Microwave-promoted synthesis of amino-substituted 2-pyridone derivatives via palladium-catalyzed amination reaction

Article abstract of DOI:10.1016/j.tetlet.2005.04.141

A rapid and efficient synthesis of amino-substituted 2-pyridones was demonstrated by palladium-catalyzed amination reaction under microwave irradiation. This high-speed synthesis provided a number of amino-substituted 2-pyridones from the corresponding bromo-2-benzyloxypyridines via palladium-catalyzed amination followed by hydrogenolysis of benzyl ether.

Full text of DOI:10.1016/j.tetlet.2005.04.141

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 4621–4625
Microwave-promoted synthesis of amino-substituted
2-pyridone derivatives via palladium-catalyzed amination reaction
Jung-Nyoung Heo,* Young Seob Song and Bum Tae Kim
Bioorganic Science Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, South Korea
Received 10 March 2005; revised 20 April 2005; accepted 28 April 2005
Available online 23 May 2005
Abstract—A rapid and efficient synthesis of amino-substituted 2-pyridones was demonstrated by palladium-catalyzed amination
reaction under microwave irradiation. This high-speed synthesis provided a number of amino-substituted 2-pyridones from the cor-
responding bromo-2-benzyloxypyridines via palladium-catalyzed amination followed by hydrogenolysis of benzyl ether.
Ó 2005 Elsevier Ltd. All rights reserved.
A rapid and efficient synthesis of novel building blocks is
still on tremendous demands in pharmaceutical and
agrochemical research areas. In recent years, amino-
substituted 2-pyridones have attracted attention due to
their promising features as an important core structure
for the development of biologically active molecules.1
Pharmaceuticals with the 2-pyridone skeleton have
emerged as antitumor,2 antifungal,3 antibacterial,4 anti-
viral,5 and antithrombotic6 agents. Although many syn-
thetic methods for the preparation of aminopyridine
derivatives have been reported, there is still rare for
the common preparation of amino-substituted 2-pyri-
dones.7 Therefore we envisioned that the palladium-cata-
lyzed amination of bromopyridine with microwave
irradiation would be utilized as a key step for the synthe-
sis of amino-substituted 2-pyridones.8,9 This microwave-
promoted heating technology has become a powerful
tool for the high-speed synthesis of novel chemical enti-
ties.10 Many synthetic efforts using microwave were
extensively focused on the amination of aryl bromides,
chlorides, or triflates in the presence of a palladium cata-
lyst.11 Herein, we describe a convenient and efficient
synthesis of a series of amino-substituted 2-pyridones
via microwave-promoted palladium-catalyzed amina-
tion of 5- or 6-bromo-2-benzyloxypyridines followed
by hydrogenolysis of benzyl ether.
The prerequisite 5- or 6-bromo-2-benzyloxypyridines
were prepared by simple modifications of previous litera-
ture methods (Scheme 1). Selective O-benzylation was
accomplished by the reaction of 5-bromo-2-pyridone 1
with benzyl bromide in the presence of silver carbonate
in a dark to provide 2-benzyloxy-5-bromopyridine 2.12
On the other hand, 2-benzyloxy-6-bromopyridine 4
was easily obtained from 2,6-dibromopyridine 3 via
mono-nucleophilic substitution with sodium benzyl-
oxide in high yield.13
With bromopyridines in hand, we first carried out pal-
ladium-catalyzed amination of 2 with morpholine
under microwave irradiation using conditions devel-
oped by Buchwald (Pd2(dba)3, ( )-2,20-bis(diphenyl-
phosphino)-1,10-binaphthyl (BINAP), NaO-t-Bu, and
toluene).14 It is well-known that the use of bis-
(phosphine) ligand such as BINAP is essential for
the success of aminations of bromopyridines due to
the formation of pyridine–palladium complexes.14a
Br
Br
BnBr
Ag2CO3
C6H6
O
N
BnO
BnO
N
N
H
87%
1
2
BnOH, NaH
THF
78%
Br
N
Br
Br
Keywords: 2-Pyridone; Aminopyridine; Palladium-catalyzed amina-
tion; Microwave irradiation; Buchwald–Hartwig amination.
3
4
*
Corresponding author. Tel.: +82 42 860 7085; fax: +82 42 861
0307; e-mail: heojn@krict.re.kr
Scheme 1.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.04.141

