An underrated cheap Lewis acid: Molecular bromine as a robust catalyst for bis(indolyl)methanes synthesis

Article abstract of DOI:10.1016/j.catcom.2014.06.005

A discovery that inexpensive elemental bromine can act as a potent Lewis acid catalyst is disclosed. Under the catalysis of only 2 mol% of Br ₂, indoles reacted rapidly with carbonyl compounds to give bis(indolyl)methanes with extremely high efficiency and wide substrate scope. Moreover, a Br₂-catalyzed aqueous-phase reaction is also presented to further demonstrate the power of this novel catalyst.

Full text of DOI:10.1016/j.catcom.2014.06.005

Catalysis Communications 55 (2014) 11–14
Contents lists available at ScienceDirect
Catalysis Communications
journal homepage: www.elsevier.com/locate/catcom
Short Communication
An underrated cheap Lewis acid: Molecular bromine as a robust catalyst
for bis(indolyl)methanes synthesis
⁎
⁎
Deqiang Liang , Wenzhong Huang , Lin Yuan, Yinhai Ma, Jingmei Ma, Deman Ning
Department of Chemistry, Kunming University, Kunming 650214, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A discovery that inexpensive elemental bromine can act as a potent Lewis acid catalyst is disclosed. Under the
catalysis of only 2 mol% of Br2, indoles reacted rapidly with carbonyl compounds to give bis(indolyl)methanes
with extremely high efficiency and wide substrate scope. Moreover, a Br2-catalyzed aqueous-phase reaction is
also presented to further demonstrate the power of this novel catalyst.
Received 23 April 2014
Received in revised form 7 June 2014
Accepted 9 June 2014
Available online 17 June 2014
© 2014 Elsevier B.V. All rights reserved.
Keywords:
Elemental bromine
Bis(indolyl)methanes
Indole functionalization
Bromine effect
Aqueous-phase reaction
1. Introduction
Bis(indolyl)methane derivatives have been widely found in various
terrestrial and marine natural resources [17–19], and have many appli-
Elemental halogens are vital reagents in the history of chemistry [1,
2]. In modern synthetic chemistry, however, only molecular iodine is
frequently used as a catalyst, which is much safer and convenient to
use, but expensive [1,3,4]. In violent contrast, inexpensive elemental
bromine is not welcome for its high vapor pressure and corrosivity,
and has rarely been used in a catalytic manner except in oxidation
reactions [5–9], although its solid alternatives, such as N-
bromosuccinimide (NBS) [10] and complexes of bromine with various
Lewis bases [5,11–14], have been increasingly employed. All these alter-
natives are prepared from molecular bromine and thus associated with
higher costs and/or cumbersome procedures. In fact, when it is simply
diluted with corresponding solvents and treated with sodium thiosul-
fate in a work-up step, a catalytic amount of bromine hardly does
harm to the operator and environment.
Very recently, Jamison et al. demonstrated a NBS- or Br2-catalyzed
method for the synthesis of cyclic carbonates from epoxides and CO2,
it was believed that the epoxides were activated by electrophilic
bromine [15]. In another report, a Br2-catalyzed conversion of a tert-
butyl protecting group to an acetyl protecting group for thiols in acetyl
chloride and the presence of acetic acid was developed [16]. Though in
these seminal works the catalytic activity of Br2 was not unique [15] or
strong acid conditions were required [16], they suggested that Br2 is
quite underrated and might serve as a potent Lewis acid catalyst in
organic synthesis.
cations in pharmaceuticals with diverse activities, such as anticancer
[20], antileishmanial [21], and antihyperlipidemic [22]. Including I2
[23,24], CuBr2 [25], and several alternatives to Br2 [26–29], a broad
range of acids can catalyze the synthesis of bis(indolyl)methanes from
indoles and carbonyl compounds [30]. Most of these methods, however,
require high catalyst loadings and/or long reaction times.
Herein, we report the unexpected discovery that Br2 exhibited
abnormally high activity as a catalyst in the synthesis of bis(indolyl)
methanes, and an aqueous-phase reaction is also presented. This is not
the first time the element of bromine surprises chemists, not long ago
Liu et al. revealed the peculiar catalytic performances of HBr and
CuBr2 in some C\C bond-forming reactions, which depended on the
nature of the counterion [31,32]. Our work together with Liu's findings
will provide further clues for a full appreciation of this curious bromine
effect.
