Scope and limitation for FeSO4-mediated direct arylation of heteroarenes with arylboronic acids and its synthetic applications

Article abstract of DOI:10.1246/bcsj.20130166

FeSO₄-mediated direct arylation of heteroarenes with arylboronic acids in the presence of K₂S₂O₈ has been developed. A slow addition of an aqueous solution of an iron complex was crucial in the arylation. Scope and limitation of the heteroarenes and arylboronic acids are discussed. Furthermore, the direct arylation was applied to the formal total synthesis botryllazine B and sodium channel inhibitor.

Full text of DOI:10.1246/bcsj.20130166

© 2013 The Chemical Society of Japan
Bull. Chem. Soc. Jpn. Vol. 87, No. 2, 301-313 (2014)
301
Scope and Limitation for FeSO4-Mediated Direct Arylation of
Heteroarenes with Arylboronic Acids and Its Synthetic Applications
Kimihiro Komeyama,*1 Yuya Nagao,1 Manabu Abe,2 and Ken Takaki*1
1Department of Applied Chemistry, Graduate School of Engineering, Hiroshima University,
1-4-1 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8527
2Department of Chemistry, Graduate School of Science, Hiroshima University,
1-3-1 Kagamiyama, Higashi-Hiroshima, Hiroshima 739-8526
Received June 14, 2013; E-mail: kkome@hiroshima-u.ac.jp
FeSO4-mediated direct arylation of heteroarenes with arylboronic acids in the presence of K2S2O8 has been
developed. A slow addition of an aqueous solution of an iron complex was crucial in the arylation. Scope and limitation
of the heteroarenes and arylboronic acids are discussed. Furthermore, the direct arylation was applied to the formal total
synthesis botryllazine B and sodium channel inhibitor.
Heterobiaryl compounds are one of the most important
structural motifs found in many medicinal and natural pro-
ducts.1 For the construction of these skeletons, transition-metal-
catalyzed cross-couplings between aryl halides and metalated
arenes such as Kumada-Corriu, Negishi, Suzuki-Miyaura,
Stille, and Hiyama couplings are the most reliable method-
ology.2 Nevertheless, they are unfavorable from the point
of view of cost and atom-economy since they require that
activating groups such as halogen and metallic functions must
be present on both coupling fragments. Thus, more ecofriendly
and economic methodologies have been desired and inves-
tigated in the past few decades. For these reasons, recently,
much more attention has been paid to the direct arylation of
C-H bonds for heterobiaryl synthesis, which has emerged as
an atom-economical alternative protocol to the above cross-
couplings.3 Among them, although ubiquitous metal catalysts
have accomplished the direct arylation,4 most of them require
harsh reaction conditions. Therefore, the development of more
practical methods for direct C-H arylation promoted by ubiqui-
tous metals has been explored.
On the other hand, it is known that aryl radical species
can react with heteroarenes to give heterobiaryls under mild
conditions as shown in Minisci reaction.5 Although these
radical reactions generally involve aryldiazonium salts and
aroyl peroxides as aryl radical sources, they are difficult to
prepare, handle, and show a narrow scope to access numerous
aryl radicals. In contrast, Shirakawa and Hayashi successfully
demonstrated the catalytic generation of aryl radicals from
arylboronic acids by means of Fe(OTf)3/(t-BuO)2, which
could be applied to the direct arylation of simple arenes like
benzene as solvent.6 Baran also reported the direct arylation of
heteroarenes and benzoquinones using aryl radicals delivered
from arylboronic acids by AgNO3/K2S2O8.7 These methods are
simple and powerful procedures for the preparation of hetero-
biaryl skeletons, except for requiring large amount of the
coupling partner and employing rare metal catalyst such as Ag,
respectively. Recently. Zhang and Yu reported a similar
arylation mediated by heterogeneous FeS/K2S2O8,8 but the
reaction required longer reaction time (40 h) because of the
low solubility of the iron. We already have demonstrated that
the direct arylation of benzoquinones with arylboronic acids by
water-soluble FeSO4 leads to monoarylated benzoquinones in a
short time.9 Herein, we would like to report a direct arylation of
heteroarenes with arylboronic acids using our FeSO4/K2S2O8
system and its synthetic application for a concise synthesis
of botryllazine B and sodium channel inhibitor. Furthermore,
we wish to discuss the reaction mechanism based on DFT
calculations.
Results and Discussion
Based on our previous work,9 we first investigated suitable
reaction conditions for the FeSO4-mediated direct arylation of
4-cyanopyridine (1a) with PhB(OH)2 (2a) in the presence of
K2S2O8. These results are summarized in Table 1. An aqueous
solution of FeSO4¢7H2O (0.4 M) was slowly added to a mix-
ture of 1a and 2a (1.5 equiv) in the presence of trifluoroacetic
acid (TFA: 1.5 equiv) and K2S2O8 (3.0 equiv) under air. After
complete addition, additional stirring carried out for 5 h. 4-
Cyano-2-phenylpyridine (2-3aa) was obtained in 67% yield
with a regioisomer 3-3aa in 27% yield after neutralization
(Table 1, Entry 1). Although PhCl, MeNO2, and CCl4 were
similarly effective solvents (Entries 2-4), AcOH, t-BuOH, ace-
tone, and MeCN were disfavored in the arylation (Entries 5-8).
It should be mentioned that the slow addition and stoichiometric
amount of FeSO4¢7H2O were necessary in the arylation to
proceed efficiently as shown in our previous observations.9
Thus, the quick addition of the iron solution caused a lower
product yield (Entry 9). The catalytic reaction afforded a trace
amount of the arylated product 3aa, wherein most of both
substrates remained unchanged (Entry 10). The ffect of other
iron and transition-metal complexes was examined. However,
FeCl2, Fe(OAc)2, [Fe(phen)3]SO4, [Fe(acac)2],10 CoSO4¢7H2O,
Published on the web October 19, 2013; doi:10.1246/bcsj.20130166

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Bull. Chem. Soc. Jpn. Vol. 87, No. 2 (2014)
FeSO4-Mediated Direct Arylation of Heteroarenes
Table 1. Optimization of Solvent in the Direct Arylation of
4-Cyanopyridine (1a) with PhB(OH)2 (2a)
Table 2. Examples of FeSO4-Mediated Direct Arylation of
Various Heteroarenes 1 with PhB(OH)2 (2a)a)
slow addition
CN
CN
slow addition
B(OH)2
Y
Y
FeSO4 7H2O (1 equiv)
X
X
FeSO4 7H2O (1 equiv)
+
PhB(OH)2
3
2
Ph
R
R
+
TFA (1.5 equiv)
K2S2O8 (3 equiv)
DCM/H2O, rt, 2-5 h
then NaOH aq.
2a
N
N
organic solvent/H2O
TFA (1.5 equiv)
K2S2O8 (3 equiv)
rt, 5 h, then NaOH aq.
(1.5 equiv)
N
N
3
1
2a
3aa
1a
(1.5 equiv)
Entry
1
Heteroarene 1
Products and yield
Yield of 3aa/%
[2-3aa:3-3aa]a)
Conv. of 1a/%a)
C(O)Ph
C(O)Ph
Entry
Solvent
1
2
3
4
5
6
7
8
9b)
10c)
DCM
PhCl
MeNO2
CCl4
AcOH
t-BuOH
Acetone
MeCN
DCM
97
94
86
81
58
50
32
54
36
8
94 [71:29]
87 [74:26]
64 [78:22]
59 [85:15]
15 [80:20]
8 [50:50]
3 [N.D.]
Ph
Ph
N
N
1b
1c
3ba 35%
CO2Me
CO2Me
2
N
3 [N.D.]
25 [80:20]
Trace [®]
N
1c
3ca 48%
Cl
DCM
Cl
3
a) Determined by GC using decane as an internal standard.
Value of square bracket indicates regioisomer ratio of the pro-
ducts. b) The iron solution was quickly added. c) FeSO4¢7H2O
(0.2 equiv) was used.
3b)
Ph
2
N
N
1d
3da 69% [2-3da:3-3da = 94:6]
3da 72% [2-3da:3-3da = 91:9]
tBu
4b),c)
1d
tBu
MnSO4¢5H2O, Mn(OAc)2¢4H2O, and Ce(OAc)3¢H2O did not
work well in the direct arylation (<20% yield of the product).
In all reactions, the homo-coupling product, biphenyl, derived
from 2a, was observed by GC-MS in trace amounts (<5%).
With optimized conditions in hand, the scope of several
heteroarenes 1 in the Fe-mediated direct arylation was exam-
ined (Table 2). The arylation well tolerated carbonyl, halogen,
and alkyl groups 3ba-3ea. Thus, pyridines having ketone and
ester functions afforded monoarylated products 3ba and 3ca,
albeit in moderate yields. In contrast, 4-chloropyridine hydro-
chloride (1d) gave a mixture of regioisomers 2-3da and 3-3da
without the addition of TFA, in which the arylation mainly
proceeded at the 2-position. In addition, this reaction was
proven to be scalable on a gram scale (1 g of 1d), delivering
72% yield of the desired product with similar regioselectivity.
When an electron-rich pyridine like 4-tert-butylpyridine (1e)
was used, besides the formation of monoarylated 2-3ea,
bisarylated product 2,6-3ea was detected as a minor product.11
Although unsymmetrical pyridines such as 1f and 1g provided
many regioisomers, the arylation selectively occurred at the
sterically less hindered position of the pyridine ring. Other
heteroarenes such as pyrazines 1h-1j and pyrimidines 1k and
1l also participated in the arylation, in which the former hetero-
arenes were mainly arylated at the 6-position and the latter
selectively afforded the 4-adducts. Importantly, the presence of
amino group did not prevent the reaction, providing 2-amino-4-
phenylpyrimidine (3la) in 36% yield.
Ph
5
6
7
2
6
N
N
1e
1f
3ea 42%
[2-3ea:2,6-3ea = 90:10]
4
3
5
Ph
6
MeO2C
N
MeO2C
N
N
3fa 39%
[4-3fa:5-3fa:3-3fa:6-3fa
= 69:18:9:4]
4
Me(O)C
Ph
Me(O)C
2
6
N
3ga 55%
[6-3ga:2-3ga:2,6-3ga:4,6-3ga
= 48:29:16:7]
1g
N
N
N
2
8d)
N
Ph
1h
1i
3ha 65%
N
5Ph
3
N
N
6
9
MeO2C
N
MeO2C
3ia 80%
[6-3ia:3-3ia:5-3ia = 65:18:17]
N
5Ph
3
N
N
6
10
NC
N
Next, scope and limitation of arylboronic acids were
explored (Table 3). Most arylations with 1d provided a mixture
of 2- and 3-adducts, except for 3dl, in which the 3-adduct was
detected by GC-MS but it could not be isolated due to the
trance amount. para-Substituted arylboronic acids afforded
much higher yields of products than meta- and ortho-ones. In
NC
1j
3ja 84%
[6-3ja:3-3ja:5-3ja = 67:23:10]
Continued on next page:

