Selective Synthesis of Bis(indolyl)methanes under Solvent Free Condition Using Glucopyranosylamine Derived cis-Dioxo Mo(VI) Complex as an Efficient Catalyst

Article abstract of DOI:10.1007/s10562-015-1648-7

cis-Dioxomolybdenum(VI) complex of 4,6-O-ethylidene-β-d-glucopyranosylamine derived ligand has been used as an efficient catalyst in the selective synthesis of a series of bis(indolyl)methanes (BIMs) by condensing indole derivatives with carbonyl compounds. The adopted synthetic procedure is green in nature as solvent free reactions have been carried out using naturally occurring d-glucose derived ligands. Total 15 BIMs have been synthesised including four new ones, which have been characterized by mp, FTIR, NMR and mass spectroscopy. The catalyst has afforded good to excellent yield of BIMs in short reaction time and the former has been recycled five times without any significant loss in it's catalytic efficiency.

Full text of DOI:10.1007/s10562-015-1648-7

Catal Lett
DOI 10.1007/s10562-015-1648-7
Selective Synthesis of Bis(indolyl)methanes Under Solvent Free
Condition Using Glucopyranosylamine Derived cis-Dioxo Mo(VI)
Complex as an Efficient Catalyst
Noorullah Baig1 Ganesh M. Shelke1 Anil Kumar1 Ajay K. Sah1
•
•
•
Received: 22 September 2015 / Accepted: 29 October 2015
Ó Springer Science+Business Media New York 2015
Abstract cis-Dioxomolybdenum(VI) complex of 4,6-O-
ethylidene-b-D-glucopyranosylamine derived ligand has
been used as an efficient catalyst in the selective synthesis of
a series of bis(indolyl)methanes (BIMs) by condensing
indole derivatives with carbonyl compounds. The adopted
synthetic procedure is green in nature as solvent free reac-
tions have been carried out using naturally occurring D-
glucose derived ligands. Total 15 BIMs have been synthe-
sised including four new ones, which have been character-
ized by mp, FTIR, NMR and mass spectroscopy. The
catalyst has afforded good to excellent yield of BIMs in short
reaction time and the former has been recycled five times
without any significant loss in it’s catalytic efficiency.
Keywords Glucopyranosylamine Á
Bis(indolyl)methanes Á Solvent free reaction Á
cis-Dioxomolybdenum(VI) complex
1 Introduction
Bis(indolyl)methanes (BIMs) are important class of com-
pounds, which attracts the attention of chemists, biologist
and pharmacists due to its application as anti-cancer, anti-
bacterial, anti-inflammatory and analgesic agent [1–7].
Researchers are not only isolating this class of compounds
from natural sources [8–10], but also developing new
methodologies to synthesize them in laboratories. Con-
densation of indole derivatives with carbonyl compounds
leads to the formation of BIMs, and reports are available,
where CuBr2 [11], I2 [12], CAN [13], NBS [14], InCl3,
In(OTf)3 [15], and BF3 [16] have been used as the catalyst
for such reactions. Few drawbacks of these methodologies
include the use of high temperature, volatile organic sol-
vents, toxic reagents, tedious work-up, poor yields etc., and
hence developments of new procedures are desired to cir-
cumvent the limitations.
Graphical Abstract
R1
CHO
R
N
H
R
R
R1
N
H
N
H
R = H, OCH
OBn, Cl
3, Br,
110
R1 = H, Cl, NO2
°
C
Yield = 89-97%
15 Examples
Mo-Catalyst
Solven free
Under green methodologies, few reports are available
where synthesis of BIMs has been carried out under neat
reaction condition using organic and inorganic catalysts
like oxalic acid, trityl chloride, ionic liquids, I2, HBF4–
SiO2, ZnO, CeCl3Á7H2O–NaI–SiO2, modified zirconia etc.
