A facile one-pot method to synthesise 2-alkylated indole and 2,2′-bis(indolyl)methane derivatives using ketones as electrophiles and their anion sensing ability

Article abstract of DOI:10.1039/c6ra16192h

Indole derivatives are of great importance because of their biological activity and application in technology. This study explores the synthesis of 2-alkylated indoles derivatives and 2,2′-bis(indolyl)methanes, and their application in anion sensing. The synthesis of a wide range of 2-alkylated indoles and some 2,2′-bis(indolyl)methanes, which cannot be synthesized by previously reported methods, was for the first time accomplished employing dipole exchange of the indole ring towards electrophilic substitution. Some of the indole derivatives exhibited selective recognition and sensing ability towards F^- and HSO₄^- anions through naked-eye detectable color changes. The sensing details of the indole derivatives were also evaluated using UV-Vis spectroscopy and ¹H NMR titration techniques.

Full text of DOI:10.1039/c6ra16192h

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A facile one-pot method to synthesis of 2-alkylated indole and
2,2'-bis(indolyl)methane derivatives using ketones as electrophile
and its anion sensing ability
Received 00th January 20xx,
Accepted 00th January 20xx
Sinan Bayindir,a,b and Nurullah Saracoglu*a
DOI: 10.1039/x0xx00000x
www.rsc.org/
Indole derivatives are of great importance because of their biological activity and application in technology. This study
explores the synthesis of 2-alkylated indoles derivatives and 2,2′-bis(indolyl)methanes, and their application in anion
sensing. The synthesis of a wide range of 2-alkylated indoles and some 2,2′-bis(indolyl)methanes, which cannot be
synthesized by previous reported methods, was first time accomplished employing a dipole exchange of the indole ring
towards electrophilic substitution. Some of the indole derivatives exhibited selective recognition and sensing ability
−
towards F− and HSO4 anions through a naked-eye detectable color changes. The sensing details of the indole derivatives
were also evaluated using UV-Vis spectroscopy and 1H NMR titration techniques.
strategy also provided the most important alternative option for
accessing chiral 2-substituted indoles.18 Herein, we aim to develop a
Introduction
Indole and its derivatives are frequently present in the structure of
pharmaceutics, agricultural chemicals, functional substances and
natural products.1-3 Therefore, many studies have reported the
effective derivatization of indole, and the development of new
synthetic methods and application of new indole derivatives have
been explored extensively since indole was discovered in 1869.4-6
Bis(indolyl)methane alkaloids and substituted indole derivatives
were previously discovered, and because of their importance in
biology and technology applications, there has been an increasing
interest to develop cheap, effective, and facile methods for
synthesis of new derivatives.7-12 But, the directly synthesis of 2-
substituted indoles from indole are extremely difficult and limited.
Consequently, the most frequently used methods to access 2-
substituted indoles are often based on the construction of the
heterocycles via cyclization reactions (Scheme 1a).13,14 Despite its
importance and widespread use, asymmetric bis(3-indolyl)
methanes and symmetric/asymmetric bis(2-indolyl)methanes
remain difficult to synthesize effectively, except for synthesis of
symmetric bis(3-indolyl)methanes. In the literature, the studies
concerning the synthesis of bis(2-indolyl)methanes are very
restricted and these indoles are currently substituted at the 3-
position (Scheme 1b).15
highly efficient, facile and atom economical protocol to prepare 2-
alkylated indoles and bis(2-indolyl)methanes (Scheme 1d). The
synthesis of 2-alkylindoles are previsualized from Friedel-Crafts
reaction between 4,7-dihydroindol (1) and ketones such as
cyclic/acyclic aliphatic ketones, bisaryl ketones and aryl-alkyl
ketones via redox isomerization including the dehydration and
hydrogen shift as in situ. The preparation of bis(2-indolyl)methanes
is predicted via two consecutive Friedel-Crafts alkylation of two
equivalent of 4,7-dihydroindole (1) with one equivalent of a ketone
followed by an oxidation step.
In our previous studies, we developed an efficient protocol for
the preparation of 2-substituted indoles through Michael-type
addition of 4,7-dihydroindole (1) using Michael acceptors as
electrophile followed by an oxidation step (Scheme 1c).16,17 Our
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1). Notably, when the reaction was carried out at 80 oC in
acetonitrile in the presence of the Bi(NO3)3 5H2O, the desired
.
