Magnetically recoverable iron nanoparticle catalyzed cross-dehydrogenative coupling (CDC) between two Csp3-H bonds using molecular oxygen

Article abstract of DOI:10.1055/s-0030-1258128

The oxidative C-C bond formations between Csp³-H bond adjacent to nitrogen and Csp³-H bond of nitroalkanes are catalyzed efficiently by magnetically recoverable iron nanoparticles using oxygen. The catalyst can be magnetically remove

Full text of DOI:10.1055/s-0030-1258128

2002
CLUSTER
Magnetically Recoverable Iron Nanoparticle Catalyzed Cross-Dehydrogena-
tive Coupling (CDC) between Two Csp3–H Bonds Using Molecular Oxygen
C
ross-Dehydrog
i
enativ
e
e
Coupling
q
between
T
w
o
Csp
–
3a
H
Bonds ng Zeng,a,b Gonghua Song,*b Audrey Moores,a Chao-Jun Li*a
a
Department of Chemistry, McGill University, 801 Sherbrooke St. West, Montreal, QC, H3A 2K6, Canada
Fax +1(514)3983797; E-mail: cj.li@mcgill.ca
Shanghai Key Laboratory of Chemical Biology, Institute of Pesticides and Pharmaceuticals, East China University of Science
and Technology, Shanghai 200237, P. R. of China
b
Fax +86(21)64252603; E-mail: ghsong@ecust.edu.cn
Received 19 April 2010
strategies have successfully demonstrated the applications
of the Fe3O4 nanoparticle-immobilized or -supported cat-
alysts for reactions.9 Recently, the direct use of Fe3O4
nanoparticles without modification as magnetically re-
coverable catalysts for organic reactions have also been
reported. We10 and others11 developed the strategy of di-
rectly using Fe3O4 nanoparticles as efficient recyclable
catalysts for three-component coupling of aldehyde,
alkyne, and amine (A3-coupling) and C–N cross-coupling
reactions. However, the scope and the application of this
strategy are still very limited. Herein, we wish to report
robust and magnetically recoverable Fe3O4 nanoparticle
catalyzed CDC reactions between Csp3–H bond and
Csp3–H bond using an atmosphere of oxygen as oxidant
(Scheme 2). The nanoparticle catalyst was directly reused
nine times without the need of reactivation.
Abstract: The oxidative C–C bond formations between Csp3–H
bond adjacent to nitrogen and Csp3–H bond of nitroalkanes are cat-
alyzed efficiently by magnetically recoverable iron nanoparticles
using oxygen. The catalyst can be magnetically removed and recy-
cled easily for nine times without decreasing activity.
Key words: iron nanoparticles, oxygen, cross-coupling, C–C bond
formation
The development of more direct catalytic approaches to-
ward the synthesis of chemical products represents one of
the key efforts of achieving chemical sustainability.1 On
the other hand, the use of more benign catalysts and the
simple separation of catalysts from reaction mixtures pro-
vide both economical and ecological benefits.2
Carbon–carbon bond formation is an important part of
many chemical syntheses.3 In recent years, C–C bond for-
mation based on the reaction of C–H bonds has attracted
great interest.4 Toward the formation of C–C bonds by di-
rectly using two different C–H bonds under oxidative con-
ditions, we5 and others6 have developed various cross-
dehydrogenative-coupling (CDC) reactions. Such a strat-
egy would avoid the prefunctionalization of starting mate-
rials and thus shorten the syntheses and increase overall
efficiency (Scheme 1). Copper and iron salts were found
to be effective catalysts for various CDC reactions in the
presence of oxidants such as hydrogen peroxide, dioxy-
gen, tert-butylhydroperoxide, and 2,3-dichloro-5,6-dicyano-
benzoquinone (DDQ).
Fe3O4 nanoparticles
Csp3-H + Csp3-H
Csp3
Csp3
+
this work
H2O
O2
Scheme 2 Oxidative CDC between two Csp3–H bonds using oxy-
gen as oxidant
Figure 1 Photo of A: Fe3O4 nanoparticles in reaction solution; B:
Fe3O4 nanoparticles dispersed in reaction solution; C: Fe3O4 nanopar-
ticles adsorbed on the magnetic stirring bar when reaction is comple-
ted; D: a magnet attracted the magnetic stirring bar and Fe3O4
nanoparticles.
cat. M
[O]
+
C
C
C
H
H C
Scheme 1 CDC reactions
In recent years, the magnetic Fe3O4 nanoparticles (magne-
tite nanoparticles) have been extensively studied.7 Due to
the ease of magnetical separation from the reaction mix-
ture, the strategy of magnetical separation is simpler and
typically more effective than filtration or centrifugation as
it prevents the loss of the catalyst (Figure 1).8 Various
Tetrahydroisoquinoline, a common substructure of natu-
ral products and pharmaceuticals, was chosen as a sub-
strate in these reactions. To begin our study, we used 2-
phenyl-1,2,3,4-tetrahydroisoquinoline (1a) and nitro-
methane (2a) as standard substrates to search for suitable
reaction conditions for the Fe3O4 nanoparticle catalyzed
CDC reactions (Table 1). Using 10 mol% of Fe3O4 nano-
particles and under one atmosphere of molecular oxygen
at 60 °C for 24 hours gave 11% (NMR) yield of the de-
sired CDC reaction product 3a (Table 1, entry 1). Encour-
SYNLETT 2010, No. 13, pp 2002–2008
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x
.x
x
.2
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1
0
Advanced online publication: 09.07.2010
DOI: 10.1055/s-0030-1258128; Art ID: Y01110ST
© Georg Thieme Verlag Stuttgart · New York