[17]. Researchers have performed such reactions in envi-
ronmentally benign solvents like water, glycerol [18] and
ionic liquids [17, 19], and also explored the reactions at
room to moderate temperature [17, 20]. Recently, ammo-
nium niobium oxalate catalyzed synthesis of BIMs under
conventional heating in water and under ultrasonic irradi-
ation in glycerol has been reported by Mendes et al, [18].
Electronic supplementary material The online version of this
article (doi:10.1007/s10562-015-1648-7) contains supplementary
material, which is available to authorized users.
& Ajay K. Sah
ajay_ksah@yahoo.com; asah@pilani.bits-pilani.ac.in
1
Department of Chemistry, Birla Institute of Technology and
Science, Pilani Campus, Pilani, Rajasthan 333 031, India
123

N. Baig et al.
This report suggests that the reaction under ultrasonic
irradiation condition completes much faster than that under
conventional heating condition with comparable yields.
Molybdenum complexes control several biochemical
reactions in the form of nitrogenase, nitrate reductase,
DMSO reductase, xanthine oxidase etc. [21, 22]. Several
molybdenum complexes have also been used in industrial
ammoxidation of olefins [23], olefin epoxidation [24],
olefin metathesis [25] etc. D-Glucose is a naturally occur-
ring compound and only few reports are available on the
molybdenum complexes of its derivatives [26–28]. The
catalytic reactions of sugar derived molybdenum com-
plexes are in it’s infant stage and to the best of our
knowledge only two reports are available in this area. Zhao
et al., have reported the epoxidation of cyclooctene and cis-
, trans-b-methylstyrene using D-glucose derived ligands
[26], and we have explored the selective oxidation of
organic sulfides into corresponding sulfoxides [27] using
cis-dioxomolybdenum(VI) complexes of 4,6-O–ethyli-
dene-b-D-glucopyranosylamine derived ligands. Generally
sugar derived complexes are assumed to be labile, however
these two reports went against the general belief, which
prompted us to explore new applications of such com-
plexes in catalysis. Along this line, we successfully syn-
thesized a series of BIMs using 4,6-O-ethylidene-N-(2-
product into the organic phase. The combined organic
solution was concentrated under reduced pressure and pure
product was isolated by column chromatography using n-
hexane–ethyl acetate (8:2) as eluent on silica gel column.
2.2 Synthesis of 3,30-(Phenylmethylene)bis(5-
(benzyloxy)-1H-indole) (3dA)
This compound was synthesized following the above
mentioned general procedure using benzaldehyde (0.050 g,
0.5 mmol), 5-(benzyloxy)-1H-indole (0.223 g, 1.0 mmol),
and Mo-catalyst (0.023 g, 0.05 mmol). Yield: 0.241 g
(91.0 %); mp 68–70 °C; IR (KBr; cm-1) 3418, 1481, 1180;
1H NMR (CDCl3, 400 MHz): d 7.76 (br, 2H, NH),
7.44–7.19 (m, 17H, ArH), 6.99–6.91 (m, 4H, ArH), 6.58
(br, 2H, ArH), 5.78 (s, 1H, methylene CH), 4.95 (s, 4H,
benzyl CH2); 13C NMR (CDCl3, 100 MHz) d 152.8, 143.9,
137.6, 132.0, 128.7, 128.5, 128.3, 127.7, 127.4, 126.2,
124.5, 119.2, 112.6, 111.8, 103.5, 70.8, 40.3; HRMS m/z
calcd. for (M?) C37H30N2O2 534.2307; found 534.2326.
