A new practical synthesis of triaryl and trisindolylmethanes under solvent-free reaction conditions

Article abstract of DOI:10.1039/c1ob06280h

An efficient and practical synthesis of triaryl and trisindolylmethanes is reported via the bisarylation of aryl aldehydes with activated arenes. The new method features mild solvent-free reaction conditions, in most cases nearly stoichiometric reagent ra

Full text of DOI:10.1039/c1ob06280h

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PAPER
A new practical synthesis of triaryl and trisindolylmethanes under solvent-free
reaction conditions†
Margherita Barbero,* Silvano Cadamuro, Stefano Dughera, Claudio Magistris and Paolo Venturello
Received 28th July 2011, Accepted 5th September 2011
DOI: 10.1039/c1ob06280h
An efficient and practical synthesis of triaryl and trisindolylmethanes is reported via the bisarylation of
aryl aldehydes with activated arenes. The new method features mild solvent-free reaction conditions, in
most cases nearly stoichiometric reagent ratios, catalytic amount of the readily available,
easily-handled, recoverable and reusable Brønsted acid catalyst o-benzenedisulfonimide.
Experimental evidence and theoretical calculations suggested
Introduction
the possible formation of superelectrophilic O,C-diprotonated
Triaryl and triheteroarylmethanes (TRAMs) are valuable scaffolds
aldehydes.14 Recently, Olah and coworkers reported the
which have attracted attention from the scientific community not
hydroxyalkylation of activated or weakly deactivated aromatics
only for their interesting chemical properties, but also for the
by aromatic mono- and dicarbaldehydes in the presence of
widespread applications they have found in many fields,1 such
BF3–H2O (1 : 1 complex; 50 equiv.; in a pressure tube and under
as useful protective groups,2 photochromic agents,3 dyes,4 and
closed conditions).15 This stable complex has been used in a dual
building blocks for dendrimers and NLOs.5 Ring hydroxylated
role, as a suitable protic solvent/protosolvating medium and as a
TRAMs exhibit antioxidant, antitumor, antitubercular, antivi-
strong Brønsted acid catalyst.
ral, antifungal and anti-inflammatory activities.6 Triarylmethane
An excess of TfOH under pressure,16 TFA and other protic
frameworks are usually obtained from the acid-catalysed bisaryla-
acids,6,17 PTSA18 and 84% sulfuric acid19 have also been used.
tion of activated aryl aldehydes and the reaction is called hydrox-
Heterogeneous solid Brønsted acid catalysts include silica gel-
yalkylation. It is in fact a multistep Friedel–Crafts alkylation and
supported NaHSO4,20 polystyrene-supported sulfonic acid,21 silica
follows a typical aromatic electrophilic substitution mechanism.
sulfuric acid,22 perfluorinated sulfonic acid resin (Nafion-H).23
The reaction does not stop at the first step, and the intermediate
Unsymmetrical TRAMs have been prepared using ZnBr2/SiO2
diarylmethanol immediately reacts with a second molecule of
and AcBr,24 whilst symmetrical and unsymmetrical TRAMs
the aromatic compound, giving rise to a bisarylation product.
Furthermore the reaction benefits from a high atom efficiency and
only produces one molecule of water as a by-product.
using FeCl3/Ac2O:25 the reaction mechanisms involves the in situ
formation of an a-bromobenzyl acetate or a geminal diacetate,
respectively, as the reactive intermediate species.
The reaction has been extensively studied since 18867 and lit-
All the above TRAMs synthetic methods, however, suffer from
erature methods include superacidic systems, Brønsted and Lewis
one or more known disadvantages, such as the need for a large
excess of the aromatic substrate, poor selectivity, harsh reaction
acid catalysts and solid-supported catalysts. AuCl3,8 Yb(OTf)3,9
11
ClSiMe3,10 B(C6F5)3 and molecular iodine12 have been used
conditions (e.g. high temperatures, pressure vessels), large catalyst
as Lewis acids in catalytic amounts. A dual-reagent catalytic
amounts and the disposal of the excess aromatic compound or
combination of [Ir(COD)Cl]2-SnCl4 has also been reported to
catalyse the Friedel–Crafts alkylation of arenes and heteroarenes;
a complexation/interaction of the carbonyl functionality at the
tin center has been suggested as a plausible mechanism.13
solvents and/or toxic metal waste.
