The role of magnetic nanoparticles (MNP) as reducing agents in an MNP-supported Pd-catalyst for the reductive homocoupling of aryl halides

Article abstract of DOI:10.1139/v11-133

A palladium pincer catalyst grafted onto the surface of magnetic nanoparticles (MNPs) has been developed. This material effectively catalyzes the reductive homocoupling of various aryl halide substrates, with the MNP support acting as the reducing agent. The catalyst can be recycled up to five times in the absence of additional reducing agent to give almost quantitative yields of biaryl homocoupling products. After the reducing power of the MNP has been depleted, the supported Pd complex remains an effective catalyst for Suzuki-Miyaura cross-coupling.

Full text of DOI:10.1139/v11-133

138
The role of magnetic nanoparticles (MNP) as
reducing agents in an MNP-supported Pd–catalyst
for the reductive homocoupling of aryl halides
Jie Zheng, Shengyue Lin, Bi-Wang Jiang, Todd B. Marder, and Zhen Yang
Abstract: A palladium pincer catalyst grafted onto the surface of magnetic nanoparticles (MNPs) has been developed. This
material effectively catalyzes the reductive homocoupling of various aryl halide substrates, with the MNP support acting as
the reducing agent. The catalyst can be recycled up to five times in the absence of additional reducing agent to give almost
quantitative yields of biaryl homocoupling products. After the reducing power of the MNP has been depleted, the supported
Pd complex remains an effective catalyst for Suzuki–Miyaura cross-coupling.
Key words: magnetic nanoparticles, reducing agent, supported Pd catalyst, reductive homocoupling, aryl halides.
Résumé : On a développé un catalyseur à tenaille à base de palladium greffé sur la surface de nanoparticules magnétiques
(NPM). Ce matériau catalyse d’une façon efficace l’homocouplage réducteur de divers substrats d’halogénures d’aryle et les
nanoparticules magnétiques agissent alors comme agent réducteur. Le catalyseur peut aussi être recyclé jusqu’à cinq fois,
sans addition de nouvel agent réducteur, pour conduire à des rendements pratiquement quantitatifs de produits biaryles d’ho-
mocouplage. Une fois que le pouvoir réducteur des nanoparticules magnétiques a disparu, le complexe de palladium présent
sur le support continue à être un catalyseur efficace pour la réaction de couplage croisé de Suzuki–Miyaura.
Mots‐clés : nanoparticules, agent réducteur, catalyseur de palladium, réducteur, homocouplage.
[Traduit par la Rédaction]
alysts not only can perform with superior catalytic activities
compared with their corresponding bulk metals,6 but also
provide increased loading capacity. Herein, we report our
new MNP-supported Pd pincer complex, which can catalyze
the reductive homocoupling of aryl halides in high yields and
can be recycled up to five times in the absence of added re-
ducing agents without loss of activity. We show that Pd
leaching is not responsible for the subsequent loss of activity
for reductive homocoupling as the supported catalyst remains
active for Suzuki–Miyaura cross-coupling catalysis.
Introduction
Palladium-catalyzed coupling reactions are among the
most useful synthetic methods for the formation of carbon–
carbon and carbon–heteroatom bonds and are widely utilized
to assemble a vast range of important molecules in pharma-
ceutical, agricultural, natural product, and material sciences.1
Using homogeneous palladium catalysis, a high reaction rate,
turnover number (TON), selectivity, and yield are often pos-
sible after addition of the appropriate ligand.2 However, the
main drawback of homogeneous catalysis is associated with
the separation and recycling of the catalyst. This aspect leads
to a loss of expensive metal (and ligands), as well as to the
presence of metal impurities in the products. The complete
removal of residual metals is a major problem especially for
pharmaceutical products, where carryover of metal impurities
may cause serious problems in the production of many for-
mulations.3
Results and discussion
The MNPs utilized for immobilizing the Pd–catalyst were
synthesized via a thermal decomposition approach according
to the procedure reported by Cai and Wan.7 Thus, the reac-
tion of Fe(acac)3 in triethylene glycol leads to the MNP. The
formed MNPs were characterized by transmission electron
microscopy (TEM), and the TEM image (Fig. 1) shows that
they are relatively uniform with an average size of 6 1 nm.
The synthesis of the NCN pincer ligand commenced as
outlined in Scheme 1.
Recently, magnetic nanoparticles (MNPs)4 have emerged
as new catalyst supports because of their facile separation
from the reaction mixture with the aid of an external mag-
net.4 In this regard, we initiated a systematic program to de-
velop novel types of grafted metal–catalysts on MNP,5 and to
apply them in metal-catalyzed reactions, as such types of cat-
The commercially available 5-aminoisophthalic acid 1 was
first converted to its diethyl ester 2,8 followed by LiAlH4
Received 28 April 2011. Accepted 10 July 2011. Published at www.nrcresearchpress.com/cjc on 8 December 2011.
J. Zheng, S. Lin, B.-W. Jiang, and Z. Yang. Laboratory of Chemical Genomics and Nano-micro Material Research Center, School of
Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University, Shenzhen, China, 518055.
T.B. Marder. Department of Chemistry, Durham University, South Road, Durham DH1 3LE, UK.