2-alkylated indole 3a was isolated in 97% yield (Table 1, Entry
11).
Table 1. Optimization of reaction conditionsa
Entry
Catalyst
Solvent
Temp.
(oC)
25
25
25
80
80
80
80
80
80
25
80
Time
Yieldb (%)
1
2
3
4
5
6
7
8
9
TFA
AlCl3
ZrCl4
CH2Cl2
CH2Cl2
CH2Cl2
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
CH2Cl2
MeCN
30 min.
30 min.
5h
30 min.
30 min.
5h
5h
5h
5h
12h
0[c,d]
5[c,d]
25
ZrCl4
15[c,d]
17[c,d]
80
PhCOOH
Cu(OTf)2
InCl3
75
78
88
0
BiCl3
Zn(OTf)2
.
10
11
Bi(NO3)3 5H2O
Scheme 1. Strategies for the synthesis of 2-alkyl indoles and 2,2'-
.
Bi(NO3)3 5H2O
5h
97
bis(indolyl)methanes
aConditions: 4,7-dihydro-1H-indole (1, 1 equiv), cyclohexanone (2a, 1
equiv), catalyst (10% mmol) and solvent (10 mL). bIsolalated yields of 2-
cyclohexyl-1H-indole (3a). cComplex reaction mixture. dUnder N2
Molecules such as indole, carbazole, bisindole and
indolocarbazole form an import class of hydrogen bond donors. In
addition to their biological properties, bis(indolyl)methane and alkyl
indoles are very attractive compounds for chemosensing.19-25
Because of their sensitivity and selectivity, these compounds have
served in the determination of ions hazardous to the environment
and health. Within this context, there is just an increasing interest
in the synthesis of colorimetric sensors for detection of anions.
Anions play an important role in chemical and biological systems,
and fluoride, acetate and bisulphate anions sometimes play a role
in environmental systems. For example, fluoride ion has an
important application in the food and toxicity industry. Among the
various anions, bisulphate ion is of particular interest because of its
essential role in biological and industrial areas. Upon decomposition
of bisulphate ion at high pH, toxic sulfate ion (SO42−) is released,
which can cause respiratory paralysis.11 For these reasons, we are
concerned with determining whether new indole derivatives have
specific chemoselectivity for ions by using spectroscopic analysis
methods, including UV-vis and NMR titration as well as the color
change observed by the naked eye.
With the optimized reaction conditions in hand, we next explored
the scope and limitations of the reaction by using 1 (1.0 equiv) and
various ketones (1.0 equiv) and the desired products (3a-l, 3o-p)
were obtained in high yields (Table 2). In contrast, the reaction of 2-
acetylpyrrole (2m) failed to produce the desired product 3m under
the optimized conditions and only lead to the recovery of the
starting material (Table 2). We assume that the possible resonance
contribution for 2m could decrease the reactivity of carbonyl
carbon toward the nucleophilic attack of dihydroindole 1. When N-
Boc-2-acetylpyrrole (2n) reacted with 1, the formation of a trace
amount product 3n was estimated by 1H NMR spectra (Table 2).
Table 2. Substrate scope by varying ketones (1 equiv) with 1 (1 equiv)
Results and discussions
At first, 4,7-dihydro-1H-indole (1) as staring material was
obtained by Birch reduction of indole (12) with Li in liquid
ammonia.16 Our effort was initially focused on the alkylation of
4,7-dihydro-1H-indole (
reaction. As shown in Table 1, after treatment of
1
) with cyclohexanone (2a) as a model
(1.0 equiv)
1
.
with 2a (1.0 equiv) in the presence of Bi(NO3)3 5H2O (10% mol)
in methylene chloride at room temperature, the desired
alkylation product was not observed (Table 1, Entry 10). When
the reaction was carried out using TFA (trifluoroacetic acid),
AlCl3 and PhCOOH as catalysts at room temperature, a
complex product mixture was obtained. Therefore,
optimization study was performed by varying the parameters
such as reaction time, catalyst, temperature and solvent (Table
2 | J. Name., 2012, 00, 1-3
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.