4622
J.-N. Heo et al. / Tetrahedron Letters 46 (2005) 4621–4625
Table 1. Palladium-catalyzed amination of 2-benzyloxy-5-bromopyridine with morpholinea
HN
O
O
Br
N
+
Pd, BINAP
NaOt-Bu
toluene
BnO
N
BnO
N
BnO
N
Microwave
2
5a
6
Entry
Pd source
Ligandf
Base
Temperature (°C)
Time (min)
Yield of 5ab (%)
1
Pd2(dba)3
Pd2(dba)3
Pd(OAc)2
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd(OAc)2
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
BINAP
BINAP
BINAP
BINAP
BINAP
BINAP
BINAP
BINAP
BINAP
A
NaO-t-Bu
NaO-t-Bu
NaO-t-Bu
NaO-t-Bu
NaO-t-Bu
NaO-t-Bu
NaO-t-Bu
NaO-t-Bu
NaO-t-Bu
NaO-t-Bu
NaO-t-Bu
NaO-t-Bu
NaO-t-Bu
Cs2CO3
150
150
150
130
130
120
80e
10
5
65c
80
2
3
5
50c
81
4
10
5
5
73d
6
10
18 h
10
10
10
10
10
10
10
10
10
10
89
7
89
8
120
110
120
120
120
120
120
120
120
120
49d
69d
90
9
10
11
12
13
14
15
16
17
B
52d
12d
14d
15d
23d
14d
11d
C
D
BINAP
A
Cs2CO3
K2CO3
K3PO4
A
A
a Reaction conditions: Pd (1 mol %), ligand (1.5 mol %), bromopyridine 2 (1 mmol), morpholine (1.2 mmol), base (1.4 mmol), toluene (3 mL).
b Isolated yield.
c Debrominated by-product 6 was detected (entry 3; 25%).
d Starting material 2 remained (entry 5; 7%).
e The reaction was performed under conventional oil-bath heating.
f Used ligands.
Ph2P
PPh2
PCy2
P(t-Bu)2
PPh2
PPh2
O
PPh2 Me2N
Fe
PPh2
C
D
BINAP
A
B
As summarized in Table 1, microwave reaction in a
sealed tube at 150 °C for 10 min provided the desired
aminopyridine 5a in 65% yield along with debromi-
nated by-product 6 (entry 1). When carried out at
150 °C for 5 min, the reaction afforded the desired
product in better yield (entry 2). As an alternative pal-
ladium source, the use of Pd(OAc)2 under the same
reaction conditions gave 5a in 50% yield and the
debrominated by-product 6 in 25% yield (entry 3).
Based on these observations, Pd2(dba)3 is superior to
Pd(OAc)2 as the palladium source for the micro-
wave-promoted amination reaction. To optimize
microwave heating temperature, we continued to
examine reactions at various temperatures and reac-
tion times (entries 4–9). Decreasing reaction tempera-
ture to 130 °C for 10 min also gave 5a in good
yield (entry 4). However, shortening microwave expo-
sure to 5 min at the same temperature resulted in low-
er yield (73%) due to the incompletion of the reaction
(entry 5). When the reaction was run at 120 °C for
10 min, the best result was obtained to provide 5a in
89% yield with all consumption of starting material
(entry 6). This result was compatible with that of
the conventional oil-bath heating conditions (entry
7). Further decreasing the reaction temperature to
110 °C led to lower yield due to incompletion of the
reaction (entry 9). It is noteworthy that finely con-
trolled reaction temperature and time (120 °C,
10 min) are critical factors for high yielding of the
Pd-catalyzed amination of bromopyridine 2 under
microwave irradiation.
Next, we examined several phosphine ligands and bases
using the selected Pd-catalyst/temperature/time set. Of
five phosphine ligands screened, BINAP and amino-
phosphine ligand A gave the best results (entries 6 and
10), while the reactions employing other ligands (B, C,
and D) were incomplete (Table 1, entries 10–13). Base
effects using Cs2CO3, K2CO3, or K3PO4 were clearly
showed that the reaction progress became very slow
and starting bromopyridne 2 remained significantly
(Table 1, entries 14–17). Consequently, the optimum
reaction set for the palladium catalyzed amination of
bromopyridine is Pd2(dba)3, BINAP or ligand A,
NaO-t-Bu at 120 °C for 10 min.
With the optimized conditions, we investigated the
Pd-catalyzed amination of bromopyridine
2 with