K. Komeyama et al.
Continued:
Bull. Chem. Soc. Jpn. Vol. 87, No. 2 (2014)
303
addition, potassium aryltrifluoroborate, instead of the boronic
acid, also participated in the arylation, leading to 3df in slightly
higher yield.12 2-Aminopyrimidine (1l) and 2-cyanopyrazine
(1j) allowed the regioselective arylation with different aryl-
boronic acids such as 2k and 2c, giving rise to 3lk and 3jc,
respectively. Unfortunately, the present Fe-mediated aryla-
tion with electron-deficient arylboronic acids possessing NO2
CO2Me, CN, C(O)Me, and CF3 at the para- and meta-positions
failed as shown in our previous arylation of benzoquinones.9
The electron-deficient arylboronic acids remained unchanged.
According to these experimental results, a plausible mecha-
nism for the Fe-mediated direct arylation of heteroarenes with
arylboronic acids is proposed in Scheme 1. A single electron
Entry
Heteroarene 1
Products and yield
N
Ph
N
2
4
N
11
N
3ka 65%
[4-3ka:2-3ka = 78:22]
1k
1l
N
N
4
12
H2N
N
Ph
H2N
N
3la 36%
a) Isolated yields are shown. Value of square bracket indicates
regioisomer ratio of the products. b) 4-Chloropyridine HCl
salt (1d) was used without the addition of TFA. c) One gram
(7.0 mmol) of 1d was subjected. d) 2a (3.0 equiv) was used.
2¹
•¹
transfer of Fe2+ to S2O8 producing a stronger oxidant SO4
would initiate the arylation (step a, Scheme 1).13 The gener-
•¹
ated SO4 would react with arylboronic acids 2 to give the
Table 3. Scope and Limitation of Arylboronic Acids 2 in the FeSO4-Mediated Direct Arylation of
Heteroarenes 1a)
slow addition
B(OH)2
R'
X
X
N
FeSO4 7H2O (1 equiv)
X
X
+
R
R
R'
TFA (1.5 equiv)
K2S2O8 (3 equiv)
DCM/H2O, rt, 3-5 h
then NaOH aq.
N
1
3
2
Substrates
Entry
1b)
Products and yield
Heteroarene 1
Arylboronic acid 2
Cl
Cl
3
Me
(HO)2B
(HO)2B
Me
2b
2
N
N
3db 89%
1d
[2-3db:3-3db = 88:12]
Cl
3
2b)
1d
1d
1d
OMe
OMe
2
N
2c
3dc 75%
[2-3dc:3-3dc = 73:27]
Cl
3
3b)
Cl
(HO)2B
(HO)2B
Cl
2d
2
N
3dd 89%
[2-3dd:3-3dd = 90:10]
Cl
3
4b),c)
Br
Br
2e
2
N
3de 30%
[2-3de:3-3de = 87:13]
Cl
Me
Me
Me
3
5b)
1d
1d
2
(HO)2B
KF3B
N
2f
3df 57%
[2-3df:3-3df = 77:23]
6b)
3df 64% [2-3df:3-3df = 69:31]
Continued on next page:

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Bull. Chem. Soc. Jpn. Vol. 87, No. 2 (2014)
Continued:
FeSO4-Mediated Direct Arylation of Heteroarenes
Products and yield
Substrates
Entry
Heteroarene 1
Arylboronic acid 2
Cl
Cl
Cl
3
6b)
1d
2
(HO)2B
N
2g
3dg 52%
[2-3dg:3-3dg = 85:15]
Cl
Br
Br
3
7b)
8b)
9b)
1d
1d
1d
2
(HO)2B
(HO)2B
N
2h
2i
3dh 31%
[2-3dh:3-3dh = 87:13]
Cl
Me
Me
3
2
N
3di 65%
[2-3di:3-3di = 85:15]
Cl
OMe
MeO
(HO)2B
3
2
N
2j
3dj 55%
[2-3dj:3-3dj = 78:22]
Cl
Cl
Cl
3
10b)
1d
2
N
(HO)2B
(HO)2B
2k
2l
3dk 60%
[2-3dk:3-3dk = 83:17]
Cl
Me
Me
Me
3
11b)
1d
2
N
Me
3dl 44%
[2-3dl:3-3dl = 99:trace]
N
Cl
N
H2N
N
12
13
2k
2c
H2N
N
1l
3j
3lk 30%
N
3
5
OMe
N
N
6
NC
N
3jc 48%
NC
[6-3jc:3-3jc:5-3jc
= 100:trace:trace]
a) Isolated yields are shown. Value of square bracket indicates regioisomer ratio of the products.
b) 4-Chloropyridine HCl salt (1d) was used without the addition of TFA. c) 2e (3.0 equiv) was used.
aryl radical species (step b). The aryl radical could attack the
protonated heteroarenes, leading to the radical cation A (step c).
Sequent oxidation of A by molecular oxygen14 and neutraliza-
tion would provide the arylated heteroarenes 3. However, there
were some questions in the Fe-promoted direct arylation: (1)
the necessity of slow addition of the stoichiometric amount of
iron reagent and (2) the limitation of the available aryl boronic
acids as compared to the Ag-mediated arylation.7,15
Regarding the former question, the standard redox potential
of Fe2+ (Fe3+/Fe2+: 0.8 V) is much lower than that of Ag+
(Ag2+/Ag+: 2.0 V),16 which indicates that Ag2+ is a much
stronger oxidant than Fe3+. Thus, Ag2+ could promote step
(d) in Scheme 1 to regenerate the catalytically active Ag+,17
whereas Fe3+ could not work as an oxidant for the intermediate
A to provide Fe2+ species. If Fe2+ was generated, the iron
•¹
catalyst must carry out the arylation. In addition, SO4 is a

K. Komeyama et al.
Bull. Chem. Soc. Jpn. Vol. 87, No. 2 (2014)
305
X
X
N
neutralization
step (e)
X
X
R
R
N
H
Ar
Ar
2–
S2O8
3
Fe2+
HOO•
O2
X
step (d)
X
step (a)
Fe3+
R
2–
N
SO4
1
H
X
ArB(OH)2 2
X
H
•–
R
Ar•
SO4
step (c)
step (b)
–O3SOB(OH)2
N
H
Ar
A
Scheme 1. Plausible reaction mechanism of the iron-mediated direct arylation of heteroarenes with arylboronic acids.
R
R
B
O
O S O
O
O
O S O
O
step (b-2)
step (b-1)
B
+
R
R
–O2SOBR2
O
R
R
R
B
Fe2+
Fe3+
R
O S O B
O
R
R
C
Scheme 2. The detail of step (b) in Scheme 1.
stronger oxidant than S2O8 . If a large amount of Fe2+ existed
(R = NO2 or CN) were calculated to be 8.7 or 8.0 kcal mol ,
2¹
¹1
in the reaction, SO4 would quickly react with Fe2+ to liberate
the inert SO4 . The consideration would support the necessity
of stoichiometric FeSO4 and its slow addition.
respectively, which were higher than those for the other cases
(R = H, MeO, or Cl). Furthermore, the endothermic reactions
were found for the electron-withdrawing substituted case (R =
CN or NO2). In contrast, the exothermic reactions were calcu-
lated for the other cases (R = H, Cl, or MeO). The substituent
(R) effect on the energy barrier was attributed not to the relative
stability on the aryl radicals (RC6H4•), but to the relative
stability on the anionic intermediates B¤. Thus, the small sub-
stituent effect on the stability of the aryl radical, less than
ca. 1 kcal mol¹1, was proved by the isodesmic reaction of eq 1.
The electron-withdrawing substituents such as R = NO2 and
CN clearly retarded the homolytic C-B bond cleavage. The
inhibition would cause a reduction of the intermediate B (or B¤)
to provide the inert arylboronate anions C by Fe(II) gradu-
ally added (Scheme 2). The computational results reflect the
limitation of the available arylboronic acids in the Fe-mediate
arylation.
•¹
2¹
Regarding the latter question: the limitation of the available
boronic acids in the arylation (Table 3), it is well known that
organoboranes react with oxygen-centered radicals to afford
carbon radicals (R•) through the formation of anionic radical
intermediate B (Scheme 2).18 The nucleophilic attack of the
oxygen lone pair on the vacant orbital of the boron atom would
be first [step (b-1)], at least, the reaction with electron-deficient
arylboronic acids could favor the formation of B rather than
with electron-rich ones. However, the electron-deficient aryl-
boronic acids were inert in the Fe-mediated arylation (vide
infra).
To obtain more insight into the substituent (R) effect of
the boronic acids, steps b-1 and b-2 (Scheme 2) were computed
for the model compound B¤ at the UB3LYP/6-31G(d)19 level
of theory (Figure 1). Fluorine atoms on the boron were used
in place of hydroxy groups for the computations to see the
substituent effect on the energy barrier (E‡ in kcal mol¹1) for
the homolytic bond-cleavage step.20 The geometries of station-
ary points and transition states were all located and vibrational
analyses were performed with the Gaussian 0921 suite of pro-
grams. The formation of anionic intermediate B¤ from the reac-
R
R
H
H
+
+
ð1Þ
H
H
E = (C6H6 + RC6H4•) (C6H5• + RC6H5)
•¹
tion of ArBF2 with SO4 is exothermic (15.8-30.0 kcal mol¹1),
R
H
NO2
0.8
MeO
1.1
Cl
CN
0.6
and could spontaneously proceed (Figure 1, left). For the
homolytic cleavage of the C-B bond of B¤, the energy barriers
for the strong electron-withdrawing group substituted cases
E /kcal mol-1
0.0
0.9

