Porous chitosan microspheres supported-palladium catalyst for the C-N cross-coupling of aryl halides with secondary amines

Article abstract of DOI:10.3184/174751913X13571448166475

Porous chitosan microspheres-supported palladium catalysed the amination of aryl halides with a wide variety of secondary amines to yield the corresponding cross-coupling products under aerobic conditions. Both aryl bromides and iodides gave good to excellent yields of N,N-disubstituted anilines. The procedure can tolerate common functional groups such as chloro, methoxyl and nitro. The heterogeneous catalysis is efficienct and the catalyst could be recycled seven times without obvious decreased conversion.

Full text of DOI:10.3184/174751913X13571448166475

JOURNAL OF CHEMICAL RESEARCH 2013
RESEARCH PAPER 99
FEBRUARY, 99–101
Porous chitosan microspheres supported-palladium catalyst for the C–N
cross-coupling of aryl halides with secondary amines
Kai Cheng, Minfeng Zeng and Chenze Qi*
Zhejiang Key Laboratory of AlternativeTechnologies for Fine Chemicals Process, Shaoxing University, Shaoxing, 312000, P. R. China
Porous chitosan microspheres-supported palladium catalysed the amination of aryl halides with a wide variety of
secondary amines to yield the corresponding cross-coupling products under aerobic conditions. Both aryl bromides
and iodides gave good to excellent yields of N,N-disubstituted anilines. The procedure can tolerate common func-
tional groups such as chloro, methoxyl and nitro. The heterogeneous catalysis is efficienct and the catalyst could be
recycled seven times without obvious decreased conversion.
Keywords: C–N cross-coupling, supported palladium catalysis, recyclable catalyst, N,N-disubstituted anilines
Arylamines are highly useful and valuable reactive inter-
mediates, are widely present in natural products1–3 and also
have numerous important industrial applications such as in
antioxidants,4,5 photography,6 advanced materials,7 agrochemi-
cals8 and pharmaceuticals.9,10 Thus the development of more
economical and environmentally benign methods for the
synthesis of arylamines is of interest both academically and
industrially.
The traditional approaches for the construction of aryl
carbon–nitrogen chemical bonds usually require harsh reac-
tion conditions and/or activated substrates, which are often
inefficient or unreliable.11 Most recently, illustrated by the
recipient of the 2010 Nobel Prize in chemistry, palladium-
catalysed cross-couplings have been demonstrated to be one of
the most important reactions for the construction of carbon–
carbon and/or carbon–heteroatom bonds in synthetic organic
chemistry, not least due to their enormous efficiency and
selectivity as well as tolerance for many common functional
groups.12,13 However, in spite of their robustness and high effi-
ciency, the palladium-catalysed cross-couplings of aryl halides
with amines still have some limitations.
were obtained using the weaker bases, of the corresponding
acetates and carbonates (entries 4–7, Table 1).
The optimised conditions for the Pd-catalysed cross-cou-
pling amination can also be applied to many other secondary
amines as is evident in Table 2. Indeed, these palladium-
catalysed reactions took place with high functional group
tolerance. Substituting a morpholine ring for the piperidine
ring resulted in a negligible effect on the isolated amination
yield (entry 2, Table 2). But the introduction of an o-methyl
substituent slightly decreased the amination yield (entry 3,
Table 2), presumably due to the increased steric hindrance.
The isolated amination yield was found to be 73% when a
fused benzene ring is introduced (entry 4, Table 2). A slight
decrease of the isolated yield was observed for the shrinkage
of six member- into five member-ring (entries 5 and 6, Table
2). The relative size of the amine’s alkyl groups appears to
have only small effects on cross-coupling amination yields
(entries 7–10, Table 2). Nevertheless, the cross-coupling
amination of dicyclohexylamine resulted in a relatively lower
yield (~64%) (entry 11, Table 2), clearly due to the severe
steric hindrance of the two cyclohexyl groups.