Corresponding authors: Todd B. Marder (e-mail: todd.marder@durham.ac.uk) and Zhen Yang (e-mail: zyang@pku.edu.cn)
This article is part of a Special Issue dedicated to Professor Tak-Hang Chan.
Can. J. Chem. 90: 138–144 (2012)
doi:10.1139/V11-133
Published by NRC Research Press

Zheng et al.
139
Table 1. Homocoupling reaction of iodonitrobenzene.
Fig. 1. Transmission electron microscopy (TEM) image of magnetic
nanoparticles (MNPs).
cat. 8
K2CO3, DMF
O2N
NO2
O2N
I
110 °C, 12 h
14
13
Cycle
Conversion (%)a
1
2
3
>99
>99
>99
4
5
>99
>99
Note: All reactions were performed in DMF (3 mL) at 110 °C using
MNP–Pd (300 mg, 2.0 mol % Pd loading), substrate (0.3 mmol), and
K2CO3 (0.36 mmol). MNP, magnetic nanoparticle.
1
aDetermined by H NMR.
refluxing toluene to afford the desired MNP-supported Pd–
catalyst 8 as a black powder. The Pd loading level of the
catalyst is 0.020 mmol/g, determined by elemental analysis.
To test the efficiency and reactivity of the newly generated
magnetic catalyst 8 in Pd-catalyzed coupling reactions, we
first selected the Suzuki–Miyaura reaction because of its im-
portance in the synthesis of unsymmetrical biaryls.10
Thus, when aryl iodide 9 was reacted with phenyl boronic
acid 10 under typical Suzuki–Miyaura coupling conditions in
the presence of catalyst 8, the expected product 11 was ob-
tained in 70% yield, together with the formation of 15% of
the symmetrical biaryl product 12, derived, surprisingly,
from the reductive homocoupling of the aryliodide.
Scheme 1. Synthesis of magnetic nanoparticle (MNP) - grafted NCN
pincer – Pd catalyst 8.
COOH
OH
COOEt
SOCl2
EtOH
LiAlH4
THF
H N
H N
2
H N
2
2
0
oC to reflux
5 h
rt, 6 h
75%
OH
COOH
COOEt
3
2
1
97%
1. Ac2O, Et3N
THF, rt , 1 h
83%
2. SOCl2, pyridine
CH2Cl2, 0 oC to rt
5h, 76%
Symmetric biaryls Ar–Ar generated from oxidative homo-
coupling of the arylboronic acid ArB(OH)2 are typically ob-
served in Suzuki–Miyaura reactions, as they result from the
process that reduces Pd(II) catalyst precursors to Pd(0) active
catalysts.10 However, the reductive homocoupling product de-
rived from the aryl halide is seldom reported in Suzuki–
Miyaura reactions.11
1. pyrazole
K2CO3, CH3CN
70 oC, 24 h
86%
N
N
Cl
Cl
succinic
anhydride
N
N
AcHN
H N
2
Et3N, THF
reflux, 36 h
(93%)
2. KOH, EtOH
reflux, 20 h
92%
4
5
We attributed the formation of the homocoupling product
12 to the grafted magnetite nanocatalyst 8. We also envisaged
that the MNP derived from Fe3O4 might play the role of the
reducing agent. We therefore decided to explore the feasibil-
ity of carring out the useful reductive homocoupling of aryl
halides without the addition of any other reducing agents.
Thus, 13 was selected as the substrate, and the reaction
was carried out in DMF for 12 h at 110 °C in the presence
of K2CO3 and catalyst 8 (2.0 mol %). To our delight, the ex-
pected symmetric biaryl product 14 was obtained in quantita-
tive yield (Table 1). It is noteworthy that the same catalyst
could be recycled five times without loss of catalytic activity.
However, when the catalyst was continually applied to this
reaction more than five times, the reductive homocoupling
yield was decreased dramatically, indicating that the reducing
capability of the MNPs had diminished. We also noticed that
the color of the nanoparticles changed from black to red-
brown after the homocoupling reaction, which suggested that
Fe3O4 might be undergoing oxidation to Fe2O3. To prove our
hypothesis, we characterized the nanoparticles by X-ray dif-
fraction.
N
N
N
N
O
O
N
N
DCC, DMF
HO
HN
O
HN
HN
Amino-MNP
rt, 24 h
O
N
N
6
7
Pd(PhCN)2Cl2
toluene,
reflux, 24 h
Fe3O4
MNP
N
MeO
O
N
toluene, reflux
24 h
MeO Si
MeO
NH
2
HN
O
Pd
N
HN
Cl
O
Fe3O4
O
Si (CH ) -NH
2 3
8
2
N
O
Amino-MNP
reduction to afford diol 3 in 75% overall yield in two steps.
