CeIII-promoted oxidation. Efficient aerobic one-pot eco-friendly synthesis of oxidized bis(indol-3-yl)methanes and cyclic tetra(indolyl) dimethanes

Article abstract of DOI:10.1039/c2gc36131k

Indoles and benzaldehyde derivatives undergo an efficient one-pot smooth condensation and a further atmospheric-pressure aerobic dehydrogenation with CeCl₃ in i-PrOH, to afford the corresponding oxidized bis(indol-3-yl)methanes. Use of 2,2′-bisindole as the heterocyclic precursor provides cyclic tetra(indolyl)dimethane derivatives, which further undergo partial oxidation to the related calix-shaped macrocycles, carrying an all cis 1,3,7-cyclodecatriene core and supporting a 2,2′-biindolylidene moiety. The syntheses of these high value-added compounds is operationally simple and can be performed at room temperature under mild, neutral and environmentally friendly conditions.

Full text of DOI:10.1039/c2gc36131k

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PAPER
CeIII-promoted oxidation. Efficient aerobic one-pot eco-friendly synthesis of
oxidized bis(indol-3-yl)methanes and cyclic tetra(indolyl)dimethanes†
Claudio C. Silveira,*a Samuel R. Mendes,b Marcos A. Villetti,a Davi F. Backa and Teodoro S. Kaufman*c
Received 15th June 2012, Accepted 2nd August 2012
DOI: 10.1039/c2gc36131k
Indoles and benzaldehyde derivatives undergo an efficient one-pot smooth condensation and a further
atmospheric-pressure aerobic dehydrogenation with CeCl3 in i-PrOH, to afford the corresponding
oxidized bis(indol-3-yl)methanes. Use of 2,2′-bisindole as the heterocyclic precursor provides cyclic
tetra(indolyl)dimethane derivatives, which further undergo partial oxidation to the related calix-shaped
macrocycles, carrying an all cis 1,3,7-cyclodecatriene core and supporting a 2,2′-biindolylidene moiety.
The syntheses of these high value-added compounds is operationally simple and can be performed at
room temperature under mild, neutral and environmentally friendly conditions.
that porphyrinoid 5 is able to bind CuII, ZnII and NiII ions,4d
while cyclic tetraindole 6 has also been prepared, as an analog of
Introduction
The indole scaffold is a prominent and privileged structural
motif, widely found in numerous natural products and various
synthetic compounds, which exhibit a range of important bio-
logical activities or bear technological interest. Therefore, facile
access to complex indole derivatives is regarded as highly
relevant.1
The indole moiety is the basic unit of cyclic oligoindole
derivatives. The few available examples reveal them as interest-
ing synthetic targets due to their spectroscopic features, stacking
interactions, self-association and conformational properties, as
well as for their potential as ligands or ion-sensing scaffolds.2
Among the cyclic tetrameric indoles (Fig. 1), the 5,6-dihydroxy-
indole derivative 1 has been proposed to account for the struc-
tural and spectral properties of eumelanins, the black insoluble
semiconductor biopolymers of human skin, hair and eyes, and a
cyclic pentamer analog has been recently synthesized.3a–e In
addition, the symmetric cyclic tetra(indolyl)tetramethane com-
pound 2 (CTet) was shown to possess antiproliferative activity,
inducing G1 cell-cycle arrest.3f–h
the natural plant growth regulator and antitumor agent cauler-
pin.2d,4e,f
The synthesis of stable conformers of the sulfur-bridged
cyclic tetraindole structure 7,5a the preparation of macrocycle 85b
and the regiocontrolled RhII-carbenoid mediated synthesis of
indolophanes 9 have also been reported; among the latter, chan-
ging the length of the spacer resulted in modifications of the
shape and size of the cavity.5c Interestingly, the seemingly
complex calix[4]indole 10 was synthesized by a facile acid-cata-
lyzed tetramerization of the corresponding 7-hydroxymethyl
indole.2a
The indole motif is also present in bis(indol-3-yl)methanes
(BIMs) and in their oxidized derivatives, which are useful as
dyes6a–c and colorimetric chemosensors.6d–g
BIMs have been synthesized in moderate to very good yields
by condensation of indoles and aldehydes in the presence of a
wide range of promoters, including Ce(NH4)2(NO3)6 (CAN), I2,
H4[Si(W3O10)3], ion-exchange resins, zeolites, montmotillonite-
K10, ionic liquids, InF3, InCl3, In(OTf)3, LiClO4, NBS and
CuBr, among others.7 However, to date, the preparation of oxi-
dized BIMs requires an additional reaction step from the corre-
sponding BIMs, which has been invariably reported to take
place in low to moderate yields. Currently, conditions for the
synthesis of oxidized BIMs are restricted to FeIII oxidation6b and
dehydrogenation with single-electron oxidants such as TCQ or
DDQ.8a–c Noteworthy, oxidizing conditions involving peroxidic
reagents such as (t-BuO)2, TBHP and PhCOOO-t-Bu do not
yield oxidized BIMs.8d
We have recently disclosed the synthesis of BIMs using
CeCl3·7H2O/glycerol as a recyclable catalytic system.9 In view
of our interest in the development of new, more efficient and
cleaner methods for classical transformations and new appli-
cations of CeIII in organic synthesis,10 and taking into account
the unique redox properties of the CeIII/CeIV pair, we decided to
On the other hand, it was suggested that macrocylic indoles 3
can be manipulated to promote molecular recognition and ion
binding,4a it was demonstrated that 4 and its congeners offer
high selectivity towards different anions,2c,4b,c and it was shown
aDepartamento de Química, Universidade Federal de Santa Maria,
97105-900 Santa Maria, RS, Brazil. E-mail: silveira@quimica.ufsm.br;
Tel: +55-55-3220-8754
bDepartamento de Química, Universidade do Estado de Santa Catarina,
89219-710 Joinville, SC, Brazil. E-mail: samuel.mendes@udesc.br
cInstituto de Química Rosario (CONICET-UNR), Suipacha 531,
S2002LRK Rosario, SF, Argentina. E-mail: kaufman@iquir-conicet.gov.ar;
Tel: +54-341-4370477
†Electronic supplementary information (ESI) available: Selected spectra
of intermediates and final product. CCDC reference numbers 878735
and 878736 (12a and 18b1). For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c2gc36131k
2912 | Green Chem., 2012, 14, 2912–2921
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radical process in which a 3-methyl radical is formed first, fol-
lowed by a second one-electron oxidation affording the imine-
methide (3-methylene indolenine) species,14 we hypothesized
that CeIII could promote a mild radical reaction leading to oxi-
dized BIMs, using molecular oxygen as the final oxidant.
