Pd/Fe3O4 supported on nitrogen-doped reduced graphene oxide for room-temperature isocyanide insertion reactions

Article abstract of DOI:10.1039/c5cy01973g

A versatile Pd/Fe₃O₄ supported on N-doped reduced graphene oxide (N-rGO) catalyst was developed to carry out the synthesis of quinazolinones and phenanthridines under extremely mild conditions through isocyanide insertion cascades. T

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Pd/Fe3O4 supported on nitrogen doped reduced graphene oxide
for room temperature isocyanide insertion reactions†
Karandeep Singh,a Ajay K. Singh,b Devendra Singh,c Rakhi Singh,d and Siddharth Sharmaa*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A versatile Pd/Fe3O4 supported on N-doped reduced graphene in this perspective. Herein, we report the preparation of a
oxide (N-rGO) catalyst was developed to carry out the synthesis of versatile Pd/Fe3O4 supported on N-doped reduced graphene
quinazolinones and phenanthridines under extremely mild oxide (N-rGO) catalyst and its application for the synthesis of
conditions through isocyanide insertion cascades. The supported several N-heterocycles from relatively simple starting material
Pd/Fe3O4 nanoparticles could be easily recovered from the under mild conditions through isocyanide insertion cascades
reaction mixture and reused several times without any loss in (Figure 1). It is worth to mention here that several metal
catalytic acitivity.
assisted methods for the synthesis of quinazolinones and
phenanthridines require harsh conditions and high
temperature.14-18 Whereas our catalytic system provides these
heterocycles under very mild condition and at ambient
temperature.
Quinazolinones and phenanthridines are ubiquitous structural
motifs found in numerous synthetic and natural products of
biological importance.1-2 Several alkaloids such as, 2-methyl-
4(3H)-quinazolinone,3 bouchardatine,4 luotonin (A, B, E),5
auranthine,6 circumdatin (C, F),7 and sclerotigenin8 contain
these heterocycles as the key structural units of their
pharmacophores.
Owing their importance and utility, a number of synthetic
routes have been developed to access these heterocycles.9
Condensation of 2-aminobenzamide with carboxylic acids
using strong dehydrating agents lies amongst the classical
syntheses of quinazolinones.10 In modified versions of this
approach, 2-aminobenzamide has been coupled with
aldehydes11 or aryl acid chloride.12 Recently metal catalyzed
benzylic C-H amidation,13 carbonylative coupling of amines and
aryl halides,14-15 and isocyanide insertion reactions16 were
developed to access quinazolinone derivatives. The reported
methods have their own disadvantages such as harsh reaction
conditions, high reaction temperature, non-recyclability of the
catalyst and expensive ligands. Thus, the development of an
easily recoverable and reusable heterogeneous catalytic
system for the synthesis of quinazolinones is a challenging task
Figure 1. Metal assisted reaction design for isocyanide
insertion.
Immobilization of catalytically active transition metals on the
heterogeneous support has drawn significant interest over the
past decades.19 Recently, the employment of N-doped reduced
graphene oxide (N-rGO) as a metal support was found to be
highly promising due to the spin density and charge
distribution of carbon atoms influenced by the neighbour
nitrogen dopants.20 It induces the high activation of metals on
aDepartment of Chemistry, U.G.C. Centre of Advance Studies in Chemistry, Guru
Nanak Dev University, Amritsar, India, 143005.
bDepartment of Chemical Engineering, Pohang University of Science and
Technology (POSTECH), Pohang, Korea, 790-784.
cDepartment of Chemistry, Pohang University of Science and Technology
(POSTECH), Pohang, Korea 790-784.
d Department of Chemistry, DDU Gorakhpur University, Gorakhpur 273 009, India
E Mail: sidcdri@gmail.com
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
†This paper is dedicated to the memory of Prof. M. S. Hundal
This journal is © The Royal Society of Chemistry 20xx
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the graphene surface and allows reactions to occur under mild isolated, when Fe3O4/N-rGO used as
a
catalyst.