An efficient acylation–chlorination sequence subsequently
elaborated 3 into bis(chloromethyl)aniline 4 in 63% overall
yield.9 Compound 4 then underwent nucleophilic substitu-
tion of pyrazole, followed by hydrolysis to give bispyrazol-
substituted aniline 5 in 79% yield (two steps). The substituted
aniline 5 was then coupled with succinic anhydride in the
presence of Et3N to give amide 6 in 93% yield. Amide 6
was coupled to the MNP under standard conditions7 to
deliver 7, which was then treated with Pd(PhCN)2Cl2 in
As shown in Fig. 2, the diffraction peaks indicate that the
magnetite particles have been oxidized to maghemite after
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140
Can. J. Chem. Vol. 90, 2012
Fig. 2. X-ray diffraction patterns. (a) The magnetic nanoparticles
before catalytic reactions. (b) The magnetic nanoparticles after five
catalytic cycles. The inset shows a magnification of the region 2q =
20°–32° of curve (b).
Fig. 3. Photograph of the system before and after reaction and se-
paration of the magnetic nanoparticles.
before
reaction
after
reaction
separation with
a small magnet
Table 2. Homocoupling reaction of aryl halides.
MNP-Pd cat
K2CO3, DMF
R
X
R
R
110 oC
Entry
R
X
I
I
I
I
I
I
I
Br
Br
Time (h)
12
12
12
12
12
24
24
24
Yield (%)a
>99
>99
>99
>99
>99
>99
>99
>99
1
2
3
4
5
6
7
8
9
COOEt (15)
COOMe (16)
CF3 (17)
F (18)
H (19)
Me (20)
OMe (21)
NO2 (22)
CHO (23)
five catalytic cycles, as evidenced by the observation of the
enhancement of characteristic (210) and (211) diffraction
peaks of maghemite in the XRD patterns of the nanoparticles
after the coupling reaction.12
After the homocoupling reaction, catalyst 8 was simply at-
tracted to the side of the vial by an external magnet (Fig. 3),
the reaction mixture was transferred out of the flask, and the
remaining catalyst was washed three times with CH2Cl2 be-
fore recharging with the substrate and the solvent.
To verify the role of MNP-grafted catalyst 8 in this cou-
pling reaction, we then carried out comparison reactions.
Thus, catalyst 8 was replaced with NCN pincer ligand and
Pd(PhCN)2Cl2, respectively, to carry out the same reaction
as depicted in Table 1. As a result, no coupling product 14
was observed, indicating that neither the NCN pincer ligand
nor Pd(PhCN)2Cl2 can catalyze the observed homocoupling
individually.
To clarify further if the leached Pd species is the active
catalyst, we carried out the following reaction. Accordingly,
the coupling reaction was carried out under the conditions
listed in Table 1. After one catalytic cycle, the MNP-grafted
catalyst 8 was removed with a magnet. The remaining solu-
tion was analyzed by GC–MS, and the result indicated that
the conversion of the homocoupling reaction is 99%. To this
solution were added the same amounts of 13 and K2CO3, and
the formed mixture first underwent GC–MS analysis and
then was heated at 110 °C for 12 h. The analytical results in-
dicated that no homocoupling reaction proceeded by compar-
ison of their GC–MS spectra before and after the reaction
(Figs. 4–6). Thus, Pd species leached from the MNP-grafted
catalyst 8 as an active catalyst could be precluded.
24
>99
Note: All reactions were performed in DMF (3 mL) at 110 °C using
MNP–Pd (300 mg, 2.0 mol % Pd loading), substrate (0.3 mmol), and
K2CO3 (0.36 mmol). MNP, magnetic nanoparticle.
aDetermined by NMR.
Scheme 2. Syntheses of compounds 11 and 12.
H COC
3
COMe
B(OH)
2
K2CO3 (2.0 equiv.)
catalyst 8 (4.4 mol %)
11
+
(ca. 70%)
(ca. 15%)
+
DMF, H2O
12 h, 100 °C
H COC
COCH
3
3
I
10
9
12
reaction of 13 by replacing catalyst 8 with a combination of
amino-MNP 6 and PdCl2(PhCN)2. The expected homocou-
pling indeed took place; however, considerable palladium ag-
gregation was observed, and the catalyst system could not be
recycled. Next, we also carried out the Suzuki–Miyaura reac-
tion depicted in Scheme 2 with deactivated catalyst 8 (i.e.,
after five cycles in the homocoupling reaction). In this case,
the coupling reaction between substrates 9 and 10 was cata-
lyzed with deactivated catalyst 8 in the presence of DMF,
K2CO3, and distilled water, the normal Suzuki–Miyaura
product 12 was formed, and the previously observed homo-
coupling product 13 was not observed, indicating that (i) the
MNPs in 8 serve as both the catalyst support and the reduc-
ing agent and (ii) Pd leaching is not responsible for the deac-
tivation of the catalyst for the reductive homocoupling
process.
To profile the substrate scope, we selected nine additional
substrates (15–23) for the homocoupling reactions under the
conditions listed in Table 2. To our delight, all of the sub-
strates gave essentially quantitative yields of the coupling
products13 (Table 2).
To evaluate whether the MNP plays a critical role in this
reductive homocoupling process, we carried out the coupling
Published by NRC Research Press

Zheng et al.
141
Fig. 4. GC–MS spectra for the homocoupling reaction with or without magnetic nanoparticle (MNP) - grafted Pd–complex 8. (Top) Spectra of
the homocoupling product 4,4'-dinitrobiphenyl after one cycle with MNP-grafted Pd–complex 8 as catalyst. (Center) Spectra after removal of
MNPs from the reaction mixture and addition of 1-iodo-4-nitrobenzene (0.3 mmol). The mixture was analyzed by GC–MS. (Bottom) After
addition of K2CO3 (0.36 mmol) to the reaction mixture and the reaction was stirred at 110 °C for another 12 h. The mixture was analyzed by
GC–MS.