306
Bull. Chem. Soc. Jpn. Vol. 87, No. 2 (2014)
FeSO4-Mediated Direct Arylation of Heteroarenes
R = NO2
R = CN
R = H
20
R = Cl
R
E‡ /kcal mol-1
2.08
3.67
2.57
8.03
8.68
H
R = MeO
MeO
Cl
O
O S O
CN
NO2
O
+
O
O S O
O
F
F2B
R
B
F
R
10
R = H
R = MeO
R = Cl
0
O
F
F
O S O B
O
+
R = CN
R
R = NO2
F
O
-10
O S O
O
B
F
R
B'
Figure 1. Substituent effect on the energy barrier of the C-B bond homolytic cleavage reaction, calculated at the UB3LYP/
6-31G(d).
OMe
O
O
OMe
a
b
N
N
N
N
+
MeO
MeO
48%
with 26%
84%
(HO)2B
2c (3.0 equiv)
6-3ic
1i
regioisomer 3-3ic
OMe
OH
O
O
ref. 24
N
N
N
N
MeO
HO
4
botryllazine B (5)
Scheme 3. Formal synthesis of botryllazine B (5) via the Fe-mediated direct arylation. Reagents and conditions: (a) FeSO4¢7H2O
(1.0 equiv), K2S2O8 (6.0 equiv), PhCl/H2O, rt, 2 h, and then NaOH aq.; (b) p-MeOPhMgBr (1.1 equiv, slow addition), THF,
¹40 °C-rt, overnight.
Finally, the synthetic utility of the Fe-mediated direct
arylation was demonstrated by the formal total synthesis of
botryllazine B (5)22 (Scheme 3) and sodium channel inhibitor
723 (Scheme 4). Based on our results: the site-selective arylation
of monosubstituted pyrazines in Tables 1 and 2, we envisioned
that the selective arylation protocol could be applied to the
concise synthesis of botryllazine B (5). The synthesis of 5 has
been achieved by Turck, in which the combination of two Pd-
catalyzed couplings was conducted as key steps for access to
5.24 The Fe-mediated direct arylation of methyl 2-pyrazinecar-

K. Komeyama et al.
Bull. Chem. Soc. Jpn. Vol. 87, No. 2 (2014)
307
Cl
N
Cl
2-3dm
(HO)2B
F
a
1) b
+
F
2) c
66%
O
N
Cl-
60%
(2 steps)
H
with 7%
O
2m (3.0 equiv)
regioisomer 3-3dm
1d
O
N
Cl
N
6
ref. 28
sodium channel inhibitor 7
F
NC
H2N
F
N
O
O
O
Scheme 4. Formal synthesis of sodium channel inhibitor 7 via the Fe-mediated direct arylation. Reagents and conditions:
(a) FeSO4¢7H2O (1.0 equiv), K2S2O8 (6.0 equiv), DCM/H2O, rt, 5 h, and then NaOH aq.; (b) m-CPBA (1.5 equiv), DCE, rt, 24 h;
(c) TMSCN (2.0 equiv), Me2NC(O)Cl (1.3 equiv), DCM, 0 °C-rt, 24 h.
boxylate (1i) with 4-methoxyphenylboronic acid (2c) under
identical conditions afforded the desired 2-arylated pyrazine 2-
Experimental
3ic in 48% yield with 3-arylated regioisomer 3-3ic (27% yield).
The remaining ester function of 2-3ic was treated with Grignard
reagent (slow addition) at ¹40 °C to provide ketone 4, which
is a synthetic precursor of botryllazine B (5).24 Additionally,
we also accomplished the formal synthesis of sodium channel
inhibitor 7. As shown in Scheme 4, 4-chloropyridine hydro-
chloride (1d), which is commercially available in large
quantities, participated in the present direct arylation without
the loss of the carbon-chlorine bond. Coupling partner 2m
was easily prepared by Ullmann coupling25 and borylation.26
These two fragments were coupled under the modified condi-
tions to give 2-aryl-4-chloropyridine 2-3dm in 66% yield along
with a regioisomer (3-3dm: 7%).27 Oxidation of 2-3dm with
m-CPBA and cyanation with TMSCN provided 2-aryl-4-chloro-
6-cyanopyridine 6 in 60% yield in 2 steps. The obtained 6 could
be transformed into sodium channel inhibitor 7 by means of
Fagnou’s protocol.28
General.
Nuclear magnetic resonance spectra were
acquired on a Varian-400 (1H NMR: 399.823 MHz; 13C NMR:
100.55 MHz) spectrometer, or a Varian-500 (1H NMR: 499.824
MHz; 13C NMR: 125.68 MHz) using residual chloroform (for
1H NMR, 7.26 ppm) and CDCl3 (for 13C NMR, 77.0 ppm) as
an internal standard. Low-resolution mass spectra (LRMS)
were recorded on a Shimadzu GCMS-QP-5050 (70 eV). High-
resolution mass spectra (HRMS) were acquired on an LTQ
Orbitrap XL (Thermo Fisher Scientific Co., Inc.) at the Natural
Science Center for Basic Research and Development (N-
BARD) of Hiroshima University. Melting points were recorded
on a YANAKO micro melting point apparatus, and uncorrect-
ed. Flash column chromatography was performed with silica
gel 60 (KANTO Chemical Co., 40-50 nm). TLC monitoring
was carried out with silica gel aluminium sheets (Merck,
type 60F254). GC was performed on a Shimadzu GC-2014. All
solvents were distilled from activated MS 4 ¡ and stored under
N2. All metal complexes, heteroarenes, and arylboronic acids,
except for 2m,25,26 were purchased and used as received.
Representative Procedure for the FeSO4-Mediated Direct
Arylation of 4-Cyanopyridine (1a) with PhB(OH)2 (2a).
TFA (0.75 mmol) was added to a DCM/distilled H2O solution
(2.5 mL, v/v = 1:1) of 1a (0.5 mmol), and then stirred for 15
min. 2a (0.75 mmol), K2S2O8 (1.5 mmol) were added under
air, sequentially an aqueous solution of FeSO4¢7H2O in
distilled H2O (1.25 mL) was slowly added by syringe pump
(10 ¯L min¹1). After complete addition, the reaction mixture
was stirred for 5 h at ambient temperature. The mixture was
neutralized by NaOH solution (1.0 M), the obtained aqueous
phase was extracted with ether. The combined ethereal solution
was dried over Na2SO4 and filtered. After evaporating the
solvent, the arylated products 2-3aa and 3-3aa were isolated by
flash chromatography (hexane:EtOAc = 5:1) in 67% and 27%
yields, respectively.
Conclusion
In summary, we have developed a practical method for
the direct arylation of heteroarenes using the combination of
FeSO4¢7H2O and K2S2O8 under mild conditions without
avoiding air and moisture. In the reaction, the slow addition
and the stoichiometric amount of the iron were necessary to
carry out the arylation efficiently. Furthermore, the substrate
scope and limitation for various heteroarenes and arylboronic
acids were demonstrated, in which the electron-rich arylboronic
acids were much favored over electron-deficient substrates.
Finally, the Fe-mediated direct arylation was applied to the
formal total synthesis of botryllazine B and sodium channel
inhibitor. These protocols did not require rare metal reagents
or could reduce the number of steps using expensive metal
complexes. We believe that these results described herein are
valuable for the development of new iron-mediated organic
reactions. Further investigations for synthetic applications of
the Fe-mediated and -catalyzed radical reactions are ongoing
in our laboratory.
4-Cyano-2-phenylpyridine (2-3aa).
solid (Mp: 65-67 °C); Rf value (hexane:EtOAc = 5:1) = 0.56;
1H NMR (CDCl3, 399.857 MHz): ¤ 8.86 (1H, d, J = 4.0 Hz),
Isolated as yellow