Aerobic oxidation processes are attractive because they
employ molecular oxygen, the most available and renewable
oxidant, and therefore is the terminal oxidant of choice from an
economic and ecological point-of-view. They are also atom-
efficient and produce water as a reaction by-product. Due to its
ready accessibility, safety issues and convenience of use, the syn-
thetic process gains additional value when pure dioxygen can be
replaced with atmospheric air.15
Results and discussion
Our initial expectations were fulfilled, in an exploratory test,
when the stirring of a mixture of BIM 11a and CeCl3·7H2O (1.0
equiv.) in i-PrOH under air at room temperature for 1.5 hours,
afforded 99% of a more polar product, to which structure 12a
was assigned based on its NMR spectral data analysis
(Scheme 1). The key role of Ce(III) became clear when a control
experiment, without the promoter, was left under stirring for
1 hour and the production of 12a was not observed. Only after
addition of the cerium salt did the solution turn reddish and
product generation was observed.
Single crystal X-ray analysis of 12a (Fig. 2) confirmed the
proposed structure. The observed dihedral angles C1–C2–C10–
C2#, C1–C2–C10–C11, and C12–C11–C10–C2 were −20.53°,
159.47° and 120.34°, respectively, with similar bond lengths for
C2–C10 and C2#–C10 (1.4076 Å).16 The small torsion angle
observed between both indole moieties, which has also been
found in CuII complexes of oxidized BIMs,8b avoids steric repul-
sion between H–C1 and H–C1#.
Fig. 1 Representative examples of cyclic tetraindolyl derivatives.
Scheme 1 Air-mediated room temperature oxidation of BIM 11a
promoted by CeCl3·7H2O in i-PrOH.
develop suitable conditions for a CeIII-mediated one-pot access
to oxidized BIMs and cyclic tetra(indolyl)dimethanes.
It has been shown that the reaction of 3-alkyl indoles with
IBX under CeCl3 promotion afforded products other than
3-methyleneindolenines11a and that Ce(AcO)3/TBHP promotes
the oxidative functionalization of indoles at C3.11b On the other
hand, recent reports provide information on the use of the CeCl3/
i-PrOH system as an efficient promoter for the α-hydroxylation
of 1,3-dicarbonylic moieties, in the presence of air as a source of
dioxygen,12 and the group of Maiti disclosed the use of the VO-
(acac)2-CeCl3 reagent for the aerobic synthesis of glycal-based
chiral benzimidazoles.13
Therefore, and taking into account that physiological dehydro-
genation of 3-methylindole by cytochrome P450 is a two-step
Fig. 2 X-Ray crystal structure of the oxidized BIM product 12a.
Green Chem., 2012, 14, 2912–2921 | 2913
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Table 1 Optimization of the one-pot synthesis of oxidized BIMs (12)
Entry no.
R
Promoter (no. equiv.)
Oxidant
Solvent
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
H
CeCl3·7H2O (1.0)
CeCl3·7H2O (1.0)
CeCl3·7H2O (0.5)
CeCl3·7H2O (0.5)
CeCl3·7H2O (0.5)
CeCl3·7H2O (0.5)
Anh. CeCl3 (1.0)
Anh. CeCl3 (1.0)
Anh. CeCl3 (1.0)
Anh. CeCl3 (1.0)
Anh. CeCl3 (2.0)
Anh. CeCl3 (0.5)
Anh. CeCl3 (0.1)
Anh. CeCl3 (1.0)
CAN (1.0)
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Air
Dioxygen
Air
i-PrOH
i-PrOH
MeNO2
PEG400
MeCN
Glycerol
i-PrOH
EtOH
MeOH
t-BuOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
5.0
5.0
24
24
24
69
72
—
30a
—
95a
98
98
95
93
98
69
49
97
Me
Me
Me
Me
Me
Me
H
H
H
Me
Me
Me
Me
H
24
1.5
3.5
5.0
7.0
1.5
5.0
5.0
1.25
3.0
9
10
11
12
13
14
15
b
—
a Isolated yields of the BIM product. b No product (BIM/oxidized BIM) was observed.
The high efficiency and extreme simplicity of this new reac-
tion, together with the known ability of CeCl3·7H2O to promote
the formation of BIMs,9 prompted us to explore the possibility
of performing the transformation as a one-pot process, from ben-
zaldehyde derivatives and indoles.
the yield of 11b to 98% (Table 1, entry 7). Under these con-
ditions, other low molecular weight alcohols could also be
employed as solvents; however, longer reaction times were
required for the transformation to reach completion (Table 1,
entries 8–10).
To our delight, subjecting a mixture of benzaldehyde (13a,
0.5 mmol) and indole (14a, 1.0 mmol) to reaction with 1.0
equiv. of CeCl3·7H2O, at room temperature, resulted in 69% of
12a after 5 hours (Table 1, entry 1).
