Metal-free C–H arylation of aminoheterocycles with arylhydrazines

Article abstract of DOI:10.1016/j.tet.2016.05.056

A direct C–H arylation of aminoheterocycles with arylhydrazine hydrochlorides was developed. The reaction proceeds via a homolytic aromatic substitution mechanism involving aryl radicals as the intermediates. The new reaction takes place readily at room t

Full text of DOI:10.1016/j.tet.2016.05.056

Accepted Manuscript
Metal-free C–H arylation of aminoheterocycles with arylhydrazines
Toshihide Taniguchi, Mitsutaka Imoto, Motonori Takeda, Fukashi Matsumoto, Takeo
Nakai, Masatoshi Mihara, Takumi Mizuno, Akihiro Nomoto, Akiya Ogawa
PII:
S0040-4020(16)30463-X
10.1016/j.tet.2016.05.056
TET 27783
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 8 April 2016
Revised Date: 13 May 2016
Accepted Date: 20 May 2016
Please cite this article as: Taniguchi T, Imoto M, Takeda M, Matsumoto F, Nakai T, Mihara M, Mizuno T,
Nomoto A, Ogawa A, Metal-free C–H arylation of aminoheterocycles with arylhydrazines, Tetrahedron
(2016), doi: 10.1016/j.tet.2016.05.056.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Metal-free C–H arylation of aminoheterocycles
with arylhydrazines
Leave this area blank for abstract info.
Toshihide Taniguchi,* Mitsutaka Imoto, Motonori Takeda, Fukashi Matsumoto, Takeo Nakai, Masatoshi
Mihara, Takumi Mizuno,* Akihiro Nomoto, and Akiya Ogawa

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Metal-free C–H arylation of aminoheterocycles with arylhydrazines
Toshihide Taniguchi,*,a,c Mitsutaka Imoto,a Motonori Takeda,a Fukashi Matsumoto,b Takeo Nakai,b
Masatoshi Mihara,b Takumi Mizuno,*,b Akihiro Nomoto,c and Akiya Ogawac
a Seika Corporation, 1-1-82 Kozaika, Wakayama 641-0007, Japan
b Osaka Municipal Technical Research Institute, 1-6-50 Morinomiya, Joto-ku, Osaka 536-8553, Japan
c Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A direct C–H arylation of aminoheterocycles with arylhydrazine hydrochlorides was developed.
The reaction proceeds via a homolytic aromatic substitution mechanism involving aryl radicals
as the intermediates. The new reaction takes place readily at room temperature in air and in the
presence of an inexpensive base. Moreover, the reactivity of this radical arylation correlated with
the HOMO energy of aminoheterocycles. This method provides not only a rapid access to
diverse arylated heterocycles, but also an atom-efficient alternative to conventional transition-
metal-catalyzed cross-coupling between halides and organometallics.
Available online
Keywords:
C–H arylation
aminoheterocycle
homolytic aromatic substitution
arylhydrazine
2009 Elsevier Ltd. All rights reserved
.
HOMO energy
1. Introduction
Substituted heterocycles are valuable building blocks in many
fields such as medicinal chemistry and materials science. In
particular, an important subgroup of substituted heterocycles is
diaminoheterocycles. For example, lamotrigine was developed as
an anticonvulsant for the treatment of bipolar depression.8
Moreover, compounds A and B are selective Nav1.8 modulators9
(Figure 1).
The use of transition-metal catalysts helped to rapidly develop
aromatic coupling reactions, which are very important in organic
chemistry, e.g., Mizoroki–Heck reaction,1 Suzuki–Miyaura
coupling,2 and Negishi coupling.3 The great success of cross-
coupling reactions using transition-metal catalysts led to the
Nobel Prize in chemistry in 2010. To use these reactions in
industrial scale, however, researchers in companies often face to
the following problems: 1) Most of the transition-metal catalysts,
e.g., Pd catalysts, are very expensive, and some of them are toxic.
2) The removal of transition metal residues from the target
products is very costly. Therefore, the development of aromatic
substitutions in the absence of transition-metal catalysts is
strongly desired from practical perspective.
N
N
O
N
NH2
N
N
N
O
O
NH
O
NH
NH2
N
N
Cl
Cl
NH2
Cl
NH2
F3CO
A conceptually different approach about aromatic substitution
is the direct C–H radical arylation of arenes involving a
homolytic aromatic substitution (HAS) mechanism.4 A similar
type of reaction was first reported by Gomberg and Bachmann in
1924.5 Recently, much attention has been paid to the use of
arylhydrazines as the radical sources in HAS mechanism.6 New
elegant arylations of anilines with arylhydrazines or
aryldiazonium salts have been reported to be a valuable
alternative to transition-metal-based arylations.7 In the reported
reaction systems, the free amino functionality of anilines led to
high ortho regioselectivities, and 2-arylanilines have been
synthesized in reasonable yields.
Lamotrigine
Compound A
Compound B
Figure 1. Lamotrigine and compounds A and B.
Our company manufactures aromatic diamines, which are not
only useful as the raw materials of functional plastics, but also
significant as the polymer intermediates for aerospace
applications and information technology. Therefore, we studied
the practical arylation of heterocyclic diamines without using
transition-metal catalysts. Particularly, the challenge was to
perform the radical arylation of aminoheterocycles with
regioselectivity. Recently, the direct arylation of pyridines with

2
Tetrahedron
ACCEPTED MANUSCRIPT
arylhydrazine hydrochlorides under mild conditions was
Next, 2-aminopyridine 2b underwent cross-coupling reaction
reported, although the regioselectivity of this arylation reaction
at the 3-position preferentially, affording 3ab and 3cb in
moderate yields (entries 10 and 11). Moreover, 5-substituted and
5,6-disubstituted 2-aminopyridines produced the corresponding
products 3ac, 3ad, 3ae, 3af, and 3bf in moderate yields (entries
12–16). Further, 3-aminopyridine 2g underwent cross-coupling
reaction at the 2-position preferentially, furnishing 3ag–3cg in
moderate-to-good yields (entries 17–19). A reported oxidative
chlorination of 2g with hydrochloric acid and hydrogen peroxide
showed similar regioselectivity, resulting in the chlorination of
2g at the 2-position.11 As shown in entries 17–19, 4-isomers
was not satisfactory.6f
2. Results and discussion
First, the arylation of 2,6-diaminopyridine 2a (10 equiv) with
p-chlorophenylhydrazine hydrochloride 1a in the presence of
potassium carbonate at 25 °C for 24 h in air was investigated. To
our delight, a regioselective reaction occurred, affording 2,6-
diamino-3-(4′-chlorophenyl)pyridine 3aa in a high yield (78%,
Table 1, entry 1). Herein, we report the arylation of
aminoheterocycles with arylhydrazine hydrochlorides as the
radical source in detail. To the best of our knowledge, this is the
first example of the radical arylation of aminoheterocycles with
arylhydrazines.
3ag′–3cg′ and 6-isomers 3ag′′–3cg′′ were obtained as the minor
products. Interestingly, 3-aminoquinoline 2h afforded 4-
substituted product 3ah in a good yield (entry 20). The radical
intermediate obtained by the reaction of 2h might be resonance-
stabilized, and 4-isomer 3ah was obtained selectively. Moreover,
In the selection of solvents, a combination of DMSO and
potassium carbonate6c,6g worked well the present radical
arylation, producing 3aa in a good yield (78%, entry 1). When
DMF or DMA was used instead of DMSO, the yield of 3aa
decreased (entries 2 and 3). Acetonitrile provided 3aa in a
moderate yield6b,6d,7f (entry 4). Because 2a is soluble in water, the
use of water as a solvent was also investigated for the arylation.
However, the arylation in water almost did not proceed (entry 5).