It is not uncommon to find certain aryl halide substrates that
are incompatible with the palladium catalytic system, includ-
ing those with ortho-substituents, secondary alcohols, amines,
amides, carboxylic acids or active methylene groups. Since
palladium is a relatively expensive and toxic transition metal,
it is highly desirable to develop cheaper, more selective and
environmentally friendly transition metal catalysts for such
important chemical transformations. Recently, we reported
that porous chitosan microspheres-supported palladium het-
erogeneous catalysts have been evaluated using the Ullmann
reductive homocoupling and the Heck cross-coupling reac-
tions.14,15 Further study, however, was needed of the activities,
stabilities and recyclability of the porous chitosan micro-
spheres-supported palladium catalysts. Here we present an
efficient synthesis for a variety of arylamines by supported-
palladium-catalysed cross-coupling amination of aryl halides
without the need for inert-gas protection.
The scope and limitation of the aryl halides employed have
also been investigated for the Pd-catalysed cross-coupling
amination and the results are summarised in Table 3. A series
of para-substituted aryl bromides were examined in order to
obtain additional insight into the catalytic mechanism. The
system bearing either an electron-withdrawing or an electron-
donating group can be coupled with piperidine in excellent
yield (entries 1–7, Table 3). Common functional groups,
including chloro, methoxyl and nitro, were perfectly tolerated
under the optimised reaction conditions, indicating the supe-
rior reactivity and selectivity of the system. An essentially
Table 1 Effects of various bases on the yield of the palladium-
catalysed cross-coupling amination of bromobenzene with
piperidinea
Results and discussion
Initial studies on the influence of the reaction conditions were
optimised with bromobenzene and piperidine as the model
substrates by using 2.0 mol% of the porous chitosan micro-
spheres-supported palladium catalyst in DMSO at 100 °C
without inert gas protection. A series of inexpensive and com-
mercially available bases were first screened for the reaction
and the results are summarised in Table 1. Among the bases
screened, the best performances with the yields up to 97%
were obtained for the strong bases Cs2CO3, t-BuONa and
t-BuOK (entries 1–3, Table 1). It is worth noting that only
slightly reduced cross-coupling amination yields (79–89%)
Entry
Base
Yield/%b
1
2
3
4
5
6
7
Cs2CO3
t-BuONa
t-BuOK
K2CO3
Na2CO3
NaOAc
KOAc
94
92
97
87
79
80
89
a Reaction conditions: piperidine (1.0 mmol), bromobenzene
(0.5 mmol), base (1.0 mmol), chitosan-Pd (2.0 mol%) and DMSO
(2.0 mL) at 100 °C for 12 h. b The cross-coupling amination
yields were determined by GC.
* Correspondent. E-mail: qichenze@163.com

100 JOURNAL OF CHEMICAL RESEARCH 2013
Table 2 Supported Pd-catalysed cross-coupling amination of
Table 3 Supported Pd-catalysed cross-coupling amination of
bromobenzene with various aminesa
aryl bromides and iodides with piperidinea
Entry
R-Halide
Yield/% b
Entry
1
Amine
Product
Yield/% b
97
1
2
3
4
5
6
7
C6H5Br
97
86
98
82
95
83
85
4-MeO–C6H4Br
4-Me–C6H4Br
4-Cl–C6H4Br
4-NO2–C6H4Br
2-Cl–C6H4Br
2-NO2–C6H4Br
2
3
95
86
8
86
9
10
11
12
13
14
15
C6H5I
87
89
91
80
83
86
80
4-MeO–C6H4I
4-Me–C6H4I
4-Cl–C6H4I
4
5
6
73
84
88
4-NO2–C6H4I
2-Cl–C6H4I
2-NO2–C6H4I
16
83
7
8
Et2NH
n-Bu2NH
i-Bu2NH
i-Pr2NH
Cy2NH
Et2NPh
n-Bu2NPh
i-Bu2NPh
i-Pr2NPh
Cy2NPh
89
80
74
70
64
a Reaction conditions: piperidine (0.6 mmol), aryl halides
(0.5 mmol), t-BuOK (1.0 mmol), chitosan-Pd (2.0 mol%) and
DMSO (2.0 mL) at 100 °C for 12 h. b GC cross-coupling amina-
tion yields.
9
10
11
a Reaction conditions: amines (0.6 mmol), bromobenzene
(0.5 mmol), t-BuOK (1.0 mmol), chitosan-Pd (2.0 mol%) and DMSO
(2.0 mL) at 100 °C for 12 h. b GC cross-coupling amination
yields.