conditions. Considering the advantages associated with N-rGO Aforementioned catalytic study indicates that the only role of
support, we immobilized Pd on N-rGO and evaluated its Fe3O4 may be in the magnetic separation of catalyst. After 24
catalytic activity over several isocyanide insertion reactions h, the product 3a was isolated in 86% with Pd/Fe3O4/N-rGO
(For detail synthesis procedure and characterization of the (Table 1, entry 11), in comparison to 72% with Pd/N-rGO
catalyst, see supporting information). In order to achieve (Table 1, entry 7). To our delight, model reaction for the
magnetically controlled separation of the heterogeneous synthesis of 3a was equally compatible at room temperature
catalyst from the reaction system, magnetite (Fe3O4) particles with Pd/N-rGO as a catalyst (Table-1, entry 12). Effect of bases
were also loaded on N-rGO. The morphology and and solvents were investigated using Pd/Fe3O4/N-rGO as a
microstructures of Pd/Fe3O4/N-rGO were unambiguously catalyst. Many bases such as Cs2CO3, K2CO3 and K3PO4 were
characterized by scanning electron microscopy (SEM) and high- used for the optimization studies however, the best results
resolution transmission electron microscopy (HRTEM). Most were obtained with Cs2CO3 (Table 1, entry 12). Solvent studies
NPs were effectively dispersed with no agglomeration (Figure suggest that dioxane as solvent furnished the product 3a with
2a). Ordered crystalline structure of N-rGO was demonstrated maximum yield (Table 1, entry 12). Better results were not
by interlayer distance 0.37 nm of restored graphitic layers obtained by increasing the amount of synthesized
(Figure 2c), which is consistent with the literature.21 The heterogeneous catalyst (Table-1, entry 13). Poor yield of 3a
atomic scale image by STEM with a probe correction and ~0.1 was obtained when iodo benzene was replaced with bromo
nm point resolution provided the evidence for close proximity benzene (table 1, entry 20) as the coupling partner.
between the Pd and the Fe3O4 particles. The brighter part Table 1. Optimization of reaction condition for the formation of
(yellow circle) corresponds to Pd atoms (Figure 2b) and the quinazolinone 3a.a
less bright part to Fe atoms (Figure 2b) because the intensity is
directly proportional to the square of the atomic number of
the elements. X-ray photoelectron spectroscopy (XPS)
investigations confirmed that Pd/Fe3O4/NrGO contained C, N,
Pd, Fe and O as the main elements (Figure S8 in the Supporting
Entry
Catalyst
Solvent
Base
Yieldb
Information). The palladium content of the Pd/Fe3O4/NrGO
was 2.72 wt % (0.25 mmol g-1) as verified by ICP-AES analysis.
1
2
3
4
5
-
Pd(Ph3)4
Pd(MeCN)2Cl2
Pd2(dba)3
PdCl2
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
0
36
12
26
Trace
6
7
Pd(OAc)2
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
DMSO
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
41
72
NR
29
12
86
84
84
51
56
56
63
38
14
77
Pd/N-rGO
8
Fe3O4/N-rGO
Pd2+/GO
9
10
11
12c
13d
14
15
17
18
19
20e,f
21e,g
Pd/C
Pd/Fe3O4/N-rGO
Pd/Fe3O4/N-rGO
Pd/Fe3O4/N-rGO
Pd/Fe3O4/N-rGO
Pd/Fe3O4/N-rGO
Pd/Fe3O4/N-rGO
Pd/Fe3O4/N-rGO
Pd/Fe3O4/N-rGO
Pd/Fe3O4/N-rGO
Pd/Fe3O4/N-rGO
Figure 2. TEM image of Pd/Fe3O4/N-rGO: (a) low resolution; (b)
Atomic sensitive HAADF image; (c) high resolution image.
K3PO4
Effort was initiated with benchmark reaction of 2-
isocynobenzamide (1a) and aryl iodide (2a) in the presence of
commercially available palladium catalysts (Table 1). Best
conversion of the reaction with Pd catalyst was attained in the
presence of 10 mol% Pd(OAc)2 in dioxane at 1000C and the
product 3a was isolated in 41% yield (Table 1, entry 6). To
establish an approximate activity ranking among the
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DMF
Toluene
Dioxane
Dioxane
synthesized catalysts, model reaction was performed with 1 areaction conditions: 2-isocynobenzamide 1a (1.2 mmol, slow addition),
mol% heterogeneous Pd catalysts at 900C (Table 1, entry 7-11). aryliodide 2a (1.0 mmol), Pd catalyst (10 mol% homogeneous Pd catalyst, 1
The highest activity was attained with Pd/Fe3O4/N-rGO (Table mol% heterogeneous Pd catalyst), and base (2.0 mmol) in solvents (5 mL)
1, entry 11) as catalyst. However no reaction product 3a was under N2 for 24h (Entry 1-6, Temp = 1000C, Entry 7-11, Temp. = 90°C. Entry
2 | J. Name., 2012, 00, 1-3
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b
12-19, Temp = RT. bIsolated yield. cRoom temperature. dCatalyst loading was mol%), and base (2.0 mmol) in solvents (5 mL) for 24h at RT. Isolated yield.
2 mol%. e Bromo benzene was used in place of iodobenzene.freaction time cReaction was completed in 14h.
36h. gTemperature was 90°C. NR = no reaction, RT = room temperature
In heterogeneous catalysis, the reusability of the catalyst is an
Figure 3. Evaluation of the substrate scope.a,b
important issue from the economic and sustainability point of
view. The durability of the catalyst was evaluated by using the
model reaction substrate followed by its separation from the
reaction mixture with an external permanent magnet (Fig.S11).
