Efficient, rapid, and solvent-free synthesis of substituted bis(indolyl)methanes using sulfated anatase titania as a solid acid catalyst

Article abstract of DOI:10.1080/15533174.2013.862710

A rapid and solvent-free green synthesis of bis(indolyl)methanes using sulfated anatase titania (TiO₂-SO4^2-) as solid acid catalyst under simple physical grinding has been developed. The advantage of this method is short reaction tim

Full text of DOI:10.1080/15533174.2013.862710

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Efficient, Rapid, and Solvent-Free Synthesis of
Substituted Bis(indolyl)methanes Using Sulfated
Anatase Titania as a Solid Acid Catalyst
K. Ravia, B. Krishnakumara & M. Swaminathana
a Photocatalysis Laboratory, Department of Chemistry, Annamalai University,
Annamalainagar, Tamil Nadu, India
Accepted author version posted online: 09 Mar 2015.
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To cite this article: K. Ravi, B. Krishnakumar & M. Swaminathan (2015) Efficient, Rapid, and Solvent-Free Synthesis of
Substituted Bis(indolyl)methanes Using Sulfated Anatase Titania as a Solid Acid Catalyst, Synthesis and Reactivity in Inorganic,
Metal-Organic, and Nano-Metal Chemistry, 45:9, 1380-1386, DOI: 10.1080/15533174.2013.862710
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Synthesis and Reactivity in Inorganic, Metal-Organic, and Nano-Metal Chemistry (2015) 45, 1380–1386
Copyright © Taylor & Francis Group, LLC
ISSN: 1553-3174 print / 1553-3182 online
DOI: 10.1080/15533174.2013.862710
Efficient, Rapid, and Solvent-Free Synthesis of Substituted Bis
(indolyl)methanes Using Sulfated Anatase Titania as a Solid
Acid Catalyst
K. RAVI, B. KRISHNAKUMAR, and M. SWAMINATHAN
Photocatalysis Laboratory, Department of Chemistry, Annamalai University, Annamalainagar, Tamil Nadu, India
Received 21 September 2013; accepted 10 October 2013
A rapid and solvent-free green synthesis of bis(indolyl)methanes using sulfated anatase titania (TiO2-SO42¡) as solid acid catalyst
under simple physical grinding has been developed. The advantage of this method is short reaction time with excellent yield and
safety, inexpensive cost, and use of easily recyclable nanocatalytic material. Higher activity of sulfated titania over TiO2 is found to
be due to its increased Brønsted acidity.
Keywords: bis(indolyl)methanes, simple physical grinding, TiO2-SO42¡, green synthesis, reusability
Introduction
considered as solid “super acids.” Super acidity of modified
[25]
€
metal oxides is attributed mainly to Bronsted acidity. Sig-
2¡
Bis(indolyl)methanes are potential candidates for screening nificant progress has been made in the use of TiO2-SO4 as
by the medicinal chemists owing to their widespread medici- solid acid catalyst in the synthesis of heterocyclic compounds
nal applications.[1–3] They have been isolated from plants and as this catalyst is found to be highly cost effective, recover-
marine sources.[4–7] Due to their vast biological activity asso- able and reusable at room temperature when compared to
ciated with medicinal application[8,9] there exists a continuing other catalysts.[26] In addition, TiO2-SO42¡ is easier to handle
interest for a synthetic method using milder, selective, non- than sulfuric acid and can be separated easily from the reac-
hazardous, inexpensive, recyclable, and eco-friendly catalyst. tion mixture by simple filtration. It has also been reported
Various methods for synthesis of bis(indolyl)methanes have that sulfate loading of TiO2 using sulfuric acid increases
[27]
€
been reported using acid catalysts in the electrophilic substi- Bronsted acidic sites much more than its Lewis acidic sites.
tution of indoles with various aldehydes.[10–13] Other catalysts In continuation of our interest in exploring novel synthetic
like Ln(OTf)3,[11] LiClO4,[12] In(OTf)3,[14] Dy(OTf)3,[15] methods for green chemical synthesis,[26,28–30] of various het-
InCl3,[16]
InF3,[17]
EAN,[18]
SBA-15/SO3H,[19] erocyclics using solid acid catalysts, we herein report a sim-
CuBF4cSiO2, Ph-PMO-SO3H,[21] H6P2W18O62,[22] [Bmim] ple, rapid, and efficient method for synthesizing bis(indolyl)
[20]
_
BF4, [bmim]PF6,[23] [acmim]Cl, and [hmim]HSO4
have methanes under ambient and solvent free conditions
[24]
also been reported for the synthesis of bis(indolyl)methanes. (Scheme 1).
However most of these methods have several disadvantages
such as the use of toxic metal ions, expensive solvents, longer
reaction times, tedious work up, low yield, higher catalyst
quantity, and the formation of waste. Additionally the main
drawback of most of the existing methods is that the catalysts
decompose during the aqueous workup and their recovery is
often impossible. Anatase titania and their modified forms
have gained increasing interest because of their enhanced
activity in typically acid catalyzed reactions and they are
Experimental
Indole, benzaldehyde, substituted benzaldehyde, other aro-
matic aldehydes, ethylacetate (laboratory grade), and Ana-
laR grade titanium isopropoxide (Himedia 98.0%), 2-
propanol (Spectrochem 99.5%) were used as received. The
2¡
sulfated titania TiO2-SO4 was prepared according to the
procedure reported from our laboratory by sol-gel method
and the results of characterization by FT-IR, XRD, SEM,
EDS, HR-TEM, AFM, and BET surface area measurements
were discussed in our earlier papers.[26,29,30] All products
were characterized by GC-MS analysis (see supplementary
data, Figures S1–18) and some selected products were charac-
terized by 1H and 13C NMR spectra.
Address correspondence to Dr. M. Swaminathan, Department
of Chemistry, Annamalai University, Annamalainagar 608 002,
India. E-mail: chemres50@gmail.com
Color versions of one or more of the figures in the article can be
found online at www.tandfonline.com/lsrt.

