An insight on the influence of surface Lewis acid sites for regioselective C–H bond C3-cyanation of indole using NH4I and DMF as combined cyanide source over Cu/SBA-15 catalyst

Article abstract of DOI:10.1016/j.mcat.2017.11.007

The Cu dispersed on mesoporous SBA-15 has demonstrated the regioselective C–H bond C₃-cyanation of indoles by in-situ generation of –CN using DMF and NH₄I in presence of O₂. Pyridine adsorbed diffuse reflectance infrared spectroscopy (DRIFTS) results revealed that surface Cu²⁺ species are acting as Lewis acid sites in the in-situ generation of cyano- group for the synthesis of indole nitriles. A direct correlation between Cu metal surface area and the indole nitrile yields are established and the dual role of copper is substantiated by N₂O titration and XPS techniques. The 10 wt%Cu/SBA-15 demonstrated superior performance when compared to Pd, Ru supported on SBA-15. The 10 wt%Cu/SBA-15 catalyst showed consistent activity and selectivity after the 4th cycle.

Full text of DOI:10.1016/j.mcat.2017.11.007

Molecular Catalysis 445 (2018) 43–51
Contents lists available at ScienceDirect
Molecular Catalysis
journal homepage: www.elsevier.com/locate/mcat
Research paper
An insight on the influence of surface Lewis acid sites for
regioselective C H bond C -cyanation of indole using NH I and DMF
3
4
as combined cyanide source over Cu/SBA-15 catalyst
a
a
a
a
b
Venu Boosa , Vishali Bilakanti , Vijay Kumar Velisoju , Naresh Gutta , Sreedhar Inkollu ,
a,∗
Venugopal Akula
a
Catalysis Laboratory, Inorganic and Physical Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad, 500 007, Telangana, India
Department of Chemical Engineering, BITS Pilani Hyderabad Campus, Hyderabad, 500078, India
b
a r t i c l e i n f o
a b s t r a c t
Article history:
The Cu dispersed on mesoporous SBA-15 has demonstrated the regioselective C H bond C -cyanation
3
Received 18 August 2017
Received in revised form 25 October 2017
Accepted 3 November 2017
of indoles by in-situ generation of CN using DMF and NH4I in presence of O2. Pyridine adsorbed diffuse
2+
reflectance infrared spectroscopy (DRIFTS) results revealed that surface Cu species are acting as Lewis
acid sites in the in-situ generation of cyano- group for the synthesis of indole nitriles. A direct correlation
between Cu metal surface area and the indole nitrile yields are established and the dual role of copper is
substantiated by N2O titration and XPS techniques. The 10 wt%Cu/SBA-15 demonstrated superior perfor-
mance when compared to Pd, Ru supported on SBA-15. The 10 wt%Cu/SBA-15 catalyst showed consistent
activity and selectivity after the 4th cycle.
Keywords:
Regioselective C3-cyanation
Cu-SBA-15
Indole
Lewis acid
©
2017 Elsevier B.V. All rights reserved.
NH4I-DMF-cyanaide source
1
. Introduction
to the cyanation reactions [9]. In these procedures, several cyano
sources were employed e.g. metal cyanides (NaCN, KCN, CuCN,
+
The derivatives of indole nitriles exhibit broad range of bio-
TMSCN, K [Fe(CN) ]), BnCN, t-BuNC, electrophilic CN reagents
4
6
logical activities and they are present in many agrochemicals,
dyes, pharmaceuticals and natural products as a backbone of their
structural frameworks and are also widely used in organic syn-
thesis [1]. Additionally, 3-cyanoindoles are key intermediates for
the preparation of functional groups, such as aldehydes, amines,
ketones, amidines, amides, tetrazoles and their carboxyl deriva-
tives [2]. Notably, 3-cyanosubstituted indoles are core structures
in many biologically active compounds currently being developed
as estrogen receptor ligands, hepatitis C virus inhibitors, or ther-
apeutic agents for cardiovascular diseases [3,4]. Aryl nitriles are
generally prepared from classical organic transformations, such as
Sandmeyer [5] and Rosenmund-von Braun reaction [6], which are
pre-functionalized starting materials for the cyanation of aryldia-
zonium salts or aryl halides by stoichiometric amounts of CuCN.
However, these reactions suffer from the toxic CuCN source at high
temperature with prolonged times and also multiple procedures.
Recently, the transition-metal-catalyzed cyanation of aryl
halides [7], borons [8] or mesylates provide a promising alternative
(NCTs, BrCN), and combined cyano sources (NH I/DMF, DMF,
4
NH HCO /DMSO, TMEDA/(NH ) CO ). Metal cyanides are fre-
4
3
4
2
3
quently used as cyanide sources in various organic transformations.
