A Pd/Cu-Free magnetic cobalt catalyst for C-N cross coupling reactions: synthesis of abemaciclib and fedratinib

Article abstract of DOI:10.1039/d1gc00518a

Herein, the synthesis of a nano-catalytic system comprising magnetic nanoparticles as the core and edible natural ligands bearing functional groups as supports for cobalt species is described. Subsequent to its characterization, the efficiency of the catalyst was investigated for C-N cross-coupling reactions using assorted derivatives of amines and aryl halides. This novel and easily accessible Pd- and Cu-free catalyst exhibited good catalytic activity in these reactions using γ-valerolactone (GVL) at room temperature; good recyclability bodes well for the future application of this strategy. The introduced catalytic system is attractive in view of the excellent efficiency in an array of coupling reactions and its versatility is illustrated in the synthesis of abemaciclib and fedratinib, which are FDA-approved new and significant anti-cancer medicinal compounds that are prepared under green reaction conditions.

Full text of DOI:10.1039/d1gc00518a

Green Chemistry
View Article Online
View Journal | View Issue
PAPER
A Pd/Cu-Free magnetic cobalt catalyst for C–N
cross coupling reactions: synthesis of abemaciclib
and fedratinib†
Cite this: Green Chem., 2021, 23,
222
5
a
a,b
a
Zahra Khorsandi,
Rajender S. Varma
Acbdol R. Hajipour,
*
*
Mohamad Reza Sarfjoo and
Herein, the synthesis of a nano-catalytic system comprising magnetic nanoparticles as the core and
edible natural ligands bearing functional groups as supports for cobalt species is described. Subsequent
to its characterization, the efficiency of the catalyst was investigated for C–N cross-coupling reactions
using assorted derivatives of amines and aryl halides. This novel and easily accessible Pd- and Cu-free
catalyst exhibited good catalytic activity in these reactions using γ-valerolactone (GVL) at room tempera-
ture; good recyclability bodes well for the future application of this strategy. The introduced catalytic
system is attractive in view of the excellent efficiency in an array of coupling reactions and its versatility is
illustrated in the synthesis of abemaciclib and fedratinib, which are FDA-approved new and significant
anti-cancer medicinal compounds that are prepared under green reaction conditions.
Received 8th March 2021,
Accepted 17th June 2021
DOI: 10.1039/d1gc00518a
rsc.li/greenchem
In this regard, the use of inexpensive 3d transition-metals
Introduction
8
9,10
11–19
such as iron, nickel
and copper
has exhibited signifi-
In recent decades, cross-coupling reactions using noble tran- cant progress. However, various disadvantages of most of
sition-metal catalysts have been gaining importance in aca- these methods limit their applications, for example, appli-
1
demic and industrial synthetic chemistry. More than half of cation of higher temperatures, longer reaction times, usage of
all the C–C and C–heteroatom bond-forming reactions in drug stoichiometric amounts of metal catalysts, low catalyst
discovery studies involve palladium-catalyzed cross-coupling efficiency, and consumption of volatile solvents and expensive
2
reactions. Due to the broad use of heterocyclic compounds in ligands. Thus, the development of a more efficient, convenient
medicinally important derivatives and natural products, the Pd-free method is desirable. Although Cu is a known tra-
development of facile approaches for the construction of C–N ditional catalyst for C–N and C–O cross-coupling reactions, the
bonds has become one of the attractive research topics in the propensity of copper to promote oxidative homocoupling and
3
–6
−1
synthetic organic chemistry.
the greater toxicity of Cu (safe value is set at around 5 mg kg )
Conventionally, the Pd-catalyzed C–N coupling of amines in comparison with that of Co (safe value is set at around
and aryl halides is an efficient and versatile reaction pro- 150 mg kg− ) motivated us to shift our research focus to the
1
2
0
cedure. Besides their high cost and scarcity, the use of palla- development of Cu-free catalytic systems. Cobalt catalytic
dium catalysts can lead to contamination of pharmaceutical systems were found to be efficient and non-toxic, with cobalt
compounds. These conditions provide a strong motivation for being a stable metal and a low-cost alternative to palladium
7
21–27
finding alternative valuable catalytic systems.
for deployment in organic chemistry.
Very recently, Szostak et al. reported the Kumada cross-
coupling of aryl tosylates with alkyl and aryl Grignard reagents.