In conclusion, the Pd-catalysed cross-coupling amination of
aryl halides with a wide range of secondary amines has been
achieved. The porous chitosan microspheres-supported palla-
dium catalysis process proceeded with high efficiency without
the need for additional ligands. Moreover, the inexpensive and
simple operation of this environmental friendly Buchwald–
Hartwig amination would appear to make it attractive for
industrial applications.
identical amination yield (90
8%) was obtained for the
unsubstituted and for four para-substituted phenyl bromides
(R=H, OCH3, CH3, Cl and NO2) (entries 1–5, Table 3). Simi-
larly, introduction of an o-chlorine, o-nitro or a fused benzene
ring resulted in negligible effects on the isolated cross-
coupling amination yields (entries 6–8, Table 3). The catalytic
system also coped with substituted aryl iodides (entries 9–16,
Table 3). For example, 80–91% yield of amination products
was obtained with para-substituted aryiodides (entries 9–13,
Table 3).
The reaction of piperidine with iodobenzene was chosen as
a model reaction to test the scope for recycling the heteroge-
neous catalyst. It was found that the recovered chitosan-Pd
heterogeneous catalyst, after a thorough wash with ethanol and
drying at 100 °C after each run, conserved > 80% catalytic
activity over seven cycles. This suggested that palladium leach-
ing is not significant, presumably due to the strong chelation of
the chitosan amino and hydroxyl groups with the palladium
species.
The reaction presumably proceeds through steps similar to
those known for palladium-catalysed C–N coupling reactions,
the first step being the formation of the cationic arylpalladium
complex (A) through the oxidative insertion of the active Pd0
species into the aryl halide, ArX (Scheme 1). Then, the
arylpalladium complex A couples with the secondary amine
(e.g. piperidine) to form intermediate B, leading to the Pd(II)
intermediate C by neutralisation of the acidic by-product HX
by a base. In the final step, extrusion of the cross-coupled
amination product occurs to regenerate the reductive Pd0 active
species to complete the catalytic redox cycle.
Scheme 1

JOURNAL OF CHEMICAL RESEARCH 2013 101
(d, J = 7.2 Hz, 4H), 1.98–2.38 (m, 2H), 1.32–1.41 (m, 4H), 0.92 (d,
J = 6.8 Hz, 12H); HRMS (EI) Calcd for C14H23N (M+) 205.1830;
found 205.1828.
Experimental
Chitosan (pharmaceutical grade, 95% deacetylated, 1.2×105) was pur-
chased from the Zhejiang Aoxing Biotechnology Company (Zhejiang,
China). Polyethylene glycol (MW: 2.0×104) and glutaraldehyde were
purchased from the Chinese Pharmacy Group Shanghai Reagent
Company (Shanghai, China). Palladium chloride (PdCl2) was pur-
chased from the Zhejiang Metallurgical Research Institute (Zhejiang,
China). The porous chitosan-supported palladium catalyst was pre-
pared as described previously.14 Acetic acid and DMSO were obtained
from the Guangdong Xilong Chemical Company (Guangdong, China).
All other solvents and chemicals are analytical grade or the best grade
available and used without further purification.
N,N-Diisopropylaniline (T2-10, CAS: 4107-98-6): 1H NMR: δ
7.42 (d, J = 7.2 Hz, 2H), 7.32 (t, J = 7.6 Hz, 2H), 7.10 (t, J = 7.2 Hz,
1H), 4.85–5.28 (m, 1H), 4.01–4.42 (m, 4H), 1.31 (d, J = 5.2 Hz, 12H);
HRMS (EI) Calcd for C12H19N (M+) 177.1517; found 177.1515.
N,N-Dicyclohexylaniline (T2-11, CAS: 63302-13-6): 1H NMR:
δ 7.41 (d, J = 7.2 Hz, 2H), 7.31 (t, J = 7.6 Hz, 2H), 7.08 (t, J = 7.2 Hz,
1H), 4.82–5.20 (m, 1H), 3.24–3.69 (m, 1H), 1.83 (d, J = 10.0 Hz, 8H),
1.67–1.71 (m, 4H), 1.33–1.44 (m, 4H), 1.18–1.25 (m, 4H); HRMS
(EI) Calcd for C18H27N (M+) 257.2143; found 257.2146.
