Catalytic efficiency of β-cyclodextrin hydrate-chemoselective reaction of indoles with aldehydes in aqueous medium

Article abstract of DOI:10.1016/j.tetlet.2020.152231

The catalytic efficiency of β-cyclodextrin hydrate has been investigated towards the eco-compatible synthesis of bis-(indolyl)methanes in aqueous medium by the chemoselective reaction of indoles with differently substituted aryl and alkyl aldehydes under

Full text of DOI:10.1016/j.tetlet.2020.152231

Journal Pre-proofs
Catalytic efficiency of β-cyclodextrin hydrate-chemoselective reaction of in‐
doles with aldehydes in aqueous medium
Asit Kumar Das, Nayim Sepay, Sneha Nandy, Avishek Ghatak, Sanjay Bhar
PII:
S0040-4039(20)30698-5
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.152231
TETL 152231
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
6 May 2020
3 July 2020
8 July 2020
Please cite this article as: Das, A.K., Sepay, N., Nandy, S., Ghatak, A., Bhar, S., Catalytic efficiency of β-
cyclodextrin hydrate-chemoselective reaction of indoles with aldehydes in aqueous medium, Tetrahedron Letters
(2020), doi: https://doi.org/10.1016/j.tetlet.2020.152231
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover
page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version
will undergo additional copyediting, typesetting and review before it is published in its final form, but we are
providing this version to give early visibility of the article. Please note that, during the production process, errors
may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2020 Elsevier Ltd. All rights reserved.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Catalytic Efficiency of β-cyclodextrin Hydrate-Chemoselective
Leave this area blank for abstract info.
Reaction of Indoles with Aldehydes in Aqueous Medium
Asit Kumar Das,a Nayim Sepay,b Sneha Nandy,b Avishek Ghatakc and
Sanjay Bhar b,*

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Catalytic Efficiency of β-cyclodextrin Hydrate-Chemoselective Reaction of
Indoles with Aldehydes in Aqueous Medium
Asit Kumar Das,a Nayim Sepay,b Sneha Nandy,b Avishek Ghatakc and Sanjay Bhar b,*
a
Department of Chemistry, Krishnath College, Berhampore, Murshidabad-742101, India
b
Department of Chemistry, Jadavpur University, Kolkata-700032, India
c
Department of Chemistry, Dr. A. P. J. Abdul Kalam Govt. College, New Town, Kolkata- 700156, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The catalytic efficiency of β-cyclodextrin hydrate has been investigated towards the eco-
compatible synthesis of bis-(indolyl)methanes in aqueous medium by the chemoselective
reaction of indoles with differently substituted aryl and alkyl aldehydes under mild reaction
conditions. The catalytic attributes of β-cyclodextrin hydrate were also demonstrated through
molecular docking and DFT studies. Reactions were slower in D2O than in H2O. Aryl and alkyl
ketones remained unaffected under the present condition. Excellent chemoselectivity has been
established through intermolecular as well as intramolecular competition experiments.
Calculation of Green Chemistry Metrices showed high atom economy and small E-factor for the
reaction.
Available online
Keywords:
Aldehydes
Catalysis
Chemoselectivity
Water
2009 Elsevier Ltd. All rights reserved.
ionic liquids,9h,9i and many others transition metal-free
Introduction
protocols9j-9q have been developed during the last few years.
Several homogeneous and heretogeneous systems, such as Fe,10a
Cu,10b Zn,10c Ag,10d Sc,10e Mo,10f Pd,10g Nb,10h Ni-Dy complex,10i