Analogously p-tolualdehyde (13b) furnished 72% of 12b
(Table 1, entry 2). TLC monitoring of the reaction indicated the
formation of an intermediate, which was isolated and identified
as the corresponding bis(indol-3-yl)methane 11b.
The performance of the reaction was also tested in the pres-
ence of over- and sub-stoichiometric amounts of CeCl3. Addition
of the promoter in excess did not improve the reaction perform-
ance (Table 1, entry 11), while use of sub-stoichiometric
amounts of CeCl3 afforded lower yields of product after longer
reaction times (Table 1, entries 12 and 13).
Interestingly enough, only a small decrease in the required
reaction time was achieved by carrying out the reaction in a pure
molecular oxygen atmosphere (Table 1, entry 14), while quite
In view of these promising results, a systematic investigation
was carried out in order to examine the effects of the reaction
solvent, source of dioxygen and amount of catalyst on the
product yields. Use of glycerol or PEG 400 only afforded the
3,3′-bis(indol-3-yl)methane 11b, and no reaction was detected in
MeCN and MeNO2 (Table 1, entries 3–6).
surprisingly, the use of CAN as a source of cerium did not afford
18
the expected BIM
(Table 1, entry 15).
when i-PrOH was employed as solvent
Therefore, it was concluded that the optimum reaction per-
formance was obtained when a solution of the reactants and
1.0 equiv. of anhydrous CeCl3 in i-PrOH was vigorously stirred
at room temperature, under air. The established protocol was
17
In addition, it was observed that the use of anhydrous CeCl3
dramatically reduced the reaction time to 1.5 h, while increasing
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Table 2 Air-mediated one pot synthesis of oxidized BIMs 12a–f
Entry
no.
Product
no.
Time
(h)
Yielda
(%)
R
R1
R2
X
1
2
3
4
5
6
12a
12b
12c
12d
12e
12f
H
H
H
H
Me
H
H
H
H
H
H
H
Me
Cl
N
N
N
N
2.0
2.0
5.0
2.0
96
98
93
97
91
89
OMe
OMe N+–Me 3.0
p-Tolyl OMe
N
4.0
a Isolated yields of the oxidized BIM product.
applied to other indoles (Table 2), including N-methylindole
(Table 2, entry 5) and 5-(p-tolyl)indole (Table 2, entry 6), and
different benzaldehyde derivatives.
In all cases, the oxidized BIMs (12a–f) were obtained in
excellent yields after stirring at room temperature for 2.0–4.0 h.
Notably, however, the reaction with p-chlorobenzaldehyde took
more time to undergo completion towards 12c,19 mainly due to a
slower oxidation step, as revealed by TLC monitoring of the
transformation. On the other hand, N-methylindole gave the
quaternarized product 12e.
Encouraged by the results of the transformations involving
simple indoles, and with the aim of expanding the scope of this
CeIII-based reaction, the study of the behavior of 2,2′-bisindole
(2,2′-bisindolyl, 15) as the starting indole component was
undertaken.
Literature precedents indicate that in bi-indole derivatives car-
rying a spacer between both indolyl moieties, the intramolecular
condensation of the indole with aldehydes is favored over the
intermolecular alternative.20a–c However, reaction of 13b with 15
under the previously established conditions towards oxidized
BIMs did not afford the expected product 16b20d (Scheme 2).
Instead, the 10-membered ring 2,2′-biindolylidene derivative
17b, bearing a 1,3,7-cyclodecatriene core was obtained. Most
probably, the product resulted from connection of the two mo-
lecules of the bis-indole scaffold with a pair of methine bridges
provided by the aldehyde, through the intermediacy of the cyclic
derivative 18b. Interestingly enough, isomeric cyclodecatrienes
like the pregeijerenes A and B have been isolated from Pimpi-
nella cumbrae Link, Amyris diatrypa, Chromolaena odorata and
Juniperus erectopatens, among others.21
Compounds 17 and 18 can be accessed as syn and anti diaster-
eomers, the former having C2v symmetry. Despite both possible
diastereomers of 18b [18b1 (syn) and 18b2 (anti)] being con-
comitantly formed (in different proportions) during the conden-
sation step, only one diastereomer of 17b is produced after the
dehydrogenation of the diastereomeric intermediates, probably
the result of a process involving the formation of a BIM-type
Scheme 2 Synthesis of the oxidized cyclic indolylmethane 17b.
product (19b), followed by double bond rearrangement of this
partially oxidized BIM intermediate. The structures of the tetra
(indolyl)dimethanes 17b and 18b were unambiguously esta-
blished by spectroscopic (NMR) and GC-MS means.
Re-examination of the reaction conditions revealed that
i-PrOH outperformed glycerol, MeNO2 and MeCN as solvents,
while the 1 : 1 : 1 molar stoichiometry between 2,2′-bisindole,
aldehyde and CeCl3 furnished the best product yields.
The design and synthesis of macrocycles containing aromatic/
heteroaromatic ring systems constitute an intriguing branch of
organic and supramolecular chemistry; therefore, the scope of
the transformation was extended to some other aldehydes under
these optimized conditions (Table 3).
The observed results were very similar to those achieved in
the reactions with indole, except that the oxidation was slower
and longer reaction times were required (7.5 to 11.0 h).