Finally, bis- and trisindolylmethanes (usually 3,3¢-BIMs and
3,3¢,3¢¢-TIMs) have proven themselves to be of great interest
thanks to their wide range of applications. The numerous syn-
Mineral Brønsted acids (such as HF, H2SO4, H3PO4) have
thetic strategies towards their preparation, powerful biological
been predominantly used as the catalysts for a very long
activity and different properties have recently been extensively
time. The detailed mechanism of the reaction was investigated
reviewed.26 The standard acid-catalysed indole reaction with
in-depth by Olah and coworkers, by running the reaction in
carbonyl compounds is a useful synthetic method and a huge
various superacidic systems (triflic acid, Magic acid, and so on).
number of Lewis or Brønsted acid catalysts has been reported.
Similarly, the reactions of substituted indoles with 3-formylindole
give asymmetric TIMs.26 In the same review, a ca◦talyst-free BIM
Dipartimento di Chimica Generale e Chimica Organica dell’Universita`, Uni-
versita` di Torino, Via P. Giuria 7, 10125, Torino, Italy. E-mail: margherita.
formation was reported to occur in glycerol at 90 C.27
barbero@unito.it
Despite the high number of literature methods, the demand
† Electronic supplementary information (ESI) available: General proce-
dures, 1H, 13C NMR and MS spectra of products 5a–j, 6a–c, 7a–b, 8a–c,
9a, 11a–d. See DOI: 10.1039/c1ob06280h
for new efficient, mild, metal-free and environmentally friendly
protocols for TRAM, BIM and TIM synthesis, via electrophilic
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Table 1 Reagents 2a–f, 3a–b, and 4a–j
Table 2 Reaction condition optimisation for 5d synthesis
2
Ar
3
3a
3b
Ar
4
Ar¢H
Entry Molar ratio 2a : 4d 1 (mol%)
T/◦C
t (h)
Yielda (%)
2a
2b
2c
2d
2e
2f
4-NO2C6H4
4-ClC6H4
C6H5
4-MeOC6H4
4-HOC6H4
3-Indolyl
4-NO2C6H4
4-MeOC6H4
4a
4b
4c
4d
4e
4f
4g
4h
4i
1,2,4-(MeO)3C6H3
1,3-(MeO)2C6H4
1,2-(MeO)2C6H4
C6H5OMe
1
2
3
4
5
1 : 10
1 : 10
1 : 2 mL
1 : 2 mL
1 : 2 mL
10
50
10
50
50b
130
130
130
130
130
24
1.5
24
1.5
1.5
86 (5.9 : 1)
91 (5.6 : 1)
89 (6.9 : 1)
90 (7.6 : 1)
100 (5.2 : 1)
C6H5OH
Indole
1-Methylindole
2-Methylfuran
Thiophene
a Yields refer to pure isolated product by column chromatography (eluent
PE : AcOEt 6 : 4). In parentheses p,p and o,p isomer ratio is reported
(calculated by 1H NMR spectra). b Silica-gel supported OBS (10% w/w).
4j
2-Methylindole
substitution reaction, is high. In order to continue our ongoing
studies in the field of organocatalysis,28a which are aimed at
developing mild and practical protocols in neat conditions, we
have decided to explore the synthetic features of the use of o-
benzenedisulfonimide (OBS, 1)28b as an environmentally friendly
Brønsted acid catalyst in Friedel–Crafts hydroxyalkylation reac-
tions (Scheme 1 and Table 1). Furthermore, a new bench-stable
solid-supported catalyst, namely silica-gel supported OBS, has
been prepared and tested to improve the easy handling, storing,
recovery and recycling of this catalyst under clean and easy work-
up conditions.29
Reaction temperature of 100 ◦C and room temperature only
led to trace amount or a complete absence of product. In all
the reactions, the formation of diarylated regioisomer products
was observed, as the expected consequence of an electrophilic
aromatic substitution pathway. The para,para derivative was
always predominant with respect to the ortho,para isomer, whereas
the ortho,ortho was never detected; a larger anisole excess increased
the selectivity (entries 3 and 4 compared to 1 and 2). The reaction
was then carried out in the presence of silica-gel supported
OBS following the optimised conditions. The Brønsted acid was
adsorbed onto SiO2 in a 10% w/w amount, simply by dissolving it
in water, stirring with SiO2 and by evaporating the solvent under
vacuum. Then its catalytic efficiency was tested and a quantitative
product yield was recovered (entry 5).
