Iron-catalyzed C-H bond activation for the ortho-arylation of aryl pyridines and imines with Grignard reagents

Article abstract of DOI:10.1002/asia.201100470

Direct arylation of the ortho-C-H bond of an aryl pyridine or an aryl imine with an aryl Grignard reagent has been achieved by using an iron-diamine catalyst and a dichloroalkane as an oxidant in a short reaction time (e.g., 5 min) under mild conditions (0 °C). The use of an aromatic co-solvent, such as chlorobenzene and benzene, and slow addition of the Grignard reagent are essential for the high efficiency of the reaction. The present arylation reaction has distinct merits over the previously developed reaction that used an arylzinc reagent, such as its reaction rate and atom economy. Selective C-H bond activation occurs in the presence of a leaving group, such as a tosyloxy, chloro, and bromo group. Studies on a stoichiometric reaction and kinetic isotope effects shed light on the reaction intermediate and the C-H bond-activation step.

Full text of DOI:10.1002/asia.201100470

DOI: 10.1002/asia.201100470
À
Iron-Catalyzed C H Bond Activation for the ortho-Arylation of Aryl
Pyridines and Imines with Grignard Reagents
Naohiko Yoshikai, Sobi Asako, Takeshi Yamakawa, Laurean Ilies, and
Eiichi Nakamura*[a]
Abstract: Direct arylation of the ortho-
Grignard reagent are essential for the
high efficiency of the reaction. The
present arylation reaction has distinct
merits over the previously developed
reaction that used an arylzinc reagent,
such as its reaction rate and atom econ-
À
À
C H bond of an aryl pyridine or an
omy. Selective C H bond activation
aryl imine with an aryl Grignard re-
agent has been achieved by using an
iron-diamine catalyst and a dichloroal-
kane as an oxidant in a short reaction
time (e.g., 5 min) under mild condi-
tions (08C). The use of an aromatic co-
solvent, such as chlorobenzene and
benzene, and slow addition of the
occurs in the presence of a leaving
group, such as a tosyloxy, chloro, and
bromo group. Studies on a stoichiomet-
ric reaction and kinetic isotope effects
shed light on the reaction intermediate
À
Keywords: biaryls
tion cross-coupling
reagent · iron
·
C H activa-
À
and the C H bond-activation step.
·
·
Grignard
Introduction
of iron that is naturally abundant, environmentally benign,
and non-toxic.[5–7] We have recently demonstrated the versa-
tility of iron for the oxidative directed arylation reaction of
aryl pyridine and imine derivatives [Eq. (1)],[8] which we de-
veloped on the basis of our experience of low-valent iron
catalysis since the late 1990s.[5e,9] The catalytic system con-
sisting of an iron salt and a diamine ligand (phen or dtbpy)
as catalyst precursors and 1,2-dichloro-2-methylpropane as
À
Aryl aryl bond formation is a useful synthetic reaction be-
cause of the ubiquity of biaryls in functional molecules.[1]
À
Typically, an aryl aryl bond has been constructed by a tran-
sition-metal-catalyzed cross-coupling reaction of an aryl
halide and an arylmetal reagent.[2] More recently, direct con-
À
À
version of an aryl C H bond into an aryl aryl bond is re-
ceiving attention[3] because such reactions alleviate the need
for the prefunctionalization (halogenation and/or metala-
tion) of the aromatic substrates. However, reactions report-
ed so far typically rely on the use of expensive transition
metal catalysts (e.g., Pd, Rh, Ru)[4] and require harsh reac-
tion conditions. These problems can be resolved by the use
À
an oxidant allows facile displacement of the ortho-C H
bonds of aryl pyridine and imine derivatives with an arylzinc
reagent prepared from a zinc salt and the corresponding
Grignard reagent under very mild conditions (08C). Howev-
er, the reaction has one unattractive feature, that is, it re-
quires the use of large amounts of the zinc salt (2.5–3 equiv)
and the aryl Grignard reagent (5–6 equiv) for the generation
of the reactive arylzinc reagent. Our earlier attempts to use
solely the Grignard reagent failed because of iron-catalyzed
oxidative homocoupling of the Grignard reagent.[10]
[a] Dr. N. Yoshikai,+ S. Asako, T. Yamakawa,+ Dr. L. Ilies,
Prof. Dr. E. Nakamura
Department of Chemistry, School of Science
The University of Tokyo
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Fax : (+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
Nanyang Technological University
Singapore 637371 (Singapore)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201100470.
