One-pot synthesis of fused 2-pyridones from heteroarylacrylic acid via curtius rearrangement & microwave-assisted thermal electrocyclization

Article abstract of DOI:10.3987/COM-16-S(S)13

We investigated the one-pot synthesis of several fused 2-pyridone ring systems based on a Curtius rearrangement, followed by a microwave-assisted thermal electrocyclization of a 2-aza-6?-electron system including isocyanate. We synthesized seven heterocyclic compounds containing a fused 2-pyridone ring. In these results, the one-pot synthesis of fused 2-pyridone ring system 5 from (E)-acrylic acids 1 under microwave irradiation conditions was more effective than the conventional reaction conditions in terms of the yield and the reaction time.

Full text of DOI:10.3987/COM-16-S(S)13

HETEROCYCLES, Vol. 95, No. 1, 2017
251
HETEROCYCLES, Vol. 95, No. 1, 2017, pp. 251-267. © 2017 The Japan Institute of Heterocyclic Chemistry
Received, 1st July, 2016, Accepted, 9th August, 2016, Published online, 19th October, 2016
DOI: 10.3987/COM-16-S(S)13
ONE-POT
SYNTHESIS
OF
FUSED
2-PYRIDONES
FROM
HETEROARYLACRYLIC ACID VIA CURTIUS REARRANGEMENT
AND MICROWAVE-ASSISTED THERMAL ELECTROCYCLIZATION
Takashi Nishiyama,a Noriyuki Hatae,b Kaori Hayashi,a Manami Obata,a
Kimiko Taninaka,a Masahiro Yamane,a Shota Oda,a Takumi Abe,b Minoru
Ishikura,b Satoshi Hibino,a and Tominari Choshia*
aGraduate School of Pharmacy Pharmaceutical Sciences, Faculty of Pharmacy and
Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima 729-0292,
b
Japan Faculty of Pharmaceutical Sciences, Health Sciences University of
Hokkaido, Ishikari-Tobetsu, Hokkaido 061-0293, Japan
E-mail: choshi@fupharm.fukuyama-u.ac.jp
We dedicate this paper to Professor Dr. Masakatsu Shibasaki on the celebration of
his 70th birthday.
Abstract – We investigated the one-pot synthesis of several fused 2-pyridone ring
systems based on a Curtius rearrangement, followed by a microwave-assisted
thermal electrocyclization of a 2-aza-6π-electron system including isocyanate. We
synthesized seven heterocyclic compounds containing a fused 2-pyridone ring. In
these results, the one-pot synthesis of fused 2-pyridone ring system 5 from
(E)-acrylic acids 1 under microwave irradiation conditions was more effective
than the conventional reaction conditions in terms of the yield and the reaction
time.
INTRODUCTION
Fused pyridines are emerging as useful pharmacophores in the synthetic studies of biologically active
compounds.1–3 We are interested in the synthesis of biologically active fused heterocyclic compounds,
including natural products, based on a thermal electrocyclization of either hexatriene or azahexatriene
systems incorporating a principal aromatic or heteroaromatic moiety.

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HETEROCYCLES, Vol. 95, No. 1, 2017
Eloy's pyrido-annelation
O
O
SOCl2
NaN3
X
OH
Hetero
Ar
Hetero
Ar
or
X=Cl, OCO2Et
ClCO2Et
Et3N
1
2
O
Bu3N
N3
Hetero
Ar
Hetero
Ar
Hetero
Ar
solvent
NH
N
C
230−240 °C
O
O
3
4
5
Scheme 1
In 1970, Eloy and co-workers reported the synthesis of fused pyridones 5 from acyl azide 3 via a Curtius
rearrangement, followed by thermal electrocyclization (Scheme 1).4 Thereafter, several researchers have
reported the synthesis of biologically active compounds containing a fused heterocyclic ring, using
modified Eloy’s pyrido-annelation.1,3 Conventionally, the isocyanates 4 were generated by thermal
decomposition of the acyl azides 3, which were obtained from acyl chloride 2 or acid anhydride 2 with
sodium azide, via Curtius rearrangement.4 Conversely, we focus on the direct conversion of isocyanates
obtained by heating the carboxylic acids in the presence of diphenylphosphoryl azide (DPPA) via Curtius
rearrangement, which was developed by Shioiri and co-workers.5 Therefore, we investigated the synthesis
of fused 2-pyridone ring systems 8 based on a thermal electrocyclization of an 2-aza-6π-electron system 7
including an isocyanate. The isocyanate 7 was generated from 6 using Shioiri’s reaction (Scheme 2). So
far, we have achieved the synthesis of PhIP and DMIP having an imidazo[4,5-b]pyridine,6 grossularines
having an α-carboline,7 and imiquimod having an imidazo[4,5-c]quinolone8 using a thermal
electrocyclization of a 2-aza-6π-electron system involving an isocyanate.
R2
R2
R2
N
DPPA
Et3N
R1
O
R1
R1
O
Δ
Hetero
Ar
Hetero
Ar
Hetero
Ar
C
N
H
solvent
CO2H
7
6
8
NMe2
NH
NH2
N
N
N
Me
N
R
O
N
NH2
Me
N
N
N
N
R
H
grossuraline 1: R=indol-3-yl
grossuraline 2: R=4-hydroxyphenyl
Me
PhIP: R=Ph
DMIP: R=Me
imiquimod
Scheme 2

