Direct arylation of substituted pyridines with arylboronic acids catalyzed by iron(II) oxalate

Article abstract of DOI:10.1002/cjoc.201400528

The direct arylation of substituted pyridines with several arylboronic acids has been developed. This transformation could proceed readily at ambient temperature using inexpensive reagents: iron(II) oxalate as a catalyst, potassium persulfate as a co-oxidant, which can afford the arylated products in mild to good yields. The mechanism is presumed to proceed through a nucleophilic radical addition to the pyridines with in situ reoxidation.

Full text of DOI:10.1002/cjoc.201400528

NOTE
DOI: 10.1002/cjoc.201400528
Direct Arylation of Substituted Pyridines with Arylboronic
Acids Catalyzed by Iron(II) Oxalate
Yibo Huang,*a,b Dan Guan,a and Liang Wangb,c
a Department of Pharmacy, Changzhou Institute of Engineering and Technology, Changzhou,
Jiangsu 213164, China
b Jiangsu Provincial Key Laboratory of Fine Petrochemical Engineering, Changzhou, Jiangsu 213164, China
c School of Petrochemical Engineering, Changzhou University, Changzhou, Jiangsu 213164, China
The direct arylation of substituted pyridines with several arylboronic acids has been developed. This transfor-
mation could proceed readily at ambient temperature using inexpensive reagents: iron(II) oxalate as a catalyst, po-
tassium persulfate as a co-oxidant, which can afford the arylated products in mild to good yields. The mechanism is
presumed to proceed through a nucleophilic radical addition to the pyridines with in situ reoxidation.
Keywords direct arylation, substituted pyridine, arylboronic acid, Iron(II) oxalate
Introduction
powerful protocol for access to arylated products except
for the use of silver.
Recently, the direct arylation of C－H bonds has
been widely researched using transition metal catalysis,
which provides a new class of C－C bond forming reac-
tions.[1-5] Some transition metals, such as Pd and Ru
have exhibited powerful catalytic ability in the coupling
process. But, some drawbacks such as relatively high
price, considerable toxicity and complex ligands have
limited their applications. Therefore, the development of
a more practical method for direct arylation has been
desired.
Inspired by Baran’s idea, we began to investigate the
feasibility of arylation catalyzed by iron(II) oxalate.
Satisfactorily, it can promote the arylation of quiones
under the mild condition in our previous work.[25]
Herein, we will go on focusing on the arylation of het-
erocycles using iron(II) oxalate as a catalyst, potassium
persulfate as a co-oxidant and TFA as an additive.
Experimental
Iron-based catalysts have drawn much attention as
cheap, non-toxic, and environmentally friendly material
in the past years, which had been applied on some C－C
crossing coupling reactions.[6-10] But, many transforma-
tions are concerned with the complex ligands. Recently,
General information
All reagents were purchased from commercial sup-
pliers. The progress of the reactions was monitored by
TLC (silica-coated glass plates and visualizing under
1
UV light). H NMR, 13C NMR spectra were measured
[12]
some ligand-free iron salts such as FeS[11] and FeSO4
on a Bruker AM 300 or AM 400 NMR spectrometer
with CDCl3 as solvent and recorded relative to internal
TMS standard. Mass spectroscopy data of the products
were collected on an Agilent 6890-5973N GC/MS-EI
instrument. HRMS were recorded on Bruker ultrafle
Xtreme MALDI-TOF-TOF.
have been reported to promote the direct arylation of
quinones as green catalysts using arylboronic acids as
parterns.
Pyridine moieties are very important units in bio-
logically active compounds, functional materials, and
pharmaceuticals. The direct arylation of pyridine moie-
ties could provide an effective method to facilitate the
heterobiaryls.[13-20] In previous reports, some transition
metals have been utilized to finish this transformation
with organohalides and organometallic species.[21,22]
However, the methods for direct aryaltion of pyridines
are sparse. Very recently, Baran groups demonstrated
the direct arylation of benzoquinones and heteroarenes
using AgNO3/K2S2O8.[23,24] They provided a simple and
General procedure for arylation of substituted pyri-
dines with arylboronic acids
To a 25 mL flask were sequentially added substi-
tuted pyridine (0.5 mmol), arylboronic acid (1.5 mmol),
and iron(II) oxalate (0.5 mmol). The mixture solvent of
DCM∶H2O (1∶1, V/V, 3 mL) was added, followed by
TFA (0.5 mmol) and potassium persulfate (1.5 mmol).
The reaction mixture was then stirred at 25 ℃ for 48 h,
*
E-mail: ybhuang_czie@163.com; Tel.: 0086-0519-86332295; Fax: 0086-0519-86332818
Received August 2, 2014; accepted September 26, 2014; published online December 12, 2014.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201400528 or from the author.
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Chin. J. Chem. 2014, 32, 1294—1298