Mechanistically, the formation of homocoupling products
from aryl iodides might proceed through a process of sequen-
tial oxidative additions of aryl iodide to a MNP-grafted Pd–
complex, accompanying by the in situ MNP-mediated reduc-
tion of the formed aryl palladium halide, and the generated
MNP-grafted PdAr2 species could undergo reductive elimina-
tion to give a reduced MNP-grafted Pd species and the
biaryl, Ar–Ar. It is not useful at this time to speculate further
on the nature of the Pd intermediates, as it is not clear
whether a Pd(0)–Pd(II) or Pd(II)–Pd(IV) cycle is operating.
In summary, the Pd–pincer complex grafted onto MNP 8
exhibited good catalytic activity for the homocoupling of
aryl halides to give symmetric biaryl compounds in the ab-
sence of additional reducing agents. This catalyst can be re-
cycled up to five times without loss of catalytic activity. Our
studies should stimulate further research in heterogeneous
catalysis using MNP-grafted catalysts.
Fig. 5. GC–MS spectrum report for Fig. 4.
Experimental section
Experimental procedures
Materials and general procedure
All reactions were carried out under a nitrogen atmosphere
with dry solvents under anhydrous conditions unless other-
wise noted. All chemicals were commercially available and
used without further purification. Solvents used in all the re-
actions were dried by standard procedures.
Reactions were monitored by thin-layer chromatography
(TLC) carried out on 0.25 mm Tsingdao silica gel plates
(60F-254) using UV light as the visualizing agent. Tsingdao
silica gel (60, particle size 0.040–0.063 mm) was used for
flash column chromatography.
Reagents were purchased at the highest commercial quality
and used without further purification, unless otherwise stated.
NMR spectra were recorded on a Brüker Avance 300 (1H,
300 MHz; 13C, 75.5 MHz) or a Brüker Avance 500 (1H,
500 MHz; 13C, 125 MHz). XRD was carried out on a D/max
2500PC X-ray diffractometer at room temperature.
Synthesis of diethyl-5-(amino)isophthaloate (2)
To a stirred solution of 5-(amino)isophthalic acid 1 (5.0 g,
27.5 mmol) in absolute ethanol (100 mL) was added thionyl
chloride (6.0 mL, 82.5 mmol) dropwise at 0 °C, and the
formed mixture was stirred at reflux for 5 h. The solvent
was removed in vacuum, the crude residue was dissolved in
ethyl acetate, and the organic layer was washed with a satu-
rated aqueous solution of sodium carbonate and then dried
over sodium sulfate. The solvent was removed under vacuum
1
to give diester 2 as a white solid in 97% yield. H NMR
(300 MHz, CDCl3) d: 8.07 (t, J = 1.2 Hz, 1H), 7.53 (d, J =
1.2 Hz, 2H), 4.39 (q, J = 7.2 Hz, 4H), 3.94 (bs, 2H), 1.41 (t,
J = 7.2 Hz, 6H). 13C NMR (75 MHz, CDCl3) d: 166.02,
146.58, 131.72, 120.50, 119.59, 61.14, 14.24. HRMS (m/z)
calcd for C12H16NO4 [M + H+]: 238.1079; found: 238.1074.
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142
Can. J. Chem. Vol. 90, 2012
Fig. 6. The color changes of MNP-grafted Pd–complex 8 before and
after the homocoupling reaction. (a) Before reaction (black color).
(b) MNP-grafted Pd–complex 8 heated to 110 °C in DMF for 60 h
without color change (black color). (c) After the homocoupling re-
action for five cycles, the color of MNP-grafted Pd–complex 8 was
brownish.
addition of water (30 mol), and the organic phase was then
sequentially washed with water (2 × 30 mL), 1 N HCl (2 ×
10 mL), and brine (2 × 10 mL), and the organic phase was
finally dried over Na2SO4. The solvent was removed in vac-
uum, and the residue was purified by flash chromatography
on silica gel to give 4 (1.66 g) in 76% yield. 1H NMR
(300 MHz, DMSO-d6) d: 7.53 (s, 2H), 7.16 (s, 1H), 4.54 (s,
4H), 2.19 (s, 3H). 13C NMR (75 MHz, DMSO-d6) d: 168.51,
138.85, 138.54, 124.24, 119.65, 45.51, 24.53. HRMS (m/z)
calcd for C10H12Cl2NO [M + H+]: 232.0296; found:
232.0293.