Nevertheless, almost all these methods suffer from limitations. An
important issue to be resolved is the high affinity of the cyanide ion
for the transition metal, which often results in rapid deactivation of
catalyst. Moreover, most of the cyano sources, in particular NaCN,
KCN and CuCN have notorious toxicity. For example Zn(CN)2 leads
to heavy metal waste and Me SiCN is sensitive to moisture and
3
easily liberates hydrogen cyanide. Although K [Fe(CN) ] is excep-
4
6
tionally nontoxic, its slow solubility in organic solvent limits its
usage. Acetone cyanohydrins [10] would greatly decrease the util-
ity of the aforementioned transformations. To this end, a number
of CN-containing small organic molecules such as cyanohydrins
[11], CH CN [12], as well as molecule without a CN group such
3
as formamide [13], DMF [14] and nitromethane [15] have been
shown to be effective CN sources for aromatic cyanation reac-
tions. In addition, more complicated strategies for generating a CN
group from combined sources have been reported to achieve aro-
matic cyanation reactions, e.g., DMF + NH3 [16], DMF + NH I [17],
4
DMF + NH HCO3 [18,19]. However, the search for methods using
4
∗ Corresponding author.
E-mail address: akula.iict@gov.in (V. Akula).
safer and easy handling CN sources remains highly desirable. C
H
http://dx.doi.org/10.1016/j.mcat.2017.11.007
2
468-8231/© 2017 Elsevier B.V. All rights reserved.

4
4
V. Boosa et al. / Molecular Catalysis 445 (2018) 43–51
activation of sp2 centres presents unique challenges. Selective and
direct cyanation of highly abundant C−H bonds of (hetero) arenes
has emerged as a powerful tool to achieve atom and step econ-
omy in organic synthesis. Most of these processes involve either the
use of expensive noble metals or non-eco-friendly reagents. There-
fore, the development of inexpensive acidic metal catalysts for the
selective cyanation of indoles has become a topic of interest.
In this investigation, SBA-15 has been chosen as the support
material for various metals such as Cu, Ru, Pd and Ni are examined
Scheme 1. Cyanation of N-methylindole.
for the regioselective C -cyanation of indole. In the comparative
3
analysis, Cu/SBA-15 demonstrated a better nitrile yield than the
Ru/SBA-15, Ni/SBA-15 and Pd/SBA-15 catalysts thus showing eco-
nomic viability of the catalyst. A significant amount of work on
cyanation reactions has been reported by Chang and co-workers.
They have used DMF and ammonia or ammonium salts as the com-
bined ‘CN’ source to realize the cyanation of the carbon–hydrogen
2. Experimental section
2.1. Catalyst preparation
The mesoporous siliceous SBA-15 support was prepared accord-
ing to the procedure reported by Zhao et al. [36]. In a typical method,
using 2.0 g Pluronic P123 tri-block co-polymer surfactant dissolved
in 15 g water, followed by the addition of 60 g of 2 M HCl. Under con-
stant stirring, 4.25 g TEOS was added and the mixture was stirred
continuously for 24 h at 40 C. The gel mixture was then subjected
to heat treatment in an autoclave at 100 C for 48 h. After filtra-
tion, the obtained gel was dried in an air oven at 80 C for 12 h.
The dried SBA-15 solid was calcined in air flow at 550 C for 8 h.
(
heteroatom) bond [20]. Cyanation of aromatic halides by employ-
ing ammonium bicarbonate and DMF (or) DMSO as the combined
CN’ source was also achieved [18,20]. These methods for cyana-
‘
◦
tion reactions involve the combined ‘CN’ source composed of DMF
or DMSO which provides the ‘C’ unit of ‘CN’, while the ‘N’ unit comes
from ammonia or ammonium salts. We have examined the cyana-
tion of aromatic C H bonds by using a combination of NH HCO
◦
◦
◦
4
3
and DMSO as the ‘CN’ source over a Pd(II) on Mg–La mixed oxide
21]. Recently, we have explored supported copper catalyst for the
cyanation of arenes using NH HCO and N,N-dimethylformamide
The resultant mesoporous silica (SBA-15: conformed by powder
XRD) was used as support. A series of copper loadings e.g. 2.5, 5,
7.5, 10 and 12.5 wt% were prepared by wet impregnation method
using Cu(NO3)·3H2O as copper precursor. The solid was dried in an
[
4
3
as a CN source [22]. Transition-metal-catalyzed direct C H activa-
tion and functionalization has become a powerful tool in organic
synthesis [23]. In particular, the building of C C and C-heteroatom
bonds directly from two simple carbon-hydrogen (C H) bonds
or C H and H Nu (Nu B, O, N, S) bonds provides an unusu-
ally attractive pathway by virtue of its step economy, lower cost,
and a decrease in waste production [24]. Jianbo Wang and co-
workers reported the Pd-catalyzed cyanation using K [Fe(CN) ] as
◦
◦
oven at 100 C for 12 h and subsequently calcined at 450 C for 5 h
in static air. The elemental analysis of prepared catalysts is inves-
tigated using atomic absorption spectroscopy and the results are
listed in Table S1. The complete details on the characterization of
the catalysts are given in Supporting Information.
