Iron-catalyzed nitrogen-directed coupling of arene and aryl bromides mediated by metallic magnesium

Article abstract of DOI:10.1002/adsc.201100791

2-Arylpyridines, 2-alkenylpyridine, and aromatic imines can be coupled with aryl bromides in the presence of an iron catalyst, metallic magnesium, a diamine ligand and an organic dihalide oxidant at 0 °C. The use of a 1:1 mixture of tetrahydrofuran and 1,

Full text of DOI:10.1002/adsc.201100791

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DOI: 10.1002/adsc.201100791
Iron-Catalyzed Nitrogen-Directed Coupling of Arene and Aryl
Bromides Mediated by Metallic Magnesium
Laurean Ilies,a Motoaki Kobayashi,a Arimasa Matsumoto,a Naohiko Yoshikai,b
and Eiichi Nakamuraa,*
a
Department of Chemistry, School of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Fax : (+81)-3-5800-6889; phone: (+81)-3-5800-6889; e-mail: nakamura@chem.s.u-tokyo.ac.jp
Present Address: Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences,
b
Nanyang Technological University, Singapore 637371, Singapore
Received: October 12, 2011; Published online: February 23, 2012
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201100791.
Abstract: 2-Arylpyridines, 2-alkenylpyridine, and
aromatic imines can be coupled with aryl bromides
in the presence of an iron catalyst, metallic magne-
sium, a diamine ligand and an organic dihalide oxi-
dant at 08C. The use of a 1:1 mixture of tetrahydro-
To achieve this transformation, we need to recon-
cile the reductive conditions that use metallic magne-
sium with the oxidative conditions for the C H acti-
vation event, and we found that a judicious choice of
the oxidant and of the reaction conditions can effect
this reaction efficiently. Thus, the reaction of ben-
zo[h]quinoline (1.08 g, 6.0 mmol) with bromobenzene
À
À
furan and 1,4-dioxane is essential for this C H
bond activation reaction. The reaction has wider
scope of the substrate compared with the reaction
using a separately prepared Grignard reagent, and
proceeds with lower catalyst loading (2.5 mol%).
in the presence of 2.5 mol% of FeACHTNUTRGNEUNG(acac)3 as a catalyst,
2.5 mol% of 4,4’-di-tert-butyl-2,2’-bipyridyl (dtbpy) as
a ligand, magnesium turnings as an additive, and 1,2-
dichloroisobutane (DCIB) as an oxidant in THF/1,4-
dioxane at 08C gave the ortho-arylated product 2 in
92% isolated yield (1.41 g, Scheme 1). The same reac-
tion performed with 0.40 mmol of 1 also gave 2 in
96% yield (Table 1, entry 1). Although it is likely that
a Grignard reagent formed first[9] and took part in the
iron-catalyzed reaction, the wider substrate scope of
À
Keywords: aryl bromides; biaryls; C H activation;
iron; magnesium
À
Transition metal-catalyzed directed C H bond activa- the reaction (see below) may suggest that the present
tion for C C bond formation has attracted much at- reaction does not involve the formation of a discrete
[1]
À
tention recently[2] for the synthesis of biaryl deriva- Grignard reagent.
tives.[3] While precious metals have been extensively
used for this reaction, there has been recent interest[4]
in catalysis based on first-row transition metals, which
are inexpensive, abundant and non-toxic.[5] We have
been exploring iron catalysis[6] for some time, and re-
À
ported several C H bond activation protocols using
organometallic reagents.[7] We report here an iron/di-
ACHTUNGTRENNUNGamine-catalyzed regioselective oxidative coupling of
aryl bromides[8] with 2-arylpyridines, 2-alkenylpyri-
dine, or aromatic imine derivatives in the presence of
metallic magnesium and THF/1,4-dioxane as solvent
(Scheme 1). The reaction takes place at 08C using
2.5 mol% of an iron salt and tolerates the presence of
