni, S.; Chintharlapalli, S.; Cho, S. D.;
Safe, S.; Kamat, A. M. Mol. Cancer Ther. 2008, 7, 3825.
(5) Sivaprasad, G.; Perumal, P. T.; Prabavathy, V. R.;
Mathivanan, N. Bioorg. Med. Chem. Lett. 2006, 16, 6302.
(6) Kamal, A.; Khan, M. N. A.; Srinivasa, R. K.; Srikanth, Y. V.
V.; Kaleem, A. S.; Pranay, K. K.; Murthy, U. S. N. J. Enzyme
Inhib. Med. Chem. 2009, 24, 559.
(23) (a) Muthupandi, P.; Alamsetti, S. K.; Sekar, G. Chem.
Commun. 2009, 3288. (b) Muthupandi, P.; Sekar, G. Org.
Biomol. Chem. 2012, 10, 5347.
(7) Bell, R.; Carmeli, S.; Sar, N. J. Nat. Prod. 1994, 57, 1587.
(8) Chen, I.; McDougal, A.; Wang, F.; Safe, S. Carcinogenesis
1998, 19, 1631.
(9) (a) Bonnesen, C.; Eggleston, I. M.; Hayes, J. D. Cancer Res.
2001, 61, 6120. (b) Carter, T. H.; Liu, K.; Ralph, W. Jr;
Chen, D.; Qi, M.; Fan, S.; Yuan, F.; Rosen, E. M.; Auborn,
K. J. J. Nutr. 2002, 132, 3314.
(24) Domino reactions have attracted a great deal of attention
because they provide a high degree of molecular complexity
from structurally simple molecules. These reactions are
typically economic and more environmentally friendly as
they avoid the isolation of unstable intermediates and reduce
production costs. See: (a) Tietze, L. F. Chem. Rev. 1996, 96,
Synthesis 2013, 45, A–I
© Georg Thieme Verlag Stuttgart · New York

PAPER
115. (b) Breinbauer, R. Synthesis 2007, 794. (c) Mueller, T.
Domino Synthesis of Bisindolylmethanes
I
explain the low yield at 100 °C. Intermediate 20a might be
J. J. Angew. Chem. Int. Ed. 2007, 46, 2977.
(d) Bogdanowicz-Szwed, K.; Krasodomska, M.;
somewhat stable at 80 °C, the temperature at which it gives
the maximum yield. At lower temperature, product
formation may be sluggish.
Krasodomski, W. Wiad. Chem. 1997, 51, 643. (e) Pellissier,
H. Chem. Rev. 2013, 113, 442. (f) Parsons, P. J.; Penkett, C.
S.; Shell, A. J. Chem. Rev. 1996, 96, 195. (g) Tietze, L. F.;
Duefert, S. C.; Clerc, J.; Bischoff, M.; Maass, C.; Stalke, D.
Angew. Chem. Int. Ed. 2013, 52, 3191.
(27) Ganguly, N. C.; Mondal, P.; Barik, S. K. Green Chem. Lett.
Rev. 2012, 5, 73.
(28) Ramachandiran, K.; Muralidharan, D.; Perumal, P. T.
Tetrahedron Lett. 2011, 58, 5.
(25) Secondary alcohol 20a is highly unstable to column
chromatographic purification and the sodium borohydride
reduction of 3-acetylindole in EtOH at r.t. gave single
compound 20a, which was used directly in the control
experiment without any further purification.
(29) Xu, H. Y.; Zi, Y.; Xu, X. P.; Wang, S. Y.; Ji, S. J.
Tetrahedron 2013, 69, 1600.
(30) Thirupathi, P.; Kim, S. S. J. Org. Chem. 2010, 75, 5240.
(31) Mendes, S. R.; Thurow, S.; Fortes, M. P.; Penteado, F.;
Lenardão, E. J.; Alves, D.; Perin, G.; Jacob, R. G.
Tetrahedron Lett. 2012, 53, 5402.
(26) The reaction intermediate might be unstable at 100 °C and
may decompose before it reacts. This speculation might
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, A–I