Synthesis of 3,5-bis[(1H-pyrazol-1-yl)methyl]aniline (5)
To a solution of 4 (1.16 g, 5 mmol) in CH3CN (30 mL)
was added potassium carbonate (1.73 g, 12.5 mmol) and pyr-
azole (0.68 g, 10 mmol), and the mixture was refluxed for
24 h. The reaction mixture was filtered, and the solid was
washed with CH3CN (3 × 10 mL). The filtrate was concen-
trated in vacuum, and the residue was purified by flash chro-
matography on silica gel to give the intermediate dipyrazole
Synthesis of 3,5-bis(hydroxymethyl)aniline (3)
To a slurry of LiAlH4 (2.39 g, 63 mmol) in THF
1
(1.27 g) in 86% yield. H NMR (300 MHz, CDCl3) d: 8.60
(s, 1H), 7.48–7.47 (m, 2H), 7.39–7.38 (m, 2H), 7.16 (s, 2H),
(200 mL),
a solution of diethyl-5-(amino)isophthaloate
6.65 (s, 1H), 6.26–6.25 (m, 2H), 5.15 (s, 4H), 2.00 (s, 3H).
(5.0 g, 21 mmol) in dry THF (100 mL) was added slowly at
0 °C with vigorous stirring. After this addition, the mixture
was stirred initially at the same temperature for an additional
30 min and then at room temperature for 6 h. The reaction
was quenched by the slow addition of ethyl acetate (20 mL)
with vigorous stirring to consume the excess LiAlH4. After
stirring at the room temperature for 2 h, a saturated NH4Cl
solution (50 mL) was then added to hydrolyze the aluminum
salt. After stirring for another 1 h, the resulting slurry was
filtered through a pad of silica gel, and the pad was washed
with ethyl acetate (3 × 100 mL). The filtrate was concen-
trated, and the residue was purified by flash chromatography
13C NMR (75 MHz, CDCl3) d: 168.85, 139.67, 139.37,
137.97, 129.78, 121.47, 117.98, 106.05, 55.32, 24.18.
HRMS (m/z) calcd for C16H18N5O [M + H+]: 296.1511;
found: 296.1511.
To a solution of the dipyrazole prepared above (1.18 g,
4 mmol) in 95% ethanol (50 mL) was added KOH (2.24 g,
40 mmol), and the mixture was refluxed for 20 h. The reac-
tion mixture was neutralized by addition of a concentrated
solution of HCl. The solvent was removed in vacuum, and
the residue was extracted with CH2Cl2 (3 × 30 mL). The
combined extracts were washed with a saturated solution of
Na2CO3 (3 × 50 mL) and then dried over Na2SO4. The sol-
vent was removed in vacuum, and the residue was purified
by flash chromatography on silica gel to give 5 (0.93 g) in
1
on silica gel to give compound 3 (2.41 g) in 75% yield. H
NMR (300 MHz, DMSO-d6) d: 6.40 (s, 3H), 4.95 (t, J =
5.4 Hz, 4H,), 4.34 (br, 2H), 4.32 (br, 2H). 13C NMR
(75 MHz, DMSO-d6) d: 148.62, 143.21, 112.85, 111.01,
63.68. HRMS (m/z) calcd for C12H12NO2 [M + H+]:
154.0868; found: 154.0867.
1
92% yield. H NMR (300 MHz, CDCl3) d: 7.54–7.53 (m,
2H), 7.38–7.37 (m, 2H), 6.46 (s, 1H), 6.38 (s, 2H), 6.28–
6.27 (m, 2H), 5.19 (s, 4H), 3.69 (s, 2H). 13C NMR
(75 MHz, CDCl3) d: 147.34, 139.44, 138.43, 129.27,
116.61, 113.50, 105.88. 55.60. HRMS (m/z) calcd for
C14H16N5 [M + H+]: 254.1406; found: 254.1403.
Synthesis of N-acetyl-3,5-bis(chloromethyl)anilide (4)
To a solution of 3 (1.90 g, 12.4 mmol) in THF (100 mL)
was sequentially added Et3N (1.8 mol, 12.4 mmol) and acetic
anhydride (1.2 mL, 12.4 mmol) at room temperature, and the
mixture was stirred for 1 h. The reaction mixture was filtered,
and the solid was washed with THF. The combined filtrates
were concentrated and purified by flash chromatography on
silica gel to give the amide (2.01 g) in 83% yield as a white
Synthesis of 4-{3,5-bis[(1H-pyrazol-1-yl)methyl]
phenylamino})-4-oxobutanoic acid (6)
To a solution of 5 (0.76 g, 3 mmol) in dry THF (15 mL)
was added triethylamine (0.5 mL, 3.5 mmol) and succinic an-
hydride (0.3 g, 3 mmol), and the mixture was refluxed for
36 h. A saturated solution of NH4Cl (10 mL) was added,
and the mixture was extracted with EtOAc (3 × 20 mL). The
filtrate was concentrated in vacuum, and the residue was pu-
rified by flash chromatography on silica gel to give acid 6
1
solid. H NMR (300 MHz, DMSO-d6) d: 9.85 (s, 1H), 7.41
(s, 2H), 6.92 (s, 1H), 5.15 (t, J = 5.7 Hz, 2H), 4.43 (d, J =
5.7 Hz, 4H), 2.02 (s, 3H). 13C NMR (75 MHz, DMSO-d6) d:
168.51, 143.19, 139.43, 119.51, 115.84, 63.34, 24.40.
HRMS (m/z) calcd for C10H14NO3 [M + H+]: 196.0974;
found: 196.0964.
