Transition-Metal-Free Synthesis of Pyridine Derivatives by Thermal Cyclization of N -Propargyl Enamines

Article abstract of DOI:10.1055/s-0039-1691575

A transition-metal-free synthesis of pyridine derivatives by 6- endo - dig cyclization of N -propargyl enamines was developed. This method is environmentally friendly and is a high atom economy reaction that is easily accessed to provide pyridine derivatives in moderate to good yield by heating N -propargyl enamines in solvent without additives. The total synthesis of onychine was achieved in 51% yield in only two steps by using this method.

Full text of DOI:10.1055/s-0039-1691575

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2020, 52, A–I
paper
A
en
Y. Chikayuki et al.
Paper
Synthesis
Transition-Metal-Free Synthesis of Pyridine Derivatives by
Thermal Cyclization of N-Propargyl Enamines
Yuya Chikayuki
Thermal Cyclization
Takakane Miyashige
EWG
EWG
1) neat, rt
Shiori Yonekawa
+
2) nitrobenzene
190 °C, air
Akiko Kirita
O
R
N
R
NH2
Natsuko Matsuo
20 examples
up to 95% yield
EWG: CONHR, COR, CO2R, CN
Hiroyoshi Teramoto
Shigeru Sasaki
one-pot synthesis
additive-free
metal-free cyclization
high atom economy
under air atmosphere
Kimio Higashiyama
Takayasu Yamauchi*
simple operation
Institute of Medicinal Chemistry, Hoshi University,
Ebara, Shinagawa, Tokyo 142-8501, Japan
yamauchi@hoshi.ac.jp
Received: 16.11.2019
Accepted after revision: 27.12.2019
Published online: 21.01.2020
O
O
N
DOI: 10.1055/s-0039-1691575; Art ID: ss-2019-f0633-op
CF3
N
N
H
N
N
Abstract A transition-metal-free synthesis of pyridine derivatives by
6-endo-dig cyclization of N-propargyl enamines was developed. This
method is environmentally friendly and is a high atom economy reac-
tion that is easily accessed to provide pyridine derivatives in moderate
to good yield by heating N-propargyl enamines in solvent without addi-
tives. The total synthesis of onychine was achieved in 51% yield in only
two steps by using this method.
O
P2Y12 receptor antagonist
O
N
NH2
H
H
N
N
Key words enaminone, onychine, high atom economy, green chemis-
try, one-pot synthesis, additive-free
O
F
histone deacetylase inhibitor
CH3
H3C
N
Pyridine, a nitrogen-containing heterocycle, is frequent-
ly found in natural products and bioactive compounds, but
it is also an important part of the skeleton found in mole-
cules used in a broad range of fields including pharmaceuti-
cals, agrichemicals, and functional materials.1 Moreover,
pyridines are also employed as key intermediates to pre-
pare biologically active compounds, such as purinergic
P2Y12 receptor antagonists,2 histone deacetylase inhibitors,3
and phosphodiesterase 10A PET tracers (Figure 1).4 Toward
these practical applications, a great deal of effort has been
devoted by many researchers to the development of various
pyridine derivatives.
Enaminones are readily obtained by condensation of
amines, and -ketoamides, -diketones, and -ketoesters
have been used as important synthons for ambident nucle-
ophiles.5 In the past few decades, synthesis of pyridine de-
rivatives by cyclization using transition metals has been re-
ported.6 In 2008, Cacchi et al. reported the selective trans-
formation from N-propargyl -enaminone into pyridines by
using CuBr as a catalyst.7a Additionally, Kelgokmen et al.
achieved the synthesis of polysubstituted pyridine deriva-
tives by a cyclization reaction with ZnCl2 (Scheme 1).7b In
O
N
N
18F
N
phosphodiesterase 10A tracer
Figure 1 Chemical structures of biologically active compounds con-
taining pyridine
general, although transition-metal-catalyzed reactions are
an efficient strategy to synthesize heterocycles, they have
serious drawbacks such as the use of an expensive, environ-
mentally unfriendly and poisonous reagent and potential
contamination of the final drug product.8 From the view-
point of the development of sustainable chemistry and the
pharmaceutical industry, metal-free conditions are strong-
ly desired to achieve target chemical conversion.9 Several
syntheses of pyridine derivatives by transition-metal-free
reactions have been reported, but the use of NaOH10 or 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU)11 is required, and
some of the reactions have to be carried out under an inert
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Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Y. Chikayuki et al.
Paper
Synthesis
gas. To solve these problems, we have developed a strategy
for synthesizing pyridine derivatives by using only solvent
and substrate without other additives.
Table 1 Screening of the Reaction Conditionsa
O
O
solvent
N
Ph
N
Ph
H
H
Cacchi's work (ref 7a)
N
N
H
1a
2a
O
CuBr
DMSO, 60 °C
O
HN
Ph
Entry
Solvent
Temp. (°C)
Time (h)
Yield (%)
N
Ph
1
2
3
4
5
6
7
8
ethylene glycol
DMF
140
140
140
140
140
140
140
190
16
6
trace
trace
trace
16
Kelgokmen's work (ref 7b)
DMAc
23
18
22
44
45
1.5
Ph
O
DMSO
Ph
N
O
ZnCl2
DCM, 40 °C
o-dichlorobenzene
anisole
20
Ph
HN
Ph
14
Ph
nitrobenzene
nitrobenzene
21
Ph
41
This work
a Reactions were carried out by heating 1a (0.4 mmol) in solvent (40 mL)
under air.