HETEROCYCLES, Vol. 95, No. 1, 2017
253
Recently, it has been established that microwave (µW) irradiation facilitates unique chemical processes
with special attributes such as enhanced reaction rates, higher yields, greater selectivity, and ease of
manipulation. We have recently reported the construction of several fused 2-pyridone ring systems, such
as furo[3,2-h]isoquinoline,9 phenanthridine,10 benzo[c]phenanthridine,11 azaanthraquinone,12 β-carboline,13
and pyrano[2,3,4-ij]isoquinoline alkaloids,14 using a microwave-assisted thermal electrocyclization of a
1-aza-6π-electron system. In addition, we have reported the total synthesis of isocryptolepine by a
one-pot synthesis of an indolo[3,2-c]quinolone ring system based on a Curtius rearrangement followed by
microwave-assisted thermal electrocyclization of 2-aza-6π-electron system.15
O
µW (−) or (+)
DPPA
Et3N
OH
Δ
Hetero
Ar
Hetero
Ar
Hetero
Ar
NH
N
solvent
C
O
O
1
4
5
Scheme 3
In the present work, we describe the one-pot synthesis of various fused pyridine ring systems 5 based on a
Curtius rearrangement followed by microwave-assisted thermal electrocyclization of
a
a
2-aza-6π-electron system 4 including isocyanate, and the results are compared with those performed
using a conventional method (Scheme 3).
RESULTS AND DISCUSSION
We planned to synthesize fused heteroaromatic compounds using the proposed method. The key
isocyanate intermediate was prepared from a 3-heteroarylacrylic acid by Curtius rearrangement, using
Shioiri’s condition. We selected six heterocyclic compounds such as furan, pyrrole, thiophene,
benzofuran, benzothiophene, and indole as the aromatic heterocycles. Wittig reaction of the known
heteroarylcarbaldehyde
with
(ethoxycarbonylmethylidene)triphenylphosphorane
afforded
the
(E)-heteroarylacrylate 9a–g.16 Subsequent hydrolysis of the (E)-heteroarylacrylate 9a–g with 20%
aqueous NaOH in MeOH gave the (E)-acrylic acid 1a–g (Table 1).

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HETEROCYCLES, Vol. 95, No. 1, 2017
Table 1. Synthesis of (E)-acrylate 9 and (E)-acrylic acid 1
Ph3P CHCO2Et
20% NaOH
CO2Et
CO2H
Ar CHO
Ar
Ar
THF
80 °C, 12 h
MeOH
rt, 5 h
1
9
Yield (%) of 1
1a 1),3)
Yield (%) of 9
Ar CHO
9a 1)
9b 2)
9c 1)
9d 1)
9e
80
99
95
75
99
99
78
62
93
99
89
70
96
79
O
1b 3)
N
Bn
1c 1),3)
1d1),3)
1e 3)
S
O
S
3)
9f
1f
N
Bn
9g
1g
N
MOM
1) ref.16a, 2) ref.16b, 3) ref. 4a
Synthesis of furo[3,2-c]pyridin-4-one
The furo[3,2-c]pyridine derivatives are emerging as useful pharmacophores in several therapeutic areas
such as antipsychotic molecules,1a protease kinase inhibitors,1b and antibacterial compounds.1c Eloy and
co-workers reported the synthesis of furo[3,2-c]pyridin-4-one (5a) from (E)-3-(2-furyl)acrylic acid (1a) in
three steps (Scheme 1).4 Treatment of 1a with SOCl2 give the acyl chloride 2, which was reacted with
NaN3 to obtain the acyl azide 3. Subsequently, treatment of the acyl azide 3 with Bu3N in diphenyl ether
at 230–240 °C was provided the desired furopyridone 5a in 45% yield (Table 2, entry 11). This result
proceeded by Curtius rearrangement to generate the isocyanate 4a, followed by an electrocyclization of

HETEROCYCLES, Vol. 95, No. 1, 2017
255
4a. In addition, Rao and co-workers also synthesized the furopyridone 5a from acryl azide 3 shown in
Scheme 1 in 80% yield using modified Eloy’s condition (entry 12).1c
Table 2. Synthesis of furo[3,2-c]pyridin-4-one (5a)
O
µW (−) or (+)
O
DPPA
Et3N
C
N
NH
Δ
CO2H
solvent
60 °C, 15 min
O
O
O
1a
4a
5a
Entry
Temp. (°C)
Time (h)
Solvents
µW
Yield (%) of 5a
−
+
+
+
−
−
+
+
−
+
−
−
1
2
1,2-dichlorobenzene
1,2-dichlorobenzene
1,2-dichlorobenzene
1,2-dichlorobenzene
bromobenzene
bromobenzene
bromobenzene
bromobenzene
toluene
180
180
20
1
80
51
3
180
2
99
4
150
1
49
5
150
1
64
6
150
20
1
72
7
150
98
8
100
1
35
9
100
5
19
10
11
12
toluene
100
4
10
diphenyl ether
diphenyl ether
230-240
230
1
451)
802)
1
1) Treatment of 3-(2-furyl)acryloyl azide with tributylamine in diphenyl ether at 230−240
°C affored pyridone 5a.
2) To a solution of tributylamine in diphenyl ether heated at 230 °C was added a solution
of 3-(2-furyl)acryloyl azide in dichloromethane over a period of 30 min. The reaction
mixture was continued to stir at the same temperature for another 30 min.
We investigated the one-pot synthesis of furopyridone 5a from (E)-3-(2-furyl)acrylic acid (1a), and the
conditions for this reaction were optimized (reaction time, temperature, solvent, and microwave
parameters). First, treatment of 1a with DPPA and Et3N in 1,2-dichlorobenzene at 60 °C for 15 min
generated the isocyanate 4a in situ (monitored the disappearance of acrylic acid by TLC), which was then
heated at 180 °C for 20 h. As a result, the furopyridone 5a was obtained in 80% yield (entry 1).
Subsequently, when the reaction was performed in 1,2-dichlorobenzene at 180 °C, under microwave
irradiation, 5a was obtained in 99% yield and the reaction time was reduced from 20 h to 2 h compared to
conventional condition (entry 3). When this reaction was performed in the same solvent at 150 °C, under
microwave irradiation, yield of 5a was decreased from 99% to 49% (entry 4). Second, the use of
bromobenzene instead of 1,2-dichlorobenzene as solvent was investigated under various cyclization

