Facile Synthesis of Onychines

Article abstract of DOI:10.1055/s-0037-1612058

The FeCl ₃ -mediated condensation of an α-phenylenamino ester and an enone proceeds efficiently to afford a 2-phenylnicotinate. The subsequent intramolecular Friedel-Crafts reaction yielded an onychine framework. Modifications at the 2-, 3-, and 8-positions of the onychine framework were easily achieved by altering the enamino esters and enones, which facilitated the discovery of potentially bioactive compounds.

Full text of DOI:10.1055/s-0037-1612058

SYNTHESIS
0
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9
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1
1
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3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–G
paper
A
en
M. Arita et al.
Paper
Synthesis
Facile Synthesis of Onychines
Me
O
Me
N
Mao Aritaa
Soichi Yokoyamaa,b
Haruyasu Asahara*a,b,c
Nagatoshi Nishiwaki*a,b
O
1) FeCl3
MeCN
150 °C
R3
R2
R3
R2
O
EtO
0
0
0
0-0
0
0
2-1
8
0
8-
7
3
7
3
2) PPA
220 °C
0
0
0
0-0
0
0
2-6
0
5
2-8
6
9
7
NH2
R8
R2 = H, Me, Ph
R3 = H, Me
R1
a School of Environmental Science and Engineering, Kochi University of
Technology, Kami, Kochi 782-8502, Japan
R8 = H, OH, OR
nishiwaki.nagatoshi@kochi-tach.ac.jp
b Research Center for Material Science and Engineering, Kochi University
of Technology, Kami, Kochi 782-8502, Japan
c Department of Applied Chemistry, Graduate School of Engineering,
Osaka University, Yamadaoka 2-1, Suita, Osaka 565-0871, Japan
Received: 07.11.2018
Accepted after revision: 06.12.2018
Published online: 19.02.2019
treated under basic conditions, 1Aa is synthesized in a sin-
gle step, which involves the rearrangement of the crotyl
group followed by intramolecular condensation forming a
pyridine ring (Method c).10 Onychine (1Aa) is also obtained
by forming a C–C bond between the pyridine ring and the
substituent; palladium-catalyzed intramolecular cross-cou-
pling of 3-(2-bromobenzoyl)-4-methylpyridine (Method d)11
and intramolecular Friedel–Crafts acylation of ethyl 4-
methyl-2-phenylnicotinate (Method e)12 have been report-
ed. Thus, while several routes to obtain onychine have been
established, the difficulty in obtaining the starting materi-
als limits the synthesis of versatile substituted onychines.
DOI: 10.1055/s-0037-1612058; Art ID: ss-2018-f0746-op
Abstract The FeCl3-mediated condensation of an α-phenylenamino
ester and an enone proceeds efficiently to afford a 2-phenylnicotinate.
The subsequent intramolecular Friedel–Crafts reaction yielded an
onychine framework. Modifications at the 2-, 3-, and 8-positions of the
onychine framework were easily achieved by altering the enamino
esters and enones, which facilitated the discovery of potentially bioac-
tive compounds.
Key words onychine, polysubstituted nicotinates, iron(III) chloride,
intramolecular Friedel–Crafts reaction, enone
Me
Cl
O
O
MeB(OH)2
Pd cat.
Onychine is an alkaloid isolated from the root bark of
trees belonging to the Annonaceae family, such as Onychop-
etalum amazonicum,1 Guatteria dielsina Rodrigues, W. A.,2
and Cleistopholis patens,3 which are large trees found
throughout West Africa. The structure of onychine was
determined as 4-aza-1-methylfluorenone later by Koyama
et al.4 Onychine also serves as a precursor of eupolauridine,
isolated from members of the Annonaceae family such as
Eupomatia laurina R. Br.5 and Cananga odorata Hook. F. et
Thomas.6 Recently, onychine derivatives have attracted
much attention because of their high bioactivity, including
antifungal activity and cytotoxicity.7 From the standpoint
of finding new biologically active compounds, the develop-
ment of a facile synthetic method for versatile substituted
onychines is urgently required.
(a)
(b)
(c)
N
N
1Aa
1Aa
Me
Me
O
KMnO4
N
N
N
Me
O
O
base
O
N
1Aa
1Aa
O
Me
Me
O
O
Pd cat.
(d)
H
Br
N
N
Several synthetic methods for onychine (1Aa) are
shown in Scheme 1. In Methods a8 and b,9 1Aa is obtained
by modification of 4-azafluorenone derivatives; however, it
is not easy to construct the fundamental framework before-
hand. Other approaches, including the construction of a 4-
azafluorenone framework, are also reported (Methods c–e).
When O-crotyloxime derived from 1, 3-indanedione was
O
Me
Me
EtO
H
H+
(e)
N
N
1Aa
Scheme 1 Commonly routes for the synthesis of onychine (1Aa)
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–G

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M. Arita et al.
Paper
Synthesis
Among these routes, Method e is rather considered to
have potential from the viewpoint of modification of the
onychine framework. In Scheme 2, commonly used syn-
thetic methods for the precursor, 4-methyl-2-phenylnico-
tinates, are shown. Although Hantzsch reaction (Method f)
is the most commonly used method for synthesizing nicoti-
nates, the products always have two ester functions, and
the control of regioselectivity is necessary.13 The Suzuki–
Miyaura cross-coupling reaction (Method g),14 three com-
ponent condensation of zinc enolate (Method h),15 and con-
densation of enamino ester with β-keto ester (Method i)16
are also acceptable; however, modification of the starting
2-bromonicotinate, enyne, and keto ester is not easily
achieved (Scheme 2). This prevents the introduction of de-
sired substituents at the preferred position of the onychine
framework via Method e.