CLUSTER
Cross-Dehydrogenative Coupling between Two Csp3–H Bonds
2003
Table 1 Optimization of Reaction Conditionsa
aged by this initial result, we began to optimize the
reaction conditions. Higher yields were obtained when the
reactions were carried out at elevated temperature
(Table 1, entries 2–4). The best NMR yield (99%) was
generated at 100 °C (entry 5). The use of tert-butyl perox-
ide instead of O2 as an oxidant decreased the NMR yield
to 78% (Table 1, entry 6). tert-Butyl hydroperoxide
(TBHP) was found to be an almost inactive oxidant in this
iron-catalyzed CDC reaction (Table 1, entry 7). The use
of molecular oxygen provide a more atom-economical
and safer process than other oxidants.1a,2a When using oth-
er solvents such as toluene, water, acetonitrile, or metha-
nol, decreased yields were obtained (Table 1, entries 8–
11). It is worth noting that this reaction also proceeded ef-
ficiently in air without the need of pure oxygen gas
(Table 1, entry 12). The optimized reaction conditions in-
clude using nitroalkane as solvent and 1 atm O2 as oxidant
at 100 °C. To preclude the possibility that the results of
these Fe3O4 nanoparticle catalyzed reactions may be af-
fected by trace quantities of copper,12 we tested 99.99%
Fe3O4 powder to catalyze this CDC reaction under the op-
timized reaction conditions, which gave 89% NMR yield
(Table 1, entry 13). Considering Fe3O4 nanoparticles have
a much larger surface area than their powder form, which
can provide a higher catalytic activity, we conclude that
the reaction was catalyzed by Fe3O4 nanoparticles rather
than by trace copper impurities. Furthermore, g-Fe2O3
nanoparticles were also an effective catalyst in this reac-
tion, affording the corresponding product 3a in good yield
(Table 1, entry 14). The g form iron oxide nanoparticles
can also be separated easily by the magnetic method and
reused. Interestingly, O2 was shown to be able to mediate
this reaction to result in a moderate yield at an elevated
temperature (Table 1, entry 15) in the absence of any cat-
alyst.6q
iron catalyst (10 mol%)
MeNO2
+
N
24 h
N
Ph
Ph
1a
2a
NO2
3a
Entry
Temp
(°C)b
Oxidant
Solvent
Yield
(%)c
1
2
60
70
O2
O2
O2
O2
O2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
toluene
H2O
11
19
3
80
20
4
90
76
5
100
100
100
100
100
100
100
100
100
100
100
99
6
tert-butyl peroxide
78
7
TBHP
O2
trace
65
8
9
O2
82
10
11
12
13
14
15
O2
MeCN
MeOH
MeNO2
MeNO2
MeNO2
MeNO2
66
O2
28
O2
91d
89e
90f
41g
O2
O2
O2
a Conditions: 2-phenyl-1,2,3,4-tetrahydroisoquinoline (0.2 mmol),
