One-pot synthesis of bisindolylmethanes from benzyl alcohols and indoles using catalytic iodine and molecular oxygen under visible light irradiation

Article abstract of DOI:10.1055/s-0032-1317508

Bisindolylmethanes can be directly synthesized from benzyl alcohol and indole in up to 86% yield using molecular oxygen, visible light, and catalytic iodine, which serves as both an oxidant and a Lewis acid. Georg Thieme Verlag KG · Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1317508

LETTER
▌2975
letter
One-Pot Synthesis of Bisindolylmethanes from Benzyl Alcohols and Indoles
Using Catalytic Iodine and Molecular Oxygen under Visible Light Irradiation
One-Pot Synthesis of Bisindolylmethanes
Tomoya Nobuta, Akitoshi Fujiya, Norihiro Tada, Tsuyoshi Miura, Akichika Itoh*
Gifu Pharmaceutical University 1-25-4, Daigaku-nishi, Gifu 501-1196, Japan
Fax +81(58)2308108; E-mail: itoha@gifu-pu.ac.jp
Received: 05.09.2012; Accepted: 28.09.2012
molecular iodine as a Lewis acid,3o we anticipated that
Abstract: Bisindolylmethanes can be directly synthesized from
molecular iodine, which catalyzes the aerobic photooxi-
benzyl alcohol and indole in up to 86% yield using molecular oxy-
dation of benzyl alcohol to benzaldehyde and then is re-
gen, visible light, and catalytic iodine, which serves as both an oxi-
dant and a Lewis acid.
generated,8e could also be utilized for the condensation
step between an indole and benzaldehyde (Scheme 1).
Key words: photooxidation, iodine, molecular oxygen, bisindolyl-
Herein, we describe the one-pot aerobic photooxidative
synthesis of bisindolylmethanes from benzyl alcohols and
indoles using a catalytic amount of iodine as both the ox-
idant and a Lewis acid.
methane, benzyl alcohol
Indole derivatives play an important role as key interme-
diates in organic synthesis, and are also used as antibiotics
and pharmaceuticals.1 In particular, bisindolylmethanes
are found in bioactive metabolites of terrestrial and ma-
rine origin that have been isolated during the last few
years.2 Thus, several methods for the synthesis of bisin-
dolylmethanes have been reported. In general, these pro-
cesses involve the condensation of carbonyl compounds
with a two-fold excess of the indole using an appropriate
catalyst.3 In recent years, C–H bond activation has attract-
ed great interest in organic synthesis, and the C–H bond
activation/C–heteroatom bond cleavage of tertiary amines
or ethers to bisindolylmethanes with a transition metal
catalyst/oxidant, such as Pd(OAc)2/Cu(OAc)2,4 Cu-
Br/TBHP,5 or FeCl2/(t-BuO)2,6 has been reported. How-
ever, the oxidative coupling of alcohols and indoles to
bisindolylmethane, which generates only water as a by-
product, has been rare,7 and to the best of our knowledge,
no selective, catalytic method has been reported to date.
NH
cat. I2
O2, visible light
then indole
Ar
OH
Ar
NH
cat. I2
cat. I2
O2, visible light
N
H
Ar CHO
Scheme 1 One-pot photooxidative synthesis of bisindolylmethanes
Table 1 shows the results of the investigation of the reac-
tion conditions for the one-pot aerobic photooxidative
synthesis of bisindolylmethane (3aa) from 4-tert-butyl-
benzyl alcohol (1a) and indole (2a) as test substrates. The
reaction conditions were examined with 4-tert-butylben-
On the other hand, we have developed various aerobic zyl alcohol (1a) in the presence of iodine sources under an
photooxidation processes under an oxygen atmosphere oxygen atmosphere (O2 balloon) and visible light irradia-
using visible light irradiation with iodine sources.8 Molec- tion for 20 hours, followed by addition of indole (2a).
