A Pd(ii)/Mg-La mixed oxide catalyst for cyanation of aryl C-H bonds and tandem Suzuki-cyanation reactions

Article abstract of DOI:10.1039/c5nj00585j

A palladium(ii)/magnesium-lanthanum mixed oxide (Pd(ii)/Mg-La) catalyst is a reusable catalyst for cyanation of aromatic C-H bonds by using the combination of NH₄HCO₃ and DMSO as the ''CN'' source. Moderate to good yields of aromatic nitriles were obtained. An excellent regioselectivity was achieved using the present protocol. A tandem process involving Suzuki coupling followed by a cyanation reaction was also developed using the heterogeneous (Pd(ii)/Mg-La) catalyst. This cascade process resulted in the formation of aromatic nitrile from simple 2-halopyridine. The catalyst was recovered by centrifugation and reused for three consecutive cycles with nearly consistent activity and selectivity. This journal is

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A Pd(II)/Mg–La mixed oxide catalyst for cyanation
of aryl C–H bonds and tandem Suzuki–cyanation
reactions†
Cite this:DOI: 10.1039/c5nj00585j
Ramineni Kishore,a Jagjit Yadav,b Boosa Venu,a Akula Venugopala and
M. Lakshmi Kantam*ac
A palladium(II)/magnesium–lanthanum mixed oxide (Pd(II)/Mg–La) catalyst is a reusable catalyst for cyanation
of aromatic C–H bonds by using the combination of NH4HCO3 and DMSO as the ‘‘CN’’ source. Moderate
to good yields of aromatic nitriles were obtained. An excellent regioselectivity was achieved using the pre-
sent protocol. A tandem process involving Suzuki coupling followed by a cyanation reaction was also
developed using the heterogeneous (Pd(II)/Mg–La) catalyst. This cascade process resulted in the formation
of aromatic nitrile from simple 2-halopyridine. The catalyst was recovered by centrifugation and reused for
three consecutive cycles with nearly consistent activity and selectivity.
Received (in Montpellier, France)
8th March 2015,
Accepted 27th April 2015
DOI: 10.1039/c5nj00585j
www.rsc.org/njc
of haloarenes using the metal bound precursor MCN (M = Cu, Na,
K, Zn), TMSCN or K4Fe(CN)6 as the source of the ‘‘CN’’ unit.8–13
Introduction
Aryl nitriles are valuable intermediates in synthetic organic
Transition-metal-catalyzed C–H bond functionalization reac-
chemistry since the nitrile group is an important precursor for tions have now emerged as one of the most efficient tools in the
a broad range of functional group transformations leading formation of C–C and C–hetero atom bonds.14 However, direct
to the formation of amines, aldehydes, acids, ketones, amides cyanation of aryl C–H bonds is comparatively underdeveloped
and heterocycles.1 Aryl nitriles are also key motifs in pharma- compared to other types of C–H functionalization reactions.
ceuticals, agrochemicals, dyes and natural products.2 The The first example of Cu-mediated direct C–H bond cyanation
classical methods for the synthesis of nitrile containing com- was reported by Yu’s group in 2006. They used 2-arylpyridine as
pounds requires pre-functionalization of the arenes with aryl a substrate and TMSCN or CH3NO2 as the ‘‘CN’’ source.15 Other
iodides/bromides (Rosenmund–von Braun reaction)3 and aryl cyanide sources such as metal cyanides,16 isocyanides,17 TsCN,18
diazonium compounds (Sandmeyer reaction).4 Other precursors Me3SiN3,19 BrCN20 and acetone cyanohydrine21 have been used in
such as aldehydes (Schmidt reaction), aldoximes or primary transition-metal-catalyzed oxidative cyanation through C–H bond
carboxamides are also used in cyanation reactions.5–7 In industry, activation. In pursuit of greener and safer ‘‘CN’’ sources for
the ammoxidation reaction is used to synthesise nitriles from cyanation reactions, recently, Chang and his co-workers reported
toluene derivatives in the presence of oxygen and ammonia using an elegant and effective cyanation process through Pd catalyzed
heterogeneous catalysts at high temperature (around 500 1C) and direct C–H bond functionalization using a combination of DMF
high pressure. However, these approaches suffer from multiple and ammonia22 or ammonium iodide23 as a ‘‘CN’’ source. Very
synthetic steps, high cost, harsh reaction conditions, limited recently, Jiao et al. reported the novel cyanation of heterocycles by
functional group tolerance, and use of toxic cyano sources. using DMF as the cyanating source and as a solvent.24 Cheng et al.