nitromethane (0.4 mmol), and Fe3O4 nanoparticles (0.02 mmol) were
stirred in 0.5 mL of solvent for 24 h; O2: 1 atm.
b Temperature of oil bath.
A variety of compounds were tested as substrates for the
Fe3O4 nanoparticle catalyzed oxidative cross-dehydroge-
native-coupling reactions under optimized reaction condi-
tions, and the results are summarized in Table 2. The
reaction of 1,2,3,4-tetrahydroisoquinoline derivatives
with nitromethane generated the desired coupling prod-
ucts 3a,d,e,g,i,l in excellent isolated yields (Table 2, en-
tries 1, 4, 5, 7, 9, and 12). When nitroethane was used, the
desired products of 3b,h,j,m were obtained in good yields
(the ratios of two diastereoisomers are 1.4–2:1; Table 2,
entries 2, 8, 10, and 13). The use of nitropropane also gave
the desired compounds with moderate to good yields
(Table 2, entries 3, 6, and 11). Nitromethane was found to
be the most active nitroalkane among the three ones. Sub-
strates 1c with an N-p-methoxyphenyl substituent and 1e
with an N-m-methoxyphenyl substituent were found to be
more reactive than the simple phenyl-substituted ana-
logue for this CDC reaction. N-Methyl-1,2,3,4-tetrahy-
droisoquinoline reacted with nitromethane to give
unspecified decomposition products. In the case of 1-phe-
nylpyrrolidine, the desired product was obtained in a low
yield and some unidentified byproducts were formed
(Table 2, entry 14).
c NMR yields based on 1a using an internal standard.
d In air.
e 99.99% Fe3O4 powder (0.02 mmol) was used as catalyst.
f Fe2O3 nanoparticles (0.02 mmol) were used as catalyst.
g No iron catalyst was used; reactions were conducted in the dark;
average NMR yield of three experiments.
In addition to nitroalkanes, this Fe3O4 nanoparticle cata-
lyzed oxidative CDC reaction was also applicable to ace-
tone (Table 3). 2-Phenyl-1,2,3,4-tetrahydroisoquinoline
(1a) and 2-(4-methoxyphenyl)-1,2,3,4-tetrahydroisoquin-
oline (1c) reacted with acetone, generating the desired
products in 48% and 65% yields, respectively.
When the magnetic stirring was stopped, the magnetic
Fe3O4 nanoparticles were adsorbed on the magnetic stir-
ring bar.13 The nanoparticles were then washed with ethyl
acetate, air-dried, and used directly for the next round of
reaction without further purification. It was shown that the
ligand-free Fe3O4 nanoparticle catalyst could be recov-
ered and reused nine times without significant loss of cat-
alytic activity (Figure 2).
Synlett 2010, No. 13, 2002–2008 © Thieme Stuttgart · New York

