Mono-6-deoxy-6-aminopropylamino-Β-cyclodextrin as a supramolecular catalyst for the synthesis of indolyl 1H-pyrrole via one-pot four component reaction in water

Article abstract of DOI:10.1016/j.catcom.2017.10.001

We report here the synthesis of mono-6-deoxy-6-aminopropylamino-β-cyclodextrin (Pr-β-CD) as a supramolecular organic base catalyst. Pr-β-CD was characterized by FT-IR, NMR, MALDI-TOF mass spectrometry and SEM analysis. Using this Pr-β-CD, biologically important indolyl 1H-pyrrole derivatives were synthesized with good to excellent yields in an aqueous medium via one-pot four-component reaction. Furthermore, the catalytic mechanism was elucidated in detail by using 2D NMR (ROESY), FE-SEM and FT-IR studies. The credit of the presented protocol includes the use of novel efficacious, reusable eco-friendly supramolecular carbohydrate catalyst, and precludes the use of organic solvents and column chromatography.

Full text of DOI:10.1016/j.catcom.2017.10.001

Accepted Manuscript
Mono-6-deoxy-6-aminopropylamino-β-cyclodextrin
as
a
supramolecular catalyst for the synthesis of indolyl 1H-pyrrole via
one-pot four component reaction in water
Vijay Vilas Shinde, Daham Jeong, Sang Woo Joo, Eunae Cho,
Seunho Jung
PII:
DOI:
Reference:
S1566-7367(17)30412-0
doi:10.1016/j.catcom.2017.10.001
CATCOM 5212
To appear in:
Catalysis Communications
Received date:
Accepted date:
30 August 2017
1 October 2017
Please cite this article as: Vijay Vilas Shinde, Daham Jeong, Sang Woo Joo, Eunae Cho,
Seunho Jung , Mono-6-deoxy-6-aminopropylamino-β-cyclodextrin as a supramolecular
catalyst for the synthesis of indolyl 1H-pyrrole via one-pot four component reaction in
water. The address for the corresponding author was captured as affiliation for all authors.
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ACCEPTED MANUSCRIPT
Mono-6-deoxy-6-aminopropylamino-β-cyclodextrin as a supramolecular
catalyst for the synthesis of Indolyl 1H- pyrrole via one-pot four component
reactionin water
Vijay Vilas Shindea, Daham Jeongb, Sang woo Joob, Eunae Choa and Seunho Junga,b*
aInstitute for Ubiquitous Information Technology and Applications (UBITA) & Center for Biotechnology
Research in UBITA (CBRU), Konkuk University, Seoul 143-701, South Korea.
bDepartment of Bioscience and Biotechnology, Microbial Carbohydrate Resource Bank(MCRB), Konkuk
University, Seoul 143-701, South Korea
Email: shjung@konkuk.ac.kr

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Abstract
We report here the synthesis of mono-6-deoxy-6-aminopropylamino-β-cyclodextrin (Pr-β-CD) as a
supramolecular organic base catalyst. Pr-β-CD was characterized by FT-IR, NMR, MALDI-TOF mass
spectrometry and SEM analysis. Using this Pr-β-CD, biologically important indolyl 1H-pyrrole
derivatives were synthesized with good to excellent yields in an aqueous medium via one-pot four-
component reaction. Furthermore, the catalytic mechanism was elucidated in detail by using 2D NMR
(ROESY), FE-SEM and FT-IR studies. The credit of the presented protocol includes the use of novel
efficacious, reusable eco-friendly supramolecular carbohydrate catalyst, and precludes the use of organic
solvents and column chromatography.
Keywords: mono-6-deoxy-6-aminopropylamino-β-cyclodextrin, supramolecular organic base catalyst,
indolyl 1H- pyrrol, one-pot synthesis.