Efforts have therefore been directed towards catalytic routes for pioneered the combined use of NH4HCO3 and DMSO as the
synthesising aryl nitriles via transition-metal-catalyzed cyanation source of cyanide in the Pd-catalyzed direct cyanation of indoles.25
These cyanating processes not only obviate the need to pre-
functionalize the arenes but also use non-toxic single or combined
‘‘CN’’ sources. However, despite their exceptional performance,
there are several challenges that have prevented the widespread
practical application of the transition-metal-catalyzed oxidative
cyanation process through C–H bond activation. One such
challenge arises due to the inability to recover and reuse
expensive transition-metals. Industry favors catalytic processes
induced by a heterogeneous catalyst over the homogeneous one
a Inorganic and Physical Chemistry Division, Indian Institute of Chemical
Technology, Hyderabad – 500607, India. E-mail: mlakshmi@iict.res.in;
Fax: +91-40-2716-0921; Tel: +91-40-2719-3510
b Polymers and Functional Materials Division, Indian Institute of Chemical
Technology, Hyderabad – 500607, India
c Department of Chemical Sciences, Tezpur University, Napaam 784028, Assam,
India. E-mail: mlk@tezu.ernet.in
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c5nj00585j
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Scheme 1 Pd(II)/Mg–La mixed oxide catalyzed cyanation of aryl C–H
bonds.
in view of its ease of handling, simple workup, and regener-
ability. Recently, highly basic magnesium–lanthanum mixed
oxide (Mg–La mixed oxide) has found excellent application as a
solid base catalyst for various organic transformations.26–28
Different transition-metal impregnated Mg–La mixed oxide
catalysts have also been developed and used as effective hetero-
geneous catalysts in Heck29a and Kumada coupling29b and
oxidation reactions.29c Recently, we have explored the activity
of air- and moisture-stable palladium impregnated on a Mg–La
mixed oxide catalyst (Pd/Mg–La) in the chemoselective hydro-
genation of olefinic bonds and the oxidative sp2 C–H bond
acylation reaction.30 In search for a suitable heterogeneous
catalyst for the cyanation of aryl C–H bonds in the presence
of other functional groups, we envisaged that Pd(II)/Mg–La
mixed oxide could exhibit interesting catalytic activities.
Herein, we have explored the activity of this Pd(II)/Mg–La mixed
oxide catalyst towards the cyanation of aromatic C–H bonds by
using a combination of NH4HCO3 and DMSO as the ‘‘CN’’
source to provide aromatic nitriles (Scheme 1).
Fig. 1 XRD patterns of the fresh and used Pd(II)/Mg–La mixed oxide
catalysts.
Fig. 2 TEM images of the Pd(II)/Mg–La mixed oxide: (a) fresh and (b) used
catalyst.
Results and discussion
Preparation of catalysts
The Mg–La mixed oxide was synthesized by co-precipitation of
Mg- and La nitrates.29a The Pd-doped Mg–La mixed oxide catalyst
(Pd(II)/Mg–La mixed oxide) was prepared by an impregnation
method (see Experimental section, ESI†).
