Enzymatic approach to cascade synthesis of bis(indolyl)methanes in pure water

Article abstract of DOI:10.1039/c9ra10014h

A mild, efficient, and green protocol was developed for the synthesis of bis(indolyl)methanes catalyzed by lipase TLIM through the cascade reactions of indole with aldehydes in pure water. This methodology offers many superiorities such as excellent yields, wide substrate range, simple procedure, reusable and minimal amount of catalyst, and the ability to be scaled up.

Full text of DOI:10.1039/c9ra10014h

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Enzymatic approach to cascade synthesis of
bis(indolyl)methanes in pure water†
Cite this: RSC Adv., 2020, 10, 10848
*
*
Yajie Fu, Zeping Lu, Ke Fang, Xinyi He, Huajin Xu and Yi Hu
Received 29th November 2019
Accepted 10th March 2020
A mild, efficient, and green protocol was developed for the synthesis of bis(indolyl)methanes catalyzed by
lipase TLIM through the cascade reactions of indole with aldehydes in pure water. This methodology offers
many superiorities such as excellent yields, wide substrate range, simple procedure, reusable and minimal
amount of catalyst, and the ability to be scaled up.
DOI: 10.1039/c9ra10014h
rsc.li/rsc-advances
catalyze the cascade reactions of indole with aromatic alde-
hydes to synthesize bis(indolyl)methanes.20 Le et al.21 found
1. Introduction
that a-chymotrypsin in aqueous ethanol exhibited prominent
promiscuity for the synthesis of bis(indolyl)methanes.
However, both of them could only obtain low to moderate
yields for reactions of indole with aromatic aldehydes bearing
electron-donating substituents as well as aliphatic aldehydes,
and large amount of non-recyclable lipase was needed. In
continuation of our interest in lipase-catalyzed C–C bond
forming reactions,22 we herein report that cascade reactions of
indole with aromatic aldehydes can be catalyzed by lipase
TLIM in pure water to synthesize bis(indolyl)methanes
effectively.
Bis(indolyl)methanes make great contributions in the elds of
pharmacological industry and material science. They may act as
agonists of the immunostimulatory orphan G protein-coupled
receptor GPR84,1 as antagonists of Leishmania donovani pro-
mastigotes as well as axenic amastigotes,2 and also as probes for
monitoring the interactions of related molecules with transport
and response-mediating proteins.3 In addition, bis(indolyl)
methanes play a brilliant role in the treatment of prostate
cancer,4 colon cancer,5 pancreatic cancer6 and breast cancer.7
Bis(indolyl)methanes are generally obtained from cascade
reactions of indole with carbonyl compounds catalyzed by
protic or Lewis acids, which may be easily captured by nitrog-
enous compounds so as to bring some problems for the
synthesis of bis(indolyl)methanes.8 Recently, various novel
catalysts have been reported to synthesize bis(indolyl)meth-
anes, such as aza-crown ether ionic liquids supported on
magnetic Fe3O4@SiO2 core–shell particles,9 nanocomposites
ZrO2–Al2O3–Fe3O4,10 1-hexenesulphonic acid sodium salt under
ultrasound irradiation,11 SDS,12 zeolite,13 graphene oxide,14
AgOTf,15 LASSC catalytic system,16 meglumine catalyst,17
NADES,18 etc. However, there are some shortcomings in the
most of catalytic methods mentioned above including expen-
sive or complicated catalyst used, relative high temperature and
excessive substrate needed, volatile organic solvent employed,
etc. Therefore, it is meaningful to develop a green and efficient
method to synthesize bis(indolyl)methanes.
2. Materials and methods
2.1 Materials
Porcine pancreas lipase (PPL), Amano Lipase PS from Bur-
kholderia cepacia (BCL) and Candida rugosa lipase (CRL) were
purchased from Sigma. Lipase from Thermomyces lanuginosus
immobilized on particle silica gel (TLIM), lipase from Rhizomucor
miehei immobilized on anion exchange resin (RMIM), lipase B
from Candida antarctica immobilized on a macroporous acrylic
resin (Novozym 435) and papain were purchased from Novo
Nordisk. Bovine serum albumin (BSA) was purchased from
Shanghai Huixing. Other reagents were commercially available
and were used without further purication.
