Prolinium Triflate: A protic ionic liquid which acts as water-tolerant catalyst in the alkylation of indoles

Article abstract of DOI:10.1007/s13738-013-0239-z

Prolinium triflate (ProTf) was easily prepared by addition of triflic acid to an aqueous solution of l-proline. The latter is employed as a catalyst for the condensation of indoles with aldehydes or ketones in aqueous media to form a series of bisindolyl methanes in high yields.

Full text of DOI:10.1007/s13738-013-0239-z

J IRAN CHEM SOC
DOI 10.1007/s13738-013-0239-z
ORIGINAL PAPER
Prolinium Triflate: a protic ionic liquid which acts
as water-tolerant catalyst in the alkylation of indoles
Morteza Shiri
Received: 19 November 2012 / Accepted: 8 February 2013
Ó Iranian Chemical Society 2013
Abstract Prolinium triflate (ProTf) was easily prepared
by addition of triflic acid to an aqueous solution of L-pro-
line. The latter is employed as a catalyst for the conden-
sation of indoles with aldehydes or ketones in aqueous
media to form a series of bisindolyl methanes in high
yields.
also be employed as catalysts has been an important topic
in this field of research.
One of the best type of catalysts which act efficiently in
aqueous media is metal triflates.[Mx(CF3SO3)y] [7]. Few
ionic liquids with the triflate anion ([CF3SO3]-; OTf) are
known in literature [8]. For example recently Li et al. [9–11]
have investigated the catalytic activity of proline triflate.
Indoles and their derivatives are very important bio-
logical compounds that occur widely in natural products.
There are also many man made indolyl derivatives which
display interesting physiological activities and they have
found attractive applications in medicinal chemistry
[12–20]. Friedel–Crafts alkylation of indoles by employing
aldehydes or ketones is one of the methods of choice for
the synthesis of bisindolyl methanes (BIMs). Many
advances in the strategy of BIMs synthesis were published
as a result of the variation of the catalyst and due to new
synthetic methods [19, 20]. Herein we present prolinium
triflate as an ionic liquid which efficiently catalyze the
condensation of indoles with aldehydes or ketones in
aqueous media.
Keywords Indole ꢀ Condensation ꢀ Ionic liquid ꢀ
Alkylation ꢀ Prolinium triflate
Introduction
Ionic liquids (ILs) [salts with a low melting point (below
100 °C)] recently gained much attention and are mainly
used as solvents in organic reactions because of some
special advantages such as low vapor pressure, high ther-
mal and chemical stability or non-flammability [1–5].
Environmentally acceptable properties of ILs motivated
chemists to investigate their application in other fields such
as catalysis [6]. However, there are some limitations
associated with the use of ILs as catalysts. For instance,
low activities urge people to use more than the stoichi-
ometric amounts of ILs for achieving good efficiency in
organic reactions. This complication is potentially the
result of a lack of potential activation sites on the sub-
strates. Also in some cases ILs are sensitive to air and
moisture leading to the inactivation of the reaction if care is
not taken. Therefore the design of more active ILs that can
Experimental
Chemical materials were purchased from Merck Chemical
Company in high purity. Fourier transform infrared
(FT-IR) spectra were obtained using a Shimadzu FT-IR
8300 spectrophotometer. The NMR spectra were recorded
on a Bruker Avance 400 MHz spectrometer. High-resolu-
tion mass spectrometric data were obtained using a Bruker
micro TOF-Q II instrument operating at ambient temper-
atures. The progress of the reaction was monitored by TLC
and purification was achieved by silica gel column
chromatography.
M. Shiri (&)
Department of Chemistry, Faculty of Science, Alzahra
University, Vanak, 1993893973 Tehran, Iran
e-mail: mshiri@alzahra.ac.ir
123