2.2. Catalyst activity studies
4
6
cyanating agent and selectively introduce a cyano group into the
-position of indoles with high efficiency [25]. Khorshidi showed
the selective 3-cyanation of indoles was achieved under Ru catalyst
26]. Chaitanya and Anbarasan demonstrated the Rh catalyzed cya-
nation of indoles [27]. Yang et al. reported the Lewis acid catalyzed
direct cyanation of indoles [28]. Shen and co workers reported
the Cu-catalyzed cyanation of indoles using acetonitrile as a cyano
source [29].
3
A 10 mL round bottom flask was charged with N-methylindole
(40 mg, 0.3 mmol), Cu/SBA-15 (150 mg), NH4I (0.36 mmol), DMF
(2 mL) and O2 as oxidizing agent. The round bottom flask was kept
[
◦
for stirring at 130 C. After 12 h of run, the reaction was monitored
by TLC; 5 mL of ethyl acetate was added to the reaction mixture. The
catalyst was separated by centrifugation followed by the treatment
of the reaction mixture with 10 mL of brine solution. The organic
layer is separated by ethyl acetate (3 × 5 mL). The combined ethyl
acetate extract was dried with anhydrous Na2SO4 and it was con-
centrated under reduced pressure. The pure product was isolated
by flash column chromatography on silica gel using ethyl acetate-
hexane (3:1) as an eluent (pale yellow oil, 92% yield). The catalyst
was washed with distilled water for several times then dried in an
In recent years, mesoporous silica materials have attracted
the catalysis community because of mesoporous silica (SBA-15)
exhibits interesting textural properties, such as thick framework
walls, uniform-sized pores (4–30 nm), large specific surface areas
2
−1
(
above 1000 m g ), high thermal stability and diffusion limi-
tations and is widely used as catalyst supports, drug delivery
materials [30–32], SBA-15 supported metals have revealed excel-
lent activity and stability of the catalytic oxidation of organic
compounds [33,34] and catalytic transfer hydrogenation and
cyclization [35]. Herein, we report SBA-15 supported Cu cata-
lysts for the selective 3-cyanation of indole C H bonds by using a
◦
oven at 100 C and used for the next cycle. Following the similar
procedure the cyanation reaction was tested for 3 recycles.
3. Results and discussion
combination of NH I and DMF as the ‘CN’ source in the presence
3.1. Powder X-ray diffraction (XRD)
4
of oxygen is an attractive, atom-economic and environmentally
benign oxidant due to the fact that it is cheap, widely available
The low angle XRD patterns of pure SBA-15 and Cu loaded SBA-
15 samples are displayed in Fig. 1A. The XRD pattern of parent
SBA-15 exhibited a well-resolved sharp intense diffraction peak at
(
20vol% of air) and clean (only water as by-product) to pro-
vide indole nitriles in good yields (Scheme 1). The Cu loaded
SBA-15 samples are characterized by BET-surface area, powder
◦
◦
2ꢀ = 0.8 along with two other low intense peaks at 2ꢀ = 1.59 and
◦
X-ray diffraction (XRD), H -temperature programmed reduction
1.8 corresponding to the (100), (110) and (200) reflections respec-
2
(
H -TPR), NH -temperature programmed desorption (NH -TPD),
tively which can be indexed to a mesoporous 2D hexagonal pore
structure. However, there is no major change observed in the struc-
ture of SBA-15 in Cu loaded samples suggesting hexagonal structure
is intact and stable.
Fig. 1B shows the wide angle XRD patterns of parent SBA-15 and
calcined Cu/SBA-15 samples. The broad X-ray diffraction peak at
2
3
3
transmission electron microscopy (TEM), N O pulse titration for
2
Cu metal surface area, X-ray photoelectron spectroscopy (XPS),
pyridine adsorbed diffuse reflectance Fourier transformed infrared
spectroscopy (DRIFTS).

V. Boosa et al. / Molecular Catalysis 445 (2018) 43–51
45
Fig. 1. (A) low angle and (B) wide angle XRD patterns of (a) 0.0 (b) 2.5 (c) 5.0 (d) 7.5 (e) 10.0 and (f) 12.5 wt%Cu supported on SBA-15.