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1. Introduction
A pyrrole possessing one nitrogen atoms in a five membered heterocyclic ring found in many natural
compounds such as vitamin B12, alkaloids1, chlorophyll, L-tryptophan2 , is an important pharmacophore
and shows various clinical properties such as anti-HIV3, antibacterial4 , antifungal5 and antioxidant6.
Another clinically important substructure is indole, which is widely used in material science7,
pharmaceutical research and agricultural chemicals8. A molecular scaffold both bioactive 3-substituted
indole and tetra substituted pyrrole may integrate the properties of both units in a single frame that may
lead to the formation of new molecules with promising biological profiles.
In view of such medicinal significance of these compounds, few methods have been reported to targeting
their individual synthesis as well as in combine form9. However, these methods suffer from drawbacks of
being carried out in multiple steps; prolonged reaction time, harsh reaction condition/reagent and non-
recoverable catalyst and solvent, use of silica gel for purification and generating a large number of
byproducts and low overall yield of the final product. Moreover, in our knowledge there are no single
reports on combined synthesis of 3-substituted of indole by poly substituted pyrrole. With an interesting
biological point of view on the indole and poly substituted pyrrole molecules, we scheme designing a
simple synthetic route to construct these scaffolds.
Among several approaches multicomponent domino reaction (MDRs) are an atom economical and
powerful tool in modern organic chemistry10. MDRs are processes in which more than three substrates are
combined in single pot and produce targeted molecule. This reaction system allowed different C-C or C-
hetero bonds formation during product generation11. Moreover, MDRs allow the green chemistry
principle in which they are more environmentally friendly, cost-effective, less time and material
consuming and generating less waste. In this concern, researcher focuses on avoiding the toxic solvent
and metal catalyst and use of ecofriendly solvent like water and biodegradable catalyst which can be
recycled.
Cyclodextrins are cyclic oligosaccharides composed of 6, 7 and 8 α-D-glucopyranose units forming a
macrocycle known as α-, β-, and γ-CD respectively, and are interconnected via α-(1→4) glycosidic
bonds12. Among the CDs, β-CD is commonly used in pharmaceutical13, chemical14, food15 and cosmetics16
due to its good availability, low toxicity, and easy biodegradability. Native β-CD has a truncated cone
shape with narrow and wide rim. Outer side of rim is hydrophilic and inner side cavity is hydrophobic. In
cavity of host (β-CD), guest molecule can form inclusion complex through noncovalent bond interaction
which helps to enhance the solubility of guest (drug) molecule in water17. Moreover, modified β-CD as a
catalyst have been used in organic transformations, such as carbon-carbon bond formations, asymmetric
synthesis18, condensations19, oxidation20, and also used as a ligand21. Recently, amino functionalized β-
CD and its metal complex were used as a catalyst in C-C bond formation reaction through cross-coupling

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and one-pot multicomponent reaction 22-24. However, they use organic solvent or co-catalyst metal, and it
takes long reaction time. Therefore, novel catalyst development for one-pot synthesis is still challengeable
from a sustainable chemistry viewpoint. Herein, we report on the preparation and characterization of
supramolecular catalyst mono-6-deoxy-6-aminopropylamino-β-cyclodextrin (Pr-β-CD). In addition, we
describe its utility in the efficient one-pot four-component synthesis of indolyl 1H- pyrrol scaffolds in
water (Table 2).
2. Experimental
2.1 Synthesis and characterization of mono-6-deoxy-6-aminopropylamino-β-cyclodextrin
(Pr-β-CD)
The catalyst mono-6-deoxy-6-aminopropylamino-β-cyclodextrin (Pr-β-CD) was prepared in two concise
steps which are depicted in Scheme 1.
Scheme 1. Synthesis of catalyst Pr-β-CD.
2.1.1 Mono-6-O-p-toluenesulfonyl-β-cyclodextrin (tosyl-β-CD)was prepared by adopting the
literature25
In a 1 L three-necked round-bottom flask, β-CD (10.0 g, 8.8 mmol) was dissolved in 250 mL of water by
heating it to 60 °C under vigorous stirring. After cooling to room temperature, finely powdered 1-(p-
toluenesulfonyl)imidazole (6 g, 27 mmol) was added to the suspension. After 6 h, a solution of
sodiumhydroxide (4.5 g, 112.5 mmol) in 12.5 mL of water was added over 20 min. After 10 min, the
unreacted 1-(p-toluenesulfonyl)imidazole was separated by filtration. Ammonium chloride (12.05 g, 225
mmol) was then added to the reaction mixture to quench the reaction. The resulting mixture was
concentrated by blowing a stream of air onto the surface overnight, after which the product precipitated
from the solution. The suspension was filtered, and the solid was washed with ice water and acetone
twice. The vacuum-dried tosyl β-CD was obtained at a 28.2% yield.