10
Bi(NO3)3 5H2O
MeCN
80
5h
74
aConditions: 1) 4,7-dihydro-1H-indole (1, 2 equiv), cyclohexanone (2a, 1
equiv), catalyst (10% mmol) and solvent (10 mL) and then 2) PBQ (p-
benzoquinone, 2.5 equiv) and CH2Cl2 (25 mL). bIsolalated yields of 2,2'-
c
(cyclohexane-1,1-diyl)bis(1H-indole) (4a). Complex reaction mixture. d2-
Cyclohexyl indole (3a) occurred.
Furthermore, although the reactions were performed over a
wide range of ketones, the desired 2,2'-(bis-1H-indolyl)methanes
4a-d were only able to be obtained from with cyclic or acyclic
aliphatic ketones 2a-d (Table 4, entry 1-4). In the case of the other
ketones 2e-o, while the reactions only gave the 2-alkylated indole
derivatives 3e-o, the excess of dihydroindole 1 was recovered
(Table 4, entry 5-10). Similar results were likewise obtained from
with excess equivalents, regardless of solvent and temperature
conditions.
Table 4. Substrate scope by varying ketones (1 equiv) with 1 (2 equiv)
.
aConditions: 1 (1.0 mmol), 2 (1.0 mmol), Bi(NO3)3 5H2O (10% mmol),
MeCN (10 mL), 80 oC, under air; isolated yields are shown.
We next examined the reaction between 1 (2.0 equiv) and
ketones (1.0 equiv) to yield bis(2-indolyl)methanes. The reaction of
1 (2.0 equiv) and 2a (1.0 equiv) was selected as model reaction, and
carried out by changing the parameters such as reaction time,
catalyst, temperature and solvent. Although the formation of the
expected 2,2'-(cyclohexane-1,1-diyl)bis(4,7-dihydro-1H-indole) was
confirmed by 1H NMR spectra, the purification of the crude product
by column chromatography on the silica gel failed. Therefore, we
attempted to oxidize the crude product and to isolate the
corresponding bis(2-indolyl)methane. Among the tested
parameters as shown results in Table 3, the best result was
obtained in refluxing acetonitrile with the catalyst of bismuth
nitrate for 5 h to give 4a in a yield of 74% followed by the usual
work-up and the oxidation of the crude product with p-
benzoquinone (PBQ) in methylene chloride (Entry 10).
.
aConditions: 1) 1 (2.0 mmol), 2 (1.0 mmol), Bi(NO3)3 5H2O (10% mmol),
MeCN (10 mL), 80 oC, under air; 2) PBQ (2.5 equiv) and CH2Cl2 (25 mL),
isolated yields are shown. Ketones 2e-o provided 2-alkylated indoles.
A possible mechanism for the formation of the 2-alkylated
indole 2a and bisindolylmethane 4a was formulated in Scheme 2.
The formation of the 2-alkylated indole 2a may proceed via an
intermolecular Friedel-Crafts product 5 between pyrrole 1 and
electrophile 2a in the presence of the catalyst followed by a redox
isomerization involving hydration and proton shift steps. In the
presence of a Lewis acid, the intermediate 5 may be captured by a
second equivalent of 1 as a nucleophile to afford bis-pyrrolyl-
methane 7, which readily oxidised to 4a with PBQ. As mentioned
above, the aryl-aryl or aryl-alkyl ketones under same conditions do
not yield the expected bisindolylmethane derivatives in each case,
but rather give the corresponding 2-alkylated indoles. We assume
that the carbocation intermediate formed in the first step of the
Friedel-Crafts reaction has a key role, in that it directly influences
the progress of the reaction. Some representatives of the
carbocation intermediates can be seen in Figure 1. We predict that
the intermediate 6a possess a coplanar structure, which can
tolerate both reaction pathway. In case of the intermediate 6h or
6p, we propose that these carbocations are to be propeller-shaped
due to steric crowding of the ortho hydrogens. Thus, these
intermediates are twisted out of coplanarity, and their resonance
stabilisation is decreased. With this closed geometry as a result of
Table 3. Optimization of reaction conditionsa
Entry
Catalyst
Solvent
Temp. (oC)
Time
Yieldb (%)
1
2
3
4
5
6
7
TFA
AlCl3
ZrCl4
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
MeCN
MeCN
MeCN
25
25
25
80
80
80
80
30 min.