The application of lipase in C–C bond formation reaction is
attracting more and more attention due to its mild reaction
conditions, lack of coenzyme requirements and the ability to
work not only in aqueous systems but also in organic
solvents.19 PPL was employed in aqueous 1,4-dioxane to
2.2 Characterization
The melting points were determined on a WRS-1B digital
melting point instrument and were not corrected. The 1H NMR
and 13C NMR spectra were measured on a Bruker Advance 2B
300 MHz instrument with CDCl3 as solvent and TMS as internal
standard. The HRMS were measured on Agilent LC/MS mass
spectrometer. The progress of the reaction was monitored by
TLC using pre-coated Haiyang GF254 silica gel plates. HPLC
data was obtained using Dionex Liquid Chromatography (Dia-
monsil C18(2) (4.6 ꢀ 250 mm, 5 mm), water with 0.1% formic
State Key Laboratory of Materials-Oriented Chemical Engineering, School of
Pharmaceutical Sciences, Nanjing Tech University, Nanjing 210009, China. E-mail:
huyi@njtech.edu.cn; dg1224097@smail.nju.edu.cn
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c9ra10014h
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acid/methanol (v/v ¼ 1/4, 20 min, radiant elution), 40 ꢁC,
254 nm).
2.3 General procedure for the synthesis of bis(indolyl)
methanes
A mixture of indole (2 mmol), aldehyde (1 mmol) and lipase (10
ꢁ
mg) in pure water (5 mL) was stirred at 55 C. The progress of
the reaction was monitored by TLC (ethyl acetate–petroleum
ether, 1/2). Upon completion of the reaction, the reaction
mixture was ltered, and the residue achieved was then dis-
solved in 1,4-dioxane (10 mL) to separate the product and
lipase. By simple ltration, lipase was recovered and applied to
the next run directly. Aer evaporation, to recover 1,4-dioxane,
the crude products could be obtained and further puried by
column chromatography (eluent, ethyl acetate–petroleum ether,
1/3) on silica gel (200–300 mesh).
Scheme 1 Enzymatic reaction of p-chlorobenzaldehyde with 1H-
indole.
since it worked as a heterogeneous catalyst. As a result, lipase
TLIM was chosen as the promoter (Table 2).
3.2 Screening of solvent for the cascade synthesis of
bis(indolyl)methanes
In our previous research,22c lipase TLIM showed the best result
in n-hexane to catalyze the Knoevenagel–Michael cascade reac-
tions of 1,3-diketones with aromatic aldehydes to generate 80–
97% yields of xanthone derivatives. While in this study, TLIM
showed better catalytic activity in water, and only 12% yield
could be obtained n-hexane. Additionally, comparable yield also
could be obtained when toluene was used as reaction media.
Surprisingly, no product could be detected in solvents having
a good solubility for the substrates and products like 2-prop-
anol, acetonitrile, DMF, THF and DMSO. PPL was employed in
aqueous 1,4-dioxane to synthesize bis(indolyl)methanes.20 Le
et al.21 found that a-chymotrypsin in aqueous ethanol exhibited
prominent promiscuity for the synthesis of bis(indolyl)meth-
anes. However, no product in 1,4-dioxane and trace product in
ethanol were detected in this research. Water has the worst
solubility for the substrates and products, which may contribute
to the progress of the reaction.