ular iodine is an inexpensive and low toxicity reagent, and Among the iodine sources and solvents examined, molec-
has served various functions in organic synthesis, includ- ular iodine and EtOAc were found to afford the desired
ing as an oxidant and a Lewis acid.9 In multistep synthe- product 3aa most efficiently (entries 1–11 and 15–21). As
sis, from the perspective of green chemistry, it is desirable a result of these detailed examinations, it was determined
that the reagent used in the upstream reaction be recycled that 0.2 equivalent of molecular iodine was the most ef-
to catalyze the downstream reaction.10 Using this ap- fective (entries 11–13), and 3aa was obtained in high
proach, we reported a one-pot and metal-free synthetic yield by slightly increasing the quantity of 2a (entry 14).
protocol for the preparation of acetophenones from sty-
renes using molecular iodine for aerobic photooxidation
and deiodination, in which the molecular iodine is as-
Table 2 presents the scope and limitations of the one-pot
aerobic photooxidative synthesis of bisindolylmethanes 3
from benzyl alcohols 1 and indoles 2 under the optimized
sumed to work as an oxidant in the aerobic photooxidation
reaction conditions.11 In general, the corresponding bis-
and a Lewis acid in the deiodination steps.8a To synthesize
indolylmethanes 3 were obtained in good to high yields
using benzyl alcohol with an alkyl or bromo group on the
bisindolylmethane from aldehydes and indoles with
benzene ring (entries 1–4) and 2-naphtalene methanol
(1e) (entry 5) at room temperature. Because 4-chloro-
benzyl alcohol (1f) was oxidized slowly when using 0.2
equivalent of molecular iodine, only 0.1 equivalent of mo-
SYNLETT 2012, 23, 2975–2979
Advanced online publication: 23.11.2012
DOI: 10.1055/s-0032-1317508; Art ID: ST-2012-U0743-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

2976
T. Nobuta et al.
LETTER
lecular iodine was used in the aerobic photooxidation (2b) and indole-3-propionic acid (2c), participated in the
step, and another 0.1 equivalent of I2 was added in the reaction, and the corresponding bisindolylmethanes (3gb
condensation step (entry 6). 4-Methoxybenzyl alcohol and 3hc), which are substituted in the C-2 position of the
(1g) and 4-nitrobenzyl alcohol (1h) were converted to the indole derivative, were obtained in moderate yields (en-
corresponding bisindolylmethane in good yields after tries 9 and 10).
heating to 40 °C for an extended time (entries 7 and 8).
Even 3-substituted indoles, such as indole-3-butyric acid
Furthermore, N-methylindole (2d) was also converted to
the corresponding bis-indolylmethane (3cd) in 86% yield
(entry 11). Unfortunately, pyrrole (2e) was a poor sub-
strate (entry 12).
Table 1 Study of the Reaction Conditionsa
To examine the reaction mechanism, benzaldehyde (4b)
was subjected to condensation with indole (2a; Scheme
2). It was found that no corresponding bisindolylmethane
(3ba) was obtained without molecular iodine, while the
condensation proceeded smoothly in the presence of a cat-
alytic amount of I2 and/or 55% aq HI. These results sug-
gest that molecular iodine catalyzes the condensation of
benzaldehyde with indole.