and Dy(OTf)3-ILs,10j were also reported for the similar
transformations. Even though these reported protocols are
satisfactory, but they also suffer from certain disadvantages such
as high temperature,9a,10g long reaction time,9p,9q,10c,10g,10i,10j harsh
reaction condition,10g use of expensive metal catalysts,10e-10j
limitation in gram scale production,9a,10a,10d,10h,10i,10j insufficient
Cyclodextrins (CDs) are
a
family of macrocyclic
oligosaccharides linked together by α-1,4 glucopyranose subunits
and produced enzymatically from starch. β-Cyclodextrin (β-CD)
consists of seven D-glucopyranose units forming a cyclic, hollow
cone-shaped cavity and possessing hydrophilic exterior due to
upper and lower rims decorated with hydroxyl groups as well as
hydrophobic internal pocket that embrace substrates selectively1
through inclusion complexes. But, β-Cyclodextrin hydrate (β-
CDH) contains exchangeable hydrogen atoms2 associated with
protonic conductivity which is similar to that of hydrated
proteins. The water molecules are present inside and outside of β-
CD hydrate (β-CDH) provides an efficient path for the extended
movement of protons which is also responsible for the protonic
conductivity via a concerted and co-operative translocation of
protons through the so-called flip-flop hydrogen bond.3 The
catalytic applications4 of CDs for the synthesis of biologically
important compounds have been reported. But surprisingly the
catalytic attributes of β-cyclodextrin hydrate, which behaves
differently from β-cyclodextrin, have not been explored much
after the maiden report from our group.5
Friedel-Crafts reaction is one of the cornerstone reactions for
fundamental carbon-carbon (C-C) bond formation and
construction of important classes of building blocks.6 Bis-
(indolyl)methanes (BIMs) are prominent and privileged structural
motif in bioactive metabolites as well as compounds of both
terrestrial and marine origin.7 A broad range of biologically and
pharmacologically active compounds, such as anticancer,8a
antitumor,8b antifungal,8c and HIV-1 integrase inhibitor8d also
carry this structural unit. Therefore, various synthetic strategies
such as solid acids,9a,9b Lewis acids,9c,9d,9e,9f hetero-polyacids,9g
recovery
of
catalyst,10b,10d,10e,10g,10i
lack
of
chemoselectivity,9a,9h,9m,9n,10a,10d,10f,10j,10k and involvement of
organic solvents9e,9g,10b,10d,10e,10g,10k having poor scope to recover
and recycle. Therefore, an operationally simple, catalytically
efficient, and eco-compatible protocol for the chemoselective
synthesis of bis-(indolyl)methanes through the three component
reaction11 involving indoles12 is of great demand from the
standpoint of sustainability. The use of β-cyclodextrin hydrate (β-
CD hydrate) as a mildly acidic, efficient and recyclable catalyst
during an organic reaction in aqueous medium has been reported5
for the first time from our group. In continuation of our
investigations in this direction we report herein the synthesis of
bis-(indolyl)methanes using β-CD hydrate as an eco-friendly
catalyst through chemoselective Friedel-Crafts alkylation of
substituted indoles with differently substituted aromatic and
aliphatic aldehydes in aqueous medium where the assistive role
of water molecules present inside the cavity of β-CD hydrate was
established.
Results and Discussion:
We initiated our experiments by investigating the Friedel-
Crafts alkylation reaction between 2-methylindole 1a (1 mmol)
with 4-methoxybenzaldehyde 2a (0.5 mmol) in water at 60oC in
the presence of different catalysts with the variation of reaction