Solvent-Free Synthesis of Bis(indolyl)methanes
1381
Sch. 1. TiO2-SO42¡ catalyzed synthesis of bis(indolyl)methanes.
Typical Procedure for the Preparation of 3,30-
(phenylmethylene)bis(1H-indole), 3a
(t, 2H), 6.66 (s, 2H), 5.89 (s, 1H, Ar–CH); 13C NMR
(100 MHz, CDCl3): d 144.0, 136.7, 128.3, 127.1, 126.2,
124.1, 123.6, 122.0, 120.8, 119.8, 119.3, 111.0, 40.2; GC-
MS (m/z): 322 (MC).
A mixture of 1 mmol of benzaldehyde and 2 mmol of indole
with 100 mg of TiO2-SO42¡ were mixed and ground in a pes-
tle and mortar at room temperature. The progress of the reac-
tion was monitored by TLC. After completion of the
reaction, ethyl acetate was added to the mixture and agitated.
The catalyst was filtered off and washed with ethylacetate
and the washings were combined. The combined organic
extracts were dried over anhydrous sodium sulfate and con-
centrated under vacuum. Product was obtained as thick vis-
cous oil, which on standing solidified as pink solid. The
3,30-(2-Chlorophenylmethylene)bis(1H-indole), 3c. Pink solid;
1H NMR (400 MHz, CDCl3): d 7.92 (bs, 2H, NH), 7.35–
7.43 (m, 4H), 7.08–7.23 (m, 6H), 6.99–7.04 (t, 2H), 6.63 (s,
2H), 6.34 (s, 1H, Ar–CH); 13C NMR (100 MHz, CDCl3):
d 141.3, 136.7, 133.9, 130.4, 129.5, 127.5, 127.0, 126.7,
123.8, 122.1, 120.8, 119.9, 119.3, 118.4, 111.1, 36.7; GC-
MS (m/z) D 322 (MC).
3,30-(2-Methylphenylmethylene)bis(1H-indole),3n. Pink solid;
1H NMR (400 MHz, CDCl3): d 7.82 (bs, 2H, NH), 7.33–
7.39 (m, 4H), 7.10–7.24 (m, 6H), 6.98–7.05 (t, 2H), 6.53–
6.55 (s, 2H), 6.01 (s, 1H), 2.38 (s, 3H, CH3); 13C NMR
(100 MHz, CDCl3): d 142.08, 136.74, 136.10, 130.21,
128.42, 127.21, 126.11, 125.87, 124.17, 123.91, 122.02,
120.77, 119.83, 119.23, 111.07, 36.22, 19.59; GC-MS (m/
z): 336 (MC).
1
structure of product obtained was confirmed by H NMR,
13C NMR, and GC-MS analysis.
3,30-(Phenylmethylene)bis(1H-indole), 3a. Pink solid; 1H
NMR (400 MHz, CDCl3): d 7.92 (bs, 2H, NH), 7.34–7.41
(m, 6H), 7.28–7.29 (m, 2H), 7.21–7.22 (m, 3H), 6.98–7.02
2¡
Sch. 2. Plausible reaction mechanism for synthesis of bis(indolyl)methane using TiO2-SO4
.