2. Experimental
2.1. General procedure in CH3CN (taking 3a as an example)
A 25-mL flask, equipped with a magnetic stirring bar, was charged
with 1H-indole 1a (117 mg, 1.0 mmol), CH3CN (4.0 mL), and benzalde-
hyde 2a (0.056 mL, 0.55 mmol), followed by addition of a solution of Br2
(0.0010 mL) in CH3CN (1.0 mL). The reaction mixture was stirred at
50 °C for 1 min. After 1a was consumed, as indicated by thin-layer chro-
matography (TLC), the reaction mixture was quenched with aqueous
Na2S2O3, cooled to room temperature, poured into 30 mL water under
⁎
Corresponding authors. Tel.: +86 871 65098482.
E-mail addresses: ldq5871@126.com (D. Liang), cxhwz@126.com (W. Huang).
http://dx.doi.org/10.1016/j.catcom.2014.06.005
1566-7367/© 2014 Elsevier B.V. All rights reserved.

12
D. Liang et al. / Catalysis Communications 55 (2014) 11–14
stirring, and extracted with CH2Cl2 three times. The extract was dried
over anhydrous MgSO4. After removal of solvents, the residue was
purified by column chromatography on silica gel (petroleum ether–
ethyl acetate = 9/1, V/V) to afford the product 3a as a pink solid
(158 mg, 98% yield).
a stronger Brønsted acid, only provided 36% yield of 3a even after a
prolonged reaction time of 6 h (not shown). To our great delight, by in-
creasing catalyst loading to 2 mol%, 3a was afforded in nearly quantita-
tive yields within 1 min with either Br2 or HBr as a catalyst (entry 2).
Interestingly, upon reversing the addition order of benzaldehyde 2a
and Br2, the reaction was retarded (entry 2, note f), indicating that
mechanistically Br2 should first coordinate to the carbonyl oxygen to
initiate this rapid transformation.
2.2. General procedure in water (taking 3a as an example)
An excellent yield was still obtained when the reaction was per-
formed at room temperature and in a longer reaction time of 30 min
(entry 3). The remarkable role of Br2 could not be replaced by I2 [23,
24] (entry 4) or NBS [26] (entry 5), and CuBr2 [25] (entry 6), FeCl3
(entry 7) and trifluoroacetic acid (TFA, entry 9) were not suitable cata-
lysts as well. Although BF3·Et2O (entry 8), 4-methylbenzenesulfonic
acid (TsOH, entry 10) and H2SO4 (entry 11) were active enough to
enable full conversion of 1a, significantly longer reaction times were
required. Next, other solvents instead of CH3CN were examined. It
proved that with Br2 as a catalyst, CH2Cl2, tetrahydrofuran (THF) and
N,N-dimethylformamide (DMF) were all applicable solvents, which
was not the case under the catalysis of HBr except THF (entries 12–
14). Ethanol for both catalysts was not usable (entry 15). A minute
quantity of water (i.e., water contained in 40% aqueous HBr in the
same loading as Br2) hardly affected these Br2-catalyzed reactions
(entries 1, 2, 12–14, notes e and g). All the results above confirm the
unique catalytic performance of Br2, which is superior to all the Lewis
acids and Brønsted acids tested, including Liu's catalyst, thus ruling
out the possibility of HBr generated in situ being the true catalyst. At
this stage, the origin of the extraordinary activity of Br2 remains unclear,
yet it might be related to the strong electronegativity of bromine.
A 25-mL flask, equipped with a magnetic stirring bar, was charged
with 1H-indole 1a (117 mg, 1.0 mmol), H2O (1.0 mL), benzaldehyde
2a (0.056 mL, 0.55 mmol), followed by addition of a solution of Br2
(0.0051 mL) in H2O (4.0 mL). The reaction mixture was refluxed
under stirring for the indicated time (6 h, see Table 3). Then it was
quenched with aqueous Na2S2O3, cooled to room temperature, and ex-
tracted with CH2Cl2 three times. The extract was dried over anhydrous
MgSO4. After removal of solvents, the residue was purified by column
chromatography on silica gel (petroleum ether–ethyl acetate = 9/1,
V/V) to afford the product 3a as a pink solid (150 mg, 93% yield).