X-ray diffraction patterns
The X-ray diffraction patterns of the fresh and used Pd(II)/
Mg–La catalysts revealed the presence of both La2O2(CO3) and
PdO phases (Fig. 1). Diffraction lines appeared at 2y = 29.551,
22.841, 13.11 [ICDD # 23-0435] and their corresponding inter
planar spacing values (d) 0.302, 0.389 and 0.675 nm are
attributed to the lanthanum oxide carbonate phase. The diffrac-
tion peaks are observed due to the PdO phase at 2y = 31.71,
45.541, 27.331 with the corresponding d values of 0.282, 0.199,
0.326 nm that are in good agreement with ICDD # 46-1211.
There is no change in the crystal structure of PdO and
La2O2(CO3) phases in both fresh and used form of catalysts.
Fig. 3 The XPS spectra of (Pd 3d5/2, 3d3/2) (a) fresh and (b) used Pd(II)/
Mg–La mixed oxide catalysts.
Interestingly, it is observed that the shape of the particles remains
unchanged. This suggests that the structure and morphology of
the palladium particles remains same even after recycling.
Transmission electron microscope
X-ray photoelectron spectroscopic analysis
The transmission electron microscopy (TEM) images of fresh and The X-ray photoelectron spectroscopic (XPS) analysis of the
used (after 1st cycle) Pd(II)/Mg–La catalysts are shown in Fig. 2a fresh and used (after 4th cycle) Pd(II)/Mg–La mixed oxide
and b. The average Pd particle size is measured by TEM and found catalyst is presented in Fig. 3. The complete XPS spectrum of
to be 25 and 33 nm for fresh and used catalysts respectively. Pd(II)/Mg–La (Fig. S1, ESI†) shows XPS signal at a binding
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energy of 50.5 eV which corresponds to magnesium in the wherein the yield is only 20%. Remarkably, changing the
oxidised form.30c
solvent from DMSO to DMF had a detrimental effect on the
The presence of PdO species on the near surface of the fresh yield of the product as only 58% yield was obtained (Table 1,
catalyst is confirmed by the appearance of XPS signals at entry 9). The use of other heterogeneous palladium catalysts
336.2 eV and 341.8 eV, which corresponds to Pd 3d5/2 and Pd such as Pd(II)/MgO and Pd(II)/La2O3 exhibited inferior yields of
3d3/2 binding energies respectively. The XPS of the recovered the product than the Pd(II)/Mg–La mixed oxide catalyst (Table 1,
catalyst after the fourth cycle showed the 3d5/2 and 3d3/2 peaks entries 10 and 11). It is important to note that the presence of
at 336 eV and 341.2 eV respectively.30d
both palladium and copper is necessary for the formation of
the product (Table 1, entries 12 and 13).
Optimization of conditions
Substrate scope
The optimization studies were performed by using 2-phenyl-
pyridine as the model substrate. When 30 mg of Pd(II)/Mg–La
mixed oxide catalyst (5.5 mol% of Pd), 1 equiv. of Cu(OAc)2ÁH2O
and a combination of NH4HCO3 (1 equiv.) and DMSO (2 mL) as
the cyanating agent were used, the desired product 2-(pyridin-2-yl)-
benzonitrile was obtained in 43% yield (Table 1, entry 1).
Encouraged by this result, several optimization studies were
conducted by altering the oxidant, nitrogen source and solvents.
Results from these studies are summarized in Table 1. An
improvement in the product yield is observed when the amount
of Cu(OAc)2ÁH2O and NH4HCO3 is increased from 1 equivalent to
2 and 2.1 equivalents respectively (Table 1, entries 1–3).
As seen in Table 1, the choice of oxidant has a crucial role in
the reaction outcome. Excellent yield of the product was obtained
when the oxidant is either Cu(NO3)2Á3H2O or Cu(OAc)2ÁH2O
(Table 1, entries 1–4). However, we chose to continue the reaction
with Cu(NO3)2Á3H2O, since it is considerably cheaper than
Cu(OAc)2ÁH2O. When the amount of palladium was reduced,
a decrease in the yield of the product was observed (Table 1,
entry 4). Performing the reaction at a lower temperature of
120 1C or for a shorter period of 12 h has a detrimental effect on
the product yield (Table 1, entry 5). Interestingly, there is no
reaction observed using other oxidants such as K2S2O8 and aqu-
eous tert-butyl hydroperoxide (TBHP) (Table 1, entries 6 and 7).