Chem. Asian J. 2011, 6, 3059 – 3065
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FULL PAPERS
Our recent findings[11] suggested a remedy. Namely, sever-
al modifications made on the original catalytic systems al-
lowed us to use an aryl Grignard reagent for stereospecific
Grignard reagent (over 5–60 min).[12] Furthermore, the aryl
À
aryl bond formation takes place very quickly at 08C, com-
pleting at the end of the addition of the Grignard reagent.
This simpler system is more suitable for mechanistic studies,
and has allowed us to obtain some information on the
À
arylation of an olefinic C H bond with a stoichiometry
closer to the theoretical minimum (i.e., 2 equiv), with a high
reaction rate and under mild conditions (08C, <5 min,
Scheme 1). The key modifications include: 1) the use of an
À
nature of the reaction intermediate and the C H bond-acti-
vation step of the catalytic reaction.
Results and Discussion
Optimization of Reaction Conditions
In the first set of experiments, we examined the phenylation
of 2-phenylpyridine (1a) with PhMgBr, adding PhMgBr
(1.25m in THF, 3 equiv) to a mixture of 1a, FeACHTUNGTRENNUNG(acac)3
À
Scheme 1. Iron-catalyzed stereospecific arylation of olefinic C H bond.
(10 mol%), ligand (10 mol%), and 1,2-dichloro-2-methyl-
propane[13] (2 equiv) in tetrahydrofuran or in a mixture of
tetrahydrofuran and a co-solvent quickly over approximate-
ly 30 seconds [Eq. (2)]
aryl Grignard reagent instead of an arylzinc reagent, 2) slow
addition of the reagent over a period of 5 min, and 3) the
use of chlorobenzene as a co-solvent. These modifications
allowed us to use far less Grignard reagent (2.4–3.2 equiv of
PhMgBr) than our original conditions using the zinc re-
agent, partly because the second modification suppresses ox-
idative homocoupling of the Grignard reagent. The use of
chlorobenzene appears to stabilize an iron intermediate and
hence contributes to the enhancement of the overall effi-
ciency of the reaction.
With the new finding in hand, we have made possible the
use of an aryl Grignard reagent for the direct arylation of
À
aromatic C H bonds. Herein, we report that the cross-cou-
Screening bidentate aromatic amine ligands revealed that
dtbpy affords the monophenylated product 2a in a 45%
yield (Table 1, entry 1), whilst other ligands, such as phen,
pling of aryl pyridine and imine derivatives with an aryl
Grignard reagent can be achieved (Scheme 2) if the reaction
is performed in the presence of an aromatic co-solvent, such
as chlorobenzene and benzene, with slow addition of the
2,2’-bipyridyl
(bpy),
and
4,4’-dimethyl-2,2’-bipyridyl
(dmbpy), are much less effective, because of the formation
of biphenyl by iron-catalyzed oxidative homocoupling
Table 1. Conditions for iron-catalyzed phenylation of 2-phenylpyridine
with phenylmagnesium bromide [Eq. (2)].[a]
Entry
Ligand[b]
Solvent
Yield [%][c]
À
Ph Ph
2a
3a
1
2
3
4
5
6
7
8
dtbpy
bpy
phen
THF
THF
THF
THF
benzene/THF
toluene/THF
Et2O/THF
n-hexane/THF
benzene/THF
benzene/THF
benzene/THF
45
19
17
10
83
66
39
32
70
87
88
1
0
0
0
4
91
134
142
120
51
Scheme 2. Iron-catalyzed direct arylation of aryl pyridine and imine de-
rivatives with Grignard reagent.
dmbpy
dtbpy
dtbpy
dtbpy
dtbpy
dtbpy
dtbpy
dtbpy
2
65
Abstract in Japanese:
<1
<1
2
6
12
102
107
63
53
47
9[d]
10[e]
11[f]
[a] Conditions: 1a (0.4 mmol), FeACHTUNRGTNEUNG(acac)3 (0.04 mmol), ligand
(0.04 mmol), PhMgBr (1.25m in THF, 1.2 mmol), 1,2-dichloro-2-methyl-
propane (0.8 mmol), solvent (3 mL). PhMgBr was added over ca. 30 s.