The reaction times and product yields were well correlated to
the structure of the starting aldehyde, with the p-chlorobenzalde-
hyde derivative 17c isolated in the lowest yield, also being the
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Table 3 Synthesis of cyclic oxidized tetra(indolyl)dimethanes 17a–d
products. Its crystal structure also evidenced the syn orientation
of both tolyl moieties and the half-chair–boat–half-chair confor-
mation of the 1,3,6,8-cyclodecatetraene core, exhibiting a
“twisted saddle” form22 and allowing an all cis configuration of
the double bonds, yielding an overall molecular shape of a cup,
reminiscent of that of the calix[4]indoles.2a
This arrangement, which lacks intra-annular hydrogens, has
two bis-indole moieties embraced together through methine
bridges. These bis-indole moieties in 18b adopt cisoid confor-
mations with N1–C8–C16–N2 torsion angles of 69.5°. Each bis-
indole moiety has a chiral axis and both axes bear the same
configuration. In this way, two alternate indole fragments esta-
blish themselves in a quasi-parallel orientation (the angle formed
between both planar moieties is 12.5°), while the remaining pair
of heterocyclic fragments point away from each other, forming
an angle between their planes of 93.9°.
Entry no.
Product no.
R
Time (h)
Isolated yield (%)
Each half of the molecule of 18b1 can be defined by two
planes; one through atoms C16, C8, C7 and C17′ and one
through atoms C8, C16, C15 and C17. The two planes are
inclined at an angle of 74.1° to each other. The C15–C17 and
C7′C17 bonds are equivalent within experimental error, while
the C8–C16 distance is that of a standard C(sp2)–C(sp2) single
bond (1.47 Å).
1
2
3
4
17a
17b
17c
17d
H
Me
Cl
9.0
8.0
11.0
7.5
62
67
53
69
OMe
On the other hand, the methinic hydrogens of 17b, observed
as a singlet resonating at δH 5.49 ppm, suggested their stereo-
chemical assignment as anti and confirmed the proposed cyclic
structure for these partially oxidized tetraindoles.
Employing the synthesis of 12a as an example, a two-stage
(condensation-oxidation) reaction mechanism for this one-pot
transformation can be proposed (Scheme 3). In the first stage,
the mode of action of CeCl3 follows the general pattern of
activity of other Lewis and protic acids which catalyze the syn-
thesis of BIMs.23
Upon CeIII-activation of the carbonyl moiety (i) of the alde-
hyde (13a), the reaction with indole (14a) should produce the
corresponding azafulvene through the intermediacy of Lewis
acid coordinated species like ii and iii. Concomitantly, water is
produced as a result of the condensation and the CeIII promoter
is liberated, entering again in the catalytic cycle.
Protonation of the azafulvene yields the azafulvenium ion iv,
which, in turn, reacts with a second indole molecule to form the
bis(indol-3-yl)methane (11a),24 through the intermediacy of an
indolinium derivative (v).
Fig. 3 X-Ray molecular conformation of the major diastereomer of
tetra(indolyl)dimethane intermediate 18b1.
A detailed picture of the following oxidation stage of 11a
towards the related oxidized BIM (12a) is still unclear. However,
mechanistic images can be drawn taking into account that under
assistance of the promoter and in the presence of dioxygen, the
abstraction of the activated methinic hydrogen of the BIM is
very likely to take place, yielding vi, a very stable radical inter-
mediate (or a carbocation by further oxidation) and a CeIV
species.
The driving force of conjugation would then allow the latter
to perform a second hydrogen abstraction (or a deprotonation),
furnishing 12a and releasing H2O2 together with the promoter as
a CeIII species, which can re-enter into the cycle. The so formed
hydrogen peroxide could further participate in this transforma-
tion11b and/or ultimately decompose to water.
more reluctant to undergo cyclization and subsequent dehydro-
genation (Table 3, entry 3). Interestingly, the oxidized macro-
cycles 17 did not undergo further transformation under the
CeCl3–O2/i-PrOH system nor when submitted to the more con-
ventional DDQ/MeCN oxidation conditions. This could be a
result of the high strain suffered by the macrocycle. Medium-
sized ring compounds (eight to eleven members) are among the
most strained cycles. In addition, the strain of these 10-mem-
bered macrocycles (17a–d) is exacerbated by the presence of
8 sp2 carbon atoms.
Attempts to obtain suitable crystals of compounds 17 for
X-ray structure analysis were unsuccessful. However, the X-ray
crystal structure of 18b1, the major diastereomer of intermediate
18b (Fig. 3), unequivocally confirmed the cyclic nature of the
Incorporation of aromatic heterocyclic systems into extended
organic π systems is driven by the intriguing electronic and
2916 | Green Chem., 2012, 14, 2912–2921
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Table 4 UV-Vis and fluorescence characteristic maxima of the indole
derivatives 12a–c, 12f and 17aa
UV-vis
λmax/nm (log ε)
Fluorescence
(λmax/nm)
Entry no.
Comp. no.
1
2
3
4
5
12a
12b
12c
12f
286 (3.92)
288 (3.82)
288 (3.70)
301 (3.93)
353 (4.49)
345; 406sh
347
—
363
447
17a
a Samples were dissolved in DMSO for UV (1.5 × 10−4 M) and
fluorescence (1.5 × 10−5 M) determinations.
Fig. 4 Fluorescence spectrum of a 1.5 × 10−5 M solution of cyclic oxi-
dized tetra(indolyl)dimethane 17a in DMSO.
shift of the maximum of almost 15 nm (λmax = 301 nm), as a
consequence of its most extended conjugated system.
The fluorescence spectra of 12a,b exhibited maxima at
345 nm, while that of 12f showed an emission maximum at
363 nm. Interestingly, however, 12c did not exhibit fluorescence,
probably due to the presence of the chlorine atom in the
molecule.
Scheme 3 Proposed two-stage reaction mechanism for the one-pot
CeIII-promoted room temperature aerobic synthesis of oxidized bis-
(indol-3-yl)methane derivative 12a from benzaldehyde (13a) and indole
(14a) through the intermediacy of BIM 11a.