They succeeded in introducing an efficient cobalt catalytic
system, but it deployed expensive N-heterocyclic carbene
a
Department of Chemistry, Isfahan University of Technology, Isfahan 415683111,
Iran. E-mail: haji@cc.iut.ac.ir
b
28
Department of Neuroscience, University of Wisconsin, Medical School, 1300
ligands and suffered from non-reusability of the catalyst.
University Avenue, Madison, 53706-1532 WI, USA
In 2020, Chu et al. developed the dehydrogenative coupling
c
Regional Centre of Advanced Technologies and Materials, Czech Advanced
of aromatic diamines and primary alcohols catalyzed by the
Technology and Research Institute, Palacký University in Olomouc, Šlechtitelů 27,
7
2
9
homogeneous Co(II) complex.
83 71 Olomouc, Czech Republic. E-mail: Varma.Rajender@epa.gov
Almost all available cobalt catalytic systems deploy homo-
†
Electronic supplementary information (ESI) available. See DOI: 10.1039/
d1gc00518a
geneous cobalt species; despite good efficiency, they suffer
5222 | Green Chem., 2021, 23, 5222–5229
This journal is © The Royal Society of Chemistry 2021

View Article Online
Green Chemistry
Paper
from disadvantages such as their high propensity for aggrega- expensive nature and toxicity of Pd-based catalysts, the intro-
tion, low stability, and recycling problems which can lead to a duction of efficient, environmentally safe, and low-cost Pd-free
reduction in their catalytic activities.
catalysts is valuable. Herein, a thorough investigation of the
Various solid supports have been used to overcome these efficiency of the synthesized magnetic cobalt catalyst in C–N
problems via immobilization of metal nanoparticles. In this coupling reactions was carried out and its synthetic applica-
regard, magnetic nanoparticles (MNPs) have attracted much bility to produce the two aforementioned valuable drugs
attention as a supporting catalyst material due to their numer- (Scheme 1) was evaluated.
ous merits such as low cost and toxicity, high surface area,
facile separation process, ease of preparation, and easy
3
0,31
functionalization procedure.
Coating of MNPs with
organic compounds is necessary to avoid MNP agglomeration Results and discussion
during the catalytic reaction.
From the point of view of green chemistry, abundantly
available natural carbohydrate compounds are suitable for
The catalyst preparation process is shown in Scheme 2. The
magnetic nanoparticles were reacted with mannitol through a
simple and mild protocol. Then, the magnetic hydroxyl-rich
carbohydrate hybrid was reacted with CoCl2 to generate the
final solid catalyst which is termed Co-MTL@MNPs; detailed
synthesis procedures are provided in the ESI.†
The process steps for the preparation of Co-MTL@MNPs
were examined using the relevant analysis such as FT-IR,
elemental analysis and TGA. The FT-IR spectrum of the cata-
lyst preparation steps is given in Fig. 1.
3
2–36
coating the MNPs,
namely their environmentally friendly nature, low cost, and
stability, only few reports on their applications are
and despite their various advantages
a
3
7–40
available.
Encouraged by our previous knowledge attained on the use
4
1–45
of cobalt heterogeneous catalysts,
herein, a novel, sustain-
able, and inexpensive heterogeneous cobalt catalyst was pre-
pared using MNPs possessing various safe and readily avail-
able ligands including mannitol, sorbitol, xylitol, tartaric acid,
malic acid, and citric acid. After preparation and appropriate
characterization, their efficiency in C–N cross-coupling reac-
tions was explored.
Over the past years, scientists have been encouraged to find
alternative cleaner procedures for the traditional chemical
syntheses by using greener solvents,
In the spectra of pure MNPs (Fig. 1(a)), the Fe–O vibration
−
1
mode is indicated by the appearance of bands at 572 cm . In
−
1
the spectra of b (MTL@MNPs), the bands at 1000–1300 cm
are related to the C–O group vibrations, and the vibration
mode of O–H appeared at 3431 cm− (Fig. 1(b)). The FT-IR
spectra of the catalyst are shown in Fig. 1(c) which affirms the
expected structure.
1
4
6–53
and performing
organic reactions in an eco-friendly manner using safe sol-
vents is now of paramount interest. One of the non-toxic and
very suitable solvent alternatives to classic polar aprotic sol-
vents is γ-valerolactone (GVL). Moreover, it is accessible via a
low-cost efficient process with many excellent properties which
5
4,55
make it an ideal solvent of choice for large-scale synthesis.
Most of the reported cross-coupling reaction procedures
require elevated temperatures and inert reaction conditions.