EWG
HN
R1
N
clization yield would make it difficult to judge the differ-
ences in reactivity. Therefore, we decided to proceed with
using 1c, which was estimated to be more stable (Table 2).
When the reaction was carried out at 170 °C, the reaction
was not completed; when the temperature was raised to
190 °C, the starting material disappeared and 2c was ob-
tained in 42% yield (entry 1). The reaction was then carried
out at 190 °C, and the yield of 2c was improved further (en-
try 2). From this result, it was established that 190 °C was
the most efficient temperature for the cyclization condi-
tion. When the experiment was carried out in the presence
nitrobenzene, 190 °C
R2
EWG
R2
R1
Scheme 1 Conversion of N-propargylenamines into pyridine derivatives
In preliminary studies, N-benzyl-3-(propargylamino)-
but-2-enamide (1a), easily prepared by the condensation of
N-benzyl-3-oxobutanamide and propargylamine, was cho-
sen as the model substrate for the optimization of the reac-
tion conditions; the results are summarized in Table 1. Ini-
tially, after heating of 1a with ethylene glycol as a solvent at
140 °C, only a trace of pyridine derivative was obtained
without pyrrole (entry 1). When an aprotic polar solvent
such as DMF, DMAc or DMSO was used, a cyclized product
was formed in trace, trace and 16% yield, respectively (en-
tries 2–4). It was found that cyclized product 2a was ob-
tained, albeit in low yield, by using an aromatic solvent
such as o-dichlorobenzene, anisole, or nitrobenzene (en-
tries 5–7). Based on these results, an aromatic compound
was found to be suitable as the solvent in this reaction, and
nitrobenzene was used to further improve the yield. As
shown in entry 7, since the progress of the reaction was
slow at 140 °C, the temperature was increased to 190 °C,
the reaction time was shortened and the yield improved
(entry 8). In the 1H NMR spectra of the crude product in this
reaction, nothing was observed other than cyclized pyri-
dine. We anticipate that thermal decomposition of the sub-
strate or intermediates occurred.
Table 2 Screening of the Reaction Temperature and Nitrobenzene
Concentrationa
O
O
nitrobenzene
Ph
Ph
N
N
H
1c
2c
Entry
Conc. (M)
Temp. (°C)
Time (h)
Yield (%)
1
2
3
4
5
6
7b
0.01
0.01
0.02
0.04
0.08
0.2
170–190
190
18
15
20
19
14
15
8
42
70
47
53
46
50
51
190
190
190
Encouraged by the results, which demonstrated the fea-
sibility of a straightforward synthesis of pyridine by cy-
clization of 1a, we decided to study the conditions further
using nitrobenzene as solvent. However, when optimizing
the conditions using 1a, there was concern that the low cy-
190
0.2
190
a Reactions were carried out by heating 1c (0.4 mmol) in nitrobenzene under
air.
b Reaction was performed under microwave irradiation.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

C
Y. Chikayuki et al.
Paper
Synthesis
EWG
R
EWG
EWG
R
nitrobenzene
190 °C
+
N
O
R
N
NH2
H
1
2
EWG = amide, ketone, ester, nitrile
O
O
O
Ph
N
O
O
O
2c, R = H, 70%
2d, R = Me, 74%
2e, R = OMe, 79%
2f, R = F, 65%
2g, R = Cl, 67%
S
O
N
Ph
Ph
H
H
N
N
N
Ph
2h, 72%a
N
N
N
R
2a, 41%
2b, 18%
2i, 73%
2j, 73%
O
N
O
O
O
O
O
O
O
OR
N
N
N
N
N
N
N
O
R
2o, R = Et, 50%
2p, R = i-Pr, 48%
2q, R = t-Bu, 18%
2r, 56%a
2k, 56%
2l, 45%
2m, 68%
2n, 32%
2s, R = H, 64%
2t, R = Cl, 95%
Scheme 2 Synthesis of pyridine derivatives. Reagents and conditions: Reactions were carried out with crude 1 in nitrobenzene by heating at 190 °C
under air. Isolated yield for two steps are given. a Enamines were synthesized from propargylamine and the corresponding ynones.
of a reduced amount of solvent, 2c was obtained with the
highest yield when 40 mL of nitrobenzene was used (en-
tries 2–7).
in a high yield. Thus, this method does not require complex
operations, and should be useful to easily access various
natural products using a limited number of steps.
Based on the optimal conditions (Table 2, entry 2), the
generality of this reaction and the scope of its application
for intramolecular cyclization was investigated; the results
are summarized in Scheme 2. First, the enamines were pre-
pared from propargylamine and -keto carbonyl com-
pounds or ynones. Then, nitrobenzene was added to the ob-
tained crude enamines and the mixture was heated at
190 °C open to the atmosphere. Amides 2a and 2b were ob-
tained low yields; however, pyridine derivatives were ob-
tained in good yields from aryl and heterocyclic ketones 2c–
j. Among the alkyl ketones, 2k, 2l and 2m were obtained
with moderate to good yields; however, cyclization of cyclic
ketone 1n resulted in low yield. In the cyclization of the es-
ters 1o–q, moderate yields were obtained along with a
small amount of carboxylic acid. Additionally, it seems that
the tert-butyl ester 1q decomposed at high temperature, re-
sulting in a remarkably low yield. When N-propargyl cya-
noenamines 1s and 1t were used as the starting material,
the corresponding 3-cyanopyridine derivatives were ob-
tained with excellent yield.