1-(4-Methoxyphenyl)piperidine (T3-2, CAS: 5097-25-6): 1H NMR:
δ 7.39 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 9.2 Hz, 2H), 3.80 (s, 3H), 3.71
(t, J = 5.2 Hz, 4H), 1.66–1.72 (m, 6H); HRMS (EI) Calcd for C12H17NO
(M+) 191.1310; found 191.1310.
The quantitative analysis of the reaction products was performed on
an Agilent 6890/5975 GC/MS instrument with a programmable split/
splitless injector. The injector-port temperature was set at 270 °C. The
oven-temperature program was initially set at 80 °C and ramped to
220 °C at 5 °C min−1, and maintained at 220 °C for 2 min at each step.
Proton NMR spectra were recorded in CDCl3 on a Bruker AVANCE
III 400 MHz spectrometer. Proton chemical shifts are reported in parts
per million (ppm) relative to tetramethylsilane with the residual
solvent peak as the internal reference. Multiplicities are reported as:
singlet (s), doublet (d), triplet (t) and multiplet (m). HRMS (EI) data
were collected on a high resolution mass spectrometer MAT95XP,
Thermo Finnigan, USA.
1
1-(p-Tolyl)piperidine (T3-3, CAS: 31053-03-9): H NMR: δ 7.33
(d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.4 Hz, 2H), 3.73 (t, J = 5.2 Hz, 4H),
2.33 (s, 3H), 1.66–1.72 (m, 6H); HRMS (EI) Calcd for C12H17N (M+)
175.1361; found 175.1362.
1-(4-Chlorophenyl)piperidine (T3-4, CAS: 55376-34-6): 1H NMR:
δ 7.36 (d, J = 8.8 Hz, 2H), 7.27 (d, J = 8.8 Hz, 2H), 3.76 (t, J = 5.6 Hz,
4H), 1.66–1.72 (m, 6H); HRMS (EI) Calcd for C11H14ClN (M+)
195.0815; found 195.0814.
1-(4-Nitrophenyl)piperidine (T3-5, CAS: 6574-15-8): 1H NMR:
δ 8.18 (d, J = 9.2 Hz, 2H), 7.49 (d, J = 9.2 Hz, 2H), 3.89 (t, J = 5.2 Hz,
4H), 1.72–1.78 (m, 6H); HRMS (ESI) Calcd for C11H14N2O2 (M+)
206.1055; found 206.1053.
C–N cross-coupling reaction; general reaction
A mixture of aryl halide (0.5 mmol), chitosan-Pd (2 mol%), t-BuOK
(1 mmol) and aniline (0.6 mmol) was stirred in DMSO (2 mL) at
100 °C for 6 h. Afterwards, the reaction solution was filtered and
water (2 mL) was added to the filtrate. The solution was extracted by
Et2O (3 × 2 mL). The organic phase was combined and evaporated
under reduced pressure. The residue was purified on a SiO2 column to
afford the desired product and the yield was determined by GC.
1-(2-Chlorophenyl)piperidine (T3-6, CAS: 54121-55-0): 1H NMR:
δ 7.43 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.19 (t, J = 8.4 Hz,
1H), 7.05 (t, J = 8.0 Hz, 1H), 3.83 (t, J = 5.2 Hz, 4H), 1.67–1.73 (m,
6H); HRMS (EI) Calcd for C11H14ClN (M+) 195.0815; found
195.0817.
1
1-(2-Nitrophenyl)piperidine (T3-7, CAS: 15822-77-2): H NMR:
δ 7.66 (d, J = 7.6 Hz, 1H), 7.54 (d, J = 7.2 Hz, 1H), 7.45 (t, J = 7.2 Hz,
1H), 7.17 (t, J = 7.2 Hz, 1H), 3.83 (t, J = 5.2 Hz, 4H), 1.68–1.74 (m,
6H); HRMS (EI) Calcd for C11H14N2O2 (M+) 206.1055; found
206.1059.
Pd/PCMS separation and reuse; general procedure
After completion, the chitosan microspheres were separated from the
reaction mixture. They were rinsed with ethanol 3 times; followed by
a treatment in an oven at 110 °C for about 20 min before the next
run.