While a few procedures have been conducted under room-
5
6
temperature conditions, this strategy is considered green as Scheme 1 The structures of fedratinib and abemaciclib.
it avoids the generation of hazardous materials and by-pro-
5
7,58
ducts at elevated temperatures.
Moreover, the avoidance of
an inert atmosphere bodes well for its application on a large-
scale, thus conforming to an upward trend in green chemistry.
One of the important pharmaceutical compounds, which
have been synthesized through the C–N cross-coupling reac-
tion is fedratinib, which is a JAK2 inhibitor anti-cancer agent
5
9,60
that was recently approved by the FDA.
A practical syn-
thetic route for fedratinib preparation was developed in two
steps based on the Pd-catalyzed C–N cross-coupling reaction
6
1
by TargeGen Inc. Abemaciclib is another FDA approved
pharmaceutical which is a cyclin-dependent kinase (CDK)
selective ATP inhibitor used for the treatment of hormone-
receptor-positive breast cancer and could be synthesized via a
Pd-catalyzed C–N coupling reaction. The only accepted and
efficient method for the large-scale preparation of these com-
6
2
pounds involves the use of a palladium salt. Considering the Scheme 2 Synthesis of the catalyst.
This journal is © The Royal Society of Chemistry 2021
Green Chem., 2021, 23, 5222–5229 | 5223

View Article Online
Paper
Green Chemistry
removal of the organic species; these observations confirmed
the stability of the catalyst at elevated temperatures. The total
−
1
amount of organic moieties on the catalyst was 4.21 mmol g
,
as determined by elemental analysis. The results of the TGA
and elemental analysis showed acceptable agreement with the
elemental analysis results. The phase of the catalyst was deter-
mined from its XRD spectrum. The characteristic diffraction
peaks at 30.25°, 35.73°, 43.6°, 47.84°, 53.95°, 57.6°, 63.2°, and
3 4
67.4° were attributed to Fe O , and the peaks at 2θ of 62.80°,
58.85, 37.70, and 33.50 were ascribed to the cobalt species
(
Fig. 2b). The magnetic properties of the catalyst were investi-
gated by VSM. The reduction of the magnetic behaviour of the
catalyst in comparison with that of raw magnetic nanoparticles
22.1 emu g− vs. 69.4 emu g ) confirmed the organic coating
1
−1
(
of the catalyst (Fig. 2c).
The investigation of the XPS of cobalt in the catalyst
showed two spin–orbit doublets arising from 2p and 2p1/2.
3
/2
3
+
+
The Co 2p3/2 component corresponded to Co and Co
2
, thus,
and Co species. Based
on available knowledge, the presence of a shoulder is related
3 4
to the presence of the CoO phase. The Fe 2p peak for Fe O
+
3+
Fig. 1 FT-IR spectra: (a) magnetic nanoparticles (MNPs); (b) mannitol-
coated magnetic nanoparticles (MNPs@MNL); and (c) the final catalyst
confirming the presence of the Co
2
(
MNPs@MNL-Co).
2
+
3+
disintegrated into Fe and Fe peaks that confirmed the for-
4
5,46
mation of Fe O .
The Co loading of the catalyst was
3
4
−
1
The TGA and elemental analysis are used to investigate the measured by ICP and it was about 1.38% (0.22 mmol g
number of organic moieties in the catalyst. The TGA diagram, (Fig. 3).
in Fig. 2a, shows the weight loss of the catalyst as a function of
The FE-SEM and TEM images were used for surface mor-
)
temperature in the range 30–800 °C. The first step of weight phology characterization, and the images of the sizing
loss in these cases is related to the elimination of adsorbed diagram of the catalyst are shown in Fig. 4; the average-size of
water and the additional weight loss is attributed to the the nanoparticles was ∼13 nm.
Fig. 2 (a) TGA thermogram; (b) XRD pattern; and (c) room temperature magnetization curve of the catalyst.
Fig. 3 The XPS spectra of the catalyst.
5224 | Green Chem., 2021, 23, 5222–5229
This journal is © The Royal Society of Chemistry 2021

View Article Online
Green Chemistry
Paper
Fig. 4 TEM images; FE-SEM images; and the nanoparticle size diagram of the catalyst.