J IRAN CHEM SOC
General procedure
H
CF3SO3
H
CO2
H
CO2
CF3SO3-
H2
N
N
H
Preparation of prolinium triflate (ProTf)
(ProTf)
Triflic acid (Tf) (1 mL, 10 mmol) was added with a syringe
to 10 mL aqueous solution of L-proline (10 mmol) at 0 °C,
while the solution was stirred. The resultant solution was
stirred for a further 30 min at room temperature. Water was
then removed under vacuum on a rotavap. Further removal
of water was achieved using a freeze dryer to obtain gave
2.61 g, 99 % ProTf as white glassy solid. Mp: 63–65 °C,
[a]2D0 -17.93 (c 8.45, MeOH).
Scheme 1 Synthesis of Prolinium Triflate
cat. (10 mol%)
CHO
solvent
+
N
r
t
H
HN
NH
1a
2a
3a
FT-IR (KBr): 3461, 3081, 1740, 1251, 1031, 640.
1H NMR (400 MHz, CD3OD): d = 1.94–2.04 (m, 3H);
2.31–2.34 (m, 1H); 3.21–3.30 (m, 2H); 4.25–4.29 (m, 1H).
13C NMR (100 MHz, CD3OD): d = 24.5, 29.2, 47.19,
60.76, 121.78, 171.4.
cat.
solvent Time (h) Yield (%)
L-proline
L-proline
ProTf(s)
ProTf(aq)
ProTf(aq)
CH3CN 24
0
H
24
24
5
0
2O
75
92
71
CH3CN
CH3CN
H
19F NMR (377 MHz, CD3OD): d = -80.1.
2O
24
Scheme 2 Optimisation of reaction conditions for the synthesis of
BIM 3a
Condensation of carbonyl compounds and indoles
acid was chosen as the acid source due to its regular and
efficient application in water tolerant catalytic synthesis.
After addition of triflic acid to the aqueous solution of
L-proline and subsequent removal of excess water an
amorphous solid was observed (Scheme 1). The solid
melted at 62–65 °C and showed optical rotation. FT-IR
showed a broad pick in 2,400–3,200 cm-1 reflected to acid
and also two picks at 3,461 and 1,740 cm-1 which refer to
To a stirring mixture of indoles (2.1 mmol) and aldehydes
or ketones (1 mmol) in CH3CN (2 mL), 0.1 mmol ProTf
(0.5 mL aqueous solution of ProTf (%5 w/w) was added.
After 5 h the reaction was quenched by adding water
(10 mL). The product was then extracted with EtOAc
(2 9 10 mL), and the extract dried with anhydrous
Na2SO4. The filtrate was evaporated and residue was
purified utilizing short column chromatography (EtOAc
and n-hexane as eluent.
N–H and C=O respectively. The peaks in 1H NMR and 13
C
NMR spectrometers were assigned to the corresponding
hydrogen and carbon atoms respectively. However ele-
mental analyses did not give satisfactory results due to the
highly hydroscopic property of the product.
Spectral data for selected compounds
3g FT-IR (KBr): 3,347 cm-1.1H NMR (400 MHz,
CDCl3): d = 3.67 (s, 3H); 3.87 (s, 3H); 6.35 (s, 1H), 6.79
(m, 2H), 6. 90 (m, 2H), 6.97 (m, 1H), 7.00 (m, 2H), 7.14
(m, 2H), 7.33 (m, 2H), 7.44 (m, 2H), 7.88 (s, br, 2H).13C
NMR (100 MHz, CDCl3): d = 55.7, 60.8, 65.8, 110.1,
110.9, 119.1, 119.6, 120.0, 121.7, 121.8, 123.5, 123.6,
127.1, 136.6, 138.0, 146.6, 152.6. HRMS calculated for
C25H22N2O2 [M ? H]? 382.1681, found 383.1896.
In continuation of our studies on indole chemistry
[18–25], the catalytic activity of the prepared prolinium
triflate (ProTf) was examined on the condensation reaction
of indole with benzaldehyde (Scheme 2). BIM 3a was
obtained in 75 % yield after 24 h in the presence of 10 %
ProTf in CH3CN. Surprisingly addition of some drop of
water to the reaction mixture dramatically increased yield
up to 92 % and reduced the reaction time to 5 h. The
possibility of performing the reaction in water as solvent in
the presence of ProTf was examined but the reaction was
not completed and after 24 h BIM 3a was produced in only
71 % yield (Scheme 1). For comparison the effectiveness
of ProTf was measured with respect to L-proline as the
3l FT-IR (KBr): 3361.1H NMR (400 MHz, CDCl3):
d = 2.11 (s, 6H), 3.71 (s, 3H), 5.91 (s, 1H), 6.81 (m, 2H),
6.86 (m, 2H), 7.11 (m, 2H), 7.38 (m, 2H), 7.71 (s, 2H).13C
NMR (100 MHz, CDCl3): d = 12.3, 38.4, 55.2, 109.9,
113.4, 113.7, 119.0, 119.3, 120.5, 128.9, 129.9, 131.7,
135.0, 135.8, 157.8.HRMS calculated for C26H24N2O
[M ? H]? 380.1889, found 381.1911.
catalyst. When the reaction was performed with -proline
L
as catalyst and with either CH3CN or in water as solvent,
the reaction did not yield any product under the same
conditions. Eventually the best results were gained by
using a mixture of acetonitrile and solution of ProTf in
water (‘‘Experimental section’’).
Results and discussion
Due to generation of labile hydrogen in the proposed ionic
liquid, proline was chosen as the nitrogen source and triflic
123