1-(Naphthalen-1-yl)piperidine (T3-8, CAS: 62062-39-9): 1H NMR:
δ 8.57 (d, J = 9.2 Hz, 1H), 7.81 (d, J = 9.2 Hz, 1H), 7.66 (d, J = 7.6 Hz,
1H), 7.41–7.50 (m, 4H) 3.88 (t, J = 5.2 Hz, 4H), 1.69–1.75 (m, 6H);
HRMS (EI) Calcd for C15H17N (M+) 211.1361; found 211.1357.
1
1-Phenylpiperidine (T2-1, CAS: 4096-20-2): H NMR: δ 7.43 (d,
J = 8.0 Hz, 2H), 7.33 (t, J = 8.0 Hz, 2H), 7.14 (t, J = 7.2 Hz, 1H), 3.77
(t, J = 5.2 Hz, 4H), 1.68–1.74 (m, 6H). HRMS (EI) Calcd for C11H15N
(M+) 161.1204; found 161.1200.
1
This study was financially supported by the National Science
Foundation of China (grant numbers 21172149 and 21203123)
and the Science Technology Department of Zhejiang Province
(grant number 2012R10014-15).
4-Phenylmorpholine (T2-2, CAS: 92-53-5): H NMR δ 7.45 (t,
J = 7.2 Hz, 2H), 7.36 (d, J = 7.6 Hz, 2H), 7.20 (t, J = 7.2 Hz, 1H), 3.86
(t, J = 5.2 Hz, 4H), 3.78 (t, J = 5.2 Hz, 4H). HRMS (EI) Calcd for
C10H13NO (M+) 163.0997; found 163.0998.
2-Methyl-1-phenylpiperidine (T2-3, CAS: 14142-16-6): 1H NMR:
δ 7.43 (d, J = 7.2 Hz, 2H), 7.33 (t, J = 8.0 Hz, 2H), 7.14 (t, J = 7.2 Hz,
1H), 4.18–4.37 (m, 1H), 3.83–7.90 (m, 1H), 3.70–3.76 (m, 1H), 1.55–
1.89 (m, 1H), 1.36 (d, J = 6.8 Hz, 3H); HRMS (EI) Calcd for C12H17N
(M+) 175.1361; found 175.1359.
Received 20 November 2012; accepted 14 December 2012
Paper 1201629 doi: 10.3184/174751913X13571448166475
Published online: 13 February 2013
2-Phenyl-1,2,3,4-tetrahydroisoquinoline (T2-4, CAS: 3340-78-1):
1H NMR: δ 7.47 (d, J = 7.2 Hz, 2H), 7.34–7.38 (m, 3H), 7.20–7.25 (m,
3H), 7.17 (t, J = 7.2 Hz, 1H), 4.96 (s, 2H), 4.11 (t, J = 6.0 Hz, 2H),
3.07 (t, J = 6.0 Hz, 2H); HRMS (EI) Calcd for C15H15N (M+) 209.1204;
found 209.1206.
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6
1-Phenylpyrrolidine (T2-5, CAS: 4096-21-3): 1H NMR: δ 7.24 (t,
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1
1-Phenyl-2,5-dihydro-1H-pyrrole (T2-6, CAS: 103204-12-2): H
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J = 7.2 Hz, 1H), 5.96 (s, 2H), 4.56 (d, J = 10.0 Hz, 4H); HRMS (EI)
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1
N,N-Diethylaniline (T2-7, CAS: 91-66-7): H NMR: δ 7.40 (d,
J = 8.4 Hz, 2H), 7.32 (t, J = 8.0 Hz, 2H), 7.11 (t, J = 7.2 Hz, 1H),
3.72–3.77 (m, 4H), 1.25 (t, J = 7.2 Hz, 6H); HRMS (EI) Calcd for
C10H15N (M+) 149.1204; found 149.1214.
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N,N-Dibutylaniline (T2-8, CAS#613-29-6): H NMR: δ 7.40 (d,
J = 8.4 Hz, 2H), 7.32 (t, J = 8.0 Hz, 2H), 7.11 (t, J = 7.2 Hz, 1H), 3.69
(t, J = 7.2 Hz, 4H), 1.61–1.69 (m, 4H), 1.32–1.41 (m, 4H), 0.95 (t, J =
7.2 Hz, 6H); HRMS (EI) Calcd for C14H23N (M+) 205.1830; found
205.1831.
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