aryl fluoride, chloride, and even bromide groups. The
use of 1,4,-dioxane is essential to achieve this transfor-
mation.
Scheme 1. Iron-catalyzed directed coupling of arenes and
aryl bromides mediated by metallic magnesium.
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Laurean Ilies et al.
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Table 1. Effect of the reaction parameters on the iron-cata-
lyzed phenylation of benzo[h]quinoline with bromobenzene.
Table 2. Iron-catalyzed ortho-arylation of benzo[h]quinoline
with various organic halides.[a]
Entry
Conditions
2 [%][b]
1 [%][b]
1
2
3
4
5
6
7
8
standard[a]
96[c]
17
0
1
THF as a solvent
1,4-dioxane as a solvent
no Fe, Mg, or dtbpy
no oxidant
82
100
>95
86
3
0
11
94
100
52
Fe
FeCl3
Fe(acac)2
ACHTUNGTRENNUNG
(acac)3 low purity[d]
0
48
G
[a]
Standard reaction
(0.40 mmol), bromobenzene (3.0 equiv.), FeACHTUNGTRENNUNG
conditions:
benzo[h]quinoline
(acac)3 (2.5
mol%, Aldrich, >99.9%), dtbpy (2.5 mol%), magnesium
turnings (3.3 equiv.), DCIB (2.0 equiv.) in THF/1,4-diox-
ane (1:1) at 08C, vigorous stirring for 24 h.
NMR yield.
Isolated yield.
Kanto, 94% purity.
[b]
[c]
[d]
The use of 1,4-dioxane in addition to THF is the
crucial difference between this protocol and those
using Grignard reagents or organozinc reagents,
which we reported recently to give the best results in
THF or THF/arene.[7] As summarized in Table 1, the
THF/1,4-dioxane mixture is essential to obtain a
quantitative yield (entry 1), as compared with the
data for THF or dioxane alone as solvent (entries 2
and 3). Diethyl ether instead of 1,4-dioxane was
found to be inefficient (data not shown). One may
conjecture that 1,4-dioxane selectively removes
MgBr2 and hence generates Ph2Mg. However, Ph2Mg
in THF/1,4-dioxane gave only a low yield (32%) of
the desired product. In the absence of the iron salt,
ligand, or magnesium additive, the reaction did not
proceed at all (entry 4). In the absence of the oxi-
dant,[10] only a trace amount of product was observed
(entry 5). FeACHTUNGTRENNUNG(acac)3 of lower purity and FeCl3 gave es-
sentialy the same results (entries 6 and 7), whereas an
Fe(II) salt gave a lower yield (entry 8).
With the optimized conditions in hand, we next in-
vestigated the scope of the organic halide in the reac-
tion with benzo[h]quinoline (Table 2). As already de-
scribed, bromobenzene gave the ortho-phenylated
benzo[h]quinoline 2 in quantitative yield, and the re-
action could be performed on 1-g scale with similar
yield (entry1). Iodobenzene could also be utilized
(entry 2), but the yield was decreased and a large
amount of biphenyl was formed. Chlorobenzene was
entirely unreactive (entry 3) and it was recovered to-
gether with substrate 1. Both electron-rich (entries 4,
5, 7) and electron-deficient (entries 8–10) aromatic
[a]
Reaction conditions: benzo[h]quinoline (0.40 mmol), or-
ganic halide (3.0 equiv.), FeACHTNUGTRENUNG(acac)3 (2.5 mol%), dtbpy
(2.5 mol%), metallic magnesium (3.3 equiv.), DCIB
(2.0 equiv.) in THF/1,4-dioxane (1:1) at 08C, vigorous
stirring.
[b]
[c]
[d]
[e]
Isolated yield.
Reaction using 1 g of 1.
NMR yield.
10 mol% of FeACHTNUTRGNE(UNG acac)3 was used.
bromides reacted with similar yields. The reaction was tries 8 and 10), chloride (entry 9), and sterically-hin-
sensitive to steric factors (entry 6), as previously ob- dered bromide (entry 12) were tolerated. An-oxygen-
À
served for iron-catalyzed directed C H activation re- containing heterocycle (entry 11) and a sulfur-contain-
actions.[7] Notably, halide groups such as fluoride (en- ing heterocycle (entry 13), which could not be intro-
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Adv. Synth. Catal. 2012, 354, 593 – 596