For catalytic studies and finding the most efficient catalyst, benzene (1.1 mmol). The effect of various catalysts was exam-
the magnetic nanoparticles were functionalized with the ined, and the results are summarized in Table 1, entries 1–6;
various mentioned hydroxyl-rich small carbohydrate molecules the best yield of the product was achieved using the catalyst
and their influence was studied in the C–N cross-coupling containing the mannitol ligand. The model reaction was per-
model reaction, the reaction of indole (1.0 mmol) and bromo- formed in the presence of cobalt supported on magnetic nano-
particles without any ligands (Table 1, entry 1), and poor
product efficiency was observed, which confirmed the positive
a
effect of the ligand in promoting the reaction. Next, the mag-
netic-free catalyst was also prepared and its efficiency was
examined (Table 1, entry 7), and no significant difference
between the operation of this catalyst and our best catalyst
showed virtually no effect of the iron element on the improve-
ment of the reaction. In further studies on the catalyst, the
effect of various amounts of the catalyst was investigated in a
model reaction, and 10 mg amount was found to be the suit-
able quantity (Table 2).
Table 1 Screening of the catalysts
The same reaction was then conducted at various tempera-
tures. Given that carrying out the reaction under mild reaction
conditions was of importance, the reaction was performed at
room temperature, and in comparison, no considerable
improvement was achieved at 50 °C or at 80 °C. Then, the
influence of different solvents was assessed, from the perspec-
tive of green chemistry, as finding an effective, environmen-
tally-friendly and readily available solvent was a high priority.
Among the various tested solvents, including DMA, DMF, NMP
and GVL, GVL appeared to be the best option. The effect of the
base was also investigated and K CO was chosen as the suit-
2 3
able base. The optimized reaction conditions of the model
reaction are presented in Table 2.
After finding the best reaction conditions, its generality and
versatility in the synthesis of numerous amino derivatives was
examined (Table 3). The aryl halides contain substituents with
different electronic properties and they reacted efficiently with
indole and high yields of the products were obtained.
b
b
Entry
Catalyst
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
MNPs@MTL-Co
MNPs@STL-Co
MNPs@XTL-Co
MNPs@TA-Co
MNPs@MA-Co
MNPs@CA-Co
MNL-Co
8
86
80
84
71
69
54
87
39
10
10
10
10
10
8
MNP@Co
12
a
Reaction carried out with indole (1.0 mmol) and bromobenzene
1.1 mmol), using 10 mg of catalyst (0.22 mol% Co) under the opti-
mized reaction conditions, under air. GC yields obtained by using
decane as an internal standard.
(
b
This journal is © The Royal Society of Chemistry 2021
Green Chem., 2021, 23, 5222–5229 | 5225

View Article Online
Paper
Green Chemistry
a
Table 2 Optimization of the reaction conditions
According to the results, it appears that the electronic pro-
perties of the precursors had no significant influence on the
reaction outcomes.
To expand the substrate range, the reactions of diphenyla-
mine and several aryl halides were also explored under the
optimized reaction conditions, and products were obtained
with good to excellent conversions (Table 4). The generality of
the reaction was studied by using a variety of aryl halides and
imidazoles (Table 5). The reaction of imidazole with iodo- and
bromobenzene resulted in the desired products in good yields.
Gratifyingly, the introduced easy-to-prepare heterogeneous
catalytic system, created from the safe and easily available
ligand and cobalt, exhibited high activity in multiple C–N
b
Catalyst
Base
T
Yield
Entry (mg per Co mol%) (mmol)
Solvent
(°C) (%)
1
2
3
15 (0.33)
10 (0.22)
5 (0.11)
K
K
K
3
PO
3
PO
3
PO
4
4
4
(4)
(4)
(4)
DMF
DMF
DMF
120
120
120
97
93
88
4
5
6
10 (0.22)
10 (0.22)
10 (0.22)
K
K
K
3
PO
3
PO
3
PO
4
4
4
(4)
(4)
(4)
DMA
NMP
GVL
120
120
120
90
87
95
7
8
9
1
10 (0.22)
10 (0.22)
10 (0.22)
10 (0.22)
—
NaHCO
Na CO
GVL
3
(4) GVL
120
120
120
120
93
89
—
90
2
3
(4)
GVL
GVL
0
1
2
3
K
K
K
K
2
2
2
2
CO
CO
CO
CO
3
3
3
3
(4)
(3)
(2)
(5)
Table 4 N-Arylation of diphenylamine with aryl halides catalyzed by
MNPs@MTL·Co
a
1
1
1
10 (0.22)
10 (0.22)
10 (0.22)
GVL
GVL
GVL
120
120
120
82
63
91
1
1
1
1
4
5
6
7
10 (0.22)
10 (0.22)
10 (0.22)
10 (0.22)
K
K
K
K
2
2
2
2
CO
CO
CO
CO
3
3
3
3
GVL
GVL
GVL
GVL
90
60
45
r.t.
