Nano-iron oxide as a recyclable catalyst for intramolecular C-N cross-coupling reactions under ligand-free conditions: One-pot synthesis of 1,4-dihydroquinoline derivatives

Article abstract of DOI:10.1002/adsc.200900481

The ligand-free nanoparticle ferroferric oxide catalytic system has been developed to promote the intramolecular C-N cross-coupling reaction. With this protocol, various 1,4-dihydroquinoline derivatives were synthesized from o-halobenzaldehydes and β-enam

Full text of DOI:10.1002/adsc.200900481

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DOI: 10.1002/adsc.200900481
Nano-Iron Oxide as a Recyclable Catalyst for Intramolecular
À
C N Cross-Coupling Reactions under Ligand-Free Conditions:
One-Pot Synthesis of 1,4-Dihydroquinoline Derivatives
Xiao-Jin Wu,a Ran Jiang,a Bing Wu,b Xiao-Ming Su,a Xiao-Ping Xu,a,*
and Shun-Jun Jia,*
a
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials
Science, Soochow University, Suzhou 215123, Peopleꢀs Republic of China
Fax : (+86)-512-6588-0307; e-mail: chemjsj@suda.edu.cn orxuxp@suda.edu.cn
Analytic & Testing Center, Soochow University, Suzhou 215123, Peopleꢀs Republic of China
b
Received: July 10, 2009; Revised: November 4, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900481.
Abstract: The ligand-free nanoparticle ferroferric
processes. The main limitation of the system relates
to the facts that only a few successful examples with
aryl bromides and aryl chlorides as the electrophilic
partners have been reported so far, and that it gener-
ally involves eco-disadvantageous ligands such as
N,N’-dimethylethylenediamine to catalyze the cou-
pling reaction effectively.[6] Although significant prog-
ress in the field of iron-catalyzed C N cross-coupling
reaction has been achieved, these limitations still lead
to continued interest and challenges.
oxide catalytic system has been developed to pro-
À
mote the intramolecular C N cross-coupling reac-
tion. With this protocol, various 1,4-dihydroquino-
line derivatives were synthesized from o-halobenz-
ACHTUNGTRENNUNG
À
À
Keywords: C N-cross-coupling; 1,4-dihydroquino-
line derivatives; ligand-free conditions; nano-iron
oxide; synthesis
Recently, nanoparticles have been employed as
novel catalysts for various organic transformations,[7]
which inspired us to focus our attention on the aspect
À
of an iron oxide nanoparticle-catalyzed C N cross-
coupling reaction. As we know, nanoscale catalysts
À
The transition metal-catalyzed C N cross-coupling can provide higher surface areas and lower coordinat-
process is considered as an important methodology, ing sites, which are responsible for the higher catalytic
which has been widely applied in pharmaceutical and activity.[8] In contrast to our expectations, until now,
medicinal chemistry.[1] Although remarkable success the investigation of iron oxide nanoparticle as cata-
in both palladium[2] and copper[3] catalyzed versions lysts for the C N cross-coupling process has never
À
of this strategy has been achieved, the development been reported.
of alternative catalysts involving more cheap, non-
On the other hand, since Buchwald constructed N-
À
toxic, and environmentally friendly metals is still benzylindoline via an intramolecular C N cross-cou-
highly desired. Since the pioneering work of Kochi in pling reaction in 1995,[9] this protocol has made a
1971, iron salts have emerged as a ready available, large impact on the synthesis of nitrogen heterocy-
low price and environmentally friendly catalyst for cles.[10] Quinoline, as an important drug intermedi-
many organic transformations.[4] In the past few years, ate,[11] has been prepared via many approaches.[12]
Taillefer firstly reported a novel iron-copper coopera- However, very few studies on the synthesis of the
À
À
tive catalysis to accomplish the C N cross-coupling quinoline ring by a C N cross-coupling reaction were
reaction. The potential drawback of this methodology reported.[13] Therefore, we wished to develop a new
is the demand of using two metals in the catalyst approach to construct the quinoline ring via the intra-
system.[5] Shortly thereafter Bolm actualized the C N molecular C N cross-coupling reaction involving the
cross-coupling reaction utilizing exclusively iron as iron oxide nanoparticle catalytic system. To the best
the metal of choice. This iron catalyst appears promis- of our knowledge, b-enaminones, as a highly efficient
ing for industrial-scale synthesis and further research synthon, have been extensively applied for the con-
could focus on operationally simple and cost-effective struction of nitrogen-containing heterocycles.[14] In
À
À
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Nano-Iron Oxide as a Recyclable Catalyst for Intramolecular C N Cross-Coupling
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Scheme 1. Synthesis of 1,4-dihydroquinoline derivative B.