J IRAN CHEM SOC
Table 1 Condensation of
indoles and aldehydes in the
presence of ProTfa
Entry
Aldehydes
Indoles
Product
Isolated
Mp (°C)
(Found)
Mp (°C)[ref]
(Reported)
yield (%)
H
C
O
1
90
93
95
240-
243
244-246
[25]
N
H
HN
HN
HN
NH
NH
NH
3b
CHO
2
3
182-
184
183-185
[26]
N
H
c
3
e
M
O
CHO
211-
213
213-216
[26]
e
M O
e
OM
N
H
3d
r
B
CHO
4
5
r
B
r
B
88
0
215
-
208-210
[27]
N
H
HN
NH
e
3
H
C
O
-
N
H
NO2
O2N
NO2
HN
NH
3f
e
OM
e
e
OM
6
93
185-
187
-
e
M
O
CHO
N
H
OM
HN
N
H
3
g
CHO
7
8
85
93
248-
250
250-253
[27]
N
H
HN
NH
3h
CHO
e
OM
187-
189
186-188
[25]
N
H
e
M
O
HN
NH
3i
H
C
O
9
90
97-99
95-97
[25]
N
H
HN
NH
3
j
123

J IRAN CHEM SOC
Table 1 continued
Entry
Aldehydes
Indoles
Product
Isolated
Mp (°C)
(Found)
Mp (°C)[ref]
(Reported)
yield (%)
H
C
O
10
92
174-
176
175-177
[25]
N
H
HN
NH
3k
CHO
e
OM
11
91
191-
193
-
N
H
e
M
O
HN
NH
Cl
3l
Cl
12
13
88
73-75
72-74
74-76
[25]
CHO
N
H
HN
N
H
m
3
a
Reaction conditions:
78b
71-73
[25]
H
C
O
Aldehydes (1 mmol),
indoles (2.1 mmol), 0.5 mL
ProTf(aq) (0.1 mmol of
ProTf), CH3CN (2 mL), rt,
5 h
N
H
HN
N
H
n
3
b
12 h
In the next step, the general applicability of this con-
densation reaction was investigated (Table 1). It was
observed that benzaldehyde reacted with activated indoles
such as 2-methylindole, 5-methylindole and 5-methoxy-
lindole and also the deactivated 5-bromoindole to form
3b–3e in high yields (Table 1, entries 1–4). But the reaction
of benzaldehyde with 7-nitroindole failed (Table 1, entry
5). Condensation of 2,3-dimethoxybenzaldehyde, 1-naph-
thaldehyde, 4-methoxybenzaldehyde, 4-methyl-benzalde-
hyde and also 2-chlorobenzaldehyde with indole and
2-methylindole yielded corresponding triaryl methanes
3g–3m in 85–93 % yields (Table 1, entries 6–12).
3,30-(Heptane-1,1-diyl)bis(1H-indole) (3n) has been isolated
from the n-heptanal and indole in 78 % yield (Table 1,
entry 13).
Following a similar strategy, we next focused on the
synthesis of more complex BIMs. In the first synthetic
variant, isatin (4a) reacted easily with indole to form 5a in
90 % yield (Scheme 3) [29]. A similar satisfactory result
was obtained for the condensation of 4a with 2-methylin-
dole. In addition BIMs 5c and 5d were isolated from the
reaction of 1-methylisatin with the corresponding indoles
in 94 and 91 % yields (Scheme 3) [29].
The ProTf was recovered from the aqueous layer by
removal of water under reduced pressure and recycled
three times with almost no loss of activity for the synthesis
Scheme 3 Reaction of indoles
and isatines catalyzed with
ProTf
HN
O
ProTfaq
R2
(10 mol% cat.)
R2
+
O
NH
N
H
N
R1
rt, 5 h
CH3CN,
O
R2
N
R1
4a,b
2a,b
5
a
c
b
=
=
R1
R2
H
H
H
Me, H
Me
,
,
,
yield (%)
90, 89, 94
123

J IRAN CHEM SOC
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Conclusion
In summary, prolinium triflate has been purified and
characterized as an ionic liquid which catalyzes the con-
densation of indoles and aldehydes or ketones to form
triaryl methanes in high yields. Application of water to the
catalyst has improved the efficiency of the catalyst both in
terms of decreased reaction times and increased yields.
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Acknowledgments I thank the Iran National Science Foundation
(INSF) and Alzahra University for financial support. I also sincerely
thank professor H. G. Kruger from the Catalysis and Peptide Research
Unit, School of Health Sciences, UKZN, Durban, South Africa for
proof-reading the manuscript and for his valuable suggestions.
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