An easy and efficient synthesis of bisindolylmethanes and tetraindolylmethane Tr?ger's base catatlyzed by AgBF4

Article abstract of DOI:10.1002/jccs.201190142

This work presents a highly efficient and simplemethod for the synthesis of bisindolylmethanes, catalyzed by AgBF₄, with excellent yields. Various substituted aldehydes and ketones with indole under this reaction condition is elucidated. This r

Full text of DOI:10.1002/jccs.201190142

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Journal of the Chinese Chemical Society, 2011, 58, 899-905
899
An Easy and Efficient Synthesis of Bisindolylmethanes and
Tetraindolylmethane Tröger’s Base Catatlyzed by AgBF4
Ajam C. Shaikh and Chinpiao Chen*
Department of Chemistry, National Dong Hwa University, Shoufeng, Hualien 974, Taiwan, Republic of China
Received January 27, 2011; Accepted June 23, 2011; Published Online July 5, 2011
This work presents a highly efficient and simple method for the synthesis of bisindolylmethanes, cata-
lyzed by AgBF4, with excellent yields. Various substituted aldehydes and ketones with indole under this
reaction condition is elucidated. This reaction occurs efficiently under mild reaction conditions, such as
are applied with methoxy or furfural, which commonly undergoes cleavage under strongly acidic reaction
conditions. The presented approach was suitable for the synthesis of complex systems, such as tetraindo-
lylmethane Tröger’s Base.
Keywords: AgBF4; Condensation; Indole; Carbonyl compounds; Tröger’s base; Bisindole.
1. INTRODUCTION
The first isolation of hallucinogenic bisindolylal-
NBS,32 KHSO4,33 InF3,34 ZrCl4,35 1-butyl-3-methylimida-
zolium tetrafluoroborate,36 MoO2(acac)2,37 MgSO4,38 p-
TsOH,39 triphenylmethyl chloride,40 lanthanum perfluoro-
octanoate,41 H3PO4-SiO2,42 ruthenium(III) chloride hy-
drate,43 carbohydrate-based tolylsulfonyl hydrazines,44 so-
dium dodecylsulfate,45 SbCl3,46 3-(n-hexyl)-1-methylimi-
dazolium hydrogensulfate,47 heteropoly acids,48 iron(III)
fluoride,49 1-dodecanesulfonic acid,50 CeCl3.7H2O,51
SmI2(THF)2,52 and sodium tetrakis[3,5-bis(trifluorometh-
yl)phenyl]borate.53 Many of the methods used have such
disadvantages as long reaction periods,54 the use of expen-
sive reagents7f or preformed reagents,55–56 and poor yields
of bisindolylmethanes (around 2%).2a Although some of
these reactions are performed under mild conditions, most
of them require a long period for completion, tedious
work-up, the formation of side products and only modest
yields of the products (Table 1). Therefore, a convenient,
rapid and efficient method for preparation of bisindole-
methane is still sought. Because of the wide range of bio-
logical interest in these compounds, this study pursues a
mild, efficient and expedient protocol for synthesizing bis-
indolylmethanes.
kanes from a fungus in 19771 and the subsequent isolation
of other bisindolylalkanes, including some bioactive mem-
bers, from natural sources2 have attracted considerable sci-
entific attention. Some indole derivatives, such as 3-substi-
tuted indoles derivatives, are of pharmaceutical interest in
several therapeutic areas.3 They are known to exhibit vari-
ous biological activities including antibacterial, cytotoxic,
antioxidative and insecticidal activites.4 The feasibility of
electrophilic substitution at the 3-position of indole is such
that it is widely used in organic synthesis.5
Bisindolylmethanes have been obtained by reactions
of indoles with various aldehydes or ketones in the pres-
ence of either protic6 or Lewis acids.7 With the rapid devel-
opment in the field of catalytic and synthetic chemistry, re-
searchers have started to pay more attention to the develop-
ment of eco-friendly and reusable catalysts to eliminate or
minimize problems of environmental pollution. In particu-
larly, indoles and carbonyl compounds have been success-
fully condensed using catalysts such as amberlyst (sulfonic
acid form),8 AuCl3,9 diammonium hydrogen phosphate,10
FeCl3,11 I2,12 montmorillonite K10,13 sulfamic acid,14
TCT,15 zeolite,16 CAN,17 triflates,18 ferric dodecyl sulfo-
nate,19 ion exchange resins,20 aminocatalysis by benzoic
hydrazide derived catalyst,21 ionic liquids,22 antimony sul-
fate,23 CuBr2,24 HMTAB,25 nitrates,26 PPh3-HClO4,27 silica
supported sodium hydrogen sulfate and amberlyst-15,28
tetrabutylammonium triborimide,29 Yb-amberlist,30 ZnO,31
Silver tetrafluoroborate is a fluorodesulfurization re-
agent;57 is used in the synthesis of 1,6-diketones from
siloxycyclopropanes;58 is a potent promoter of chemical
glycosylation;59 causes the silver ion-induced rearrange-
ment of N-chloramines;60 causes the silver-induced allyla-
tion of b-bromo ethers with allylsilanes,61 and has other im-