2.3 Synthesis of 3,30-((4-
Chlorophenyl)methylene)bis(5-(benzyloxy)-1H-
indole) (3dB)
hydroxybenzylidene)-b-D-glucopyranosylamine
derived
This compound was synthesized using 4-chlorobenzalde-
hyde (0.070 g, 0.5 mmol), 5-(benzyloxy)-1H-indole
(0.223 g, 1.0 mmol), and Mo-catalyst (0.023 g,
0.05 mmol). Yield: 0.266 g (93.5 %); mp 89–90 °C; IR
(KBr; cm-1) 3410, 1481, 1180; 1H NMR (CDCl3,
400 MHz) d 7.83 (br, 2H, NH), 7.42–7.32 (m, 10H, ArH),
7.28–7.23 (m, 6H, ArH), 6.96 (dd, J = 8.8, 2.4 Hz, 2H,
ArH), 6.89 (d, J = 2.4 Hz, 2H, ArH), 6.58 (d, J = 1.6 Hz,
2H, ArH), 5.73 (s, 1H, methylene CH), 4.98 (s, 4H, benzyl
CH2); 13C NMR (CDCl3, 100 MHz) d 152.8, 142.4, 137.5,
132.0, 131.7, 130.0, 128.4, 128.4, 127.7, 127.6, 127.2,
124.5, 118.6, 112.8, 111.8, 103.4, 70.8, 39.7; HRMS m/z
calcd. for (M ? H)? C37H30ClN2O2 569.1996; found
569.1983.
Mo(VI) complex (Mo-catalyst; Fig. 1) as catalyst. We have
optimized the coupling conditions of indole derivatives and
carbonyl compounds with respect to catalytic loading,
reaction solvent and recyclability of catalyst, to afford the
best yields of BIMs. Hence, this paper deals with the
details of first catalytic application of sugar derived
Mo(VI) complex in BIMs synthesis.
2 Experimental
2.1 General Procedure for the Selective Synthesis
of BIMs Under Optimized Condition
A mixture of respective aldehyde (0.5 mmol), indole
(1.0 mmol) and Mo-catalyst (0.05 mmol) were stirred at
110 °C for appropriate time period. The resultant semisolid
was triturated with ethyl acetate (3 9 5 mL) to transfer the
2.4 Synthesis of 3,30-((4-
Nitrophenyl)methylene)bis(5-(benzyloxy)-1H-
indole) (3dC)
This compound was synthesized using 4-nitrobenzaldehyde
(0.075 g, 0.5 mmol), 5-(benzyloxy)-1H-indole (0.223 g,
1.0 mmol), and Mo-catalyst (0.023 g, 0.05 mmol). Yield:
0.276 g (95.8 %); mp 93–94 °C; IR (KBr; cm-1) 3418,
Fig. 1 Structure of (4,6-O-
ethylidene-N-(2-
hydroxybenzylidene)-b-D-
glucopyranosylamine derived
cis-dioxo Mo(VI) complex
1
1512, 1481, 1342, 1180; H NMR (CDCl3, 400 MHz) d
8.11 (d, J = 8.8 Hz, 2H, NH), 7.91 (s, 2H, ArH), 7.44 (d,
J = 8.8 Hz, 2H, ArH), 7.39–7.27 (m, 12H, ArH), 6.97 (dd,
J = 8.8, 2.2 Hz, 2H, ArH), 6.82 (d, J = 2.4 Hz, 2H, ArH),
6.63 (d, J = 2.0 Hz, 2H, ArH), 5.84 (s, 1H, methylene
123

Selective Synthesis of Bis(indolyl)methanes Under Solvent Free Condition Using…
CH), 5.01–4.95 (s, 4H, benzyl CH2); 13C NMR (100 MHz,
CDCl3) d 153.0, 151.6, 146.4, 137.4, 131.9, 129.4, 128.4,
127.7, 127.4, 127.0, 124.4, 123.6, 117.5, 113.0, 112.0,
103.1, 70.7, 40.2; HRMS m/z calcd. for (M?) C37H29N3O4
579.2158; found 579.2183, and 602.2092 (M ? Na?).