Then, a representative number of variously substituted aromatic
(and heteroaromatic) aldehydes 2a–f were reacted with activated
aromatic and heteroaromatics (4a–j; Table 1), in the presence of
OBS (Scheme 1). In all the reactions, the catalytic amount of OBS
was not lowered below 10% mol, although highly activated aryl
aldehydes and aromatics could react in the presence of less catalyst.
Details of the reaction conditions and isolated yields of products
5–11 (Table 3) are reported in Table 4.
Scheme 1 Triaryl and trisindolylmethane synthesis via OBS catalysed
bisarylation of aryl aldehydes (or their dimethyl acetals).
Results and discussion
The obtained results are strictly depending on the substituent
electronic effects of the starting reagents towards electrophilic
hydroxyalkylation.
First, 4-nitrobenzaldehyde (2a) and anisole (4d) were reacted
to give TRAM 5d, as a model reaction of the OBS catalysed
Friedel–Crafts hydroxyalkylation. The reagents were chosen as
the first is a highly electrophilic alkylating agent and the second
a sufficiently activated aromatic substrate (Scheme 2). Following
literature suggestions, anisole excess was reacted with 2a in the
presence of 1, which was used as the catalyst, in neat conditions.
The effect of reagent ratio, heating and catalyst loading were
considered as reported in Table 2. Both a temperature of 130 ◦C
and the catalytic amount of 1 were crucial to the completion of the
reaction in reduced times (entries 2 and 4 compared with 1 and 3;
Table 2).
First, the OBS-catalysed hydroxyalkylation of aromatics was
tested using the highly electrophilic 4-nitrobenzaldehyde (2a).
Reactions were initially performed at 130 ◦C in the presence of
an excess of the aromatic substrate, like the trial reactions (entries
1 and 8). Whereas anisole required these harsh conditions, it was
observed that, using 2a, room temperature, nearly stoichiometric
amounts of reagents and neat conditions were sufficient to obtain,
under stirring, the same good results in the reaction with highly
activated aromatics 4a, 4b and 4e, and heteroaromatics 4f, 4g and
4h (entries 2, 4, 9, 11, 13 and 15). The reaction was immediate and
reached completion in very short times. In some cases, the deep
coloured thick reaction mixture suddenly became solid and lost
its colouring.
By using less activated 4c and 4i, heating at 130 ◦C or at 4i reflux
temperature was needed and a higher catalyst amount increased
product yields (entries 6–7 and 17–18). As highlighted for anisole,
regioisomers were produced when phenol was used (4e; entries 8
and 9). The yields of column chromatography purified products
5a–h were always good to high, only 5i was isolated in modest yield
(entry 18). Unfortunately, the OBS-catalysed hydroxyalkylation of
deactivated substrates such as benzene, p-xylene or chlorobenzene
was not achieved.
Scheme 2 Model reaction between aldehyde 2a and anisole (4d).
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Table 3 Products 5a–j, 6a–c, 7a–b, 8a–c, 9a, 11a–d
Some of the above reactions were then run in the presence of
OBS adsorbed onto silica 10% w/w. The catalytic activity of this
heterogeneous system was comparable to OBS alone (entries 3,
5, 10, 12, 14 and 16), whilst the recovery and recyclability of the
catalyst were improved. Indeed, at the end of the reaction, after
the extraction of the organic phase and a few washings with small
amounts of solvent, the solid catalyst was dried and immediately
recycled in another five subsequent reactions without significant
loss of catalytic activity (entry 14).