Corresponding author. Tel.: +918697179547; fax: +91-33-
24137902; e-mail: sanjay.bhar@jadavpuruniversity.in

2
Tetrahedron Letters
time and catalyst loading to obtain the corresponding bis-
(indolyl)methanes 3a (Table 1).
It was observed that the reactions were faster in the presence
of β-CD hydrate in H2O as well as in D2O compared to β-CD.
Furthermore, the progress of the reaction was monitored at
different time intervals using β-CD and β-CD hydrate separately
as catalyst under the optimized reaction condition using H2O as
well as D2O as the reaction medium (Figure 1). It was evident
from Figure 1 that the reactions in H2O were faster than in D2O
and better conversion was achieved in the former case. Hence,
the isotope effect rendered by the reaction medium has been
observed. The extent of conversion using β-CD as catalyst in
H2O was moderate. Hence the essentiality of water molecules
inside the cavity of β-CD hydrate was conclusively proved.
Table 1 Optimization of reaction conditionsa
Entry
Catalyst
Mole
(%)
Time
(h)
Yield of 3a
(%)b
1
2
- -
- -
2
10
3
- -
52
β-CD
3
β-CD
6
6
61
4
β-CD
8
6
68
5
β-CD hydrate
β-CD hydrate
β-CD hydrate
β-CD hydrate
α- CD
2c
4c
6c
8c
10
10
6
6
80
6
3
92
7
5
92
8
3
93
Figure 1 Plot of the percentage conversion of 3a with time using 1a (1.0
mmol), 2a (0.5 mmol) and catalyst (4 mol %) at 600C in solvent (3 mL); (a)
β-CD hydrate in H2O; (b) β-CD in H2O; (c) β-CD hydrate in D2O.
9
10
10
8
25
10
11
12
γ-CD
20
β- CD hydrate bears negligible toxicity as evident from its
MSDS.14 This is sparingly soluble in water under ambient
condition but becomes completely miscible in aqueous reaction
medium at the reaction temperature (60oC). Thus it offers the
advantages of homogeneous catalysts during the reaction as well
as the benefits of heterogeneous catalysts during isolation of the
products and separation of the catalyst. After the completion of
the reaction, the reaction mixture was cooled in ice-water and
crude product was dissolved in ethyl acetate. The precipitated
catalyst was separated by filtration, washed with ethyl acetate,
dried and reused directly in a fresh reaction with a little variation
of yield (Figure 2). The reactions took place in aqueous condition
and did not require inert environment and any organic co-solvent
as the reaction medium. It utilizes ethyl acetate as an eco-friendly
solvent for the isolation of the product. Moreover, the reactions
are highly atom-efficient and generate water as the sole and
innocuous side-product. Therefore, this novel β-CD hydrate
catalyzed metal-free Friedel-Crafts alkylation reaction in aqueous
medium seems to be eco-compatible in terms of reaction
medium, operational simplicity, and recyclability of catalysts and
solvents of insignificant toxicity. The green metrics calculated for
the optimized reaction (between 1a and 2a) show high atom
economy and small E-factor (See the Supplementary Materials).
So this metal-free catalytic protocol in aqueous medium is
proved to be highly sustainable from the standpoints of efficacy,
less toxicity, economical viability, recyclability of the catalyst as
well as minimized waste formation.
18-crown-6
Starch
Trace
--
6
8
aReaction conditions: 1a (1.0 mmol), 2a (0.5 mmol), catalyst (as indicated),
water (3mL) at 60oC. bIsolated yield. cBased on the molecular formula
C42H70O35·11H2O 13
As shown in Table 1, the reaction did not occur at all in the
absence of any catalyst (Entry 1), the unreacted substrates were
isolated intact. The reaction was less responsive in presence α-
CD (Entry 9), γ-CD (Entry 10) and 18-crown-6 (Entry 11). With
β-CD, 3a was obtained with moderate yield (entries 2-4).
Surprisingly, when β-CD hydrate was used as a catalyst in lesser
amount (2 mol %) the yield of the reaction was significantly
increased to 80% (entry 5) but no reaction took place in the
absence of β-CD hydrate even at higher temperature (80°C).
Therefore, the necessity, efficacy and applicability of β-CD
hydrate for this organic transformation were firmly established.
Looking for an improvement in yield, the amount of catalyst was
increased. Best result was obtained using 4 mol % of β-CD
hydrate where the yield was increased to 92% in lesser time
(entry 6). Excess catalyst beyond this proportion (4 mol %) did
not afford to better substrate conversion and increment of the
yield (entries 7, 8). Hence the optimized condition for further
studies has been chosen according to entry 6. Using starch as the
catalyst in place of β-cyclodextrin hydrate, the reaction did not
occur at all and the unreacted substrates were isolated intact
(entry 12). The greater catalytic efficacy of β-CD hydrate in the
present metal-free reaction in aqueous medium (entries 5-8)
compared to β-CD (entries 2-4) is at par with our previous
experience.5 To further establish the efficacy of β-CD hydrate,
we next carried out a comparative study between β-CD and β-CD
hydrate using 1a (1 mmol) and 2a (0.5 mmol) in presence of H2O
and D2O at 60oC (Table 2).
Table 2 Comparative study between β-CD and β-CD hydratea
Entry
Catalyst
Solvent
(3 mL)
H2O
D2O
H2O
Mole
(%)
4
4
Time
(h)
3
3
Conver-
sion(%)b
67
28
100
1
2
3
β-CD
β-CD
β-CD
4
3
Figure 2 Recycling of β-CD hydrate using 1a (1.0 mmol), 2a (0.5 mmol) and
β–CD hydrate (4 mol %) as catalyst at 600C for 3 hours in water (3 mL); % of
yield was the isolated yield of 3a.
hydrate
β-CD
hydrate
4
D2O
4
3
62
aReaction conditions: 1a (1.0 mmol), 2a (0.5 mmol), temperature 60oC.
The molecular docking study (Figure 3) revealed that the
presence of water molecules inside the cavity of β-CD hydrate
(β-CDH) might facilitate the inclusion of the benzaldehyde more
bMeasured by 1H NMR.