O
O
O
nitrobenzene
190 °C, 14 h
84%
EtOH
+
50°C, 17 h
61%
N
N
NH2
H
O
3
4
5
6
Scheme 3 Total synthesis of onychine
To investigate the reaction mechanism of this transfor-
mation, a control experiment was carried out using the
same method; the results are shown in Scheme 4. When
the substrate 1u, in which the terminal alkyne was 69%
deuterated, was reacted under the same conditions as 1r,
pyridine derivative 2u labeled with 66% deuterium at the
C4-position was obtained. This demonstrated that the
alkyne terminus of 1u corresponds to the C4-position of the
pyridine 2u.
66%
O
D
O
To further probe the synthetic potential of this method, we
attempted to apply it to the synthesis of a natural product.
Onychine, an azafluorenone alkaloid, was isolated from a
plant of the Annonaceae family,12 and has attracted atten-
tion for its potent antifungal and cytotoxic activities.13 Sev-
eral methods for the synthesis of onychine have been devel-
oped using a limited number of steps.14 Our method, as
shown in Scheme 3, is one of the most simple and efficient.
First, enamine 5 was obtained in a yield of 61% by dehydra-
tion condensation of commercially available but-2-yn-1-
amine (3) and 1,3-indanedione (4). Then, by applying the
above conditions to this enamine, onychine 6 was produced
72%
O
D
O
nitrobenzene
O
O
O
190 °C, 6 h
18%
N
H
N
D
O
69%
1u
2u
Scheme 4 Cyclization with deuterated enaminone 1u
On the basis of a previous study15 and the above result,
we propose that the reaction mechanism involves the steps
shown in Scheme 5. First, an aza-Claisen rearrangement
followed by tautomerization of N-propargyl enamine
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

D
Y. Chikayuki et al.
Paper
Synthesis
provides the allenic enamine 8. This rearranges by a 1,5-sig-
matropic hydrogen shift to the intermediate 9, which un-
dergoes 6 electron cyclization to the dihydropyridine 10.
Finally, oxidation occurs and pyridine derivative 2 is ob-
tained.
remove nitrobenzene (chloroform to EtOAc). The residue was purified
again by silica gel chromatography to afford the corresponding pyri-
dine 2.
N-Benzyl-2-methylnicotinamide (2a)
N-Benzyl-3-oxobutanamide (76.1 mg, 0.40 mmol) was added to prop-
argylamine (0.13 mL, 2.0 mmol) at r.t. and the mixture was stirred for
23 h. The reaction mixture was evaporated to afford 1a, which was
taken forward without further purification.
1H NMR (400 MHz, CDCl3):  = 1.98 (s, 3 H), 2.25 (t, J = 2.5 Hz, 1 H),
3.94 (dd, J = 2.5, 6.4 Hz, 2 H), 4.41–4.48 (m, 3 H), 5.18 (br, 1 H), 7.28–
7.35 (m, 5 H).
aza-Claisen
rearrangement
H
EWG
EWG
tautomerization
N
HN
H
1
7
6π-electron
cyclization
EWG
EWG
Compound 1a was reacted as described in the general procedure (1.5
h) and the product was purified by silica gel chromatography (CHCl3/
MeOH = 20:1) to afford 2a.
1,5-H shift
H2N
HN
8
9
Yield: 36.8 mg (0.16 mmol, 41%); black oil.
IR (film): 1634, 3270 cm–1
.
EWG
1H NMR (400 MHz, CDCl3):  = 2.66 (s, 3 H), 4.61 (s, 1 H), 4.63 (s, 1 H),
6.24 (br, 1 H), 7.13 (dd, J = 4.9, 7.7 Hz, 1 H), 7.31–7.37 (m, 5 H), 7.66
(dd, J = 1.7, 7.7 Hz, 1 H), 8.51 (dd, J = 1.7, 4.9 Hz, 1 H).
EWG
oxidation
N
H
N
13C NMR (100 MHz, CDCl3):  = 22.9, 44.0, 120.7, 127.7, 127.9, 128.9,
10
2
131.7, 134.7, 137.9, 150.0, 156.1, 168.5.
HRMS (ESI+): m/z [M + H]+ calcd for C14H15N2O: 227.1184; found:
Scheme 5 Plausible reaction mechanism
227.1151.
In summary, a transition-metal-free synthesis of pyri-
dine derivatives by intramolecular cyclization of N-propar-
gyl enamines was developed. This is applicable to sub-
strates with various substituents, and in the case of sub-
strates with aromatic rings, pyridine derivatives were
obtained in good yield. This method is efficacious for the
synthesis of natural products and pharmaceuticals because
it is environmentally friendly and proceeds with high atom
economy.
2-Methyl-N-phenylnicotinamide (2b)16
3-Oxo-N-phenylbutanamide (67.6 mg, 0.38 mmol) was added to
propargylamine (0.13 mL, 2.0 mmol) at r.t. and the mixture was
stirred for 7 h. The reaction mixture was evaporated to afford 1b,
which was taken forward without further purification.
1H NMR (400 MHz, CDCl3):  = 2.03 (s, 3 H), 2.27 (t, J = 2.5 Hz, 1 H),
3.98 (dd, J = 2.5, 6.4 Hz, 2 H), 4.54 (s, 1 H), 6.63 (br, 1 H), 7.03 (t, J =
7.5 Hz, 1 H), 7.23 (t, J = 7.5 Hz, 2 H), 7.44 (d, J = 7.5 Hz, 2 H), 9.32 (br,
1 H).
Compound 1b was reacted as described in the general procedure (1.5
h) and the product was purified by silica gel chromatography (CHCl3/
MeOH = 10:1) to afford 2b.