The use of HFIP (1,1,1,3,3,3-hexafluoro-2-propanol), an
effective radical stabilizer for the chelated radical–anion
oxidative coupling of phenols in the presence of an iron
catalyst,10a provided an inferior result. The product 3aa was not
obtained at all (entry 6).
2-isomer 3ah
′ was obtained as a minor product.
Table 1. Optimization of Synthesis of 3aa
Entry
Solvent Base
Temp Equiv Time Yield
(°C)
of 2a (h)
(%)a
78
1
DMSO K2CO3
25
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
20
20
5
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
48
8
2
DMF
DMA
K2CO3
K2CO3
25
44
3
25
61
Next, several bases were screened; 3aa was obtained in
moderate-to-good yields when lithium carbonate, sodium
carbonate, or cesium carbonate was used (entries 7–9). The
addition of an aqueous solution of KOH or NaOH was not
effective for the formation of 3aa (entries 10 and 11).
Triethylamine furnished 3aa in a moderate yield (entry 12).
Surprisingly, in the absence of a base, the product 3aa was
obtained in a fair yield (55%, entry 13). Excess 2a may have
worked as a base as shown in the previous report.6f High
reaction temperatures did not improve the yield of 3aa (entries 14
and 15). The best yield (85%) of 3aa was obtained when 20
equiv of 2a was used (entry 16). Under a nitrogen atmosphere, a
low yield of 3aa was obtained (entry 17). When the amount of 2a
was reduced, the yield of 3aa decreased (entries 18 and 19). Slow
addition of 1a was tried into the mixture of 2a (1equiv) and
K2CO3 for 4 h using syringe pump (entry 20). However,
improvement of the yield was not observed. Different reaction
times (48 h or 8 h) did not improve the yield of 3aa (entries 21
and 22).
4
MeCN K2CO3
25
48
5
H2O
K2CO3
K2CO3
25
trace
0
6
HFIPb
25
7
DMSO Li2CO3 25
DMSO Na2CO3 25
DMSO Cs2CO3 25
66
8
76
9
43
10
11
12
13
14
15
16
17
18
19
20
21
22
DMSO KOH
DMSO NaOH
DMSO Et3N
25
25
25
25
50
100
25
25
25
25
25
25
25
tracec
tracec
49
DMSO none
DMSO K2CO3
DMSO K2CO3
DMSO K2CO3
DMSO K2CO3
DMSO K2CO3
DMSO K2CO3
DMSO K2CO3
DMSO K2CO3
DMSO K2CO3
55
66
16
With the optimized conditions, the substrate scope and
limitations of the arylation of aminoheterocycles 2a–2k with
various arylhydrazine hydrochlorides 1a–1i were investigated
(Table 2). The arylation of 2,6-diaminopyridine 2a with
arylhydrazine hydrochlorides 1a–1e bearing electron-
withdrawing groups such as Cl, F, Br, and CN smoothly afforded
the corresponding target compounds 3aa–3ea in good-to-
excellent yields (entries 1–5). Moreover, phenylhydrazine
hydrochloride and arylhydrazine hydrochlorides bearing electron-
donating groups such as OMe and Me showed similar
reactivities, producing 3fa–3ha in good yields (entries 6–8).
However, 4-nitrophenylhydrazine 1i bearing a strong electron-
withdrawing group provided a trace amount of 3ia (entry 9). The
results clearly indicate the high radical-scavenging ability of 2,6-
diaminopyridine 2a for phenyl radicals. The attack of phenyl
radicals may be facilitated at the ortho and para positions of the
amino group in 2a.
85
40d
59
2
40
26e
1
10
10
76
74
Reaction conditions: 1a (1.0 mmol), base (3.0 mmol), and solvent (10 mL)
a
b
in air. Isolated yields based on 1a. 1,1,1,3,3,3-Hexafluoro-2-propanol.
c An aqueous solution (1 N, 3.0 mL) of KOH or NaOH was used. d Under a
nitrogen atmosphere. e DMSO (5 mL) solution of 1a was slowly added into
the mixture of 2a (1equiv) and K2CO3 in DMSO (5 mL) for 4 h.

3
Table 2. The Reaction of Arylhydrazines with Aminoheterocycles
ACCEPTED MANUSCRIPT
Yield (%)a
2a-2k
3aa-3ak
Entry
1
2
3
4
5
3aa; R1 = Cl, R2 = H
3ba; R1 = F, R2 = H
3ca; R1 = Br, R2 = H
3da; R1 = CN R2 = H
3ea; R1 = Cl, R2 = Cl
3fa; R1 = H, R2 = H
3ga; R1 = OMe, R2 = H
3ha; R1 = Me, R2 = H
3ia; R1 = NO2, R2 = H
85
76
74
60
63
R1
R2
H2N
N
NH2
H2N
N
NH2
6
7
8
9
59
58
60
2a
R1
trace
10
11
36b
37b
3ab; R1 = Cl
3cb; R1 = Br
N
NH2
2b
N
NH2
Cl
3ac; R3= Me
3ad; R3 = Cl
3ae; R3 = Br
12
13
14
37
47
49
R3
R3
2c-2e
NH2
N
N
N
NH2
R1
3af; R1 = Cl
3bf; R1 = F
Me
Me
34
30
15
16
Me
Me
2f
NH2
N
NH2
75c
55d
63e
NH2
NH2
3ag; R1 = Cl
3bg; R1 = F
3cg; R1 = Br
17
18
19
N
N
2g
R1
Cl
N
83f
20
21
3ah
NH2
NH2
N
2h
Cl
NH2
NH2
N
trace
3ai
2i
N
Cl
N
N
N
2j
56
19
22
23
3aj
N
NH2
NH2
Cl
Me
Me
3ak
N
N
2k
NH2
Me
N
NH2
Me
N
a
b
Isolated yields after purification by column chromatography, based on arylhydrazines. A small amount of isomer
was also formed, but not isolated. c 2-Isomer (3ag, 52%), 4-isomer (3ag′, 15%) and 6-isomer (3ag′′, 8%) were obtained.
d 2-Isomer (3bg, 38%), 4-isomer (3bg′, 11%) and 6-isomer (3bg′′, 6%) were formed. e 2-Isomer (3cg, 47%) , 4-isomer
(3cg′, 11%) and 6-isomer (3cg′′, 5%) were obtained. f 4-Isomer (3ah, 74%) and 2-Isomer (3ah′, 9%) were formed.

4
Tetrahedron
ACCEPTED MANUSCRIPT
Scheme 1. Large-Scale Synthesis of 3aa
In contrast, 4-aminopyridine did not afford the corresponding
Aminopyridine (2b) and 3-aminopyridine (2g) had moderate
HOMO energies, –5.74 eV and –5.77 eV, respectively, and
reacted with aryl radicals to afford the corresponding products in
moderate to good yields. Conversely, 4-aminopyridine (2i) with a
very low HOMO energy (–6.10 eV) was expected to have a low
global nucleophilicity. When 2i was used, the corresponding
product 3ai was not obtained.
product 3ai (entry 21). These results clearly show the difference
in the reactivities between 2,6-diaminopyridine 2a, 2-
aminopyridine 2b, 3-aminopyridine 2g, and 4-aminopyridine 2i.
Finally,
the
cross-coupling
reactions
with
other
aminoheterocycles 2j and 2k were carried out successfully
(entries 22 and 23).
Next, the feasibility of a large-scale synthesis (20-fold) of 3aa
was investigated (Scheme 1). Starting from 1a and 2a, the
desired 2,6-diamino-3-(4′-chlorophenyl)pyridine (3aa) was
obtained in 81% yield and excess 2a was recovered in almost
90% yield without the formation of any byproducts.
To support the radical mechanism, a radical-trapping
experiment was carried out using TEMPO. The oxidation of 1a
with TEMPO (1.5 equiv) in air under the optimized conditions
(Table 1, entry 16) afforded 4-chloro-1-(2,2,6,6-tetramethyl-
piperidinyloxy)benzene 4a in 28% yield (Scheme 2).