R/Ar
O
R/Ar
O
R/Ar
R/Ar
R/Ar
FeCl3
RO
RO
R/Ar
MeCN
150 °C, 1 h
microwave
O
R/Ar
N
R/Ar
NH2
3
2
4
in a sealed tube
O
O
NH4OAc
EtO
EtO
60 °C, 12 h
EtOH
quant.
Ar
O
Ar
NH2
2
Me
Me
R3
R2
R3
R2MgBr
MnO2
0 °C, 1 h
THF
rt, 2 d
CH2Cl2
O
O
H
3
Scheme 3 Synthesis of nicotinates 4 possessing different substituents
O
O
O
O
EtO
Ph
O
obtained in 74% yield (Table 1, entry 1). Similarly, α-methyl-
ated aldehyde 3b underwent the reaction to afford tetra-
substituted pyridine 4Ab in comparable yield (entry 2). Un-
saturated ketones 3c and 3d could also be used as substrate
to give the corresponding nicotinates 4Ac and 4Ad, respec-
tively (entries 3 and 4). In the case of 3c, the low reaction
efficiency could be due to the instability of the enone 3c,
causing it to decompose in air (entry 3). On the other hand,
the phenyl ketone 3d was sufficiently stable and showed
similar reactivity to the unsaturated aldehyde 3a (entry 4).
Next, modification of the aryl group was studied. When the
electron-rich enamino ester 2B was used, the condensation
proceeded similarly to afford the corresponding nicotinates
4Ba–4Bd (entries 5–8). Ester 2B is more reactive than 2A,
and reacted with 3c before its decomposition, which result-
ed in the formation of 4Bc in higher yield (entry 7).
Electron-poor enamino ester 2C also afforded nicotinate
4Ca without significant decrease of the yield (entry 9).
Then, the ring closure of the synthesized nicotinate
4Aa16 was attempted under acidic conditions (Table 2).
Ester 4Aa was consumed upon heating at 180 °C in poly-
phosphoric acid (PPA), and 1Aa was obtained in a yield of
20% (Table 2, entry 1). The yield of 1A increased to 45% as
the reaction temperature was increased to 220 °C (entry 2).
However, the yield of 1Aa decreased at a still higher tem-
perature (entry 3), and the optimal temperature for the ring
closure was determined to be 220 °C. Reaction time was
also studied. When the reaction was stopped at 15 minutes,
nicotinate 4Aa was almost consumed, but onychine (1Aa)
was obtained in just 6% yield. In this reaction, nicotinic acid
5 was obtained in 46% yield, suggesting that the ring closure
proceeds in two steps via the nicotinic acid intermediate 5
(entry 4). Indeed, the isolated 5 was converted into
onychine (1Aa) in 40% yield upon heating at 220 °C for 1
hour in PPA. The yield of onychine (1Aa) increased with the
(f)
1) NH4OAc
2) oxidation
EtO
OEt
O
OEt
Ph
N
H
O
OH
B
EtO2C
Ph
EtO2C
(g)
Pd cat
Ph
OH
N
Br
N
N
OZnBr
EtO2C
Ph
(h)
(i)
EtO
Ph
N
N
O
EtO2C
Ph
O
EtO
H2N
O
EtO
Ph
Scheme 2 Common routes for the synthesis of 4-methyl-2-phenylnic-
otinates
Meanwhile, we recently demonstrated an efficient syn-
thetic method for polysubstituted nicotinates through
iron(III) chloride mediated condensation of an enamino
ester 2 with an α,β-unsaturated carbonyl compound 3, both
of which are easily available commercially or by simple re-
actions. This protocol facilitates the modification of the
pyridine ring by altering substrates 2 and 3 (Scheme 3).17
Indeed, the desired alkyl/aryl groups could be introduced
into the chosen positions of the nicotinate framework 4.
This feature prompted us to study the synthesis of 2-arylat-
ed nicotinates 4 and the subsequent conversion into
onychines 1, which could overcome the disadvantages of
the conventional methods.
When the α-phenyl enamino ester 2A was reacted with
crotonaldehyde (3a) in the presence of iron(III) chloride at
150 °C, ethyl 4-methyl-2-phenylnicotinate (4Aa) was
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–G

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M. Arita et al.
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Synthesis
Table 1 Synthesis of 2-Arylated Nicotinates 4
Me
O
R3
R2
O
Me
O
FeCl
(1 equiv)
R3
R2
EtO
EtO
MeCN
150 °C, 1 h
microwave
3
N
NH2
4
R1
in a sealed tube
R1
2 (2 equiv)
Entry
Enamino ester 2
Enone 3
Product
Yield (%)
R1
R2
R3
1
2
3
4
5
6
7
8
9
H
2A
2A
2A
2A
2B
2B
2B
2B
2C
H
H
3a
3b
3c
3d
3a
3b
3c
3d
3a
4Aa
4Ab
4Ac
4Ad
4Ba
4Bb
4Bc
4Bd
4Ca
74
60
35
54
74
56
50
65
71
H
H
Me
Me
H
H
Me
Ph
H
H
OMe
OMe
OMe
OMe
NO2
H
H
Me
Me
H
Me
Ph
H
H
O
Me
N
O
Me
N
reaction time (entries 4–6), and the yield reached 56% upon
heating for 1 hour (entry 6). However, no positive effect was
observed for even longer reaction times (entry 7).