3
effectively through hydrogen bonding than simple β-CD due to
different interaction of benzaldehyde with β-CDH and β-CD with
a preferred orientation of the ligands inside the cavity. The
docked pose of benzaldehyde was more included within the
cavity of β-CDH than β-CD. The –CHO group of benzaldehyde
formed one hydrogen bond (1.78 Å) with the water molecules
present within the cavity of β-CDH (Figure 3b) whereas the same
formed two hydrogen bonds (2.17 Å and 2.86 Å) with the -
CH2OH group of β-CD located near the wider side (secondary
hydroxy rim) (Figure 3a). However, the binding modes of 2-
methylindole with β-CD and β-CDH seem to be nearly similar
(Figures 3c and 3d). The hydrogen bonding interaction of
benzaldehyde with the water molecules inside the β-CDH cavity
(which are also believed to possess more protic behavior due to
flip-flop movement) might increase the electrophilicity of the
formyl
carbon; therefore the nucleophilic attack of 2-
methylindole on benzaldehyde seems to be facilitated. The
docked pose of corresponding bis-(indolyl)methane was more
excluded through one hydrogen bonding interaction (2.86 Å) in
the β-CDH whereas it was slightly included inside the cavity of
β-CD (Figures 3e and 3f).
Figure 4 (a) Optimized structures of benzaldehyde with and without
hydrogen bonded water and (b) The frontier orbital energy level of HOMO
and LUMO of 2-methylindole and benzaldehyde with as well as without
hydrogen bonded water.
In order to explore the scope and limitations of this meal-free
eco-friendly protocol, indoles 1 were reacted with structurally
varied aldehydes 2 in aqueous medium in the presence of β-CD
hydrate as a catalyst (Table 3). As evident from Table 3, 2-
methylindole (1a) reacted efficiently with the benzaldehyde as
well as other aryl aldehydes bearing electron donating
substituents (2a-2e) and electron withdrawing substituents (2f-2i)
to give the corresponding bis-indolylmethanes with excellent
yield (3a-3i). Reaction between 1a and less electrophilic aromatic
aldehyde (2e) under the optimized condition is known as the
Ehrlich test.15
Table 3 β-CD hydrate catalysed reactions of indoles with
aldehydes
Figure 3 Docking poses showing the interaction sites of a) benzaldehyde
with β-CD, b) benzaldehyde with β-CD hydrate, c) 2-methylindole with β-
CD, d) 2-methylindole with β-CD hydrate, e) bis-(indolyl)methane with β-
CD, f) bis-(indolyl)methane with β-CD hydrate.
We tried to get a deeper insight about the beneficiary effect of
water molecules present inside the cavity of β-CD hydrate
towards this aqueous reaction using density functional theory
(DFT). The structures of 2-methylindole as well as benzaldehyde
with hydrogen bonded water at a distance of 1.78 Å (Figure 3b)
and without hydrogen bonding (Figure 3a) were optimized
(Figure 4). The result shows that the hydrogen bonding between
carbonyl oxygen and water increases the positive Mulliken
charge on the carbonyl carbon (Figure 4a, ii). Thus, due to
hydrogen bonding with the water molecule inside the cavity of β-
CD hydrate, the electrophilicity of carbonyl carbon of
benzaldehyde is increased accompanied with the greater
stabilization of its HOMO and LUMO (Figure 4b). Under
hydrogen bonded condition, HOMO and LUMO of benzaldehyde
are stabilized by 0.24 eV and 0.29 eV respectively (Figure 4b).
Therefore, the nucleophilic attack by 2-methylindole through its
high energy HOMO to the low energy LUMO of hydrogen
bonded benzaldehyde is more facilitated with respect to
benzaldehyde devoid of hydrogen bonding (Figure 4b, shown
with the dotted line). Calculations also indicate that the orbital
coefficients of frontier molecular orbitals are enhanced due to
hydrogen bonding on the carbonyl carbon atom of (ii) over (i)
and its LUMO of same symmetry with the HOMO of C2-C3 bond
in 2-methylindole (Figure 4b). These observed results provide a
supportive rationale towards the better catalytic attributes of β-
CD hydrate compared to β-CD for the present reaction.
Reaction conditions: 1 (1.0 mmol), 2 (0.5 mmol), β CD hydrate (4 mol%),
water (3 mL) at 60°C for indicated time.