3. Results and discussion
3.1 Screening of enzyme sources for the cascade synthesis of
bis(indolyl)methanes
In our previous research,22d lipase RMIM was successfully used
in pure water to catalyze the Knoevenagel–Michael cascade
reactions of 4-hydroxycoumarin with aromatic, heterocyclic or
aliphatic aldehydes to synthesize dicoumarol derivatives (81–
98%). In our initial research, the cascade reaction of 1H-indole
with 4-chlorobenzaldehyde was catalyzed by lipase RMIM in
pure water (Table 1, entry 1). However, the result was not as
satisfactory as we expected and only 51% of product was ob-
tained. Subsequently, we tried other lipases to screen more
effective catalysts. As showed in Table 1, lipases CRL, BCL,
Novozym 435, PPL, TLIM (Table 1, entries 3–7) as well as papain
(Table 1, entry 9) and BSA (Table 1, entry 10) can promote the
model reaction (Scheme 1). Lipase TLIM (lipase from Thermo-
myces lanuginosus, immobilized on particle silica gel, the cata-
lyst dosage of lipase on particle silica gel is 7%) showed the best
catalytic activity and gave the corresponding product in 56%
yield. As for the denatured TLIM (Table 1, entry 8), it demon-
strated little catalytic activity and presented similar result with
the blank control reaction (Table 1, entry 2). We supposed that
the specic tertiary structure of enzymes makes great contri-
butions in this enzyme-catalyzed reaction. The immobilized
lipase TLIM is relatively efficient and has the possibility of reuse
3.3 Screening of temperature, enzyme amount and reaction
time for the cascade synthesis of bis(indolyl)methanes
The activity of enzymes and the rate of reactions are strongly
associated with the temperature of reactions. The most suitable
Table 2 Effect of solvent source on the yield of 3a
Entry
Solventa
Yieldb (%)
1
2
3
4
5
6
7
8
9
n-Hexane
Toluene
Water
2-Propanol
Acetonitrile
1,4-Dioxane
DMF
12
51
56
0
0
0
0
0
Table 1 Effect of enzyme sources on the yield of 3a
Entry
Enzymea
Yieldb (%)
Entry
Enzymea
Yieldb (%)
1
2
3
4
5
RMIM
No enzyme
CRL
BCL
Novozym 435
51
3
37
40
43
6
7
8
9
10
PPL
49
56
7
40
41
TLIM
TLIMc
Papain
BSA
THF
DMSO
0
10
Ethanol
Trace
a
Reaction conditions: lipase (50 mg), 4-chlorobenzaldehyde (1 mmol),
b
a
1H-indole (2 mmol), water (5 mL), 45 ꢁC, 18 h. HPLC yield.
Reaction conditions: TLIM (50 mg), 4-chlorobenzaldehyde (1 mmol),
c
b
Denatured TLIM was obtained by treating with acetone for 24 h.
1H-indole (2 mmol), solvent (5 mL), 45 ꢁC, 18 h. HPLC yield.
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Table 3 Effects of enzyme amount and reaction time on the yield of
3a
reaction temperature for TLIM in pure water to produce bis(in-
dolyl)methanes is 55 C (Fig. 1). Subsequently, we investigated
ꢁ
the effect of enzyme loading on this cascade reaction. The results
seem to be equivalent when the enzyme amount is more than
10 mg (Table 3, entries 2–4). As a result, 10 mg was chosen to be
the optimized enzyme loading for 1 mmol 4-chlorobenzaldehyde
substrate of this reaction, which is noteworthy that the enzyme
amount is much lesser than other enzymatic reactions.20,21 With
the optimized conditions in hand, high yields (93%) of 3a could
be obtained aer 36 h (Table 3, entry 7).
Enzyme amount
(mg)
Entrya
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
5
10
20
30
10
10
10
10
18
18
18
18
24
30
36
48
57
73
68
70
82
88
93
92
a
Reaction conditions: TLIM, 4-chlorobenzaldehyde (1 mmol), 1H-
3.4 TLIM-catalyzed synthesis of bis(indolyl)methanes
indole (2 mmol), water (5 mL), 55 ꢁC. b HPLC yield.
Considering the overall effects of catalyst, solvents, temperature
and catalyst loading were investigated, further studies on the
exploration of substrate scopes and limitations were carried out
(Scheme 2). As can be seen in Table 4, aromatic aldehydes with
electron-withdrawing substituents (Table 4, entries 1–5) as well
as aromatic aldehydes with electron-donating substituents
(Table 4, entries 6–12) can both react easily with 1H-indole to
give corresponding products with 75–99% yields. It is worth
noting that the reported enzymatic cascade reactions couldn't
get satisfactory yields when aliphatic aldehydes and aromatic
aldehydes with electron-donating substituents react with 1H-
indole.20,21 It is extraordinary that excellent result was obtained
for aromatic aldehydes having large steric hindrance such as 4-
tert-butylbenzaldehyde (Table 4, entry 15) with 1H-indole aer
72 h. Satisfactorily, heterocyclic aldehydes which haven't been
investigated in the previous enzymatic synthesis20,21 like 2-thi-
ophenealdehyde (Table 4, entry 13) and pyridine-2-
carbaldehyde (Table 4, entry 14) could react easily with 1H-
indole to generate corresponding products in good yields aer
72 h. In addition, indole bearing different substituents (Table 4,
entries 16–20) also could react smoothly with aldehydes under
the reaction conditions with excellent yields obtained. Practi-
cally, this protocol could be applied to a gram-scale synthesis
and high yield was obtained (Table 4, entry 21). Finally, recy-
clability and reusability of TLIM were investigated for the
synthesis of 3a in a good yields (Table 4, entries 22–23). In
summary, the method developed in this paper has a wider
substrate scopes than the reported enzymatic cascade reactions
and lipase TLIM could be reused with little loss of activity.