To better understand the arylation with 2, DFT calculations at
the B3LYP/6-31G(d,p) level were carried out. Recently, a
correlation between the energy of the HOMO of a molecule and
its relative nucleophilicity was shown in the radical–anion
oxidative coupling of phenols, and a global scale of calculated
nucleophilicity, N, was determined.10 The HOMO energy levels
of the aminoheterocycles in this arylation system correlated with
their nucleophilicity. 2,6-Diaminopyridine (2a) with a high
HOMO energy (–5.14 eV) had a high global nucleophilicity. In
fact, 2a showed a high reactivity with p-chlorophenyl radical,
producing 3aa in an excellent yield (Table 2, entry 1). 2-
Based on the experimental results and previous studies on
HAS reactions,4,7 a plausible reaction mechanism for the
arylation of 2a with 1a is proposed in Scheme 3. After the
preparation of the free-base hydrazine from 1a by treating with
K2CO3, the free-base hydrazine is oxidized by air to form the
corresponding diazene. Then, the diazene is converted into
radical C by oxidation with air. The addition of radical C to 2a
provides the intermediate cyclohexadienyl radical D. The radical
D converts into cation E via single electron transfer (SET).
Finally, the elimination of a hydrogen cation from cation E
affords 3aa.
Scheme 2. Phenyl Radical-Trapping Experiment
Scheme 3. Plausible Reaction Mechanism for the Formation of 3aa

5
(3ba).
4.2.2.
2,6-Diamino-3-(4
′
-fluorophenyl)pyridine
3. Conclusion
ACCEPTED MANUSCRIPT
Compound 3ba was synthesized from 4-fluorophenylhydrazine
hydrochloride 1b (163 mg, 1.0 mmol) and 2a (2.18 g, 20.0
mmol) according to the general procedure. The excess of 2a was
almost removed by extracted with water. Purification with
column chromatography (inner diameter: 2 cm and length: 30
cm) gave 3ba (154 mg, 0.76 mmol, 76%). Recrystallized from
hexane/AcOEt=3:7, 3ba was given as a pale brown needle; Rf
(AcOEt) 0.3; mp 124.0-125.0 °C; νmax (neat) 3460, 3397, 3308,
3144, 1593, 1475, 1430, 1353, 1214 cm-1; δΗ (400 MHz, CDCl3)
4.26 (bs, 2H, N-H), 4.35 (bs, 2H, N-H), 5.98 (d, J 7.7 Hz, 1H, C-
H), 7.09 (dd, JHF 9.0 Hz, J 9.0 Hz, 2H, C-H), 7.15 (d, J 7.7 Hz,
1H, C-H), 7.36 (dd, JHF 5.5 Hz, J 9.0 Hz, 2H, C-H); δC (100
MHz, CDCl3) 98.4, 110.5, 115.7 (d, JCF 21.1 Hz), 130.4 (d, JCF
8.6 Hz), 134.7, 140.1, 154.6, 157.1, 161.7 (d, JCF 247.2 Hz); m/z
(EI) 203 (100, M+), 185 (13), 158 (18), 133 (17), 44 (54%);
HRMS (ESI): MH+, found 204.0922. C11H11FN3 requires
204.0932.
In conclusion, a metal-free arylation of aminoheterocycles
with arylhydrazine hydrochlorides was developed with air as the
oxidant. In this reaction system, the HOMO energy levels of the
aminoheterocycles correlated with their nucleophilicity. This
direct C–H arylation reaction without transition-metal catalysts
could be not only a useful and practical method but also an
alternative for Pd-catalyzed cross-coupling reactions.
4. Experimental
4.1. General
All starting materials were purchased from commercial
sources and used without further purification. IR spectra were
reported in wave numbers (cm-1). 1H NMR spectra were recorded
on 400 MHz spectrometers using CDCl3 or DMSO-d6 as solvent
referenced to TMS (0 ppm) and CHCl3 (7.26 ppm) or DMSO
(2.50 ppm). 13C NMR spectra were recorded at 100 MHz in
CDCl3 and DMSO-d6 using CDCl3 (77.0 ppm) and DMSO-d6
(39.5 ppm) as standard. Chemical shifts are reported in parts per
million (ppm). Coupling constants are reported in hertz (J, Hz).
The following abbreviations are used for the description of
signals: s (singlet), bs (broad singlet), d (doublet), dd (double
doublet), t (triplet), q (quadruplet), m (multiplet). Mass spectra
and exact mass spectra were recorded using electron impact (EI),
electrospray ionization (ESI), and direct analysis in real time
(DART). Analytical TLC was carried out on silica gel plates
using short wave (254 nm) UV light. Silica gel (230−400 mesh)
was used for column chromatography. DFT calculations were
carried out at the B3LYP/6-31G(d,p) level using the Q-Chem
4.0.1 program package.12 Optimized geometries of calculated
compounds were confirmed by the absence of imaginary
frequencies.
4.2.3.
2,6-Diamino-3-(4
′
-bromophenyl)pyridine
(3ca).
Compound 3ca was prepared from 4-bromophenylhydrazine
hydrochloride 1c (224 mg, 1.0 mmol) and 2a (2.18 g, 20.0 mmol)
according to the general procedure. The excess of 2a was almost
removed by extracted with water. By the purification with
column chromatography (inner diameter: 2 cm and length: 30
cm), 3ca (195 mg, 0.74 mmol, 74%) was obtained. Recrystallized
from hexane/AcOEt=1:1, 3ca was given as a cream color solid;
Rf (hexane/AcOEt=2:13) 0.3; mp 129.0-130.0 °C; νmax (neat)
3432, 3365, 3302, 3112, 1589, 1469, 1420, 1067 cm-1; δΗ (400
MHz, CDCl3) 4.27 (bs, 2H, N-H), 4.36 (bs, 2H, N-H), 5.99 (d, J
8.2 Hz, 1H, C-H), 7.16 (d, J 8.2 Hz, 1H, C-H), 7.29 (d, J 8.5 Hz,
2H, C-H), 7.53 (d, J 8.5 Hz, 2H, C-H); δC (100 MHz, CDCl3)
98.5, 110.2, 120.6, 130.4, 132.0, 137.8, 140.0, 154.5, 157.2; m/z
(EI) 263 (100, M+), 183 (39), 140 (45), 92 (62), 43 (68%);
HRMS (ESI): MH+, found 264.0110. C11H1179BrN3 requires
264.0131.
4.2. General procedure for the arylation of aminoheterocycles
with arylhydrazine hydrochlorides
4.2.4. 2,6-Diamino-3-(4′-cyanophenyl)pyridine (3da). Compound
A mixture of the arylhydrazine hydrochlorides (1.0 mmol),
aminopyridines (20.0 mmol), and potassium carbonate (415 mg,
3.0 mmol) in DMSO (10 mL) was stirred at 25 °C in air. The
reactions were completed after 24 h, monitored by thin layer
chromatography (TLC). Then, quenched by the addition of water,
the reaction mixture was extracted with ethyl acetate. The
organic layer was washed with water and brine solution and dried
over anhydrous MgSO4. The solvent was removed under reduced
pressure to give the crude products. Purified by column
chromatography over silica gel (hexane/AcOEt), the pure
products were afforded.
3da was obtained from 4-cyanophenylhydrazine hydrochloride
1d (170 mg, 1.0 mmol) and 2a (2.18 g, 20.0 mmol) according to
the general procedure. The excess of 2a was almost removed by
extracted with water. To the AcOEt solution including the
product, hexane was added slowly. The generated precipitate was
filtered with a funnel to give 3da (26 mg, 0.60 mmol, 60%).
