Iron-mediated direct suzuki-miyaura reaction: A new method for the ortho -arylation of pyrrole and pyridine

Article abstract of DOI:10.1021/ol100838m

(Figure presented) The first example of an iron-mediated direct Suzuki-Miyaura reaction between N-heterocyclic compounds and arylboronic acids is described, and both electron-rich and electron-deficient heteroarenes can be successfully used for the coupling reaction.

Full text of DOI:10.1021/ol100838m

ORGANIC
LETTERS
2010
Vol. 12, No. 12
2694-2697
Iron-Mediated Direct Suzuki-Miyaura
Reaction: A New Method for the
ortho-Arylation of Pyrrole and Pyridine
Jun Wen, Song Qin, Li-Fang Ma, Liang Dong, Ji Zhang, Shan-Shan Liu,
Yi-Shu Duan, Shan-Yong Chen, Chang-Wei Hu,* and Xiao-Qi Yu*
Key Laboratory of Green Chemistry and Technology, Ministry of Education, College of
Chemistry, Sichuan UniVersity, Chengdu, Sichuan 610064, P. R. China; State Key
Laboratory of Biotherapy, Sichuan UniVersity, Chengdu, Sichuan 610041, P. R. China
chwehu@mail.sc.cninfo.net; xqyu@tfol.com
Received March 11, 2010
ABSTRACT
The first example of an iron-mediated direct Suzuki-Miyaura reaction between N-heterocyclic compounds and arylboronic acids is described,
and both electron-rich and electron-deficient heteroarenes can be successfully used for the coupling reaction.
The coupling between an aryl halide and an organic boronic
acid, known as the Suzuki-Miyaura reaction,1 is one of the
most valuable synthetic processes for the construction of
C-C bonds. This reaction was used to produce biaryl
compounds, which have numerous applications in the
construction of natural products, pharmaceuticals, agro-
chemicals, and materials.2 Since the discovery of the
Suzuki-Miyaura reaction, boronic acids have been devel-
oped as powerful reagents for C-C bond formation due to
their nontoxicity, stability, and compatibility with most
functional groups.3 On the other hand, many organic halides
and pseudohalides, including aryl halides and aryl sul-
fonates,4 were developed as electrophiles for this reaction.
However, this method requires premodification of the
substrate to form the electrophiles, and the overall process
is neither atom-economical nor green. In recent years, a
significant breakthrough was obtained in the direct Suzuki-
Miyaura reaction using complexes of Pd and Ru,5 which is
an ideal and green method to construct C-C bonds through
direct functionalization of C-H bonds. However, the re-
quirements of directing group, expensive catalysts, and
relatively low yields limit the application of this method.
Iron is one of the most abundant metals on the Earth.
Owing to its low cost, availability, and environmental
benignity, iron has attracted much attention in the field of
C-C cross coupling reactions.6,7 However, the application
(1) (a) Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981, 11,
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Plietker, B., Ed.; Wiley-VCH: Weinheim, 2008. (d) Correa, A.; Manchen˜o,
O. G.; Bolm, C. Chem. Soc. ReV. 2008, 37, 1108. (e) Sherry, B. D.; Fu¨rstner,
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2003, 125, 11818. (b) Tang, Z. Y.; Hu, Q. S. J. Am. Chem. Soc. 2004, 126,
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10.1021/ol100838m  2010 American Chemical Society
Published on Web 05/19/2010