view of this, we designed A as a building block, which the intramolecular Buchwald–Hartwig reaction as
could be obtained via the Baylis–Hillman reaction[15] well,[9,17] we tried to accomplish these processes in
followed by the nucleophilic substitution reaction one-pot. As expected, the target B was generated in
from b-enaminone and o-bromobenzaldehyde, to good yield by using the original substrates [o-bromo-
carry out our trials (Scheme 1). Initially, we proved benzaldehyde (0.25 mmol), 3-(4-methoxyphenylami-
À
the feasibility of the intramolecular C N cross-cou- no)-5,5-dimethylcyclohex-2-enone (0.5 mmol)] in the
pling reaction of A with the classical Pd
A
lytic system. Considering the drawback of the palladi- (Scheme 1).
um catalyst system, we then attempted to replace it
Next, sets of experiments were performed to opti-
with the nano-Fe3O4. Fortunately, the strategy was mize the reaction conditions. As shown in Table 1, the
successfully actualized. A 1,4-dihydroquinoline deriv- nano g-Fe2O3 could also afford the target in 56%
ative B was synthesized in good yield, and the definite yield (entry 1). Compared with the reaction in the air,
structure of B was confirmed by an X-ray crystal the nano-Fe3O4-catalyzed reaction in an argon atmos-
structure analysis (Figure 1).[16] It was very interesting- phere is more efficient (entries 2 and 3). The influ-
ly to find that no extra ligand was required in our cat- ence of the amount of nano-Fe3O4 was also evaluated
alytic system. Considering that A could also be ob- (entries 3–5), 10 mol% of the catalyst was the best
tained in the presence of a base which was needed in choice.
Figure 1. The crystal structure of B.
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Table 1. Influence of the catalysts for the reaction of 1a with
2a.[a]
Table 3. Scope for nano-Fe3O4-catalyzed synthesis of 1,4-di-
hydroquinoline derivatives.[a]
Entry
Catalyst
Yield [%][b]
1
2
3
4
5
nano-g-Fe2O3 (10 mol%)
56
65
89
69
87
nano-Fe3O4 (10 mol%, air)
nano-Fe3O4 (10 mol%, argon)
nano-Fe3O4 (5 mol%, argon)
nano-Fe3O4 (15 mol%, argon)
[a]
Reaction conditions: 1a (0.25 mmol), 2a (0.5 mmol),
Cs2CO3 (3 equiv.), 3.0 mL of toluene at 1108C for 24 h.
Isolated yield.
[b]
Table 2. Optimization of conditions for the reaction of 1a
with 2a.[a]
Entry
Substrate
R
Product
Yield[b] [%]
X
Entry
Base
Solvent
Yield[b] [%]
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
1b
1b
1b
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
1a
1a
1a
1a
4-OCH3 (2a)
4-CH3 (2b)
3-CH3 (2c)
2-CH3 (2d)
H (2e)
4-Cl (2f)
3-Cl (2g)
4-Br (2h)
4-I (2i)
2-Cl (2j)
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
3a
3b
3c
3d
3e
3f
3g
3h
3i
88
86
71
78
77
70
67
73
83
54
89
82
71
73
75
70
64
72
81
48
81
78
67
64
68
65
60
63
62
47
0
1
2
3
4
5
6
7
8
9
Cs2CO3
K2CO3
K3PO4
NaOAc
t-BuOK
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
toluene
toluene
toluene
toluene
toluene
THF
CH3CN
Dioxane
NMP
89
12
51
<10
<10
<10
<10
<10
13
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
3j
10
DMSO
26
3a
3b
3c
3d
3e
3f
3g
3h
3i
[a]
Reaction conditions: 1a (0.25 mmol), 2a (0.5 mmol), nano
Fe3O4 (0.025 mmol), base (3 equiv.), solvent (3.0 mL) at
1108C under argon atmosphere for 24 h.
Isolated yield.
[b]
We next made a study on the effect of bases and
solvents in the reaction. As shown in Table 2, the uti-
lization of the commonly used bases (such as K2CO3,
K3PO4, NaOAc and t-BuOK) only gave the desired
product in poor yields (entries 2–5). Cs2CO3 was
found to be the most appropriate base. Then we
turned our attention to the solvents: THF, CH3CN
and dioxane were not suitable solvents for the reac-
tion (entries 6–8). The commonly used solvents for
the coupling reaction, such as NMP, DMSO, also gave
disappointing results (entries 9 and 10). Finally, tolu-
ene was found to be act as the optimal solvent
(entry 1).