30 min.
5h
30 min.
30 min.
5h
0[c]
10[c,d]
12[d]
34[c,d]
27[c,d]
25
ZrCl4
PhCOOH
Cu(OTf)2
InCl3
5h
55
8
9
BiCl3
Zn(OTf)2
MeCN
MeCN
80
80
5h
5h
71
70
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the steric hindrance, the empty p orbital of these carbocations is ppm, respectively, whereas the methyl carbons were resonated as
shielded from the approaching the second dihydroindole 1, and the four signals at 23.7-16.4 ppm due to chirality.
aromatization to second Friedel-Crafts reaction is preferred.
Scheme 3. Reaction of acetone (2b, 1 equiv) with 1 (2 equiv)
Scheme 2. Proposed mechanism for the formation of 3a and 4a
Figure 1. Representative carbocation intermediates
In order to synthesize 2,2'-(propane-2,2-diyl)bis(1H-indole) (4b),
the reaction of 4,7-dihydro-1H-indole (1) with acetone (2b) was
carried out (Scheme 3). The 1H NMR spectrum of the crude reaction
mixture shows a mixture of 2,2'-(propane-2,2-diyl)bis(4,7-dihydro-
1H-indole) (8a) as main product and 2-alkylated indole 3b as the
byproduct along with unreacted 1. During the separation over silica
Scheme 4. Proposed mechanism for the formation of 2-isopropyl-2-(2-
gel column, while 3b isolated in 12% yield, the main product 8a
isopropyl-1H-indol-3-yl)indolin-3-one (9)
could not be obtained. Then, the crude mixture was submitted to
the oxidation with p-benzoquinone in acetonitrile. After the
purification, 2-isopropyl-2-(2-isopropyl-1H-indol-3-yl)indolin-3-one
The probable mechanism for the formation of the unexpected
product 9 is shown in Scheme 4. We believe that this product
(9) as a novel indole derivative was isolated, as well as the targeted
occurred through a series of reactions between 2-isopropyl-1H-
bisindolylmethane 4b. The structure of 9 was established by NMR
indole (3b), acetone (2b) and indole (12). The mechanism involves
bismuth nitrate-catalyzed nucleophilic addition of 2-alkylated indole
3b to acetone to afford the intermediate 10. The subsequent
dehydration of 10 is likely to proceed via the formation of an
spectroscopy. The 1H NMR spectrum of the indole derivative 9
showed signals at 7.95 and 5.08 ppm for the NH groups of indole
and oxindole rings. The resonance signals for eight aromatic
protons were observed at 6.77-8.02 ppm. Additionally, the
azafulvenium salt which in turn undergoes further addition with
resonances of the two isopropyl methine protons were present as a
indole (12) derived from the oxidation of dihydroindole 1 by PBQ as
in situ leading to the formation of iminium intermediate 13. The
multiplet at 3.97-3.93 ppm and 3.15-3.12 ppm. Because of both the
chirality resulting from possible blocked rotation of the bond
proposed mechanism completes
a subsequent intramolecular
between the indole and oxindole rings by two isopropyl groups and
the quaternary stereogenic carbon center in oxindole ring, the
methyl protons were resonated as four doublets at 1.32, 1.22, 0.95
and 0.88 ppm. The carbon resonance signal observed at 203.4 ppm
on APT 13C NMR of indole-oxindole derivative 9 confirms the
existence of a ketone group in the molecule and the fourteen
carbon resonance signals at the olefinic area support the proposed
structure. Furthermore, the aliphatic quaternary carbon and
methine carbon signals in 9 were observed at 75.0, 34.7 and 26.7
nucleophilic addition of 13 followed by the hydration, oxidation and
oxidative C-C bond cleavage steps to afford 9.