88
88
87
86
b
Entry
X
R
Yield (%)
1
2
3
4
5
6
7
8
9
Br
Br
Br
Br
Br
Br
Br
Cl
Cl
4-OCH
H
4-NO
4-CN
4-COCH
3-CH
3-OCH
H
3
90
88
85
83
79
81
79
76
72
1
8
9
0
10 (0.22)
10 (0.22)
10 (0.22)
K
K
K
2
CO
2
CO
2
CO
3
3
3
(4)
(4)
(4)
PEG (200) r.t.
82
64
51
2
1
2
H O
r.t.
r.t.
3
2
2-MeTHF
3
3
a
The reaction was carried out with the model reaction of indole
(
(
1.0 mmol), bromobenzene (1.1 mmol), base (4 mmol), and solvent
3.0 mL), under air, for 8 h. GC yields obtained by using decane as an
4-OCH
3
b
a
The reaction was carried out with indole (1.0 mmol), bromobenzene
CO (4 mmol), GVL (3.0 mL), and 10 mg catalyst, at r.t.,
under air, for 10 h. GC yields obtained by using decane as an internal
standard.
internal standard.
(
1.1 mmol), K
2
3
b
Table 5 N-Arylation of imidazole with aryl halides catalyzed by
MNPs@MTL·Co
Table 3 N-Arylation of indole with aryl halides catalyzed by
MNPs@MTL·Co
a
a
b
b
Entry
X
R
Yield (%) Entry
X
R
Yield (%)
1
2
3
4
5
6
7
8
9
Br
Br
Br
Br
Br
Br
Br
Cl
Cl
Cl
4-OCH
H
3
82
86
87
89
83
86
81
63
66
69
1
2
3
4
5
6
7
8
9
Br
Br
Br
Br
Br
Br
Br
Cl
Cl
Cl
4-OCH
H
3
91
89
84
80
82
81
85
71
68
73
4-NO
4-CN
2
4-NO
4-CN
2
4-COCH
3-CH
3
4-COCH
3-CH
3
3
3
3-OCH
4-OCH
H
3
3-OCH
H
3
3
4-NO
4-OCH
2
10
4-NO
2
10
3
a
a
The reaction was carried out with indole (1.0 mmol), bromobenzene
CO
The reaction was carried out with indole (1.0 mmol), bromobenzene
CO (4 mmol), GVL (3.0 mL), and 10 mg catalyst, at r.t.,
(
1.1 mmol), K
under air, for 8 h. GC yields obtained by using decane as an internal under air, for 10 h. GC yields obtained by using decane as an internal
standard. standard.
2
3
(4 mmol), GVL (3.0 mL), and 10 mg catalyst, at r.t., (1.1 mmol), K
2
3
b
b
5226 | Green Chem., 2021, 23, 5222–5229
This journal is © The Royal Society of Chemistry 2021

View Article Online
Green Chemistry
Paper
a
Table 6 N-Arylation of aliphatic amines
Table 8 Recyclability of the catalyst in the model reaction of C–N
coupling reaction
a
a
Run
Yield (%)
Run
Yield (%)
1
2
3
4
86
83
82
80
5
6
7
8
73
70
63
-
b
Entry
X
R
Alkylamine
Yield (%)
1
2
3
I
H
79
71
76
a
GC yields obtained by using decane as an internal standard.
Br
Br
4-OMe
4-NO
2
a
The reaction was carried out with indole (1.0 mmol), bromobenzene
(4 mmol), GVL (3.0 mL), and 10 mg catalyst, at r.t.,
(1.1 mmol), K
COb
2 3
under air, 10 h. GC yields obtained by using decane as an internal
standard.
coupling reactions including indole (Table 3), diphenylamine
(
Table 4), and imidazole (Table 5) as substrates. This hetero-
Scheme 3 Fedratinib synthesis process.
geneous catalytic system also exhibited high activity in the
coupling of aryl halides with aliphatic amines (Table 6). The
corresponding products were obtained in moderate to excel-
lent yields under extremely mild reaction conditions in
greener media.