[b] dtbpy: 4,4’-di-tert-butyl-2,2’-bipyridyl; bpy: 2,2’-bipyridyl; phen: 1,10-
phenanthroline; dmbpy: 4,4’-dimethyl-2,2’-bipyridyl. [c] Determined by
GC using n-tridecane as an internal standard. [d] PhMgBr was added
over 5 min. [e] PhMgBr was added over 20 min. [f] PhMgBr was added
over 1 h.
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À
Iron-Catalyzed C H Bond Activation
(Table 1, entries 2–4). The use of benzene as a co-solvent
dramatically increased the yield of the phenylation products
(2a, 83%; 3a, 4%; Table 1, entry 5). Toluene was also effec-
tive (Table 1, entry 6), whilst nonaromatic solvents such as
diethyl ether and n-hexane showed adverse effects (Table 1,
entries 7 and 8).
We then found that the yield of the reaction in Table 1,
entry 5 tends to fluctuate by Æ10%, and that the rate of the
addition of PhMgBr causes this problem. Careful control of
the rate of addition made the reaction highly reproducible
(Table 1, entries 9–11). Slow addition of PhMgBr with a sy-
ringe pump over 1 hour afforded quantitative conversion of
the starting material into the phenylation products 2a
(88%) and 3a (12%; Table 1, entry 11). We also noted that
vigorous stirring of the reaction mixture is essential to ach-
ieving high yield and reproducibility of the reaction (see the
Supporting Information). The reaction took place equally
efficiently with reagent-grade (>95%) and high-purity (>
benzene were effective, affording the arylation product in
68% and 62% yields, respectively (Table 2, entries 3 and 4).
Whilst benzene and toluene gave modest results (Table 2,
entries 1 and 2), highly electron-rich (i.e., mesitylene) or
electron-deficient arenes (i.e., ortho-dichlorobenzene and
trifluoromethylbenzene) exhibited adverse effects (Table 2,
entries 5–7). With chlorobenzene as the co-solvent, the use
of a slight excess of dtbpy (15 mol%) further improved the
product yield to 78% (Table 2, entry 8). In contrast to the
conditions employing benzene as the co-solvent (Table 1),
the optimum period for the addition of the Grignard reagent
was 5 min in this case, with prolonging of the addition time
resulting in lower yields (Table 2, entries 9 and 10). The re-
action completed at the end of the Grignard addition (i.e.,
reaction timeꢀ5 min) and chlorobenzene did not undergo
cross-coupling with the Grignard reagent (only a trace
amount of 4-methoxybiphenyl was detected by GC analy-
sis).
99.9%) Fe
ACHTUNGTRENNUNG
as FeCl3 or FeACHTUNGTRENNUNG
Reaction Scope
proceeded with similar yield when PhMgCl was used as an
arylating reagent.
On the basis of the optimization studies, we used chloroben-
zene or benzene as the co-solvent and the slow-addition pro-
cedure to explore the scope of the direct arylation reaction
(Scheme 2). Table 3 summarizes the results of the arylation
of various arylpyridine derivatives. Substrates bearing meta-
methyl, methoxy, dimethylamino, and chloro substituents
1b–1e underwent exclusive monophenylation at the less-
hindered ortho position in 82–94% yield (Table 3, entries 1–
4). The meta-fluoro substrate 1 f afforded the 6-phenylation
product 2 f in moderate yield, and only a trace amount of
the 2-phenyl regioisomer was detected (Table 3, entry 5).