of iron catalysis on the C-C bond formation through C-H
bond functionalization remains a challenge.8 In this respect,
we have recently reported the iron-mediated direct arylation
of unactivated arenes.9 Although a stoichiometric amount
of iron was used and less regioselectivity was obtained
therein, such work afforded a novel protocol for the direct
Suzuki-Miyaura reaction. On the basis of our previous
studies, we present herein a convenient and easily handled
iron-mediated direct Suzuki-Miyaura reaction for the regi-
oselective 2-arylation of N-heterocyclic compounds. Nev-
ertheless, some challenges for the reaction exist, such as:
(1) the regioselectivity of the reaction; (2) the reactivity of
electron-deficient heteroarenes; (3) the toleration for free
amine on the heterocycle.10
Table 1. Iron-Catalyzed C-2 Arylation of Pyrrole with
Phenylboronic Acida
yield of
ligand yield of 4a [%]b PhOH [%]b
entry
[Fe]
1c
2
3
4
5
6
7
8
9
10
11
12e
13g
14h
Fe2(SO4)3·7H2O
Fe2(SO4)3·7H2O
FeCl3
FeCl3·6H2O
FeC2O4·2H2O
FeCl2
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L2
L2
L2
0
27
<10
<10
47
18
17
25
N.D.f
N.D.
N.D.
N.D.
17
N.D.
N.D.
N.D.
trace
10
Our previous studies showed that the formation of a proper
iron-macrocyclic polyamine (MCPA, Figure 1) complex
Fe2(CO)9
Fe2O3
FeC2O4·2H2O
FeC2O4·2H2O
FeC2O4·2H2O
FeC2O4·2H2O
FeC2O4·2H2O
FeC2O4·2H2O
81 (68)d
64
18
N.D.
trace
N.D.
N.D.
80 (66)d
trace
80
a Reaction conditions (unless otherwise stated): pyrrole (15 mmol), 1a
(0.2 mmol), [Fe] (1.0 equiv), ligand (1.0 equiv), 130 °C, 10 h, under air.
b Yield determined by GC analysis with the use of n-dodecane as an internal
standard. c With K3PO4 (4.0 equiv), pyrazole (2.0 equiv). d The data in
parentheses are isolated yields. e [Fe] (0.2 equiv), ligand (0.2 equiv). f N.D.:
not determined. g Reaction under nitrogen. h 99.999% FeC2O4·2H2O.
Figure 1. Macrocyclic polyamine (MCPA) ligands studied here.
plays a key role in this type of reaction. Thus, we first
optimized the reaction conditions including the types of iron
salt and MCPA ligand in a model reaction between phenyl-
boronic acid and pyrrole (15 mmol as slovent), and the results
are summarized in Table 1. Under the optimized conditions
for the iron-mediated direct arylation of unactivated arenes
we reported earlier,9 no arylation product was detected (entry
1). Fortunately, we found that the desired cross-coupling
product could be obtained in 27% yield (entry 2) without
the addition of base or other additives. This result encouraged
us to find an appropriate combination of the iron-MCPA
complex for the reaction. After screening of several iron
sources (entries 2-8), Fe(II) oxalate was found to be the
most efficient salt, and 47% yield of desired product was
obtained in FeC2O4-present reaction (entry 5). Further
FeC2O4-mediated reactions focused on the screening of
MCPA ligands were studied. The reactions employing four
different MCPA ligands gave desired product in low to good
yields (entries 5 and 9-11). The best result was achieved in
the reaction using pyridine-containing L2 as the MCPA
ligand, and 81% yield was obtained (entry 9). More
importantly, almost the same result was found in the reaction
using decreased amounts of iron and MCPA ligand (0.2
equiv, entry 12), indicating that the iron complex could
catalyze the reaction. It is noteworthy that phenol was found
as a main byproduct in the reactions employing Fe-L1 and
Fe-L3, but only trace phenol was detected in the reaction
under optimized conditions employing Fe-L2. Furthermore,
only trace product was obtained when the reaction was
carried out under nitrogen (entry 13), indicating that oxygen
is an indispensable oxidant for the coupling. To exclude the
possibility that the trace other metal impurity would catalyze
the reaction,11 we did the control experiment using ultrapure
FeC2O4·2H2O (99.999%) as catalyst. We were pleased that
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Chem., Int. Ed. 2009, 48, 607. (o) Loska, R.; Volla, C. M. R.; Vogel, P.
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Soc. 2008, 130, 5858. (c) Li, Z.; Yu, R.; Li, H. Angew. Chem., Int. Ed.
2008, 47, 7497. (d) Yoshikai, N.; Matsumoto, A.; Norinder, J.; Nakamura,
E. Angew. Chem., Int. Ed. 2009, 48, 2925. (e) Moreau, B.; Wu, J. Y.; Ritter,
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Org. Lett., Vol. 12, No. 12, 2010
2695