2004
T. Zeng et al.
CLUSTER
Table 2 Catalytic CDC Reactions between Tertiary Amines with Nitroalkanes under Oxygena
R2
N
fuse
R4
R2
N
R4
Fe3O4 nanoparticles (10 mol%)
H
+
R1
NO2
R1
H
NO2
100 °C, O2 (1 atm)
24 h
R3
R3
1
2
3
Entry
1
Substrate
Product15
Yield (%)b
N
Ph
90
69
59
72
91
70
79
55
93
N
Ph
NO2
1a
1a
3a
3b
3c
3d
3e
3f
N
2
3
4
5
6
7
8
9
Ph
NO2
N
Ph
1a
NO2
N
N
N
NO2
1b
N
NO2
OMe
OMe
OMe
1c
1c
N
NO2
OMe
OMe
OMe
N
N
NO2
1d
1d
3g
3h
3i
N
NO2
N
OMe
N
OMe
NO2
1e
Synlett 2010, No. 13, 2002–2008 © Thieme Stuttgart · New York

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Cross-Dehydrogenative Coupling between Two Csp3–H Bonds
2005
Table 2 Catalytic CDC Reactions between Tertiary Amines with Nitroalkanes under Oxygena (continued)
R2
N
fuse
R4
R2
N
R4
Fe3O4 nanoparticles (10 mol%)
H
+
R1
NO2
R1
H
NO2
100 °C, O2 (1 atm)
24 h
R3
R3
1
2
3
Entry
10
Substrate
Product15
Yield (%)b
N
OMe
OMe
1e
84
NO2
3j
3k
3l
N
11
12
13
1e
72
81
60
NO2
N
N
NO2
Br
Br
Br
1f
1f
N
NO2
3m
NO2
N
N
14
32
1g
3n
a Tertiary amine (0.2 mmol), nitroalkane (0.5 mL), Fe3O4 nanoparticles (0.02 mmol, under O2 (1 atm), at 100 °C (temperature of oil bath), for
24 h.
b Isolated yields based on tertiary amines.
A proposed mechanism is shown in Scheme 3. An imini-
um cation coordinated to Fe3O4 nanoparticles 6 is first
generated in situ from the tertiary amine by Fe3O4-cata-
lyzed oxidation with an oxygen molecule.5l,o Aromatic
substituents of the isoquinoline moieties can conjugate
with the iminium cation and make the intermediate more
stable. The Fe3O4 nanoparticles also catalyzed a deproto-
nation of nitroalkanes to generate intermediate 7.14 Subse-
quent coupling of the two intermediates 6 and 7 resulted
in the desired product (and regenerated the Fe3O4 nano-
particles). The iminium ion can also be trapped by acetone
to form the desired amino ketone.6b
In summary, we have demonstrated that robust, stable,
and magnetically recoverable Fe3O4 nanoparticles cata-
lyze the cross-dehydrogenative coupling (CDC) between
Figure 2 Reuse of Fe3O4 nanoparticles in the reactions: tertiary
amine 1a (0.2 mmol), nitromethane (0.5 mL), and Fe3O4 nanoparti-
Csp3–H bond and Csp3–H bond using molecular oxygen
as oxidant under mild conditions. A diverse range of
1,2,3,4-tetrahydroisoquinoline derivatives were obtained
cles (0.02 mmol) stirred under O2 (1 atm) at 100 °C (temperature of
oil bath) for 24 h. NMR yields were based on 1a.
Synlett 2010, No. 13, 2002–2008 © Thieme Stuttgart · New York

2006
T. Zeng et al.
CLUSTER
Table 3 CDC Reaction of Tetrahydroisoquinoline with Acetonea
in good to excellent yield. The separation and reuse of the
magnetic Fe3O4 nanoparticles were very effective, simple,
and economical. In addition, the use of Fe3O4 nanoparti-
cles as catalysts is also more environmentally friendly and
safer than other transition-metal catalysts. Further study
on the wider applications of this efficient strategy is under
investigation in our laboratory.
R2
R2
O
Fe3O4 nanoparticles (10 mol%)
N
H
+
R1
N
R1
100 °C, O2 (1 atm)
24 h
R3
R3
O
4
1
5
Product
Yield (%)b
Acknowledgment
We are grateful to the Canada Research Chair foundation (to C.J.L.
and A.R.M.), the CFI, FQRNT, NSERC and McGill University for
support of our research. TQZ thanks the China Scholarship Council
for a Visiting Scholarship. We thank Prof. Eric D. Salin, David A.
Duford and Yongqing Xi of the Chemistry Department at McGill
University for the ICP-AES analysis.
N
O
ph
48
5a
N
References and Notes
65
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OMe
O
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R2
OH
N
O
R1
R4
N
O
7
R3
6
R2
H
N
R1
R3
R4
H
NO2
+
1/2 O2
R2
N
R4
nano-Fe3O4
NO2
R1
R3
R2
OH
O
N
R1
6
R3
R2
N
H
R1
R3
+
1/2 O2
R2
N
R1
R3
O
nano-Fe3O4
Scheme 3 Proposed reaction mechanism
Synlett 2010, No. 13, 2002–2008 © Thieme Stuttgart · New York