1382
Ravi et al.
Results and Discussion
the Ti2p line in the case of pure TiO2 samples is observed
at 458.5 eV.[28] The BE peaks are shifted upward by the
Sulfated titania was characterized by FT-IR, XRD, SEM, presence of sulfate in the catalyst. The O1s (Figure 1c)
EDS, HR-TEM, AFM, and BET surface area measure- show two contributions at 530.4 and 532.2 eV. The main
ments and reported from our laboratory. XRD peaks peak at 530.4 eV could be ascribed to lattice oxygen in
exactly match with the anatase phase of TiO2, and sulfate TiO2, while the signal at 532.2 eV could be associated
2¡
modification does not change the phase. TiO2–SO4 has oxygen in sulfate. The binding energy peaks of the S2p
similar 2u values to TiO2 2b¡ut the peak intensities differ. (Figure 1d) are observed at 168.8 and 170.2 eV.
The FWHM of TiO2-SO4 peaks are higher than TiO2
The reaction between indole and benzaldehyde was car-
and this broadening of peaks implies the decrease in crys- ried out with different catalyst loading to determine the
talline size of TiO2. Both size reduction and retardation optimal conditions for the synthesis of bis(indolyl)meth-
of aggregation result in increase in surface area of the cat- anes. 2 mmol of indole and 1 mmol of benzaldehyde with
alyst. HR-TEM and AFM analyses reveal a globular 50 mg of sulfated titania catalyst under simple grinding
structure of the catalyst and a slight corrosion of TiO2 by resulted 90% product yield in 10 min. By increasing the
2¡
sulfate. TiO2–SO4 has a higher surface area (142.8 m2 catalyst loading to 100 mg/mmol of benzaldehyde, the
g
¡1) than bare TiO2 (86.0 m2 g¡1). The XPS survey spec- reaction was very quick with total conversion of benzalde-
trum of the TiO2-SO42¡, shown in Figure 1a, indicates the hyde giving 99% product in 3 min. However, increase in
peaks of elements Ti, O, and S. Binding energy peaks of the amount of catalyst beyond 100 mg/mmol of benzalde-
Ti2p occur at 458.6 and 463.6 eV (Figure 1b). Normally hyde did not result in any improvement in reaction yield
Fig. 1. X-Ray photoelectron spectra of TiO2-SO42¡: (a) survey spectrum, (b) Ti2p peak, (c) O1s peak, and (d) S2p peak.

Solvent-Free Synthesis of Bis(indolyl)methanes
1383
Table 1. Percentage yields of bis(indolyl)methanes from various aldehydes
Entry
1
Aldehyde
Product
Grinding time (min)
3
Yielda (%)
99
Observed mass – MC
322
2
3
4
3
3
3
90
90
80
356
356
402
5
6
7
8
3
3
3
3
80
80
60
60
402
402
448
448
(Continued on next page)

1384
Ravi et al.
Table 1. Percentage yields of bis(indolyl)methanes from various aldehydes (Continued)
Entry
Aldehyde
Product
Grinding time (min)
Yielda (%)
Observed mass – MC
9
2
92
82
367
432
10
30
6
6
83
60
372
372
11
12
13
5
4
2
2
99
99
99
99
312
336
352
14
15
16
352
(Continued on next page)