In connection with studies on the synthesis of
bisindolylmethanes, the reaction of 4,7-dihydro-1H-indole (1; 2.0
equiv) and 2-acetylfuran (2k; 1.0 equiv) gave a mixture resulting in
the formation of two unexpected products 17 and 12 along with 2-
alkylated indole 3k without the oxidation reaction (Scheme 5). This
surprising result may be due to a hydride transfer from 1 to the
4 | J. Name., 2012, 00, 1-3
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initially formed intermediate 6k to yield 17 and 12 via an (Figure 4d). A series of control studies with the naked eye and UV-
intermolecular redox-type reaction (Scheme 5).
vis showed that there was no color change observed for anions in
solutions containing only MeCN.
O
Me
O
2k (1 equiv)
Me
Me
+
12
(5%)
+
N
H
Bi(NO3
)
3.5H2O
N
H
N
H
MeCN, 80 o
C
1
O
O
3k
(85%)
17
(7%)
(2 equiv)
PBQ
H- hydride transfer
- H+
~H
form 1
Me
17
Figure 3. Clour changes obresved upon addition of 5×10-5 M anions to MeCN
(a, b) or MeCN/H2O (4:1, v/v) (c-f) of 1×10-5 M ligands [3k (a), 3l (b), 4a (c), b
(d), 4c (e) and 4d (f)]
3k
1
-H+
N
H
12
O
6k
Scheme 5. Reaction of 1 (2 equiv) with 2k (1 equiv) and proposed
mechanism for the products
Next, the sensing abilities of some of appropriate H-donor
1
receptors depicted in Figure 2 were monitored by UV–vis, H NMR
spectroscopic methods and naked-eye observation. As an initial
test, we checked the colour changes of receptors in various solvent
systems (MeCN, MeCN/H2O, DMSO, THF, THF/H2O etc.) upon the
-
addition of tetrabutylammonium (TBA) salts of F-, Cl-, Br-, I-, HSO4 ,
AcO-, CN- and SCN-. As shown in Figure 2, a noticeable color changes
by the naked eye could be detected from the interaction of 3l with
-
F-, 4b and 4c with HSO4 . The interactions between other anions and
receptors did not result in selective color changes.
(CH2)n
R
Me
Me
N
H
NH HN
NH HN
X
4a; n = 1
4d; n = 2
4b; R = Me
4c; R = Et
3k; X = O
3l; X = S
Figure 4. Change in the UV-vis absorption spectrum of ligands [3l (a), 4a (b),
4b (c) and 4c (d); (1×10-5 M)] in MeCN (a) or MeCN/H2O (4:1, v/v) (b-d)
Figure 2. Structures of the receptors
-
solution upon additions of anions (F-, Cl-, Br-, I-, HSO4 , AcO-, CN- ve SCN-;
tetrabutyl ammonium salts, 5×10-5 M)
Anion recognition properties of receptors with the
aforementioned anions in the various solvent systems were further
evaluated by UV-vis absorption spectroscopy (Figure 4). The free
receptor 3l displayed two sharp absorption peaks at 226 nm and
273 nm. Interaction of 3l (1×10-5 M) with anions caused changes to
appear in this region of the spectrum. Upon addition of F-, the sharp
peaks at 226/273 nm red shifted to 270/320 nm, which was
attributed to the color change resulting from the interaction of 3l
with F- ions that can be detected by the naked eye. Furthermore, a
new absorption peak formed at 573 nm (Figure 4a). The UV-vis
spectrum of 4a in CH3CN/H2O (4:1, v/v) showed two sharp peaks at
Following these results, UV-vis and 1H NMR spectrophotometric
titrations were conducted in order to understand the binding
-
phenomena of receptors with F- and HSO4 . First, interaction of 3l
and F- ions was carried out in a concentration of [Bu4N]F from 0 to
100 equivalents. It was observed that the sharp peaks at 226/273
nm of the receptor decreased upon interaction with 2 equivalent of
F-, and they shifted to 270/320 nm upon increasing [Bu4N]F
concentration. Furthermore, a new band formed at 573 nm, and its
intensity increased as the [Bu4N]F concentration increased. A new
peak at 573 nm and a very radical color change were attributed to
the exchange of N-H proton of indole unit, which was caused by the
interaction with F- (Figure 5a and 5b). The titrations of bis(2-
250 and 290 nm. Upon addition of SCN-, F-, HSO4 , and CN-, a new
-
peaks for 4a were observed at 515, 525, 530, and 540 nm,
respectively (Figure 4b). Although a red-shift occurred as a result of
interaction of 4a with anions, 4a was not selective. Different
solvents and pH systems were explored, but in each case, there was
no selectivity for a specific anion. It was determined that the two
sharp characteristic peaks of 4b shifted from 246/293 nm to
248/294 nm (shift to red) resulted from the interaction of 4b with
HSO4- ion, and a new interaction absorption peak formed at 520 nm
(Figure 4c). It was noted that 4c showed similar behaviors in
-
indolyl)methanes 4b (1×10-5 M) and 4c (1×10-5 M) with HSO4 were
realized with increasing concentration of [Bu4N]HSO4 from 0 to 100
equivalent. The intensity of the sharp peaks at 246/293 nm of 4b
increased upon the addition of 1 equivalent of [Bu4N]HSO4, and a
new red-shifted peak was observed at 520 nm (Figure 6a and 6b).