Benzo[h]quinoline smoothly reacted with PhMgBr to afford
the phenylation product 2g in 91% yield (Table 3, entry 6).
On the other hand, phenyl and methyl substituents on the
ortho position lowered the yield of the desired products
(Table 3, entries 8 and 9), probably for steric reasons. Pyri-
dine-bearing heteroarenes such as thiophene (1j) and indole
(1k) could also be phenylated, albeit in modest yields
(Table 3, entries 14 and 15).
The favorable effects of benzene and toluene as co-sol-
vents for the phenylation reaction prompted us to perform
further examination on other aromatic co-solvents. For this
study, we chose a lower-yielding reaction of benzo[h]quino-
line with 4-methoxyphenylmagnesium bromide for the
benchmark test (Scheme 3), and screened seven aromatic
co-solvents (Table 2, entries 1–7). We found that modestly
electron-deficient arenes such as chlorobenzene and fluoro-
Scheme 3. Iron-catalyzed ortho-arylation of benzo[h]quinoline with
4-methoxyphenylmagnesium bromide using arene/THF as a solvent.
4-Methoxyphenyl, 4-tert-butylphenyl, 4-fluorophenyl, and
À
2-naphthyl Grignard reagents took part in the C H activa-
Table 2. Effects of aromatic solvents on the reaction of benzo[h]quino-
line and 4-methoxyphenylmagnesium bromide (Scheme 3).[a]
tion in moderate to good yields (Table 3, entries 7, 10–13),
whilst 2-methoxyphenyl and 2-thienyl Grignard reagents did
not participate in the arylation reaction at all, and only af-
forded the corresponding homocoupled products. Methyla-
tion of benzo[h]quinoline with MeMgBr only took place in
5% yield, and alkylation with n-butyl and cyclohexyl
Grignard reagents did not take place at all.This catalytic
system is also applicable to an aryl imine, derived from the
corresponding ketone and para-anisidine (Table 4). The phe-
nylation of propiophenone and tetralone imines 1l and 1m
on a 0.4 mmol scale took place cleanly to give the products
2q and 2t in near quantitative yield (Table 4, entries 1 and
4). The latter reaction could be performed on a 4 mmol (ca.
1 g) scale in a good yield of 80%. Other Grignard reagents
such as para-biphenylmagnesium bromide and 4-methoxy-
Entry
Solvent
Addition time [min] Yield [%][b]
1
2
3
4
5
6
7
benzene/THF
toluene/THF
chlorobenzene/THF
fluorobenzene/THF
mesitylene/THF
5
5
50
51
68
62
15
34
19
78
66
58
5
5
5
5
5
5
20
60
ortho-dichlorobenzene/THF
trifluoromethylbenzene/THF
chlorobenzene/THF
chlorobenzene/THF
chlorobenzene/THF
8[c]
9[c]
10[c]
[a] Conditions: benzo[h]quinoline (0.4 mmol), FeACTHNURGTNEUNG(acac)3 (0.04 mmol),
ligand (0.04 mmol), 4-MeOC6H4MgBr (1.19m in THF, 1.28 mmol), 1,2-di-
chloro-2-methylpropane (0.8 mmol), solvent (2.9 mL). [b] Determined by
GC using n-tridecane as an internal standard. [c] dtbpy (15 mol%) was
used. THF=tetrahydrofuran.
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E. Nakamura et al.