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HETEROCYCLES, Vol. 95, No. 1, 2017
conditions (entries 5–8). Heating at 150 °C under microwave irradiation afforded 5a in 98% yield (entry
7). Conversely, the cyclization in toluene did not proceed efficiently under each condition of microwave
heating and conventional heating (entries 9 and 10). Furthermore, the cyclization of this substrate was
also affected by the solvent (entries 4 vs. 7 and 8 vs. 10).
Synthesis of pyrrolo[3,2-c]pyridin-4-one
The pyrrolo[3,2-c]pyridine derivatives have been investigated as pharmacophores with potential
antipsychotic activity together with thieno[3,2-c]pyridines and furo[3,2-c]pyridines.1a Eloy and
co-workers reported the synthesis of pyrrolo[3,2-c]pyridone 5b from 3-(pyrrol-2-yl)acryloyl azide (Table
3, entry 8).4
Table 3. Synthesis of pyrrolo[3,2-c]pyridin-4-one (5b)
O
µW (−) or (+)
O
DPPA
Et3N
C
N
NH
Δ
CO2H
solvent
60 °C, 15 min
N
N
N
Bn
Bn
Bn
1b
4b
5b
Entry
Temp. (°C)
Time (h)
Solvents
µW
Yield (%) of 5b
−
+
+
+
+
−
+
−
1
2
3
4
5
6
7
8
1,2-dichlorobenzene
1,2-dichlorobenzene
1,2-dichlorobenzene
bromobenzene
bromobenzene
toluene
180
180
20
1
45
24
14
27
24
14
21
481)
180
3
150
1
100
2
100
2
toluene
100
2
diphenyl ether
230-240
1) Treatment of 3-(pyrrol-2-yl)acryloyl azide with tributylamine in diphenyl ether at 230−
240 °C affored pyridone 5b.
As shown in Table 3, we investigated the one-pot synthesis of pyrrolopyridone 5b from
3-(pyrrol-2-yl)acrylic acid 1b. First, the one-pot reaction of 1b was performed in 1,2-dichlorobenzene
under conventional conditions at 180 °C to produce the desired pyrrolopyridone 5b in 45% yield (entry 1).
Second, the conditions for this reaction were optimized (reaction time, temperature, solvent, and
microwave parameters). We did not observe an improved yield from these experiments compared with
the conventional conditions (entry 1). Moreover, it was inferred that the microwave irradiation conditions
are not more effective than the conventional conditions for this substrate (entries 2–7). As the cause,
many of unknown compounds were obtained along with the pyrrolopyridone 5b.

HETEROCYCLES, Vol. 95, No. 1, 2017
257
Synthesis of thieno[3,2-c]pyridin-4-one
As aforementioned, to identify compounds with potential antipsychotic activity using 4-substituted
thienopyridines, thieno[3,2-c]pyridin-4-one was synthesized as a precursor. New and co-workers reported
the synthesis of thieno[3,2-c]pyridin-4-one 5c from 3-(2-thienyl)acryloyl azide using Eloy’s condition
(Table 4, entry 11).1a As shown in Table 4, we investigated the one-pot synthesis of thienopyridone 5c
from (E)-3-(thiophen-2-yl)acrylic acid 1c. First, the one-pot reaction of 1c was performed under
conventional conditions to produce the desired thienopyridone 5c (entries 1, 2, 5, and 6). Second, the
conditions for this reaction were optimized (reaction time, temperature, solvent, and microwave
parameters). The results from these experiments show that the microwave irradiation conditions are more
effective than the conventional conditions (entries 2 and 5) for increasing the yield and decreasing the
reaction time (entries 4 and 7). Therefore, the microwave-irradiation-based heating at 180 °C for 2 h in
1,2-dichlorobenzene was the best condition to complete the reaction (entry 4).
Table 4. Synthesis of thieno[3,2-c]pyridin-4-one (5c)
O
µW (−) or (+)
O
DPPA
Et3N
C
N
NH
Δ
CO2H
solvent
60 °C, 15 min
S
S
S
1c
4c
5c
Entry
Temp. (°C)
Time (h)
Solvents
µW
Yield (%) of 5c
−
−
+
+
−
−
+
+
−
+
−
1
2
1,2-dichlorobenzene
1,2-dichlorobenzene
1,2-dichlorobenzene
1,2-dichlorobenzene
bromobenzene
bromobenzene
bromobenzene
bromobenzene
toluene
180
180
1
20
1
6
31
37
74
45
19
52
25
21
10
22 1)
3
180
4
180
2
5
150
1
6
150
20
1
7
150
8
100
2
9
100
3
10
11
toluene
100
2
diphenyl ether
230-240
1) Treatment of 3-(thiophen-2-yl)acryloyl azide with tributylamine in diphenyl ether at
230−240 °C affored pyridone 5c.
Synthesis of benzofuro[3,2-c]pyridin-1-one
The benzofuropyridines are one of the important heterocyclic compounds, which show significant
biological and pharmaceutical properties.2 Eloy and co-workers reported the synthesis of