-
The interaction of 4c with 1 equivalent of HSO4 anion resulted in a
blue-shift and the formation of an additional new band at 505 nm
(Figure 7a and 7b). It should be noted that fluorescence studies on
the receptor-anion interactions did not show any fluorescence
emission.
-
CH3CN/H2O (4:1, v/v), and the interaction with HSO4 led to a
decrease in sharp bands at 245/289 nm and a shift to 237/272 nm
(blue-shift). A further peak formed at 505 nm due to the interaction
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responsible for observed chemical shifts upon NH-floride ion and
NH-bisulfate ion interactions (Figure 9). Thus, these interactions,
which induce polarization of N-H bond, where the partial positive
charge creates a downfield shift. Consequently, the increasing
electron density on the indole ring promotes an upfield shift of the
C-H protons and especially C3-H proton in pyrrole moiety.
Figure 5. a) UV-vis titration of the sensor 3l (1×10-5 M) in CH3CN solution
with standard solution of [Bu4N]F, b) Absorption of sensor 3l at 573 nm vs.
equivalent of fluoride anion
Figure 6. a) UV-vis titration of the sensor 4b (1×10-5 M) in CH3CN solution
with standard solution of [Bu4N]HSO4, b) Absorption of sensor 4b at 520
nm vs. equivalent of bisulfate anion
Figure 8. 1H NMR (400 MHz) spectra in CD3CN of the sensor 4b (1×10-2 M)
with presence of [Bu4N]HSO4; (a) 0 equiv. of [Bu4N]HSO4, (b) 1 equiv. of
[Bu4N]HSO4, (c) 2 equiv. of [Bu4N]HSO4, (d) 4 equiv. of [Bu4N]HSO4, (e) 6
equiv. of [Bu4N]HSO4, (f) 8 equiv. of [Bu4N]HSO4 and (g) 10 equiv. of
[Bu4N]HSO4
Figure 7. a) UV-vis titration of the sensor 4c (1×10-5 M) in CH3CN solution
with standard solution of [Bu4N]HSO4, b) Absorption of sensor 4c at 505 nm
vs. equivalent of bisulfate anion
Conclusions
To obtain insight into the binding ability of the receptors with F-
In conclusion, the synthesis studies to create 2-alkylated indoles
and bis(2-indolyl)methanes are very limited. Therefore, we have
designed and reported an effective and inexpensive method for the
synthesis of new 2-alkylated indoles and bis(2-indolyl)methanes
from 4,7-dihydroindole (1) using various ketones as the electrophile
source of the alkylation and the formation mechanisms are also
discussed. Furthermore, studies concerning the chemosensor
properties of these 2-alkylated indoles and bis(2-indolyl)methanes
were performed, and some of these derivatives show sensing of F-
-
and HSO4 , 1H NMR titration experiments were carried out in CD3CN
at 298 K. It is clear that the broad signal of NH proton of the indole
moiety disappeared when 2.0 equivalent of [Bu4N]F was added into
a solution of 3l. This indicates the formation of strong hydrogen
bond between fluoride anion and active NH group (Figure S21, ESI).