EtO
HO
SOCl2
aq 40% NaOH
reflux, 3 d
80 °C, 1 d
5 (44%)
4Aa
Table 2 Study of Reaction Conditions for the Cyclization of 4
O
Me
Me
N
O
O
Me
Me
AlCl3
PhCl
Cl
O
EtO
PPA
N
130 °C, 1 d
N
N
6
1Aa (30% based on 5)
4Aa
1Aa
Scheme 4 Synthesis of 1Aa from 4Aa via nicotinic acid 5
Entry
Temp (°C)
Time (h)
Yield of 1Aa (%) Recovery of 4Aa (%)
This protocol was applied to the substituted nicotinates
4Ab–4Ad under the obtained optimum conditions (Table 3,
entries 1–3). When nicotinates 4Ab and 4Ac were em-
ployed, yields of products 1Ab and 1Ac were somewhat
lower than that of 1Aa, which is presumably due to the ste-
ric repulsion from the adjacent methyl group or due to its
electron-donating effect (entries 1 and 2). On the contrary,
the nicotinate 4Ad15 revealed similar reactivity to 4Aa
despite the presence of a bulky phenyl group (entry 3).
When 2-(4-methoxyphenyl)nicotinate 4Ba7a,16 was subject-
ed to this ring closure, only a trace amount of 1Ba18 was de-
tected because the methoxy group serves as an electron-
withdrawing group at the meta-position (entry 4). Further-
more, hydrolysis of the methoxy group also occurred. This
problem was addressed by carrying out the reaction for a
longer duration to increase the yield of 1Ba to 31% (entry 5).
Other 2-(4-methoxyphenyl)nicotinates 4Bb–4Bd exhibited
similar reactivity to 4Ba leading to 1Bb–1Bd, respectively
1
2
3
4a
5
6
7
180
220
240
220
220
220
220
4
20
45
33
6
5
0
0
7
3
0
0
4
4
0.25
0.5
1
20
56
49
2
a An amount of 46% of nicotinic acid 5 was formed.
Since the cyclization was found to occur via nicotinic
acid 5 in PPA, another synthetic method was studied, that
involved three steps: hydrolysis of ester 4Aa, conversion
into acyl chloride 6, and intramolecular Friedel–Crafts reac-
tion (Scheme 4). However, the onychine (1Aa) was obtained
in 13% overall yield, which was lower than that of the one-
step ring closure of 4Aa conducted in PPA.
(entries 6–8). However, nicotinate 4Ca possessing
a
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M. Arita et al.
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Synthesis
stronger electron-withdrawing group afforded only a com-
plex reaction mixture under the same reaction conditions
(entry 9).
Table 4 Modification of the Phenolic Hydroxy Group
Me
N
Me
O
O
R-X (2 equiv)
base (2 equiv)
Table 3 Synthesis of Other Onychine Derivatives 1
N
1Ba
1Be–i
O
Me
RO
Me
N
HO
O
R3
R2
R3
R2
EtO
PPA
Entry RX
Base
Solvent
Temp Time Product Yield
220 °C
(°C)
(h)
(%)
N
4
1
R1
1
2
3
4
5
PrBr
K2CO3
DMF
80
80
25
25
25
14
1Be
1Bf
1Bg
1Bh
1Bi
93
R7
PhCH2Br
AllylCl
K2CO3
K2CO3
K2CO3
NEt3
DMF
14
5
67
83
53
55
Entry
Nicotinate
R1 R2
Time (h) Product
R7
acetone
DMF
R3
Yield (%)
AcCl
14
14
1
2
3
4
5
6
7
8
9
H
H
Me
Me
H
4Ab
4Ac
4Ad
4Ba
4Ba
4Bb
4Bc
4Bd
4Ca
1
1
1
1
4
4
4
4
4
H
1Ab
1Ac
1Ad
1Ba
1Ba
1Bb
1Bc
1Bd
1Ca
44
39
54
3
CF3SO2OTf
MeCN
H
Me
Ph
H
H
H
H
OMe
OMe
OMe
OMe
OMe
NO2
H
OH
OH
OH
OH
OH
NO2
1H and 13C NMR spectra were recorded on Bruker DPX-400 spectro-
meter (400 MHz and 100 MHz, respectively) in CDCl3 using TMS as an
internal standard. The assignments of the 13C NMR were performed
by DEPT experiments. A Shimadzu IR spectrophotometer equipped
with an ATR detector were used to record IR spectra. High-resolution
mass spectra were obtained on an AB SCEIX Triplet TOF 4600 mass
spectrometer. Melting points were recorded on a SRS-Optimelt auto-
mated melting point system and are uncorrected. Unless otherwise
noted, all reagents were purchased from commercial sources and
used without further purification.
H
H
31
20
13
31
0
H
Me
Me
H
Me
Ph
H
H
Although hydrolysis of a methoxy group occurred
during the cyclization of 1Ba, the formed phenolic hydroxy
group can be modified upon treatment with electrophiles
in the presence of a base (Table 4). When 1Ba was treated
with alkyl bromides in DMF, the O-alkylated products 1Be
and 1Bf were obtained (Table 4, entries 1 and 2). Allylation
was possible by treatment with allyl chloride in acetone
under mild conditions to afford 1Bg in high yield (entry 3).
O-Acetylation was also achieved in a similar manner to give
an ester 1Bh (entry 4). Trifluoromethanesulfonic anhydride
could also be used as an electrophile, and the corresponding
triflate 1Bi could be prepared (entry 5).
Ethyl 4-Methyl-2-phenylpyridine-3-carboxylate (4Aa);16 Typical
Procedure
To a solution of ethyl 3-amino-4-phenyl-2-butenoate (2A; 2.28 g, 12
mmol) in MeCN (15 mL) were added 2-butenal (3a; 0.5 mL, 6.0 mmol)
and FeCl3 (1.0 g, 6.0 mmol), and the resultant solution was heated at
150 °C for 1 h under microwave irradiation. After evaporation of the
solvent under reduced pressure, the residue was washed with H2O
(3 × 30 mL), and then extracted with chloroform (3 × 30 mL). The
combined organic layers were dried (MgSO4), filtered, and concen-
trated under reduced pressure. The crude residue was purified by
flash column chromatography on silica gel (hexane/EtOAc 8:2) to af-
ford 4Aa as a yellow oil; yield: 1.04 g (74%, 4.4 mmol).