308
Bull. Chem. Soc. Jpn. Vol. 87, No. 2 (2014)
FeSO4-Mediated Direct Arylation of Heteroarenes
8.00 (2H, dd, J = 1.6, 8.0 Hz), 7.95 (1H, s), 7.54-7.49 (3H, m),
7.45 (1H, dd, J = 1.6, 4.0 Hz); 13C NMR (CDCl3, 125.7 Hz):
¤ 158.5, 150.5, 137.2, 130.1, 129.0, 126.9, 123.1, 121.9,
121.1, 116.6; MS m/z (relative intensity) 181 (M+ + H, 17),
180 (M+, 100), 179 (82), 154 (6), 153 (17), 103 (5), 77 (13),
76 (15). HRMS Calculated for C12H8N2: 180.0687, Found:
180.0689.
4-tert-Butyl-2,6-diphenylpyridine (2,6-3ea). Isolated as
yellow oil; Rf value (hexane:EtOAc = 20:1) = 0.56; H NMR
1
(CDCl3, 499.823 MHz): ¤ 8.14 (4H, d, J = 7.5 Hz), 7.69 (2H, s),
7.50 (4H, t, J = 7.5 Hz), 7.42 (2H, t, J = 7.5 Hz), 1.43 (9H, s);
13C NMR (CDCl3, 100.536 Hz): ¤ 161.4, 157.0, 140.1, 128.7,
128.6, 127.1, 116.1, 35.1, one carbon was obscured; LRMS
m/z (relative intensity): 287 (M+, 49), 272 (M+ ¹ Me, 100),
207 (29), 153 (12), 97 (12), 83 (18), 77 (12), 57 (54); HRMS
Calculated for C21H22N: 288.1752, Found: 288.1753.
Methyl 4-Phenylpyridine-2-carboylate (4-3fa). Isolated
as yellow oil; Rf value (hexane:EtOAc = 5:1) = 0.15; 1H NMR
(CDCl3, 395.75 MHz): ¤ 8.77 (1H, d, J = 4.9 Hz), 8.38 (1H, s),
7.69 (3H, m), 7.69-7.46 (3H, m), 4.03 (3H, s); 13C NMR
(CDCl3, 125.7 Hz): ¤ 165.8, 150.2, 149.7, 148.4, 137.1, 129.6,
129.2, 127.0, 124.6, 123.1, 53.0; LRMS m/z (relative inten-
sity): 213 (M+, 3), 183 (16), 155 (100), 127 (22), 102 (45),
77 (11), 63 (5), 59 (20), 51 (10); HRMS Calculated for
C13H12NO2: 214.0860, Found: 214.0863.
4-Cyano-3-phenylpyridine (3-3aa).
Isolated as yellow
solid (Mp: 67-168 °C); Rf value (hexane:EtOAc = 5:1) = 0.23;
1H NMR (CDCl3, 395.75 MHz): ¤ 8.87 (1H, s), 8.76 (1H, d,
J = 3.4 Hz), 7.64-7.52 (6H, m); 13C NMR (CDCl3, 125.7 Hz):
¤ 150.1, 148.6, 138.6, 134.3, 129.5, 129.0, 128.7, 126.0, 118.8,
116.3; MS m/z (relative intensity): 181 (M+ + H, 13), 180
(M+, 100), 179 (53), 153 (14), 152 (15), 126 (11), 76 (12), 75
(10), 63 (10). HRMS Calculated for C12H8N2: 180.0687,
Found: 180.0685.
4-Benzoyl-2-phenylpyridine (3ba).
Isolated as yellow
solid (Mp: 86-88 °C); Rf value (hexane:EtOAc = 10:1) = 0.21;
1H NMR (CDCl3, 395.75 MHz): ¤ 8.85 (1H, d, J = 5.0 Hz),
8.03-8.00 (3H, m, J = 1.9 Hz), 7.86-7.84 (2H, m), 7.64 (1H, t,
J = 7.9 Hz), 7.53-7.41 (6H, m); 13C NMR (CDCl3, 125.7 Hz):
¤ 194.5, 148.8, 145.5, 135.5, 133.8, 133.6, 130.8, 130.1, 129.7,
128.7, 127.6, 127.4, 127.3, 123.4; LRMS m/z (relative inten-
sity): 259 (M+, 38), 230 (21), 154 (4), 127 (27), 105 (86), 77
(100), 51 (42); HRMS Calculated for C18H14NO: 260.1075,
Found: 260.1071.
Methyl 3-Phenylpyridine-2-carboxylate (3-3fa) and
Methyl 5-Phenylpyridine-2-carboxylate (5-3fa).
Isolated
as a mixture (orange oil); Rf value (hexane:EtOAc = 5:1) =
1
0.22; For 3-3fa: H NMR (CDCl3, 395.75 MHz): ¤ 8.68 (1H,
dd, J = 4.7, 1.5 Hz), 7.76 (1H, dd, J = 8.0, 1.5 Hz), 7.64-7.34
(6H, m), 3.77 (3H, s); 13C NMR (CDCl3, 125.7 Hz): ¤ 167.1,
165.6, 148.3, 148.1, 146.4, 139.8, 138.6, 136.6, 135.1, 129.8,
129.3, 129.3, 129.0, 128.7, 128.5, 128.2, 128.1, 127.4, 125.3,
125.2, 52.9, 52.6; LRMS m/z (relative intensity): 213 (M+,
14), 183 (16), 155 (100), 127 (26), 102 (3), 77 (13), 63 (4), 51
2-Phenylisonicotinic Acid Methyl Ester (2-3ca).29 Iso-
lated as yellow solid (Mp: 89-90 °C); Rf value (hexane:
1
1
EtOAc = 5:1) = 0.67; H NMR (CDCl3, 395.75 MHz): ¤ 8.84
(6); For 5-3fa: H NMR (CDCl3, 395.75 MHz): ¤ 8.97 (1H, d,
(1H, d, J = 5.1 Hz), 8.30 (1H, s), 8.06-8.05 (2H, m), 7.77 (1H,
d, J = 5.1 Hz), 7.50-7.45 (3H, m), 3.99 (1H, s); 13C NMR
(CDCl3, 125.7 Hz): ¤ 165.7, 158.4, 150.4, 138.5, 138.1, 129.4,
128.8, 126.9, 121.1, 119.7, 52.7; LRMS m/z (relative inten-
sity): 213 (M+, 62), 155 (100), 154 (30), 77 (15), 59 (15),
51 (30).
4-Chloro-2-phenylpyridine (2-3da).30 Isolated as yellow
solid (Mp: 46-47 °C); Rf value (hexane:EtOAc = 3:1) = 0.82;
1H NMR (CDCl3, 395.75 MHz): ¤ 8.60 (1H, d, J = 5.0 Hz),
7.98-7.96 (2H, m), 7.74 (1H, d, J = 1.9 Hz), 7.51-7.45 (3H,
m), 7.26-7.24 (1H, m); 13C NMR (CDCl3, 125.7 Hz): ¤ 158.9,
150.4, 144.7, 138.1, 129.6, 128.8, 126.9, 122.2, 120.8; LRMS
m/z (relative intensity): 191 (M+ + 2, 41), 189 (M+, 100), 154
(M+ ¹ Cl, 86), 127 (46), 77 (70), 63 (19), 51 (31).
J = 2.0 Hz), 8.22 (1H, d, J = 8.1 Hz), 8.03 (1H, dd, J = 8.1,
2.3 Hz), 7.64-7.34 (5H, m), 4.04 (3H, s); 13C NMR (CDCl3,
125.7 Hz): ¤ 167.1, 165.6, 148.3, 148.1, 146.4, 139.8, 138.6,
136.6, 135.1, 129.8, 129.3, 129.3, 129.0, 128.7, 128.5, 128.2,
128.1, 127.4, 125.3, 125.2, 52.9, 52.6; LRMS m/z (relative
intensity): 213 (M+, 21), 183 (28), 155 (100), 127 (38), 101 (5),
77 (15), 63 (6), 51 (6); HRMS Calculated for C13H12NO2:
214.0863, Found: 214.0863.
Methyl 6-Phenylpyridine-2-carboxylate (6-3fa). Isolated
as orange oil; Rf value (hexane:EtOAc = 5:1) = 0.59; 1H NMR
(CDCl3, 395.75 MHz): ¤ 8.07-8.04 (3H, m), 7.90 (2H, m),
7.50-7.43 (3H, m), 4.02 (3H, s); 13C NMR (CDCl3, 125.7 Hz):
¤ 166.0, 157.7, 148.0, 138.5, 137.7, 129.4, 128.8, 127.2, 123.7,
123.4, 52.8; LRMS m/z (relative intensity): 213 (M+, 33), 183
(7), 155 (100), 127 (30), 102 (4), 77 (19), 63(6), 51(7); HRMS
Calculated for C13H12NO2: 214.0863, Found: 214.0864.
3-Acetyl-6-phenylpyridine (6-3ga) and 3-Acetyl-2,4-di-
phenylpyridine (4,6-3ga). Isolated as a mixture as white solid
(Mp: 98-120 °C); Rf value (hexane:EtOAc = 5:1) = 0.29; For
4-Chloro-3-phenylpyridine (3-3da). Isolated as yellow
1
oil; Rf value (hexane:EtOAc = 3:1) = 0.49; H NMR (CDCl3,
395.75 MHz): ¤ 8.56 (1H, s), 8.48 (1H, d, J = 5.6 Hz), 7.49-
7.43 (6H, m); 13C NMR (CDCl3, 125.7 Hz): ¤ 151.4, 149.1,
135.4, 129.5, 128.9, 128.4, 128.4, 127.0, 124.8; LRMS m/z
(relative intensity): 191 (M+ + 2, 36), 189 (M+, 100), 154
(M+ ¹ Cl, 20), 127 (22), 77 (21), 63 (12), 51 (8). HRMS
Calculated for C11H8ClN: 189.0345, Found: 189.0344.
1
6-3ga: H NMR (CDCl3, 395.75 MHz): ¤ 9.23 (1H, d, J = 1.5
Hz), 8.29 (1H, dd, J = 8.3, 2.0 Hz), 8.06 (2H, d, J = 7.0 Hz),
7.84 (1H, d, J = 8.3 Hz), 7.56-7.36 (3H, m), 2.67 (3H, s);
13C NMR (CDCl3, 125.7 Hz): ¤ 196.5, 160.9, 150.1, 149.3,
138.1, 136.4, 130.5, 130.1, 129.0, 128.9, 128.9, 128.7, 128.7,
128.5, 128.5, 127.3, 123.2, 122.6, 120.1, 26.7; LRMS m/z
(relative intensity): 197 (M+, 80), 182 (M+ ¹ Me, 100), 154
(30), 127 (50), 77 (29), 63(12), 51(24); HRMS Calculated for
C13H12NO: 198.0913, Found: 198.0916. For 4,6-3ga: 1H NMR
(CDCl3, 395.75 MHz): ¤ 8.74 (1H, d, J = 5.0 Hz), 7.56-7.36
(10H, m), 7.28 (1H, d, J = 5.0 Hz), 2.67 (3H, s); 13C NMR
4-tert-Butyl-2-phenylpyridine (2-3ea).7c
Isolated as
yellow oil; Rf value (hexane:EtOAc = 5:1) = 0.64; 1H NMR
(CDCl3, 499.824 MHz): ¤ 8.61 (1H, d, J = 5.0 Hz), 8.00-7.98
(2H, m), 7.71 (1H, s), 7.50-7.39 (3H, m), 7.24-7.23 (1H, m),
1.38 (9H, s); 13C NMR (CDCl3, 125.7 Hz): ¤ 160.6, 157.5,
149.5, 140.0, 128.6, 128.6, 127.0, 119.3, 117.7, 30.5; LRMS
m/z (relative intensity): 211 (M+, 72), 196 (M+ ¹ Me, 100),
168 (12), 155 (13), 127 (3), 91 (9), 83 (15), 77 (10).