FULL PAPERS
Table 3. Direct arylation of 2-arylpyridine derivatives with arylmagnesi-
um bromides.[a]
Table 4. Direct arylation of aryl imines with arylmagnesium bromides.[a]
Entry
Substrate[b]
Product
Yield [%][c]
Entry
Substrate
Product
Yield
[%][b]
1
2q 98
1
2
3
4
5
1b
1c
1d
1e
1 f
2b (R=Me)
94
90
89
82
58
2c (R=OMe)
2d (R=NMe2)
2e (R=Cl)
2
3
4
5
2r 93
1l
2 f (R=F)
6
7
2g (Ar=Ph)
2h (Ar=4-
MeOC6H4)
91
76
1g
2s 68
8
9
1h
1i
2i (R=Ph)
2j (R=Me)
56[c]
25[c]
1m
1n
2t 94 (80)[d]
2k (Ar=4-
MeOC6H4)
2l (Ar=4-
10
11
46
68
2u 88
1c
tBuC6H4)
12
13
2m (Ar=4-FC6H4)
2n (Ar=2-naph-
thyl)
58
56
6
7
1o
1p
2v 70
2w 19
14
15
1j
2o
35[c]
[a] The reaction was carried out on a 0.4 mmol scale using chlorobenzene
or benzene as the co-solvent and the slow-addition procedure, followed
by hydrolysis with 3 m aq. HCl (for details, see the Supporting Informa-
tion). [b] PMP=p-methoxyphenyl. [c] Yield of isolated product. [d] The
reaction was performed on a 4 mmol scale. Ts=para-methylsulfonyl.
1k
2p
19
[a] The reaction was carried out on a 0.4 mmol scale using chlorobenzene
or benzene as the co-solvent and the slow-addition procedure (for details,
see the Supporting Information). [b] Yield of isolated product. [c] Ob-
tained as a mixture with starting material and yields were determined by
1H NMR analysis.
and coordinated by the directing group.[3] To probe this pu-
tative intermediate, we performed a series of stoichiometric
experiments (Scheme 4 and Table 5). First, PhMgBr
3,5-dimethylphenylmagnesium bromide reacted with the
propiophenone imine 1l to give the corresponding arylation
products 2r and 2s in 93% and 68% yields, respectively
(Table 4, entries 2 and 3). The reaction tolerated the pres-
ence of electrofugal leaving groups such as tosyloxy and
chloro substituents, and yielded the desired products 2u and
2v in good yields (Table 4, entries 5 and 6). Even an aromat-
(4 equiv) was added to a mixture of 1a, FeACTHNGURETNNU(G acac)3 (1 equiv),
and dtbpy (2 equiv) in PhCl over a period of 3 minutes.
After stirring for 10 seconds, the reaction was immediately
quenched with D2O to afford 1a, the phenylation product
2a, and biphenyl in 82%, 6%, and 90% yields, respectively
(Table 5, entry 1). A deuterium atom was incorporated into
À
ic C Br bond was tolerated, whilst its presence lowered the
yield of the product 2w, because the homocoupling reaction
of PhMgBr was faster than the desired phenylation reaction,
for unknown reasons (Table 4, entry 7). In no case could we
observe nucleophilic addition of the Grignard reagent to the
C=N bond.
À
Insight into the Reaction Intermediate and the C H Bond-
Activation Step
À
The accepted wisdom of directed C H bond activation calls
for the formation of an ortho-metalated intermediate where
the metal is covalently bonded to the ortho-carbon atom
Scheme 4. Trapping of the ortho-metalated intermediate.
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À
Iron-Catalyzed C H Bond Activation
Table 5. Stoichiometric reaction of 2-phenylpyridine with PhMgBr in the
presence or absence of iron complex (Scheme 4).[a]
Entry
x
y
t1
t2
Yield [%][b]
1a [%D][c]
2a
Ph Ph
À
1
2
3
4
5
1
1
1
1
0
2
2
2
0
0
3 min
3 min
3 min
5 min
5 min
10 s
1 h
82 (59)
80 (86)
27 (20)
86 (0)
6
6
59
0
90
92
114
138
0
40 s[d]
30 s
30 s
>95 (0)
0
[a] The reaction was performed on a 0.2 mmol scale. [b] Determined by
GC using n-tridecane as an internal standard. [c] Determined by
1H NMR analysis. [d] Stirring for 10 s, addition of 1,2-dichloro-2-methyl-
propane, and additional stirring for 30 s were followed by the addition of
D2O.
the ortho position of 1a in 59%. When the same reaction
was stirred for 1 hour before quenching, the proportion of
the deuterium atom increased to 86%, while the yields of
the products did not change (Table 5, entry 2). When 1,2-di-
chloro-2-methylpropane was added before quenching with
D2O, the recovery of 1a decreased to 27% whilst the yield
of 2a increased to 59% (Table 5, entry 3). In the absence of
dtbpy, oxidative dimerization (biphenyl formation) took
place, and neither phenylation nor deuterium incorporation
occurred (Table 5, entry 4). Not unexpectedly, the reaction
of 1a with PhMgBr without any catalyst resulted in quanti-
tative recovery of 1a without deuterium incorporation
(Table 5, entry 5).