After having optimized the conditions, we contin-
ued to examine the generality of the reaction, as
shown in Table 3. We firstly introduced a series of o-
halobenzaldehydes to the strategy. It was worthwhile
to note that there was not much obvious decrease in
activity among aryl bromides, chlorides and iodides in
our catalytic conditions (entries 1, 11, 12), although
aryl chlorides were inactive in the traditional iron-
À
3j
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
4-NO2 (2k)
4-CN (2l)
4-COMe (2m)
4-COOEt (2n)
0
0
0
[a]
Reaction conditions: 1 (0.25 mmol), 2 (0.5 mmol), nano-
Fe3O4 (0.025 mmol), Cs2CO3 (0.75 mmol), toluene
(3.0 mL) at 1108C under argon for 24 h.
Isolated yield.
[b]
mediated C N coupling reaction. Then the functional catalytic system has a good tolerance toward electron-
compatibility of b-enaminones to the approach was donating groups and a few weak electron-withdrawing
explored with 2-iodobenzaldehyde as substrate. This groups (4-OMe, 4-Me, 4-I, 4-Br, 4-Cl, 3-Me and 3-Cl)
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Nano-Iron Oxide as a Recyclable Catalyst for Intramolecular C N Cross-Coupling
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on the b-enaminones (entries 1–3, 6–9), but it is not
compatible with strong electron-withdrawing groups,
such as 4-NO2, 4-CN, 4-COMe, 4-COOEt (entries 31–
34). Moreover, 5,5-methyl-3-(phenylamino)-cyclohex-
2-enone could also afford the target in good yield
(entry 5). In order to study the steric influence of the
approach, we next tested several b-enaminones with
substituent groups in different positions. Notably, our
catalytic system was also efficient for a 2-substituted
b-enaminone which reacted to furnish the correspond-
ing product in 78% yield (entry 4). Unfortunately, this
catalytic system was less effective for the 2-chloro-
substituted b-enaminone (entry 10), which maybe the
result of both steric and electron-withdrawing influen-
ces. Satisfactory yields were also obtained in the reac-
tions of 2-bromo- or 2-chlorobenzaldehyde with b-en-
aminones (entries 11–30). The influence of steric and
electronic effects was similar to the reaction results
when using 2-iodobenzaldehyde as substrate. There-
fore, the representative examples illustrated the gen-
erality of this reaction. Taking the poor solubility of
nano-Fe3O4 in toluene into consideration, we ex-
plored the recyclability of the unmodified magnetite.
To our delight, we found that the yields were almost
constant in a range between 80% and 89% after 5
cycles of the reaction for the preparation of com-
pound 3a, with the magnetite being maintained inside
the flask by the help of a magnet (Figure 2).
In order to explore the possible degradation of the
naked magnetite under the reaction conditions, we
observed SEM images of the unmodified magnetite
and the 5-fold reused one (Figure 3). This did not
show any marked difference between them, which in-
dicated that there was no significant sinter process
under the reaction conditions. The simple recyclability
makes this catalyst suitable for continuous industrial
processes.
Figure 3. SEM images of unmodified nanopowder magnetite
(above) and the same magnetite after having been used in 5
cycles (below).
reaction mixture (see the Typical Experimental Proce-
Furthermore, we explored if the reaction occurred dure in the Experimental Section) was first refluxed
in solution, completely or in part, with the nanoparti- in toluene for an hour, then hot-filtered. Subsequent-
cles leached from the solid surface.[18] A simple test ly, we subjected the resulting solution to standard
with the reaction of 1a and 2a was carried out: The conditions.[19] The system was then stirred at 1108C
for 24 h, after work-up, but only a 35% yield of de-
sired product was obtained. Therefore, we considered
that the reaction only occurs in solution partly.
Finally, a possible reaction mechanism for the for-
mation of 1,4-dihydroquinoline derivatives from o-
halobenzaldehyde and a wide range of b-enaminones
was proposed (Scheme 2).
First, the intermediate A was generated through
Baylis–Hillman-type reaction and nucleophilic substi-
tution of another b-enaminone. Then, the intramolec-
À
ular C N cross-coupling reaction catalyzed by nano-
Fe3O4 was accomplished to generate the final product.
The possible way is proposed as follows: a low-oxida-
Figure 2. Investigation to the reuse of nano-Fe3O4 in the re-
tion state iron species [Fe] B was firstly generated by
rapid electron transfer between the Fe sites in
Fe3O4,[20] then oxidative addition of 2-substituted aryl
actions: 1a (0.25 mmol), 2a (0.5 mmol), nano-Fe3O4
(0.025 mmol), Cs2CO3 (3 equiv.), 3.0 mL of toluene at 1108C
under argon for 24 h.
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Xiao-Jin Wu et al.