In summary, a facile method for synthesizing onychines
was developed by the condensation of an enamino ester
with an α,β-unsaturated carbonyl compound in the pres-
ence of FeCl3, followed by intramolecular Friedel–Crafts
reaction. This method facilitates the modification of the on-
ychine framework by altering only the starting enamino
esters and enones, although the electron-withdrawing
group on the 2-phenyl group prevented the second cycliza-
tion step. Furthermore, hydrolysis of a methoxy group was
found to occur during the cyclization when 2-(4-methoxy-
phenyl)nicotinate was heated in PPA. The hydroxy group
was easily modified upon treatment with electrophiles
such as alkyl halides, acetyl chloride, and triflic anhydride,
which consequently afforded diverse onychine derivatives.
The present method will be useful for research of biological
activity of onychine and its derivatives.
1H NMR (CDCl3, 400 MHz): δ = 8.50 (1 H, d, J = 4.8 Hz), 7.52–7.49 (2 H,
m), 7.36–7.32 (3 H, m), 7.06 (1 H, d, J = 4.8 Hz), 4.18 (2 H, q, J = 7.2 Hz),
2.36 (3 H, s), 0.94 (3 H, t, J = 7.2 Hz).
13C NMR (CDCl3, 100 MHz): δ = 156.6 (C), 149.5 (CH), 145.5 (C), 140.0
(C), 129.2 (C), 128.6 (CH), 128.3 (CH), 123.6 (CH), 61.3 (CH2), 19.3
(CH3), 13.6 (CH3).
Ethyl 4,5-Dimethyl-2-phenylpyridine-3-carboxylate (4Ab)
Yield: 0.92 g (60%, 3.6 mmol): colorless plates; mp 59.1–59.9 °C.
IR (ATR): 1722, 1244, 698 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 8.45 (1 H, s), 7.57–7.55 (2 H, m), 7.42–
7.36 (3 H, m), 4.13 (2 H, q, J = 7.1 Hz), 2.32 (3 H, s), 2.31 (3 H, s), 1.02
(3 H, t, J = 7.1 Hz).
13C NMR (CDCl3, 100 MHz): δ = 169.61 (C), 154.4 (C), 150.2 (CH),
143.5 (C), 140.1 (C), 130.7 (C), 129.3 (C), 128.3 (CH), 128.24 (CH),
128.23 (CH), 61.4 (CH2), 16.6 (CH3), 16.2 (CH3), 13.6 (CH3).
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M. Arita et al.
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Synthesis
HRMS (ESI/TOF): m/z [M + H]+ calcd for C16H18NO2: 256.1132; found:
256.1139.
13C NMR (CDCl3, 100 MHz): δ = 169.8 (C), 159.8 (C), 156.9 (C), 152.3
(C), 142.7 (C), 133.0 (C), 130.9 (CH), 130.6 (CH), 129.6 (CH), 128.2 (C),
127.4 (C), 113.7 (CH), 61.2 (CH2), 55.3 (CH3), 23.6 (CH3), 16.8 (CH3),
14.9 (CH3), 13.8 (CH3).
Ethyl 4,5,6-Trimethyl-2-phenylpyridine-3-carboxylate (4Ac)
HRMS (ESI/TOF): m/z [M + H]+ calcd for C18H22NO3: 300.1594; found:
Yield: 0.56 g (35%, 2.1 mmol); colorless solid; mp 96.4–96.9 °C.
300.1580.
IR (ATR): 1724, 1259, 698 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 7.56–7.54 (2 H, m), 7.40–7.35 (3 H, m),
4.10 (2 H, q, J = 7.2 Hz), 2.60 (3 H, s), 2.31 (3 H, s), 2.27 (3 H, s), 0.99 (3
H, t, J = 7.2 Hz).
13C NMR (CDCl3, 100 MHz): δ = 169.6 (C), 157.1 (C), 152.9 (C), 142.9
(C), 140.5 (C), 128.7 (C), 128.3 (CH), 128.21 (CH), 128.17 (CH), 127.6
(C), 61.3 (CH2), 23.6 (CH3), 16.8 (CH3), 14.9 (CH3), 13.6 (CH3).
Ethyl 2-(4-Methoxyphenyl)-4-methyl-6-phenylpyridine-3-carbox-
ylate (4Bd)
Yield: 1.35 g (65%, 3.9 mmol); yellow oil.
IR (ATR): 1718, 1514, 1268, 1250, 1177, 1093, 694 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 8.09 (2 H, d, J = 6.8 Hz), 7.67 (2 H, d, J =
8.8 Hz), 7.53 (1 H, br q, J = 0.4 Hz), 7.48–7.41 (3 H, m), 6.96 (2 H, d, J =
8.8 Hz), 4.20 (2 H, q, J = 7.1 Hz), 3.85 (3 H, s), 2.47 (3 H, br d, J = 0.4 Hz),
1.11 (3 H, t, J = 7.1 Hz).
HRMS (ESI/TOF): m/z [M + H]+ calcd for C17H20NO2: 270.1489; found:
270.1483.
13C NMR (CDCl3, 100 MHz): δ = 169.4 (C), 157.0 (C), 160.2 (C), 156.0
(C), 146.2 (C), 138.8 (C), 133.0 (C), 129.9 (CH), 129.3 (CH), 128.7 (CH),
127.2 (CH), 127.1 (C), 119.6 (CH), 113.7 (CH), 61.4 (CH2), 55.4 (CH3),
19.7 (CH3), 13.9 (CH3).
HRMS (ESI/TOF): m/z [M + H]+ calcd for C22H22NO3: 348.1594; found:
348.1596.
Ethyl 4-Methyl-2,6-diphenylpyridine-3-carboxylate (4Ad)15
Yield: 1.03 g (54%, 3.3 mmol); yellow oil.