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900 J. Chin. Chem. Soc., Vol. 58, No. 7, 2011
Shaikh and Chen
Table 1. Various Lewis acids catatlyzed synthesis of bisindolylmethanes using aldehydes and ketones with
indole
Entry
Lewis Acid
Temp (°C)
Solvent
Time (h)
Yield (%)
Reference
1
Ln(OTf)3
AuCl3
rt
rt
EtOH/H2O
CH3CN
Various
[omim]PF6
DMSO/H2O
CH3CN
ionic liquids
EtOH/H2O
H2O
12-36
12
47-99
64-93
96
7f
9
2
3
FeCl3
20
rt
1.25
0.25-10
0.08-1
1
11
11
17
18b
18c
18e
19
23
24
25b
31
34
35
37
38
41
43
46
51
52
62
4
FeCl3·6H2O
CAN
78-98
99
5
rt
6
Sc(OTf)3
Dy(OTf)3
Zr(OTf)3
Fe(DS)3
40
rt
71-88
84-99
4-99
80-97
75-96
38-95
75-95
63-99
99
7
1-24
24-72
2-12
1.1-9
0.25-8
1.1-9
0.33-2
13
8
rt
9
rt
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Sb2(SO4)3
CuBr2
rt
MeOH
CH3CN
MeOH
free
rt
Sb(SO3)4
ZnO
rt
80
20
20
20
50
20
reflux
20
75
rt
InF3
H2O
ZrCl4
CH3CN
H2O
6
87
MoO2(acac)2
MgSO4
20
90
free
20
94
La(PFO)3
RhCl3.H2O
SbCl3
EtOH
0.5
95
MeOH
3
77
CH3CN
glycerol
CH2Cl2
AcOH
1
96
CeCl3.7H2O
SmI2(THF)2
AgBF4-C17H18Br2N4Pd
2
96
0.5-18
24
79-91
20
25
portant uses. Biffis et al. reported the AgBF4-NHC carbene
complexes induced the reaction between indoles and ethyl
phenylpropiolate to produce diaddition product.62 A new
and efficient method for the synthesis of bisindolylmeth-
anes, presented herein, represents a further use for silver
tetrafluoroborate (Scheme I).
Table 2. Optimal conditions in the synthesis of 3b
O2N
O
H
AgBF4
H
+
solvent, temp.
N
H
N
H
N
H
1
NO2
2b
3b
Time
Catalyst
(mol%)
Temp
(°C)
Yield
(%)
AgBF4 catalyzed synthesis of bisindolyl-
methanes
Scheme I
Entry
Solvent
(h)
1
2
3
4
5
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
8
8
20
20
10
5
rt
rt
45
98
96
73
96
10
20
3
rt
rt
10
reflux
bisindolylmenthane within 10 h (Table 2, entry 2-4). Tem-
perature is a critical factor in the efficiency of the reaction,
and at reflux temperature, the reaction proceed to comple-
tion within a short time (3 h) (Table 2, entry 4-5).
2. RESULTS AND DISCUSSION
The optimal conditions for synthesizing bisindolyl-
methane using p-nitrobenzaldehyde (3b) and indole in the
presence of AgBF4 (10%) in acetonitrile resulted in a poor
yield (45%), but synthesis in methylene chloride gave a
98% yield at room temperature. (Table 2, entry 1-2). The
optimal amount of catalyst for the reaction is 10 mol%,
which is associated with clean and efficient conversion to
The scope of application of the presented method is
demonstrated by using the various substituted aromatic,
heteroaromatic and aliphatic carbonyl compounds to react
with indole. The results that are summarized in Table 3