Among the cyclic compounds, the luminiscent properties of
17a were verified (Fig. 4). This partially oxidized tetra(indolyl)-
dimethane derivative exhibited an ideal excitation wavelength of
353 nm (logε = 4.49) with an emission maximum in the visible
region of the spectrum (447 nm).
photophysical properties of the resulting products.6e These pro-
perties have also been studied in natural indole derivatives25
bearing these characteristics.3a–c
Therefore, the room temperature photoluminiscent properties
of the oxidized BIMs, including 17a, were also studied
(Table 4). The determinations were performed in DMSO due to
the much lower solubility of the BIMs in other solventes;
however, no spectral shifts were detected when the compounds
were dissolved in EtOAc or CH2Cl2.
It was observed that the UV-visible spectra exhibited absorp-
tion bands in the 280–300 nm region. The relatively high values
of the molar absorptivity coefficient and absence of a solvent-
mediated spectral shift effect suggested that the absorption could
be attributed to a π–π* excitation.
Conclusions
In conclusion, we have developed a very simple and highly
efficient methodology for the synthesis of oxidized bis(indol-3-
yl)methanes and partially oxidized cyclic tetra(indolyl)-
dimethane derivatives, carrying various functional groups, which
involves a new application of CeIII in organic synthesis and
features the utilization of dioxygen as oxidant. To the best of our
knowledge, this report is the first convenient one-pot process for
the synthesis of these heterocycles and entails the first
Compounds 12a–c exhibited their excitation maxima at 287
1 nm (logε = 3.87 0.05), while 12f displayed a bathochromic
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preparation of oxidized BIMs using molecular oxygen from air
as the oxidant.
This process, which uses a benign solvent (i-PrOH) and non-
toxic and inexpensive CeCl3 as the pre-catalyst, can be regarded
as environmentally benign, eco-conscious and optimal with
respect to economic issues.
Furthermore, the synthesis takes place at room temperature,
from commercially available precursors, and the products are
obtained in good to excellent yields. No precautions need to be
taken to exclude moisture from the reaction medium.
This contribution should pave the way for the ready construc-
tion of more complex oxidized BIMs and partially oxidized
cyclic tetra(indolyl)dimethanes, to unlock their potential appli-
cations as bioactive compounds, novel functional materials for
selective sensors, or as emission layers for organic light-emitting
diodes in microelectronics.26
7′-H), 7.04 (t, J = 7.8, 2H, 5-H and 5′-H), 7.30 (t, J = 7.8, 2H,
6-H and 6′-H), 7.57 (d, J = 7.3, 2H, 3′′-H and 5′′-H),* 7.63 (t, J
= 7.3, 2H, 2′′-H and 6′′-H),* 7.68 (d, J = 7.8, 2H, 4-H and 4′-H),
7.77 (t, J = 7.3, 1H, 4′′-H) and 8.36 (s, 2H, 2-H and 2′-H); 13C
NMR (δ): 115.7, 121.4, 122.6, 123.9, 125.7, 127.8, 129.5,
132.2, 132.6, 139.2, 143.0, 147.4 and 162.8; EI-MS (m/z, rel.
int., %): 320 (M+, 33), 291 (7), 243 (5), 158 (8), 84 (70), 66
(100) and 46 (22); HRMS found m/z 321.1379; C23H17N2
[(M + H)+] requires m/z 321.1386.
3-[(1H-Indol-3-yl)(4-methyl-phenyl)methylene]-3H-indole (12b).
M.p.: 202 °C (dec); IR (KBr, ν): 3390, 1628, 1481, 1408, 1199,
1
1123 and 752 cm−1; H NMR (δ): 2.53 (s, 3H, 4′′-Me), 6.75 (d,
J = 7.8, 2H, 7-H and 7′-H), 7.12 (t, J = 7.8, 2H, 5-H and 5′-H),
7.35 (t, J = 7.8, 2H, 6-H and 6′-H), 7.49 (d, J = 8.0, 2H, 2′′-H
and 6′′-H),* 7.55 (d, J = 8.0, 2H, 3′′-H and 5′′-H),* 7.77 (d, J =
7.8, 2H, 4-H and 4′-H), 8.51 (s, 2H, 2-H and 2′-H) and 14.64 (s,
1H, NH); 13C NMR (δ): 21.8, 115.0, 121.5, 121.7, 124.5, 125.9,
127.2, 130.4, 133.4, 135. 8, 140.4, 144.8, 147.0 and 169.3;
EI-MS (m/z, rel. int., %): 334 (M+, 70), 333 (100), 317 (7), 291
(9), 243 (10), 159 (14) and 132 (7); HRMS found m/z 335.1545;
C24H19N2 [(M + H)+] requires m/z 335.1543.
Experimental section
General information
Melting points were taken on MQAPF-301 melting point appar-
atus and are reported uncorrected. 1H and 13C NMR spectra were
recorded on a Bruker DPX-400 (400 MHz) spectrometer, with
the samples dissolved in DMSO-d6; marked assignments (* or #)
may be exchanged. IR spectra were recorded on a Shimadzu
Prestige 21 FT-IR spectrophotometer, with the samples as KBr
pellets. Low resolution mass spectra were run on a Shimadzu
GCMS-QP2010 Plus mass spectrometer. High-resolution mass
spectral data were obtained in a Bruker microTOF-Q IIT instru-
ment, employing sodium formate as reference. X-Ray diffraction
data were acquired with a Bruker Kappa APEX II CCD diffracto-
meter, fit with a graphite monochromator and a Mo-Kα radiation
source (λ = 0.71073 Å). Excitation-emission spectra were
obtained with a Varian Cary Eclipse spectrofluorometer, employ-
ing 1 cm quartz cuvettes. UV-visible spectra were taken with a
Cary 50 Bio spectrometer, employing 1 cm quartz cuvettes. All
reagents for synthesis were obtained commercially and used
without further purification. Chromatographic purification was
conducted by column chromatography using 60–120 mesh silica
gel. Reaction progress was monitored by thin layer chromato-
graphy on Merck silica gel 60 F254 plates using UV light
(254 and 360 nm) for detection.