Solvent-Free Synthesis of Bis(indolyl)methanes
1385
Observed mass – MC
328
Table 1. Percentage yields of bis(indolyl)methanes from various aldehydes (Continued)
Entry
17
Aldehyde
Product
Grinding time (min)
Yielda (%)
99
5
18
30
36
338
Reaction conditions: Indole D 2 mmol, aldehyde D 1 mmol, TiO2-SO42¡ D 0.1 g, room temperature, grinding.
aYield are with respect to aldehyde.
and time. When reaction was carried out with bare TiO2 with intermediate c and deprotonation give bis(indolyl)
2¡
at room temperature under grinding for 30 min the yield methane product. Solid acid catalyst TiO2-SO4
pro-
was only 65%. No reaction occurred without catalyst. To motes protonation, dehydration, and deprotonation.
validate the scope of this method, this reaction was car-
Reusability of the catalyst was examined for five runs
ried out with various substituted aromatic aldehydes 1a– (Table 2). The catalyst was separated from the reaction
2¡
1r, indole 2, and TiO2-SO4 under the optimized condi- mixture by filtration and dried at 100ꢁC for 1 h. The per-
tions by simple grinding to produce corresponding bis centage of the recovered catalyst was more than 95% after
(indolyl)methanes 3a–3r (Table 1, entries 2–18). There is each run. This recovered catalyst was used for further
no significant change in yield with the electronic nature of runs. The yield of the product was more than 95% even at
the substituents as the yields are more than 90% with p- the fifth run. To show the advantage of this solid acid cat-
2¡
NO2 and p-OCH3 benzaldehyde (Table 1, entries 9 and alyst, a comparison of efficiency of TiO2-SO4 over other
15), but the size of the substituent has some effect on the catalysts reported for the synthesis of bis(indolyl)methanes
reaction time and yield. Thus chlorobenzaldehyde gave is given in Table 3. Other catalysts required longer reac-
2¡
higher yield than bromo- and iodobenzaldehydes (Table 1, tion time and gave lesser yield than the TiO2-SO4 cata-
entries 2–8). In case of 4-fluoro-3-phenoxybenzaldehyde lyst. When compared to bare TiO2 (65% yield in 30 min),
2¡
(Table 1, entry 10) the yield was 82% in 30 min grinding. the increase in yield with TiO2-SO4 (99% in 3 min) is
The longer reaction time is due to the steric effect of phe- many fold. It is reported that the Brønsted acidity of bare
2¡
noxy group. However there is a marked decrease in reac- TiO2 and 5 wt% TiO2-SO4
are 0.77 and 5.17, respec-
2¡
tivity with 4-hydroxybenzaldehyde (Table 1, entry 18). As tively.27 The increase in Brønsted acidity of TiO2-SO4 is
reported previously the catalytic activity of TiO2 is about 7 times more than bare TiO2. Hence the higher cat-
decreased by the strong interaction of surface OH groups alytic activity is due to increased Brønsted acidic sites in
of TiO2 with phenolic compounds (Ph–OH) to form a sulfated titania, which promote protonation of carbonyl
linkage of ꢀTi–O–Ph.31,32 3-Naphthaldehydes react slower groups, followed by dehydration and deprotonation in the
than benzaldehydes, which could be due to steric effect. synthesis of bis(indolyl)methanes.
Furan-2-aldehyde and thiophene-2-aldehyde gave good
yield.
A plausible mechanism is proposed in Scheme 2 for the
synthesis of bis(indolyl)methanes. This involves the fol-
Table 2. TiO2-SO42¡ catalyst recovery and reusability
lowing steps: (a) protonation of carbonyl group of alde-
hyde by acidic TiO2-SO4 producing intermediate a, (b)
Run
1
2
3
4
5
2¡
Yielda (%)
Catalyst recovery (%)
>99
>98
>99
>97
>97
>97
>95
>96
>95
>96
nucleophilic addition of indole molecule to electron defi-
cient carbonyl group of protonated aldehyde followed by
dehydration to give intermediate b, (c) intermediate b is
protonated by sulfated titania to form N-protonated inter-
Reaction conditions: Indole D 2 mmol, benzaldehyde D 1 mmol, TiO2-
SO42¡ D 0.1 g, room temperature, grinding.
mediate c, and (d) addition of another molecule of indole aYield based on benzaldehyde.

1386
Ravi et al.
Table 3. Efficiencies of various acid catalysts in the synthesis of bis(indolyl)methanes from benzaldehyde and indole
Entry
Reaction condition
Reaction time (min)
Catalyst
Yielda(%)
2¡
1
2
3
4
5
6
7
8
TiO2-SO42¡, RT, physical grinding
EAN, RT
3
3
5
60
10
90
15
60
TiO2-SO4
EAN
99 (present work)
93[18]
Microwave oven, 450 W
Dy(OTf)3/ionic liquid
[bmim][HSO4]
Dy(OTf)3
[BTBAC]Cl-FeCl3
93[24]
98[15]
FeCl3 based IL, 60 C, [BTBAC]Cl-FeCl3
98[33]
ꢁ
Ionic liquid, RT
Ionic liquid, RT
HY-zeolite/CH2Cl2
FeCl3c6H2O
98[34]
_
In(OTf)3
90[14]
HY-zeolite
85[35]
RT D Room temperature, EAN D ethylammonium nitrate, [bmim][HSO4] D 1-butyl-3-methylimidazolium hydrogen sulfate, Dy(OTf)3 D dysprosium(III) tri-
flate, [BTBAC]Cl-FeCl3 D benzyltributylammonium chloride-ferric chloride, In(OTf)3 D indium triflate, HY-zeolite D dealuminated zeolite from PQ corpora-
tion, USA.
aYield with respect to aldehyde.
Conclusions
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In this communication, we report a green and efficient TiO2-
SO4 catalyst for the synthesis of biologically and pharma-
2¡
cologically important bis(indolyl)methanes from indole and
various substituted benzaldehydes. The advantages of this
novel and practical method include shorter reaction time,
excellent product yield, solvent-free condition and simple
physical grinding with easy workup. Easy recovery and reus-
ability of this catalyst makes this as a green process. This
method will be very useful for the large-scale production of
bis(indolyl)methanes using commercially available grinding
equipments.
Funding
M. Swaminathan is thankful to CSIR, New Delhi, for finan-
cial support through research grant no. 21(0799)/10/EMR-
II.
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