◦
ꢀ = 24 corresponds to the presence of an amorphous silica phase.
2
The XRD patterns exhibits that the diffraction signals of crystalline
CuO are not formed at 5 wt% of Cu indicating the CuO species are
present in a highly dispersed state at lower loading. At higher load-
◦
◦
ing, the samples showed reflection at 2ꢀ = 35.5 and 38.7 that are
attributed to the crystalline CuO phase over the SBA-15 support.
These diffraction peaks become sharper and intense with increase
in Cu loading on SBA-15 (Fig. 1B) revealing that large size CuO
clusters are formed.
3.2. Physicochemical characteristics of the catalysts
The N -sorption analysis of SBA-15 and copper loaded SBA-15
2
samples showed a high surface area for support material (Table 1),
than on Cu loaded SBA-15. Upon increasing copper loading, a
decrease in the surface area is however observed probably due to
the pore blocking of the support material with the copper par-
tices. The details on sorption isotherms (Fig. S1A), BJH analysis
Fig. 2. H2-TPR profiles of (a) 2.5, (b) 5.0, (c) 7.5, (d) 10 and (e) 12.5 wt%Cu supported
on SBA-15.
(
Fig. S1B and Table S2) are reported in Supporting Information. The
N O titration measurements are carried out and estimated the Cu
2
metal suface area of the catalysts (Table 1). An increase in the N O
2
uptake is observed with increase in copper loading and a higher
Cu metal surface area is observed at a 10 wt% copper loading on
SBA-15 (Table 1).
3
.3. H -temperature programmed reduction (H -TPR)
2
2
The reducibility of the CuO particles interacted with SBA-15
investigated by using H -TPR analysis and profiles are presented
2
in Fig. 2. The H -uptakes calculated (Table 1) from these curves
2
showed an increase in the H2 uptake with the increase in copper
loading suggesting the bulk property of TPR analysis. The TPR pro-
◦
file of 2.5 wt%Cu/SBA-15 catalyst shows one main peak at 290 C
◦
with a shoulder peak at 230 C, which are attributed to bulk and
finely dispersed CuO species respectively. When the copper load-
ing increased from 2.5 to 10 wt%, the main reduction peak is shifted
towards high temperature and become relatively broad. The TPR
profile of 12.5 wt%Cu/SBA-15 sample exhibited typically two stage
Fig. 3. NH3-TPD profiles of (a) Pure SBA-15 (b) bulk CuO (c) 2.5 (d) 5.0 (e) 7.5 (f) 10
and (g) 12.5 wt%Cu supported on SBA-15 samples.
◦
reduction, one around 270 C which is ascribed to the reduction of
finely dispersed CuO on the mesoporous SBA-15, while the reduc-
tion peak at 270–340 C is probably due to the copper cluster
3
.4. NH -TPD analysis of the catalysts
3
◦
interacted with SBA-15 support [37]. The broadening of the signal
and the shift in Tmax toward high temperature may be explained by
the strong metal support interaction and formation of large clusters
of CuO on the support.
The acid site distribution on Cu supported on SBA-15 is classified
◦
based on the NH3 desorption profiles as weak (<200 C), medium
◦
◦
(
200–400 C) and strong acidic sites (>400 C) (Fig. 3) and the acid
site distribution is given in Table S3. The bulk CuO has shown mostly

4
6
V. Boosa et al. / Molecular Catalysis 445 (2018) 43–51
Table 1
Physicochemical characteristics of the catalysts.
Cu wt% on SBA-15
SBET
H2 uptake
NH3 uptake c
N2O uptake/
eSCu/ m2 (gCu)−1
m2
g
−1
)a
(␮mol gcat )b
−1
mmol gcat
−1
(␮mol gcat )d
−1
(
0
2
5
7
1
1
.0
.5
.0
.5
0.0
2.5
639
568
476
425
393
385
nd
nd
nd
nd
248.3
392.6
463.2
578.9
729.6
0.51
0.62
0.74
0.96
0.92
13.8
35.4
67.2
111.6
129.6
45.2
57.9
73.4
91.4
84.9
a
b
c
Determined from N2-sorption analysis.
Calculated from H2-TPR using a calibrated Ag2O TPR curve.
Obtained from TPD of NH3 analysis.
d
e
Obtained from N2O titration.
Calculated using N2O uptake by taking the Cu cross sectional area = 6.8 × 10−20 m2 (Cu atom)−1
.
Fig. 4. Pyridine adsorbed DRIFT spectra of (a) 0.0 (b) 2.5 (c) 5.0 (d) 7.5 (e) 10 and (f)
2.5wt%Cu supported on SBA-15.