reaction using p-nitrobenzaldehyde (0.5 mmol), indole
(1 mmol) and Mo-catalyst (0.05 mmol) in methanol
(3 mL) under reflux condition. The progress of reaction
was monitored using thin layer chromatography. After 12 h
of reflux, reaction mixture was cooled, filtered and filtrate
was concentrated under reduced pressure. The product 3aC
was isolated in 87 % yield from the concentrated filtrate
using column chromatography. After this initial success of
catalytic reaction, we optimized the nature of solvent for
maximum productivity and the results are presented in
Table 1. Inspiring from the literature report on use of
molten tetra-n-butyl ammonium bromide (TBAB) for
BIMs synthesis [31], we performed this reaction using Mo-
catalyst in TBAB and obtained 96 % yield of 3aC after
10 min reaction time. Further, optimization of this reaction
under solvent free condition also led to 96 % yield of 3aC
in 10 min reaction time. Few reports are available on BIMs
synthesis using various catalyst under solvent free reaction
condition [32, 33] but to the best of our knowledge, no
report is available on molybdenum complex catalyzed such
reaction under neat condition. Since we obtained the best
yields in the presence of TBAB and solvent free condition,
we preferred to perform the reactions under neat condition,
as solvent free reactions are one of the requirements of the
green methodology. After optimizing the solvent, we
explored the amount of catalyst loading under neat condi-
tion for the same reaction system and the results are pre-
sented in Table 2. Under identical condition, no product
formation was noticed in absence of catalyst from the
model reaction, while best yield was obtained using
10 mol% of catalyst loading.
2.5 Synthesis of 3,30-((4-
Nitrophenyl)methylene)bis(5-chloro-1H-indole)
(3eC)
This compound was synthesized using 4-nitrobenzaldehyde
(0.074 g, 0.5 mmol), 5-chloro-1H-indole (0.150 g,
1.0 mmol), and Mo-catalyst (0.023 g, 0.05 mmol). Yield:
0.202 g (93.5 %); mp 129–130 °C; IR (KBr; cm-1) 3425,
1512, 1342 cm-1
; d
1H NMR (CDCl3, 400 MHz)
8.28–8.07 (m, 4H, NH and ArH), 7.47 (d, J = 8.8 Hz, 2H,
ArH), 7.36–7.27 (m, 4H, ArH), 7.17 (dd, J = 8.4, 1.6 Hz,
2H, ArH), 6.70 (d, J = 2.0 Hz, 2H, ArH), 5.88 (s, 1H,
methylene CH); 13C NMR (100 MHz, CDCl3) d 150.9,
146.7, 135.0, 129.4, 127.6, 125.4, 125.0, 123.8, 122.8,
118.8, 117.4, 112.4, 39.9; HRMS m/z calcd. for (M?)
C23H15Cl2N3O2 435.0541; found 435.0595.
3 Results and Discussion
Sugar derived molybdenum complexes are known since
more than a decade, however their applications are scarce.
The structure of Mo-catalyst has already been established
using single crystal X-ray crystallography [28] and it has
been used in two catalytic reactions [26, 27]. Inspired by
these reports, which suggest the stability and usability of
the complex as efficient catalyst; we have explored it’s
application in the synthesis of BIMs (Scheme 1). Literature
is evident that the reaction of electron deficient aldehyde
with electron rich indole derivatives affords the best yield
of BIMs [29, 30] and following this logic, we set the trial
After optimizing the reaction conditions, indole and it’s
four derivatives (1a–e) were reacted with benzaldehyde
and it’s two derivatives (2A–C) to afford fifteen BIMs
(3aA–eC) including four new ones (3dA, 3dB, 3dC and
3eC mentioned in Scheme 1), whose characterization data
is presented in this manuscript and spectra are deposited as
Scheme 1 Synthesis of BIMs
using Mo-catalyst
123