3.5 Possible mechanism for the synthesis of bis(indolyl)
methanes catalyzed by TLIM
Enzymatic synthesis of bis(indolyl)methanes was carried out
using lipase TLIM as catalyst. Based on literatures,18,20 it can be
explained by a proposed mechanism depicted in Scheme 3. We
supposed that the catalytic active site of lipase TLIM plays a vital
role in the cascade reaction. Firstly, the Gly residues and Ser
residues interacted with the carbonyl of aromatic aldehyde to
form the oxyanion hole, which could stabilized the activated
aromatic aldehyde. Then the highly nucleophilic 3-position of
indole attacked the activated aromatic aldehyde to form the
intermediate product, which interacted with His residues. Finally,
the intermediate product contacted with another molecule of
indole and joined together to form the nal product and released
a molecule of water, and the catalyst was set free for the next cycle.
4. Comparison of the catalytic
efficiency of TLIM with some reported
catalysts
Finally, we selected the reaction of 4-methoxybenzaldehyde with
indole for the synthesis of 3h as a model reaction and compared
the catalytic efficiency of TLIM with other reported catalysts in
terms of reaction time, temperature, solvent and yields (Table
5). As can be seen in Table 5, this work could generate higher
Fig. 1 Effects of temperature on the yield of 3a. Reaction conditions:
TLIM (50 mg), 4-chlorobenzaldehyde (1 mmol), 1H-indole (2 mmol),
water (5 mL), 18 h, HPLC yield.
Scheme 2 Enzymatic cascade reaction of aldehydes with indole.
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Table 4 TLIM-catalyzed synthesis of bis(indolyl)methanes
Entrya
R1
R2
R3
R4
Product
Time/h
Yieldb/%
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
OCH3
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
H
H
H
H
H
4-ClC6H5
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
36
36
36
36
36
36
36
36
36
36
72
36
72
72
72
36
36
36
36
36
36
36
36
36
36
93(90d)
85
87
99
98
98
95
95
88
88
87
75
89
72
95
3-NO2-C6H5
4-NO2-C6H5
2-F-C6H5
4-CN-C6H5
C6H6
4-CH3-C6H5
4-OCH3-C6H5
4-OH-3-OCH3-C6H4
2-OH-3-OCH3-C6H4
C3H7
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
Hc
2-Thienyl
2-Pyridyl
4-t-C4H9-C6H5
4-Cl-C6H5
4-Cl-C6H5
4-Cl-C6H5
4-Cl-C6H5
4-Cl-C6H5
4-Cl-C6H5
4-Cl-C6H5
4-Cl-C6H5
4-Cl-C6H5
4-Cl-C6H5
96d
98d
88d
90d
93d
94e
86f
81g
77h
74i
3s
3t
3a
3a
3a
3a
3a
a
Reaction conditions: TLIM (10 mg), aldehyde (1 mmol), indole (2 mmol), water (5 mL), 55 ꢁC. b HPLC yield. c Reaction conditions: TLIM (10 mg),
d
e
formaldehyde aqueous solution (37%, 3 mmol), indole (2 mmol), water (5 mL), 55 ꢁC. Isolated yield. Reaction conditions: TLIM (100 mg), 4-
f
g
chlorobenzaldehyde (10 mmol), 1H-indole (20 mmol), water (50 mL), 55 ꢁC, HPLC yield. HPLC yield of 3a (run 2). HPLC yield of 3a (run 3).
h
HPLC yield of 3a (run 4). i HPLC yield of 3a (run 5).
yield of corresponding product than most of reported methods.
Moreover, TLIM was used in pure water instead of volatile, toxic
organic solvents. Compared with chemical catalysis methods,
TLIM-catalyzed synthesis of bis(3-indolyl)methane has several
advantages such as environmental begin, simple, commercially-
available and recyclable catalyst.