With increasing additional equivalents of F-, the signals of Ha, Hb, Hd
(indole) and Hf (thiophene) of 3l showed upfield shifts, whereas the
signal of He (indole) shifted toward downfield. To elucidate the
binding mode of the bis(2-indolyl)methanes 4b and 4c with
increasing HSO4- (from 0 to 10 equivalent), 1H NMR titration spectra
were undertaken, which illustrated the characteristic structural
changes that occurred upon interaction with [Bu4N]HSO4 in CD3CN
at 298 K. While the signal of NH proton of indole of 4b continuously
shifted downfield, the signals of Ha, Hb, Hd protons exhibited upfield
shifts, and the He proton shifted slightly downfield (Figure 8). With
increasing equivalent of HSO4- , a downfield shift of the NH proton
from 9.04 to 9.48 ppm of 4c was especially observed (Figure S22,
ESI). The evidence above can be ascribed to a hydrogen bonds are
-
and HSO4 anions via naked eye detection of color changes as well
as of absorption signals. The interactions of the receptor and anions
were further studied using 1H NMR titrations. Reactions using
aldehydes are currently underway.
6 | J. Name., 2012, 00, 1-3
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equiv) in MeCN (5 mL) was added ketone (2a-p; 1.0 equiv) and
.
Bi(NO3)3 5H2O (0.1 mmol). The reaction mixture was stirred
magnetically in a flask at 80 oC. The reaction was monitored by TLC.
After the completion of the reaction, the mixture was diluted with
ethyl acetate (30 mL) and washed with water (2×50 mL). The
organic phase was collected, dried over Na2SO4, filtered and
concentrated. The crude product was dissolved in CH2Cl2 (15 mL)
and p-benzoquinone (2.0 equiv.) was added. The mixture was
stirred at the room temperature for overnight. After completion of
the reaction, the solvent was evaporated and the crude product
was dissolved with ethyl acetate (30 mL) and the organic phase was
washed with NaOH (2N, 2×30 mL), brine (30 mL), and dried over
Na2SO4. The crude product was purified by silica gel column
chromatograph and isolated compounds were given according to
elution sequence (EtOAc/Hexane) in general.
Figure 9. Plausible intermediates from the interaction between receptors
with fluoride and bisulphate anions
Experimental section
.
2,2'-(Cyclohexane-1,1-diyl)bis(1H-indole) (4a): Bi(NO3)3 5H2O (0.1
General procedure (GP1) for the synthesis of 2-alkylated indoles:
mmol)-catalyzed reaction of 4,7-dihydro-1H-indole (1; 300 mg, 2.52
mmol) with cyclohexanone (2a; 124 mg, 1.26 mmol) was performed
at 80 C for 2h in MeCN. p-Benzoquinone (272 mg, 2.52 mmol) was
To a solution of 4,7-dihydro-1H-indole (1; 1.0 equiv) in MeCN (5 mL)
.
o
was added ketone (2a-p; 1.0 equiv) and Bi(NO3)3 5H2O (0.1 mmol).
The reaction mixture was stirred magnetically in a flask at 80 oC.
The reaction was monitored by TLC. After the completion of the
reaction, the mixture was diluted with ethyl acetate (30 mL) and
washed with water (2×50 mL). The organic phase was collected,
dried over Na2SO4, filtered and concentrated. The crude product
was purified by silica gel column chromatograph and isolated
compounds were given according to the elution sequence
(EtOAc/Hexane) in general.
added to the reaction mixture (405 mg) according to GP2. After
purification, 2,2'-(cyclohexane-1,1-diyl)bis(1H-indole) (4a; 292 mg
o
(74%), red solid, m.p. = 101-102 C (CH2Cl2/hexane)) was obtained.
1H NMR (400 MHz, CDCl3): δ 7.74 (bs, NH, 2H), 7.59 (d, J = 7.9 Hz,
=CH, 2H), 7.20 (d, J = 7.9 Hz, =CH, 2H), 7.13-7.07 (m, =CH, 4H), 6.55
(s, =CH, 2H), 2.34-2.31 (m, CH2, 4H), 1.72-1.67 (m, CH2, 4H), 1.57-
1.55 (m, CH2, 2H); 13C NMR (100 MHz, CDCl3): δ 144.1, 136.1, 128.5,
121.9, 120.4, 120.0, 111.0, 99.5, 41.0, 36.8, 26.2, 23.0; IR (KBr, cm–
1): 3039, 2968, 2928, 2109, 1509, 1464, 1451, 1305, 1228, 1163,
1122, 1084, 979, 908, 870, 811; Anal. Calcd. for C22H22N2: C, 84.04;
H, 7.05; N, 8.91, found: C, 84.06; H, 7.01; N, 8.87; TLC: Rf = 0.29
(EtOAc/hexane (15%), 254 nm).