Fig. 5. The X-ray photoelectron spectra of (a) 2.5 (b) 5.0 (c) 7.5 (d) 10 and (e)
2.5 wt%Cu supported on SBA-15.
1
1
moderate acid sites which are probably Lewis acidic in nature. The
2
.5 to 12.5 wt%, an increase in the peak intensities are observed indi-
cating high proportion of acid sites at higher loadings (i.e. 10 and
2.5 wt%). These results are consistent with the results obtained
from TPD of NH3 analysis (Fig. 3).
−
1
NH3 uptake is found to be low (∼0.42 ␮mol (gcat) ) on bulk CuO
when compared to the copper supported on SBA-15 samples (Table
1
◦
S3). The minute signal in the temperature region 300–500 C is
due to drift in the baseline as the SBA-15 is known to be a neu-
tral support (Fig. 3a). The copper loaded SBA-15 samples exhibited
3.6. Transmission electron microscopic (TEM) analysis
3
types of acidic sites on the surface. Upon increasing the cop-
per loading on SBA-15 (Table 1), the surface acidity is enhanced
which is explained due to acidic sites contributed from ionic cop-
per species [38]. The TPD of NH3 results demonstrated that a high
ratio of moderate to strong acid sites are present in both 10 wt%
and 12.5 wt% Cu/SBA-15 catalysts compared to lower loadings. For
comparison, the TPD of NH3 is also carried out for 10 wt%Cu/SiO2,
The morphology of Cu/SBA-15 catalysts are analysed by TEM
analysis. As shown in (Fig. S3), the 10wt%Cu/SBA-15 catalyst dis-
plays a 2D hexagonal structure of uniform mesoporous channels
which are typical for SBA-15 type materials. This is in good agree-
ment with the data obtained from the N -physisorption and XRD
2
analysis where the preservation of silica structure after the copper
is impregnated on it. It can be seen that the copper particles are
well dispersed into the channels of SBA-15 and are stabilised by
the silica support material (SBA-15) [41–43]. The TEM image of the
used sample (recovered after the reaction) showed similar texture
and morphology indicating the stability of the catalyst under the
reaction conditions applied (Fig. S3).
1
0 wt%Cu/CeO and 10 wt%Cu/MCM-41 catalysts in which at least 2
2
signals due to NH desorption corresponding to weak and moderate
3
acid sites are observed (Fig. S2).
3.5. Pyridine adsorbed DRIFTS analysis
The nature and type of acid sites (Lewis/Brønsted) present in the
catalysts is examined using pyridine adsorbed FT-IR spectroscopy
Fig. 4). The normalized spectra showed vibrational bands in the
3.7. X-ray photo electron spectroscopic (XPS) analysis
(
−1
range 1700–1400 cm are assigned to both Brønsted and Lewis
acid sites present on the surface of the catalyst according to the
reported literature [39,40]. As shown in Fig. 4, it is evident that
SBA-15 and Cu loaded SBA-15 catalysts showed mainly Lewis acid
The fresh catalysts have been characterized by XPS analysis to
investigate the Cu oxidation state and the chemical composition
at the near surface region (Fig. 5). The binding energy values of
Cu 2p3/2 O 1s and Si 2p (Fig. S4) are in good agreement with the
reported values [22]. The Cu 2p spectra of the various Cu loaded
SBA-15 samples, indicated two main signals at 933.6 and 953.5 eV
−
1
sites (co-ordinated pyridine: ∼1450 and 1610 cm ) on the catalyst
surface with minute amount of Brønsted acidity (protonated pyri-
dine: ∼1540 and 1640 cm− ). Upon increasing the Cu loading from
1
2+
attributed to 2p3/2 and 2p1/2 states of Cu species. An increase in

V. Boosa et al. / Molecular Catalysis 445 (2018) 43–51
47
peak intensity is observed due to the high copper content in higher
Cu loading catalysts (Table S4).