The efficiency of the prepared catalyst for the C–N reaction
was compared with those of other similar Pd-free catalysts
used for this reaction. These results are presented in Table 7
and they indicate the good performance of our heterogeneous
catalyst in this context.
One of the serious problems with homogeneous catalysts as
conventional promoters in these types of syntheses is the
difficulty in separation, and hence the recyclability of the cata-
lyst was studied using the model reaction.
After the completion of the reaction, the catalyst was easily Scheme 4 Abemaciclib synthesis process.
separated via a magnetic bar, washed with hot ethanol, dried,
and applied in the next catalytic cycle. Until its seventh reuse,
no discernible decrease in activity could be detected (Table 8).
Encouraged by these promising findings and considering
FT-IR, XRD, ICP and TEM analyses were deployed for the the need to develop such methods for the synthesis of medic-
characterization of the reused catalyst, and the results are pro- inal compounds, our optimized method was applied to the
vided in the ESI.† In comparison with the analysis of fresh cat- synthesis of fedratinib and abemaciclib, which are antitumor
alysts, very little changes can be seen. In the recovered catalyst, agents recently approved by the FDA. Fedratinib is a JAK2
the cobalt content of the seven-time used catalyst was identi- inhibitor and is used for the oral treatment of adult patients
−
1
60
fied by ICP as 0.16 mmol g which in comparison with a with advanced myelofibrosis, while abemaciclib is a drug
−1
65
fresh one (0.22 mmol g ) indicates minor metal leaching. The used for the treatment for advanced breast cancers. The
TEM images of the reused catalyst are presented in the ESI;† structure and synthesis steps of these compounds are shown
the aggregation of the catalyst is not more than that of the in Schemes 3 and 4. Accordingly, the introduced cobalt cata-
fresh catalyst.
lytic system was effectively applied to the synthesis of fedrati-
Table 7 Comparison of the catalytic activity of some reported Pd-free heterogeneous catalysts in N-aryl reactions
Entry
Catalyst
Reaction conditions
EtOH/H O; hv; K CO
Yield (derivative)
Ref.
1
2
3
4
5
6
Hexaphenylbenzene-Fe
2
O
3 2
-Cu O
2
2
3
/6 h
85 (triphenylamine)
94 (diphenylamine)
93 (1-phenyl-1H-indole)
71 (1-phenyl-1H-indole)
65 (diphenylamine)
86 (indole)
63
37
12
41
Cu/ascorbic acid@MNPs
Fe /L-proline
2
H O, KOH, r.t./6 h
O
2 3
DMSO, tBuONa, 135 °C/24 h
DMSO, KOH, 80 °C, 8 h
DMF, KOH, 80 °C, 8 h
MNPs/melamine/Co
MC-81@Co/Cu
MNPs@MTL-Co
64
2
GVL, K CO
3
, r.t., 8 h.
This work
This journal is © The Royal Society of Chemistry 2021
Green Chem., 2021, 23, 5222–5229 | 5227

View Article Online
Paper
Green Chemistry
nib and abemaciclib with acceptable overall yields and the pro- 13 S. Nagao, T. Matsumoto, Y. Koga and K. Matsubara, Chem.
ducts obtained were purified by flash column chromatography. Lett., 2011, 40, 1036.
The characterization data of the products are available in the 14 F. Chen, N. Liu, E. Ji and B. Dai, RSC Adv., 2015, 5, 51512.
ESI.†
15 A. Modak, A. J. Nett, E. C. Swift, M. C. Haibach, V. S. Chan,
S. F. Thaddeus, Sh. Shekhar and S. P. Cook, ACS Catal.,
2020, 10, 10495–10499.
Conclusions
16 A. R. Sardarian, I. D. Inaloo and M. Zangiabadi, New J.
Chem., 2019, 43, 8557.
Herein, a sustainable and low energy consuming method
deploying an innovatively designed recyclable catalyst is suc-
cessfully introduced for the general C–N cross-coupling reac-
tions. A variety of derivatives obtained from these reactions
have been readily synthesized in excellent yields. Moreover,
this is the first report on the successful synthesis of fedratinib
and abemaciclib (anti-cancer agents) using a Pd/Cu-free cata-
lyst. Finally, the heterogeneity of the catalyst is confirmed
through the recyclability assessments. In general, the intro-
duced procedure is a facile, mild and green method that does
not lead to hazardous metal pollution.