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HETEROCYCLES, Vol. 95, No. 1, 2017
benzofuro[3,2-c]pyridin-1-one 5d from 3-(2-benzofuryl)acryloyl azide in 62% yield (Table 5, entry 10).4
As shown in Table 5, we investigated the one-pot synthesis of benzofuropyridone 5d from
(E)-3-(benzofuran-2-yl)acrylic acid 1d. First, the one-pot reaction of 1d was performed in
1,2-dichlorobenzene under conventional conditions at 180 °C to produce the desired benzofuropyridone
5d in 62% yield (entry 1). Second, the conditions for this reaction were optimized (reaction time,
temperature, solvent, and microwave parameters). The results indicate that the microwave irradiation
conditions are more effective than the conventional conditions (entries 1 and 5) for increasing the yield
and decreasing the reaction time (entries 3 and 6). Furthermore, the cyclization reaction of this substrate
was also affected by the solvent (entries 4 vs. 6). From the above results it is seen that heating at 180 °C
for 2 h in 1,2-dichlorobenzene under microwave irradiation was the best method to complete the reaction
(entry 3).
Table 5. Synthesis of benzofuro[3,2-c]pyridin-1-one (5d)
O
µW (−) or (+)
O
DPPA
Et3N
C
N
NH
Δ
CO2H
solvent
60 °C, 15 min
O
O
O
1d
4d
5d
Entry
Temp. (°C)
Time (h)
Solvents
µW
Yield (%) of 5d
−
+
+
+
−
+
+
−
+
−
1
2
1,2-dichlorobenzene
1,2-dichlorobenzene
1,2-dichlorobenzene
1,2-dichlorobenzene
bromobenzene
bromobenzene
bromobenzene
toluene
180
180
20
1
62
53
99
14
26
54
41
30
22
621)
3
180
2
4
150
1
5
150
1
6
150
1
7
100
2
8
100
2
9
toluene
100
1
10
diphenyl ether
230-240
1) Treatment of 3-(benzofuran-2-yl)acryloyl azide with tributylamine in diphenyl ether at 230−
240 °C affored pyridone 5d.
Synthesis of benzo[b]thieno[2,3-c]pyridin-1-one
Eloy
and
co-workers
synthesized
benzothieno[2,3-c]pyridin-1-one
5e
from
3-(benzothiophen-3-yl)acryloyl azide in diphenyl ether at 220 °C (Table 6, entry 10).4 Camaioni and
co-wokers synthesized the pyridone 5e using modified Eloy’s condition leading to the discovery of new
tankyrase inhibitors.3 As shown in Table 6, we investigated the one-pot synthesis of benzothienopyridone

HETEROCYCLES, Vol. 95, No. 1, 2017
259
5e from (E)-3-(benzothiophen-3-yl)acrylic acid (1e), and the conditions for this reaction were optimized
(reaction time, temperature, solvent, and microwave parameters). The cyclization of this substrate by
heating at temperatures higher than 150 °C afforded the desired product 5e in excellent yield (entries 1–5).
The most efficient reaction condition was the cyclization of 4e in bromobenzene at 150 °C for 1 h under
microwave irradiation (entry 6).
Table 6. Synthesis of benzothieno[2,3-c]pyridin-1-one (5e)
CO2H
µW (−) or (+)
DPPA
Et3N
Δ
N
NH
C
solvent
60 °C, 15 min
S
S
S
O
O
1e
4e
5e
Entry
Temp. (°C)
Time (h)
Solvents
µW
Yield (%) of 5e
−
−
+
−
−
+
+
−
+
−
1
2
1,2-dichlorobenzene
1,2-dichlorobenzene
1,2-dichlorobenzene
bromobenzene
bromobenzene
bromobenzene
bromobenzene
toluene
180
180
1
20
1
77
99
99
87
99
99
35
29
29
741)
3
180
4
150
1
5
150
20
1
6
150
7
100
1
8
100
2
9
toluene
100
2
10
diphenyl ether
230-240
1
1) Treatment of 3-(benzothiophen-2-yl)acryloyl azide with tributylamine in diphenyl ether at
230−240 °C affored pyridone 5e.
Synthesis of pyrido[3,4-b]indol-1-one
Pyrido[3,4-b]indole (β-carboline) is present in several natural products, and its compounds have been
synthesized using methods such as Bischler–Napieralski reaction17 and Pictet–Spengler reaction18 as a key
step. We previously reported the construction method of the pyrido[4,3-b]indole framework using thermal
electrocyclization based on 1-aza-6π-electron systems.19,20 As shown in Table 7, we investigated the
synthesis of pyrido[4,3-b]indol-1-one 5f from (E)-3-(indol-3-yl)acrylic acid 1f. First, when the reaction
was performed in 1,2-dichlorobenzene at 180 °C for 1 h under conventional heating, 5f was obtained in
73% yield (entry 1). To improve the yield, the reaction time was prolonged, but the yield decreased (entry
2). Second, the conditions for this reaction were optimized (reaction time, temperature, solvent, and
microwave parameters). The results from these optimization experiments show that the microwave

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HETEROCYCLES, Vol. 95, No. 1, 2017
irradiation conditions (entries 3 and 4) were not more effective than the conventional condition (entry 1)
in terms of the yield.
Table 7. Synthesis of pyrido[3,4-b]indol-1-one (5f)
CO2H
µW (−) or (+)
DPPA
Et3N
Δ
N
NH
C
solvent
60 °C, 15 min
N
N
N
O
O
Bn
Bn
Bn
1f
4f
5f
Entry
Temp. (°C)
Time (h)
Solvents
µW
Yield (%) of 5f
−
−
+
+
−
+
+
+
−
+
−
1
2
1,2-dichlorobenzene
1,2-dichlorobenzene
1,2-dichlorobenzene
1,2-dichlorobenzene
bromobenzene
bromobenzene
bromobenzene
bromobenzene
toluene
180
180
1
20
0.5
1
73
10
18
63
63
24
69
18
10
4
3
180
4
180
5
150
1
6
150
0.5
1
7
150
8
100
2
9
100
10
7
10
11
toluene
100
diphenyl ether
230-240
401)
1) Treatment of 3-(indol-3-yl)acryloyl azide with tributylamine in diphenyl ether at 230−240
°C affored pyridone 5f.
Synthesis of pyrido[4,3-b]indol-1-one
Pyrido[4,3-b]indole (γ-carboline) framework was synthesized using several strategies.21 However, the
construction of pyrido[4,3-b]indole framework at the C1–C1a bond position has not been reported to date.
As shown in Table 8, we investigated the one-pot synthesis of pyridone 5g using the proposed cyclization
reactoin, and the conditions for this reaction were optimized (reaction time, temperature, solvent, and
microwave parameters) (entries 1–5). From these experiments, it is observed that the microwave
irradiation conditions (entries 2, 4, and 7) were more effective than the conventional conditions (entries 1,
3, and 6) in terms of the pyridone 5g yield from the 3-(indol-2-yl)acrylic acid 1g. From these results, it is
observed that the most efficient reaction condition was the cyclization of 4g in bromobenzene at 150 °C
for 1 h under microwave irradiation (entry 4).