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2.1.2 Synthesis ofmono-6-deoxy-6-aminopropylamino-β-cyclodextrin (Pr-β-CD)
Tosyl β-CD (1.50 g, 1.17 mmol) was dissolved in propane-1,3-diamine (5 mL) under N2. The mixtures
were stirred at 50 °C for 12 h and the cooled the reaction to the room temperature. After cooling,
compound was precipitated by adding 200 mL of ethanol. This was done three times. The precipitated
crude product were purified by flash column chromatography using 70:20:10 (MeOH:H2O:NH4OH) as
eluent. Yield, 520 mg (55.7 %)
2.2 Characterization techniques
2.2.1 MALDI-TOF mass spectrometry
The synthesized Pr-β-CD was confirmed by MALDI-TOF mass spectrometry, which showed that the
pseudo-molecular ion peak of Pr-β-CD was detected at m/z 1191 (Fig.S1).
2.2.2 NMR (1H and 13C) spectroscopy
1
The H and 13C NMR spectrum was also used to confirm the synthesized Pr-β-CD. In Fig. S2, 1H NMR
spectrum, the H1 to H6 protons of the glucopyranose units are assigned at 5.07, 3.66, 3.85, 3.56, 3.97 and
3.86 ppm. The substituted ethylene protons of H7, H8 and H9 appeared at 2.92, 1.78 and 2.66 ppm.
Furthermore, the 2:7 integral ratios of the H9 protons to the H1 protons confirmed the propane-1,3-
diamine is monofunctionalized to the β-CD. 13C NMR chemical shifts of the Pr-β-CD, which is assigned
as C1-C6, 101.84, 72.09, 73.10, 81.15, 72.09 and 60.31. The substituted C7, C8 and C9 carbon appeared
at 38.10, 28.07 and 38.10 ppm, respectively. (Fig. S2)
2.2.3 FT-IR spectroscopy
The spectrum of Pr-β-CD contains the characteristic absorption band for the spectrum with O-H
stretching at 3388 cm-1, sp3 C-H stretching around 2928 cm-1 and C-O stretching around 1029 cm-1. The
N-H stretching vibrations were observed at 1640cm-1, and 1571 cm-1.(Fig. S3)
2.3. Catalytic activity of Pr-β-CD on the synthesis of indolyl 1H- pyrrole.
We have carried out a series of experiments to standardize the reaction conditions for the efficient
formation of indolyl 1H- pyrrole via one-pot, four-component reaction and results are presented in Table
1. In order to optimize the reaction conditions, we first investigated the reaction of phenylglyoxal
monohydrate (1a, 1 mmol), 5,5-dimethylcyclohexane-1,3-dione (2a, 1 mmol), indole (3a, 1 mmol) and