3-[(1H-Indol-3-yl)(4-chloro-phenyl)methylene]-3H-indole (12c).
M.p.: 148 °C (dec); IR (KBr, ν): 3360, 1632, 1481, 1408, 1199,
1123 and 752 cm−1; 1H NMR (δ): 6.74 (d, J = 7.8, 2H, 7-H and
7′-H), 7.12 (t, J = 7.8, 2H, 5-H and 5′-H), 7.34 (t, J = 7.8, 2H,
6-H and 6′-H), 7.64 (d, J = 8.2, 2H, 3′′-H and 5′′-H),* 7.72 (d, J
= 8.2, 2H, 2′′-H and 6′′-H),* 7.77 (d, J = 7.8, 2H, 4-H and 4′-H)
and 8.51 (s, 2H, 2-H and 2′-H); 13C NMR (δ): 114.7, 120.8,
121.3, 123.9, 125.3, 126.5, 129.2, 133.9, 136.9, 137.8, 140.6,
146.8 and 164.6; EI-MS (m/z, rel. int., %): 356 [(M + 2)+, 22],
354 (64), 353 (100), 317 (11), 291 (17), 243 (15), 159 (35) and
132 (19); HRMS found m/z 355.1003; C23H16ClN2 [(M + H)+]
requires m/z 355.0997.
3-[(1H-Indol-3-yl)(4-methoxy-phenyl)methylene]-3H-indole
(12d). M.p.: 213 °C (dec); IR (KBr, ν): 3394, 1597, 1481, 1411,
1
1203, 1126 and 752 cm−1; H NMR (δ): 3.96 (s, 3H, 4′′-OMe),
6.84 (d, J = 7.8, 2H, 7-H and 7′-H), 7.13 (t, J = 7.8, 2H, 5-H
and 5′-H), 7.24 (d, J = 8.7, 2H, 3′′-H and 5′′-H), 7.36 (t, J = 7.8,
2H, 6-H and 6′-H), 7.63 (d, J = 8.7, 2H, 2′′-H and 6′′-H), 7.78
(d, J = 7.8, 2H, 4-H and 4′-H), 8.45 (s, 2H, 2-H and 2′-H) and
14.58 (s, 1H, NH); 13C NMR (δ): 55.8, 114.4, 114.8, 120.8,
120.8, 123.6, 125.2, 126.7, 130.0, 135.8, 139.8, 146.1, 164.2
and 167.9; EI-MS (m/z, rel. int., %): 350 (M+, 88), 349 (100),
334 (15), 305 (55), 278 (12), 243 (12), 159 (10), 91 (30) and 43
(73); HRMS found m/z 351.1489; C24H19N2O [(M + H)+]
requires m/z 351.1492.
Typical procedure for the synthesis of oxidized bis(indol-3-yl)-
methanes (12)
Anhydrous CeCl3 (0.246 g, 1.0 mmol) was added to a solution
of indole (14, 1.0 mmol) and the benzaldehyde derivative (13,
0.55 mmol) in i-PrOH (3 mL), and the reaction was stirred at
room temperature until all the starting material was consumed
(TLC). Then, the solvent was evaporated under reduced pressure
and the residue was purified by rapid filtration through a short
column filled with silica gel (EtOAc/MeOH, 90 : 10, v/v),
furnishing the corresponding product 12.
3-[(1-Methyl-1H-indol-3-yl)-(4-methoxy-phenyl)-methylene]-
1-methyl-3H-indolium (12e). M.p.: 112 °C (dec); IR (KBr, ν):
3417, 1655, 1608, 1508, 1462, 1369, 1327, 1242, 1119 and
741 cm−1 1H NMR (δ): 3.98 (s, 3H, 4′′-OMe), 4.13 (s, 6H,
;
NMe), 6.86 (d, J = 7.8, 2H, 7-H and 7′-H), 7.21 (t, J = 7.8, 2H,
5-H and 5′-H), 7.26 (d, J = 8.7, 2H, 3′′-H and 5′′-H), 7.46 (t, J =
7.8, 2H, 6-H and 6′-H), 7.66 (d, J = 8.7, 2H, 2′′-H and 6′′-H),
7.82 (d, J = 7.8, 2H, 4-H and 4′-H) and 8.68 (s, 2H, 2-H and
2′-H); 13C NMR (δ): 34.5, 55.8, 112.7, 114.9, 119.3, 120.8,
124.2, 125.3, 126.8, 129.9, 135.6, 140.0, 148.7, 164.3 and
3-[(1H-Indol-3-yl)(phenyl)methylene]-3H-indole (12a). M.p.:
210 °C (dec); IR (KBr, ν): 3417, 1543, 1485, 1411, 1199, 1122,
1
744 and 702 cm−1; H NMR (δ): 6.67 (d, J = 7.8, 2H, 7-H and
2918 | Green Chem., 2012, 14, 2912–2921
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166.6; EI-MS (m/z, rel. int., %): 379 (M+, 57), 378 (100), 364
(24), 319 (11), 271 (58), 249 (12), 159 (11) and 77 (5); HRMS
found m/z 379.1799; C26H24ClN2O [(M + H)+] requires m/z
379.1805.