J.-N. Heo et al. / Tetrahedron Letters 46 (2005) 4621–4625
4623
various amines to obtain amino-substituted pyridines
5. The results are listed in Table 2.15 In cases of cyclic
secondary amines, amino-substituted pyridines 5a–f
were obtained in good to high isolated yields (entries
1–6). Aminations with aniline derivatives using BI-
NAP or aminophosphine ligand A also furnished
aminopyridines 5g–i in good yields (entries 7–9). When
aliphatic primary amines were used, the reactions were
less effective, probably due to their ability of b-hydride
elimination and dipyridinyl amination (entries 10–
11).14a,16 Finally, catalytic debenzylation of amino-
substituted pyridines 5 was easily accomplished to pro-
vide the corresponding 2-pyridones 7a–k in high yields
(Table 2).
lined in Table 3, amination with cyclic secondary
amines gave satisfactory results (entries 1–4). In cases
of anilines and primary amines, amination was less
effective and gave aminopyridines 8e–h in moderate
to good yields (entries 5–8). Then, catalytic debenzyla-
tion of aminopyridines 8a–h was easily achieved to af-
ford the corresponding 2-pyridones 9a–h in high yields
(Table 3).
In summary, we successfully demonstrated the simple
and rapid synthesis of amino-substituted 2-pyridone
derivatives using palladium-catalyzed amination under
microwave irradiation. Such high-speed construction
of 2-pyridone derivatives can be utilized to the discovery
of useful pharmaceuticals. Further applications of palla-
dium-catalyzed amination for the construction of novel
building blocks are under investigation in our
laboratory.
Further explorations of amination of 2-benzyloxy-6-
bromopyridine 4 with some representative amines were
carried out using the standard set developed. As out-
Table 2. Palladium-catalyzed amination of bromopyridine 2a followed by hydrogenationb
NR1R2
Br
NR1R2
HNR1R2
H2, Pd/C
Pd, ligand
NaOt-Bu
toluene
MeOH/EtOAc
rt , 4 h
O
N
H
BnO
N
BnO
N
2
5
7
µwave, 120 ˚C, 10 min
Entry
1
Amine
Ligand
Yield of 5c (%)
2-Pyridone
Yield of 7c (%)
A
90
92
O
N
O
7a
HN
O
HN
N
O
2
3
4
BINAP
BINAP
BINAP
88
69
73
7b
91
92
86
HN
HN
HN
HN
HN
HN
O
N
7c
HN
O
O
O
7d
O
N
N
O
HN
N CH3 7e
O
O
5
6
BINAP
BINAP
85
88
95
91
N CH3
O
HN
7f
N
N
O
O
N
O
HN
H
N
CH3
N
7
8
BINAP
72
89
7g
92
90
H3C
O
HN
CH3
H2N
H2N
CH3
H
N
A
7h
7i
O
HN
H
N
O
F
9
A
78
95
HN
F
N
O
7j
NH
O
10
11
A
A
71
60
89
90
O
H2N
H2N
N
HN
H
N
(n-C6H13
)
O
7k
HN
a Reaction conditions: Pd2(dba)3 (1 mol %), ligand (1.5 mol %), bromopyridine 2 (1 mmol), amine (1.2 mmol), NaO-t-Bu (1.4 mmol), toluene (3 mL),
120 °C, 10 min.
b Reaction conditions: H2 (30–40 psi), 10% Pd/C (10 wt %), MeOH–EtOAc (2:1), 4 h.
c Isolated yield.