almost the same yield was obtained (entry 14). Moreover,
such a reaction catalyzed by various trace impurities in
FeC2O4·2H2O (99.999%) has also been performed, and no
product was detected, indicating that this reaction is not likely
to be catalyzed by metal contaminants (see Supporting
Information for details).
The substrate scope was subsequently investigated under
theoptimizedconditions.TheresultsofdirectSuzuki-Miyaura
reactions between a variety of substituted arylboronic acids
and pyrrole catalyzed by Fe-L2 are summarized in Table 2
heteroarene, pyridine is rarely arylated through direct and
selective C-H arylation.12 Herein, in the presence of the
Fe-cyclen combination, high regioselective (ortho-) products
in moderate yields could be obtained from the direct arylation
of pyridine (Table 2, entries 15-18). This method provides
a new protocol for the direct arylation of electron-deficient
heteroarenes. Some further studies about the reaction of
pyridine are now in progress.
Reactions of some substituted pyrroles with phenylboronic
acid were investigated with the present iron catalytic system
(Scheme 1). It was found that the substituted pyrrole was
Table 2. Iron-Catalyzed Arylation of N-Heterocyclic
Compounds with Arylboronic Acida
Scheme 1
.
Iron-Catalyzed Arylation of Substituted Pyrroles with
Phenylboronic Acida b
,
entry
R
product
yield (%)b
80 (66)
71 (61)
56 (45)
55 (43)
67 (59)
47 (36)
84 (67)
63 (52)
28 (17)
32 (23)
83 (70)
84 (67)
61 (42)
73 (52)
1
2
3
4
5
6
7
8
H (1a)
(4a)
(4b)
(4c)
(4d)
(4e)
(4f)
(4g)
(4h)
(4i)
(4j)
(4k)
(4l)
(4m)
(4n)
(5a)
(5k)
(5g)
(5l)
3-Cl (1b)
2-Cl (1c)
4-CH3 (1d)
3-CH3 (1e)
2-CH3 (1f)
4-Br (1g)
4-F (1h)
a Yield determined by GC analysis with the use of n-dodecane as an
internal standard. The data in parentheses are isolated yields. b Reaction
under 150 °C.
9
4-OCH3 (1i)
4-CH(CH3)2 (1j)
4-COOCH3 (1k)
3-NO2 (1l)
Nap-2 (1m)
3,5-diF (1n)
H (1a)
4-COOCH3 (1k)
4-Br (1g)
3-NO2 (1l)
10
11
12
13
14
15c
16c
17c
18c
phenylated at the 2-position with excellent regioselectivity
to give the desired product in moderate to good yields. Using
R,R-disubstituted pyrrol such as 2,5-dimethyl-1H-pyrrole as
substrate (Scheme 1, 7d), only trace phenylated product was
obtained, while a mass of dimeric pyrrole was produced.
These results further proved that this catalyst system has
excellent regioselectivity to the active 2-position of pyrrole.
As there is a lack of mechanistic details about iron-
catalyzed cross-couplings through C-H bond activation, we
carried out preliminary mechanistic studies to have an insight
into the mechanism of this iron-catalyzed direct arylation.
The reaction was unaffected by the addition of free radical
scavenger TEMPO (20%), suggesting that no free radical
intermediate was involved in the reaction. In addition, oxygen
was found to be indispensable for the coupling because only
trace product was obtained when the reaction was carried
out under nitrogen. It is known that iron species with terminal
oxo ligands can be formed via reactive iron complexes with
dioxygen,13 and the Suzuki-Miyaura reaction is able to be
41, o/(m + p) ) 80:20d
45, o/(m + p) ) 95:5d
26, o/(m + p) ) 90:10d
42, o/(m + p) ) 80:20d
a Reaction conditions: pyrrole (15 mmol), 1 (0.2 mmol), FeC2O4·2H2O
(0.2 equiv), L2 (0.2 equiv), 130 °C, 10 h, under air. b Yield determined by
GC analysis with the use of n-dodecane as an internal standard. The data
in parentheses are isolated yields. c Pyridine (1 mL), acetic acid (1 mL), 1
(0.2 mmol), FeCl3·6H2O (0.5 equiv), L1 (0.5 equiv), 110 °C, 10 h, under
air. d The ratio of regioisomers was determined by GC.
(entries 1-14). Moderate to good yields were obtained in
most reactions without the formation of 3-arylation products.
Electron-withdrawing substituents might benefit the reaction
(entries 7, 11, and 12), while the electron-donating group
might show inhibition effects (entries 9 and 10). Some ortho-
substituted arylboronic acids also gave moderate yields of
2-arylation product 4 in spite of the steric hindrance (entries
3 and 6).
The iron-mediated cross-coupling between arylboronic
acids and pyridine was also studied. As an electron-deficient
(13) (a) Du Bois, J.; Mizoguchi, T. J.; Lippard, S. J. Coord. Chem. ReV
2000, 200-202, 443. (b) Costas, M.; Mehn, M. P.; Jensen, M. P.; Que, L.
Chem. ReV. 2004, 104, 939. (c) MacBeth, C. E.; Golombek, A. P.; Young,
V. G., Jr.; Yang, C.; Kuczera, K.; Hendrich, M. P.; Borovik, A. S. Science
2000, 289, 938.
(12) (a) Mukhopadhyay, S.; Rothenberg, G.; Gitis, D.; Baidossi, M.;
Ponde, D. E.; Sasson, Y. J. Chem. Soc., Perkin Trans. 2000, 2, 1809. (b)
Godula, K.; Sezen, B.; Sames, D. J. Am. Chem. Soc. 2005, 127, 3648. (c)
Yanagisawa, S.; Ueda, K.; Taniguchi, T.; Itami, K. Org. Lett. 2008, 10,
4673. (d) Berman, A. M.; Lewis, J. C.; Bergman, R. G.; Ellman, J. A. J. Am.
Chem. Soc. 2008, 130, 14926. (e) Li, M.; Hua, R. Tetrahedron Lett. 2009,
50, 1478.
(14) (a) Miyaura, N. J. Organomet. Chem. 2002, 653, 54. (b) Braga,
A. A. C.; Morgon, N. H.; Ujaque, G.; Maseras, F. J. Am. Chem. Soc. 2005,
127, 9298. (c) Braga, A. A. C.; Morgon, N. H.; Ujaque, G.; Lledo´s, A.;
Maseras, F. J. Organomet. Chem. 2006, 691, 4459.
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Org. Lett., Vol. 12, No. 12, 2010