Scheme 5. Intramolecular and intermolecular kinetic isotope effects.
2a (0.088 mmol) and 2a (0.028 mmol), the ratio of which in-
dicated an intramolecular KIE value of 3.1 (Scheme 5a).
The intermolecular competitive reaction of 1a and [D5]-1a
was performed under similar conditions to give a KIE value
of 3.4 (Scheme 5b). The similarly large magnitude of the in-
tramolecular and intermolecular KIE values indicates that
coordination of the pyridyl group to the iron catalyst takes
Several mechanistic implications can be inferred from the
above stoichiometric experiments, which indicate the pres-
À
ence of a stable intermediate that bears an ortho C metal
bond and decomposes into the ortho-phenylation product
under oxidative conditions. First, the deuterium incorpora-
tion into the ortho position of 1a (Table 5, entries 1 and 2)
supports the formation of an ortho-metalated intermediate.
The intermediate forms only when the iron salt and the
dtbpy ligand are present, as shown by the control experi-
ments (Table 5, entries 4 and 5). The deuterium incorpora-
tion of 59%, achieved when the reaction time was 3 minutes
(Table 5, entry 1), is consistent with the high reaction rate of
the arylation reaction. Furthermore, the higher level of the
deuterium incorporation for the 1 hour reaction (Table 5,
entry 2) indicates that the ortho-metalated intermediate is
stable enough at 08C. This intermediate quickly decomposes
to give the ortho-phenylation product 2a upon addition of
1,2-dichloro-2-methylpropane (Table 5, entry 3). Putting the
above considerations together, the intermediate appears to
be an iron complex bearing 2-(2-pyridyl)phenyl and phenyl
À
place in a reversible manner, and that the following C H
bond-cleavage step is the first irreversible step of the cata-
lytic cycle,[17] where the C H bond is significantly elongated.
À
On the basis of the above mechanistic experiments as well
as the previous study on the ortho-arylation reaction with an
arylzinc reagent,[8a] we suggest a possible catalytic cycle, as
shown in Scheme 6. Reversible coordination of the pyridyl
group of the substrate to the iron center of an aryliron spe-
cies (I, II) is followed by irreversible metalation of the ortho
position with concomitant elimination of an arene mole-
cule.[18–20] The ortho-ferrated intermediate III undergoes re-
ductive elimination upon interaction with 1,2-dichloro-2-
methylpropane to afford the ortho-arylation product, isobu-
tene, and dichloroiron species IV. Transmetalation of IV and
the Grignard reagent regenerates the active species I. The
undesirable oxidative homocoupling of the Grignard reagent
occurs if the species I directly reacts with the dichloroal-
kane. The relevance between the reaction mechanism and
the key reaction conditions (the aromatic solvent and the
slow addition) need further clarification. At this time, we
speculate that the aromatic solvent serves as a ligand that
stabilizes a low-valent iron species,[21] and that the slow addi-
tion is necessary for controlled formation of the reactive
iron species.[9c,18]
À
ligands, which undergoes aryl aryl bond-forming reductive
elimination upon interaction with the dichloroalkane (see
below).
Intra- and intermolecular kinetic isotope effects (KIEs)
À
on the arylation reaction shed light on the iron-mediated C
H bond-activation step as well as on the preceding coordina-
tion of the pyridyl group to the iron catalyst
(Scheme 5).[15,16] The reaction of [D]-1a (0.37 mmol) with
1.2 equivalents of PhMgBr in a benzene/tetrahydrofuran
mixture afforded a mixture of the phenylation products [D]-
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E. Nakamura et al.