1H NMR (CDCl3, 400 MHz): δ = 8.10–8.07 (2 H, m), 7.97–7.93 (1 H, m),
7.70–7.68 (2 H, m), 7.17 (1 H, s), 7.48–7.40 (5 H, m), 4.14 (2 H, q, J =
7.1 Hz), 2.49 (3 H, s), 1.03 (3 H, t, J = 7.1 Hz).
13C NMR (CDCl3, 100 MHz): δ = 169.0 (C), 157.1 (C), 156.6 (C), 146.3
(C), 140.4 (C), 138.6 (C), 129.3 (CH), 128.6 (CH), 128.5 (CH), 128.2
(CH), 127.4 (C), 127.2 (CH), 120.1 (CH), 61.3 (CH2), 19.7 (CH3), 13.7
(CH3).
Ethyl 4-Methyl-2-(4-nitrophenyl)pyridine-3-carboxylate (4Ca)
Yield: 1.22 g (71%, 4.3 mmol); yellow oil.
IR (ATR): 1725, 1523, 1349 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 8.60 (1 H, d, J = 5.4 Hz), 8.28 (2 H, d, J =
8.8 Hz), 7.76 (2 H, d, J = 8.8 Hz), 7.24 (1 H, d, J = 5.4 Hz), 4.16 (2 H, q, J =
7.1 Hz), 2.46 (3 H, s), 1.08 (3 H, t, J = 7.1 Hz).
Ethyl 2-(4-Methoxyphenyl)-4-methylpyridine-3-carboxylate
(4Ba)16
Yield: 1.20 g (74%, 4.4 mmol); yellow solid; mp 57.7–58.3 °C.
13C NMR (CDCl3, 100 MHz): δ = 13.8 (CH3), 19.5 (CH3), 61.8 (CH2),
123.5 (CH), 123.8 (C), 124.8 (CH), 129.4 (CH), 146.2 (C), 146.3 (C),
147.9 (C), 149.9 (CH), 154.3 (C), 167.8 (C).
1H NMR (CDCl3, 400 MHz): δ = 8.53 (1 H, d, J = 5.0 Hz), 7.54 (2 H, d, J =
8.9 Hz), 7.09 (1 H, d, J = 5.0 Hz), 6.94 (2 H, d, J = 8.9 Hz), 4.17 (2 H, q, J =
7.1 Hz), 3.84 (3 H, s), 2.40 (3 H, s), 1.01 (3 H, t, J = 7.1 Hz).
HRMS (ESI/TOF): m/z [M + H]+ calcd for C15H14N2O4: 287.1026; found:
287.1025.
13C NMR (CDCl3, 100 MHz): δ = 168.9 (C), 160.1 (C), 156.1 (C), 149.5
(CH), 145.3 (C), 132.6 (C), 129.6 (CH), 123.1 (CH), 113.7 (CH), 61.4
(CH2), 55.3 (CH3), 19.3 (CH3), 13.8 (CH3).
4-Methyl-2-phenylpyridine-3-carboxylic Acid (5)
Ethyl 2-(4-methoxyphenyl)-4,5-dimethylpyridine-3-carboxylate
(4Bb)
To a solution of NaOH (3.2 g, 80 mmol) in H2O (8 mL) was added ethyl
4-methyl-2-phenylpyridine-3-carboxylate (4Aa; 484 mg, 2.0 mmol),
and the resultant solution was heated at 100 °C for 3 d. After washing
with CH2Cl2 (3 × 30 mL), the pH value of the aqueous layer was adjust-
ed to 4, and concentrated under reduced pressure. The residue was
extracted with hot MeOH (3 × 10 mL), and the MeOH was evaporated.
The residue was subjected to flash column chromatography on silica
gel (MeOH/CH2Cl2 1:3) to afford 5 as a white powder; yield: 188 mg
(44%, 0.88 mmol); mp 100.5–101.2 °C.
1H NMR (DMSO-d6, 400 MHz): δ = 8.50 (2 H, d, J = 4.9 Hz), 7.70–7.68
(2 H, m), 7.43–7.41 (3 H, m), 7.26 (1 H, d, J = 4.9 Hz), 3.17 (1 H, s), 2.34
(3 H, s).
13C NMR (DMSO-d6, 100 MHz): δ = 170.3 (C), 153.5 (C), 148.3 (CH),
143.6 (C), 140.0 (C), 128.3 (CH), 128.2 (CH), 127.9 (CH), 123.6 (CH),
18.9 (CH3).
Yield: 0.96 g (56%, 3.4 mmol); yellow solid; mp 75.6–76.3 °C.
IR (ATR): 1719, 1248, 1176 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 8.42 (1 H, s) 7.52 (2 H, d, J = 8.8 Hz),
6.93 (2 H, d, J = 8.8 Hz), 4.17 (2 H, q, J = 7.2 Hz), 3.83 (3 H, s), 2.30 (3 H,
s), 2.29 (3 H, s), 1.09 (3 H, t, J = 7.2 Hz).
13C NMR (CDCl3, 100 MHz): δ = 169.4 (C), 159.9 (C), 153.9 (C), 150.2
(CH), 143.3 (C), 132.7 (C), 130.2 (C), 129.6 (CH), 129.5 (CH), 129.0 (C),
113.9 (CH), 113.7 (CH), 61.4 (CH2), 55.3 (CH3), 16.6 (CH3), 16.2 (CH3),
13.8 (CH3).
HRMS (ESI/TOF): m/z [M + H]+ calcd for C17H20NO3: 286.1438; found:
286.1424.
Ethyl2-(4-Methoxyphenyl)-4,5,6-trimethylpyridine-3-carboxylate
(4Bc)
4-Methyl-5H-indeno[1, 2-b] pyridin-5-one (Onychine, 1Aa);8–12
Yield: 0.90 g (50%, 3.0 mmol); yellow solid; mp 85.9–86.8 °C.