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Scheme 2. Possible mechanism for the formation of 1,4-dihydroquinoline derivatives.
halide to B occurred. Subsequently, the classical Experimental Section
cross-coupling route involving coordination and de-
protonation of the arylamine fragment, followed by General Experimental Methods
reductive elimination was performed to get the final
All reactions were carried out under an argon atmosphere.
All o-halobenzaldehydes, were purchased from Aldrich or
Alfa. The nano-Fe3O4 catalyst and b-enaminones were pre-
pared according to the known methods.[22] The average di-
ameter of Fe3O4 particles is about 100 nm and they have a
narrow size distribution. Analytical thin-layer chromatogra-
phy was performed using glass plates precoated with 200–
400 mesh silica gel impregnated with a fluorescent indicator
(254 nm). Melting points were recorded on an electrother-
mal digital melting point apparatus and are uncorrected. IR
spectra were recorded on a Varian FT-1000 spectrophotome-
ter using KBr optics. NMR spectra were recorded in CDCl3
on a Varian Inova-400 NMR spectrometer with TMS as an
internal reference. High resolution mass spectra were ob-
tained using Microma GCT-TOF instrument. X-ray diffrac-
tion data were recorded on a Rigaku Mercury CCD area de-
tector with graphite monochromated Mo-Ka radiation.
product.[21]
In summary, ligand-free nano-Fe3O4 has been
shown to be an active, stable and recyclable catalyst
À
for the intramolecular C N cross-coupling reaction
for the first time. By using of this catalytic system, we
have developed a novel and efficient method for the
synthesis of various 1,4-dihydroquinoline derivatives
from o-halobenzaldehyde and a wide range of b-en-
aminones. Noteworthy, the novel Fe catalyst is highly
efficient for the inactive aryl chlorides and arylamine
derivatives. The simple recyclability also makes this
catalyst suitable for continuous industrial processes.
Further study on the wider applications of the catalyt-
ic system is currently in progress.
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Nano-Iron Oxide as a Recyclable Catalyst for Intramolecular C N Cross-Coupling
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Typical Experimental Procedure for the Synthesis of
Quinoline Derivative 3a
A mixture of 1a (0.25 mmol), 2a (0.5 mmol), nano-Fe3O4
(5.8 mg, 0.025 mmol), Cs2CO3 (144.7 mg, 0.75 mmol) and tol-
uene (3.0 mL) was stirred at 1108C under argon for 24 h.
After that, the mixture was poured into water, and extracted
with ethyl acetate, then the organic phase was dried by an-
hydrous MgSO4, filtered and evaporated under vacuum, the
residue was purified by flash column chromatography (ethyl
acetate/petroleum ether=1:6 v/v) to afford the product 3a.
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Acknowledgements
The work was partially supported by the National Natural
Science Foundation of China (No. 20672079), Nature Science
of Jiangsu Province for Higher Education (No.
05KJB150116), Nature Science Key Basic Research of Jiang-
su Province for Higher Education (No. 06KJA15007), the
Specialized Research Fund for the Doctoral Program of
Higher Education (No. 20060285001), and Key Project in
Science & Technology Innovation Cultivation Program of
Soochow University.
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D
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[16] CCDC 736552 contains the supplementary crystallo-
graphic data for compound 3a in this paper. These data
can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif or from The Director, CCDC, 12
Union Road, Cambridge, CB2 1EZ, UK [E-mail: lin-
stead@ccdc.cam.ac.uk or deposit@ccdc.cam.ac.uk; fax:
(+44)-01223–336–033]. Structural parameters for 3a:
data collection: Rigaku Mercury CCD area detector;
crystal size: 0.30ꢄ0.25ꢄ0.18 mm3; C37H40N2O4, Mr=
and FeACTHNURGTNE(UNG III), respectively. But both of them showed
lower activity than that of Fe3O4 in this transformation,
which, to some extent, implies that a cooperation
should exist between Fe(II) and FeACTHNUTRGEN(UNG III) in Fe3O4. The
cooperation may be the exhibition of rapid electron
transfer.
[21] The loading level of Cu in nano-iron oxide was deter-
mined via ICP-AES: 2.53ꢄ10À5 mmol Cu/mmol Fe.
Thus, the effect of Cu was examined for the reaction of
1a with 2a in the presence of Cs2CO3 (3.0 equiv.), and
toluene (3 mL): 16% yield (10 mol% nano-Cu), 32%
yield (10 mol% CuI) and 43% yield (10 mol% nano-
CuO). These results suggest that nano-Fe3O4 plays the
key role in the present reaction, but we cannot rule out
the effect of Cu completely.
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576.71, monoclinic, space group
P
21/c, a=
3156
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