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Cross-Dehydrogenative Coupling between Two Csp3–H Bonds
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Fe3O4 [<50 nm particle size (TEM)], Fe2O3 (<50 nm particle
size) and other reagents were purchased from Sigma-Aldrich
and used without further purification. 2-Aryl-1,2,3,4-
tetrahydroisoquinolines were prepared by the literature
method.16 To a reaction tube charged with a magnetic stir bar
and Fe3O4 nanoparticles (0.02 mmol, 10 mol%), 1,2,3,4-
tetrahydroisoquinoline derivatives (0.2 mmol), and
nitroalkane or acetone (0.5 mL) were added. Then the tube
was filled up with molecular oxygen and stoppered. The
reaction mixture was stirred at 100 °C (temperature of oil
bath) for 24 h. The Fe3O4 nanoparticles were adsorbed on the
magnetic stirring bar when the stirring was stopped. After
cooled to r.t., the reaction solution was filtered through
Celite in a pipette eluting with EtOAc. The volatile was
removed in vacuo, and the residue was purified by column
chromatography on silica gel (eluent: hexane–EtOAc = 5:1)
to give the corresponding product. Fe3O4 nanoparticles were
washed with EtOAc, air-dried, and used directly for the next
round of reaction without further purification.
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Chem. Rev. 2008, 108, 2064. (c) Sun, S.; Zeng, H. J. Am.
Chem. Soc. 2002, 124, 8204 . For selected reviews on Fe
catalysis, see: (d) Bolm, C.; Legros, J.; Le Paih, J.; Zani, L.
Chem. Rev. 2004, 104, 6217. (e) Sarhan, A. A. O.; Bolm, C.
Chem. Soc. Rev. 2009, 38, 2730. (f) Morris, R. H. Chem.
Soc. Rev. 2009, 38, 2282. (g) Cheng, Z. Y.; Li, Y. Z. Chem.
Rev. 2007, 107, 748. (h) Sherry, B. D.; Fürstner, A. Acc.
Chem. Res. 2008, 41, 1500.
White solid. Isolated by flash column chromatography
(hexane–EtOAc = 5:1, Rf = 0.7). 1H NMR (400 MHz): d =
7.26–7.15 (m, 5 H), 6.62–6.60 (m, 1 H), 6.53–6.52 (m, 1 H),
6.41–6.39 (m, 1 H), 4.42 (s, 2 H), 3.82 (s, 3 H), 3.57 (t,
J = 5.6 Hz, 2 H), 2.99 (t, J = 6.0 Hz, 2 H) ppm. 13C NMR
(100 MHz): d = 160.8, 151.9. 134.9, 134.5, 130.0, 128.5,
126.6, 126.4, 126.1, 108.0, 103.3, 101.5, 55.2, 50.6, 46.4,
29.2 ppm. HRMS (APCI): m/z calcd for C16H18NO [M + 1]+:
240.1383; found: 240.1381.
2-(3-Methoxyphenyl)-1-(nitromethyl)-1,2,3,4-
tetrahydroisoquinoline (3i)
Isolated by flash column chromatography (hexane–
Synlett 2010, No. 13, 2002–2008 © Thieme Stuttgart · New York