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Synthesis Bisindolylmethanes, Tröger’s Base by AgBF4
J. Chin. Chem. Soc., Vol. 58, No. 7, 2011 901
Table 3. AgBF4 catatlyzed synthesis of bisindolylmethanes using
various substituted aldehydes and ketones with indole
Time Yield
Entry
Substrate
Product
(h)
(%)
1
2
3a
3b
1.5
94
CHO
2a
O2N
Cl
CHO 2b
CHO
2
1.5
3
96
97
95
3
4
2c
3c
2d
3d
NC
CHO
CH3
CHO
5
2e
3e
2
94
Fig. 1. Proposed mechanism for AgBF4 catalyzed syn-
thesis of bisindolylmethanes.
O
S
CHO
CHO
6
7
2f
3f
4
4
92
84
base 8 with four equivalents of indole under similar condi-
tions in good yield. Initially, compound 7 was synthesized
by the condensation of 4-bromoaniline with paraformalde-
hyde using TFA as solvent.63 Lithium-halogen exchange of
7, followed by quenching by N-formyl piperidine, fur-
nished dialdehyde 8. Further reaction of compound 8 with
four equivalents of indole and 20 mol% of silver tetrafluo-
roborate under the aforementaioned conditions afforded 9
in good yield.
2g
3g
8
9
2h
2i
3h
3i
4.5
4
93
96
CHO
CHO
O
2j
10
3j
5
83
clearly reveal the scope of the reaction using various sub-
stituted aldehydes and ketones to react with indole in the
presence of AgBF4 at room temperature. Heterocyclic alde-
hydes, such as furfural and 2-thiophenecarboxaldehyde,
performed well in this reaction without the formation of
any side products. The reaction conditions were mild enough
to prevent damage to the methoxy or acid-sensitive moi-
eties, such as furfural, which commonly undergoes cleav-
age under strongly acidic reaction conditions. The reaction
of cyclohexanone with indole is more sluggish than that
with aldehydes.
AgBF4 catalyzed synthesis of tetraindolyl-
methane Tröger’s Base
Scheme II
The following mechanism of to the silver tetrafluoro-
borate-catalyzed synthesis of bisindolylmenthane is pro-
posed. First, an aldehyde or ketone was activated by the sil-
ver tetrafluoroborate and underwent an elecotrophilic sub-
stitution reaction at the 3-position of the indole. After de-
hydration, intermediate 5 was formed and was further acti-
vated by silver tetrafluoroborate to become an electrophile,
which was attacked by a second molecule of indole, to form
bisindolylmenthane 3.
3. CONCLUSIONS
In summary, the electrophilic substitution reactions
The possible use of this reaction in synthesizing more
complex systems was studied. For example, tetraindolyl
compounds are formed by the condensation of Tröger’s
of indole with aromatic, heteroaromatic and aliphatic car
bonyl compounds were successfully carried out in the pres
-
-