NH
iodine source
O2, visible light, 20 h
then indole (2a) (2 equiv)
10 min
Ar
Ar
OH
solvent
(Ar = 4-t-BuC6H4)
3aa
ArCHO
4a
NH
1a
Entry
Iodine source (equiv) Solvent
Yield (%)b
3aa
4a
NH
iodine source
indole (2a) (2 equiv)
1
2
LiI (0.2)
NaI (0.2)
KI (0.2)
CsI (0.2)
MgI2 (0.2)
CaI2 (0.2)
PhI (0.2)
NIS (0.2)
55% aq HI (0.2)
CI4 (0.2)
I2 (0.2)
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
MeCN
acetone
MeOH
CH2Cl2
i-PrOH
hexane
H2O
0
0
0
Ph
Ph CHO
0
EtOAc, 10 min
NH
3
0
0
4b
iodine source
I2 (0 equiv)
3ba
4b
68%
1%
4
0
0
0%
59%
61%
I2 (0.2 equiv)
5
0
4
55% aq HI (0.4 equiv)
0%
6
0
26
trace
75
63
0
Scheme 2 Study of the reaction mechanisms
7
0
8
0
Scheme 3 shows the postulated reaction mechanism for
this one-pot aerobic photooxidative synthesis of bis-
indolylmethanes 3 from benzyl alcohols 1 and indoles us-
ing catalytic molecular iodine based on the results
mentioned above. First, benzyl alcohols 1 are oxidized to
benzaldehydes 4 under an oxygen atmosphere using mo-
lecular iodine and visible light irradiation. The in situ gen-
erated HI is then reoxidized to I2 under the aerobic
photooxidative conditions.8e In the condensation step, the
aldehydes are activated by molecular iodine and/or hydro-
gen iodide, enabling electrophilic addition of the indole to
give the intermediate 5. After loss of water, the azafulvene
derivative 6 is generated and immediately undergoes ad-
dition of a second indole moiety to form the bisindolyl-
methane 3.3o
9
15
10
11
12
13
14c
15
16
17
18
19
20
21
58
60
7
I2 (0.1)
0
59
0
I2 (0.3)
31
I2 (0.2)
88 (86)
trace
0
I2 (0.2)
25
I2 (0.2)
5
42
0
I2 (0.2)
trace
I2 (0.2)
0
0
0
0
0
In conclusion, we report herein a facile one-pot, aerobic
photooxidative synthesis of bisindolylmethanes from ben-
zyl alcohols and indoles under a molecular oxygen atmo-
sphere using catalytic molecular iodine and visible light
irradiation. This novel reaction is interesting, because it
uses catalytic molecular iodine for both steps; as an oxi-
dant in the aerobic photooxidation and as a Lewis acid in
the condensation reaction. Further application of this pho-
tooxidation methodology to other reactions is now in
progress in our laboratory.
I2 (0.2)
55
0
I2 (0.2)
I2 (0.2)
0
a A solution of 4-tert-butylbenzyl alcohol (1a; 0.3 mmol), iodine (0.2
equiv) in solvent (5 mL) under an O2 atmosphere was stirred and ir-
radiated externally with 22-W fluorescent lamps. After 20 h, the in-
dole (2 equiv) was added and stirred for 10 min.
b 1H NMR yields. Number in parenthesis shows the isolated yield.
c The amount of indole used was 2.2 equiv.
Synlett 2012, 23, 2975–2979
© Georg Thieme Verlag Stuttgart · New York

LETTER
One-Pot Synthesis of Bisindolylmethanes
2977
Table 2 Scope and Limitationsa
I
2 (0.2 equiv)
O2, visible light, 20 h
then indole derivative 2 (2.2 equiv)
temp, time
bisindolylmethane
Ar
OH
EtOAc
1
3
Entry Ar
Indole derivative
Temp (°C) Time
Product
Yield (%)b
1
r.t.
r.t.
r.t.
r.t.
r.t.
60
40
40
4-t-BuC6H4
Ph
1a
10 min 3aa
86
84
80
74
80
51
73
62
2
1b
10 min 3ba
10 min 3ca
10 min 3da
10 min 3ea
NH
3
4-MeC6H4
4-BrC6H4
2-naphthyl
1c
4
1d
Ar
N
H
NH
5
1e
2a
6
4-ClC6H4
1f
2.5 h
2.5 h
36 h
3fa
3ga
3ha
7
4-MeOC6H4
4-O2NC6H4
1g
8
1h
CO2H
3
HO2C
NH
CO2H
9d
1g
1h
1c
1c
4-MeOC6H4
40
40
r.t.
r.t.
36 h
3gb
31
42
86
18
3
3
N
H
HN
2b
MeO
CO2H
2
HO2C
NH
CO2H
2
10
4-O2NC6H4
36 h
3hc
2
N
H
HN
2c
O2N
NMe
N
Me
11
4-MeC6H4
10 min 3hd
NMe
Me
2d
NH
HN
N
H
12
4-MeC6H4
10 min 3ce
Me
2e
a A solution of substrate 1 (0.3 mmol) and iodine (0.2 equiv) in EtOAc (5 mL) under an O2 atmosphere was stirred and irradiated externally with
22-W fluorescent lamps. After 20 h, the indole derivative (2.2 equiv) was added, and the mixture was stirred.