Oxidized tetra(indolyl)dimethane derivative 17a
M.p.: 235–238 °C (dec); IR (KBr, ν): 3421, 1612, 1577, 1512,
1446, 1338, 1249, 1176, 1033 and 748 cm−1; 1H NMR (δ): 5.52
(s, 2H, 5-H and 10-H), 6.10 (d, J = 8.0, 2H, 2′′′-H and 6′′′-H),*
6.28 (d, J = 8.0, 2H, 7′-H), 6.58–6.64 (m, 4H, 7′′-H, 3′′′-H* and
5′′′-H*), 6.68–6.74 (m, 4H, 5′-H and 5′′-H), 6.93–7.04 (m, 8H,
6′′-H, 4′′′-H,* 8′′′-H,* 9′′′-H,* 10′′′-H,* 11′′′-H,* 12′′′-H*),
7.13–7.20 (m, 4H, 6′-H and 4′′-H), 7.58 (d, J = 8.4, 2H, 4′-H)
and 12.40 (s, 2H, 2 × NH); 13C NMR (δ): 47.9, 68.9, 112.3,
118.8, 119.3, 120.5, 120.9, 122.2, 123.7, 123.9, 125.5, 125.6,
126.3, 126.7, 128.1, 128.6, 129.6, 129.6, 135.6, 136.2, 138.8,
156.1 and 169.8; EI-MS (m/z, rel. int., %): 638 (M+, 100), 561
(11), 434 (17), 344 (9), 319 (19), 231 (3) and 77 (2); HRMS
found m/z 639.2546; C46H31N4 [(M + H)+] 639.2543.
3-[(1H-(5-p-Tolylindol)-3-yl)(4-methoxy-phenyl)methylene]-
3H-(5-p-tolylindole) (12f). M.p.: 115 °C (dec); IR (KBr, ν):
3399, 1627, 1600, 1504, 1450, 1396, 1207, 1168, 1134 and
1
810 cm−1; H NMR (δ): 2.24 (s, 6H, 2 × ArMe), 3.98 (s, 3H,
4′′-OMe), 6.96 (s, 2H, 4-H and 4′-H), 7.05–7.10 (m, 4H, 6-H,
7-H, 6′-H and 7′-H), 7.29 (d, J = 8.5, 2H, 3′′-H and 5′′-H), 7.63
(d, J = 8.5, 2H, 2′′-H and 6′′-H), 7.70 (d, J = 8.5, 2H, 3′′-H and
5′′-H of p-tolyl), 7.88 (d, J = 8.5, 2H, 2′′-H and 6′′-H of p-tolyl)
and 8.38 (s, 2H, 2-H and 2′-H); 13C NMR (δ): 20.2, 55.9, 114.6,
114.7, 119.6, 120.8, 124.0, 126.2, 126.6, 129.1, 131.0, 136.1,
136.2, 136.4, 137.5, 138.9, 146.1, 164.3 and 166.2; EI-MS (m/z,
rel. int., %): 530 (M+, 100), 485 (9), 439 (50), 395 (14), 257
(11), 149 (10), 97 (14) and 43 (50); HRMS found m/z 531.2420;
C38H31N2O [(M + H)+] requires m/z 531.2431.
Oxidized tetra(indolyl)dimethane derivative 17b
M.p.: 241–243 °C (dec); IR (KBr, ν): 3305, 2866, 1616, 1581,
1
1446, 1334, 1238, 1157 and 748 cm−1; H NMR (δ): 2.13 (s,
6H, 2 × ArMe), 5.49 (s, 2H, 5-H and 10-H), 5.96 (d, J = 8.0,
2H, 2′′′-H and 6′′′-H),# 6.29 (d, J = 8.0, 2H, 7′-H), 6.43 (d, J =
8.0, 2H, 3′′′-H and 5′′′-H),* 6.61 (d, J = 7.6, 2H, 7′′-H),
6.68–6.74 (m, 4H, 5′-H and 5′′-H), 6.85 (d, J = 7.6, 2H, 8′′′-H
and 12′′′-H),# 6.94–6.98 (m, 4H, 6′′-H, 9′′′-H* and 11′′′-H*),
7.06 (d, J = 7.6, 2H, 4′′-H), 7.19 (t, J = 8.0, 2H, 6′-H), 7.57 (d, J
= 8.0, 2H, 4′-H) and 12.35 (s, 2H, 2 × NH); 13C NMR (δ): 20.3,
47.5, 69.0, 112.3, 118.8, 119.3, 120.7, 120.9, 122.2, 123.7,
123.9, 125.5, 126.4, 127.3, 128.2, 128.6, 129.4, 129.6, 132.7,
135.3, 136.3, 138.7, 156.2 and 170.0; EI-MS (m/z, rel. int., %):
666 (M+, 100), 575 (8), 448 (15), 333 (21) and 230 (3); HRMS
found m/z 667.2842; C48H35N4 [(M + H)+] requires m/z
667.2856.
Typical procedure for the synthesis of oxidized tetra(indolyl)-
dimethanes (17)
CeCl3 (0.246 g, 1.0 mmol) was added to a solution of 2,2′-bis-
indole (15, 0, 232 g, 1.0 mmol) and the benzaldehyde derivative
(13, 1.1 mmol) in i-PrOH (3 mL), and the reaction was stirred at
room temperature until all the starting material was consumed
(TLC). Then, water (10 mL) was added and the reaction products
were extracted with EtOAc (3 × 10 mL). The combined organic
extracts were dried over MgSO4, then the solvent was evaporated
under reduced pressure and the residue was purified by column
chromatography (Hexanes/EtOAc, 85 : 15, v/v) to afford the cor-
responding product 17.