Iron-Catalyzed Nitrogen-Directed Coupling of Arene and Aryl Bromides
Table 3. Iron-catalyzed ortho-phenylation of various arylpyr-
iron catalysis. The use of 1,4-dioxane as a cosolvent of
THF is essential. This reaction has a clear synthetic
advantage over the previous ones using a Grignard
reagent prepared separately from an aryl halide
before the coupling reaction. This practically useful
idines and aromatic imines with bromobenzene.[a]
À
protocol may be applicable to related C H activation
reactions using iron[7] and cobalt[11] catalysts.
Experimental Section
Typical Procedure
In a two-neck, round-bottom flask were placed benzo[h]qui-
noline (1.08 g, 6.0 mmol), bromobenzene (1.90 mL,
18.0 mmol), FeACTHUNRGTNEUNG(acac)3 (54 mg, 0.15 mmol), 4,4’-di-tert-butyl-
2,2’-dipyridyl (41 mg, 0.15 mmol), THF (30 mL), 1,4-dioxane
(30 mL), and 1,2-dichloroisobutane (1.50 mL, 12.0 mmol).
Magnesium turnings (0.48 g, 19.8 mmol) were added to this
mixture at 08C. The color of the reaction mixture gradually
turned from red brown to purple over 30 min. After vigo-
rous stirring for 24 h, an aqueous solution of potassium
sodium tartrate tetrahydrate, an aqueous solution of ammo-
nium chloride, and water were successively added. After ex-
traction with ethyl acetate three times, the combined organic
layers were concentrated under reduced pressure to obtain a
pale orange oil. The crude material was purified by silica gel
column chromatography (eluent: 5% ethyl acetate/hexane)
to afford 10-phenylbenzo[h]quinoline as a colorless solid;
yield: 1.41 g (92%). The spectral data were in accordance
with those reported in the literature.[12]
[a]
Reaction conditions: arylpyridine, alkenylpyridine, or ar-
omatic imine (0.40 mmol), bromobenzene (3.0 equiv.),
FeACHTUNGTRENNUNG(acac)3 (2.5 mol%), dtbpy (2.5 mol%), metallic magne-
sium (3.3 equiv.), DCIB (2.0 equiv.) in THF/1,4-dioxane
(1:1) at 08C, vigorous stirring.
[b]
[c]
Isolated yield.
Isolated as a mixture of mono- and diphenylated product.
The yield was determined by 1H NMR.
Ar=p-methoxyphenyl.
After hydrolysis with aqueous HCl.
About 30% of debrominated product was also observed.
Acknowledgements
[d]
[e]
[f]
We thank MEXT (KAKENHI Specially Promoted Research)
grants 22000008 to E.N., 23750100 to L.I.) and the Global
COE Program for Chemistry Innovation. A. M. thanks the
Japan Society for the Promotion of Science for Young Scien-
tists for the research fellowship (No. 21·8684).
duced using the corresponding organometallic re-
agents, could be introduced using the present reaction
conditions, albeit in low yield. Alkylation with iodo-
methane proceeded in low yield (entry 14). Alkenyl
bromides did not react under these conditions, and
only a homocoupling product was observed.
Next, we investigated the scope of the arene sub-
strate (Table 3). 2-Phenylpyridine (entry 1) gave
mainly a monophenylated product, together with a
small amount of the diphenylated product. An elec-
tron-rich heterocyclic arene (entry 2) could also be
employed. A cyclic alkenyl substrate (entry 3) reacted
with low yield. Aromatic imines (entries 4 and 5)
gave the corresponding ortho-phenylated ketones
after hydrolysis. A bromide group was partially toler-
ated on the imine substrate (entry 5).
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