3. Results and discussion
At the outset of the present investigation, 1H-indole 1a and benzal-
dehyde 2a were employed as model substrates to screen reaction condi-
tions (Table 1). We were astonished to find that under the catalysis of
only 1 mol% of Br2 in CH3CN at 50 °C, the condensation reaction reached
completion rapidly within 20 min and bis(indolyl)alkane 3a was
formed in excellent yield (92%, entry 1). With this impressive result in
hand, we evaluated Liu's catalyst and proved that HBr (40% aqueous)
was also a robust catalyst in this transformation, albeit with a slightly
lower reaction rate (entry 1, note d), while the use of HI (40% aqueous),
Table 1
Table 2
Optimization of reaction conditions.a
Scope of the Br2-catalyzed synthesis of bis(indolyl)methanes 3.a
Entry
Acid
Solvent
T (°C)
t (min)
Yield of 3ab (%)
Entry
1
R1
H
R2
2
R3
R4
t (min)
3
Yieldb (%)
1c
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Br2
Br2
Br2
I2
NBS
CuBr2
FeCl3
BF3·Et2O
TFA
TsOH
H2SO4
Br2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
THF
50
50
rt
20 (30)d
1 (10)f (1)d
30
360
360
360
360
60
360
92e (90)d
98g (95)f (97)d
90
1
2
3
4
5
6
7
8
1a
H
H
H
H
H
H
H
2a
2a
2a
2a
2a
2a
2a
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
1
5
1
120
1
10
5
1
1440
1
1
3a
3b
3c
3d
3e
3f
3g
3h
3i
98
95
97
95
92
98
95
90
76
96
98
97
1b 2-Ph
1c 2-Me
1d 2-CO2Et
1e 5-MeO
50
50
50
50
50
50
50
50
50
50
50
50
48 (49)h
79 (16)h
51 (44)h
45 (52)h
94
1f
5-NO2
1g 6-Cl
1h
1i
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me 2a
Piv 2a
69 (27)h
92
93
9
Ph
120
60
10
11
12
13
14
15
16
17
18
19
20
21
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
H
H
H
H
H
H
H
H
H
H
H
H
2b
2c
2d
2e
2f
2g
2h
2i
4-ClPh
4-NO2Ph
3-NO2Ph
2-NO2Ph
4-MePh
4-MeOPh
2-Furyl
PhCH_CH
H
3j
3k
3l
120 (360)d
30 (30)d
20 (360)d
360 (360)d
96g (60)d
91g (90)d
93g (84)d
27 (22)h (70)d
1
1
Br2
Br2
Br2
3m 98
DMF
EtOH
10
30
10
60
960
3n
3o
3p
72
65
86
Complex
92
74
85
58
a
Reaction conditions: 1a (1.0 mmol), 2a (0.55 mmol), catalyst (0.02 mmol), solvent
(5 mL).
2j
2k
2l
3q
3r
3s
3t
b
c
Isolated yields.
1 mol% of catalyst was used.
Me
(CH2)5
Me 1440
720
Ph
d
e
f
HBr (40% aqueous) was used instead of Br2.
Almost identical results were obtained when 0.0012 mL H2O was additionally added.
2a was added a fewer seconds later than Br2.
Almost identical results were obtained when 0.0024 mL H2O was additionally added.
Recovery of 1a.
2m Me
1440
a
Reaction conditions: 1 (1.0 mmol), 2 (0.55 mmol), Br2 (0.02 mmol), CH3CN (5 mL),
g
h
50 °C.
b
Isolated yields.

D. Liang et al. / Catalysis Communications 55 (2014) 11–14
13
Under the optimized conditions (Table 1, entry 2), a range of reac-
tions was carried out with various indoles 1 and carbonyl compounds
2 (Table 2). It proved that indoles 1 having phenyl (entry 2), electron-
donating (entries 3 and 5) or electron-withdrawing groups (entries 4,
6 and 7) on either phenyl or pyrrolyl ring reacted with benzaldehyde
2a to afford the corresponding bis(indolyl)methanes 3b–g in ex-
cellent to nearly quantitative yields, and the presence of electron-
withdrawing substituents led to longer reaction times (entries 4, 6
and 7). Desired product 3h was delivered in 90% yield in 1 min from
N-methylindole 1h (entry 8), whereas when indolic nitrogen was
protected by pivalyl group, great sluggishness was observed (entry 9).
Then, other carbonyl compounds 2 were evaluated. While reactions of
1a with aldehydes bearing electron-deficient aromatic substituents
reached completion immediately in nearly quantitative yields (entries
10–13), electron-rich aromatic (entries 14 and 15) and heteroaromatic
aldehydes (entry 16) were less favorable. Unfortunately, when an α,β-
unsaturated aldehyde 2i was used, a complex mixture was yielded
(entry 17). In the case of paraformaldehyde 2j, bis(indolyl)methane
3q was formed in 92% yield within 16 h (entry 18). It is worthy of notice
that electrophiles 2 could also be ketones, including acetone 2k (entry
19), cyclohexanone 2l (entry 20) and acetophenone 2m (entry 21),
and the related products 3r–t were delivered in moderate to good
yields.