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ammonium acetate (4a, 1 mmol) at 60 °C without catalyst under solvent-free conditions in order to
recognize the capability of the catalyst. The reaction did not proceed even after prolonged reaction time
and no desired product was formed. When the reaction was performed in the presence of Pr-β-CD and
water as solvent at 80 °C, it proceeded effectively to produce the desired product (5a) in high yields.
Encouraged by this result, we attempted to optimize the reaction by screening the same set of reaction
with various organic bases such as ethylenediamine, propane-1,3-diamine, triethylamine, and piperidine,
and the results are summarized in Table 1. However, difficulties arose in the work-up procedure. After
cooling the reaction mixture, it gave a gummy material which stuck to the magnetic stir bar and
precipitation of the product was not occurred. Among all the screened catalysts, Pr-β-Cyclodextrin was
found the best in view of reaction time and product yield (Table 1, entry 6). Moreover, the optimal molar
loading of Pr-β-Cyclodextrin was determined by performing the model reaction using 0.5, 1.5, and 2
mol% of Pr-β-Cyclodextrin in water at 80 °C condition; 89, 87, and 89% yields, respectively, were
obtained. Increasing the amount of catalyst above 0.5 mol % had no more effect on the reaction. Then we
investigated the influence of various organic solvents at different reaction temperatures on the model
reaction with 0.5 mol % of Pr-β-Cyclodextrin. In the various solvents such as EtOH, EtOH:H2O (1:1),
DMSO and DMF, the reaction rate was relatively slow and resulted in lower product yields (Table 1,
entries 13-16). We also investigated different temperatures for the model reaction (Table 1, entries 17-
20). It was observed that fast reaction occurred on raising the temperature from room temperature to 60
°C and the yield of preferred product increased significantly. From all these establishments, we concluded
that 0.5 mol % of Pr-β-Cyclodextrin, at 60 °C in water as a solvent are optimized reaction condition
(Table 1, entry 19).
Table 1 Optimization of the reaction conditions for the synthesis of compound 5aa.
Entry Catalyst (mol%)
Solvent
Temperature Time Yieldb (%)
(°C)
(h)
1
-
-
60
14
-

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2
-
EtOH
H2O
EtOH
H2O
H2O
H2O
H2O
H2O
H2O
80
80
80
80
80
80
80
80
80
80
80
80
14
12
12
14
3
-
3
-
-
4
β-Cyclodextrin (1)
β-Cyclodextrin (1)
Pr-β-Cyclodextrin (1)
Ethylenediamine
Propane-1,3-diamine
Triethylamine
Piperidine
2
5
8
6
89
7
8
41
8
9
37
9
7
51
10
11
12
13
14
15
16
17
18
19c
20
8
18
Pr-β-Cyclodextrin (0.5, 1.5, 2) H2O
3
89, 87, 89
Et-β-Cyclodextrin (1)
Pr-β-Cyclodextrin (0.5)
Pr-β-Cyclodextrin (0.5)
Pr-β-Cyclodextrin (0.5)
Pr-β-Cyclodextrin (0.5)
Pr-β-Cyclodextrin (0.5)
Pr-β-Cyclodextrin (0.5)
Pr-β-Cyclodextrin (0.5)
Pr-β-Cyclodextrin (0.5)
H2O
5
78
EtOH
7
73
H2O:EtOH (1:1) 80
6
52
DMSO
DMF
H2O
80
80
Rt
40
60
90
7
73
6
79
NA
7
NA
H2O
72
H2O
3
89, 89, 88, 87, 87
89
H2O
3
aReaction conditions: Phenylglyoxal monohydrate (1a, 1 mmol), 5,5-dimethylcyclohexane-1,3-dione (2a,
1 mmol), indole (3a, 1 mmol) and ammonium acetate (4a, 1 mmol). b Isolated yield. cCatalyst was reused
five times.
With these optimized conditions in hand, we examined the scope of this MDR process by using various
easily available starting materials. As revealed in Table 2, the reaction resulted in corresponding desired
products in good to excellent yields. This transformation is easy to perform simply by subjecting a
mixture of phenylglyoxal monohydrate 1, various 1,3-dicarbonyl compounds 2, indoles 3, and ammonium
acetate or different aniline 4 in water at 60 °C with catalyst. As shown in Table 2 (entries 1−5), we
explored the indole 3 substrate scope, 5,5-dimethylcyclohexane-1,3-dione 2a, Phenylglyoxal
monohydrate 1 and ammonium acetate 4a were used as model substrates, with the results indicating the
tolerance of some functional groups on position five of the indole 3 including Br, CN, OH and position
two by phenyl. Further, we examined the generality of this system. Various 1,3-dicarbonyl compounds,
either as 1,3-diketones (Table 2, entries 10) or β-keto esters (Table 2, entries 11). Then we examined the