.
2-Cyclohexyl-1H-indole (3a): Bi(NO3)3 5H2O (0.1 mmol)-catalyzed
reaction of 4,7-dihydro-1H-indole (1; 200 mg, 1.68 mmol) with
cyclohexanone (2a; 165 mg, 1.68 mmol) was performed at 80 oC for
5h in MeCN according to GP1. After purification, 2-cyclohexyl-1H-
indole (3a; 325 mg (97%), yellow viscous liquid) was obtained. 1H
NMR (400 MHz, CDCl3): δ 7.91 bs, NH, 1H), 7.53 (d, J = 7.7 Hz, =CH,
1H), 7.30 (d, J = 7.7 Hz, =CH, 1H), 7.13-7.04 (m, =CH, 2H), 6.23 (s,
=CH, 1H), 2.75-2.69 (m, CH, 1H), 2.10-2.07 (m, CH2, 2H), 1.87-1.74
(m, CH2, 2H), 1.54-1.29 (m, CH2, 6H); 13C NMR (100 MHz, CDCl3): δ
145.3, 135.7, 128.8, 121.1, 120.1, 119.8, 110.5, 97.7, 37.5, 29.9,
26.5, 26.3; IR (KBr, cm–1): 3335, 2921, 2871, 1624, 1452, 1431,
1397, 1356, 1163, 1122, 908, 858, 811; Anal. Calcd. for C14H17N: C,
84.37; H, 8.60; N, 7.03; found: C, 84.32; H, 8.10; N, 7.27; TLC: Rf =
0.72 (EtOAc/hexane (5%), 254 nm).
Acknowledgements
We are grateful to the Department of Chemistry and Atatürk
University and Bingöl University for financial support for this
work.
Notes and references
.
2-(1-(Thiophen-2-yl)ethyl)-1H-indole (3l): Bi(NO3)3 5H2O (0.1
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o
1
a pale red solid, m.p. = 65-66 C (CH2Cl2/hexane)) was obtained. H
NMR (400 MHz, CDCl3): δ): δ 7.82 (bs, NH, 1H), 7.57 (d, J = 7.7 Hz,
=CH, 1H), 7.27-7.26 (m, =CH, 1H), 7.25 (d, J = 1.1 Hz, =CH, 1H), 7.15-
7.06 (m, =CH, 2H), 6.98-6.96 (m, =CH, 1H), 6.91-6.90 (m, =CH, 1H),
6.41 (s, =CH, 1H), 4.59-4.54 (m, CH, 1H), 1.80 (d, J = 7.0 Hz, CH3, 3H);
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124.4, 124.3, 121.8, 120.5, 120.0, 110.8, 99.4, 34.8, 22.5; IR (KBr,
cm–1): 3082, 3028, 2972, 2839, 1605, 1479, 1452, 1384, 1332, 1309,
1256, 1232, 1184, 1023, 882, 824; Anal. Calcd. for C14H13NS: C,
73.97; H, 5.76; N, 6.16; S, 14.11, found: C, 73.88; H, 5.72; N, 6.24; S,
14.13; TLC: Rf = 0.52 (EtOAc/hexane (15%), 254 nm).
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General procedure (GP2) for the synthesis of 2,2'-
bis(indolyl)methanes: To a solution of 4,7-dihydro-1H-indole (1; 2.0
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R1
R2
N
H
(1 equiv.)
2-alkyl indoles
O
R1 = alkyl, aryl
R2 = alkyl, aryl
- H2O
[O]
R1
R2
N
H
R1 = alkyl, aryl
R2 = alkyl, aryl
R1
NH
R2
(2 equiv.)
HN
2,2'-bis(indolyl)methanes
R1 = alkyl
R2 = alkyl