K. Komeyama et al.
Bull. Chem. Soc. Jpn. Vol. 87, No. 2 (2014)
Found: 215.0820.
2-Cyano-6-phenylpyrazine (6-3ja). Isolated as yellow oil;
Rf value (hexane:EtOAc = 6:1) = 0.48; 1H NMR (500 MHz,
CDCl3): ¤ 9.13 (1H, d, J = 1.5 Hz), 8.93 (1H, d, J = 1.5 Hz),
8.14-8.04 (2H, m), 7.62-7.50 (3H, m); 13C NMR (126 MHz,
CDCl3): ¤ 154.7, 147.5, 142.4, 134.4, 131.6, 129.4, 128.2,
127.5, 115.8; LRMS m/z (relative intensity): 181 (M+, 100),
154 (19), 103 (95), 77 (12); HRMS Calculated for C11H8N3:
182.0718, Found: 182.0719.
2-Cyano-3-phenylpyrazine (3-3ja). Isolated as yellow oil;
Rf value (hexane:EtOAc = 6:1) = 0.24; 1H NMR (500 MHz,
CDCl3): ¤ 8.85 (1H, d, J = 2.3 Hz), 8.66 (1H, d, J = 2.3 Hz),
8.03-7.95 (2H, m), 7.62-7.52 (3H, m); 13C NMR (126 MHz,
CDCl3): ¤ 157.0, 146.5, 142.9, 134.3, 131.1, 129.0, 129.0,
127.9, 116.3; LRMS m/z (relative intensity): 181 (M+, 100),
154 (16), 103 (50), 77 (11); HRMS Calculated for C11H8N3:
182.0718, Found: 182.0720.
2-Cyano-5-phenylpyrazine (5-3ja). Isolated as yellow oil;
Rf value (hexane:EtOAc = 6:1) = 0.33; 1H NMR (500 MHz,
CDCl3): ¤ 9.22 (1H, s), 8.83 (1H, s), 8.11-8.02 (2H, m),
7.61-7.51 (3H, m); 13C NMR (126 MHz, CDCl3): ¤ 153.4,
145.7, 144.5, 134.1, 131.3, 130.1, 129.4, 127.2, 115.6; LRMS
m/z (relative intensity): 181 (M+, 100), 154 (13), 128 (22), 103
(53), 77 (14); HRMS Calculated for C11H8N3: 182.0718,
Found: 182.0718.
309
(CDCl3, 125.7 Hz): ¤ 196.5, 160.9, 150.1, 149.3, 138.1, 136.4,
130.5, 130.1, 129.0, 128.9, 128.9, 128.7, 128.7, 128.5, 128.5,
127.3, 123.2, 122.6, 120.1, 29.7; LRMS m/z (relative intensity):
273 (M+, 17), 272 (M+ ¹ H, 19), 258 (M+ ¹ Me, 100), 230
(28), 207 (6), 202 (22), 127 (15), 101 (6), 77 (11).
3-Acetyl-2-phenylpyridine (2-3ga).31 Isolated as yellow
oil; Rf value (hexane:EtOAc = 5:1) = 0.22; H NMR (CDCl3,
395.75 MHz): ¤ 8.77 (1H, dd, J = 4.8, 1.7 Hz), 7.87 (1H, dd,
J = 7.8, 1.7 Hz), 7.58-7.56 (2H, m), 7.48-7.47 (3H, m), 7.35
(1H, dd, J = 7.8, 4.8 Hz), 2.06 (3H, s); 13C NMR (CDCl3,
125.7 Hz): ¤ 203.7, 157.2, 150.9, 139.6, 136.3, 136.2, 129.4,
129.1, 128.8, 121.9, 30.3; LRMS m/z (relative intensity): 197
(M+, 38), 182 (M+ ¹ Me, 100), 154 (22), 127 (18), 77 (20),
63 (11), 50 (13); HRMS Calculated for C13H12NO: 198.0913,
Found: 198.0915.
1
3-Acetyl-2,6-diphenylpyridine (2,6-3ga).
Isolated as
white solid (94-99 °C); Rf value (hexane:EtOAc = 5:1) = 0.51;
1H NMR (CDCl3, 395.75 MHz): ¤ 8.14 (2H, d, J = 7.8 Hz),
7.95 (1H, d, J = 8.0 Hz), 7.79 (1H, d, J = 8.0 Hz), 7.68 (2H,
m), 7.49-7.46 (6H, m), 2.10 (3H, s); 13C NMR (CDCl3,
125.7 Hz): ¤ 203.6, 158.1, 157.2, 140.0, 138.3, 137.4, 134.5,
129.7, 129.4, 129.4, 128.8, 128.7, 127.3, 118.2, 30.3; LRMS
m/z (relative intensity): 273 (M+, 28), 272 (M+ ¹ H, 50), 258
(M+ ¹ Me, 100), 230 (14), 207 (11), 202 (29), 191 (10), 126
(12), 103 (10), 77 (28), 75 (16), 51 (34); HRMS Calculated for
C19H16NO [M + H]: 274.1232, Found: 274.1226.
4-Phenylpyrimidine (4-3ka).7c Isolated as yellow oil; Rf
value (hexane:EtOAc = 5:1) = 0.10; 1H NMR (500 MHz,
CDCl3): ¤ 9.28 (1H, d, J = 1.4 Hz), 8.77 (1H, d, J = 5.3
Hz), 8.13-8.06 (2H, m), 7.73 (1H, dd, J = 5.4, 1.4 Hz), 7.54-
7.50 (3H, m); 13C NMR (101 MHz, CDCl3): ¤ 163.8, 159.0,
157.4, 136.4, 131.1, 129.0, 127.1, 117.0; LRMS m/z (relative
intensity): 156 (100), 129 (51), 102 (38), 77 (24).
2-Phenylpyrazine (3ha). Isolated as yellow oil; Rf value
(hexane:EtOAc = 5:1) = 0.26; H NMR (500 MHz, CDCl3): ¤
1
9.03 (1H, d, J = 1.6 Hz), 8.63 (1H, dd, J = 2.5, 1.6 Hz), 8.50
(1H, d, J = 2.5 Hz), 8.06-7.98 (2H, m, 2H), 7.61-7.39 (3H, m);
13C NMR (126 MHz, CDCl3): ¤ 152.8, 144.1, 142.9, 142.2,
136.3, 129.9, 129.0, 126.9; LRMS m/z (relative intensity): 157
(M+ + 1, 12), 156 (M+, 100), 129 (14), 104 (12), 103 (29), 77
(39), 76 (15).
2-Phenylpyrimidine (2-3ka).
Isolated as yellow oil;
Rf value (hexane:EtOAc = 5:1) = 0.21; 1H NMR (500 MHz,
CDCl3): ¤ 8.81 (1H, d, J = 4.8 Hz), 8.47-8.40 (1H, m), 7.52-
7.47 (2H, m), 7.19 (1H, t, J = 4.8 Hz); 13C NMR (101 MHz,
CDCl3): ¤ 164.7, 157.2, 137.5, 130.8, 128.6, 128.1, 119.1;
LRMS m/z (relative intensity): 156 (100), 129 (6), 103 (50),
77 (9).
Methyl 6-Phenylpyrazine-2-carboxylate (6-3ia) and
Methyl 3-Phenylpyrazine-2-carboxylate (3-3ia). Isolated
as a mixture (yellow oil); Rf value (hexane:EtOAc = 5:1) =
1
0.21; For 6-3ia: H NMR (500 MHz, CDCl3): ¤ 9.33 (1H, d,
J = 1.5 Hz), 9.12 (1H, d, J = 1.5 Hz), 8.13-8.06 (2H, m), 7.55-
7.51 (3H, m), 4.05 (3H, s); 13C NMR (101 MHz, CDCl3): ¤
166.6, 155.1, 145.5, 141.2, 140.8, 135.1, 130.9, 127.4, 128.4,
53.0; LRMS m/z (relative intensity): 214 (67), 200 (14), 199
(100), 183 (14), 156 (62), 155 (71), 129 (11), 128 (26), 104
(30), 103 (29), 77 (39), 76 (15). For 3-3ia: 1H NMR (500 MHz,
CDCl3): ¤ 8.75 (1H, d, J = 2.4 Hz), 8.58 (1H, d, J = 2.4 Hz),
7.64-7.59 (2H, m), 7.50-7.45 (3H, m), 3.83 (3H, s); 13C NMR
(101 MHz, CDCl3): ¤ 164.4, 153.5, 145.2, 144.2, 141.6, 136.8,
129.6, 129.1, 128.5, 52.9; LRMS m/z (relative intensity): 214
(29), 156 (100), 155 (13), 128 (32), 103 (17), 102 (22), 101
(11), 77 (18), 76 (11); HRMS Calculated for C12H11N2O2:
215.0821, Found: 215.0822.
Methyl 5-Phenylpyrazine-2-carboxylate (5-3ia). Isolated
as yellow oil; Rf value (hexane:EtOAc = 5:1) = 0.33; 1H NMR
(500 MHz, CDCl3): ¤ 9.22 (1H, s), 9.19 (1H, s), 8.12-8.04 (2H,
m), 7.58-7.47 (3H, m), 4.06 (3H, s); 13C NMR (101 MHz,
CDCl3): ¤ 164.8, 144.9, 143.9, 143.1, 130.5, 129.8, 129.2,
128.4, 127.3, 53.1; LRMS m/z (relative intensity): 214 (27),
157 (11), 156 (100), 155 (23), 129 (11), 128 (22), 103 (11), 102
(15), 77 (18); HRMS Calculated for C12H11N2O2: 215.0821,
2-Amino-4-phenylpyrimidine (4-3la). Isolated as white
solid (Mp: 161-162 °C); Rf value (hexane:EtOAc = 1:1) =
1
0.24; H NMR (500 MHz, CDCl3): ¤ 8.35 (1H, d, J = 5.2 Hz),
7.99 (2H, ddt, J = 4.9, 3.5, 1.5 Hz), 7.51-7.44 (2H, m), 7.05
(1H, d, J = 5.2 Hz), 5.15 (2H, brs); 13C NMR (126 MHz,
CDCl3): ¤ 165.5, 163.3, 158.7, 137.2, 130.6, 128.7, 127.0,
107.7; LRMS m/z (relative intensity): 171 (M+, 71), 170 (100),
102 (18), 77 (14).
4-Chloro-2-(4-tolyl)pyridine (2-3db).7c Isolated as white
solid (Mp: 49-51 °C); Rf value (hexane:EtOAc = 10:1) = 0.63;
1H NMR (CDCl3, 395.75 MHz): ¤ 8.56 (1H, d, J = 5.4 Hz),
7.87 (2H, d, J = 8.3 Hz), 7.71 (1H, d, J = 1.6 Hz), 7.29 (2H,
d, J = 8.3 Hz), 7.21 (1H, dd, J = 5.7, 1.8 Hz), 2.41 (3H, s);
13C NMR (CDCl3, 125.7 Hz): ¤ 158.9, 150.3, 144.5, 139.6,
135.2, 129.5, 126.8, 121.9, 120.4, 21.2; LRMS m/z (relative
intensity): 205 (M+ + 2, 18), 203 (M+, 100), 167 (M+ ¹ Cl,
9), 139 (6), 115 (6), 91 (5), 84 (4), 63 (4), 51 (7).
4-Chloro-3-(4-tolyl)pyridine (3-3db).7c Isolated as yellow
1
oil; Rf value (hexane:EtOAc = 5:1) = 0.49; H NMR (CDCl3,
395.75 MHz): ¤ 8.55 (1H, s), 8.45 (1H, d, J = 5.0 Hz), 7.41