1
1
1
2
2
7 M. Nasrollahzadeh, A. R. Vartooni, A. Ehsani and
M. Moghadam, J. Mol. Catal. A: Chem., 2014, 387, 123–129.
8 R. Mostafalu, B. Kaboudin, F. Kazemi and T. Yokomatsu,
RSC Adv., 2014, 4, 49273.
9 K. Shimizu, K. Shimura, M. Nishimura and A. Satsuma,
RSC Adv., 2011, 1, 1310.
0 K. A. C. De Schamphelaere and C. R. Janssen, Environ. Sci.
Technol., 2006, 40, 4514.
1 L. M. Kumar and B. R. Bhat, Appl. Organomet. Chem., 2017,
827, 41.
2
2
2 R. M. Ansari and B. R. Bhat, J. Chem. Sci., 2017, 129, 1483.
3 S. Asghar, S. B. Tailor, D. Elorriaga and R. B. Bedford,
Angew. Chem., Int. Ed., 2017, 56, 16367.
Conflicts of interest
2
2
2
2
2
2
3
4 A. Mohammadinezhad and B. Akhlaghinia, Green Chem.,
2017, 19, 5625.
There are no conflicts to declare.
5 G. S. S. Treesa, M. Neetha, S. Saranya and G. Anilkumar,
ChemistrySelect, 2020, 5, 7400.
6 H. Hosseini Moghadam, S. Sobhani and J. M. Sansano, ACS
Omega, 2020, 5, 18619.
7 C. Dorval, M. Tricoire, J. M. Begouin, V. Gandon and
C. Gosmini, ACS Catal., 2020, 10, 12819.
8 A. Piontek, W. Ochędzan-Siodłak, E. Bisz and M. Szostak,
ChemCatChem, 2021, 13, 202.
Acknowledgements
We gratefully acknowledge the funding support received for
this project from the Isfahan University of Technology (IUT),
IR Iran.
9 M. Zuo, W. Guo, Y. Pang, R. Guo, Ch. Hou, Sh. Sun, H. Wu,
Zh. Sun and W. Chu, New J. Chem., 2020, 44, 144.
0 R. B. N. Baig and R. S. Varma, Green Chem., 2013, 15, 398.
Notes and references
1
2
3
4
A. Meijere, S. Bräse and M. Oestreich, Metal-Catalyzed 31 R. Hudson, Y. Feng, R. S. Varma and A. Moores, Green
Cross-Coupling Reactions and More, Wiley, 2014. Chem., 2014, 16, 4493.
A. Piontek, E. Bisz and M. Szostak, Angew. Chem., Int. Ed., 32 R. B. N. Baig and R. S. Varma, Green Chem., 2013, 15, 839.
2
018, 57, 11116.
P. Ruiz-Castillo and S. L. Buchwald, Chem. Rev., 2016, 116,
2561.
S. D. Roughley and A. M. Jordan, J. Med. Chem., 2011, 54,
451.
33 M. G. Dekamin, M. Azimoshan and L. Ramezani, Green
Chem., 2013, 15, 811.
34 J. Ye, B. Wang, J. Xiong and R. C. Sun, Carbohydr. Polym.,
2015, 135, 57.
35 F. Bellia, D. La Mendola, C. Pedone, E. Rizzarelli,
M. Saviano and G. Vecchio, Chem. Soc. Rev., 2009, 38,
2756.
1
3
5
6
7
D. G. Brown and J. Boström, J. Med. Chem., 2016, 59, 4443.
J. P. Corbet and G. Mignani, Chem. Rev., 2006, 106, 2651.
B. Schlummer and U. Scholz, Adv. Synth. Catal., 2004, 346, 36 G. F. Zhang, Y. X. Luan, X. W. Han, Y. Wang, X. Wen,
1
599.
C. R. Ding and J. R. Gao, Green Chem., 2013, 15, 2081.
37 A. R. Hajipour, M. Check and Z. Khorsandi, Appl.
Organomet. Chem., 2017, 31, 3769.
8
9
D. S. Surry and S. L. Buchwald, Chem. Sci., 2011, 2, 27.
J. F. Hartwig, Carbon–heteroatom bond formation cata-
lyzed by organometallic complexes, Nature, 2008, 455, 314– 38 C. C. Chen, L. Lin, R. P. Ye, M. L. Sun, J. X. Yang, F. Li and
22. Y. G. Yao, J. Catal., 2020, 389, 421.
0 J. Bariwal and E. Eycken Van der, Chem. Soc. Rev., 2013, 42, 39 T. Nemcsok, Z. Rapi, G. Keglevich, A. Grün and P. Bakó,
283. Chirality, 2018, 30, 407.
1 J. Zhang, S. Wang, Y. Zhang and Z. Feng, J. Org. Chem., 40 X. Ge, S. Zhang, X. Chen, X. Liu and C. Qian, Green Chem.,
020, 9, 1519. 2019, 21, 2771.