1H and 13C NMR spectra were measured with a Bruker BioSpin
AVANCE III-400 spectrometer at 400 and 100 MHz, respectively. All
NMR spectra were measured in CDCl3. Chemical shifts are reported
downfield from TMS (0 ppm) for 1H NMR. For 13C NMR, chemical
shifts are reported relative to CDCl3 (77.2 ppm). Mass spectra were re-
corded with a JEOL JMS-T100LP mass spectrometer by electrospray
ionization (ESI). Infrared spectra were measured with a Perkin–Elmer
Spectrum Two. Microwave-assisted reactions were performed in a Bi-
otage Initiator 1 EXP using a sealed reaction vessel. Purification was
achieved by column chromatography using 63–210 mm silica gel 60N
(Kanto Chemical Co. Inc.). All melting points were measured with a
Yanagimoto Micro melting point apparatus without collection. Unless
otherwise noted, all materials were purchased from commercial
sources, and commercially available reagents were used without fur-
ther purification.
Yield: 14.2 mg (0.067 mmol, 18%); black oil.
1H NMR (400 MHz, CDCl3):  = 2.67 (s, 3 H), 7.15–7.20 (m, 2 H), 7.38
(t, J = 7.8 Hz, 2 H), 7.62 (d, J = 7.9 Hz, 2 H), 7.74 (d, J = 7.4 Hz, 1 H), 7.97
(br, 1 H), 8.53 (dd, J = 1.5, 4.9 Hz, 1 H).
3-Benzoyl-2-methylpyridine (2c)17
1-Phenyl-1,3-butanedione (64.4 mg, 0.40 mmol) was added to prop-
argylamine (0.21 mL, 3.3 mmol) at r.t. and the mixture was stirred for
13 h. The reaction mixture was evaporated to afford 1c, which was
taken forward without further purification.
1H NMR (400 MHz, CDCl3):  = 2.17 (s, 3 H), 2.32 (t, J = 2.5 Hz, 1 H),
4.09 (dd, J = 2.5, 6.1 Hz, 2 H), 5.76 (s, 1 H), 7.37–7.46 (m, 3 H), 7.84–
7.89 (m, 2 H), 11.38 (br, 1 H).
Compound 1c was reacted as described in the general procedure (8 h)
and the product was purified by silica gel chromatography (n-hexane/
EtOAc = 1:1) to afford 2c.
Cyclization of N-Propargyl Enamine; General Procedure
Propargylamine and -ketocarbonyl compound were stirred at r.t.
without solvent. After evaporating, crude N-propargyl enamine 1 was
stirred in nitrobenzene (40 mL) at 190 °C. The progress of reaction
was monitored by TLC. After completion of the reaction, the reaction
mixture was cooled and passed through a short silica gel column to
Yield: 54.8 mg (0.28 mmol, 70%); black oil.
1H NMR (400 MHz, CDCl3):  = 2.55 (s, 3 H), 7.24 (dd, J = 4.7, 7.4 Hz,
1 H), 7.50 (t, J = 7.7 Hz, 2 H), 7.60–7.66 (m, 2 H), 7.77–7.82 (m, 2 H),
8.65 (dd, J = 1.8, 4.9 Hz, 1 H).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

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Y. Chikayuki et al.
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Synthesis
(2-Methylpyridin-3-yl)(p-tolyl)methanone (2d)
1H NMR (400 MHz, CDCl3):  = 2.54 (s, 3 H), 7.16 (t, J = 8.8 Hz, 2 H),
7.24 (dd, J = 4.9, 7.7 Hz, 1 H), 7.62 (dd, J = 1.7, 7.7 Hz, 1 H), 7.82 (dd, J =
5.4, 8.9 Hz, 2 H), 8.64 (dd, J = 1.8, 4.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3):  = 23.3, 116.0 (d, J = 22.0 Hz), 120.4,
132.7 (d, J = 9.5 Hz), 133.3 (d, J = 2.9 Hz), 133.7, 135.9, 150.6, 156.4,
166.1 (d, J = 256.5 Hz), 195.4.
1-(p-Tolyl)butane-1,3-dione (69.1 mg, 0.39 mmol) was added to
propargylamine (0.13 mL, 2.0 mmol) at r.t. and stirred for 21 h. The
reaction mixture was evaporated to afford 1d, which was taken for-
ward.
1H NMR (400 MHz, CDCl3):  = 2.16 (s, 3 H), 2.31 (t, J = 2.5 Hz, 1 H),
2.38 (s, 3 H), 4.08 (dd, J = 2.5, 6.1 Hz, 2 H), 5.75 (s, 1 H), 7.20 (d, J =
8.0 Hz, 2 H), 7.77 (d, J = 8.2 Hz, 2 H), 11.34 (br, 1 H).
HRMS (ESI+): m/z [M + H]+ calcd for C13H11FNO: 216.0825; found:
216.0820.
Compound 1d was reacted as described in the general procedure
(17 h) and the product was purified by silica gel chromatography
(n-hexane/EtOAc = 2:1) to afford 2d.
(4-Chlorophenyl)(2-methylpyridin-3-yl)methanone (2g)
1-(4-Chlorophenyl)butane-1,3-dione (78.7 mg, 0.40 mmol) was add-
ed to propargylamine (0.20 mL, 3.0 mmol) at r.t. and the mixture was
stirred for 20 h. The reaction mixture was evaporated to afford 1g,
which was taken forward without further purification.