To a solution of the amide prepared above (1.84 g,
9.4 mmol) and pyridine (1.7 mL, 21 mmol) in CH2Cl2
(50 mL) was added thionyl chloride (1.5 mL, 21 mmol) in a
dropwise manner at 0 °C, and the mixture was stirred at
room temperature for 5 h. The reaction was quenched by the
1
(0.98 g) in 93% yield. H NMR (500 MHz, DMSO-d6) d:
9.95 (s, 1H) 7.75–7.74 (m, 2H), 7.44–7.43 (m, 2H), 7.33 (s,
2H), 6.78 (s, 1H), 6.25–6.24 (m, 2H), 5.24 (s, 4H), 2.49–
2.48 (m, 4H). 13C NMR (125 MHz, DMSO-d6) d: 174.28,
170.74, 140.25, 139.56, 138.99, 130.69, 121.85, 117.84,
106.04, 55.20, 31.56, 29.35. HRMS (m/z) calcd for
C18H20N5O3 [M + H+]: 354.1566; found: 354.1561.
Published by NRC Research Press

Zheng et al.
143
Synthesis of iron oxide nanocrystals
Synthesis of 4,4'-dinitrobiphenyl (14)
1H NMR (300 MHz, CDCl3) d: 8.37 (d, J = 8.1 Hz, 4H),
7.79 (d, J = 8.1 Hz, 4H). 13C NMR (75 MHz, CDCl3) d:
148.00, 144.95, 128.31, 124.37.
A typical procedure for the synthesis of MNPs was as fol-
lows: Fe(acac)3 (7.1 g, 20 mmol) and triethylene glycol
(250 mL) were directly added to a three-necked round-
bottomed flask equipped with a condenser, mechanical stir-
rer, thermograph, and heating mantle, and the mixture was
stirred under argon. The mixture was slowly heated to
180 °C first and kept at that temperature for 30 min and
then quickly heated to reflux (~280 °C) and kept at reflux
for another 30 min. After cooling to room temperature, a
black homogeneous colloid (magnetite nanoparticles) was
formed. To this solution was added ethyl acetate (500 mL),
and the formed flocculation was separated from the solution
with a magnet. The black precipitate was first redispersed in
ethanol and then precipitated with ethyl acetate. This wash-
ing procedure was repeated twice to remove excess triethy-
lene glycol and by-products completely, and the resulting
MNPs were obtained by drying the precipitate in vacuum.
Synthesis of 4,4'-diethylcarboxylatebiphenyl (15)
1H NMR (300 MHz, CDCl3) d: 8.15–8.12 (m, 4H), 7.70–
7.67 (m, 4H), 4.41 (q, J = 7.2 Hz, 4H), 1.42 (t, J = 7.2 Hz,
6H). 13C NMR (75 MHz, CDCl3) d: 166.3, 144.2, 130.1,
129.9, 127.1, 61.0, 14.3. HRMS (m/z) calcd for C18H19O4
[M+]: 299.12834; found: 299.12738.
Synthesis 4,4'-dimethylcarboxylatebiphenyl (16)14
1H NMR (300 MHz, CDCl3) d: 8.14–8.11 (m, 4H), 7.70–
7.67 (m, 4H), 3.94 (s, 6H). 13C NMR (75 MHz, CDCl3) d:
166.81, 144.29, 130.13, 129.64, 127.18, 52.15. HRMS (m/z)
calcd for C16H15O4 [M+]: 271.09704; found: 271.09627.
Synthesis of 4,4'-ditrifluoromethylbiphenyl (17)14
1H NMR (300 MHz, CDCl3) d: 7.74 (d, J = 8.3 Hz, 4H),
7.70 (d, J = 8.3 Hz, 4H). 13C NMR (75 MHz, CDCl3) d:
143.2, 130.2 (q, J = 32.2 Hz), 127.5, 125.9 (q, J = 3.7 Hz),
122.2 (q, J = 272 Hz).
Synthesis of amino-functionalized iron oxide nanocrystals
Iron oxide nanocrystals (1.0 g) were refluxed with 3-
aminopropyltrimethoxysilane (4.0 mL, 0.023 mmol) in dry
toluene (6.0 mL) for 1 day, and the solids were separated
by applying an external magnetic field and washed with
dry acetone (6 × 30 mL). The resulting product was dried
in vacuum for 1 h.
Synthesis of 4,4'-difluorobiphenyl (18)14
1H NMR (300 MHz, CDCl3) d: 7.51 (m, 4H), 7.14 (t, 4H,
J = 8.7 Hz). 13C NMR (75 MHz, CDCl3) d: 164.00 (d, J =
246.4 Hz), 136.35 (d, J = 3.3 Hz), 128.5 (d, J = 8.1 Hz),
115.61 (d, J = 21.4 Hz).
General procedure for the synthesis of MNP-supported
palladium catalyst
Synthesis of biphenyl (19)14
1H NMR (300 MHz, CDCl3) d: 7.85 (d, 4H, J = 7.5 Hz),
7.72 (t, 4H, J = 7.5 Hz), 7.52 (t, 2H, J = 7.3 Hz). 13C NMR
(75 MHz, CDCl3) d: 141.2, 128.7, 127.2, 127.1.