Typical Procedure
IR (ATR): 1718, 1515, 1248, 1173 cm–1
.
A solution of ethyl 4-methyl-2-phenylpyridine-3-carboxylate (4Aa;
33.2 mg, 0.14 mmol) in polyphosphoric acid (1 mL) was heated at
220 °C for 1 h. After the pH value of the mixture was adjusted to 8, the
mixture was extracted with CH2Cl2 (3 × 15 mL). The combined organic
1H NMR (CDCl3, 400 MHz): δ = 7.51 (2 H, d, J = 8.8 Hz), 6.92 (2 H, d, J =
8.8 Hz), 4.14 (2 H, q, J = 7.1 Hz), 3.82 (3 H, s), 2.58 (3 H, s), 2.29 (3 H, s),
2.25 (3 H, s), 1.07 (3 H, t, J = 7.1 Hz).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–G

F
M. Arita et al.
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Synthesis
layers were dried (MgSO4), filtered, and concentrated under reduced
pressure to afford onychine (1Aa) as yellow needles; yield: 15.3 mg
(56%, 0.078 mmol); mp 137.2–137.4 °C.
1H NMR (CDCl3, 400 MHz): δ = 8.34 (1 H, d, J = 5.3 Hz), 7.79 (1 H, dd,
J = 7.4, 1.1 Hz), 7.62 (1 H, dd, J = 7.4, 1.1 Hz), 7.51 (1 H, ddd, J = 7.4, 7.4,
1.1 Hz), 7.35 (1 H, ddd, J = 7.4, 7.4, 1.1 Hz), 6.91 (1 H, d, J = 5.3 Hz),
2.63 (3 H, s).
13C NMR (CDCl3, 100 MHz): δ = 192.8 (C), 164.7 (C), 151.9 (CH), 148.2
(C), 142.4 (C), 135.1 (CH), 134.8 (C), 131.1 (CH), 126.1 (C), 126.0 (CH),
123.8 (CH), 121.3 (CH), 17.4 (CH3).
8-Hydroxy-3,4-dimethyl-5H-indeno[1, 2-b] pyridin-5-one (1Bb)
Yield: 6.3 mg (20%, 0.028 mmol); yellow needles; mp 144.0–144.9 °C.
IR (ATR): 1719, 1515, 1295, 1250, 1176 cm–1
.
1H NMR (DMSO-d6, 400 MHz): δ = 10.2–10.3 (1 H, br), 8.29 (1 H, s),
7.59 (1 H, d, J = 7.8 Hz), 7.05–7.02 (2 H, m), 2.53 (3 H, s), 2.25 (3 H, s).
13C NMR (DMSO-d6, 100 MHz): δ = 193.0 (C), 163.3 (C), 160.0 (C),
152.6 (CH), 145.9 (C), 136.5 (C), 133.3 (C), 131.9 (C), 124.5 (C), 121.7
(CH), 121.2 (CH), 110.4 (CH), 15.3 (CH3), 12.9 (CH3).
HRMS (ESI/TOF): m/z [M + H]+ calcd for C14H15NO2: 226.0862; found:
226.0872.
3,4-Dimethyl-5H-indeno[1, 2-b] pyridin-5-one (1Ab)
8-Hydroxy-2,3,4-trimethyl-5H-indeno[1,2-b]pyridin-5-one (1Bc)
Yield: 12.9 mg (44%, 0.062 mmol); yellow needles; mp 144.6–
145.3 °C.
Yield: 4.4. mg (13%, 0.02 mmol); yellow solid; mp 143.0–143.4 °C.
IR (ATR): 1720, 1271 cm–1
.
IR (ATR): 1711, 746 cm–1
.
1H NMR (DMSO-d6, 400 MHz): δ = 10.7–9.8 (1 H, br), 7.54 (1 H, d, J =
8.7 Hz), 7.01–6.99 (2 H, m), 2.52 (3 H, s), 2.52 (3 H, s), 2.17 (3 H, s).
13C NMR (DMSO-d6, 100 MHz): δ = 193.0 (C), 162.2 (C), 160.7 (C),
159.9 (C), 145.4 (C), 136.7 (C), 133.2 (C), 129.3 (C), 122.9 (C), 121.5
(CH), 120.8 (CH), 110.4 (CH), 23.7 (CH3), 13.7 (CH3), 13.1 (CH3).
1H NMR (CDCl3, 400 MHz): δ = 8.28 (s, 1 H), 7.78 (1 H, dd, J = 7.6, 1.2
Hz), 7.66 (1 H, dd, J = 7.6, 1.2 Hz), 7.55 (1 H, ddd, J = 7.6, 7.6, 1.2 Hz),
7.38 (1 H, ddd, J = 7.6, 7.6, 1.2 Hz), 2.58 (3 H, s), 2.27 (3 H, s).
13C NMR (CDCl3, 100 MHz): δ = 193.7 (C), 163.4 (C), 153.0 (CH), 146.7
(C), 143.1 (C), 135.1 (C), 134.9 (CH), 133.3 (C), 130.4 (CH), 125.6 (C),
123.7 (CH), 120.4 (CH), 16.1 (CH3), 13.4 (CH3).
HRMS (ESI/TOF): m/z [M + H]+ calcd for C15H14NO2: 240.1019; found:
HRMS (ESI/TOF): m/z [M + H]+ calcd for C14H12NO: 210.0913; found:
240.1029.
210.0912.
8-Hydroxy-2-phenyl-4-methyl-5H-indeno[1,2-b]pyridin-5-one
(1Bd)
2,3,4-Trimethyl-5H-indeno[1, 2-b] pyridin-5-one (1Ac)
Yield: 12.5 mg (31%, 0.043 mmol); yellow solid; mp 191.2–191.7 °C.