2008
T. Zeng et al.
CLUSTER
EtOAc = 5:1, Rf = 0.4). Light yellow oil. 1H NMR (400
MHz): d = 7.28–7.17 (m, 4 H), 7.14–7.12 (m, 1 H), 6.60 (dd,
J = 8.4, 2.4 Hz, 1 H), 6.54 (m, 1 H), 6.42 (dd, J = 8.0, 2.0 Hz,
1 H), 5.54 (dd, J = 7.2, 6.8 Hz, 1 H), 4.87 (dd, J = 12.0, 7.2
Hz, 1 H), 4.55 (dd, J = 11.6, 6.8 Hz, 1 H), 3.80 (s, 3 H), 3.66–
3.58 (m, 2 H), 3.00 (ddd, J = 16.4, 8.8, 6.4 Hz, 1 H), 2.68 (dt,
J = 16.4, 5.2 Hz, 1 H) ppm. 13C NMR (100 MHz): d = 160.9,
149.7, 135.2, 132.9, 130.2, 129.2, 128.2, 127.0, 126.7,
107.5, 104.0, 101.4, 78.8, 58.3, 55.2, 42.1, 26.6 ppm. HRMS
(APCI): m/z calcd for C17H19N2O3 [M + 1]+: 299.1390;
found: 299.1391.
5.24 (m), 3.85–3.83 (m), 3.58–3.52 (m), 3.52–3.04 (m),
2.96–2.86 (m) ppm. 13C NMR (100 MHz): d = 126.2 ppm.
HRMS (APCI): m/z calcd for C18H21N2O3 [M + 1]+:
313.1547; found: 313.1549.
2-(3-Methoxyphenyl)-1-(1-nitropropyl)-1,2,3,4-
tetrahydroisoquinoline (3k)
The ratio of isolated diastereomers is 1.6. Isolated by flash
column chromatography (hexane–EtOAc = 5:1, Rf = 0.4).
Light yellow oil.
Major isomer: 1H NMR (400 MHz): d = 5.12 (d, J = 9.6 Hz,
1 H), 4.86 (m, 1 H), 3.77 (s, 3 H) ppm. 13C NMR (100 MHz):
d = 160.5, 150.3, 135.5, 133.8, 130.1, 129.3, 128.5, 128.2,
125.9, 108.3, 103.9, 102.2, 92.9, 62.2, 55.2, 42.3, 25.8, 24.5
ppm.
2-(3-Methoxyphenyl)-1-(1-nitroethyl)-1,2,3,4-
tetrahydroisoquinoline (3j)
The ratio of isolated diastereomers is 1.7. Isolated by flash
column chromatography (hexane–EtOAc = 5:1, Rf = 0.4).
Light yellow oil.
Minor isomer: 1H NMR (400 MHz): d = 5.22 (d, J = 9.2 Hz,
1 H), 4.67 (m, 1 H), 3.81 (s, 3 H) ppm. 13C NMR (100 MHz):
d = 160.7, 150.3, 134.6, 132.1, 129.8, 128.6, 128.2, 127.2,
126.6, 106.8, 102.8, 100.8, 96.1, 60.7, 55.1, 43.5, 26.9, 25.0
ppm.
Major isomer: 1H NMR (400 MHz): d = 5.05 (dq, J = 14.8,
6.4 Hz, 1 H), 3.79 (s, 3 H), 1.55 (d, J = 6.4 Hz, 3 H) ppm. 13
NMR (100 MHz): d = 160.7, 150.2, 134.7, 131.9, 130.0,
128.7, 128.2, 126.6, 107.9, 104.0, 101.8, 85.4, 62.8, 55.2,
42.7, 26.5, 16.3 ppm.
C
Other overlapped peaks: 1H NMR (400 MHz): d = 7.26–7.08
(m), 7.01–7.18 (m), 7.00–6.98 (m), 6.62–6.52 (m), 6.40–
6.35 (m), 3.87–3.47 (m), 3.12–3.06 (m), 2.93–2.85 (m),
2.26–2.06 (m), 1.86–1.78 (m), 0.96–0.92 (m) ppm. 13C NMR
(100 MHz): d = 10.6 ppm. HRMS (APCI): m/z calcd for
C19H23N2O3 [M + 1]+: 327.1703; found: 327.1703.
(16) Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett. 2002,
4, 581.
Minor isomer: 1H NMR (400 MHz): d = 4.88 (dq, J = 14.8,
6.4 Hz, 1 H), 3.82 (s, 3 H), 1.71 (d, J = 6.8 Hz, 3 H) ppm. 13
NMR (100 MHz): d = 160.8, 150.5, 135.6, 133.8, 130.1,
129.1, 128.3, 127.3, 107.2, 103.1, 101.1, 88.9, 61.2, 55.2,
43.5, 26.9, 17.5 ppm.
C
Other overlapped peaks: 1H NMR (400 MHz): d = 7.27–7.08
(m), 7.01–7.00 (m), 6.62–6.52 (m), 6.40–6.37 (m), 5.25–
Synlett 2010, No. 13, 2002–2008 © Thieme Stuttgart · New York

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