yield of cyanation product is observed (Table 3, entry 1, 24–25) and
further increase in temperature to 140 C, no significant change in
◦
catalytic activity is found (Table 3, entry 26). The reaction time has
also influenced the catalytic activity and formation of desired prod-
uct. At 5 h of reaction time, the yield of product is 25% (Table 3, entry
27). Further increase in reaction time to 16 h, an improved yield
(60% and 95%) of the product is observed (Table 3, entry 28 and
29). The 10 wt%Cu/SBA-15 has been examined at a higher substrate
loading of 2 mmol with ∼1 g of catalyst that showed excellent yield
(89%) towards the desired compound without byproduct formation
(Table 3, entry 30). We have eliminated the ambiguity related to the
influence of other Lewis acid catalyst by testing the activity over ␣-
AlF3 under similar experimental conditions. Using the solid Lewis
acid catalyst i.e. ␣-AlF3 no activity (Table 3, entry 31) towards the
desired product was observed; emphasizing the prominent role of
3
.8. Activity measurements
Table 2 indicates the dependence of the cyanation activity over
various loadings of copper on SBA-15 for the C H bond cyanation
of N-methylindole at 130 C. The pure SBA-15 is found to be inac-
◦
tive for the formation of 3-cyanoindole product. The 3-cyanoindole
formation is found to increase with increase in copper loading up
to a 10 wt% and further increase in Cu loading to 12.5 wt% leads
to no significant changes in the activity. These results therefore
imply that the 10 wt%Cu loading on SBA-15 is an optimum compo-
sition, which established higher yields compared to other loadings
on SBA-15.
Further the reaction parameters are optimized by using N-
Methylindole as the model substrate. Using 150 mg of Cu/SBA-15
catalyst, a combination of NH I (0.36 mmol) and DMF (2 mL) as the
2+
Cu in the in situ generation of CN group and subsequent for-
mation of indole nitriles. In-situ generation of CN group has also
been confirmed using TLC test, which is also cross checked with the
cyanide ion identification test reported by Chahal and Sankar [44].
The influence of Cu2+ species for this reaction is also carried
out over Cu(II) salts such as CuCl2 2H O and Cu(NO ) 3H O
4
cyanating agent and O2 as oxidant; are used achieved 92% yield
of the desired product i.e. 3-cyano-1-methylindole (Table 3, entry
1
). Under similar experimental conditions, using DMSO as the cya-
2
3
2
2
nating agent, lower yield of the product is obtained compared to
which showed about 22 and 18% yields towards the desired prod-
uct respectively (Table 3, entries 32 and 33). These results thus
indicating the bulk Cu2+ species are not much effective for the C3-
cyanation of indoles when compared to the copper dispersed on
SBA-15 catalysts.
DMF (Table 3, entry 2). When DMF is used in presence of H O,
2
4
0% yield is obtained (Table 3, entry 3) and no activity towards
the desired product is observed using acetonitrile (CH CN) as the
3
cyanating agent (Table 3, entry 4). From these results it is evident
that DMF is a suitable “C” source for the 3-cyanoindole reaction. The
influence of oxidizing agent is investigated by employing different
4. Substrate scope
oxidizing agents such as TBHP, Ag O and H O which were found
2
2
2
to show low activity compared to O2 as oxidizing agent (Table 3,
entry 5, 6 and 7). When O2 is replaced with under N2 atmosphere,
very low yield (15%) of the product observed is observed (Table 3,
entry 8). These results thus indicate that O2 is a suitable green oxi-
dant for the 3-cyanoindole reaction. No activity towards the desired
The substituted indoles were subjected to the optimized reac-
tion conditions and the results are illustrated in Fig. 6. The reaction
can be utilized for cyanation of substituted indoles. The regios-
electivity towards the C -cyanation products were exclusively
3
observed in electron rich and electron deficient substituent on
indole rings. It is observed that electron-rich group substituted
substrates reacted more efficiently than electron-deficient group
substituted substrates which is consistent with the rule of elec-
trophilic iodination of indoles. The substrates bearing methyl (-Me)
groups furnished the desired 3-cyanaindoles 69% and 65% yields
product is observed when the “N” source of NH I is replaced with
4
NH OAc and/or NH Cl (Table 3, entry 9, 10). In presence of the aq.
4
4
NH solution, the catalyst displayed poor yield (40%) of the product
3
(Table 3, entry 11). When the reaction is carried out in the absence
of “N”; reaction did not take place (Table 3, entry 12). Therefore,
these results reveal that the presence of NH I is necessary to get
4
(
Fig. 6b and Fig. 6c). To some extent, the reaction is sensitive
the desired product. In summary, the above findings of the cyana-
th
to methoxy substitution on the 4 position of the indole ring
tion reaction suggest that an array of DMF and NH I are feasible
4
(
5
Fig. 6d), delivering the product in a slightly lower yield than its
position of counterpart (Fig. 6e). The reaction of substrates with
‘
CN’ source for this cyanation reaction in combination with O2 as
th
oxidizing agent.
halogen analogues (F and Cl) performed smoothly to the expected
-cyanoindole product 72% and 70% yields respectively (Fig. 6f and
g). In contrast, the electron withdrawing substituent such as −NO
In the absence of copper, no selectivity towards the desired
product is observed over SBA-15 as catalyst (Table 3, entry 13).