2 C. Y. Gao, X. Cao and L. M. Yang, Org. Biomol. Chem., 2009, 41 A. R. Hajipour and Z. Khorsandi, Tetrahedron Lett., 2020,
, 3922. 61, 151396.
3
1
1
1
9
2
7
5228 | Green Chem., 2021, 23, 5222–5229
This journal is © The Royal Society of Chemistry 2021

View Article Online
Green Chemistry
Paper
4
4
4
4
4
2 A. R. Hajipour and Z. Khorsandi, Appl. Organomet. Chem., 54 M. Bagherzadeha, H. Mahmoudi, S. Ataie, M. Bahjatia,
2
020, 34, 5398.
R. Kiaa, P. R. Raithby and L. Vaccaroc, Mol. Catal., 2019,
3 A. R. Hajipour, Z. Khorsandi, Z. Abeshtiani and S. Zakeril,
J. Inorg. Organomet. Polym., 2020, 30, 2163–2171.
4 A. R. Hajipour, Z. Khorsandi and H. Farrokhpour, New J.
Chem., 2019, 43, 8215.
474, 110406.
55 Sh. Shadpoor, A. Pirouzi, H. Hamze and D. Mazaheri,
Chem. Eng. Res. Des., 2021, 165, 61.
56 F. Nouri, Sh. Rostamizadeh and M. Azad, Mol. Catal., 2017,
5 A. R. Hajipour, Z. Khorsandi, F. Fakhari, M. Mortazavi and
H. Farrokhpour, ChemistrySelect, 2018, 3, 6279.
6 P. R. Boruah, A. A. Ali, S. Bishwajit and D. Sarma, Green
Chem., 2015, 17, 1442.
443, 286.
57 C. F. Poole and N. Lenca, TrAC, Trends Anal. Chem., 2015,
71, 144.
58 G. Brahmachari, ACS Sustainable Chem. Eng., 2015, 3,
4
4
7 R. S. Varma, ACS Sustainable Chem. Eng., 2016, 4, 5866.
8 L. Y. Xie, S. Peng, F. Liu, Y. F. Liu, M. Sun, Z. L. Tang, 59 F. Passamonti and M. Maffioli, Blood, 2018, 131, 2426.
S. Jiang and Z. Cao, ACS Sustainable Chem. Eng., 2019, 7, 60 H. A. Blair, Drugs, 2019, 79, 1719.
2350.
7
193.
61 A. Tefferi, Compositions and Methods for Treating
Myelofibrosis, WO2012060847, 2012.
4
5
5
5
5
9 F. Messa, G. Dilauro, F. M. Perna, P. Vitale and V. Capriati,
ChemCatChem, 2020, 12, 1979.
0 K. Kubota, R. Takahashi, M. Uesugi and H. Ito, ACS
Sustainable Chem. Eng., 2020, 8, 16577.
1 M. Niakan, M. Masteri-Farahani, S. Karimi and 63 G. Singh, M. Kumar and V. Bhalla, Green Chem., 2018, 20,
H. Shekaari, J. Mol. Liq., 2021, 324, 115078. 5346.
2 M. Niakan, M. Masteri-Farahani, H. Shekaari and 64 L. Esrafili, A. Morsali, F. D. Firuzabadi and P. Retailleau,
S. Karimi, Carbohydr. Polym., 2021, 251, 117109. ACS Appl. Mater. Interfaces, 2020, 12, 43115.
3 J. M. Tukacs, B. Marton, E. Albert, I. Toth and L. T. Mika, 65 S. Yuan, B. Yu and H. M. Liu, Eur. J. Med. Chem., 2020, 205,
J. Organomet. Chem., 2020, 923, 121407. 112667.
62 M. P. Goetz, M. Toi, M. Campone, J. Sohn, S. Paluch-
Shimon, J. Huober, I. H. Park, O. Trédan, S. C. Chen and
L. J. Manso, Clin. Oncol., 2017, 35, 3638.
This journal is © The Royal Society of Chemistry 2021
Green Chem., 2021, 23, 5222–5229 | 5229