b Isolated yields.
c 0.1 equiv of I2 was used in the first step, and another 0.1 equiv of I2 was added in the second step.
d The reaction was carried out on 0.15 mmol scale.
e 4-Chlorobenzyl alcohol (18%) was recovered.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2975–2979

2978
T. Nobuta et al.
LETTER
NH
N
NH
I2 or HI
indole 2
indole 2
Ar
OH
Ar
O
visible light
Ar
OH
Ar
Ar
1
4
H2O
NH
5
6
3
I2
HI
visible light
H2O
O2
Scheme 3 Plausible mechanistic pathway
48, 1131. (e) Nakayama, H.; Itoh, A. Chem. Pharm. Bull.
2006, 54, 1620.
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Zhang, D.-X.; Cao, L.-P.; She, N.-F.; Wu, A.-X. Org. Lett.
2010, 12, 4026.
Acknowledgment
The authors would like to thank Enago (www.enago.jp) for the Eng-
lish language review.
References and Notes
(11) General Procedure: A solution of 4-tert-butylbenzyl
alcohol (1a; 0.3 mmol) and I2 (0.06 mmol) in anhyd EtOAc
(5 mL) in a pyrex test tube, purged with an O2 balloon, was
stirred and irradiated externally with four 22-W fluorescent
lamps for 20 h. Indole (0.66 mmol) was added, and stirred
for 10 min at r.t. The reaction mixture was washed with aq
Na2S2O3 and concentrated in vacuo. Purification of the crude
product by PTLC (hexane–EtOAc, 4:1) provided 3,3′-bis-
(indolyl)-4-tert-butylphenylmethane (3aa; Rf 0.33; yield:
98.1 mg, 86%).
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Meraj, S.; Prasad, A. R. Synthesis 2006, 4121. (h) Nair, V.;
Vidya, N.; Abhilash, K. G. Synthesis 2006, 3647. (i) Zhang,
Z.-H.; Yin, L.; Wang, Y.-M. Synthesis 2005, 1949. (j) Ji, S.-
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G.; Giuliani, A.; Marcantoni, E.; Sambri, L. Synthesis 2004,
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3,3′-Bis(indolyl)-4-tert-butylphenylmethane (3aa): 1H
NMR (400 MHz, CDCl3): δ = 7.54 (br s, 2 H), 7.36 (d, J =
7.7 Hz, 2 H), 7.26–7.09 (m, 8 H), 6.98–6.94 (m, 2 H), 6.47
(s, 2 H), 5.80 (s, 1 H), 1.27 (s, 9 H).
3,3′-Bis(indolyl)phenylmethane (3ba): 1H NMR (400
MHz, CDCl3): δ = 7.44 (br s, 2 H), 7.34–7.08 (m, 11 H), 6.95
(t, J = 7.3 Hz, 2 H), 6.39 (s, 2 H), 5.80 (s, 1 H).
3,3′-Bis(indolyl)-4-methylphenylmethane (3ca): 1H NMR
(400 MHz, CDCl3): δ = 7.41 (br s, 2 H), 7.34 (d, J = 8.2 Hz,
2 H), 7.17–7.05 (m, 6 H), 7.02 (d, J = 7.7 Hz, 2 H), 6.95 (t,
J = 7.2 Hz, 2 H), 6.40 (s, 2 H), 5.78 (s, 1 H), 2.27 (s, 3 H).
3,3′-Bis(indolyl)-4-bromophenylmethane (3da): 1H NMR
(400 MHz, CDCl3): δ = 7.50 (br s, 2 H), 7.24–7.02 (m, 10 H),
6.89 (m, 2 H), 6.34 (s, 2 H), 5.68 (s, 1 H).
3,3′-Bis(indolyl)-2-naphthylmethane (3ea): 1H NMR (500
MHz, DMSO-d6): δ = 10.90 (br s, 2 H), 7.85–7.73 (m, 4 H),
7.57 (d, J = 8.6 Hz, 1 H), 7.40–7.35 (m, 6 H), 7.04 (t, J = 7.4
Hz, 2 H), 6.91–6.84 (m, 4 H), 6.05 (s, 1 H).