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substrate 4, we replace the ammonium acetate by different aniline (Table 2, entries 12-21). In all these
cases, the product yields were up to 81–97%.
a
Table 2 Synthesis of indolyl 1H- pyrrol derivatives
Entry
1,3-Dicarbonyl
Indole
NH4OAC/ Aniline
Product Time
(h)
Yieldb
(%)
89
96
87
84
86
95
97
90
87
95
81
97
90
96
91
97
96
93
94
92
90
1
2
3
4
5
6
7
8
Dimedone
Dimedone
Dimedone
Dimedone
1H-indole
NH4OAC
NH4OAC
NH4OAC
NH4OAC
NH4OAC
NH4OAC
NH4OAC
NH4OAC
NH4OAC
NH4OAC
NH4OAC
4-methoxyaniline
4-methoxyaniline
4-methoxyaniline
4-methoxyaniline
Aniline
3
2
3.5
4
2.5
2
5a
5b
5c
5d
5e
5f
5-bromo-1H-indole
1H-indole-5-carbonitrile
5-Hydroxyindole
2-phenyl-1H-indole
1H-indole
5-bromo-1H-indole
1H-indole-5-carbonitrile
5-Hydroxyindole
5-bromo-1H-indole
5-bromo-1H-indole
1H-indole
5-bromo-1H-indole
1H-indole
1H-indole-5-carbonitrile
1H-indole
1H-indole
1H-indole
Dimedone
1,3-Cyclohexanedione
1,3-Cyclohexanedione
1,3-Cyclohexanedione
1,3-Cyclohexanedione
2,4-Pentanedione
Ethyl acetoacetate
Dimedone
Dimedone
1,3-Cyclohexanedione
Dimedone
Dimedone
1,3-Cyclohexanedione
Dimedone
Dimedone
Dimedone
2
5g
5h
5i
3.5
3.5
3
9
10c
11c
12
13
14
15
16
17
18
19
20
21
5j
3.5
2.5
3
3
3.5
2
2.5
2
3.5
3
5k
5l
5m
5n
5o
5p
5q
5r
5s
5t
Aniline
Benzylamine
4-methoxyaniline
Benzylamine
Aniline
2-phenyl-1H-indole
5-bromo-1H-indole
5-bromo-1H-indole
Dimedone
3
5u
aReaction conditions: Phenylglyoxal monohydrate (1, 1 mmol), 1,3-Dicarbonyl (2, 1 mmol), Indole (3a, 1
b
mmol) and ammonium acetate/aniline (4, 1 mmol). Pr-β-CD (0.5 mol %), 4 mL Water, 60 °C. Isolated
yields and cpurified by column chromatography.
Furthermore, Pr-β-CD was recovered simply as precipitates from the aqueous layer by the addition of
ethanol (20 mL). The recovered catalyst was filtered, washed with ethanol (3 × 5 mL) and dried under
vacuum at 70 °C for 6 hours, after which it could be reused. The reusability of Pr-β-CD was tested in four

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further reaction cycles. The final cyclized product (Table 1, entry 19), was obtained in 89%, 88%, 87%
and 87% yields in successive cycles, thus proving the reusability of the catalyst.
The reaction mechanism is shown in scheme 2 (see supporting information). To further demonstrate the
role of the Pr-β-CD in the reaction, the inclusion complexation of the reactants and Pr-β-CD was
evaluated. The formation of inclusion complex of Pr-β-CD with phenylglyoxal monohydrate (PG) was
demonstrated by 2D ROESY NMR spectroscopy in Fig. 1.
Noticeable Nuclear Overhauser Effect (NOE) interactions between inner cavity protons (H3 & H5) of Pr-
β-CD and aromatic protons of phenylglyoxal monohydrate are observed in fig. 4. In addition, there is no
NOE correlation between H-1 proton of Pr-β-CD and Phenylglyoxal, as we know H1 proton is exterior
part of cavity of Pr-β-CD. Obtaining this result from 2D ROESY NMR could confirm the complex
formation of phenylglyoxal monohydrate inside the cavity of Pr-β-CD.
Fig. 1. 2D ROESY NMR spectrum of Pr-β-CD/Phenylglyoxal inclusion complex in D2O.
Furthermore, we investigated the vibrational changes upon the complexation using FT-IR spectroscopy26.
The FT-IR spectra of PG, Pr-β-CD, PG/Pr-β-CD physical mixture and PG/Pr-β-CD complex are shown in
Fig. 2. The blue line spectrum of PG contains the characteristic absorption band for the spectrum with O-