Yield: 12.2 mg (39%, 0.055 mmol); yellow needles; mp 154.5–
155.4 °C.
IR (ATR): 1709, 1570, 1290, 1250, 803 cm–1
.
IR (ATR): 1706, 886, 745 cm–1
.
1H NMR (DMSO-d6, 400 MHz): δ = 10.9–9.8 (1 H, br), 8.14–8.12 (2 H,
m), 7.73 (1 H, d, J = 8.0 Hz), 7.67 (1 H, s), 7.59–7.55 (3 H, m), 7.08–7.06
(2 H, m), 2.62 (3 H, s).
13C NMR (DMSO-d6, 100 MHz): δ = 192.2 (C), 165.5 (C), 160.5 (C),
159.2 (C), 147.4 (C), 137.7 (C), 137.2 (C), 133.1 (C), 129.9 (CH), 128.8
(CH), 127.1 (CH), 123.8 (C), 122.2 (CH), 121.0 (CH), 120.7 (CH), 110.4
(CH), 17.0 (CH3).
1H NMR (CDCl3, 400 MHz): δ = 7.70 (1 H, d, J =7.4 Hz), 7.56 (1 H, d, J =
7.4 Hz), 7.44 (1 H, ddd, J = 7.4, 7.4, 1.2 Hz), 7.28 (1 H, ddd, J = 7.4, 7.4,
1.2 Hz), 2.51 (3 H, s), 2.50 (3 H, s), 2.13 (3 H, s).
13C NMR (CDCl3, 100 MHz): δ = 192.8 (C), 161.3 (C), 160.1 (C), 145.1
(C), 142.1 (C), 134.2 (C), 133.6 (CH), 129.9 (C), 129.1 (CH), 123.0 (C),
122.4 (CH), 119.2 (CH), 23.0 (CH3), 13.3 (CH3), 12.6 (CH3).
HRMS (ESI/TOF): m/z [M + H]+ calcd for C19H14NO2: 288.1019; found:
288.1018.
HRMS (ESI/TOF): m/z [M + H]+ calcd for C15H14NO: 224.1069; found:
224.1070.
4-Methyl-2-phenyl-5H-indeno[1, 2-b] pyridin-5-one (1Ad)19
4-Methyl-8-propoxy-5H-indeno[1,2-b]pyridin-5-one (1Be);
Typical Procedure
Yield: 20.6 mg (54%, 0.076 mmol); yellow solid; mp 121.3–121.6 °C.
To a solution of 7-hydroxy-4-methyl-5H-indeno[1, 2-b] pyridin-5-
one (1Ba; 1.0 mg, 4.7 μmol) in DMF (1 mL), 1-bromopropane (0.71 μL,
9.5 μmol) was added, and the resultant solution was heated at 80 °C
for 14 h. After evaporation, the residue was washed with H2O (10 mL),
and then extracted with CHCl3 (3 × 10 mL). The combined organic lay-
ers were dried (MgSO4), filtered, and concentrated under reduced
pressure to afford 1Be as a yellow solid; yield: 1.1 mg (93%, 4.3 μmol);
mp 79.7–80.5 °C.
1H NMR (CDCl3, 400 MHz): δ = 8.11 (2 H, d, J = 6.6 Hz), 7.93 (1 H, d, J =
7.4 Hz), 7.69 (1 H, d, J = 7.4 Hz), 7.57 (1 H, t, J = 7.4 Hz), 7.52–7.38 (5 H,
m), 2.67 (3 H, s).
13C NMR (CDCl3, 100 MHz): δ = 193.1 (C), 165.7 (C), 160.8 (C), 147.8
(C), 143.2 (C), 138.5 (C), 135.6 (C), 134.7 (CH), 130.7 (CH), 129.8 (CH),
128.8 (CH), 127.3 (CH), 124.5 (C), 123.5 (CH), 122.2 (CH), 120.9 (CH),
17.6 (CH3).
IR (ATR): 1716, 1567 cm–1
.
8-Hydroxy-4-methyl-5H-indeno[1, 2-b] pyridin-5-one (1Ba)
1H NMR (CDCl3, 400 MHz): δ = 8.34 (1 H, d, J = 5.2 Hz), 7.71 (1 H, d, J =
8.4 Hz), 7.20 (1 H, d, J = 2.4 Hz), 7.06 (1 H, dd, J = 2.4, 8.4 Hz), 6.87 (1 H,
d, J = 5.2 Hz), 3.99 (2 H, t, J = 6.4 Hz), 2.60 (3 H, s), 1.84 (2 H, tq, J = 6.4,
7.2 Hz), 1.06 (3 H, t, J = 7.2 Hz).
Yield: 9.2 mg (31%, 0.043 mmol); yellow solid; mp 225.2–225.7 °C.
1H NMR (DMSO-d6, 400 MHz): δ = 8.40 (1 H, d, J = 5.3 Hz), 7.64 (1 H, d,
J = 7.4 Hz), 7.08–7.04 (3 H, m), 2.67 (3 H, s).
13C NMR (DMSO-d6, 100 MHz): δ = 192.6 (C), 165.1 (C), 160.4 (C),
152.8 (CH), 146.6 (C), 136.4 (C), 133.2 (C), 124.9 (C), 124.7 (CH), 122.1
(CH), 121.1 (CH), 110.4 (CH), 16.6 (CH3).
13C NMR (CDCl3, 100 MHz): δ = 193.2 (C), 165.8 (C), 161.9 (C), 152.7
(CH), 147.3 (C), 136.9 (C), 135.3 (C), 126.1 (C), 124.8 (CH), 122.1 (CH),
120.9 (CH), 109.5 (CH), 70.2 (CH2), 22.5 (CH2), 17.3 (CH3), 10.4 (CH3).