Then, 4-chlorobenzaldehyde (2b) was reacted, under the same
conditions as 2a, with the aromatic compounds 4a, 4e and 4g
(entries 19–21). Despite the weaker electron withdrawing effect
of the chloro substituent, the desired TRAMs were obtained
in good to quantitative yields both in the presence of OBS
or silica-supported OBS. TRAM 6b has been reported as an
antiviral.30 Benzaldehyde (2c) was similarly reacted with aromatics
4a and 4f (entries 22–24). The results were good, but heating was
necessary in the first case to reduce reaction time. Less activated 4-
methoxybenzaldehyde (2d) was reacted with 4a, 4e and 4f. Heating
was required to obtain TRAMs 8a and 8b in good yields (entries
25–26), whereas 8c was obtained in milder conditions (entry
27). Finally, the antimicrobial31 TRAM 9a was prepared from
4-hydroxybenzaldehyde (2e) and 4f at 40 ◦C in order to favour the
mixing of the reagents.
and with 4e at room temperature were instantaneous (entries 29
and 30), whilst the reaction of the aldehyde 2d with 4a did not
complete at room temperature and when stopped after 24 h only
gave rise to 8a in a 50% yield. Unfortunately, with deactivated
aromatics such as 4i, acetal hydrolysis was the only observed
reaction. 4-Nitrobenzaldehyde dimethyl acetal (3a), however, did
not prove to be a useful alternative to the parent aldehyde 2a
(entry 31 compared to entry 4). Furthermore, the hydrolysis was
the only observed process in the reaction with 4i. The difference in
acetal behaviour is probably due to the different electronic effects
the methoxy and the nitro groups have on the acetal protonation
in the first step of the reaction, giving rise to an inversion in the
parent aldehyde reactivity order. The use of acetals can therefore
be useful in the case of aldehydes bearing electron-donating
substituents which induce lower reactivity in the Friedel–Crafts
hydroxyalkylation.
When we performed the reaction with aldehydes, immediate
colour and density changes in the reaction mixtures were observed
which led us to investigate the reaction further. The reactions with
indoles, in particular, were seen to produce a thick, deep orange
coloured mixture simply by mixing the reagents. Therefore we
decided to carry out some reactions starting from particularly ac-
tivated reagents, in the absence of any catalyst, in neat conditions.
To the best of our knowledge, Friedel–Crafts hydroxyalkylation
reactions without catalyst are reported here for the first time (in
the paper cited above, the reactions were run in glycerol under
heating and the role of the protic solvent in promoting aldehyde
activation, through hydrogen bonding, was considered a plausible
explanation).27
Aldehyde acetals are well-known highly electrophilic aldehyde
substitutes.28a Therefore, acetals 3a and 3b were tested in order
to evaluate their applicability in hydroxyalkylation reactions.
Obtained results were as expected (Scheme 1, Table 4). The
reactions of 4-methoxybenzaldehyde dimethyl acetal (3b) with 4a
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Table 4 Synthesis of products 5–9
Entry
Reagents
Molar ratio 2 (or 3) : 4
1 (mol%)
T/◦C
t (min)
Products
Yield (%)a
1
2
3
4
5
6
7
8
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2c
2c
2c
2d
2d
2d
2e
3b
3b
3a
2a
2a
2a
4a
4a
4a
4b
4b
4c
4c
4e
4e
4e
4f
1 : 10
1 : 2.2
1 : 2.2
1 : 10
1 : 10
1 : 10
1 : 10
1 : 10
1 : 10
1 : 10
1 : 2.5
1 : 2.5
1 : 2.5
1 : 2.5
1 : 3
10
10
10b
10
10b
10
50
10
10
10b
10
10b
10
10b
10
10b
10
50
10b
10
10
10
10
10
10
10
10
10
10
10
10
130
r.t.
r.t.
r.t.
r.t.
130
130
130
r.t.
r.t.
r.t.
r.t.
r.t
15
15
15
120
120
30 h
6 h
20
7 h
7 h
5
5a
5a
5a
5b
5b
5c
5c
5e
5e
5e
5f
100
100
96
100
100
76
95
94 (10 : 6)
100 (10 : 1)
97 (10 : 3)
95
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
4f
5
5
5
5f
90
4g
4g
4h
4h
4i
5g
5g
5h
5h
5i
96
r.t.
r.t.
r.t.
85
99c
60
30
6 h
120
75
20
5
3.5 h
20 h
5
120
30
5
120
5
87
100
41
74
90
77 (10 : 3)
100
93
93
75
1 : 3
1 : 2 mL
1 : 2 mL
1 : 2.5
1 : 10
1 : 2.2
1 : 10
1 : 10
1: 2.2
1 : 10
1 : 10
1 : 2.2
1 : 2.2
1 : 2.2
1 : 10
1 : 10
1 : 2
4i
85
5i
4a
4e
4g
4a
4a
4f
r.t.