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H stretching at 3373 cm-1, C=O stretching also appeared at 1717 cm-1, and the two peaks observed at 1590
and 1427 cm-1 were assigned to aromatic ring of PG. Pr-β-CD showing characteristic absorption band for
O-H stretching at 3388 cm-1, sp3 C-H stretching around 2928 cm-1 and C-O stretching around 1029 cm-1.
The N-H stretching vibrations were observed at 1640cm−1 and 1571 cm−1. The FT-IR spectrum of the
physical mixture (Green line) contained absorption peaks with reduced intensity levels at a position
identical to that of the native PG, which indicates that the simple mixture of PG and Pr-β-CD does not
change the physical properties of PG. However, the characteristic absorption peaks at 1590 and 1427 cm-1
disappeared in the FT-IR spectra of the PG/Pr-β-CD complex, indicating that the environment of PG was
modified. These results suggest that the presence of intensive molecular interactions in the complex can
be attributed to the formation of hydrophobic interactions.
450
400
350
300
250
200
150
PG
Pr-β-CD
PM
100
50
0
COM
-50
3450
2450
1450
450
Wavenumber (cm-1)
Fig. 2. FT-IR spectra of Pr-β-CD, PG, PG/Pr-β-CD physical mixture and PG/Pr-β-CD complex.
Then we investigate the morphological studies of inclusion complex using Scanning electron microscopy
(SEM)27. The SEM images Pr-β-CD, PG, PG/Pr-β-CD physical mixture and PG /Pr-β-CD complex are
shown in fig.S4.(see supporting information) Pr-β-CD appeared as porous planar particles (Fig. S4 (a)).
PG showed the needle shaped particles (Fig. S4 (b)), and the physical mixture of PG/Pr-β-CD clearly
showed the surface morphologies of both PG and Pr-β-CD (Fig. S4 (c)). However, the PG/Pr-β-CD
complex in (Fig. S4 (d)) appeared as amorphous (pores disappear) particles that were totally different
from the sizes and shapes of both PG and PG/Pr-β-CD, which further confirmed the clear formation of the
complex.
3. Conclusion
In conclusion, we synthesized mono-6-deoxy-6-aminopropylamino-β-cyclodextrin as supramolecular
catalyst, can successfully function as novel catalysts for the synthesis of biologically active indolyl 1H-

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pyrrole via the one-pot reaction in an aqueous medium. The catalyst could be recycled easily without
significant loss of efficacy and with high recovery rate after 5 cycles. Moreover, the reaction mechanism
was elucidated extensively by spectroscopic analysis. This protocol retained excellences of simple
operations, environmentally benign conditions, a broad substrate scope, and high yields.
Supplementary data
All Compounds NMR spectra were provided as Supplementary data.
Acknowledgements
This study was supported by the KU Brain Pool Program of Konkuk University. It was also supported by
the Bio & Medical Technology Development Program of the NRF funded by the Korean government,
MSIP (2015M3A9B8031831), and Basic Science Research Program through the NRF funded by the
Ministry of Science, ICT, & Future Planning (NRF-2015R1C1A1A02037375). SDG.
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Graphical abstract

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Highlights

Mono-6-deoxy-6-aminopropylamino-β-cyclodextrin (Pr-β-CD) as a supramolecular organic base
catalyst were synthesized.
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Pr-β-CD catalyzed the synthesis of indolyl 1H-pyrrol derivatives.
Pr-β-CD as a catalyst can be easily recovered and reused.
Two C-C and C-N bond formed in one-pot reaction precluding the organic solvent.
Reaction mechanism was elucidated extensively by spectroscopic analysis.