HETEROCYCLES, Vol. 95, No. 1, 2017
261
Table 8. Synthesis of pyrido[4,3-b]indol-1-one (5g)
O
µW (−) or (+)
O
DPPA
Et3N
C
N
NH
Δ
CO2H
solvent
60 °C, 15 min
N
N
N
MOM
1g
MOM
MOM
4g
5g
Entry
Temp. (°C)
Time (h)
Solvents
µW
Yield (%) of 5g
−
+
−
+
+
−
+
1
2
3
4
5
6
7
1,2-dichlorobenzene
1,2-dichlorobenzene
bromobenzene
bromobenzene
bromobenzene
toluene
180
180
150
150
100
100
100
20
1
38
68
52
84
42
16
32
1
1
2
2
toluene
2
CONCLUSION
We focused on the synthetic method for isocyanates developed by Shioiri and co-workers and
investigated the one-pot synthesis of various fused 2-pyridone ring systems based on a Curtius
rearrangement, followed by a microwave-assisted thermal electrocyclization of a 2-aza-6π-electron
system including isocyanate. We synthesized seven heterocyclic compounds containing a fused
2-pyridone moiety, which have interesting pharmaceutical potential. Except for 3-(pyrrol-2-yl)acrylic
acid 1b, one-pot synthesis of fused 2-pyridone ring system 5 from (E)-acrylic acids 1 under microwave
irradiation conditions proved to be more effective than the conventional conditions in terms of the yield
and the reaction time. We could establish an efficient one-pot synthesis method for various types of
aromatic heterocyclic fused 2-pyridone. Currently, we are investigating the total synthesis of natural
products and a research study of biologically active compounds based on these heterocyclic fused
2-pyridone ring.
EXPERIMENTAL
General Methods: All non-aqueous reactions were carried out under an atmosphere of nitrogen in dried
glassware unless otherwise noted. Solvents were dried and distilled according to standard protocols.
Analytical thin-layer chromatography was performed with Silica gel 60PF254 (Merck). Silica gel column
chromatography was performed with Silica gel 60 (70–230 mesh, Kanto Co. Lit.). All melting points
were determined on Yanagimoto micro melting point apparatus and are uncorrected. Proton nuclear
magnetic resonance (1H-NMR) spectra were recorded on a JEOL AL-300 at 300 MHz. Chemical shifts

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are reported relative to Me4Si (δ 0.00). NMR spectra were measured with CDCl3 unless otherwise noted.
Multiplicity is indicated by one or more of the following: s (singlet); d (doublet); t (triplet); q (quartet); m
(multiplet); br (broad). Carbon nuclear magnetic resonance (13C-NMR) spectra were recorded on a JEOL
AL-300 at 75 MHz. Chemical shifts are reported relative to CDCl3 (δ 77.0) and DMSO-d6 (δ 39.7).
Infrared spectra were recorded with ATR method using a Shimadzu FTIR-8000 spectrophotometer and
Technologies DuraScop. Low and high-resolution mass spectra were recorded on JEOL JMS-700
spectrometers by direct inlet system.
General procedure for (E)-heteroarylacrylate 9 by Wittig reaction: A solution of arylcarbaldehyde
(10.4 mmol) and (ethoxycarbonylmethylene)triphenylphosphorane (14.6 mmol) in THF (20 mL) was
heated at 80 °C for 12 h. After cooling to an ambient temperature, the reaction mixture was quenched
with water, and then was extracted with EtOAc. The organic layer was washed with brine, dried over
Na2SO4, and evaporated in vacuo. The residue was purified by column chromatography (silica gel, 30 g)
using EtOAc-hexane (3:97, v/v) as an eluent to give the (E)-acrylate 9.
Ethyl (E)-3-(2-furyl)acrylate 9a
IR (ATR) ν: 1702 cm–1. 1H-NMR (300 MHz, CDCl3) δ: 1.32 (3H, t, J = 7.2 Hz), 4.25 (2H, q, J = 7.2 Hz),
6.31 (1H, d, J = 15.6 Hz), 6.46 (1H, dd, J = 1.5, 3.5 Hz), 6.61 (1H, d, J = 3.5 Hz), 7.43 (1H, d, J = 15.6
Hz), 7.48 (1H, d, J = 1.5 Hz). 13C-NMR (75 MHz, CDCl3) δ: 14.2, 60.4, 112.2, 114.6, 115.9, 131.0, 144.6,
150.9, 167.1. MS (EI) m/z: 166 (M+); HRMS (EI) Calcd for C9H10O3: 166.0630. Found: 166.0634.
Ethyl (E)-3-(N-benzylpyrrol-2-yl)acrylate 9b
IR (ATR) ν: 1697 cm–1. 1H-NMR (300 MHz, CDCl3) δ: 1.28 (3H, t, J = 7.2 Hz), 4.18 (2H, q, J = 7.2 Hz),
5.21 (2H, s), 6.13 (1H, d, J = 15.6 Hz), 6.25 (1H, dd, J = 1.7, 3.8 Hz), 6.73 (1H, dd, J = 1.7, 3.8 Hz), 6.83
(1H, dd, J = 1.7, 3.8 Hz), 7.05 (2H, d, J = 6.4 Hz), 7.27–7.35 (3H, m), 7.57 (1H, d, J = 15.6 Hz).
13C-NMR (75 MHz, CDCl3) δ: 14.3, 50.6, 60.1, 109.9, 111.8, 113.3, 126.3, 126.4, 127.7, 128.8, 129.1,
132.1, 137.3, 167.6. MS (EI) m/z: 255 (M+); HRMS (EI) Calcd for C16H17NO2: 255.1259. Found:
255.1247.
Ethyl (E)-3-(2-thienyl)acrylate 9c
IR (ATR) ν: 1702 cm–1. 1H-NMR (300 MHz, CDCl3) δ: 1.33 (3H, t, J = 7.0 Hz), 4.25 (2H, q, J = 7.0 Hz),
6.24 (1H, d, J = 15.8 Hz), 7.05 (1H, dd, J = 3.7 Hz), 7.25 (1H, d, J = 3.7 Hz), 7.37 (1H, d, J = 3.7 Hz),
13
7.89 (1H, d, J = 15.8 Hz). C-NMR (75 MHz, CDCl3) δ: 14.3, 60.4, 117.0, 128.0, 128.3, 130.8, 137.0,
140.0, 166.8. MS (EI) m/z: 182 (M+); HRMS (EI) Calcd for C9H10O2S: 182.0402. Found: 182.0418.
Ethyl (E)-3-(benzofuran-2-yl)acrylate 9d
IR (ATR) ν: 1714 cm–1. mp 69–71 °C (EtOAc). 1H-NMR (300 MHz, CDCl3) δ: 1.35 (3H, t, J = 7.2 Hz),
4.28 (2H, q, J = 7.2 Hz), 6.58 (1H, d, J = 15.7 Hz), 6.94 (1H, s), 7.24 (1H, t, J = 7.7 Hz), 7.36 (1H, t, J =