8) and N-pivalylindole 1i (entry 9) also gave their corresponding
products 3h and 3i in 90% and 42% yields, respectively. On the other
hand, all tested aromatic (entries 10–13) or heteroaromatic aldehydes
(entry 14) were found to be adept in efficiently furnishing bis(indolyl)
methanes 3j, k, n–p in moderate to excellent yields, and the substituent
effects observed were similar to the ones in CH3CN (see Table 2, entries
10, 11, 14–16). In these aqueous-phase reactions, however, it is also
possible that the mixture of HBr and HBrO catalyzed the condensations,
as the use of both of them gave excellent yields (entry 1, note c and d).
4. Conclusions
In summary, we have presented an unexpected Br2-catalyzed
synthesis of bis(indolyl)methane derivatives from indoles and carbonyl
compounds. This reaction is associated with low catalyst loading,
extremely high efficiency and broad substrate scope, and could be
conducted in either organic solvents or water. The robust activity of
Br2 demonstrated as an underrated Lewis acid might inspire more
novel Br2-catalyzed organic reactions and provide clues for further
research on the curious bromine effect. Further investigations of the
mechanism and new applications of Br2
as a Lewis acid are in progress.
Acknowledgments
Water is cheap, non-toxic, and not flammable, and it is therefore an
attractive media for the development of environmentally benign chem-
ical processes [33]. To highlight the power of this novel Lewis acid cata-
lyst, we sought to perform this Br2-catalyzed reaction in aqueous
medium (Table 3). We were pleased to find that with 10 mol% of cata-
lyst, on treatment of 1H-indole 1a (entry 1) or indoles 1 bearing phenyl
(entry 2), electron-donating (entries 3 and 5) or modest electron-
withdrawing groups (entry 7) with 2a in water at reflux, the expected
products 3a–c, e, g were generated smoothly in good to excellent yields.
In the cases of more electron-deficient indoles 1d and 1f, however, no
reactions occurred (entries 4 and 6). Use of N-methylindole 1h (entry
The authors are grateful for the support from the General Projects of
Yunnan Education Department (2013Y252), the Applied Basic Research
Programs of Yunnan Science and Technology Department (2013FZ103),
and the Scientific Research Funds of Kunming University (XJL12014).
Appendix A. Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.catcom.2014.06.005.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
References
[1] M.W. Justik, Annu. Rep. Prog. Chem. Sect. A: Inorg. Chem. 109 (2013) 92–100.
[2] R.T. Sanderson, J. Chem. Educ. 41 (1964) 361–366.
[3] S.U. Tekale, S.S. Kauthale, S.A. Dake, S.R. Sarda, R.P. Pawar, Curr. Org. Chem. 16
(2012) 1485–1501.
Table 3
Synthesis of bis(indolyl)methanes 3 in water.a
[4] F.C. Küpper, M.C. Feiters, B. Olofsson, T. Kaiho, S. Yanagida, M.B. Zimmermann, L.J.
Carpenter, G.W. Luther III, Z. Lu, M. Jonsson, L. Kloo, Angew. Chem. Int. Ed. 50
(2011) 11598–11620.
[5] Y. Yuan, X. Shi, W. Liu, Synlett (2011) 559–564.
[6] M. Uyanik, R. Fukatsu, K. Ishihara, Chem. Asian J. 5 (2010) 456–460.
[7] S. Hirashima, S. Hashimoto, Y. Masaki, A. Itoh, Tetrahedron 62 (2006) 7887–7891.
[8] R. Mu, Z. Liu, Z. Yang, Z. Liu, L. Wu, Z. Liu, Adv. Synth. Catal. 347 (2005) 1333–1336.
[9] A. Bravo, B. Dordi, F. Fontana, F. Minisci, J. Org. Chem. 66 (2001) 3232–3234.
[10] I.V. Koval', Russ. J. Org. Chem. 38 (2002) 301–337.
[11] A. Rostami, Y. Navasi, D. Moradi, A. Ghorbani-Choghamarani, Catal. Commun. 43
(2014) 16–20.
[12] M.B. Teimouri, P. Akbari-Moghaddam, M. Motaghinezhad, Tetrahedron 69 (2013)
6804–6809.
[13] S. Gazi, R. Ananthakrishnan, RSC Adv. 2 (2012) 7781–7787.