Direct Arylation of Substituted Pyridines with Arylboronic Acids Catalyzed by Iron(II) Oxalate
and then it was cooled to room temperature and filtered
with aid of DCM (5 mL). The filtrate was washed with a
saturated solution of NaHCO3 (10 mL×2) and the
aqueous layer was exacted again with DCM (10 mL×2).
The combined organic layer was concentrated under
reduced pressure, and then was dried over Na2SO4. The
crude product was purified by column chromatography
using the eluent [V(hexane)∶V(ethylacetate)/75∶25].
The identity and purity of the known products were con-
firmed by GC-MS, 1H NMR, 13C NMR and HRMS.
to 1.0 equiv., the yield decreased gradually (entries 5－
7). The solvent system of chlorobenzene/H2O and
α,α,α-trifluorotoluene/H2O could work as well as
DCM/H2O (entries 5, 8－9). If the loading amounts of
FeC2O4•2H2O varied from 0.5, 1.0 to 2.0 equiv., the
corresponding yields were 66%, 79% and 80% (entries
5, 10－11). When potassium persulfate was replaced by
the other oxidants such as ammonium persulfate, the
reaction could not proceed at all (entry 12).
Next, we investigated the scope of 4-cyanopyridine
with various arylboronic acids under the optimized con-
ditions. The results are summarized in Table 2. Most of
the reactions could proceed smoothly to afford the ex-
pected products in mild or good yields. Meanwhile, the
use of halogenated phenylboronic acid led to decreased
yields (entries 2－4). This was because halogenated
phenylboronic acids facilitated the production of the
biphenyl by-products. In addition, the arylboronic acids
with electron-donating groups could gave better results
than those with electron-withdrawing groups (entries 5
－8). Furthermore, among the obtained products, the
ratio of C-2 arylated product versus C-3 arylated prod-
uct was about 1.2∶1 to 5.2∶1. For entries 1 and 7, this
transformation exhibited good regioselectivity. But,
when using the double amounts of catalyst for entry 1,
there was no change of the regioselectivity.
In addition, this method was also suitable for some
pyridine derivatives. As shown in Table 3, some pyri-
dine derivatives and pyrazine could afford the corre-
sponding products with mild yields. The modified pyri-
dines containing 4-COOEt, 4-CH3CO and trifluoro-
methyl substituted groups gave moderate results (entries
2－4). In addition, the most arylated products were C-2
addition products (entries 3－4). Only low amount of
C-3 addition products could be obtained (entry 2). For
entry 5, the only C-2 addition products could be ob-
tained using pyrazine as substrate in this transformation
with 32.2% yield. When doubling the catalyst loading
amount, we did not observe the change of the regiose-
lectivity.
Finally, we examined the reaction mechanism using
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) as a
radical scavenger. When 2.0 equiv. of TEMPO was
added to the model reaction of 4-cyanopyridine and
phenylboronic acid, a trace amount of product was ob-
tained. This result showed that the coupling process
may proceed via a radical pathway. A plausible mecha-
nistic path could be demonstrated in Scheme 1, which
was analogous to the initial reports.[11,12] The sulfate
Results and Discussion
Firstly, we investigated the model reaction of
4-cyanopyridine and phenylboronic acid to optimize the
conditions. These results are summarized in Table 1.
And shown in Table 1, we could not obtain the desired
products without the iron catalyst (Table 1, entry 1).
Among the several iron salt catalysts, the trace product
was obtained using Fe2(SO4)3 as a catalyst (entry 2), and
low yield was obtained mediated by Fe(OAc)2 (entry 3).
But FeSO4·7H2O and FeC2O4·2H2O could afford the
products with low to good yields (entries 4－5). In ad-
dition, the ratio of C-2 arylated product versus C-3 ary-
lated product was about 3.5∶1 and 3.8∶1 respectively
(entries 4－5). Furthermore, using 1.0 or 2.0 equivalents
of FeC2O4•2H2O, the yield was 79% and 80% respec-