catalyzed by the oxo-metal complex in the absence of a
base.14 To find out the effective catalytic species, we utilized
ESI-MS to monitor the reaction process. The consecutive
formation of iron complex Fe-L2 and oxoiron species
FeO-L2 was clearly observed by HRMS (Figure S2,
Supporting Information (SI)).15 Further, the formation of
oxoiron could also be detected by UV/vis spectroscopy
(Figure S3 and S4, SI).15 These findings suggested that the
oxoiron complex might be the most probable active species
in the reaction.16
Two different pathways are possible for the C-H bond
cleavage step, namely, oxidative addition and σ-bond me-
tathesis. DFT calculations were utilized to study this step.
Results showed that the transferable hydrogen on the pyrrole
should move to the oxygen of the oxoiron complex without
any tendency to form an iron-hydride intermediate, indicating
the C-H activation by σ-bond metathesis. On the basis of
these results, we speculated that the reaction started with
the oxidation of an iron complex to form oxoiron species
derived from oxygen, followed by an electrophilic attack of
the oxoiron complex on C-2 position of heteroarenes with
the assistance of a heteroatom. After subsequent deprotona-
tion, a tertiary complex consisting of iron, heterocycle, and
MCPA ligand was formed. Thereafter, in the presence of
arylboronic acid, transmetalation and elimination of the iron
complex would provide the desired product (Scheme 2).
Figure 2. Free-energy diagrams of the Suzuki reaction calculated
at the B3LYP(PCM)/6-311+G(d,p) level. The relative energies (in
kJ/mol) are listed in parentheses. (The blue curve represents the
quartlet surface, the red one represents the sextet surface.)
reaction. The largest energy barriers on the potential energy
surface (PES) were predicted to be 130.9 and 126.6 kJ/mol
for the quartet and sextet state, representing the rate-
determining step of the formation of metallo-benzene moiety
via TS3.
In conclusion, we developed a novel iron catalyst system
for the regioselective arylation of N-heterocyclic compounds.
Both electron-rich and electron-deficient heteroarenes can
be successfully used for the coupling reaction. To the best
of our knowledge, this is the first example of an iron-
mediated direct Suzuki-Miyaura reaction between N-het-
erocyclic compounds and arylboronic acids. Additionally,
preliminary mechanistic studies suggest that the oxoiron
compound is the catalytically active species for this reaction.
A full catalytic cycle of the iron-catalyzed direct Suzuki-
Miyaura coupling between pyrrole and phenylboronic acid
has been analyzed by means of DFT calculation, and an
unprecedented catalytic C-H activation process of N-
heteroaromatics by iron is revealed. Further studies to
elucidate the mechanism and to expand the synthetic scope
of this reaction are currently under investigation.
Scheme 2.
Proposed Catalytic Cycle of the Couplinga
a L ) ligand.
Acknowledgment. This work was financially supported
by the National Science Foundation of China (Nos. 20725206,
20732004, and 20772085), Program for Changjiang Scholars
and Innovative Research Team in University, the Key Project
of Ministry of Education in China, and Scientific Fund of
Sichuan Province for Outstanding Young Scientist.
To further understand the mechanism of the iron-catalyzed
direct Suzuki-Miyaura reaction, open-shell DFT calculations
were carried out to give a qualitative similar mechanistic
picture of the reaction for the quartet and sextet state. The
energy diagrams of the reaction are depicted in Figure 2.15
Analyses of the reaction energy profiles indicated that the
quartet was the lowest spin state in the major part of the
Supporting Information Available: Experimental pro-
cedures, synthetic and spectroscopic data for various com-
pounds, and supplementary spectral data. This material is
available free of charge via the Internet at http://pubs.acs.org.
(15) See Supporting Information for details.
(16) Ghosh, A.; Oliveira, F. T. d.; Yano, T.; Nishioka, T.; Beach, E. S.;
`
Kinoshita, I.; MuEnck, E.; Ryabov, A. D.; Horwitz, C. P.; Collins, T. J.
J. Am. Chem. Soc. 2005, 127, 2505.
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2697