FULL PAPERS
NaHCO3. After extraction with ethyl acetate and Et2O, the organic layer
was washed with brine, dried over MgSO4, and concentrated under re-
duced pressure. The crude product was purified by column chromatogra-
phy on silica gel (toluene as an eluent) to afford the title compound as a
colorless oil (93.3 mg, 94%). The spectral data were in accordance with
those reported in the literature.[22]
General Procedure for Iron-Catalyzed Direct Arylation with an Aryl
Grignard reagent in PhCl/THF: 8-Phenyl-3,4-dihydronaphthalen-1ACHTUNGTRENNUNG(2H)-
one (2t)
In a Schlenk flask were placed 4,4’-di-tert-butyl-2,2’-bipyridyl (16.1 mg,
0.06 mmol), (E)-N-(3,4-dihydro-1(2H)-naphthalenylidene)-4-methoxy-
benzenamine (100 mg, 0.40 mmol), chlorobenzene (3.2 mL), and Fe-
(acac)3 (14.1 mg, 0.04 mmol). The resulting mixture was cooled to 08C,
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
followed by addition of 1,2-dichloro-2-methylpropane (93 mL,
0.80 mmol). PhMgBr (1.53m in THF, 0.84 mL, 1.28 mmol) was added to
the vigorously stirred solution with a syringe pump over 5 min. The reac-
tion mixture was directly subjected to acidic hydrolysis with 3 m hydro-
chloric acid, and then extracted with ethyl acetate and Et2O. The organic
layer was washed with brine, dried over Na2SO4, and concentrated under
reduced pressure. The crude product was purified by column chromatog-
raphy on silica gel (n-hexane/AcOEt=49:1 to 19:1) to afford the title
compound as a colorless solid (83.6 mg, 94%). The spectral data were in
accordance with those reported in the literature.[16a]
Scheme 6. Possible catalytic cycle.
Conclusions
Trapping of ortho-Metalated Intermediate with D2O (Table 5)
In summary, an iron-catalyzed cross-coupling reaction of
aryl pyridines and imines with aryl Grignard reagents has
been developed, and the new conditions revealed herein
have significant assets over the same transformation ach-
ieved by the use of organozinc reagents. The key elements
of the development are the use of an aromatic co-solvent,
such as chlorobenzene and benzene, and the slow addition
of the Grignard reagent. Under the optimized catalytic con-
A THF solution of PhMgBr (0.76m, 1.05 mL, 0.8 mmol) was added to a
solution of 2-phenylpyridine (31.0 mg, 0.2 mmol), FeACTHNUGTRENUNG(acac)3 (70.5 mg,
0.2 mmol), and 4,4’-di-tert-butyl-2–2’-bipyridyl (107 mg, 0.4 mmol) in
PhCl (3.0 mL) over 3 min at 08C. After a certain period of time (10 s or
1 h), the reaction was quenched with D2O followed by the addition of sa-
turated aqueous solution of potassium sodium tartrate and water. The or-
ganic layer was collected and analyzed by GC using n-tridecane as an in-
1
ternal standard to determine the yield, and by H NMR to determine the
deuterium incorporation into the recovered substrate.
À
ditions, the aryl aryl bond formation with the Grignard re-
Intramolecular Kinetic Isotope Effect (Scheme 5a)
agent takes place faster than that with the zinc reagent, and
immensely faster than those catalyzed by precious metals at
elevated temperatures. The stoichiometric experiments sug-
gested the formation of an iron complex bearing an ortho
In a Schlenk flask were placed 4,4’-di-tert-butyl-2,2’-bipyridyl (11.1 mg,
0.04 mmol), 2-(2-deuteriophenyl)pyridine (58.5 mg, 0.37 mmol), benzene
(2.0 mL), THF (0.3 mL), and FeACHTUNTRGNEUNG(acac)3 (14.3 mg, 0.04 mmol). The result-
ing mixture was cooled to 08C, and 1,2-dichloro-2-methylpropane (93 mL,
0.80 mmol) was added. A solution of PhMgBr in THF (0.76m, 0.63 mL,
0.48 mmol) was added to the vigorously stirred solution with a syringe
pump over 22.5 min. The reaction mixture was diluted with diethyl ether
and quenched by the addition of saturated aqueous solution of NaHCO3.