4
Tetrahedron Letters
Similarly, unsubstituted indole (1b) was found equally efficient
A plausible mechanism for this β-CD hydrate catalyzed
aqueous reaction is depicted in Scheme 3. Based on the aforsaid
investigations (Figures 3b and 4a, ii), it is presumed that
nucleophilic attack from higher energy HOMO of 2-methylindole
to lower energy LUMO of benzaldehyde (due to its hydrogen
bonding with the water molecules inside the cavity of β-CD
hydrate) is enhanced and the intermediate (A) was rapidly formed
in the first step. Subsequent dehydration of the intermediate (A)
forms the corresponding 3-arylidene-3H-indole (B), which on
further nucleophilic attack by another 2-methylindole affords the
to participate in the same protocol to yield the corresponding
products (3n-3s). Phenolic-OH groups remained unaffected
during this reaction and the reaction was very facile even with the
–OH group at the ortho-position (3p-3r). Acid-sensitive
heteroaryl moieties also survived during this reaction which
paved the way towards the efficient construction of important
molecular skeletons densely loaded with heterocycles (3j, 3k and
3t) in good yields. Hydrolysable group like methylenedioxy also
remained unaffected in the aqueous reaction medium to produce
3l in good yield. It is extremely important to note the remarkable
survival of another acid-sensitive hydrolysable functional group
–CN in this aqueous protocol, where the corresponding product
3h was obtained with 92% yield. The survival of -CN was
confirmed by the signal at δ119.4 (specific for –CN) in the 13C-
NMR spectrum of 3h. With terephthaldehyde (2i), the bis-
(indolyl)methane (3i) was obtained in high yield (90%) where
one –CHO participated in the reaction and the other –CHO
remained unaffected in spite of using higher concentration of 1a.
product.
Ph
O
NH
N
H
Ph
H
Me Me
Me
-CD hydrate
N

H
H
Ph

H
O
O

1
Me

A sharp singlet at δ9.96 in H NMR spectrum as well as a signal
Ph
H
N
at δ197.0 in 13C NMR spectrum confirmed the presence of one
formyl group in 3i. Such a regioselectivity was also observed in
3r. This is an extremely important attribute of the present
protocol in contrast to many reported methods where no such
regioselectivity was observed.10d,e Aliphatic aldehyde (2m) also
reacted quite efficiently in the present protocol with 1a to
produce 3m in 86% yield. Highly vulnerable groups like O-
benzyl and O-allyl were also tolerated under the optimized
reaction condition to furnish the products 3u and 3v in 87% and
86% yields respectively. The bis-(indolyl)methane (3q), obtained
B
H
H
O
Ph
Me
Me
N
N
H
A
Scheme 3 Plausible mechanism for the synthesis of bis-(indol-3-yl)-
methane catalysed by β-CD hydrate.
To demonstrate the practical utility and scalability of our
newly developed protocol, a gram scale reaction between 1a and
2a was carried out (Scheme 4). The reaction mixture was
extracted with EtOAc and the crude product 3a was further
purified by filtration chromatography on a short column of silica
gel using ethyl acetate-hexane as eluent.
in 89% yield through the reaction between
3,4-
dihydroxybenzaldehyde and 1b, has been reported to exhibit
excellent biological activity such as HIV-1 integrase inhibition.9e
Interestingly, aryl alkyl ketone, diaryl ketone and dialkyl
ketone (acetophenone, benzophenone and 2-butanone
respectively) as well as ester (methyl benzoate) did not react with
indole under this β-CD hydrate catalyzed aqueous protocol where
the substrates were recovered totally unaffected. Encouraged by
the above observations, we ventured to investigate the
chemoselectivity of our newly developed aqueous protocol.
Intermolecular competition reaction was carried out with a
mixture of 2-methylindole (1a), benzaldehyde (2d) and
acetophenone (2w) under the optimised reaction condition which
produced 3d (derived from benzaldehyde) exclusively and
acetophenone (2w) was recovered totally unaffected (Scheme 1).
Scheme 4 Gram-scale applicability of β-CD hydrate catalysed protocol.
The comparison of our present metal-free protocol with some of
the earlier reports is summarized in Table 4.
Table 4 Comparison of the catalytic efficiency of various
catalyst reported in the literature for the synthesis of 3,3'-(p-
tolylmethylene)bis(1H-indole)
Entry
Catalyst
--
Solvent
Time (h),
Temp(oC)
0.5h, U.S.,
RT
Yield
(%)
91
Ref.
9n
1
2
Ethyl lactate:
Scheme
1 Intermolecular competition experiment to demonstrate
H2O
--
chemoselectivity.
[DABCO-
H][HSO4]
2h, 90oC
79
9o
The aforesaid protocol was further applied to the
intramolecular competition experiment with 4-
3
4
5
6
7
α-chymotrypsin
H2O
H2O
24h, 70oC
36h, 55oC
12h, RT
4h, RT
90
95
86
72
89
9p
9q
Lipase enzyme
ZnO-RGO
acetylbenzaldehyde (2x) where only the formyl group reacted
selectively with 1a leading to the product 4 exclusively with 90%
yield leaving the ketomethyl moiety totally intact (Scheme 2).
This is a vital and additional attribute of the said protocol in
contrast to many of the earlier reports9a,9h,9m,9n,10a,10d,10f,10j,10k where
no such chemoselectivity was observed.
EtOH:H2O
CH3CN
H2O
10c
10k
TPPMS/CBr4
β-CD hydrate
3h, 60oC
This
work
Some of the studies listed in Table 4 (entries 1-6) involved the
use of costly catalyst,9p,9q,10c,10k multistep synthesis of catalyst,9o,
10c,10k
long reaction time,9p,9q,10c lack of chemoselectivity,9n,10k and
the tedious product isolation procedure9o for the synthesis of
BIMs. The present β-cyclodextrin hydrate-catalyzed metal-free
protocol in aqueous medium mostly does away with these
shortcomings (entry 7). Therefore, the present protocol seems to
have enough potential to be a better, economically viable, eco-
Scheme
2 Intramolecular competition experiment to demonstrate
chemoselectivity.