1H NMR (400 MHz, CDCl3):  = 2.17 (s, 3 H), 2.33 (t, J = 2.5 Hz, 1 H),
4.09 (dd, J = 2.5, 6.2 Hz, 2 H), 5.71 (s, 1 H), 7.37 (d, J = 8.6 Hz, 2 H), 7.80
(d, J = 8.6 Hz, 2 H), 11.38 (br, 1 H).
Yield: 61.2 mg (0.29 mmol, 74%); black oil.
IR (film): 1605, 1661 cm–1
.
1H NMR (400 MHz, CDCl3):  = 2.44 (s, 3 H), 2.53 (s, 3 H), 7.23 (dd, J =
5.0, 7.5 Hz, 1 H), 7.28 (d, J = 7.9 Hz, 2 H), 7.62 (dd, J = 1.8, 7.7 Hz, 1 H),
7.69 (d, J = 8.2 Hz, 2 H), 8.63 (dd, J = 1.8, 4.9 Hz, 1 H).
13C NMR (100 MHz, CDCl3):  = 21.9, 23.4, 120.5, 129.6, 130.3, 134.4,
134.5, 136.0, 145.0, 150.4, 156.4, 196.8.
Compound 1g was reacted as described in the general procedure
(18 h) and the product was purified by silica gel chromatography
(n-hexane/EtOAc = 2:1) to afford 2g.
HRMS (ESI+): m/z [M + H]+ calcd for C14H14NO: 212.1075; found:
212.1069.
Yield: 62.0 mg (0.27 mmol, 67%); black oil.
IR (film): 1586, 1670 cm–1
.
(4-Methoxyphenyl)(2-methylpyridin-3-yl)methanone (2e)
1H NMR (400 MHz, CDCl3):  = 2.54 (s, 3 H), 7.24 (dd, J = 4.9, 7.7 Hz,
1 H), 7.47 (d, J = 8.9 Hz, 2 H), 7.62 (dd, J = 1.7, 7.7 Hz, 1 H), 7.73 (d, J =
8.9 Hz, 2 H), 8.66 (dd, J = 1.8, 4.8 Hz, 1 H).
1-(4-Methoxyphenyl)butane-1,3-dione (79.6 mg, 0.41 mmol) was
added to propargylamine (0.18 mL, 2.8 mmol) at r.t. and the mixture
was stirred for 7 h. The reaction mixture was evaporated to afford 1e,
which was taken forward without further purification.
13C NMR (100 MHz, CDCl3):  = 23.5, 120.6, 129.2, 131.5, 133.6, 135.4,
1H NMR (400 MHz, CDCl3):  = 2.16 (s, 3 H), 2.31 (t, J = 2.5 Hz, 1 H),
3.84 (s, 3 H), 4.07 (dd, J = 2.5, 6.1 Hz, 2 H), 5.73 (s, 1 H), 6.91 (d, J =
8.9 Hz, 2 H), 7.85 (d, J = 8.9 Hz, 2 H), 11.29 (br, 1 H).
136.1, 140.5, 150.8, 156.7, 195.9.
HRMS (ESI+): m/z [M + H]+ calcd for C13H11ClNO: 232.0529; found:
232.0530.
Compound 1e was reacted as described in the general procedure
(14 h) and the product was purified by silica gel chromatography
(n-hexane/EtOAc = 2:1) to afford 2e.
Phenyl(2-phenylpyridin-3-yl)methanone (2h)
1,3-Diphenylprop-2-yn-1-one (82.5 mg, 0.40 mmol) was added to
propargylamine (0.13 mL, 2.0 mmol) at r.t. and the mixture was
stirred for 15 h. The reaction mixture was evaporated to afford 1h,
which was taken forward without further purification.
1H NMR (400 MHz, CDCl3):  = 2.31 (t, J = 2.5 Hz, 1 H), 3.95 (dd, J = 2.5,
6.3 Hz, 2 H), 5.85 (s, 1 H), 7.39−7.49 (m, 8 H), 7.90 (dd, J = 1.5, 8.1 Hz,
2 H), 11.33 (br, 1 H).
Yield: 74.0 mg (0.32 mmol, 79%); black oil.
IR (film): 1598, 1658 cm–1
.
1H NMR (400 MHz, CDCl3):  = 2.52 (s, 3 H), 3.89 (s, 3 H), 6.95 (d, J =
9.0 Hz, 2 H), 7.22 (dd, J = 5.0, 7.4 Hz, 1 H), 7.60 (dd, J = 1.7, 7.6 Hz, 1 H),
7.77 (d, J = 9.0 Hz, 2 H), 8.63 (dd, J = 1.8, 4.9 Hz, 1 H).
13C NMR (100 MHz, CDCl3):  = 23.3, 55.7, 114.1, 120.5, 129.9, 132.6,
134.6, 135.7, 150.3, 156.2, 164.3, 195.7.
Compound 1h was reacted as described in the general procedure
(8 h) and the product was purified by silica gel chromatography
(n-hexane/EtOAc = 3:1) to afford 2h.
HRMS (ESI+): m/z [M + H]+ calcd for C14H14NO2: 228.1025; found:
228.1026.
Yield: 75.1 mg (0.29 mmol 72%); black oil.
IR (film): 1426, 1666 cm–1
.