Recrystallized from AcOEt, 3da was given as a pale orange
solid; Rf (hexane/AcOEt=1:3) 0.4; mp 221.5-222.5 °C; νmax
(neat) 3429, 3377, 3174, 2225, 1570, 1471, 1442 cm-1; δΗ (400
MHz, DMSO-d6) 5.37 (bs, 2H, N-H), 5.76 (bs, 2H, N-H), 5.85
(d, J 8.0 Hz, 1H, C-H), 7.13 (d, J 8.0 Hz, 1H, C-H), 7.57 (d, J 8.5
Hz, 2H, C-H), 7.78 (d, J 8.5 Hz, 2H, C-H); δC (100 MHz,
DMSO-d6) 97.7, 106.0, 107.4, 119.3, 128.6, 132.5, 139.5, 144.8,
155.2, 158.9; m/z (EI) 210 (100, M+), 192 (21), 155 (13), 139
(13), 44 (96%); HRMS (ESI): MH+, found 211.0958. C12H11N4
requires 211.0978.
4.2.1.
2,6-Diamino-3-(4
′
-chlorophenyl)pyridine
(3aa).
Compound 3aa was synthesized from 4-chlorophenylhydrazine
hydrochloride 1a (179 mg, 1.0 mmol) and 2,6-diaminopyridine
2a (2.18 g, 20.0 mmol) according to the general procedure. The
excess of 2a was almost removed by extracted with water. By the
purification with column chromatography (inner diameter: 2 cm
and length: 30 cm), 3aa (188 mg, 0.85 mmol, 85%) was
obtained. Recrystallized from hexane/AcOEt=1:1, 3aa was given
as a pale brown crystal; Rf (hexane/AcOEt=1:3) 0.3; mp 116.5-
117.5 °C (Lit.13 114-115 °C); νmax (neat) 3469, 3427, 3303, 3103,
1591, 1467, 1421, 1082 cm-1; δΗ (400 MHz, CDCl3) 4.26 (bs, 2H,
N-H), 4.35 (bs, 2H, N-H), 5.98 (d, J 8.0 Hz, 1H, C-H), 7.16 (d, J
8.0 Hz, 1H, C-H), 7.34 (d, J 9.0 Hz, 2H, C-H), 7.38 (d, J 9.0
Hz, 2H, C-H); δC (100 MHz, CDCl3) 98.5, 110.2, 129.0, 130.1,
132.5, 137.3, 140.0, 154.5, 157.1; m/z (EI) 219 (100, M+), 183
(15), 140 (27), 92 (29), 43 (52%); HRMS (ESI): MH+, found
220.0610. C11H11ClN3 requires 220.0636.
4.2.5.
2,6-Diamino-3-(3
′
,4
′
-dichlorophenyl)pyridine
(3ea).
Compound 3ea was prepared from 3,4-dichlorophenylhydrazine
hydrochloride 1e (213 mg, 1.0 mmol) and 2a (2.18 g, 20.0 mmol)
according to the general procedure. The excess of 2a was almost
removed by extracted with water. Purification with column
chromatography (inner diameter: 2 cm and length: 30 cm) gave
3ea (161 mg, 0.63 mmol, 63%). Recrystallized from
hexane/AcOEt=1:3, 3ea was given as a white solid; Rf
(hexane/AcOEt=1:3) 0.3; mp 126.0-127.0 °C; νmax (neat) 3417,
3338, 3132, 1574, 1460, 1435, 1022 cm-1; δΗ (400 MHz, DMSO-
d6) 5.32 (bs, 2H, N-H), 5.67 (bs, 2H, N-H), 5.82 (d, J 8.4 Hz, 1H,
C-H), 7.08 (d, J 8.4 Hz, 1H, C-H), 7.34 (dd, J 2.2 Hz, J 8.5 Hz,

6
Tetrahedron
ACCEPTED MANUSCRIPT
1H, C-H), 7.56 (d, J 2.2 Hz, 1H, C-H), 7.58 (d, J 8.5 Hz, 1H, C-
1H, C-H), 7.33 (dd, J 2.0 Hz, J 7.3 Hz, 1H, C-H), 7.39 (d, J 8.8
H); δC (100 MHz, DMSO-d6) 97.4, 105.4, 128.4, 129.8, 130.6,
131.1, 139.4, 140.4, 155.1, 158.7; m/z (EI) 253 (100, M+), 217
(16), 174 (24), 109 (20), 91 (16), 43 (84%); HRMS (ESI): MH+,
found 254.0223. C11H10Cl2N3 requires 254.0246.
Hz, 2H, C-H), 7.44 (d, J 8.8 Hz, 2H, C-H), 8.08 (dd, J 2.0 Hz, J
5.0 Hz, 1H, C-H); δC (100 MHz, CDCl3) 114.6, 120.6, 129.3,
130.1, 133.8, 136.5, 137.8, 147.7, 155.7; m/z (EI) 204 (57, M+),
203 (100), 168 (46), 115 (15), 84 (34%); HRMS (ESI): MH+,
found 205.0510. C11H10ClN2 requires 205.0527.
4.2.6. 2,6-Diamino-3-phenylpyridine (3fa). Compound 3fa was
given from phenylhydrazine hydrochloride 1f (145 mg, 1.0
mmol) and 2a (2.18 g, 20.0 mmol) according to the general
procedure. The excess of 2a was almost removed by extracted
with water. Purification with column chromatography (inner
diameter: 2 cm and length: 30 cm) gave 3fa (109 mg, 0.59 mmol,
59%). Recrystallized from hexane/AcOEt=1:3, 3fa was given as
a white needle; Rf (hexane/AcOEt=1:3) 0.3; mp 113.5-114.5 °C
(Lit.13 114-115 °C); νmax (neat) 3429, 3379, 3309, 3130, 1593,
1469, 1408 cm-1; δΗ (400 MHz, CDCl3) 4.25 (bs, 2H, N-H), 4.41
(bs, 2H, N-H), 5.99 (d, J 7.8 Hz, 1H, C-H), 7.20 (d, J 7.8 Hz, 1H,
C-H), 7.28-7.31 (m, 1H, C-H), 7.40-7.42 (m, 4H, C-H); δC (100
MHz, CDCl3) 98.4, 111.6, 126.7, 128.8, 128.9, 138.8, 140.1,
154.6, 157.0; m/z (EI) 185 (100, M+), 140 (17), 92 (17), 43
(29%); HRMS (ESI): MH+, found 186.1029. C11H12N3 requires
186.1026.
4.2.10. 2-Amino-3-(4′-bromophenyl)pyridine (3cb). Compound
3cb was prepared from 1c (224 mg, 1.0 mmol) and 2b (1.88 g,
20.0 mmol) according to the general procedure. The excess of 2b
was almost removed by extracted with water. Purification with
column chromatography (inner diameter: 3 cm and length: 30
cm) gave 3cb (92 mg, 0.37 mmol, 37%). Recrystallized from
hexane/AcOEt=9:1, 3cb was given as a white needle; Rf
(hexane/AcOEt=1:2) 0.34; mp 126.0-127.0 °C; νmax (neat) 3433,
3284, 3129, 1631, 1576, 1443, 1071 cm-1; δΗ (400 MHz, CDCl3)
4.54 (bs, 2H, N-H), 6.75 (dd, J 5.0 Hz, J 8.0 Hz, 1H, C-H), 7.33
(d, J 8.0 Hz, 1H, C-H), 7.33 (d, J 8.0 Hz, 2H, C-H), 7.59 (d, J 8.0
Hz, 2H, C-H), 8.08 (dd, J 2.0 Hz, J 5.0 Hz, 1H, C-H); δC (100
MHz, CDCl3) 114.6, 120.6, 121.9, 130.4, 132.3, 137.0, 137.7,
147.7, 155.6; HRMS (ESI): MH+, found 248.9996. C11H1079BrN2
requires 249.0022.
4.2.7.