To a solution of ligand 6 (0.043 g, 0.12 mmol) in DMF
(4.0 mL) was added dicyclohexylcarbodimide (0.027 g,
0.13 mmol), and the resulting solution was stirred at room
temperature for 1 h. To this solution was added the amine-
terminated MNP (0.3 g), and the mixture was stirred at room
temperature for 24 h. After the reaction, the solid was sepa-
rated by applying an external magnetic field and washed with
dry dichloromethane (6 × 10 mL). The residue was dispersed
in dry toluene (10 mL), followed by addition of Pd(PhCN)2Cl2
(0.013 g, 0.017 mmol), and the resulting mixture was
stirred at reflux for 24 h. The formed MNP-supported cata-
lyst 8 was magnetically separated and washed with dry di-
chloromethane (6 × 10 mL).
Synthesis of 4,4'-dimethylbiphenyl (20)14
1H NMR (300 MHz, CDCl3) d: 7.47 (d, J = 8.1 Hz, 4H),
7.23 (d, 4H, J = 8.1 Hz), 2.38 (s, 6H). 13C NMR (75 MHz,
CDCl3) d: 138.22, 136.62, 129.36, 126.73, 20.99. HRMS (m/z)
calcd for C14H13 (–): 181.10212; found: 181.10043.
Synthesis of 4,4'-dimethoxylbiphenyl (21)14
1H NMR (300 MHz, CDCl3) d: 7.51 (d, 4H, J = 8.8 Hz),
6.97 (d, 4H, J = 8.8 Hz), 3.85 (s, 6H). 13C NMR (75 MHz,
CDCl3) d: 158.7, 133.5, 127.7, 114.1, 55.3.
Procedure for using the MNP-supported palladium
catalyst in homocoupling reactions
Synthesis of 4,4'-diformylbiphenyl (23)
1H NMR (300 MHz, CDCl3) d: 10.10 (s, 2H), 8.00 (d, J =
8.4 Hz, 4H), 7.81 (d, J = 8.4 Hz, 4H). 13C NMR (75 MHz,
CDCl3) d: 191.6, 145.5, 135.9, 130.3, 127.9. HRMS (m/z)
calcd for C14H11O2 (M + H+): 211.07591; found: 211.07479.
To a solution of the aryl halide (0.3 mmol) and K2CO3
(50 mg, 0.36 mmol) in DMF (3 mL) was added catalyst 8
(0.300 g), and the mixture was heated at 110 °C for 12 or
24 h under a nitrogen atmosphere. After the reaction, a mag-
net was used to separate the catalyst, which was then washed
with dry CH2Cl2 (10 mL). The combined organic phases
were washed with water, dried with Na2SO4 and then evapo-
rated. All of the coupling products have been previously re-
ported.13
Supplementary data
Supplementary data (experimental procedures and 1H
NMR and 13C NMR spectra) are available with the article
through the Journal Web site at http://nrcresearchpress.com/
doi/suppl/10.1139/v11-133.
Synthesis of 4,4'-diacetylbiphenyl (12)
Acknowledgment
1H NMR (300 MHz, CDCl3) d: 8.09 (d, 4H, J = 8.3 Hz),
7.75 (d, 4H, J = 8.3 Hz), 2.66 (s, 6H). 13C NMR (75 MHz,
CDCl3) d: 196.5, 143.3, 135.5, 127.9, 126.3, 25.6.14
This work was funded by the National Science Foundation
of China (Grants 20225318, 20325208, and 20902007). We
Published by NRC Research Press

144
Can. J. Chem. Vol. 90, 2012
Stevens, P. D.; Yen, M.; Gao, Y. Chem. Commun. (Camb.)
2005 (35), 4432. doi:10.1039/b504128g; (c) Hu, A.; Yee, G.
T.; Lin, W. J. Am. Chem. Soc. 2005, 127 (36), 12486. doi:10.
1021/ja053881o; (d) Abu-Reziq, R.; Alper, H.; Wang, D. S.;
Post, M. L. J. Am. Chem. Soc. 2006, 128 (15), 5279. doi:10.
1021/ja060140u; (e) Phan, N. T. S.; Gill, C. S.; Nguyen, J. V.;
Zhang, Z. J.; Jones, C. W. Angew. Chem. Int. Ed. 2006, 45
(14), 2209. doi:10.1002/anie.200503445; (f) Shokouhimehr,
M.; Piao, Y. Z.; Kim, J.; Jang, Y. J.; Hyeon, T. Angew. Chem.
Int. Ed. 2007, 46 (37), 7039. doi:10.1002/anie.200702386; (g)
Zhang, X. B.; Yan, J. M.; Han, S.; Shioyama, H.; Xu, Q. J. Am.
Chem. Soc. 2009, 131 (8), 2778. doi:10.1021/ja808830a; (h)
Zhang, Y.; Zhao, Y. W.; Xia, C. G. J. Mol. Catal. Chem. 2009,
306 (1–2), 107. doi:10.1016/j.molcata.2009.02.032.
also thank the National Science and Technology Major Proj-
ect “Development of Novel Vaccines, Antibodies and Thera-
peutic Agents against Influenza Infection” (2009ZX10004-
016), the National Basic Research Program of China (973
Program, Grant No. 2010CB833201), and the Shenzhen
Basic Research Program (Nos. JC200903160352A,
JC201005260097A, and CXB201005260053A). T.B.M.
thanks the Royal Society for a Wolfson Research Merit
Award, the Engineering and Physical Sciences Research
Council (EPSRC) for an Overseas Research Travel Grant,
and the Royal Society of Chemistry for a Journals Grant for
International Authors.