4624
J.-N. Heo et al. / Tetrahedron Letters 46 (2005) 4621–4625
Table 3. Palladium-catalyzed amination of bromopyridine 4a followed by hydrogenationb
HNR1R2
H2, Pd/C
NR1R2
Pd, ligand
NaOt-Bu
toluene
MeOH/EtOAc
rt , 4 h
O
N
BnO
N
Br
BnO
N
NR1R2
H
4
8
9
µwave, 120 ˚C, 10 min
Entry
1
Amine
Ligand
BINAP
Yield of 8c (%)
2-Pyridone
Yield of 9c (%)
N
O
80
95
HN
O
9a
NH
O
N
2
3
4
5
BINAP
BINAP
BINAP
A
87
92
80
75
9b
97
92
95
97
HN
HN
HN
NH
O
N
9c
NH
O
N
N CH3
9d
N CH3
NH
O
CH3
H
N
N
9e
H3C
NH
NH
O
O
H
N
H2N
F
6
A
92
9f
95
F
H
N
N
7
8
A
A
67d
65
9g
80
85
O
H2N
H2N
N
NH
NH
O
O
O
H
N
n-C6H13
9h
a Reaction conditions: Pd2(dba)3 (1 mol %), ligand (1.5 mol %), bromopyridine 4 (1 mmol), amine (1.2 mmol), NaO-t-Bu (1.4 mmol), toluene (3 mL),
120 °C, 10 min.
b Reaction conditions: H2 (30–40 psi), 10% Pd/C (10 wt %), MeOH–EtOAc (2:1), 4 h.
c Isolated yield.
d Dipyridinyl amine was detected by HPLC/MS (9%).
Gleeson, J.-P. R., III; Sakata, S. K.; Chen, L.; Guzman,
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Acknowledgements
We thank the Center for Biological Modulators (CBM2-
A100-001) for the support of this work.
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amine (1.2 mmol), and NaO-t-Bu (1.4 mmol) sequentially.
The mixture was dissolved in toluene (3 mL) and degassed
with argon over 5 min. Then, the reaction vial was sealed
and placed in the microwave reactor and irradiated at
120 °C for 10 min. After cooled to rt, the mixture was
diluted with EtOAc and filtered through a short Celite
pad. The solution was concentrated in vacuo and the
residue was purified by silica gel flash column chromato-
graphy with EtOAc/hexanes as eluents to give aminopyri-
dine 5. Spectral data for 5a: 1H NMR (500 MHz, CDCl3):
d 7.79 (d, 1H, J = 2.9 Hz), 7.46–7.28 (m, 6H), 6.76 (d, 1H,
J = 8.9 Hz), 5.33 (s, 2H), 3.87 (t, 4H, J = 4.7 Hz), 3.06 (t,
4H, J = 4.7 Hz); 13C NMR (125 MHz, CDCl3): d 158.4,
142.5, 137.6, 134.2, 129.2, 128.4, 127.9, 127.7, 111.2, 67.6,
66.9, 50.5; MS (EI) m/z M+ for C16H18N2O2 Calcd 270.14.
Found 270.2 (9), 179.1 (21), 124.1 (17), 90.9 (100).
To a solution of aminopyridine 5 (1 mmol) in MeOH
(4 mL) and EtOAc (2 mL) was added 10% Pd/C (10 wt %).
The mixture was stirred for 4 h under hydrogen pressure
(30–40 psi) and filtered through a short Celite pad. The
solution was concentrated in vacuo and the residue was
purified by silica gel flash column chromatography with
MeOH/CHCl3 as eluents to give 2-pyridone 7. Spectral
data for 7a: 1H NMR (500 MHz, CDCl3): d 7.40 (dd, 1H,
J = 9.7, 3.1 Hz), 6.87 (d, 1H, J = 3.1Hz), 6.59 (d, 1H,
J = 9.8 Hz), 3.83 (t, 4H, J = 4.6 Hz), 2.88 (t, 4H, 4.7 Hz);
13C NMR (125 MHz, CDCl3): d 163.1, 137.5, 135.0, 120.7,
120.2, 66.7, 51.0; MS (EI) m/z M+ for C9H12N2O2 Calcd
180.09. Found 179.8 (23), 121.9 (48), 121.0 (49), 93.2 (29),
67.2 (25), 43.1 (100).
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15. General procedure: All amination reactions were con-
ducted by using Biotage Initiator EXPTM microwave
reactor. To a thick-well borosilicate glass vial (5 mL)
was added bromopyridine (1 mmol), Pd2(dba)3 (1 mol %),
BINAP (1.5 mol %) or aminophosphine A (1.5 mol %),
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