HRMS (ESI/TOF): m/z [M + H]+ calcd for C16H16NO2: 254.1175; found:
254.1183.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–G

G
M. Arita et al.
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Synthesis
8-Benzyloxy-4-methyl-5H-indeno[1, 2-b] pyridin-5-one (1Bf)
Yield: 0.95 mg (67%, 3.2 μmol); yellow needles; mp 140.3–141.1 °C.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1612058.
IR (ATR): 1708, 1566, 1292, 999, 740 cm–1
.
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1H NMR (CDCl3, 400 MHz): δ = 8.34 (1 H, d, J = 5.2 Hz), 7.73 (1 H, d, J =
8.0 Hz), 7.45–7.36 (5 H, m), 7.29 (1 H, d, J = 2.4 Hz), 7.14 (1 H, dd, J =
2.4, 8.0 Hz), 6.87 (1 H, d, J = 5.2 Hz), 5.14 (2 H, s), 2.59 (3 H, s).
References
13C NMR (CDCl3, 100 MHz): δ = 193.0 (C), 165.7 (C), 161.4 (C), 152.8
(CH), 147.4 (C), 136.9 (C), 136.2 (C), 135.8 (C), 128.7 (CH), 128.3 (CH),
127.5 (CH), 126.1 (C), 124.9 (CH), 122.1 (CH), 121.3 (CH), 109.9 (CH),
70.6 (CH2), 17.3 (CH3).
HRMS (ESI/TOF): m/z [M + H]+ calcd for C20H16NO2: 302.1175; found:
302.1175.
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Maia, J. G. S. Phytochemistry 1976, 15, 1186.
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4-Methyl-8-(3-propenyloxy)-5H-indeno[1,2-b]pyridin-5-one (1Bg)
Yield: 0.98 mg (83%, 3.9 μmol); yellow needles; mp 80.9–81.9 °C.
IR (ATR): 1710, 1599, 1567 cm–1
.
(6) Leboeuf, M.; Cavé, A. Lloydia 1976, 39, 459.
1H NMR (CDCl3, 400 MHz): δ = 8.34 (1 H, d, J = 5.6 Hz), 7.72 (1 H, d, J =
8.4 Hz), 7.22 (1 H, d, J = 2.4 Hz), 7.08 (1 H, dd, J = 8.4, 2.4 Hz), 6.88 (1 H,
d, J = 5.6 Hz), 6.05 (1 H, ddt, J = 17.6, 10.4, 5.2 Hz), 5.42 (1 H, ddt, J =
17.6, 1.6, 1.6 Hz), 5.34 (1 H, ddt, J = 10.4, 1.6, 1.6 Hz), 4.62 (2 H, ddd, J =
5.2, 1.6, 1.6 Hz), 2.60 (3 H, s).
13C NMR (CDCl3, 100 MHz): δ = 193.1 (C), 165.7 (C), 161.3 (C), 152.8
(CH), 147.4 (C), 136.9 (C), 135.7 (C), 132.5 (CH), 126.1 (C), 124.9 (CH),
122.1 (CH), 121.2 (CH), 118.2 (CH2), 109.7 (CH), 69.27 (CH2), 17.3
(CH3).
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HRMS (ESI/TOF): m/z [M + H]+ calcd for C16H15NO2: 252.1019; found:
252.1031.
8-Acetoxy-4-methyl-5H-indeno[1,2-b]pyridin-5-one (1Bh)
Yield: 0.63 mg (53%, 2.5 μmol); yellow oil.
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dron 2004, 60, 2181.
IR (ATR): 1766, 1716, 1600, 1570, 1195, 740 cm–1
.
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1H NMR (CDCl3, 400 MHz): δ = 8.41 (1 H, d, J = 5.2 Hz), 7.84 (1 H, d, J =
8.0 Hz), 7.43 (1 H, d, J = 2.4 Hz), 7.28 (1 H, dd, J = 8.0, 2.4 Hz), 6.96 (1 H,
d, J = 5.2 Hz), 2.62 (3 H, s), 2.33 (3 H, s).
13C NMR (CDCl3, 100 MHz): δ = 190.9 (C), 167.9 (C), 163.7 (C), 152.0
(CH), 151.9 (C), 146.8 (C), 138.3 (C), 135.4 (C), 126.8 (CH), 125.3 (C),
124.7 (CH), 120.8 (CH), 116.5 (CH), 20.0 (CH3), 16.3 (CH3).
HRMS (ESI/TOF): m/z [M + H]+ calcd for C15H12NO3: 254.0811; found:
254.0821.
4-Methyl-8-(trifluoromethanesulfonyloxy)-5H-indeno[1, 2-b]
pyridin-5-one (1Bi)
Yield: 0.89 mg (55%, 2.6 μmol); yellow needles; mp 95.3–96.0 °C.
IR (ATR): 1716, 1573, 1213, 1139, 732 cm–1
.
1H NMR (CDCl3, 400 MHz): δ = 8.47 (1 H, d, J = 5.2 Hz), 7.94 (1 H, d, J =
8.0 Hz), 7.59 (1 H, d, J = 8.0 Hz), 7.49 (1 H, d, J = 8.0, 2.4 Hz), 7.04 (1 H,
d, J = 5.2 Hz), 2.65 (3 H, s).
13C NMR (CDCl3, 100 MHz): δ = 190.7 (C), 163.8 (C), 153.5 (CH), 151.2
(C), 148.2 (C), 142.8 (C), 136.9 (C), 127.5 (CH), 126.4 (CH), 122.5 (CH),
117.1 (CH), 17.5 (CH3).
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Soedin. 1990, 950.
HRMS (ESI/TOF): m/z [M + H]+ calcd for C14H9F3NO4S: 344.0198;
found: 344.0208.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–G