[14] S.A. Snyder, D.S. Treitler, A.P. Brucks, J. Am. Chem. Soc. 132 (2010) 14303–14314.
[15] J.A. Kozak, J. Wu, X. Su, F. Simeon, T.A. Hatton, T.F. Jamison, J. Am. Chem. Soc. 135
(2013) 18497–18501.
[16] A. Błaszczyk, M. Elbing, M. Mayor, Org. Biomol. Chem. 2 (2004) 2722–2724.
[17] T.R. Garbe, M. Kobayashi, N. Shimizu, N. Takesue, M. Ozawa, H. Yukawa, J. Nat. Prod.
63 (2000) 596–598.
[18] G. Bifulco, I. Bruno, R. Riccio, J. Lavayre, G. Bourdy, J. Nat. Prod. 58 (1995) 1254–1260.
[19] R. Bell, S. Carmeli, N. Sar, J. Nat. Prod. 57 (1994) 1587–1590.
[20] A. Kamal, Y.V.V. Srikanth, M.J. Ramaiah, M.N.A. Khan, M.K. Reddy, M. Ashraf, A.
Lavanya, S.N.C.V.L. Pushpavalli, M. Pal-Bhadra, Bioorg. Med. Chem. Lett. 22 (2012)
571–578.
[21] S.B. Bharate, J.B. Bharate, S.I. Khan, B.L. Tekwani, M.R. Jacob, R. Mudududdla, R.R.
Yadav, B. Singh, P.R. Sharma, S. Maity, B. Singh, I.A. Khan, R.A. Vishwakarma, Eur. J.
Med. Chem. 63 (2013) 435–443.
[22] K.V. Sashidhara, A. Kumar, M. Kumar, A. Srivastava, A. Puri, Bioorg. Med. Chem. Lett.
20 (2010) 6504–6507.
[23] S. Ji, S. Wang, Y. Zhang, T. Loh, Tetrahedron 60 (2004) 2051–2055.
[24] B.P. Bandgar, K.A. Shaikh, Tetrahedron Lett. 44 (2003) 1959–1961.
[25] L. Mo, Z. Ma, Z. Zhang, Synth. Commun. 35 (2005) 1997–2004.
Entry
1
R1
H
R2
2
R3
R4 t (h)
3
Yieldb (%)
1
2
3
4
5
6
7
8
1a
H
H
H
H
H
H
H
2a
2a
2a
2a
2a
2a
2a
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
6
24
6
24
6
24
24
6
24
6
3a
93 (95)c (90)d
1b 2-Ph
1c 2-Me
1d 2-CO2Et
1e
1f
1g
1h
1i
1a
1a
1a
1a
1a
3b 77
3c 90
3d nr
3e
3f
3g 71
3h 90
3i
3j
3k 93
3n 67
3o 60
3p 81
5-MeO
5-NO2
6-Cl
H
H
H
H
H
H
92
nr
Me 2a
Piv 2a
9
42
90
10
11
12
13
14
H
H
H
H
H
2b 4-ClPh
2c
2f
2g 4-MeOPh
2h 2-Furyl
4-NO2Ph
4-MePh
6
24
24
24
H
a
Reaction conditions: 1 (1.0 mmol), 2 (0.55 mmol), Br2 (0.1 mmol), H2O (5 mL),
100 °C.
b
c
Isolated yields.
HBr was used instead of Br2.
HBrO was used instead of Br2.
d

14
D. Liang et al. / Catalysis Communications 55 (2014) 11–14
[26] H. Koshima, W. Matsusaka, J. Heterocycl. Chem. 39 (2002) 1089–1091.
[27] S.K. Kundu, S. Islam, A. Hajra, A. Majee, Russ. J. Org. Chem. 46 (2010) 126–128.
[28] X. Lin, S. Cui, Y. Wang, Synth. Commun. 36 (2006) 3153–3160.
[31] C. Xu, H. Yuan, Y. Liu, M. Wang, Q. Liu, RSC Adv. 4 (2014) 1559–1562.
[32] H. Yuan, M. Wang, Y. Liu, L. Wang, J. Liu, Q. Liu, Chem. Eur. J. 16 (2010) 13450–13457
(and references cited therein).
[29] B.P. Bandgar, S.V. Bettigeri, N.S. Joshi, Monatsh. Chem. 135 (2004) 1265–1273.
[30] H. Gong, Z. Xie, Chin. J. Org. Chem. 32 (2012) 1195–1207.
[33] C. Li, T. Chan, Comprehensive Organic Reactions in Aqueous Media, Second ed.
Wiley-Interscience, New Jersey, 2007.