5. Spectroscopic data for new
products
5.1 3,30-((2-Fluorophenyl)methylene)bis(1H-indole) (3d)
1
ꢁ
Yield: 0.99 mmol (99%); red solid; mp 76–77 C. H NMR (300
MHz, CDCl3) d 7.93 (s, 2H), 7.38 (dd, J ¼ 13.0, 8.1 Hz, 4H), 7.24–
7.13 (m, 4H), 7.09 (d, J ¼ 9.6 Hz, 1H), 7.00 (q, J ¼ 6.9, 6.1 Hz, 3H),
6.73 (s, 2H), 6.23 (s, 1H). 13C NMR (75 MHz, CDCl3) d 160.2,
158.2, 137.5, 129.8, 129.6, 128.6, 127.4, 125.6, 122.7, 121.2,
119.2, 115.4, 114.3, 111.6, 30.8. HRMS (EI-TOF): m/z calcd for
C
23H17N2F [M + Na]+: 340.3921, found 340.3930.
5.2 3,30-((4-Chlorophenyl)methylene)bis(2-methyl-1H-
indole) (3p)
1
ꢁ
Yield: 0.3686 g (96%); red solid; mp 162–163 C. H NMR (300
MHz, CDCl3) d 7.78 (s, 2H), 7.28 (s, 2H), 7.24 (d, J ¼ 8.9 Hz, 4H),
7.07 (t, J ¼ 7.4 Hz, 2H), 7.00 (d, J ¼ 7.8 Hz, 2H), 6.94–6.86 (m,
2H), 5.98 (s, 1H), 2.07 (s, 6H). 13C NMR (75 MHz, CDCl3) d 135.0,
131.8, 130.4, 129.3, 128.2, 120.7, 119.2, 112.9, 110.0, 104.6, 38.7,
12.4. HRMS (EI-TOF): m/z calcd for C25H21N2Cl[M + Na]+:
384.1400, found 384.1389.
5.3 3,30-((4-Chlorophenyl)methylene)bis(5-chloro-1H-indole)
(3s)
Yield: 0.3816 g (90%); pink solid; mp 175–176 ꢁC. 1H NMR (300
MHz, CDCl3) d 7.96 (s, 2H), 7.30 (d, J ¼ 7.2 Hz, 4H), 7.26 (s, 2H),
Scheme 3 Possible mechanism for the synthesis of bis(indolyl)meth-
anes catalyzed by TLIM.
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Table 5 Comparison of the catalytic efficiency of TLIM with some reported catalysts
Entry
Catalyst
Time/h
Temperature/ꢁC
Solvent
Yield/%
Ref.
1
2
3
4
5
6
7
Lipase TLIM
SDS
Zeolites
Lipase PPL
a-Chymotrypsin
MoS2–RGO
[DABCO-H][HSO4]
36
18
1.5
72
32
2
55
rt
rt
50
50
rt
Water
MeOH
CH2Cl2
Aqueous 1,4-dioxane
Aqueous ethanol
Water
—
95
78
85
50
75
89
74
This work
12
13
20
21
23
24
2
90
7.22 (d, J ¼ 8.5 Hz, 2H), 7.19–7.06 (m, 2H), 6.65 (s, 2H), 5.74 (s,
1H). 13C NMR (75 MHz, CDCl3) d 141.3, 136.8, 128.70, 128.6,
127.4, 127.2, 124.2, 121.2, 120.8, 119.6, 113.7, 112.2, 34.8. HRMS
(EI-TOF): m/z calcd for C23H15N2Cl3[M + Na]+: 424.0311 found
424.0315.
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Diindolylmethane (Ring-DIMs) in Hormone-Responsive
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In summary, we have successfully developed an environmen-
tally friendly and highly efficient method to synthesize bis(in-
dolyl)methanes, which could make for some drawbacks of the
reported enzyme-catalyzed synthesis of bis(indolyl)methanes.
This protocol can generate bis(indolyl)methanes with wide
substrate range in excellent yields in pure water using very small
amount of recyclable lipase. What's more, this enzymatic
approach to cascade synthesis of bis(indolyl)methanes could be
scaled up.
Conflicts of interest
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cancer prevention, J. Nutr. Biochem., 2005, 16(2), 65–73.
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of Indole with Aldehydes and Schiff's Bases, Synth.
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There are no conicts to declare.
Acknowledgements
This research was nancially supported by the National Natural
Science Foundation of China (No. 21676143), the Self-owned
Research Project from Key Laboratory of Materials-Oriented
Chemical Engineering (No. ZK201603), the Jiangsu Synergetic
Innovation Center for Advanced Bio-Manufacture, and the Qing
Lan Project of Jiangsu Province.
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aza-crown ether complex cation ionic liquids: preparation
10852 | RSC Adv., 2020, 10, 10848–10853
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