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7.7 Hz), 7.48 (1H, d, J = 7.7 Hz), 7.55 (1H, d, J = 15.7 Hz), 7.58 (1H, d, J = 7.7 Hz). 13C-NMR (75 MHz,
CDCl3) δ: 14.3, 60.6, 111.0, 111.4, 119.0, 121.7, 123.3, 126.4, 128.3, 131.2, 152.4, 155.5, 166.7. MS (EI)
m/z: 216 (M+); HRMS (EI) Calcd for C13H12O3: 216.0786. Found: 216.0794.
Ethyl (E)-3-(benzo[b]thien-3-yl)acrylate 9e
IR (ATR) ν: 1702 cm–1. 1H-NMR (300 MHz, CDCl3) δ: 1.36 (3H, t, J = 7.3 Hz), 4.30 (2H, q, J = 7.3 Hz),
6.55 (1H, d, J = 16.1 Hz), 7.39–7.50 (2H, m), 7.76 (1H, s), 7.89 (1H, d, J = 5.9 Hz), 7.97 (1H, d, J = 16.1
Hz), 8.04 (1H, d, J = 5.9 Hz); 13C-NMR (75 MHz, CDCl3) δ: 14.3, 60.6, 118.7, 122.0, 123.0, 124.9, 125.0,
128.0, 131.6, 136.3, 137.1, 140.5, 167.1. MS (EI) m/z: 232 (M+); HRMS (EI) Calcd for C13H12O2S:
232.0558. Found: 232.0568.
Ethyl (E)-3-(N-benzylindol-3-yl)acrylate 9f
IR (ATR) ν: 1697 cm–1. mp 79–81 °C (EtOAc). 1H-NMR (300 MHz, CDCl3) δ: 1.34 (3H, t, J = 7.2 Hz),
4.26 (2H, q, J = 7.2 Hz), 5.32 (2H, s), 6.43 (1H, d, J = 16.0 Hz), 7.14–7.16 (2H, m), 7.24–7.35 (6H, m),
7.41 (1H, s), 7.90 (1H, d, J = 16.0 Hz), 7.94 (1H, d, J = 3.3 Hz). 13C-NMR (75 MHz, CDCl3) δ: 14.4, 50.4,
60.0, 110.4, 112.1, 113.0, 120.7, 121.4, 123.1, 126.3, 126.9, 128.0, 128.9, 132.4, 136.1, 137.6, 137.9,
168.2. MS (EI) m/z: 305 (M+); HRMS (EI) Calcd for C20H19NO2: 305.1416. Found: 305.1432.
Ethyl (E)-3-(N-methoxymethylindol-2-yl)acrylate 9g
IR (ATR) ν: 1702 cm–1. 1H-NMR (300 MHz, CDCl3) δ: 1.35 (3H, t, J = 7.2 Hz), 3.28 (3H, s), 4.28 (2H, q,
J = 7.2 Hz), 5.56 (2H, s), 6.54 (1H, d, J = 15.8 Hz), 6.99 (1H, s), 7.15 (1H, t, J = 7.7 Hz), 7.29 (1H, t, J =
7.7 Hz), 7.46 (1H, d, J = 7.7 Hz), 7.62 (1H, d, J = 7.7 Hz), 7.83 (1H, d, J =15.8 Hz). 13C-NMR (75 MHz,
CDCl3) δ: 14.4, 50.3, 56.0, 73.9, 106.9, 109.9, 113.2, 117.7, 121.3, 121.7, 124.6, 127.7, 134.7, 139.5,
168.3. MS (EI) m/z: 259 (M+); HRMS (EI) Calcd for C15H17NO3: 259.1208. Found: 259.1212.
General procedure for (E)-heteroarylacrylic acid 1: To a solution of (E)-acrylate 9 (8.9 mmol) in
MeOH (10 mL) was added 20% aqueous NaOH solution (5 mL), and then was stirred at rt for 5 h. The
reaction mixture was diluted with water, and then was acidified with 10% HCl aqueous solution to
precipitate the carboxylic acid. The precipitate was filtrated off to give the crude acrylic acid 1.
(E)-3-(2-Furyl)acrylic acid 1a
1
R (ATR) ν: 1681, 3073 cm–1. mp 139–140 °C (MeOH). H-NMR (300 MHz, CDCl3) δ: 6.33 (1H, d, J =
15.7 Hz), 6.49 (1H, dd, J = 1.8, 3.6 Hz), 6.67 (1H, d, J = 3.6 Hz), 7.51 (1H, d, J = 15.7 Hz), 7.52 (1H, d, J
13
= 1.8 Hz); C-NMR (75 MHz, CDCl3) δ: 112.4, 114.8, 115.8, 133.0, 145.3, 150.6, 172.4. MS (EI) m/z:
138 (M+); HRMS (EI) Calcd for C7H6O3: 138.0317. Found: 138.0324.
(E)-3-(N-Benzylpyrrol-2-yl)acrylic acid 1b
1
IR (ATR) ν: 1666 cm–1. mp 182–183 °C (EtOAc-hexane). H-NMR (300 MHz, CDCl3) δ: 5.22 (2H, s),
6.11 (1H, d, J = 15.5 Hz), 6.27 (1H, t, J = 3.9 Hz), 6.79 (1H, d, J = 3.9 Hz), 6.88 (1H, t, J = 3.9 Hz), 7.04