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902 J. Chin. Chem. Soc., Vol. 58, No. 7, 2011
Shaikh and Chen
ence of a catalytic amount of AgBF4 in dichloromethane at
reflux temperature. This method offers several significant
advantages over common methods, such as high conver-
sion rates, ease of handling, and clean reaction profiles,
which make it attractive for the rapid synthesis of substi-
tuted bisindolylmethanes. The presented approach was
proved to be suitable for the synthesis of complex systems,
such as tetraindolylmethane Tröger’s Base.
3.3¢-((4-Nitrophenyl)methylene)bis(1H-indoel) (3b)
M.p. 220–222 °C; IR (KBr): n = 3417, 1739, 1654,
1454, 1366, 1215, 1111 cm-1. 1H NMR (400 MHz, CDCl3):
d = 8.13 (m, 2H), 8.01 (bs, 2H), 7.50 (d, J = 8.4 Hz, 2H),
7.38 (d, J = 8.1 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 7.20 (m,
2H), 7.03 (m, 2H), 6.68 (t, J = 1.6 Hz, 2H), 5.99 (s, 1H). 13C
NMR (100.6 MHz, CDCl3): d = 151.8, 146.5, 136.6, 129.5,
126.6, 123.6, 122.3, 119.6, 119.5, 118.1, 111.2, 40.2. MS-
EI (m/z): 367 (M+, 86), 245 (59), 204 (60), 176 (24), 117
(100), 89 (82). HRMS-EI (m/z): [M]+ calcd. for C23H17N3O2,
367.1321; found 367.1310.
4. EXPERIMENTAL
4.1. General Chemical Procedures
All reactions were carried out in anhydrous solvents.
Tetrhydrofuran and diethyl ether were distilled from so-
dium-benzophenone under argon. Toluene, acetonitrile, di-
chloromethane, and hexane were distilled from calcium hy-
dride. 1H NMR spectra were acquired at 400 (indicated in
each case), and 13C NMR were acquired at 100.6 MHz on a
Bruker NMR spectrometer. Chemical shifts (d) are re-
ported in ppm relative to CDCl3 (7.26 and 77.0 ppm). Mass
spectra (MS) were determined on a Micromass Platform II
mass spectrometer at a 70 eV. High resolution mass spectra
(HRMS) were determined on a Finnigan/Thermo Quest
MAT 95XL mass spectrometer. Infrared spectra were re-
corded on a JASCO FT/IR 410 spectrometer. Flash column
chromatography was performed using MN silica gel 60
(70-230 mesh) purchased from Macherey-Nagel.
3,3¢-((3-Chlorophenyl)methylene)bis(1H-indole) (3c)
M.p. 151–153 °C; IR (KBr): 3406, 1739, 1654, 1454,
1366, 1215, 1091, 740 cm-1. 1H NMR (400 MHz, CDCl3): d
= 7.79 (bs, 2H), 7.41 (d, J = 7.9 Hz, 2H), 7.34 (t, J = 9.6 Hz,
3H), 7.22 (m, 5H), 7.06 (t, J = 7.4 Hz, 3H), 6.56 (d, J = 1.4
Hz, 2H), 5.88 (s, 1H). 13C NMR (100.6 MHz, CDCl3): d =
146.2, 136.6, 134.0, 129.5, 128.8, 127.0, 126.9, 123.7,
122.1, 119.8, 119.4, 118.8, 111.2, 39.9. MS-EI (m/z): 356
(M+, 100), 245 (76), 240 (13), 243 (18), 204 (16), 122 (12).
HRMS-EI (m/z): [M]+ calcd. for C23H17ClN2, 356.1080;
found 356.1076.
4-(Di(1H-indol-3-yl)methyl)benzonitrile (3d)
M.p. 212–214 °C; IR (KBr): 3406, 2225, 1736, 1651,
1363, 1215, 1091, 740 cm-1. 1H NMR (400 MHz, CDCl3): d
= 8.05 (bs, 2H), 7.54 (d, J = 6.4 Hz, 2H), 7.43 (d, J = 8.2 Hz,
2H), 7.34 (m, 4H), 7,20 (m, 2H), 7.02 (m, 2H), 6.63 (t, J =
1.6 Hz, 2H), 5.93 (s, 1H). 13C NMR (100.6 MHz, CDCl3): d
= 149.8, 136.7, 132.1, 129.5, 126.7, 123.7, 122.2, 119.5,
119.5, 119.2, 118.1, 111.3, 109.9, 40.3. MS-EI (m/z): 347
(M+, 100), 245 (63), 229 (24), 122 (12). HRMS-EI (m/z):
[M]+ calcd. for C24H17N3, 347.1422; found 347.1414.
3,3¢-(o-Tolylmethylene)bis(1H-indole) (3e)
4.2. General Procedure
To a solution of aldehyde (1 eq.) in dichloromethane
(5 mL), indole (2 eq.) and then catalytic AgBF4 (10 mol%)
were added at room temperature. After the reaction mixture
was refluxed for the specified time (Table 1), it was diluted
with water and the aqueous solution was extracted with
ethyl acetate. The combined organic layers were washed
with water (10 mL) and brine (10 mL), and then dried over
anhydrous MgSO4, before been evaporated in vacuo to
give a crude product, which was purified by column chro-
matography (silica gel, 5-20% EtOAc in hexane).
3,3¢-(Phenylmethylene)bis(1H-indole) (3ª)
IR (KBr): 3412, 1739, 1454, 1352, 1215, 1091, 738
cm-1. 1H NMR (400 MHz, CDCl3): d = 7.64 (bs, 2H), 7.42
(d, J = 7.8 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 7.23 (m, 4H),
7.14 (d, J = 6.5 Hz, 1H), 7.08 (m, 3H), 6.46 (d, J = 2.1 Hz,
2H), 6.08 (s, 1H), 2.44 (s, 3H). 13C NMR (100.6 MHz,
CDCl3): d = 142.2, 136.7, 136.1, 130.3, 128.4, 127.2,
126.2, 125.9, 124.0, 121.9, 119.8, 119.2, 119.0, 111.2,
36.2, 19.6. MS-EI (m/z): 336 (M+, 100), 245 (41), 243 (14),
218 (56), 217 (21). HRMS-EI (m/z): [M]+ calcd. for
C24H20N2, 336.1626; found 336.1632.
M.p. 88–90 °C ; IR (KBr): 3412, 1739, 1454, 1363,
1215, 1091 cm-1. 1H NMR (400 MHz, CDCl3): d = 7.78 (bs,
2H), 7.23 (m, 11H), 7.03 (m, 2H), 6.58 (m, 2H), 5.91 (s,
1H). 13C NMR (100.6 MHz, CDCl3): d = 144.0, 136.6,
128.7, 128.5, 128.2, 127.1, 126.1, 123.7, 121.9, 119.9,
119.6, 119.2, 111.1, 40.2. MS-EI (m/z): 322 (M+, 100), 245
(51), 243 (15), 204 (27). HRMS-EI (m/z): [M]+ calcd. for
C23H18N2, 322.1470; found 322.1475.
3,3¢-(Furan-2-ylmethylene)bis(1H-indole) (3f)
M.p. 325–326 °C; IR (KBr): 3406, 1736, 1454, 1363,
1215, 1006, 781, 740 cm-1. 1H NMR (400 MHz, CDCl3): d