Oxidized tetra(indolyl)dimethane derivative 17c
Tetra(indolyl)dimethane derivative 18b1
M.p.: 243–245 °C (dec); IR (KBr, ν): 3305, 2866, 1616, 1581,
1
1446, 1334, 1238, 1157 and 748 cm−1; H NMR (δ): 5.55 (s,
IR (KBr, ν): 3406, 3051, 2920, 1681, 1604, 1508, 1450, 1338,
1211, 1168, 1010, 790 and 740 cm−1; 1H NMR (δ): 2.29 (s, 6H,
2 × ArMe), 6.23 (s, 2H, 5-H and 10-H), 6.50 (d, J = 8.0, 2H)
6.57–6.61 (m, 2H), 6.67–6.75 (m, 8H), 6.95 (t, J = 8.0, 2H),
7.04 (d, J = 7.6, 4H), 7.21 (d, J = 8.0, 2H), 7.33 (d, J = 8.0,
4H), 10.31 (s, 2H, 2 × NH) and 10.94 (s, 2H, 2 × NH); EI-MS
(m/z, rel. int., %): 668 (M+, 50), 577 (100), 563 (11), 448 (21),
334 (16), 288 (15) and 232 (6); HRMS found m/z 691.2808;
C48H36N4Na [(M + Na)+] requires m/z 691.2832.
2H, 5-H and 10-H), 6.06 (d, J = 8.4, 2H, 2′′′-H and 6′′′-H),# 6.32
(d, J = 8.4, 2H, 7′-H), 6.61 (d, J = 7.6, 2H, 7′′-H), 6.67 (d, J =
8.4, 2H, 3′′′-H and 5′′′-H),* 6.71–6.79 (m, 4H, 5′-H and 5′′-H),
6.97–7.01 (m, 4H, 6′′-H, 8-H# and 12′′′-H#), 7.10 (d, J = 7.6,
2H, 4′′-H), 7.19–7.23 (m, 4H, 6′-H, 9′′′-H* and 11′′′-H*), 7.58
(d, J = 8.4, 2H, 4′-H) and 12.47 (s, 2H, 2 × NH); 13C NMR (δ):
47.2, 68.7, 112.5, 119.1, 119.5, 120.1, 120.8, 122.2, 124.0,
124.1, 125.3, 125.7, 126.7, 128.4, 128.5, 131.2 (3C), 134.7,
135.9, 138.9, 156.0 and 169.6; EI-MS (m/z, rel. int., %): 710
[(M + 2)+, 22], 708 (M+, 75), 706 (100), 597 (19), 468 (27), 344
(16) and 242 (6); HRMS found m/z 707.1768; C46H29Cl2N4
[(M + H)+] requires m/z 707.1764.
Tetra(indolyl)dimethane derivative 18b2
IR (KBr, ν): 3406, 3379, 3051, 1508, 1454, 1419, 1338, 790
1
and 740 cm−1; H NMR (δ): 2.17 (s, 6H, 2 × ArMe), 6.48 (s,
2H, 5-H and 10-H), 6.51 (d, J = 8.0, 2H), 6.66 (t, J = 7.6, 2H),
6.77–6.84 (m, 10H), 6.92 (t, J = 7.6, 2H), 7.00 (d, J = 7.6, 2H),
7.18 (d, J = 8.0, 2H), 7.22 (d, J = 7.6, 4H), 10.66 (s, 2H, 2 ×
NH) and 10.83 (s, 2H, 2 × NH); EI-MS (m/z, rel. int., %): 668
(M+, 47), 577 (100), 563 (11), 448 (21), 334 (16), 288 (14) and
232 (6); HRMS found m/z 707.2572; C48H36N4K [(M + K)+]
requires m/z 707.2567.
Oxidized tetra(indolyl)dimethane derivative 17d
M.p.: 237–238 °C (dec); IR (KBr, ν): 3410, 3062, 2951, 1735,
1616, 1575, 1489, 1338, 1238, 1091, 1014 and 748 cm−1; H
1
NMR (δ): 3.61 (s, 6H, 2 × ArOMe), 5.46 (s, 2H, 5-H and 10-H),
5.95 (d, J = 8.4, 2H, 3′′′-H and 5′′′-H),# 6.17 (d, J = 8.4, 2H,
2′′′-H and 6′′′-H),* 6.31 (d, J = 8.4, 2H, 7′-H), 6.59 (d, J = 7.6,
This journal is © The Royal Society of Chemistry 2012
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2H, 7′′-H), 6.68–6.76 (m, 6H, 5′-H, 5′′-H, 9′′′-H# and 11′′′-H#),
6.88 (d, J = 8.4, 2H, 8′′′-H and 12′′′-H),* 6.96 (t, J = 7.6, 2H,
6′′-H), 7.07 (d, J = 7.6, 2H, 4′′-H), 7.19 (t, J = 8.4, 2H, 6′-H),
7.55 (d, J = 8.4, 2H, 4′-H) and 12.34 (s, 2H, 2 × NH); 13C NMR
(δ): 47.1, 54.6, 69.1, 111.3, 112.0, 112.3, 118.8, 119.3, 120.9,
120.9, 122.1, 123.6, 123.8, 125.5, 127.7, 128.1, 128.5, 130.4,
130.7, 136.4, 138.7, 156.2, 157.6 and 170.0; EI-MS (m/z, rel.
int., %): 699 (M+, 57), 698 (100), 593 (52), (49), 349 (24),
232 (6) and 77 (8); HRMS found m/z 699.2753; C48H35N4O2
[(M + H)+] requires m/z 699.2754.
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Acknowledgements
The authors gratefully acknowledge UFSM, UDESC and
FAPERGS for financial support. CONICET and ANPCyT are
also acknowledged.
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