tively (entries 5 and 11). The obtained yield results did
not change distinctly.
Table 1 The optimization of reaction condition for the direct
arylation of 4-cyanopyridine and phenylboronic acida
CN
CN
CN
B(OH)2
iron catalysis
oxidant, TFA
Ph
+
+
solvent, r.t.
N
N
Ph
N
Yieldb/%
(C-2∶C-3)
Entry Iron salt (equiv.) Oxidant (equiv.) Solvent
1
2c
3
4
5
6
7
8
9
None
K2S2O8 3.0 DCM/H2O
K2S2O8 3.0 DCM/H2O
ND
Fe2(SO4)3 1.0
Fe(OAc)2 1.0
＜5
K2S2O8 3.0 DCM/H2O 35 (3.8∶1)
FeSO4•7H2O 1.0 K2S2O8 3.0 DCM/H2O 56 (3.5∶1)
FeC2O4•2H2O 1.0 K2S2O8 3.0 DCM/H2O 79 (4.5∶1)
FeC2O4•2H2O 1.0 K2S2O8 2.0 DCM/H2O 62 (4.5∶1)
FeC2O4•2H2O 1.0 K2S2O8 1.0 DCM/H2O 45 (4.5∶1)
FeC2O4•2H2O 1.0 K2S2O8 3.0 PhCl/H2O 73 (4.2∶1)
FeC2O4•2H2O 1.0 K2S2O8 3.0 CF3-Ph/H2O 70 (4.3∶1)
10 FeC2O4•2H2O 0.5 K2S2O8 3.0 DCM/H2O 66 (4.5∶1)
11 FeC2O4•2H2O 2.0 K2S2O8 3.0 DCM/H2O 80 (4.5∶1)
radical could be produced by the single electron transfer
＋
of Fe2 to S2O82 －, which initiated the transformation
＋
with the liberation of SO24－ and Fe3 . Furthermore,
12 FeC2O4•2H2O 1.0 (NH4)2S2O8 3.0 DCM/H2O
ND
a Reaction condition: 4-cyanopyridine 0.5 mmol; phenylboronic
acid 1.5 mmol; 3 mL solvent (1∶1, V∶V); 25 ℃, 48 h.
b Isolated yield. c GC yield.
the sulfate radical could react with aryl boric acids to
give the aryl radical species, which could attack pyri-
dine species to afford the intermediates. Then, the target
products could be obtained under the oxidation and de-
protonation of intermediates.
If the oxidant loading amounts varied from 3.0 equiv.
Chin. J. Chem. 2014, 32, 1294—1298
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Huang, Guan & Wang
NOTE
Table 2 The arylation of 4-cyanopyridine with various arylboronic acidsa
iron(II) oxalate
K2S2O8, TFA
CN
CN
CN
N
Ar
+
ArB(OH)2
+
DCM/water, r.t.
N
Ar
N
Product
C-2
Yieldb/%
Entry Ar
(C-2∶C-3)
C-3
CN
CN
92.5%
Ph
1
2
C6H5-
(5.2∶1)
N
Ph
N
3aa
3ab
CN
Cl
CN
60.2
4-Cl-C6H4-
3-Cl-C6H4-
4-F-C6H4-
N
(1.2∶1)
N
3bb
3cb
Cl
3ba
3ca
CN
N
CN
N
75.0
3
4
5
Cl
F
Cl
(1.5∶1)
CN
N
CN
N
77.2
(1.2∶1)
3db
F
3da
CN
N
OCH3
CN
N
82.0
4-CH3O-C6H4-
(2.0∶1)
3eb
3fb
OCH3
3ea
3fa
CN
N
OCH3
CH3
CN
N
81.5
6
3-CH3-4-CH3O-C6H3-
(1.9∶1)
OCH3
CH3
CN
N
CN
N
92.5
7
8
3-CH3-C6H4-
CH3
CF3
(3.2∶1)
3hb
3gb
CH3
3ha
CN
N
CN
N
73.2
4-CF3-C6H4-
(1.8∶1)
CF3
3ga
a 4-Cyanopyridine 0.5 mmol, arylboronic acid 1.5 mmol; iron(II) oxalate 0.5 mmol; potassium persulfate (1.5 mmol); TFA 0.5 mmol; 3
mL solvent of DCM∶H2O (1∶1, V∶V); 25 ℃, 48 h. b Isolated yield.
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Direct Arylation of Substituted Pyridines with Arylboronic Acids Catalyzed by Iron(II) Oxalate
Table 3 The arylation of substituted pyridine with phenylboronic acida
R
X
iron(II) oxalate
K2S2O8, TFA
R
X
R
X
Ph
+
PhB(OH)2
+
DCM/water, r.t.
N
N
Ph
N
X=H, N
Product
Yieldb/%
Entry
1
R
H
X
(C-2: C-3 or C-4)
C-2
C-3 or C-4
Ph
30.5%c
H
(1.5∶1)
N
N
Ph
4aa
N
4ab
COOEt
COOEt
Ph
62.4
2
3
4
5
COOEt
CH3CO
CF3
H
H
H
N
(4.2∶1)
Ph
N
4ba
4ca
4bb
COCH3
58.6
76.5
32.2
ND
ND
－
N
Ph
CF3
N
N
Ph
Ph
4da
4ea
－
N
a Pyridine 0.5 mmol, arylboronic acid 1.5 mmol; iron(II) oxalate 0.5 mmol; potassium persulfate (1.5 mmol); TFA 0.5 mmol; 3 mL sol-
vent of DCM∶H2O (1∶1, V : V); 25 ℃, 48 h. b Isolated yield. c GC yield.
Scheme 1 Proposed catalytic cycle
H+ from TFA
R
2-
Fe3+
SO4
SO4
Fe2+
R
N
R
ArB(OH)2
N
2-
Ar
SO4
S2O8
Ar
N
Ar
-O3SOB(OH)2
2-
SO4
Conclusions
Jiangsu Province Key Laboratory of Fine Petrochemi-
cal Engineering (KF1304)”.
In summary, we have described the practical method
for the direct arylation of pyridines using the cheap and
environmentally friendly catalytic system of FeC2O4•
2H2O and K2S2O8. A broad range of substrates could
react smoothly to afford the desired coupling products.
The plausible radical mechanism was also proposed.
Further studies on improving the regioselectivity of this
reaction are currently underway.
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NOTE
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