After extraction with ethyl acetate and Et2O, the combined organic
layers were washed with brine, dried over MgSO4, and concentrated
under reduced pressure. The crude product was purified by column chro-
matography on silica gel (n-hexane/AcOEt=19:1 to 4:1) to afford a mix-
ture of the monophenylated products and dtbpy as a colorless solid
À
C Fe bond as a stable reaction intermediate, which under-
À
À
goes C C bond formation upon oxidation. The C H bond-
activation step is the first irreversible step of the catalytic
cycle and shows substantial kinetic isotope effects as exam-
ined in both the intramolecular and intermolecular competi-
tive reactions. The proposed catalytic cycle is consistent with
the mechanistic information gained thus far, whilst further
studies are necessary to elucidate the nature of the reactive
intermediates and the detail of the bond cleavage and for-
mation processes.
1
(27.9 mg). H NMR analysis indicated kH/kD =3.1.
Intermolecular Kinetic Isotope Effect (Scheme 5b)
In a Schlenk flask were placed 4,4’-di-tert-butyl-2,2’-bipyridyl (10.8 mg,
0.04 mmol), 2-phenylpyridine (32.6 mg, 0.21 mmol), 2-(2,3,4,5,6-pentadeu-
teriophenyl)pyridine (33.9 mg, 0.21 mmol), benzene (2.0 mL), THF
Experimental Section
(0.3 mL), and FeACTHUNRGTNEUNG(acac)3 (14.3 mg, 0.04 mmol). The resulting mixture was
cooled to 08C, and 1,2-dichloro-2-methylpropane (93 mL, 0.80 mmol) was
added. A solution of PhMgBr in THF (0.76m, 0.42 mL, 0.32 mmol) was
added to the vigorously stirred solution with a syringe pump over 15 min.
The reaction mixture was diluted with Et2O and quenched by the addi-
tion of saturated aqueous solution of NaHCO3. After extraction with
ethyl acetate and Et2O, the combined organic layer was washed with
brine, dried over MgSO4, and concentrated under reduced pressure. The
crude product was purified by column chromatography on silica gel
(hexane/AcOEt=9:1) to afford a mixture of the monophenylated prod-
ucts and dtbpy as a colorless solid (20.0 mg). 1H NMR analysis indicated
kH/kD =3.4.
General Procedure for Iron-Catalyzed Direct Arylation with Aryl
Grignard Reagent in PhH/THF: 2-(4-Methylbiphenyl-2-yl)pyridine (2b)
In a Schlenk flask were placed 4,4’-di-tert-butyl-2,2’-bipyridyl (10.7 mg,
0.04 mmol), 2-(3-methylphenyl)pyridine (68.2 mg, 0.40 mmol), benzene
(2.0 mL), and
a 0.125m solution of FeACHTUNGTNRUEGN(acac)3 in THF (0.32 mL,
0.04 mmol). The resulting mixture was cooled to 08C, followed by addi-
tion of 1,2-dichloro-2-methylpropane (93 mL, 0.80 mmol). PhMgBr
(0.76m in THF, 1.68 mL, 1.28 mmol) was added to the vigorously stirred
solution with a syringe pump over 1 h. The reaction mixture was diluted
with Et2O and quenched by the addition of saturated aqueous solution of
3064
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Chem. Asian J. 2011, 6, 3059 – 3065

À
Iron-Catalyzed C H Bond Activation
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Acknowledgements
We thank MEXT for financial support (KAKENHI Specially Promoted
Research No. 22000008 to E.N., No. 23750100 to L.I.), and Global COE
program for Chemistry Innovation. S.A. thanks the Japan Society for the
Promotion of Science for the Research Fellowship for Young Scientists
(23·8207).
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Received: May 19, 2011
Published online: September 6, 2011
Chem. Asian J. 2011, 6, 3059 – 3065
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
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