The synthesized catalyst maintained the recyclability in the
range of 84, 85, 84, 81, 76% yields for 5 run pre-treatment,
with good results.
With the optimized reaction condition, next we surveyed the
generality of the palladium mediated coupling process. The
methodology reported here was found to be compatible with
both electron donating and -withdrawing groups on the phenyl
O
N
O
N
O
N
O
N
NH
NH
ring of
However the yields of quinazolinones were slightly lower with
electron donating aromatic iodides (Figure 3, entries 3b 3c
2 in good to excellent yield as shown in Figure 3.
NH
NH OCH3
3a
(81%)
O
3c
3d
(67%)
O
(70%)
O
3b
3f
(73%)
O
Cl
OCH3
,
NH
F
NH
NH
NH
and 3h). Having established a good scope with substituted aryl
OCH3
OCH3
N
N
N
(63%)
N
(79%)
3h
3g
halides, application of the method to heteroaryl halides (Figure
(86%)
3e
(72%)
Cl
O
O
O
O
Cl
OCH3
3, entries 3i, 3j, 3k and 3l) was also performed. Gratifyingly the
NH
NH
NH
NH
conditions optimized for aryl iodides, provided equally
significant isolated yields (68-72%) for heteroaryl iodides
without any further optimization. Formally divalent carbon
atom on isocyanides facilitates the reaction with amines in the
presence of metal catalyst known to form amidines.22 Having
demonstrated the concept of using an isocyanide insertion
approach for 2-substituted quinazolinone synthesis, we
enhanced the application to 3-substituted quinazolinones
S
O
N
N
(72%)
N
N
(68%)
c
3i
(65%)
3l
3j
(72%)
O
3k
N
N
F
O
N
O
N
O
N
N
N
(73%)
N
OCH3
N
N
5a
5b
(84%)
5d
5c
(56%)
(82%)
CH3
OCH3
O
N
O
N
O
N
N
O
N
N
(66%)
O
N
(73%)
N
5g
O
5f
5h
5e
(68%)
(77%)
CF3
O
O
O
O
(Figure 3, entries 5a-n) using suitable ortho-substituted
N
N
N
N
aromatic isocyanide and amines. It is important to note here,
the developed catalyst was equally compatible for the
synthesis of 3-substituted quinazolinones (14 compounds)
from the reaction of ethyl 2-isocyanobenzoate (1b) and various
aliphatic, aromatic and benzylic amines in good to excellent
yields.
N
Cl
N
CF3
O
N
5i
(66%)
O
N
5j
(77%)
5k
(64%)
Cl
5l
(74%)
OCH3
O
N
N
F
N
N
(69%)
5m
5n
(84%)
Next, the scope of the 2-isocyanobiphenyl
(1c), 1-(2-
isocyanophenyl)naphthalene (1d), 1-(2-isocyanophenyl)-1H-
pyrrole (1e), and 1-(2-isocyanophenyl)-1H-indole (1f) for the
isocyanide insertion and C-H activation cascade reaction was
explored using various aryl iodides. Following the optimized
protocol, a number of nitrogen heterocycles (Figure 3, entries
6a-6j) were synthesized in moderate to high yields (37-75%) at
room temperature, which is otherwise reported at 100°C using
high palladium loading and additives.23 Unambiguous proof for
the structure of phenanthridines was obtained by single crystal
X-ray analysis of the compound 6f (See supporting
information).
To further illustrate the versatility of the developed protocol,
2-isocyanobenzamide
reaction with 2-iodoindole (
2-yl)quinazolin-4(3H)-one (
(
1a
)
was undergo cross-coupling
) for the synthesis of 2-(1H-indol-
7
8
), which can be converted to the
rutaecarpine-type alkaloids bouchardatine and 7-hydroxy-8-
norrutaecarpine (Scheme 1.). Furthermore, the reaction of 2-
isocyanobenzoate
(
1c
)
with tryptamine
(
9)
furnished
aReaction conditions: ortho-functionalized aromatic isocyanides (1a-1f), quinazolinone (10) in 73% yield which is an important
aryliodide (2a-2o) or amine (4a-4n) (1.0 mmol), Pd/Fe3O4/N-rGO catalyst (1 intermediate for the synthesis of natural product
dihydrorutecarpin and rutecarpin (Scheme 1.).24
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for the isocyanide insertion cascade was first developed. This
protocol provided a new avenue for developing quinazolinones
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utilizing Pd/Fe3O4/N-rGO as recyclable catalyst in the vast area
of isocyanide insertion reactions for the synthesis of valuable
intermediates and heterocycles under mild conditions.
This work is supported by the Department of Science and
Technology (DST), Ministry of Science and Technology, India
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