Importantly, we found that NH4HCO3 is a better source of nitrogen
in the cyanation reaction than ammonia (Table 1, entries 3 and 8)
Eventually, the catalytic system consisting of Pd(II)/Mg–La
(30 mg, 5.5 mol% of Pd), Cu(NO3)2Á3H2O (2 equiv.) as the oxidant
and the combination of NH4HCO3 (2.1 equiv.) and DMSO (2 mL)
as the cyanating reagent at 140 1C temperature was chosen for
the cyanation reaction of an array of 2-phenylpyridine derivatives
and the results are summarized in Fig. 4.
With 4-methyl 2-phenylpyridine, the corresponding mono
cyano derivative was obtained in 82% yield (Fig. 4, entry 2). To
some extent, the reaction was sensitive to methyl substitution
on the meta position of the 2-phenyl ring (Fig. 4, entry 3),
delivering the product in a slightly lower yield than its para
counterpart (Fig. 4, entries 2 and 3). In contrast, for electron
deficient 4-fluoro, -chloro and -bromo substituted analogues,
Table 1 Screening of reaction parametersa
Nitrogen
source/equiv.
Entry Oxidant/equiv.
Solvent Yield (%)
1
2
3
4
5
6
7
Cu(OAc)2ÁH2O/1
Cu(OAc)2ÁH2O/2
Cu(OAc)2ÁH2O/2
Cu(NO3)2Á3H2O/2
Cu(NO3)2Á3H2O/2
K2S2O8/2
NH4HCO3/1
NH4HCO3/1
NH4HCO3/2.1
NH4HCO3/2.1
NH4HCO3/2.1
NH4HCO3/2.1
DMSO 43
DMSO 61
DMSO 92
DMSO 87, 66b, 48c
DMSO 66d, 70e
DMSO
DMSO
0
0
TBHP (70% aqueous)/2 NH4HCO3/2.1
8
9
10
11
12
13
Cu(NO3)2Á3H2O/2
Cu(NO3)2Á3H2O/2
Cu(NO3)2Á3H2O/2
Cu(NO3)2Á3H2O/2
—
NH3 (25% aq.)/2.1 DMSO 20
NH4HCO3/2.1
NH4HCO3/2.1
NH4HCO3/2.1
NH4HCO3/2.1
NH4HCO3/2.1
DMF
58
DMSO 60f
DMSO 58g
DMSO
0
Cu(NO3)2Á3H2O/2
DMSO 0h
a
Reaction conditions: 30 mg Pd(II)/Mg–La (5.5 mol% of Pd), 2-phenyl-
pyridine (0.5 mmol), solvent (2 mL), 140 1C, 18 h. b 20 mg catalyst (3.6 mol%
of Pd). c 10 mg catalyst (1.8 mol% of Pd). d 12 h reaction. e Reaction at
f
g
h
120 1C. Using Pd(II)/MgO catalyst. Using Pd(II)/La2O3 catalyst. Without
Fig. 4 Substrate scope of the cyanation reaction.
catalyst.
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moderate yields of the products were obtained (Fig. 4, entries
4–6). Other functional groups such as –CF3, –CN and –OMe also
survived the reaction conditions, giving the corresponding
cyano derivatives of 2-phenylpyridine in moderate yields
(Fig. 4, entries 7–10). Remarkably, bulkier 2-naphthyl and
1-naphthyl derivatives of pyridine also furnished the cyanation
product with moderate yields under the present reaction con-
ditions (Fig. 4, entries 11 and 12).
Scheme 2 Tandem Suzuki–cyanation reaction.