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FeSO4-Mediated Direct Arylation of Heteroarenes
(1H, d, J = 5.0 Hz), 7.35 (2H, d, J = 8.5 Hz), 7.29 (2H, d,
J = 8.5 Hz), 2.43 (3H, s); 13C NMR (CDCl3, 125.7 Hz): ¤
151.2, 148.7, 142.3, 138.4, 136.7, 132.4, 129.3, 129.1, 125.0,
21.3; LRMS m/z (relative intensity): 205 (M+ + 2, 32), 203
(M+, 100), 202 (54), 167 (M+ ¹ Cl, 60), 139 (90), 115 (50),
91 (28), 74 (33), 63 (52), 50 (37).
4-Chloro-2-(4-methoxyphenyl)pyridine (2-3dc).7c,32 Iso-
lated as orange oil; Rf value (hexane:EtOAc = 5:1) = 0.72;
1H NMR (CDCl3, 395.75 MHz): ¤ 8.53 (1H, d, J = 5.5 Hz),
7.93 (2H, d, J = 8.7 Hz), 7.66 (1H, d, J = 1.5 Hz), 7.17 (1H,
dd, J = 5.5, 1.8 Hz), 6.99 (2H, d, J = 8.7 Hz), 3.86 (3H, s);
13C NMR (CDCl3, 125.7 MHz): ¤ 160.9, 158.6, 150.3, 144.6,
130.7, 128.3, 121.5, 120.0, 114.0, 55.3; LRMS m/z (relative
intensity): 221 (M+ + 2, 27), 219 (M+, 100), 204 (M+ ¹ Me,
26), 184 (M+ ¹ Cl, 6), 176 (36), 141 (91), 114 (33), 88 (30),
76 (34), 63 (69), 51 (70).
4-Chloro-3-(4-methoxyphenyl)pyridine (3-3dc). Isolated
as orange oil; Rf value (hexane:EtOAc = 5:1) = 0.31; 1H NMR
(CDCl3, 395.75 MHz): ¤ 8.54 (1H, s), 8.44 (1H, d, J = 5.0 Hz),
7.41-7.39 (3H, m), 7.01 (2H, d, J = 8.8 Hz), 3.87 (3H, s);
13C NMR (CDCl3, 125.7 Hz): ¤ 159.7, 151.4, 148.7, 131.6,
131.1, 130.7, 127.7, 113.9, 113.7, 113.2; LRMS m/z (relative
intensity): 221 (M+ + 2, 27), 219 (M+, 100), 204 (M+ ¹ Me,
28), 176 (49), 141 (84), 114 (76), 87 (65), 74 (43), 63 (73), 50
(43); HRMS Calculated for C12H11ClNO: 220.0524, Found:
220.0525.
4-Chloro-2-(4-chlorophenyl)pyridine (2-3dd). Isolated as
white solid (Mp: 49-50 °C); Rf value (hexane:EtOAc = 5:1) =
0.74; 1H NMR (CDCl3, 395.75 MHz): ¤ 8.57 (1H, d, J =
5.2 Hz), 7.91 (2H, d, J = 8.5 Hz), 7.68 (1H, d, J = 1.9 Hz), 7.45
(2H, d, J = 8.5 Hz), 7.15 (1H, dd, J = 5.2, 1.9 Hz); 13C NMR
(CDCl3, 125.7 Hz): ¤ 157.7, 150.5, 144.9, 136.5, 135.8, 129.0,
128.2, 122.5, 120.6; LRMS m/z (relative intensity): 227
(M+ + 4, 11), 225 (M+ + 2, 56), 223 (M+, 100), 190 (M+ ¹
Cl + 2, 31), 188 (M+ ¹ Cl, 72), 153 (M+ ¹ 2Cl, 28), 126 (26),
102 (12), 94 (16), 75 (36), 63 (15), 50 (24); HRMS Calculated
for C11H8Cl2N: 224.0028, Found: 224.0027.
3-(4-Bromophenyl)-4-chloropyridine (3-3de). Isolated as
white oil; Rf value (hexane:EtOAc = 5:1) = 0.27; 1H NMR
(CDCl3, 395.75 MHz): ¤ 8.53 (1H, s), 8.50 (1H, d, J = 5.4 Hz),
7.62 (2H, d, J = 8.5 Hz), 7.43 (1H, d, J = 5.4 Hz), 7.34 (2H, d,
J = 8.5 Hz); 13C NMR (CDCl3, 125.7 Hz): ¤ 151.0, 149.4,
142.2, 134.2, 132.4, 131.7, 131.1, 123.0, 117.3; LRMS m/z
(relative intensity): 271 (M+ + 4, 27), 269 (M+ + 2, 100), 267
(M+, 77), 190 (M+ ¹ Br + 2, 5), 188 (M+ ¹ Br, 15), 153
(M+ ¹ Cl,Br, 42), 126 (41), 99 (15), 87 (17), 74 (27), 63 (25),
50 (36); HRMS Calculated for C11H8BrClN: 267.9523, Found:
267.9526.
4-Chloro-2-(3-methylphenyl)pyridine (2-3df). Isolated as
yellow oil; Rf value (hexane:EtOAc = 5:1) = 0.83; 1H NMR
(CDCl3, 395.75 MHz): ¤ 8.02 (1H, d, J = 5.7 Hz), 7.26-7.17
(3H, m), 6.82 (1H, t, J = 7.7 Hz), 6.72-6.67 (2H, m), 1.89 (3H,
s); 13C NMR (CDCl3, 125.7 Hz): ¤ 159.1, 150.4, 144.6, 138.5,
138.0, 130.3, 128.7, 127.6, 124.0, 122.1, 120.8, 21.4; LRMS
m/z (relative intensity): 205 (M+ + 2, 27), 203 (M+, 100), 188
(4), 167 (M+ ¹ Cl, 21), 139 (7), 115 (6), 100 (12), 91 (9),
88 (13), 84 (12); HRMS Calculated for C12H11ClN [M + H]:
204.0575, Found: 204.0574.
4-Chloro-3-(3-methylphenyl)pyridine (3-3df). Isolated as
orange oil; Rf value (hexane:EtOAc = 5:1) = 0.29; 1H NMR
(CDCl3, 399.857 MHz): ¤ 8.59 (1H, s), 8.54 (1H, d, J =
5.6 Hz), 7.59 (1H, d, J = 5.6 Hz), 7.41-7.25 (4H, m), 2.43 (3H,
s); 13C NMR (CDCl3, 125.7 Hz): ¤ 148.5, 146.1, 145.3, 138.5,
137.8, 134.1, 129.9, 129.8, 128.5, 126.4, 125.8, 21.4; LRMS
m/z (relative intensity): 205 (M+ + 2, 29), 203 (M+, 100), 202
(59), 167 (M+ ¹ Cl, 24), 139 (15), 115 (11), 101 (7), 91 (7),
70 (10); HRMS Calculated for C12H11ClN [M + H]: 204.0575,
Found: 204.0575.
4-Chloro-2-(3-chlorophenyl)pyridine (2-3dg). Isolated as
white solid (Mp: 76-78 °C); Rf value (hexane:EtOAc = 5:1) =
1
0.74; H NMR (CDCl3, 395.75 MHz): ¤ 8.46 (1H, d, J = 5.3
Hz), 7.87 (1H, s), 7.71 (1H, m), 7.58 (1H, d, J = 1.7 Hz), 7.28
(2H, m), 7.15 (1H, dd, J = 5.3, 1.7 Hz); 13C NMR (CDCl3,
125.7 Hz): ¤ 157.4, 150.5, 144.9, 139.8, 135.0, 130.0, 129.6,
127.1, 124.9, 122.8, 120.9; LRMS m/z (relative intensity):
227 (M+ + 4, 11), 225 (M+ + 2, 56), 223 (M+, 100), 190
(M+ ¹ Cl + 2, 31), 188 (M+ ¹ Cl, 72), 153 (M+ ¹ 2Cl, 28),
126 (26), 102 (12), 94 (16), 75 (36), 63 (15), 50 (24); HRMS
Calculated for C11H8Cl2N: 224.0028, Found: 224.0027.
4-Chloro-3-(3-chlorophenyl)pyridine (3-3dg). Isolated as
white solid (Mp: 49-50 °C); Rf value (hexane:EtOAc = 5:1) =
0.24; 1H NMR (CDCl3, 395.75 MHz): ¤ 8.54 (1H, s), 8.50 (1H,
d, J = 4.9 Hz), 7.45-7.32 (5H, m); 13C NMR (CDCl3, 125.7
Hz): ¤ 151.1, 149.7, 142.2, 137.1, 135.1, 134.3, 129.7, 129.5,
128.6, 127.7, 124.8; LRMS m/z (relative intensity): 227
(M+ + 4, 11), 225 (M+ + 2, 66), 223 (M+, 100), 190 (M+ ¹
Cl + 2, 5), 188 (M+ ¹ Cl, 20), 153 (M+ ¹ 2Cl, 33), 126 (38),
99 (18), 85 (8), 74 (23), 63 (14), 50 (13); HRMS Calculated for
C11H8Cl2N: 224.0028, Found: 224.0025.
4-Chloro-3-(4-chlorophenyl)pyridine (3-3dd). Isolated as
white solid (Mp: 48-50 °C); Rf value (hexane:EtOAc = 5:1) =
0.28; 1H NMR (CDCl3, 395.75 MHz): ¤ 8.53 (1H, s), 8.50
(1H, d, J = 5.7 Hz), 7.47-7.39 (5H, m); 13C NMR (CDCl3,
125.7 Hz): ¤ 150.6, 148.1, 142.9, 135.5, 134.9, 133.5, 130.8,
128.8, 125.1; LRMS m/z (relative intensity): 227 (M+ + 4,
10), 225 (M+ + 2, 62), 223 (M+, 100), 190 (M+ ¹ Cl + 2, 25),
188 (M+ ¹ Cl, 75), 161 (13), 153 (M+ ¹ 2Cl, 24), 126 (22),
94 (23), 75 (17), 63 (8), 51 (15); HRMS Calculated for
C11H8Cl2N: 224.0028, Found: 224.0026.
2-(4-Bromophenyl)-4-chloropyridine (2-3de). Isolated as
white solid (Mp: 31-35 °C); Rf value (hexane:EtOAc = 5:1) =
1
0.76; H NMR (CDCl3, 395.75 MHz): ¤ 8.56 (1H, d, J = 5.2
Hz), 7.86 (2H, d, J = 8.6 Hz), 7.71 (1H, d, J = 1.9 Hz), 7.61
(2H, d, J = 8.6 Hz), 7.27 (1H, m); 13C NMR (CDCl3, 125.7
Hz): ¤ 159.3, 150.3, 144.6, 138.4, 138.0, 131.2, 124.8, 122.1,
120.9; LRMS m/z (relative intensity): 271 (M+ + 4, 23), 269
(M+ + 2, 100), 267 (M+, 79), 234 (M+ ¹ Cl + 2, 19), 232
(M+ ¹ Cl, 19), 190 (M+ ¹ Br + 2, 14), 188 (M+ ¹ Br, 41),
153 (M+ ¹ Cl,Br, 49), 126 (43), 102 (13), 94 (21), 75 (31), 63
(13), 50 (41); HRMS Calculated for C11H8BrClN: 267.9523,
Found: 267.9524.
2-(3-Bromophenyl)-4-chloropyridine (2-3dh). Isolated as
white solid (Mp: 57-59 °C); Rf value (hexane:EtOAc = 5:1) =
1
0.75; H NMR (CDCl3, 395.75 MHz): ¤ 8.59 (1H, d, J = 5.1
Hz), 8.15 (1H, t, J = 1.9 Hz), 7.88 (1H, d, J = 7.9 Hz), 7.71
(1H, d, J = 1.9 Hz), 7.57 (1H, d, J = 7.9 Hz), 7.35 (1H, t,
J = 7.9 Hz), 7.28 (1H, dd, J = 4.9, 1.9 Hz); 13C NMR (CDCl3,
125.7 Hz): ¤ 157.4, 150.6, 144.9, 140.1, 132.5, 130.3, 130.1,