N. Baig et al.
Table 1 Effect of solvent on the synthesis of BIMs
Table 3 Synthesis of BIMs using Mo-catalyst under optimized
condition
S. no
Solvent
Temperature
Time (h)
Yield (%)a
Entry
R
R1
Time (h)
Product
Yield (%)
1
Water
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
110 °C
145 °C
110 °C
1
0
87
69
85
37
54
46
26
96
92
96
1
H
H
1/6
1/6
1
3aA
3bA
3cA
3dA
3eA
3aB
3bB
3cB
3dB
3eB
3aC
3bC
3cC
3dC
3eC
89
93
91
91
90
92
95
93
94
91
95
97
95
96
94
2
Methanol
Ethanol
12
12
24
24
24
24
24
1/6
1/6
1/6
2
OCH3
Br
H
3
3
H
4
Acetone
Acetonitrile
Chloroform
Tetrahydrofuran
Toluene
TBAB
4
OBn
Cl
H
1/6
1
5
5
H
6
6
H
Cl
1/6
1/6
1
7
7
OCH3
Br
Cl
8
8
Cl
9
9
OBn
Cl
Cl
1/6
1
10
11
a
TBAI
10
11
12
13
14
15
Cl
Neat
H
NO2
NO2
NO2
NO2
NO2
1/6
1/6
1
Isolated yield
OCH3
Br
OBn
Cl
1/6
1
Table 2 Summary of catalytic loading study for the synthesis of
BIMs
S. no.
Catalyst (mole%)a
Time (min)
Yield (%)b
1
2
3
4
a
0
2
10
10
10
10
0
\5
48
5
10
96
Refer Fig. 1
b
Isolated yield
supplementary information. The successful isolation of
previously reported 11 compounds were confirmed by
comparing their spectral data with the literature reports [19,
34–37]. All the reactions afforded good to excellent yields
of BIMs (89–97 %) and the details are summarized in
Table 3. The best yield was obtained from the reaction of
electron deficient aldehyde 2C with electron rich indole
derivative 1b. This finding is parallel to the established fact
by various researchers that the reaction between electron
deficient aldehyde and electron rich indole affords best
yields in BIMs synthesis. Analogously, halogen substituted
indoles (1c and 1e) took longer reaction time, as the
halogen group deactivates the indole ring via inductive
effect [38].
Fig. 2 Graphical representation of yields during catalytic recyclabil-
ity of Mo-catalyst
DMSO (supplementary information; Fig. S9) and com-
pared. No appreciable changes in the spectral pattern were
noticed however, slight shift in the kmax values were
observed for the recycled catalyst in compared to the pure
one. This study clearly supports the stability and reliability
of the Mo-catalyst.
Furthermore, we studied the recyclability of the Mo-
catalyst in the synthesis of BIMs. For recycling, the reac-
tion mixture of model reaction was extracted with ethyl
acetate and the residue (catalyst) was reused directly for the
new reaction. The catalyst was recycled five times (Fig. 2)
and no appreciable change in catalytic activity was noticed.
Under identical condition of reaction parameters, the iso-
lated yields at the end of first and fifth cycles were recorded
as 94 and 90 % respectively. UV–Visible spectra of pure
and catalyst after first and fifth cycles were recorded in
4 Conclusions
4,6-O-ethylidene-N-(2-hydroxybenzylidene)-b-D-glucopy-
ranosylamine derived cis-dioxo Mo(VI) complex has been
proven to be an efficient catalyst for the selective synthesis
of BIMs. A number of reaction conditions with respects to
solvent, time and catalytic loading have been investigated
123

Selective Synthesis of Bis(indolyl)methanes Under Solvent Free Condition Using…
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vent free condition in good to excellent yields. The cata-
lyst has been successfully recycled five times without any
appreciable loss in it’s activity and proven to be stable and
reliable. This is the first report on catalytic application of
sugar derived molybdenum (VI) complex in the synthesis
of BIMs. Here we are reporting a relatively greener pro-
cess, where catalytic reaction has been performed under
neat condition and catalyst is derived from natural occur-
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Acknowledgments A. K. Sah is grateful to the University Grants
Commission (UGC) for the financial support under Major Research
Project. We are also thankful to DST FIST and UGC SAP for their
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