In order to see the support role, different supports are also used for
copper such as HAP, Al O , SiO , Mg-LaO, CeO and MCM-41 and
3
2
(
Fig. 6h), −CN (Fig. 6i) and −COOMe (Fig. 6j) were compatible under
2
3
2
2
standard reaction conditions to obtain desired 3-cyanoindoles with
moderate yields of 65%, 63% and 50%respectively. Noteworthy, by
changing substituent on the nitrogen atom, we found that 1H indole
with free ‘NH’ did not show any activity towards the desired prod-
uct (Fig. 6k). Interestingly, the substrates with ethyl and benzyl
groups (Fig. 6l), (Fig. 6m) on the ‘N’ atom led to cyanation process
tested for the cyanation reaction (Table 3, entry 14–19). However,
the results revealed no improved yields of the desired product over
these catalysts compared to Cu/SBA-15; thus suggesting the SBA-15
as suitable support for Cu in the cyanation of N-methylindole reac-
tion. Furthermore, the influence of metal is also investigated using
the other metals such as Ni, Pd and Ru on SBA-15 and the results
of this analysis revealed inferior activity towards the desired prod-
uct compared to Cu/SBA-15 catalyst (Table 3, entry 20–22). Finally,
the superior performance of copper based catalyst towards the
desired product (i.e. 3-cyano-N-methylindole) compared to Ru, Pd
and/or Ni supported on SBA-15 catalysts may possibly explained by
a higher rate of redox cycle on Cu/SBA-15 under the experimental
conditions adopted.
nd
produced good yields 73% and 65% respectively. When the 2 posi-
tion of indole is occupied by a phenyl group substrate (Fig. 6n), the
cyanation reaction with corresponding cyano derivatives of indole
showed very good yield of 70%. Particularly, the heteroaryl indoles
could be successfully converted to the desired product in 55% yield
(
Fig. 6o).
The influence of reaction temperature is also checked for this
reaction under the optimized experimental conditions. At room
temperature, no cyanation product formation is observed over the
4.1. Reaction mechanism for N-methylindole cyanation
Based on the obtained data using various substrates under opti-
mized conditions a plausible mechanism for the cyanation reaction
is illustrated in Scheme 2. The reaction proceeds via two sequen-
1
0 wt%Cu/SBA-15 catalyst (Table 3, entry 23). When the reaction
◦
◦
temperature is increased from 80 C to 130 C, an increase in the

4
8
V. Boosa et al. / Molecular Catalysis 445 (2018) 43–51
Fig. 6. Cyanation of substituted indoles catalyzed by 10 wt%Cu/SBA-15.
2
Scheme 2. Plausible reaction mechanism for C (SP )-H Cyanation over Cu/SBA-15 catalysts.

V. Boosa et al. / Molecular Catalysis 445 (2018) 43–51
49
Table 2
Influence of copper loading on SBA-15 for cyanation activity.
Entry
Substrate
Catalyst
Oxidant
N source
Solvent
Yield (%)
1
2
3
4
5
6
N-Methylindole
N-Methylindole
N-Methylindole
N-Methylindole
N-Methylindole
N-Methylindole
SBA-15
O2
O2
O2
O2
O2
O2
NH4I/0.36
NH4I/0.36
NH4I/0.36
NH4I/0.36
NH4I/0.36
NH4I/0.36
DMF
DMF
DMF
DMF
DMF
DMF
0.0
30
47
65
92
95
2.5 wt%Cu/SBA-15
5.0 wt%Cu/SBA-15
7.5 wt%Cu/SBA-15
10 wt%Cu/SBA-15
12.5 wt%Cu/SBA-15
◦
Reaction conditions: N-Methylindole (0.3 mmol), NH4I (0.36 mmol), 150 mg of Cu/SBA-15 catalyst, DMF (2 mL), Oxidant (O2 balloon) at 130 C for 12 h.
Table 3
Optimization of reaction parameters for the cyanation N-methylindole.