130
r.t.
130
r.t.
r.t.
130
130
r.t.
40
r.t.
r.t.
r.t.
100
100
100
6a
6b
6c
7a
7a
7b
8a
8b
8c
9a
8a
8b
5b
5f
4a
4e
4f
91
82 (10 : 1)
89
73
4f
4a
4e
4b
4f
100
5
95 (10 : 1)
d
5 h
60
120
60
e
—
—
86
70
100
e
4g
4j
1 : 2
1 : 2
5g
5j
e
—
a Yields refer to pure isolated products. In parentheses p,p and o,p isomer ratio is reported (calculated by 1H NMR spectra). b Silica supported OBS. c The
catalyst was recycled for 5 subsequent runs. d The reaction was incomplete. e The reaction was carried out in the absence of catalyst.
TRAMs 5f,g,j were obtained in good yields and in short times
from aldehyde 2a and indoles 4f, 4g and 4j when the reagents were
heated in stoichiometric amounts at 100 ◦C (at r.t. the reaction did
not reach completion). However the deep red coloured reaction
mixture of 2a and 4a did not give products, even after several hours
of heating at 130 ◦C. The reactions between the less activated
aldehyde 2d and 4f or 4g proceeded, but did not complete in
comparable times.
Turning our attention to indolylmethanes, as a general mecha-
nism pathway, the first step of the acid-catalysed indole reaction
with carbonyl compounds produces, by dehydration, an intermedi-
ate azafulvenium species (10), which then immediately undergoes
the addition of a second indole moiety to produce the expected
BIM (Scheme 3).26
The reaction between 3-formylindoles and indoles produces
TIMs with the same mechanism (Scheme 3; Ar = 3-indolyl). It is
also known that trisindolylmethanes are readily cleaved by acids
giving rise to resonance stabilised ammonium ions.23 Furthermore,
symmetric and asymmetric TIMs have been isolated as a mixture
from the reaction of 3-formylindoles with substituted indoles in
the presence of different acid catalysts.32 Their formation, although
not always justified, has been attributed to the likely acidic cleavage
of the initially formed TIMs with release of an indole molecule and
subsequent reaction with a substituted indole moiety. Interested
Scheme 3 Reaction mechanism.
in these findings, we decided to further explore the applicability of
OBS as the catalyst in trisindolylmethane synthesis.
First of all, we tested the optimised reaction conditions for
TRAM synthesis, but the reaction between 2f and indole (4f) in the
presence of 1 (10 mol%) in solid state conditions did not proceed
at r.t. When heating to 55 or 100 ◦C, the reaction seemed to be
locked in an unchanging ratio between reagents and products.
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Table 5 Synthesis of trisindolylmethanes 11a
Entry Reagents 1 (mol%) t (min)
Conclusions
Products
Yields (%)b
In conclusion, a new simple and efficient triaryl and trisindolyl-
methane synthesis has been reported. The advantages of the
method are mild solvent-free reaction conditions, in most cases
nearly stoichiometric reagent ratios, catalytic amounts of the
readily available and easily-handled Brønsted acid catalyst. In our
conditions, every effort to stop the reaction at the first step was
unsuccessful and the intermediate diarylmethanol was not isolated
nor detected. Furthermore, the recoverability and recyclability of
the catalyst, both in homogeneous and heterogeneous conditions,
are noteworthy.
1
2
3
2f
2f
2f
4f 10
4j 10
4g
5
5
5 h
11a
11b
11c
92
72
90c
2
a Reaction conditions: reagent ratio 2f : 4 = 1 : 2.2, in EtOH at r.t. b Yields
refer to pure isolated products. c Only traces of 11d were detected.
Nevertheless, in ethanol as a solvent, the reaction at r.t. was
instantaneous and the yield good (Table 5, entry 1). A control
experiment carried out in EtOH in the absence of the catalyst did
not yield traces of product. Good results were also obtained by
reacting 2f and 2-methylindole (4j) at r.t. in the presence of OBS
10% (entry 2).