5
2016, 18, 2228-2231; (c) Bernt, C. M.; Bottari, G.; Barrett, J.
compatible and sustainable alternative with greater merits and
wider applicability compared to many of the earlier methods
reported for the construction of bis-(indolyl)methane framework.
A.; Scott, S. L.; Barta, K.; Ford, P. C. Catal. Sci. Technol. 2016,
6, 2984-2994; (d) Srivastava, A.; Agarwal, A.; Gupta, S. K.; Jain,
N. RSC Adv. 2016, 6, 23008-23011.
9. (a) Mendes, S. R.; Thurow, S.; Fortes, M. P.; Penteado, F.;
Lenardao, E. J.; Alves, D.; Perin, G.; Jacob, R. G. Tetrahedron
Lett. 2012, 53, 5402-5406; (b) Esmaielpour, M.; Akhlaghinia, B.;
Jahanshahi, R. J. Chem. Sci. 2017, 129, 313-328; (c) Shaikh, K.
A.; Mohammed, Z. A.; Patel, N. T.; Syed, S. A.; Patil, V. A. Res.
J. Pharm. Biol. Chem. Sci. 2010, 1, 730-736; (d) Sadaphal, S. A.;
Shelke, K. F.; Sonar, S. S.; Madje, B. R.; Shingare, M. S. Bulletin of
the Catalysis Scoeity of India, 2008, 7, 111-114; (e) Swetha, A.;
Babu, B. M.; Meshram, H. M. Tetrahedron Lett. 2015, 56, 1775-
1779; (f) Wu, Z.; Wang, G.; Yuan, S.; Wu, D.; Liu, W.; Ma, B.;
Bi, S.; Zhan, H.; Chen, X. Green Chem. 2019, 21, 3542-3546; (g)
Selvakumar, K.; Shanmugaprabha, T.; Annapoorani, R. Synth.
Commun. 2017, 47, 913-927; (h) Tran, P. H.; Nguyen, X. T. T.;
Chau, D. K. N. Asian J. Org. Chem. 2018, 7, 232-239; (i) Dabiri,
M.; Salehi, P.; Baghbanzadeh, M.; Shakouri, M.; Otokesh, S.;
Ekrami, T.; Doosti, R. J. Iran. Chem. Soc. 2007, 4, 393-401; (j)
Vaghei, R. G.; Veisi, H. J. Braz. Chem. Soc. 2010, 21, 193-201;
(k) Sujatha, K.; Perumal, P. T.; Muralidharan, D.; Rajendaran, M.
Indian. J. Chem. 2009, 48(B), 267-272; (l) Hasaninejad, A.;
Mohammadizadeh, M.R.; Babamiri, S. F. 2nd International
IUPAC Conference on Green Chemistry, Russia, 2008; 14-19; (m)
Patil, V. D.; Dere, G. B.; Rege, P. A.; Patil, J. J. Syn. Commun.,
2011, 41, 736-747; (n) Gao, G.; Han, Y.; Zhang, Z. H.
ChemistrySelect. 2017, 2, 11561-11564; (o) Xu, D. Z.; Tong, J.;
Yang, C. Synthesis, 2016, 48, 3559-3566; (p) Sun, D.; Jiang, G.;
Xie, Z.; Le, Z. Chin. J. Chem. 2015, 33, 409-412; (q) Fu, Y.; Lu,
Z.; Fang, K.; He, X.; Xu, H.; Hu, Y. RSC Adv., 2020, 10, 10848-
10853.
Conclusion
Catalytic efficiency of β-cyclodextrin hydrate has been
investigated towards the synthesis of bis-(indol-3-yl)-methanes
through the Friedel-Crafts alkylation reaction of indoles with
aryl, heteroaryl as well as alkyl aldehydes under mild reaction
condition. This newly developed atom-economical protocol
shows good chemoselectivity which has been substantiated
through intermolecular as well as intramolecular competition
experiments. Practical synthetic utility was also demonstrated by
gram scale applicability. The salient features of the present
method are procedural simplicity, excellent chemoselectivity,
tolerance of various sensitive moieties during the reaction, wide