2,6-Diamino-3-(4
′
-methoxyphenyl)pyridine
(3ga).
4.2.11. 2-Amino-3-(4′-chlorophenyl)-5-methylpyridine (3ac).
Compound 3ga was prepared from 4-methoxyphenylhydrazine
hydrochloride 1g (175 mg, 1.0 mmol) and 2a (2.18 g, 20.0 mmol)
according to the general procedure. The excess of 2a was almost
removed by extracted with water. Purification with column
chromatography (inner diameter: 2 cm and length: 30 cm) gave
3ga (125 mg, 0.58 mmol, 58%). Recrystallized from
hexane/AcOEt=1:3, 3ga was given as a pale yellow solid; Rf
(hexane/AcOEt=1:3) 0.2; mp 129.5-130.5 °C; νmax (neat) 3440,
3327, 3186, 1585, 1477, 1427, 1174 cm-1; δΗ (400 MHz, CDCl3)
3.83 (s, 3H, O-CH3), 4.21 (bs, 2H, N-H), 4.36 (bs, 2H, N-H),
5.98 (d, J 8.0 Hz, 1H, C-H), 6.95 (d, J 8.7 Hz, 2H, C-H), 7.16 (d,
J 8.0 Hz, 1H, C-H), 7.32 (d, J 8.7 Hz, 2H); δC (100 MHz, CDCl3)
55.3, 98.3, 111.3, 114.3, 129.9, 131.0, 140.0, 154.8, 156.7, 158.5;
m/z (EI) 215 (100, M+), 200 (69), 156 (12), 128 (13), 100 (13), 43
(25%); HRMS (ESI): MH+, found 216.1109. C12H14N3O requires
216.1131.
Compound 3ac was prepared from 1a (179 mg, 1.0 mmol) and 2-
amino-5-methylpyridine 2c (2.16 g, 20.0 mmol) according to the
general procedure. Purification with column chromatography
(inner diameter: 2 cm and length: 30 cm) gave 3ac (80 mg, 0.37
mmol, 37%). Recrystallized from hexane/AcOEt=1:1, 3ac was
given as a pale orange solid; Rf (hexane/AcOEt=1:1) 0.44; mp
164.0-165.0 °C; νmax (neat) 3448, 3278, 3130, 1628, 1468, 1089
cm-1; δΗ (400 MHz, CDCl3) 2.23 (s, 3H, -CH3), 4.37 (bs, 2H, N-
H), 7.18 (d, J 2.0 Hz, 1H, C-H), 7.39 (d, J 8.7 Hz, 2H, C-H), 7.43
(d, J 8.7 Hz, 2H, C-H), 7.91 (d, J 2.0 Hz, 1H, C-H); δC (100 MHz,
CDCl3) 17.3, 120.3, 123.5, 129.2, 130.0, 133.6, 136.6, 138.8,
147.2, 153.6; m/z (EI) 218 (73, M+), 217 (100), 182 (34), 91 (19),
44 (80%); HRMS (ESI): MH+, found 219.0655. C12H12ClN2
requires 219.0684.
4.2.12. 2-Amino-5-chloro-3-(4′-chlorophenyl)pyridine (3ad).
Compound 3ad was obtained from 1a (179 mg, 1.0 mmol) and 2-
amino-5-chloropyridine 2d (2.57 g, 20.0 mmol) according to the
general procedure. By the purification with column
chromatography (inner diameter: 5 cm and length: 30 cm), 3ad
(112 mg, 0.47 mmol, 47%) was obtained. Recrystallized from
hexane/AcOEt=1:1, 3ad was given as a pale yellow needle; Rf
(hexane/AcOEt=1:2) 0.76; mp 156.8-157.7 °C (Lit.14 140-
141 °C); νmax (neat) 3450, 3280, 3143, 1624, 1456, 1090, 1011
cm-1. δΗ (400 MHz, CDCl3); 4.54 (bs, 2H, N-H), 7.33 (d, J 2.6 Hz,
1H, C-H), 7.38 (d, J 8.6 Hz, 2H, C-H), 7.45 (d, J 8.6 Hz, 2H, C-
H), 8.03 (d, J 2.6 Hz, 1H, C-H); δC (100 MHz, CDCl3) 121.3,
121.6, 129.5, 129.9, 134.4, 135.2, 137.3, 145.8, 154.1; m/z (EI)
238 (68, M+), 237(100), 202 (41), 168 (27), 140 (31%); HRMS
(ESI): MH+, found 239.0123. C11H9Cl2N2 requires 239.0137.
4.2.8. 2,6-Diamino-3-(4′-tolyl)pyridine (3ha). Compound 3ha
was obtained from 4-methylphenylhydrazine hydrochloride 1h
(159 mg, 1.0 mmol) and 2a (2.18 g, 20.0 mmol) according to the
general procedure. The excess of 2a was almost removed by
extracted with water. Purification with column chromatography
(inner diameter: 2 cm and length: 30 cm) gave 3ha (119 mg, 0.60
mmol, 60%). Recrystallized from hexane/AcOEt=1:3, 3ha was
given as a cream color needle; Rf (hexane/AcOEt=1:3) 0.4; mp
119.5-120.3 °C; νmax (neat) 3464, 3425, 3309, 3111, 1591, 1471,
1419 cm-1. δΗ (400 MHz, CDCl3) 2.38 (s, 3H, -CH3), 4.21 (bs, 2H,
N-H), 4.38 (bs, 2H, N-H), 5.98 (d, J 7.8 Hz, 1H, C-H), 7.18 (d, J
7.8 Hz, 1H, C-H), 7.22 (d, J 8.5 Hz, 2H, C-H), 7.30 (d, J 8.5 Hz,
2H, C-H); δC (100 MHz, CDCl3) 21.1, 98.4, 111.6, 128.6, 129.6,
135.8, 136.4, 140.1, 154.7, 156.8; m/z (EI) 199 (100, M+), 181
(17), 99 (21), 43 (25%); HRMS (ESI): MH+, found 200.1155.
C12H14N3 requires 200.1182.
4.2.13. 2-Amino-5-bromo-3-(4′-chlorophenyl)pyridine (3ae).
Compound 3ae was prepared from 1a (179 mg, 1.0 mmol) and 2-
amino-5-bromopyridine 2e (3.46 g, 20.0 mmol) according to the
general procedure. Purification with column chromatography
(inner diameter: 5 cm and length: 30 cm) gave 3ae (140 mg, 0.49
mmol, 49%). Recrystallized from hexane/AcOEt=1:2, 3ae was
given as a pale orange needle; Rf (hexane/AcOEt=1:2) 0.79; mp
150.0-151.0 °C; νmax (neat) 3454, 3284, 3151, 1620, 1454, 1088,
1011 cm-1; δΗ (400 MHz, CDCl3) 4.59 (bs, 2H, N-H), 7.37 (d, J
8.8 Hz, 2H, C-H), 7.44 (d, J 2.4 Hz, 1H, C-H), 7.48 (d, J 8.8 Hz,
2H, C-H), 8.11 (d, J 2.4 Hz, 1H, C-H); δC (100 MHz, CDCl3)
108.5, 122.2, 129.5, 129.9, 134.4, 135.1, 139.7, 148.0, 154.4; m/z
(EI) 283 (100), 282 (59, M+), 281(76), 202 (52), 168 (45), 140
4.2.9. 2-Amino-3-(4′-chlorophenyl)pyridine (3ab). Compound
3ab was prepared from 1a (179 mg, 1.0 mmol) and 2-
aminopyridine 2b (1.88 g, 20.0 mmol) according to the general
procedure. The excess of 2b was almost removed by extracted
with water. Purification with column chromatography (inner
diameter: 2 cm and length: 30 cm) gave 3ab (74 mg, 0.36 mmol,
36%. Recrystallized from hexane/AcOEt=7:3, 3ab was given as a
white solid; Rf (hexane/AcOEt=1:1) 0.3; mp 121.0-122.0 °C; νmax
(neat) 3437, 3286, 3134, 1631, 1577, 1446, 1090 cm-1; δΗ (400
MHz, CDCl3) 4.54 (bs, 2H, N-H), 6.75 (dd, J 5.0 Hz, J 7.3 Hz,

7
(38), 84 (48%); HRMS (ESI): MH+, found 282.9605.