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13
(2H, d, J = 7.1 Hz), 7.29–7.33 (3H, m), 7.61 (1H, d, J = 15.5 Hz); C-NMR (75 MHz, CDCl3) δ: 50.7,
110.2, 111.9, 113.0, 126.4, 127.1, 127.9, 128.8, 128.9, 134.1, 137.1, 172.3. MS (EI) m/z: 227 (M+);
HRMS (EI) Calcd for C14H13NO2: 227.0946. Found: 227.0958.
(E)-3-(2-Thienyl)acrylic acid 1c
IR (ATR) ν: 1670 cm–1. mp 142–143 °C (EtOAc-hexane). 1H-NMR (300 MHz, CDCl3) δ: 6.24 (1H, d, J
= 15.6 Hz), 7.07 (1H, dd, J = 3.6, 5.1 Hz), 7.30 (1H, d, J = 3.6 Hz), 7.42 (1H, d, J = 5.1 Hz), 7.90 (1H, d,
13
J = 15.6 Hz); C-NMR (75 MHz, CDCl3) δ: 115.9, 128.2, 129.3, 131.6, 139.2, 139.4, 172.1. MS (EI)
m/z: 154 (M+); HRMS (EI) Calcd for C7H6O2S: 154.0089. Found: 154.0073.
(E)-3-(Benzofuran-2-yl)acrylic acid 1d
IR (ATR) ν: 1666 cm–1. mp 187–188 °C (EtOAc-hexane). 1H-NMR (300 MHz, CDCl3) δ: 6.60 (1H, d, J
= 15.6 Hz), 7.00 (1H, s), 7.26 (1H, t, J = 7.4 Hz), 7.39 (1H, t, J = 5.8 Hz), 7.51 (1H, d, J = 7.7 Hz), 7.61
(1H, d, J = 7.7 Hz), 7.63 (1H, d, J = 15.6 Hz); 13C-NMR (75 MHz, CDCl3) δ: 100.5, 111.4, 117.5, 121.8,
123.4, 126.7, 128.2, 133.2, 151.9, 169.8, 176.3. MS (EI) m/z: 188 (M+); HRMS (EI) Calcd for C11H8O3:
188.0473. Found: 188.0488
(E)-3-(Benzo[b]thien-3-yl)acrylic acid 1e
R (ATR) ν: 1660 cm–1. mp 219–221 °C (EtOAc-hexane). 1H-NMR (300 MHz, CDCl3) δ: 6.56 (1H, d, J =
15.9 Hz), 7.43–7.50 (2H, m), 7.84 (1H, s), 7.90 (1H, d, J = 7.2 Hz), 8.04 (1H, d, J = 7.2 Hz), 8.06 (1H, d,
J = 15.9 Hz); 13C-NMR (75 MHz, CDCl3) δ: 100.6, 111.5, 112.0, 117.5, 121.9, 123.4, 126.8, 128.3, 133.3,
152.0, 155.8. MS (EI) m/z: 204 (M+); HRMS (EI) Calcd for C11H8O2S: 204.0245. Found: 204.0233.
(E)-3-(N-Benzylindol-3-yl)acrylic acid 1f
1
IR (ATR) ν: 1698 cm–1. mp 101–102 °C (EtOAc-hexane). H-NMR (300 MHz, CDCl3) δ: 5.33 (2H, s),
6.44 (1H, d, J = 15.9 Hz), 7.05–7.26 (2H, m), 7.27–7.34 (7H, m), 7.44 (1H, s), 7.94 (1H, d, J = 5.5 Hz),
13
7.99 (1H, d, J = 15.9 Hz); C-NMR (75 MHz, CDCl3) δ: 49.2, 93.5, 110.9, 112.4, 120.0, 120.6, 122.2,
125.9, 127.1, 127.5, 128.6, 132.1, 133.3, 136.9, 137.6, 170.3. MS (EI) m/z: 277 (M+); HRMS (EI) Calcd
for C18H15NO2: 277.1103. Found: 277.1121.
(E)-3-(N-Methoxymethylindol-2-yl)acrylic acid 1g
1
IR (ATR) ν: 1673 cm–1. mp 157–158 °C (EtOAc-hexane). H-NMR (300 MHz, CDCl3) δ: 3.30 (3H, s),
5.58 (2H, s), 6.55 (1H, d, J = 15.8 Hz), 7.07 (1H, s), 7.17 (1H, t, J = 7.2 Hz), 7.32 (1H, t, J = 7.2 Hz),
7.47 (1H, d, J = 7.8 Hz), 7.64 (1H, d, J = 7.8 Hz), 7.93 (1H, d, J = 15.8 Hz); 13C-NMR (75 MHz, CDCl3)
δ: 56.0, 73.9, 106.9, 109.9, 116.3, 117.7, 121.3, 121.7, 124.6, 127.7, 134.7, 139.5, 171.7. MS (EI) m/z:
231 (M+); HRMS (EI) Calcd for C13H13NO3: 231.0895. Found: 231.0887.
General procedure for aromatic heterocycles fused pyridine 5: A solution of acrylic acid 1 (0.30
mmol), DPPA (0.90 mmol), and Et3N (0.90 mmol) in 1,2-dichlorobenzene (3 mL) were stirred at 60 °C