substrate scope as well as eco-compatibility in terms of using
water as the most innocuous reaction medium, the ready
accessibility and recyclability of the catalyst of lower toxicity
compared to most of the existing ones and minimization of waste
formation owing to high atom economy and small E-factor.
Acknowledgments
Financial assistance from RUSA 2-Programme and UGC-CAS-II
programme in Chemistry at Jadavpur University are gratefully
acknowledged. S. N. Thanks DST, INSPIRE, New Delhi for
senior research fellowship. Thanks to Mr. N. Dutta of IACS and
Mr. R. Biswas of JU for necessary assistance.
10. (a) Li, D.; Wang, J.; Chen, F.; Jing, H. RSC Adv. 2017, 7, 4237-
4242; (b) Kothandapani, J.; Ganesan, A.; Vairaprakash, P.;
Ganesan, S. S. Tetrahedron Lett. 2015, 56, 2238-2242; (c)
Bahuguna, A.; Kumar, S.; Krishnan, V. ChemistrySelect. 2018, 3,
314-320; (d) Beltra, J.; Gimeno, M. C.; Herrera, R. P. Beilstein J.
Org. Chem. 2014, 10, 2206-2214; (e) Mohapatra, S. S.; Wilson, Z.
E.; Roy, S.; Ley, S. V. Tetrahedron, 2017, 73, 1812-1819; (f)
References and notes
1. Wang, Q.; Chen, Y.; Liu, Y. Polym, Chem-UK, 2013, 4, 4192.
2. Usha, M. G.; Wittebort, R. J. J. Mol. Biol. 1989, 208, 669-678.
3. Anagnostopoulou, A.; Apekis, L.; Tsoukaris, G. IEEE Trans.
Electrical Insulation, 1992, 27, 801.
Bahuguna, A.;
Kumar, S.; Sharma, V.; Reddy, K. L.;
Bhattacharyya, K.; Ravikumar, P. C.; Krishnan, V. ACS
Sustainable Chem. Eng. 2017, 5, 8551-8567; (g) Guo, S.; Fang,
Z.; Zhou, B.; Hua, J.; Dai, Z.; Yang, Z.; Liu, C.; He, W.; Guo, K.
Org. Chem. Front. 2019, 6, 627-631; (h) Mendes, S. R.; Thurow,
S.; Penteado, F.; Silva, M. S. da.; Gariani, R. A.; Perin, G.;
Lenardao, E. J. Green Chem. 2015, 17, 4334-4339; (i) Gorantla,
N. S.; Reddy, P. G.; Abdul Shakoor, S. M.; Mandal, R.; Roy, S.;
Mondal, K. C. ChemistrySelect. 2019, 4, 7722-7727; (j) Xueling,
M.; Sanzhong, L.; Jiaqi, H.; Cheng, J. P.; Tetrahedron Lett. 2004,
45, 4567-4570; (k) Huo, C.; Sun, C.; Wang, C.; Jia, X.; Chang, W.
ACS Sustainable Chem. Eng. 2013, 1, 549-553.
4. (a) Madhav, B.; Murthy, S. N.; Kumar, B. A.; Ramesh, K.;
Nageswar, Y. V. D.; Tetrahedron Lett. 2012, 53, 3835-3838; (b)
Noel, S.; Leger, B.; Ponchel, A.; Philippot, K.; Nowicki, A. D.;
Roucoux, A.; Monflier, E. Catal. Today. 2014, 235, 20-32; (c)
Hapiot, F.; Bricout, H.; Menuel, S.; Tilloy, S.; Monflier, E. Catal.
Sci. Technol. 2014, 4, 1899-1908; (d) Kumar, A.; Shukla, R. D.
Green Chem. 2015, 17, 848-851; (e) Shinde, V. V.; Jeong, D.; Joo,
S. W.; Cho, E.; Jung, S. Catal. Commun. 2018, 103, 83-87.
5. Ghatak, A.; Khan, S.; Bhar, S. Adv. Synth. Catal. 2016, 358, 435-
443.
11. (a) Rajeswaran, W. G.; Labroo, R. B.; Cohen, L. A. J. Org. Chem.
1999, 64, 1369-1371; (b) Yadav, J. S.; Subba Reddy, B. V.;
Yadav, N. N.; Gupta, M. K. Tetrahedron Lett. 2008, 49, 2815-
2819; (c) Srihari, P.; Singh, V. K.; Bhunia, D. C.; Yadav, J. S.