146.8; HRMS (ESI): MH+, found 205.0501. C11H10ClN2
requires 205.0527.
ACCEPTED MANUSCRIPT
C11H979BrClN2 requires 282.9632.
4.2.14. 2-Amino-3-(4 -chlorophenyl)-5,6-dimethylpyridine (3af).
′
4.2.17. 3-Amino-2-(4
′
-fluorophenyl)pyridine (3bg), 3-Amino-4-
(3bg ), and 3-Amino-2-(4
, and 3bg′′
Compound 3af was prepared from 1a (179 mg, 1.0 mmol) and 2-
amino-5,6-dimethylpyridine 2f (2.44 g, 20.0 mmol) according to
the general procedure. Purification with column chromatography
(inner diameter: 2 cm and length: 30 cm) gave 3af (78 mg, 0.34
mmol, 34%). Recrystallized from hexane/AcOEt=1:1, 3af was
given as a pale orange needle; Rf (hexane/AcOEt=1:1) 0.2; mp
109.5-110.5 °C; νmax (neat) 3483, 3438, 3288, 3156, 1450, 1391,
1092 cm-1; δΗ (400 MHz, CDCl3) 2.18 (s, 3H, -CH3), 2.37 (s, 3H,
-CH3), 4.35 (bs, 2H, N-H), 7.09 (s, 1H, C-H), 7.37 (d, J 8.8 Hz,
2H, C-H), 7.40 (d, J 8.8 Hz, 2H, C-H); δC (100 MHz, CDCl3)
17.9, 21.9, 117.9, 121.5, 129.1, 130.1, 133.3, 136.8, 139.5, 153.0,
154.6; HRMS (ESI): MH+, found 233.0813. C13H14ClN2 requires
233.0840.
(4 -fluorophenyl)pyridine
′
′
′-
fluorophenyl)pyridine (3bg′′). Compounds 3bg, 3bg
′
were synthesized from 1b (163 mg, 1.0 mmol) and 2g (1.88 g,
20.0 mmol) according to the general procedure. Purification with
column chromatography (inner diameter: 3 cm and length: 30
cm) gave 3bg (71 mg, 0.38 mmol, 38%), and 3bg
mmol, 11%), and 3bg′′ (12 mg, 0.06 mmol, 6%). 3-Amino-2-(4
fluorophenyl)pyridine (3bg): Recrystallized from
′ (21 mg, 0.11
′
-
hexane/AcOEt=9:1, 3bg was given as a pale yellow needle; Rf
(hexane/AcOEt=1:3) 0.52; mp 74.4-75.4 °C; νmax (neat) 3393,
3295, 3208, 3055, 1624, 1584, 1509, 1217 cm-1; δΗ (400 MHz,
CDCl3) 3.79 (bs, 2H, N-H), 7.05 (dd, J 1.8 Hz, J 7.8 Hz, 1H, C-
H), 7.08 (dd, J 3.8 Hz, J 7.8 Hz, 1H, C-H), 7.16 (dd, JHF 8.8 Hz, J
8.8 Hz, 2H, C-H), 7.67 (dd, JHF 5.6 Hz, J 8.8 Hz, 2H, C-H), 8.12
(dd, J 1.8 Hz, J 3.8 Hz, 1H, C-H); δC (100 MHz, CDCl3) 115.7
(d, JCF 21.0 Hz), 122.8, 123.1, 130.3 (d, JCF 7.7 Hz), 134.7, 139.9,
140.1, 144.1, 162.9 (d, JCF 246.0 Hz); HRMS (ESI): MH+, found
189.0796. C11H10FN2 requires 189.0823. 3-Amino-4-(4′-
fluorophenyl)pyridine
hexane/AcOEt=9:1, 3bg
(hexane/AcOEt=1:3) 0.12; mp 108.5-109.5 °C; δΗ (400 MHz,
CDCl3) 3.81 (bs, 2H, N-H), 6.99 (d, J 5.2 Hz, 1H, C-H), 7.17 (dd,
JHF 8.8 Hz, J 8.8 Hz, 2H, C-H), 7.44 (dd, JHF 5.2 Hz, J 8.8 Hz,
2H, C-H), 8.05 (d, J 5.2 Hz, 1H, C-H), 8.15 (s, 1H, C-H); δC (100
MHz, CDCl3) 116.1 (d, JCF 21.0 Hz), 124.1, 130.2 (d, JCF 8.6 Hz),
132.6, 132.8, 138.2, 139.7, 140.2, 162.5 (d, JCF 247.0 Hz);
HRMS (ESI): MH+, found 189.0808. C11H10FN2 requires
4.2.15. 2-Amino-3-(4′-fluorophenyl)-5,6-dimethylpyridine (3bf).
Compound 3bf was prepared from 1b (163 mg, 1.0 mmol) and 2f
(2.44 g, 20.0 mmol) according to the general procedure.
Purification with column chromatography (inner diameter: 3 cm
and length: 30 cm) gave 3bf (64 mg, 0.30 mmol, 30%).
Recrystallized from hexane/AcOEt=9:1, 3bf was given as a pale
orange plate crystal; Rf (hexane/AcOEt=1:2) 0.28; mp 109.0-
110.0 °C; νmax (neat) 3480, 3292, 3169, 1454, 1216 cm-1; δΗ (400
MHz, CDCl3) 2.18 (s, 3H, -CH3), 2.38 (s, 3H, -CH3), 4.33 (bs,
2H, N-H), 7.09 (s, 1H, C-H), 7.12 (dd, JHF 8.8 Hz, J 8.8 Hz, 2H,
C-H), 7.40 (dd, JHF 5.4 Hz, J 8.8 Hz, 2H, C-H); δC (100 MHz,
CDCl3) 17.9, 21.9, 115.9 (d, JCF 21.0 Hz), 118.2, 121.4, 130.4 (d,
JCF 7.6 Hz), 134.3, 139.7, 153.1, 154.3, 162.1 (d, JCF 245.1 Hz);
HRMS (ESI): MH+, found 217.1127. C13H14FN2 requires
217.1136.
(3bg
′
):
Recrystallized
from
′ was given as a pale yellow needle; Rf
189.0823.
3-Amino-6-(4
′
-fluorophenyl)pyridine
(3bg′′):