(4-Fluorophenyl)(2-methylpyridin-3-yl)methanone (2f)
1H NMR (400 MHz, CDCl3):  = 7.21–7.26 (m, 3 H), 7.30 (t, J = 7.8 Hz,
2 H), 7.39–7.47 (m, 2 H), 7.49–7.53 (m, 2 H), 7.63–7.77 (m, 2 H), 7.86
(dd, J = 1.8, 7.7 Hz, 1 H), 8.86 (dd, J = 1.8, 4.8 Hz, 1 H).
1-(4-Fluorophenyl)butane-1,3-dione (72.6 mg, 0.40 mmol) was add-
ed to propargylamine (0.21 mL, 3.2 mmol) at r.t. and the mixture was
stirred for 4 h. The reaction mixture was evaporated to afford 1f,
which was taken forward without further purification.
13C NMR (100 MHz, CDCl3):  = 121.6, 128.3, 128.4, 128.8, 129.1,
1H NMR (400 MHz, CDCl3):  = 2.17 (s, 3 H), 2.32 (t, J = 2.5 Hz, 1 H),
4.09 (dd, J = 2.5, 6.1 Hz, 2 H), 5.71 (s, 1 H), 7.07 (t, J = 8.8 Hz, 2 H), 7.87
(dd, J = 5.5, 8.9 Hz, 2 H), 11.34 (br, 1 H).
129.8, 133.4, 134.4, 136.5, 137.1, 139.2, 150.8, 157.4, 197.2.
HRMS (ESI+): m/z [M + H]+ calcd for C18H14NO: 260.1075; found:
260.1049.
Compound 1f was reacted as described in the general procedure
(24 h) and the product was purified by silica gel chromatography
(n-hexane/EtOAc = 2:1) to afford 2f.
(2-Methylpyridin-3-yl)(thiophen-2-yl)methanone (2i)
1-(Thiophen-2-yl)butane-1,3-dione (67.2 mg, 0.40 mmol) was added
to propargylamine (0.18 mL, 2.8 mmol) at r.t. and the mixture was
stirred for 20 h. The reaction mixture was evaporated to afford 1i,
which was taken forward without further purification.
Yield: 55.8 mg (0.26 mmol, 65%); black oil.
IR (film): 1598, 1665 cm–1
.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

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Synthesis
1H NMR (400 MHz, CDCl3):  = 2.15 (s, 3 H), 2.31 (t, J = 2.5 Hz, 1 H),
4.06 (dd, J = 2.5, 6.1 Hz, 2 H), 5.64 (s, 1 H), 7.06 (dd, J = 3.7, 5.0 Hz,
1 H), 7.45 (dd, J = 1.1, 5.0 Hz, 1 H), 7.55 (dd, J = 1.1, 3.7 Hz, 1 H), 11.02
(br, 1 H).
2,2-Dimethyl-1-(2-methylpyridin-3-yl)propan-1-one (2l)
5,5-Dimethylhexane-2,4-dione (57.0 mg, 0.40 mmol) was added to
propargylamine (0.13 mL, 2.0 mmol) at r.t. and the mixture was
stirred for 16 h. The reaction mixture was evaporated to afford 1l,
which was was taken forward without further purification.
1H NMR (400 MHz, CDCl3):  = 1.14 (s, 9 H), 2.05 (s, 3 H), 2.28 (t, J =
2.5 Hz, 1 H), 3.99 (dd, J = 2.5, 6.1 Hz, 2 H), 5.23 (s, 1 H), 10.96 (br, 1 H).
Compound 1i was reacted as described in the general procedure
(8 h) and the product was purified by silica gel chromatography
(n-hexane/EtOAc = 2:1) to afford 2i.
Yield: 59.0 mg (0.29 mmol, 73%); black oil.
Compound 1l was reacted as described in the general procedure
(11 h) and the product was purified by silica gel chromatography
(n-hexane/EtOAc = 2:1) to afford 2l.
IR (film): 1410, 1641 cm–1
.
1H NMR (400 MHz, CDCl3):  = 2.61 (s, 3 H), 7.15 (dd, J = 3.8, 4.8 Hz,
1 H), 7.24 (dd, J = 4.9, 7.6 Hz, 1 H), 7.40 (dd, J = 1.0, 3.8 Hz, 1 H), 7.74
(dd, J = 1.7, 7.7 Hz, 1 H), 7.79 (dd, J = 1.1, 4.9 Hz, 1 H), 8.64 (dd, J = 1.7,
4.9 Hz, 1 H).
13C NMR (100 MHz, CDCl3):  = 23.0, 120.2, 128.3, 133.7, 135.4, 135.6,
135.7, 144.1, 150.5, 156.3, 188.7.
Yield: 32.0 mg (0.18 mmol, 45%); black oil.
IR (film): 1647, 1688 cm–1
.
1H NMR (400 MHz, CDCl3):  = 1.26 (s, 9 H), 2.46 (s, 3 H), 7.12 (dd, J =
4.7, 7.8 Hz, 1 H), 7.45 (dd, J = 1.8, 7.7 Hz, 1 H), 8.53 (dd, J = 1.7, 4.8 Hz,
1 H).
13C NMR (100 MHz, CDCl3):  = 23.3, 27.1, 45.5, 119.9, 132.6, 135.9,
149.3, 154.2, 212.8.
HRMS (ESI+): m/z [M + H]+ calcd for C11H10NOS: 204.0483; found:
204.0453.
HRMS (ESI+): m/z [M + H]+ calcd for C11H10NO: 178.1232; found:
178.1216.