Tetrahedron Lett. 2009, 50, 3763-3766.
12. Fukuyama, T.; Chen, X.; Ge Peng. J. Am. Chem. Soc. 1994, 116,
3127-3128.
13. (a) Usha, M. G.; Wittebort, R. J. J. Am. Chem. Soc. 1992, 114,
1541-1548; (b) Sabadini, E.; Cosgrove, T.; Egidio, F. C.
Carbohydr. Res. 2006, 341, 270-274.
6. (a) Friedel, C.; Crafts, J. M. J. Chem. Soc. 1877, 32, 725-791; (b)
Okauchi, T.; Itonaga, M.; Minami, T.; Owa, T.; Kitoh, K.;
Yoshino, H. Org. Lett. 2000, 2, 1485-1487; (c) Ottoni, O.; Neder,
A. D. V. F.; Dias, A. K. B.; Ruz, R. P. A. C; Aquino, L. B. Org.
Lett. 2001, 3, 1005-1007; (d) Wynne, J. H.; Stalick, W. M. J. Org.
Chem. 2002, 67, 5850-5853; (e) Mertins, K.; Iovel, I.; Kischel, J.;
Zapf, A.; Beller, M. Angew. Chem., Int. Ed. 2004, 44, 238-242; (f)
Jia, Y. X.; Xie, J. H.; Duan, H. F.; Wang, L. X.; Lin Zhou, Q. Org.
Lett. 2006, 8, 1621-1624; (g) Wang, Y. Q.; Song, J.; Hong, R.;
Hongming, Li.; Li Deng. J. Am. Chem. Soc. 2006, 128, 8156-
8157; (h) Bandini, M.; Tragni, M. Org. Biomol. Chem. 2009, 7,
1501-1507; (i) Downey, C. W.; Poff, C. D.; Nizinski, A. N. J.
Org. Chem. 2015, 20, 10364-10369; (j) Deng, X. F.; Wang, Y.
W.; Zhang, S.; Li, L.; Li, G. X.; Zhao, G.; Tang, Z. Chem.
Commun., 2020, 56, 2499-2502.
14. https://www.nwmissouri.edu/naturalsciences/sds/b/Beta-
Cyclodextrin%20hydrate.pdf
15. (a) Ehrlich, P. Med. Woche. 1901, 151; (b) Seyedeh, F. H.;
Toktam, Z.; Zahra, N. Bull. Korean Chem. Soc. 2013, 34, 117.
7. Garbe, T. R.; Kobayashi, M.; Shimizu, N. J. Nat. Prod. 2000, 63,
596-598.
8. (a) Grosso, C.; Cardoso, A. L.; Lemos, A.; Varela, J.; Rodrigues,
M. J.; Custodio, L.; Barreira, L.; Melo, T. Eur. J. Med. Chem.
2015, 93, 9-15; (b) Li, D.; Wu, T.; Liang, K.; Xia, C. Org. Lett.
Supplementary Material General experimental procedure and
the characterization data of the final compounds are available as
supporting information.

6
Tetrahedron
HIGHLIGHTS
Catalytic Efficiency of β-cyclodextrin
Hydrate-Chemoselective Reaction of
Indoles with Aldehydes in Aqueous
Medium
Asit Kumar Das, Nayim Sepay, Sneha Nandy,
Avishek Ghatak and Sanjay Bhar *
 Metal-free aqueous phase catalysis with
high atom economy
 Tolerance of various sensitive moieties
under eco-compatible condition
 Recyclable, stable and sustainable catalytic
system
 Excellent chemoselectivity as well as gram
scale applicability
 Generation of water as the sole and
innocuous side-product

7
DECLARATION OF INTEREST
STATEMENT
Name of the Journal where submitted:
Tetrahedron Letters
Title of the paper: Catalytic Efficiency of
β-cyclodextrin
Hydrate-Chemoselective
Reaction of Indoles with Aldehydes in
Aqueous Medium
Authors: Asit Kumar Das, Nayim Sepay,
Sneha Nandy, Avishek Ghatak and Sanjay
Bhar*
“This is to declare that there is no conflict of
interest in this article.”
Sanjay Bhar
Corresponding author
Department of Chemistry, Jadavpur
University, India