Experimental
General experimental
According to literature observations, we suggest that, in these
conditions, the lowest solubility of TIMs in ethanol causes their
immediate separation from the reaction medium so preventing the
acid-catalysed cleavage. In the light of these, we can hypothesize
that, under the former acidic neat conditions and heating, the
produced TIM is rapidly cleaved into the intermediate cation and
the reaction cannot reach completion. Furthermore, when 2f and
1-methylindole (4g) were reacted under the same reaction condi-
tions, the immediate formation of two products was observed: the
expected TIM 11c and the symmetric TIM 11d deriving by cleavage
of the former and reaction with excess 4g (Scheme 4). The reaction
was heated to 50 ◦C in order to maximize 11d formation and
stopped after 24 h. Products were identified by comparison with
authentic samples or by NMR spectroscopy of isolated products.
GC and GC-MS analyses confirmed indole (4f) formation in the
reaction mixture, whose presence is not otherwise explainable.
Nevertheless, TIM 11c was obtained in 90% yield by carrying out
the reaction in the presence of OBS 2 mol% (only traces of 11d
were observed in these conditions; entry 3).
All the reactions were run in vials using analytical grade reagents,
and were monitored by TLC, GC, GC-MS and NMR spec-
trometry. GC-MS spectra were recorded with an AT5973N mass
selective detector connected to an AT6890N GC cross-linked
methyl silicone capillary column. 1H NMR and 13C NMR spectra
were recorded in CDCl3 with a Bruker Avance 200 spectrometer
at 200 MHz and 50 MHz, respectively; chemical shifts are given
in ppm relative to CDCl3. TLC were performed on Fluka silica
gel TLCPET foils GF 254, 2–25 mm, layer thickness 0.2 mm,
˚
medium pore diameter 60 A. Plates were visualized using UV
light (254 nm). Column chromatography was carried out on
˚
SiO2 (pore size 70 A, 70–230 mesh). Petroleum ether refers to
◦
the fraction boiling in the range 40–60 C and is abbreviated as
PE. Commercially available reagents and solvents were purchased
from Aldrich and were used without purification or distillation
prior to use; Dowex 50 ¥ 8 ion-exchange resin was purchased from
Fluka. o-Benzenedisulfonimide (1) was prepared as described in
literature.33 Details for the reactions and yields for the pure (GC,
GC-MS, TLC, 1H NMR) isolated products are listed in Table 2, 4
Scheme 4 Proposed mechanism for 11d formation in 11c synthesis.
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and 5. Structure and purity of all the products were confirmed by
comparison of their physical and spectral data (IR, MS, 1H NMR
and 13C NMR) with those reported in literature. By the work-up of
the reaction mixtures, o-benzenedisulfonimide could be recovered,
purified by elution on Dowex ion-exchange resin and recycled in
other reactions. When OBS was used adsorbed onto SiO2, at the
end of the reaction, the solid mixture was extracted with small
portions of CH2Cl2 (6 ¥ 3 mL) under stirring; the heterogeneous
catalyst was then directly recycled after drying under vacuum.
Representative experimental data
Bis(2-methyl-3-indolyl)(4-nitrophenyl)methane (5j)34. Chro-
matographic eluent: PE-AcOEt (4 : 6); yellow solid (0.38 g,
quantitative yield); dp 239–242 C (CH2Cl2–PE) [lit.34 241–
◦
243 ◦C]; 1H NMR (200 MHz, CD3CN): d = 2.05 (s, 6H), 6.06 (s,
1H), 6.69–6.81 (m, 4H), 6.88–6.96 (m, 2H), 7.23 (d, J = 8.0 Hz,
2H), 7.37 (d, J = 9.0 Hz, 2H), 8.05 (d, J = 9.0 Hz, 2H), 9.01 (br
s, 2H); 13C NMR (50 MHz, CD3CN): d = 11.1 (2C), 38.9, 110.3
(2C), 111.2 (2C), 118.4 (2C), 118.5 (2C), 120.2 (2C), 123.0 (2C),
128.0 (2C), 129.6 (2C), 132.6 (2C), 135.2 (2C), 146.2, 152.5.