Recrystallized from hexane/AcOEt=9:1, 3bg′′ was given as a
pale orange crystal; Rf (hexane/AcOEt=1:3) 0.40; mp 98.0-
99.5 °C; δΗ (400 MHz, CDCl3) 3.74 (bs, 2H, N-H), 7.04 (dd, J
2.8 Hz, J 8.4 Hz, 1H,C-H), 7.10 (dd, JHF 8.8 Hz, J 8.8 Hz, 2H, C-
H), 7.48 (d, J 8.4 Hz, 1H), 7.86 (dd, JHF 5.6 Hz, J 8.8 Hz, 2H, C-
H), 8.16 (d, J 2.8 Hz, 1H, C-H); δC (100 MHz, CDCl3) 115.4 (d,
JCF 21.0 Hz), 120.4, 122.4, 127.6 (d, JCF 7.7 Hz), 135.7, 137.1,
141.3, 147.2, 162.7 (d, JCF 245.0 Hz); HRMS (ESI): MH+, found
189.0801. C11H10FN2 requires 189.0823.
4.2.16. 3-Amino-2-(4
(4 -chlorophenyl)pyridine
chlorophenyl)pyridine (3ag′′). Compounds 3ag, 3ag
′
-chlorophenyl)pyridine (3ag), 3-Amino-4-
(3ag ), and 3-Amino-6-(4
, and 3ag′′
′
′
′-
′
were synthesized from 1a (179 mg, 1.0 mmol) and 3-
aminopyridine 2g (1.88 g, 20.0 mmol) according to the general
procedure. Purification with column chromatography (inner
diameter: 2 cm and length: 30 cm) gave 3ag (107 mg, 0.52 mmol,
52%), and 3ag
0.08 mmol, 8%). 3-Amino-2-(4
′
(31 mg, 0.15 mmol, 15%), and 3ag′′ (17 mg,
′
-chlorophenyl)pyridine (3ag):
4.2.18. 3-Amino-2-(4
′
-bromophenyl)pyridine (3cg), 3-Amino-4-
(3cg ),and 3-Amino-6-(4
, and 3cg′′
Recrystallized from hexane/AcOEt=1:1, 3ag was given as a pale
yellow needle; Rf (hexane/AcOEt=1:3) 0.64; mp 86.6-87.5 °C;
νmax (neat) 3458, 3309, 3184, 1631, 1579, 1444, 1088 cm-1; δΗ
(400 MHz, CDCl3) 3.80 (bs, 2H, N-H), 7.05 (dd, J 1.8 Hz, J 8.0
Hz, 1H, C-H), 7.08 (dd, J 4.8 Hz, J 8.0 Hz, 1H, C-H), 7.45 (d, J
8.8 Hz, 2H, C-H), 7.64 (d, J 8.8 Hz, 2H, C-H), 8.12 (dd, J 1.8 Hz,
J 4.8 Hz, 1H, C-H); δC (100 MHz, CDCl3) 122.9, 123.3, 129.0,
129.9, 134.1, 137.0, 139.9, 140.1, 143.7; m/z (EI) 203 (100, M+),
168 (45), 84 (22), 41 (47%); HRMS (ESI): MH+, found 205.0504.
(4 -bromophenyl)pyridine
′
′
′-
bromophenyl)pyridine (3cg′′). Compounds 3cg, 3cg
′
were synthesized from 1c (224 mg, 1.0 mmol) and 2g (1.88 g,
20.0 mmol) according to the general procedure. Purification with
column chromatography (inner diameter: 3 cm and length: 30
cm) gave 3cg (117 mg, 0.47 mmol, 47%), and 3cg
mmol, 11%), and 3cg′′ (13 mg, 0.05 mmol, 5%). 3-Amino-2-
(4 -bromophenyl)pyridine (3cg): Recrystallized from
′ (27 mg, 0.11
′
hexane/AcOEt=9:1, 3cg was given as a pale yellow solid; Rf
(hexane/AcOEt=1:3) 0.60; mp 98.0-99.0 °C (Lit.15 99-101 °C);
νmax (neat) 3467, 3313, 3183, 1633, 1579, 1445, 1075 cm-1. δΗ
(400 MHz, CDCl3); 3.80 (bs, 2H, N-H), 7.05 (dd, J 2.0 Hz, J 8.0
Hz, 1H, C-H), 7.08 (dd, J 4.0 Hz, J 8.0 Hz, 1H, C-H), 7.58 (d, J
8.8 Hz, 2H, C-H), 7.61 (d, J 8.8 Hz, 2H, C-H), 8.13 (dd, J 2.0 Hz,
J 4.0 Hz, 1H, C-H); δC (100 MHz, CDCl3) 122.4, 122.9, 123.3,
130.2, 131.9, 137.5, 139.9, 140.2, 143.7; HRMS (ESI): MH+,
found 249.0016. C11H1079BrN2 requires 249.0022. 3-Amino-4-
C11H10ClN2 requires 205.0527. 3-Amino-4-(4
′-chlorophenyl)-
pyridine (3ag ): Recrystallized from hexane/AcOEt=9:1, 3ag
′
′
was given as a brown needle; Rf (hexane/AcOEt=1:3) 0.16; mp
146.5-147.5 °C; δΗ (400 MHz, CDCl3); 3.77 (bs, 2H, N-H), 7.00
(d, J 5.0 Hz, 1H, C-H), 7.41 (d, J 8.6 Hz, 2H, C-H), 7.46 (d, J 8.6
Hz, 2H, C-H), 8.07 (d, J 5.0 Hz, 1H, C-H), 8.16 (s,1H, C-H); δC
(100 MHz, CDCl3) 123.9, 129.3, 129.8, 132.3, 134.3, 135.3,
138.3, 139.6, 140.3; HRMS (ESI): MH+, found 205.0509.
C11H10ClN2 requires 205.0527. 3-Amino-6-(4′-chlorophenyl)-
(4
′
-bromophenyl)pyridine
(3cg
′
):
Recrystallized
from
pyridine (3ag′′): Recrystallized from hexane/AcOEt=9:1, 3ag′′
was given as a brown solid; mp 96.5-98.2 °C; δΗ (400 MHz,
CDCl3) 3.77 (bs, 2H, N-H), 7.05 (dd, J 3.1 Hz, J 8.3 Hz, 1H, C-
H), 7.39 (d, J 8.6 Hz, 2H, C-H), 7.51 (d, J 8.3 Hz, 1H, C-H), 7.83
(d, J 8.6 Hz, 2H, C-H), 8.17 (d, J 3.1 Hz, 1H, C-H); δC (100 MHz,
CDCl3) 120.6, 122.2, 127.2, 128.7, 133.6, 137.2, 137.9, 141.5,
hexane/AcOEt=9:1, 3cg
′
was given as a pale orange solid; Rf
(hexane/AcOEt=1:3) 0.14; mp 159.0-160.5 °C; δΗ (400 MHz,
CDCl3); 3.80 (bs, 2H, N-H), 6.99 (d, J 4.8 Hz, 1H, C-H), 7.35 (d,
J 8.6 Hz, 2H, C-H), 7.61 (d, J 8.6 Hz, 2H, C-H), 8.06 (d, J 4.8 Hz,
1H, C-H), 8.15 (s, 1H, C-H); δC (100 MHz, CDCl3) 122.4, 123.8,
130.1, 132.3, 135.7, 138.3, 139.5, 140.2; HRMS (ESI): MH+,

8
Tetrahedron
found 248.9995. C11H1079BrN2 requires 249.0022. 3-Amino-6-
4.3. A larger-scale synthesis of 3aa
ACCEPTED MANUSCRIPT
(4
′
-bromophenyl)pyridine
(3cg′′):
Recrystallized
from
Compound 3aa was prepared from a mixture of 4-
chlorophenylhydrazine hydrochloride 1a (3.58 g, 20.0 mmol),
2,6-diaminopyridine 2a (43.65 g, 400 mmol) and potassium
carbonate (8.29 g, 60.0 mmol) in DMSO (200 mL), according
to the general procedure. The reaction was completed after 24
h, monitored by thin layer chromatography (TLC). Then,
quenched by the addition of water, the reaction mixture was
extracted with ethyl acetate. The excess of 2a was isolated in
almost 90% yield by extracted with water. The organic layer
was washed with water and brine solution, and dried over
anhydrous MgSO4. The solvent was removed under reduced
pressure to give a crude product. Purified by column
chromatography (inner diameter: 5 cm and length: 30 cm)
over silica gel (hexane/AcOEt=1:4), the pure product 3aa
(3.54g, 81%) was afforded.
hexane/AcOEt=9:1, 3cg′′ was given as a pale orange block
crystal; Rf (hexane/AcOEt=1:3) 0.42; mp 133.0-134.0 °C; δΗ
(400 MHz, CDCl3) 3.78 (bs, 2H, N-H), 7.03 (dd, J 2.8 Hz, J 8.6
Hz, 1H, C-H), 7.50 (d, J 8.6 Hz, 1H, C-H), 7.53 (d, J 8.8 Hz, 2H,
C-H), 7.77 (d, J 8.8 Hz, 2H, C-H), 8.15 (d, J 2.8 Hz, 1H, C-H);
δC (100 MHz, CDCl3) 120.5, 121.8, 122.2, 127.5, 131.7, 137.2,
138.4, 141.6, 146.7; HRMS (ESI): MH+, found 249.0001.