K. Komeyama et al.
Bull. Chem. Soc. Jpn. Vol. 87, No. 2 (2014)
311
125.5, 123.1, 122.9, 120.9; LRMS m/z (relative intensity):
271 (M+ + 4, 27), 269 (M+ + 2, 100), 267 (M+, 82), 190
(M+ ¹ Br + 2, 37), 188 (M+ ¹ Br, 87), 153 (M+ ¹ Br ¹ Cl,
51), 126 (37), 102 (15), 99 (16), 94 (21), 76 (42), 63 (20), 50
(65); HRMS Calculated for C11H8BrClN (M+ ¹ 1): 267.9523,
Found: 267.9525.
3-(3-Bromophenyl)-4-chloropyridine (3-3dh). Isolated as
white solid (Mp: 62-64 °C); Rf value (hexane:EtOAc = 5:1) =
0.13; 1H NMR (CDCl3, 395.75 MHz): ¤ 8.54 (1H, s), 8.55 (1H,
d, J = 5.5 Hz), 7.61-7.57 (2H, m), 7.44 (1H, d, J = 5.1 Hz),
7.40-7.34 (2H, m); 13C NMR (CDCl3, 125.7 Hz): ¤ 151.1,
149.7, 142.2, 137.3, 135.0, 132.4, 131.5, 130.0, 128.2, 124.8,
122.4; LRMS m/z (relative intensity): 271 (M+ + 4, 30), 269
(M+ + 2, 100), 267 (M+, 97), 190 (M+ ¹ Br + 2, 8), 188
(M+ ¹ Br, 24), 153 (M+ ¹ Br ¹ Cl, 65), 126 (76), 125 (34), 99
(26), 87 (27), 74 (36), 63 (23), 50 (41); HRMS Calculated for
C11H8BrClN: 267.9523, Found: 267.9524.
4-Chloro-2-(2-methylphenyl)pyridine (2-3di).33 Isolated
as yellow oil; Rf value (hexane:EtOAc = 5:1) = 0.61; 1H NMR
(CDCl3, 399.857 MHz): ¤ 8.60 (1H, d, J = 5.7 Hz), 7.43 (1H,
s), 7.38 (1H, d, J = 7.4 Hz), 7.34-7.26 (4H, m), 2.37 (3H, s);
13C NMR (CDCl3, 125.7 Hz): ¤ 161.5, 150.0, 144.0, 139.2,
135.8, 130.9, 129.4, 128.7, 125.9, 124.3, 122.0, 20.2; LRMS
m/z (relative intensity): 205 (M+ + 2, 29), 203 (M+, 100), 202
(59), 188 (5), 167 (21), 139 (7), 115 (6), 100 (12), 88 (13),
84 (12).
4-Chloro-3-(2-methylphenyl)pyridine (3-3di). Isolated as
yellow oil; Rf value (hexane:EtOAc = 5:1) = 0.24; 1H NMR
(CDCl3, 399.857 MHz): ¤ 8.51 (1H, d, J = 5.4 Hz), 8.47 (1H,
s), 7.45 (1H, d, J = 5.4 Hz), 7.38-7.27 (3H, m), 7.14 (1H,
d, J = 7.4 Hz), 2.13 (3H, s); 13C NMR (CDCl3, 125.7 Hz):
¤ 151.0, 149.1, 143.6, 136.8, 136.6, 135.1, 130.1, 129.6,
128.8, 125.8, 124.4, 19.8; LRMS m/z (relative intensity): 205
(M+ + 2, 28), 203 (M+, 100), 202 (59), 188 (3), 167 (53), 139
(32), 115 (13), 100 (5), 89 (13), 84 (11), 70 (23); HRMS
Calculated for C12H11ClN: 204.0575, Found: 204.0574.
4-Chloro-2-(2-methoxyphenyl)pyridine (2-3dj). Isolated
as orange oil; Rf value (hexane:EtOAc = 5:1) = 0.63; 1H NMR
(CDCl3, 399.857 MHz): ¤ 8.58 (1H, d, J = 5.3 Hz), 7.88 (1H,
d, J = 1.5 Hz), 7.79 (1H, dd, J = 7.7, 1.7 Hz), 7.39 (1H, td,
J = 7.7, 1.7 Hz), 7.22 (1H, dd, J = 5.3, 1.9 Hz), 7.08 (1H, t,
J = 7.7 Hz), 7.00 (1H, d, J = 8.2 Hz), 3.88 (3H, s); 13C NMR
(CDCl3, 125.7 Hz): ¤ 157.4, 156.9, 150.0, 143.5, 131.1, 130.5,
127.7, 125.3, 121.9, 121.0, 111.4, 55.6; LRMS m/z (rela-
tive intensity): 220 (M+ + 2, 41), 219 (69), 218 (M+, 100),
190 (M+, 47), 154 (52), 127 (24), 114 (75), 77 (57). HRMS
Calculated for C12H10ClNO: 219.0451, Found: 219.0449.
4-Chloro-3-(2-methoxyphenyl)pyridine (3-3dj). Isolated
as orange oil; Rf value (hexane:EtOAc = 5:1) = 0.22; 1H NMR
(CDCl3, 395.75 MHz): ¤ 8.50 (1H, s), 8.46 (1H, d, J = 5.3 Hz),
7.44-7.40 (2H, m), 7.21 (1H, d, J = 7.4 Hz), 7.06 (1H, t,
J = 7.4 Hz), 7.01 (1H, d, J = 8.1 Hz), 3.79 (3H, s); 13C NMR
(CDCl3, 125.7 Hz): ¤ 156.9, 154.5, 151.8, 143.8, 131.0, 130.2,
124.5, 124.3, 120.5, 111.0, 55.5, one carbon was obscured;
LRMS m/z (relative intensity): 221 (M+ + 2, 27), 219 (M+,
100), 204 (M+ ¹ Me, 28), 176 (49), 141 (84), 114 (76),
87 (65), 74 (43), 63 (73), 50 (43); HRMS Calculated for
C12H11ClNO: 220.0524, Found: 220.0527.
white solid (Mp: 34-35 °C); Rf value (hexane:EtOAc = 5:1) =
0.74; H NMR (CDCl3, 395.75 MHz): ¤ 8.62 (1H, d, J = 5.3
1
Hz), 7.68 (1H, d, J = 1.9 Hz), 7.59-7.57 (1H, m), 7.50-7.48
(1H, m), 7.38-7.36 (2H, m), 7.32 (1H, dd, J = 5.3, 1.9 Hz);
13C NMR (CDCl3, 125.7 Hz): ¤ 157.4, 150.6, 144.9, 139.8,
135.0, 130.1, 129.6, 127.1, 125.0, 122.8, 120.9; LRMS m/z
(relative intensity): 227 (M+ + 4, 11), 225 (M+ + 2, 68), 223
(M+, 100), 190 (M+ ¹ Cl + 2, 34), 188 (M+ ¹ Cl, 93), 153
(M+ ¹ 2Cl, 38), 126 (31), 99 (11), 94 (16), 75 (31), 63 (12),
51 (29); HRMS Calculated for C11H7Cl2N: 224.0028, Found:
224.0027.
4-Chloro-3-(2-chlorophenyl)pyridine (3-3dk).
Isolated
1
as white oil; Rf value (hexane:EtOAc = 5:1) = 0.23; H NMR
(CDCl3, 395.75 MHz): ¤ 8.54 (1H, d, J = 5.3 Hz), 8.49 (1H, s),
7.52 (1H, dd, J = 7.5, 1.7 Hz), 7.45 (1H, d, J = 5.3 Hz), 7.41-
7.35 (2H, m), 7.28 (1H, dd, J = 7.5, 1.7 Hz); 13C NMR (CDCl3,
125.7 Hz): ¤ 151.3, 149.9, 143.4, 134.5, 134.5, 133.8, 131.3,
130.1, 129.7, 126.7, 124.4; LRMS m/z (relative intensity):
227 (M+ + 4, 18), 225 (M+ + 2, 74), 223 (M+, 100), 190
(M+ ¹ Cl + 2, 5), 188 (M+ ¹ Cl, 27), 153 (M+ ¹ 2Cl, 22),
126 (28), 99 (18), 87 (15), 75 (29), 63 (16), 50 (31); HRMS
Calculated for C11H8Cl2N: 224.0028, Found: 224.0027.
4-Chloro-2-(3,5-dimethylphenyl)pyridine (2-3dl).
Iso-
lated as yellow oil; Rf value (hexane:EtOAc = 5:1) = 0.67;
1H NMR (CDCl3, 499.82 MHz): ¤ 8.57 (1H, d, J = 5.3 Hz),
7.71 (1H, d, J = 1.7 Hz), 7.58 (2H, s), 7.22 (1H, dd, J = 5.3,
1.7 Hz), 7.09 (1H, s), 2.40 (6H, s); 13C NMR (CDCl3, 125.7
Hz): ¤ 159.3, 150.3, 144.6, 138.4, 138.0, 131.2, 124.8, 122.1,
120.9, 21.3; LRMS m/z (relative intensity): 219 (M+ + 2, 33),
217 (M+, 100), 201 (19), 182 (M+ ¹ Cl, 8), 167 (17), 152 (9),
139 (10), 77 (15), 63 (11), 51 (17); HRMS Calculated for
C13H13ClN [M + H]: 218.0737, Found: 218.0734.
2-Amino-4-(2-chlorophenyl)pyrimidine (4-3lk).
Iso-
lated as white solid; Rf value (hexane:EtOAc = 1:1) = 0.24;
1H NMR (500 MHz, CDCl3): ¤ 8.36 (1H, d, J = 5.1 Hz), 7.56
(1H, t, J = 5.6, 3.8 Hz), 7.47 (1H, dd, J = 5.8, 3.5 Hz), 7.36
(3H, dq, J = 7.3, 3.8 Hz), 6.97 (1H, d, J = 5.1 Hz), 5.21 (2H,
brs); 13C NMR (126 MHz, CDCl3): ¤ 165.4, 163.0, 158.0,
137.3, 132.0, 130.8, 130.4, 130.3, 127.1, 112.3; LRMS m/z
(relative intensity): 207 (M+ + 2, 30), 205 (M+, 100), 170 (96),
136 (15), 111 (3), 94 (6), 75 (21); HRMS Calculated for
C10H9ClN3: 206.0485, Found: 206.0484.
2-Cyano-6-(4-methoxyphenyl)pyrazine (6-3jc). Isolated
as brown oil; Rf value (hexane:EtOAc = 5:1) = 0.26; 1H NMR
(500 MHz, CDCl3): ¤ 9.07 (d, J = 1.5 Hz, 1H), 8.87 (d, J =
1.5 Hz, 1H), 8.08 (dm, J = 8.9 Hz, 2H), 7.06 (dm, J = 8.9
Hz, 2H), 3.90 (s, 3H); 13C NMR (126 MHz, CDCl3): ¤ 162.6,
154.4, 147.5, 141.7, 129.2, 127.1, 116.0, 114.9, 114.1, 55.5;
LRMS m/z (relative intensity): 211 (M+, 100), 196 (8), 168
(11), 141 (12), 133 (63); HRMS Calculated for C12H9N3O:
211.0746, Found: 211.0742.
Methyl 6-(4-Methoxyphenyl)pyrazine-2-carboxylate (6-
3ic). Isolated as a white solid; Rf value (hexane:EtOAc =
1
3:1) = 0.25; H NMR (396 MHz, CDCl3): ¤ 9.30 (1H, d, J =
1.3 Hz), 9.08 (1H, d, J = 1.4 Hz), 8.10 (2H, d, J = 8.8 Hz),
7.06 (2H, d, J = 8.8 Hz), 4.06 (3H, s), 3.90 (3H, s); 13C NMR
(126 MHz, CDCl3): ¤ 164.7, 162.1, 154.9, 145.6, 140.7, 140.0,
129.1, 127.7, 114.7, 55.5, 53.0; LRMS m/z (relative intensity):
244 (M+, 73), 186 (100), 158 (38), 132 (24); HRMS Calculated
4-Chloro-2-(2-chlorophenyl)pyridine (2-3dk). Isolated as