Entry
Substrate
Catalyst
Oxidant
N source
Solvent
Yield (%)
1
2
3
4
5
6
7
8
9
N-Methylindole
N-Methylindole
N-Methylindole
N-Methylindole
N-Methylindole
N-Methylindole
N-Methylindole
N-Methylindole
N-Methylindole
N-Methylindole
N-Methylindole
N-Methylindole
N-Methylindole
N-Methylindole
N-Methylindole
N-Methylindole
N-Methylindole
N-Methylindole
N-Methylindole
N-Methylindole
N-Methylindole
N-Methylindole
N-Methylindole
N-Methylindole
N-Methylindole
N-Methylindole
N-Methylindole
N-Methylindole
N-Methylindole
N-Methylindole
N-Methylindole
N-Methylindole
N-Methylindole
10 wt%Cu/SBA-15
10 wt%Cu/SBA-15
10 wt%Cu/SBA-15
10 wt%Cu/SBA-15
10 wt%Cu/SBA-15
10 wt%Cu/SBA-15
10 wt%Cu/SBA-15
10 wt%Cu/SBA-15
10 wt%Cu/SBA-15
10 wt%Cu/SBA-15
10 wt%Cu/SBA-15
10 wt%Cu/SBA-15
SBA-15
O2
O2
O2
O2
H2O2
TBHP
Ag2O
N2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
NH4I/0.36
NH4I/0.36
NH4I/0.36
NH4I/0.36
NH4I/0.36
NH4I/0.36
NH4I/0.36
NH4I/0.36
NH4Cl
DMF
DMSO
DMF + H2O
CH3CN
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
92
70
40
0.0
35
30
10
15
0.0
0.0
40
0.0
0.0
30
10
30
40
55
0.0
30
70
45
0.0
40
68
94
25
60
95
89
0.0
22
18
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
NH4OAC
NH3(aq)
–
NH4I/0.36
NH4I/0.36
NH4I/0.36
NH4I/0.36
NH4I/0.36
NH4I/0.36
NH4I/0.36
NH4I/0.36
NH4I/0.36
NH4I/0.36
NH4I/0.36
NH4I/0.36
NH4I/0.36
NH4I/0.36
NH4I/0.36
NH4I/0.36
NH4I/0.36
NH4I/0.36
NH4I/0.36
NH4I/0.36
NH4I/0.36
10 wt%Cu/HAP
10 wt%Cu/Al2O3
10 wt%Cu/SiO2
10 wt%Cu/CeO2
10 wt%Cu/MCM-41
10 wt%Cu/Mg-LaO
10 wt%Ni/SBA-15
10 wt%Pd/SBA-15
10 wt%Ru/SBA-15
10 wt%Cu/SBA-15
10 wt%Cu/SBA-15
10 wt%Cu/SBA-15
10 wt%Cu/SBA-15
10 wt%Cu/SBA-15
10 wt%Cu/SBA-15
10 wt%Cu/SBA-15
10 wt%Cu/SBA-15
␣-AlF3
b
c
d
e
f
g
h
i
j
j
CuCl2 2H2O
Cu(NO3)2 3H2O
a
◦
Reaction conditions: N-Methylindole (0.3 mmol), N source (0.36 mmol), 0.150 g of 10wt%Cu/SBA-15 catalyst, Solvent (2 mL), Oxidant (O2 balloon) at 130 C for 12 h.
b
Reaction at room temperature.
c
d
e
f
◦
Reaction at 80 C.
◦
◦
Reaction at 100 C.
Reaction at 140 C.
◦
5
1
1
h at 130 C.
g
h
i
◦
0 h at 130 C.
6 h at 130 C.
◦
◦
Reaction at 130 C for 12 h using N-Methylindole (2 mmol), catalyst: ∼1.0 g.
j
◦
Copper salt amount: 0.150 g, N-Methylindole (0.3 mmol), N source (0.36 mmol), Solvent (2 mL), Oxidant (O2 balloon) at 130 C for 12 h.
tial steps: initial iodination followed by cyanation. In this reaction,
ammonium iodide plays a dual role under the conditions employed:
as a source of iodide for the formation of iodine molecule as well
as a supplier of a nitrogen atom of the cyano unit. An electrophilic
aromatic substitution is believed to be involved in the iodination
of indoles to offer a 3-iodoindole intermediate. The in situ gener-
ated cyanide anion would subsequently take part in the cyanation
of N-methylindoles and it forms the intermediate (II). The inter-
mediate readily undergoes the reductive elimination process and
provides the desired 3-cyano-N-methylindole product. Subsequent
reductive elimination generates Cu(I) and it could be re-oxidized to
Cu(II) by O2 molecule to complete the catalytic cycle [1,45].
4.2. Recyclability studies
The recyclability of the catalyst is investigated over
10 wt%Cu/SBA-15 using N-methylindole, NH4I and DMF at
◦
130 C that showed the consistent activity for three consecutive
cycles (Fig. 7). In the recyclability process, the catalyst recovered
by a simple centrifugation followed by washed with distilled
◦
water, dried at 100 C for 12 h and used directly for the next
cycle without any further purification. The used catalyst is also
extensively characterized using XRD, XPS and ICP-OES analyses
and compared with the characterizations of the fresh catalyst. It
has been observed that no significant changes in the surface and
bulk properties of the used catalyst compared to its fresh form

5
0
V. Boosa et al. / Molecular Catalysis 445 (2018) 43–51
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Appendix A. Supplementary data
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