C11H1079BrN2 requires 249.0022.
4.2.19. 3-Amino-4-(4
Amino-2-(4 -chlorophenyl)quinoline (3ah
3ah were synthesized from 1a (179 mg, 1.0 mmol) and 3-
′
-chlorophenyl)quinoline (3ah) and 3-
′
′
). Compounds 3ah and
′
aminoquinoline 2h (2.88 g, 20.0 mmol) according to the general
procedure. Purification with column chromatography (inner
diameter: 5 cm and length: 30 cm) gave 3ah (189 mg, 0.74 mmol,
74%) and 3ah′ (22 mg, 0.09 mmol, 9%). 3-Amino-4-(4′-
chlorophenyl)quinoline (3ah): Recrystallized from AcOEt, 3ah
was given as a pale yellow needle; Rf (hexane/AcOEt=1:1) 0.24;
mp 217.5-218.5 °C; νmax (neat) 3448, 3289, 3178, 1625, 1581,
1479, 1380, 1347, 1085 cm-1; δΗ (400 MHz, DMSO-d6) 5.23 (bs,
2H, N-H), 7.15 (dd, J 1.6 Hz, J 7.6 Hz, 1H, C-H), 7.31-7.36 (m,
2H, C-H), 7.35 (d, J 8.2 Hz, 2H, C-H), 7.63 (d, J 8.2 Hz, 2H, C-
H), 7.84 (dd, J 1.6 Hz, J 7.6 Hz, 1H, C-H), 8.59 (s, 1H, C-H); δC
(100 MHz, DMSO-d6) 120.9, 122.8, 123.9, 126.7, 127.8, 129.0,
129.3, 132.0, 132.6, 133.4, 138.8, 141.1, 143.7; HRMS (ESI):
MH+, found 255.0666. C15H12ClN2 requires 255.0684. 3-Amino-
4.4. Radical-trapping experiment with TEMPO (4a)
To a mixture of 4-chlorophenylhydrazine hydrochloride (1a,
895 mg, 5.0 mmol) and TEMPO (1.17 g, 7.5 mmol) in DMSO
(50 mL), potassium carbonate (2.07 g, 15.0 mmol) was added.
The solution was stirred at room temperature in air for 24 h. The
resulting solution was quenched by the addition of water and
extracted with ethyl acetate. The organic layer was washed with
water and brine solution, and dried over anhydrous MgSO4. The
solvent was removed under reduced pressure to give a crude
product. Purification by column chromatography over silica gel
using hexane, 4-chloro-1-(2,2,6,6-tetramethylpiperidinyloxy)-
benzene (4a) (380 mg, 1.42 mmol, 28%) was afforded.
Recrystallized from hexane, 4a was given as a colorless plate
crystal; Rf (hexane) 0.62; mp 89.5-90.5 °C; νmax (neat) 2977,
2925, 1585, 1480, 827 cm-1; δΗ (400 MHz, CDCl3) 0.99 (s, 6H, -
CH3), 1.21 (s, 6H, -CH3), 1.38-1.44 (m, 1H, CH2), 1.53-1.68 (m,
5H, CH2), 7.11 (d, J 9.4 Hz, 2H, C-H), 7.15 (d, J 9.4 Hz, 2H, C-
H); δC (100 MHz, CDCl3) 17.0, 20.4, 32.5, 39.7, 60.4, 115.2,
124.3, 128.5, 162.2; HRMS (DART): MH+ found 268.1462.
C15H23ClNO requires 268.1463.
2-(4
3ah
′
-chlorophenyl)quinoline (3ah
was given as a yellow solid; Rf (hexane/AcOEt=1:1) 0.74;
′): Recrystallized from AcOEt,
′
δΗ (400 MHz, DMSO-d6) 5.32 (bs, 2H, N-H), 7.34-7.42 (m, 2H,
C-H), 7.41 (s, 1H, C-H), 7.57 (d, J 8.4 Hz, 2H, C-H), 7.65 (dd, J
1.6 Hz, J 7.6 Hz, 1H, C-H), 7.78 (d, J 8.4 Hz, 2H, C-H), 7.79-
7.81 (m, 1H, C-H); δC (100 MHz, DMSO-d6) 114.8, 124.7, 125.2,
126.6, 128.5, 128.6, 129.1, 130.5, 133.1, 137.5, 140.1, 141.3,
148.4; HRMS (ESI): MH+, found 255.0655. C15H12ClN2 requires
255.0684.
4.2.20. 2-Amino-3-(4′-chlorophenyl)pyrazine (3aj). Compound
3aj was prepared from 1a (179 mg, 1.0 mmol) and 2-
aminopyrazine 2j (1.90 g, 20.0 mmol) according to the general
procedure. Purification with column chromatography (inner
diameter: 2 cm and length: 30 cm) gave 3aj (116 mg, 0.56 mmol,
56%). Recrystallized from hexane/AcOEt=9:1, 3aj was given as
a color less needle; Rf (hexane/AcOEt=1:2) 0.52; mp 125.5-
126.5 °C; νmax (neat) 3303, 3153, 1643, 1525, 1433, 1088 cm-1;
δΗ (400 MHz, CDCl3) 4.76 (bs, 2H, N-H), 7.48 (d, J 8.4 Hz, 2H,
C-H), 7.68 (d, J 8.4 Hz, 2H, C-H), 7.99 (d, J 2.6 Hz, 1H, C-H),
8.03 (d, J 2.6 Hz, 1H, C-H); δC (100 MHz, CDCl3) 129.3, 129.5,
134.7, 135.1, 135.6, 139.6, 141.3, 152.2 ; m/z (EI) 205 (97, M+),
170 (38), 151 (23), 137 (30), 42 (100), 41 (97%); HRMS (ESI):
MH+, found 206.0455. C10H9ClN3 requires 206.0480.
Acknowledgments
We wish to thank Dr. Toshiyuki Iwai (Osaka Municipal
Technical Research Institute) for HRMS spectroscopic
assistance.
Supplementary data
1H-NMR, 13C-NMR spectra, and details of density functional
theory (DFT) calculations.
4.2.21.
2-Amino-5-(4′-chlorophenyl)-4,6-dimethylpyrimidine
References
(3ak). Compound 3ak was given from 1a (179 mg, 1.0 mmol)
and 2-amino-4,6-dimethylpyrimidine 2k (2.46 g, 20.0 mmol)
according to the general procedure. By the purification with
column chromatography (inner diameter: 2 cm and length: 30
cm), 3ak (45 mg, 0.19 mmol, 19%) was given. Recrystallized
from hexane/AcOEt=1:1, 3ak was given as a white solid; Rf
(hexane/AcOEt=1:4) 0.30; mp 204.7-205.5 °C; νmax (neat) 3307,
3186, 1626, 1545, 1466, 1090 cm-1; δΗ (400 MHz, CDCl3) 2.09 (s,
6H, -CH3), 4.99 (bs, 2H, N-H), 7.09 (d, J 8.6 Hz, 2H, C-H), 7.41
(d, J 8.6 Hz, 2H, C-H); δC (100 MHz, CDCl3) 22.8, 123.4, 129.0,
131.1, 133.5, 136.0, 161.3, 165.5; m/z (EI) 233 (100, M+), 197
(17), 115 (46), 42 (69%); HRMS (ESI): MH+, found 234.0768.
C12H13ClN3 requires 234.0793.
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