Interestingly, isoquinoline and quinoline could act as direct- concluded that the reaction proceeds under heterogeneous
ing groups as well, delivering the corresponding aryl nitriles in conditions and that there are no leached palladium species
79% and 73% yields respectively (Fig. 4, entries 13 and 14). in the solution.
Gratifyingly, benzo[h]quinoline also demonstrated good effi-
ciency in the current cyanation reaction and produced the
corresponding cyanated product in 63% yield (Fig. 4, entry 15).
Tandem Suzuki–cyanation reaction
Tandem reactions represent an important avenue to improve the
synthetic efficiency by rapidly increasing the molecular complexity
while minimizing the number of isolation and purification steps.31
For the preparation of starting materials for the cyanation reactions,
we have used the Pd(II)/Mg–La mixed oxide catalyzed Suzuki
coupling reaction (Fig. S1, ESI,† entries c–m and o). The hetero-
geneous Pd(II)/Mg–La mixed oxide catalyst produced excellent yields
of the coupled product. Intrigued with these results, we were
interested in developing a tandem process where starting from
2-halopyridine derivatives, cyano derivatives of 2-phenylpyridine
could be synthesised in a single pot without any intermediary
separation and isolation steps. The tandem Suzuki–cyanation reac-
tion of 2-bromopyridine produced the desired cyanated product
2-(pyridin-2-yl) benzonitrile in moderate yields of 72% (Scheme 2).
Test of recyclability
The feasibility of repeated use of the Pd(II)/Mg–La mixed oxide
catalyst in the cyanation reaction was also examined. Fig. 5
presents the results from the investigation of recycling of the
catalyst using 2-phenylpyridine as the model substrate on a
1.5 mmol scale. The Pd(II)/Mg–La mixed oxide catalyst shows
consistent activity and selectivity up to 4 cycles. After each cycle,
the Pd(II)/Mg–La mixed oxide catalyst was recovered by simple
centrifugation, washed with water (100 mL), oven-dried and
used directly for the next cycle without any further purification.
No loss of catalytic activity was observed for the catalyst in the
cyanation of aryl C–H bonds. Moreover, leaching of the palladium
metal after each cycle was determined by AAS (Table S1, ESI†).
From Table S1 (ESI†) it could be observed that the amount of Conclusions
palladium is nearly consistent in each of the cycles, which
In conclusion, we have developed a simple and efficient method
indicates the absence of leached palladium species in the solution.
To determine the heterogeneity of the catalyst, we have
carried out two experiments. In the first experiment, the reac-
tion was terminated after three hours. At this juncture, the
catalyst was separated from the reaction mixture at the reaction
temperature (140 1C) and the reaction was continued with the
filtrate for an additional 18 hours. The conversion was found to
remain almost identical before and after removal of the
catalyst. In the second experiment, the Pd(II)/Mg–La mixed
oxide catalyst was stirred at 140 1C for ten hours and the filtrate
was used for the cyanation reaction. No product formation was
observed. Hence from these two experiments, it could be
for the cyanation of aromatic C–H bonds by using a Pd(II)/Mg–La
mixed oxide catalyst using a combination of Cu(NO3)2Á3H2O as
an oxidant, NH4HCO3 and DMSO as the ‘‘CN’’ source to provide
aromatic nitriles in moderate to good yields with excellent
regioselectivity. A tandem process involving Suzuki coupling
followed by cyanation reaction was also developed using the
heterogeneous (Pd(II)/Mg–La) catalyst. The catalyst can be readily
recovered by simple centrifugation and reused with consistent
activity and selectivity for three cycles. We hope that this
methodology may find widespread use in the synthesis of
aromatic nitriles.