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for 15 min to generate in sute the isocyanate (monitored the disappearance of acrylic acid by TLC), and
then was heated under microwave irradiation at 180 °C for 1 h. After cooling to an ambient temperature,
the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography
(silica gel, 10 g) using EtOAc-hexane (1:9 v/v) as an eluent to give the pyridone 5.
Furo[3,2-c]pyridin-4-one 5a
IR (ATR) ν: 1652 cm–1. mp 223–224 °C (EtOAc-hexane). 1H-NMR (300 MHz, DMSO-d6) δ: 6.66 (1H, d,
J = 7.3 Hz), 7.01 (1H, d, J = 2.1 Hz), 7.31 (1H, d, J = 7.3 Hz), 7.55 (1H, d, J = 2.1 Hz), 12.14 (1H, br s).
13C-NMR (75 MHz, DMSO-d6) δ: 94.7, 106.8, 119.9, 122.1, 128.9, 131.5, 144.0. MS (EI) m/z: 135 (M+);
HRMS (EI) Calcd for C7H5NO2: 135.1220. Found: 135.1238.
N-Benzylpyrrolo[3,2-c]pyridin-4-one 5b
1
IR (ATR) ν: 1625 cm–1. mp 196–198 °C (EtOAc). H-NMR (300 MHz, DMSO-d6) δ: 5.24 (2H, s), 6.35
(1H, d, J = 7.3 Hz), 6.88 (1H, d, J = 3.2 Hz), 6.93 (1H, d, J = 3.2 Hz), 7.08–7.10 (3H, m), 7.26–7.36 (3H,
13
m), 11.39 (1H, br s). C-NMR (75 MHz, DMSO-d6) δ: 49.4, 93.6, 103.8, 115.6, 125.6, 127.0, 127.5,
128.6, 128.7, 137.9, 138.9, 159.5. MS (EI) m/z: 224 (M+); HRMS (EI) Calcd for C14H12N2O: 224.2630.
Found: 224.2636.
Thieno[3,2-c]pyridin-4-one 5c
IR (ATR) ν: 1637 cm–1. mp 161–163 °C (EtOAc). 1H-NMR (300 MHz, DMSO-d6) δ: 6.79 (1H, d, J = 7.0
Hz), 7.23 (1H, d, J = 7.0 Hz), 7.31 (1H, d, J = 5.3 Hz), 7.65 (1H, d, J = 5.3 Hz), 12.34 (1H, br s).
13C-NMR (75 MHz, DMSO-d6) δ: 101.0, 119.9, 121.8, 124.1, 125.1, 128.8, 130.5. MS (EI) m/z: 151
(M+); HRMS (EI) Calcd for C7H5NOS: 151.1830. Found: 151.1842.
Benzofuro[3,2-c]pyridin-1-one 5d
IR (ATR) ν: 1637 cm–1. mp 240–242 °C (CHCl3). 1H-NMR (300 MHz, DMSO-d6) δ: 6.79 (1H, d, J = 7.2
Hz), 7.39–7.48 (2H, m), 7.58 (1H, d, J = 7.2 Hz), 7.72 (1H, d, J = 7.2 Hz), 8.01–8.03 (1H, m), 11.86 (1H,
13
br s). C-NMR (75 MHz, DMSO-d6) δ: 94.5, 110.0, 111.4, 120.8, 123.6, 124.3, 125.8, 135.3, 154.1,
159.5, 162.5. MS (EI) m/z: 185 (M+); HRMS (EI) Calcd for C11H7NO2: 185.1820. Found: 185.1828.
Benzo[b]thieno[2,3-c]pyridin-1-one 5e
IR (ATR) ν: 1643 cm–1. mp 246–248 °C (CHCl3). 1H-NMR (300 MHz, DMSO-d6) δ: 7.20 (1H, d, J = 7.3
Hz), 7.46–7.63 (3H, m), 8.12 (1H, d, J = 7.3 Hz), 8.33 (1H, d, J = 7.3 Hz), 11.87 (1H, br s). 13C-NMR (75
MHz, DMSO-d6) δ: 100.2, 100.3, 123.7, 124.0, 125.2, 128.4, 131.5, 135.1, 141.0, 142.2, 158.9. MS (EI)
m/z: 201 (M+); HRMS (EI) Calcd for C11H7NOS: 201.2430. Found: 201.2430.
N-Benzylpyrido[3,4-b]indol-1-one 5f
IR (ATR) ν: 1637 cm–1. mp 251–252 °C (CHCl3-hexane). 1H-NMR (300 MHz, DMSO-d6) δ: 6.03 (2H, s),
7.06 (1H, d, J = 7.7 Hz), 7.11–7.22 (6H, m), 7.42 (1H, t, J = 7.7 Hz), 7.58 (1H, d, J = 7.7 Hz), 8.06 (1H, d,
13
J = 7.7 Hz), 8.23 (1H, s), 11.47 (1H, br s). C-NMR (75 MHz, DMSO-d6) δ: 47.1, 100.3, 111.5, 120.5,

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121.8, 121.9, 125.7, 125.7, 126.5, 127.2, 127.3, 127.5, 128.8, 130.1, 138.9, 139.9, 156.5, 175.7. MS (EI)
m/z: 274 (M+); HRMS (EI) Calcd for C18H14N2O: 274.3230. Found: 274.3234.
N-Methoxymethylpyrido[4,3-b]indol-1-one 5g
IR (ATR) ν: 1644 cm–1. mp 154–156 °C (EtOAc-hexane). 1H-NMR (300 MHz, DMSO-d6) δ: 3.30 (3H, s),
5.61 (2H, s), 6.66 (1H, d, J = 7.3 Hz), 7.36–7.62 (4H, m), 8.44 (1H, d, J = 7.3 Hz), 12.30 (1H, br s).
13C-NMR (75 MHz, DMSO-d6) δ: 55.6, 73.6, 93.0, 110.3, 119.9, 120.6, 121.5, 124.0, 128.9, 132.7, 138.1,
146.0, 159.7. MS (EI) m/z: 228 (M+); HRMS (EI) Calcd for C13H12N2O2: 228.2510. Found: 228.2522.
ACKNOWLEDGMENTS
This work was supported in part by a Grant-in-Aid for Scientific Research (C) of the Japan Society for
the Promotion of Science (grant number 15K07880 for T.C.).
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