312
Bull. Chem. Soc. Jpn. Vol. 87, No. 2 (2014)
FeSO4-Mediated Direct Arylation of Heteroarenes
for C13H13N2O3: 245.0926, Found: 245.0925.
Methyl 3-(4-Methoxyphenyl)pyrazine-2-carboxylate (3-
0.11 mmol) in DCM (0.11 mL) was added TMSCN (22.0 mg,
0.22 mmol) and cooled to 0 °C. A solution of dimethylcarba-
moyl chloride (17 mg, 0.134 mmol) in DCM (0.03 mL) was
slowly introduced into the reaction mixture with keeping the
same temperature. After addition, the mixture was stirred for
24 h at room temperature, quenched with 10% aqueous K2CO3
solution. Aqueous phase was extracted with ether, and the
combined ethereal solution was dried over anhydrous Na2SO4.
The filtrated solution was evaporated to afford crude products.
The title compound 6 (25.0 mg, 0.08 mmol) was isolated by
flash chromatography.
3ic).
Isolated as a brown oil; Rf value (hexane:EtOAc =
3:1) = 0.21; 1H NMR (396 MHz, CDCl3): ¤ 8.71 (1H, d,
J = 2.6 Hz), 8.53 (1H, d, J = 2.4 Hz), 7.59 (2H, d, J = 8.7 Hz),
7.00 (2H, d, J = 8.7 Hz), 3.87 (6H, s); 13C NMR (126 MHz,
CDCl3): ¤ 167.0, 161.0, 153.0, 145.2, 143.9, 141.0, 130.0,
129.2, 114.1, 77.3, 77.0, 76.7, 55.3, 53.0; LRMS m/z (relative
intensity): 244 (M+, 97), 229 (100), 185 (57), 158 (13), 142
(17), 133 (19); HRMS Calculated for C13H13N2O3: 245.0926,
Found: 245.0926.
Prodecure for Synthesis of 4 from 6 to 3ic. A solution
of 6-3ic (45 mg, 0.184 mmol) in THF (2 mL) was cooled
to ¹40 °C, 4-methoxyphenylmagnesium bromide (0.22 mmol,
0.2 M in THF) was slowly added over 2 h. After the addition,
the reaction mixture was gradually warmed to room temper-
ature, and to it was added saturated NH4Cl aq. Aqueous phase
was extracted with ether, and the combined ethereal solution
was dried over anhydrous MgSO4. The filtrated solution was
evaporated to afford crude products. The title compound 4
(49.6 mg, 0.155 mmol) was isolated by flash chromatography.
2-(4-Methoxybenzoyl)-6-(4-methoxyphenyl)pyrazine
(4).24 Isolated as a white solid (Mp: 113-114 °C); Rf value
4-Chloro-2-[4-(4-fluorophenoxy)phenyl]pyridine
N-
Oxide. Isolated as an orange solid (Mp: 77-80 °C); Rf value
(MeOH:EtOAc = 1:10) = 0.56; 1H NMR (CDCl3, 499.82
MHz): ¤ 8.24 (1H, d, J = 7.0 Hz), 7.81 (2H, dt, J = 8.7, 1.9
Hz), 7.42 (1H, d, J = 2.9 Hz), 7.19 (1H, dd, J = 7.0, 3.0
Hz), 7.08-7.02 (6H, m); 13C NMR (CDCl3, 125.7 Hz): ¤ 159.8
(d, J = 242.6 Hz), 159.4, 151.6 (d, J = 2.8 Hz), 149.3, 141.1,
131.8, 131.0, 126.8, 125.7, 124.3, 121.4 (d, J = 8.4 Hz), 117.2,
116.5 (d, J = 23.3 Hz); LRMS m/z (relative intensity): 317
(M+ + 2, 18), 315 (M+, 54), 299 (M+ ¹ O, 100), 270 (14),
204 (19), 188 (8), 176 (18), 153 (23), 141 (40), 126 (15), 111
(25), 95 (13), 75 (22), 63 (9), 57(11); HRMS Calculated for
C17H11O2NClF: 316.0535, Found: 316.0539.
1
(hexane:EtOAc = 3:1) = 0.28; H NMR (500 MHz, CDCl3): ¤
9.23 (1H, d, J = 1.4 Hz), 9.03 (1H, d, J = 1.4 Hz), 8.17 (2H,
d, J = 9.0 Hz), 8.10 (2H, d, J = 9.1 Hz), 7.06 (2H, d, J = 9.0
Hz), 7.00 (2H, d, J = 9.0 Hz), 3.904 (3H, s), 3.900 (3H, s);
13C NMR (126 MHz, CDCl3): ¤ 190.5, 163.8, 161.9, 153.7,
147.4, 145.5, 139.0, 133.3, 128.9, 128.8, 128.1, 114.7, 113.6,
55.53, 55.46.
4-Chloro-6-cyano-2-[4-(4-fluorophenoxy)phenyl]pyridine
(6).25 Isolated as an orange solid (Mp: 84-88 °C); Rf value
(hexane:EtOAc = 5:1) = 0.56; 1H NMR (CDCl3, 499.82
MHz): ¤ 7.98 (2H, dt, J = 8.7, 1.9 Hz), 7.87 (1H, d, J = 1.9
Hz), 7.57 (1H, s), 7.11-7.03 (6H, m); 13C NMR (CDCl3, 125.7
Hz): ¤ 160.3, 159.4, 159.3 (d, J = 242.8 Hz), 151.7 (d, J = 2.6
Hz), 145.6, 134.5, 130.6, 128.9, 126.1, 123.1, 121.3 (d, J = 8.4
Hz), 118.0, 116.6 (d, J = 23.3 Hz), 116.4; LRMS m/z (rela-
tive intensity): 301 (M+ ¹ CN + 2, 25), 299 (M+ ¹ CN, 100),
270 (12), 207 (5), 153 (10), 141 (4), 126 (4), 95 (3), 75 (5).
4-Chloro-2-[4-(4-fluorophenoxy)phenyl]pyridine
(2-
3dm). Isolated as yellow oil; Rf value (hexane:EtOAc =
1
5:1) = 0.58; H NMR (CDCl3, 499.82 MHz): ¤ 8.56 (1H, d,
J = 5.1 Hz), 7.94 (2H, m), 7.68 (1H, d, J = 1.9 Hz), 7.22 (1H,
dd, J = 5.1, 1.9 Hz), 7.09-7.03 (6H, m); 13C NMR (CDCl3,
125.7 Hz): ¤ 159.3 (d, J = 242.6 Hz), 159.2 (d, J = 0.9 Hz),
158.3, 152.2 (d, J = 2.8 Hz), 150.5, 144.7, 132.9, 128.6, 122.0,
121.0 (d, J = 8.8 Hz), 120.3, 118.1, 116.4 (d, J = 23.1 Hz); MS
m/z (relative intensity): 301 (M+ + 2, 23), 299 (M+, 100), 270
(11), 188 (11), 176 (9), 153 (10), 141 (24), 126 (13), 95 (68), 75
(56), 63 (18), 51 (38); HRMS Calculated for C17H12ClFNO:
300.0591, Found: 300.0592.
This work was partially supported by a Grant-in-Aid for
Scientific Research from the Ministry of Education, Culture,
Sport, Science and Technology of Japan. We also acknowledge
financial support for General Sekiyu R&D Encouragement
Assistance Foundation. KK is grateful for the Konica Minolta
Advanced Layer Award in Synthetic Organic Chemistry, Japan.
Supporting Information
4-Chloro-3-[4-(4-fluorophenoxy)phenyl]pyridine
(3-
3dm). Isolated as yellow solid (74-76 °C); Rf value (hexane:
1H and 13C NMR spectra for all products, data of the control
experiments, and computational details. This material is availa-
ble free of charge on the web at http://www.csj.jp/jounal/bcsj/.
1
EtOAc = 5:1) = 0.25; H NMR (CDCl3, 499.82 MHz): ¤ 8.50
(1H, d, J = 5.0 Hz), 8.41 (1H, s), 7.42-7.40 (3H, m), 7.08-7.04
(6H, m); 13C NMR (CDCl3, 125.7 Hz): ¤ 159.1 (d, J = 242.8
Hz), 158.2, 152.1 (d, J = 2.8 Hz), 151.2, 148.9, 142.3, 131.0,
129.8, 128.7, 124.9, 121.2 (d, J = 8.4 Hz), 119.2, 117.6, 116.6
(d, J = 23.5 Hz), LRMS m/z (relative intensity): 301 (M+ + 2,
24), 299 (M+, 70), 272 (15), 207 (41), 153 (22), 141 (17), 126
(25), 95 (100), 75 (79), 57 (21), 51 (31); HRMS Calculated for
C17H12ClFNO: 300.0591, Found: 300.0591.
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