Experimental section
A 10 mL round bottom flask was charged with 2-phenylpyridine
(77.59 mg, 0.5 mmol), NH4HCO3 (83 mg, 1.05 mmol, 2.1 equiv.),
Pd(II)/Mg–La (30 mg, 5.5 mol% of Pd), Cu(NO3)2Á3H2O (187.5 mg,
1 mmol, 2 equiv.) and DMSO (2 mL). The reaction mixture was
stirred at 140 1C for 18 h. After the completion of the reaction, as
monitored by TLC, 5 mL of ethyl acetate was added in the
reaction mixture. The catalyst was separated by simple centri-
fugation and the reaction mixture was treated with brine (10 mL).
The organic layer was separated and the aqueous layer was back
extracted with ethyl acetate (3 Â 5 mL). The combined ethyl
Fig. 5 Recyclability of the catalyst in the cyanation reaction.
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acetate extract was dried with anhydrous Na2SO4 (50 gm) and References
was concentrated under reduced pressure. The pure product was
1 (a) R. C. Larock, Comprehensive Organic Transformations: A
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isolated by flash column chromatography on silica gel using
ethyl acetate–hexane (10%) as an eluent (pale yellow oil, 156 mg,
87% yield).
2 (a) A. J. Fatiadi, in Preparation and Synthetic Applications of
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Recyclability test
The recyclability of the catalyst was checked using 2-phenyl-
pyridine as the model substrate on a 1.5 mmol scale. A 25 mL
round bottom flask was charged with 2-phenylpyridine (232.7 mg,
1.5 mmol), Pd(II)/Mg–La catalyst (90 mg, 5.5 mol% of Pd), Cu(NO3)2Á
3H2O (562.5 mg, 2 equiv.), NH4HCO3 (249 mg, 2.1 equiv.), DMSO
(6 mL) and stirred at 140 1C for 18 h. After the completion of the
reaction, as monitored by TLC, 15 mL of ethyl acetate was added
in the reaction mixture. The catalyst was recovered by simple
centrifugation, washed with water (100 mL), air-dried and used
directly for the next cycle without further purification. The Pd(II)/
Mg–La mixed oxide catalyst shows consistent activity and selec-
tivity up to 4 cycles. Leaching of Pd species from the solid
catalyst after the first cycle was determined by atomic absorption
spectroscopy (AAS) and was found to be negligible. The Pd
content of the fresh catalyst was 9.76% and in the case of used
catalyst after the first cycle it was found to be 9.68% as measured
by AAS. Table S1 (ESI†) contains the Pd loading of the catalysts
in each of the reaction cycles.
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General catalytic procedure for the tandem Suzuki–cyanation
reaction
A 25 mL round bottom flask was charged with 2-bromopyridine
(96 mg, 1 mmol), phenylboronic acid (182 mg, 1.5 mmol),
Pd(II)/Mg–La (40 mg), K3PO4Á7H2O (424 mg, 2 mmol) and 50%
aqueous isopropanol (3 mL). The reaction mixture was stirred
at 80 1C and was monitored by TLC. After the completion of the
reaction (3 h), the reaction mixture was brought to room
temperature and charged with NH4HCO3 (236 mg, 3 mmol),
Cu(NO3)2Á3H2O (454 mg, 2.5 mmol) and DMSO (2 mL). The
reaction was continued at 140 1C for another 18 h. After the
completion of the reaction, as monitored by TLC, 10 mL of
ethyl acetate was added and the catalyst was separated by
simple centrifugation. The reaction mixture was treated with
brine (10 mL) and the organic layer was separated. The aqueous
layer was back extracted with ethyl acetate (3 Â 5 mL). The
combined ethyl acetate extract was dried with anhydrous
Na2SO4 (50 gm) and was concentrated under reduced pressure.
The pure product was isolated by flash column chromato-
graphy on silica gel using ethyl acetate–hexane (10%) as an
eluent (pale yellow oil, 129 mg, 72% yield).
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Acknowledgements
R.K. thanks CSIR, New Delhi, for the award of Senior Research
Fellowship. B.V. thanks UGC for the award of Junior Research
Fellowship.
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