General procedure for triarylmethane 5a–i, 6a–c, 7a–b, 8a–c and
9a synthesis
General procedure for trisindolylmethane 11a–c synthesis
A mixture of aldehyde 2 (1.0 mmol), aromatic compound 4 (mmol
as in Table 4) and o-benzenedisulfonimide (1, 10 mol%, 0.022 g)
was stirred at r.t. (or under heating, as in Table 4) in a vial
until TLC analyses showed almost complete conversion of 2. The
reaction mixture was then treated with CH2Cl2–H2O (1 : 1, 20 mL).
The aqueous phase was extracted with CH2Cl2 (2 ¥ 20 mL).
The organic extracts were dried with Na2SO4 and concentrated
under reduced pressure. The crude residue was purified by column
chromatography on a short column of silica gel.
A mixture of 3-formylindole 2f (0.15 g, 1.0 mmol), aromatic
compound 4 (2.2 mmol) and o-benzenedisulfonimide (1, mol%
as in Table 5) in EtOH (2 mL) was stirred at r.t. in a vial until TLC
analyses showed almost complete conversion of 2f. The reaction
mixture was then treated with CH2Cl2–H2O (1 : 1, 20 mL). The
aqueous phase was extracted with CH2Cl2 (2 ¥ 20 mL). The organic
extracts were dried with Na2SO4 and concentrated under reduced
pressure. The crude residue was purified by column chromatogra-
phy on a short column of silica gel; eluent: PE-AcOEt (6 : 4).
Representative experimental data
Representative experimental data
Tris(3-indolyl)methane (11a)32a
. Chromatographic eluent: PE-
Bis(2,4,5-trimethoxyphenyl)(4-nitrophenyl)methane
(5a)20.
AcOEt (4 : 6); light orange solid (0.33 g, 92% yield); dp 229–
Chromatographic eluent: PE-AcOEt (6 : 4); yellow solid (0.47 g,
quantitative yield); mp 125–126 ◦C (EtOH) [lit.20 123–124 ◦C]; 1H
NMR (200 MHz, CDCl3): d = 3.58 (s, 6H), 3.61 (s, 6H), 3.83 (s,
6H), 6.04 (s, 1H), 6.32 (s, 2H), 6.49 (s, 2H), 7.13 (d, J = 9.0 Hz,
2H), 8.03 (d, J = 8.8 Hz, 2H); 13C NMR (50 MHz, CDCl3): d =
42.8, 55.9 (2C), 56.4 (2C), 56.5 (2C), 97.8 (2C), 114.2 (2C), 122.1
(2C), 123.0 (2C), 129.4 (2C), 142.6 (2C), 145.9, 148.4 (2C), 151.3
(2C), 152.7; MS (EI) m/z: (%) 469 [M+](100), 438 (40), 181 (25),
151 (25).
◦
234 C (Acetone-PE) [lit.32a 240 ◦C]; 1H NMR (200 MHz,
CD3CN): d = 6.08 (m, 1H), 6.80–6.90 (m, 6H), 6.95–7.08 (m, 3H),
7.27–7.40 (m, 6H), 9.07 (br s, 3H); 13C NMR (50 MHz, CD3CN):
d = 31.0, 111.1 (3C), 118.3 (3C), 118.7 (3C), 119.2 (3C), 121.1 (3C),
123.0 (3C), 126.8 (3C), 136.7 (3C).
Acknowledgements
This work was supported by Italian MIUR and by Universita`
degli Studi di Torino.
Bis(4-methoxyphenyl)(4-nitrophenyl)methane (5d) and isomer20.
Chromatographic eluent: PE-AcOEt (7 : 3); light yellow oil (0.32 g,
91% yield). Mixture of isomers (p,p and o,p, the former always
prevalent) not completely separable. 1H NMR (200 MHz, CDCl3):
d = 3.66 (s, 3H) (o,p), 3.74 (s, 3H) (p,p), 5.49 (s, 1H) (p,p), 5.87 (s,
1H) (o,p), 6.80 (d, J = 8.8 Hz, 4H), 6.95 (d, J = 8.8 Hz, 4H), 7.22
(d, J = 8.6 Hz, 2H), 8.07 (d, J = 8.8 Hz, 2H); MS (EI) m/z (%):
349 [M+](100), 318 (65), 227 (100) (p,p isomer); 349 [M+](100), 319
(40), 227 (55), 121 (55) (o,p isomer).
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The Royal Society of Chemistry 2011
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