(m) Farhanullah Sharon, A.; Maulik, P. R.; Ram, V. J.
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Kumar, G. M.; Madan, C. Synthesis 2001, 783.
3,3′-Bis(indolyl)-4-chlorophenylmethane (3fa): 1H NMR
(500 MHz, DMSO-d6): δ = 10.87 (br s, 2 H), 7.36–6.83 (m,
14 H), 5.85 (s, 1 H).
3,3′-Bis(indolyl)-4-methoxyphenylmethane (3ga): 1H
NMR (500 MHz, CDCl3): δ = 7.58 (br s, 2 H), 7.35–7.34 (m,
2 H), 7.21–7.09 (m, 6 H), 6.96 (t, J = 7.4 Hz, 2 H), 6.75 (d,
J = 8.0 Hz, 2 H), 6.44 (s, 2 H), 5.77 (s, 1 H), 3.70 (s, 3 H).
3,3′-Bis(indolyl)-4-nitrophenylmethane (3ha): 1H NMR
(500 MHz, DMSO-d6): δ = 10.92 (br s, 2 H), 8.12 (d, J = 8.6
Hz, 2 H), 7.58 (d, J = 8.6 Hz, 2 H), 7.34 (d, J = 8.0 Hz, 2 H),
7.26 (d, J = 8.0 Hz, 2 H), 7.04–7.01 (m, 2 H), 6.88–6.84 (m,
4 H), 6.00 (s, 1 H).
(4) Ramachandiran, K.; Muralidharan, D.; Perumal, P. T.
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2335. (d) Nakayama, H.; Itoh, A. Tetrahedron Lett. 2007,
2,2′-Bis[3-(carboxypropyl)indolyl]-4-
methoxyphenylmethane (3gb): 1H NMR (400 MHz,
DMSO-d6): δ = 12.00 (br s, 2 H), 10.43 (br s, 2 H), 7.48 (d,
J = 7.3 Hz, 2 H), 7.30 (d, J = 7.8 Hz, 2 H), 7.04–6.93 (m, 6
H), 6.87 (d, J = 8.7 Hz, 2 H), 5.97 (s, 1 H), 3.70 (s, 3 H),
2.72–2.69 (m, 4 H), 2.21 (t, J = 7.3 Hz, 4 H), 1.72–1.69 (m,
4 H).
Synlett 2012, 23, 2975–2979
© Georg Thieme Verlag Stuttgart · New York

LETTER
2,2′-Bis[3-(carboxyethyl)indolyl]-4-nitrophenylmethane
One-Pot Synthesis of Bisindolylmethanes
2979
= 7.37 (d, J = 8.0 Hz, 2 H), 7.24–7.14 (m, 6 H), 7.05 (d, J =
7.5 Hz, 2 H), 6.97–6.94 (m, 2 H), 6.50 (s, 2 H), 5.83 (s, 1 H),
3.58 (s, 6 H), 2.29 (s, 3 H).
(3hc): 1H NMR (500 MHz, DMSO-d6): δ = 12.09 (br s, 2 H),
10.78 (br s, 2 H), 8.20 (d, J = 8.6 Hz, 2 H), 7.50 (d, J = 7.4
Hz, 2 H), 7.35 (d, J = 8.6 Hz, 2 H), 7.31 (d, J = 8.0 Hz, 2 H),
7.04 (t, J = 7.4 Hz, 2 H), 6.98–6.95 (m, 2 H), 6.40 (s, 1 H),
3.01–2.88 (m, 4 H), 2.46–2.40 (m, 4 H).Bis(1-methylindol-
3-yl)-4-tolylmethane (3cd): 1H NMR (500 MHz, CDCl3): δ
5-(4-Methylphenyl)dipyrromethane (3ce): 1H NMR (500
MHz, CDCl3): δ = 7.91 (br s, 2 H), 7.13–7.09 (m, 4 H), 6.68–
6.67 (m, 2 H), 6.16–6.14 (m, 2 H), 5.91 (s, 2 H), 5.43 (s, 1
H), 2.33 (s, 3 H).
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2975–2979

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