References
(7) Cai, W.; Wan, J. Q. J. Colloid Interface Sci. 2007, 305 (2),
366. doi:10.1016/j.jcis.2006.10.023.
(1) Tsuji, J. Palladium Reagents and Catalysts: New Perspectives
for the 21st Century; Wiley: Chichester, UK, 2004.
(2) Yin, L. X.; Liebscher, J. Chem. Rev. 2007, 107 (1), 133.
(8) Aujard, I.; Baltaze, J. P.; Baudin, J. B.; Cogne, E.; Ferrage, F.;
Jullien, L.; Perez, E.; Prevost, V.; Qian, L. M.; Ruel, O. J. Am.
Chem. Soc. 2001, 123 (34), 8177. doi:10.1021/ja010019h.
(9) Bergbreiter, D. E.; Osburn, P. L.; Liu, Y. S. J. Am. Chem. Soc.
1999, 121 (41), 9531. doi:10.1021/ja991099g.
(10) (a) For reviews on the synthesis of biaryls, see Hassan, J.;
Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. Rev.
2002, 102 (5), 1359. doi:10.1021/cr000664r; (b) Jutand, A.;
Mosleh, A. J. Org. Chem. 1997, 62 (2), 261. doi:10.1021/
jo961464b.
(11) For an unusual reductive coupling of iodoacrylates, see
Batsanov, A. S.; Knowles, J. P.; Samsam, B.; Whiting, A.
Adv. Synth. Catal. 2008, 350 (2), 227. doi:10.1002/adsc.
200700464.
(12) Daou, T. J.; Pourroy, G.; Begin-Colin, S.; Greneche, J. M.;
Ulhaq-Bouillet, C.; Legare, P.; Bernhardt, P.; Leuvrey, C.;
Rogez, G. Chem. Mater. 2006, 18 (18), 4399. doi:10.1021/
cm060805r.
doi:10.1021/cr0505674.
(3) Welch, C. J.; Albaneze-Walker, J.; Leonard, W. R.; Biba, M.;
DaSilva, J.; Henderson, D.; Laing, B.; Mathre, D. J.; Spencer,
S.; Bu, X. D.; Wang, T. B. Org. Process Res. Dev. 2005, 9 (2),
198. doi:10.1021/op049764f.
(4) (a) For a recent review on the applications of MNPs, see Lu, A.
H.; Salabas, E. L.; Schuth, F. Angew. Chem. Int. Ed. 2007, 46
(8), 1222. doi:10.1002/anie.200602866; (b) Jun, Y. W.; Choi,
J. S.; Cheon, J. Chem. Commun. (Camb.) 2007 (12), 1203.
doi:10.1039/b614735f; (c) Schätz, A.; Reiser, O.; Stark, W. J.
Chem. Eur. J. 2010, 16 (30), 8950. doi:10.1002/chem.
200903462; (d) Yan, J.-M.; Zhang, X.-B.; Akita, T.; Haruta,
M.; Xu, Q. J. Am. Chem. Soc. 2010, 132 (15), 5326. doi:10.
1021/ja910513h; (e) Yan, J.-M.; Zhang, X.-B.; Han, S.;
Shioyama, H.; Xu, Q. J. Power Sources 2009, 194 (1), 478.
doi:10.1016/j.jpowsour.2009.04.023.
(5) Che, C.; Li, W. Z.; Lin, S. Y.; Chen, J. W.; Zheng, J.; Wu, J. C.;
Zheng, Q. X.; Zhang, G. Q.; Yang, Z.; Jiang, B. W. Chem.
Commun. (Camb.) 2009, (40): 5990. doi:10.1039/b911999j.
(6) (a) Selected examples for the application of MNPs as catalyst
supports, see Lu, A. H.; Schmidt, W.; Matoussevitch, N.;
Bonnemann, H.; Spliethoff, B.; Tesche, B.; Bill, E.; Kiefer, W.;
Schuth, F. Angew. Chem. Int. Ed. 2004, 43 (33), 4303. doi:10.
1002/anie.200454222; (b) Gardimalla, H. M. R.; Mandal, D.;
(13) (a) Wang, L. A.; Zhang, Y. H.; Liu, L. F.; Wang, Y. G. J. Org.
Chem. 2006, 71 (3), 1284. doi:10.1021/jo052300a; (b)
Kuroboshi, M.; Waki, Y.; Tanaka, H. J. Org. Chem. 2003,
68 (10), 3938. doi:10.1021/jo0207473; (c) Cepanec, I.; Litvic,
M.; Udikovic, J.; Pogorelic, I.; Lovric, M. Tetrahedron 2007,
63 (25), 5614. doi:10.1016/j.tet.2007.04.016.
(14) Moncomble, A.; Le Floch, P.; Gosmini, C. Chem. Eur. J. 2009,
15 (19), 4770. doi:10.1002/chem.200900542.
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