(Furan-2-yl)(2-methylpyridin-3-yl)methanone (2j)
1-(Furan-2-yl)butane-1,3-dione (60.0 mg, 0.40 mmol) was added to
propargylamine (0.13 mL, 2.0 mmol) at r.t. and the mixture was
stirred for 33 h. The reaction mixture was evaporated to afford 1j,
which was was taken forward without further purification.
1H NMR (400 MHz, CDCl3):  = 2.15 (s, 3 H), 2.31 (t, J = 2.5 Hz, 1 H),
4.07 (dd, J = 2.5, 6.1 Hz, 2 H), 5.70 (s, 1 H), 6.47 (dd, J = 1.7, 3.5 Hz,
1 H), 7.00 (dd, J = 0.6, 3.5 Hz, 1 H), 7.47 (dd, J = 0.7, 1.7 Hz, 1 H), 11.06
(br, 1 H).
Cyclohexyl(2-methylpyridin-3-yl)methanone (2m)
1-Cyclohexylbutane-1,3-dione (67.9 mg, 0.40 mmol) was added to
propargylamine (0.13 mL, 2.0 mmol) at r.t. and the mixture was
stirred for 12 h. The reaction mixture was evaporated to afford 1m,
which was taken forward without further purification.
1H NMR (400 MHz, CDCl3):  = 1.22–1.41 (m, 6 H), 1.76–1.81 (m, 4 H),
2.03 (s, 3 H), 2.15 (tt, J = 2.9, 14.6 Hz, 1 H), 2.28 (t, J = 2.5 Hz, 1 H), 3.99
(dd, J = 2.5, 6.1 Hz, 2 H), 5.06 (s, 1 H), 10.87 (br, 1 H).
Compound 1j was reacted as described in the general procedure
(9 h) and the product was purified by silica gel chromatography
(n-hexane/EtOAc = 2:1) to afford 2j.
Compound 1m was reacted as described in the general procedure
(10 h) and the product was purified by silica gel chromatography
(n-hexane/EtOAc = 2:1) to afford 2m.
Yield: 53.7 mg (0.29 mmol, 73%); black oil.
IR (film): 1649 cm–1
.
Yield: 55.4 mg (0.27 mmol, 68%); black oil.
1H NMR (400 MHz, CDCl3):  = 2.62 (s, 3 H), 6.60 (dd, J = 1.7, 3.6 Hz,
1 H), 7.07 (dd, J = 0.7, 3.6 Hz, 1 H), 7.24 (dd, J = 4.9, 7.7 Hz, 1 H), 7.72
(dd, J = 0.7, 1.6 Hz, 1 H), 7.79 (dd, J = 1.8, 7.7 Hz, 1 H), 8.64 (dd, J = 1.8,
4.9 Hz, 1 H).
13C NMR (100 MHz, CDCl3):  = 23.1, 112.7, 120.3, 121.4, 132.9, 136.0,
148.1, 150.8, 152.3, 157.0, 183.5.
IR (film): 1434, 1516, 1688, 2855, 2931 cm–1
.
1H NMR (400 MHz, CDCl3):  = 1.19–1.51 (m, 5 H), 1.66–1.75 (m, 1 H),
1.78–1.90 (m, 4 H), 2.63 (s, 3 H), 3.00 (tt, J = 3.2, 14.5 H, 1 H), 7.20 (dd,
J = 4.7, 7.8 Hz, 1 H), 7.76 (dd, J = 1.7, 7.8 Hz, 1 H), 8.57 (dd, J = 1.7,
4.9 Hz, 1 H).
13C NMR (100 MHz, CDCl3):  = 23.9, 25.7, 25.9, 28.7, 49.0, 120.6,
134.0, 134.9, 150.5, 157.2, 207.5.
HRMS (ESI+): m/z [M + H]+ calcd for C11H10NO2: 188.0712; found:
188.0685.
HRMS (ESI+): m/z [M + H]+ calcd for C13H18NO: 204.1388; found:
204.1358.
3-Acetyl-2-methylpyridine (2k)17
Acetylacetone (39.6 mg, 0.40 mmol) was added to propargylamine
(0.030 mL, 0.48 mmol) at r.t. and the mixture was stirred for 1 h. The
reaction mixture was evaporated to afford 1k, which was taken for-
ward without further purification.
1H NMR (400 MHz, CDCl3):  = 2.02 (s, 3 H), 2.02 (s, 3 H), 2.28 (t, J =
2.5 Hz, 1 H), 3.99 (dd, J = 2.5, 6.2 Hz, 2 H), 5.06 (s, 1 H), 10.77 (br, 1 H).
7,8-Dihydroquinolin-5(6H)-one (2n)16
Cyclohexane-1,3-dione (45.0 mg, 0.40 mmol) was added to propar-
gylamine (0.13 mL, 2.0 mmol) at r.t. and the mixture was stirred for
14 h. The reaction mixture was evaporated to afford 1n, which was
taken forward without further purification.
1H NMR (400 MHz, CDCl3):  = 1.95–2.03 (m, 2 H), 2.30–2.41 (m, 5 H),
3.87 (dd, J = 2.5, 5.2 Hz, 2 H), 5.17 (s, 1 H), 5.19 (br, 1 H).
Compound 1k was reacted as described in the general procedure
(4 h) and the product was purified by silica gel chromatography
(n-hexane/EtOAc = 2:1) to afford 2k.
Compound 1n was reacted as described in the general procedure
(12 h) and the product was purified by silica gel chromatography
(n-hexane/EtOAc = 2:1) to afford 2n.
Yield: 30.0 mg (0.22 mmol, 56%); black oil.
1H NMR (400 MHz, CDCl3):  = 2.60 (s, 3 H), 2.76 (s, 3 H), 7.24 (dd, J =
4.7, 7.8 Hz, 1 H), 7.97 (dd, J = 1.7, 7.8 Hz, 1 H), 8.60 (dd, J = 1.7, 4.8 Hz,
1 H).
Yield: 18.9 mg (0.13 mmol, 32%); black oil.
1H NMR (400 MHz, CDCl3):  = 2.18–2.25 (m, 2 H), 2.68–2.74 (m, 2 H),
3.14–3.20 (m, 2 H), 7.30 (dd, J = 4.8, 7.8 Hz, 1 H), 8.28 (dd, J = 1.8,
7.8 Hz, 1 H), 8.68 (dd, J = 1.8, 4.8 Hz, 1 H).
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

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Y. Chikayuki et al.
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Synthesis
Ethyl 2-Methylnicotinate (2o)18
1H NMR (400 MHz, CDCl3):  = 1.61 (s, 9 H), 2.81 (s, 3 H), 7.20 (dd, J =
4.8, 7.8 Hz, 1 H), 8.11 (dd, J = 1.8, 7.8 Hz, 1 H), 8.58 (dd, J = 1.8, 4.8 Hz,
1 H).
13C NMR (100 MHz, CDCl3):  = 25.0, 28.3, 82.1, 121.0, 127.5, 138.3,
151.4, 159.3, 166.2.
Ethyl 3-oxobutanoate (54.1 mg, 0.40 mmol) was added to propargyl-
amine (0.13 mL, 2.0 mmol) at r.t. and the mixture was stirred for 16 h.
The reaction mixture was evaporated to afford the cis/trans isomers
(1o/1o′ = 5:2), and was taken forward without further purification.
1H NMR (400 MHz, CDCl3):  (1o) = 1.23 (t, J = 7.1 Hz, 3 H), 2.01 (s,
3 H), 2.29 (t, J = 2.5 Hz, 1 H), 3.97 (dd, J = 2.5, 6.3 Hz, 2 H), 4.09 (q, J =
7.1 Hz, 2 H), 4.56 (s, 1 H), 8.63 (br, 1 H);  (1o′) = 1.26 (t, J = 7.1 Hz,
3 H), 2.31 (s, 3 H), 2.32 (t, J = 2.5 Hz, 1 H), 3.81 (dd, J = 2.5, 5.2 Hz, 2 H),
4.10 (q, J = 7.1 Hz, 2 H), 4.43 (br, 1 H), 4.65 (s, 1 H).
HRMS (ESI+): m/z [M + H]+ calcd for C11H16NO2: 194.1181; found:
194.1141.
Diethyl Pyridine-2,3-dicarboxylate (2r)19
Diethyl but-2-ynedioate (67.5 mg, 0.40 mmol) in EtOH (2 mL) was
added to propargylamine (0.026 mL, 0.40 mmol) at 0 °C. Subsequent-
ly, the mixture was stirred at r.t. for 14 h. The reaction mixture was
evaporated to afford cis/trans isomers (1r/1r′ = 10:7), which was tak-
en forward without further purification.
The mixture of 1o and 1o′ was reacted as described in the general
procedure (7 h) and the product was purified by silica gel chromatog-
raphy (n-hexane/EtOAc = 2:1) to afford 2o.
Yield: 32.9 mg (0.20 mmol, 50%); black oil.
1H NMR (400 MHz, CDCl3):  (1r) = 1.28 (t, J = 7.1 Hz, 3 H), 1.35 (t, J =
7.1 Hz, 3 H), 2.27 (t, J = 2.5 Hz, 1 H), 4.16 (q, J = 7.1 Hz, 2 H), 4.20 (dd, J
= 2.5, 6.1 Hz, 2 H), 4.30 (q, J = 7.1 Hz, 2 H), 5.35 (s, 1 H), 8.11 (br, 1 H);
 (1r′) = 1.26 (t, J = 7.1 Hz, 3 H), 1.36 (t, J = 7.1 Hz, 3 H), 2.34 (t, J =
2.5 Hz, 1 H), 3.82 (dd, J = 2.5, 5.2 Hz, 2 H), 4.13 (q, J = 7.1 Hz, 2 H), 4.34
(q, J = 7.1 Hz, 2 H), 4.50 (br, 1 H), 4.83 (s, 1 H).
1H NMR (400 MHz, CDCl3):  = 1.41 (t, J = 7.2 Hz, 3 H), 2.85 (s, 3 H),
4.39 (q, J = 7.1 Hz, 2 H), 7.22 (dd, J = 4.8, 7.9 Hz, 1 H), 8.19 (dd, J = 1.8,
7.8 Hz, 1 H), 8.60 (dd, J = 1.8, 4.8 Hz, 1 H).
Isopropyl 2-Methylnicotinate (2p)
Isopropyl 3-oxobutanoate (57.6 mg, 0.40 mmol) was added to propar-
gylamine (0.13 mL, 2.0 mmol) at r.t. and the mixture was stirred for
23 h. The reaction mixture was evaporated to afford cis/trans isomers
(1p/1p′ = 10:3), which was taken forward without further purifica-
tion.
The mixture of 1r and 1r′ was reacted as described in the general pro-
cedure (5 h) and the product was purified by silica gel chromatogra-
phy (n-hexane/EtOAc = 3:1) to afford 2r.
Yield: 49.2 mg (0.22 mmol, 56%); black oil.
1H NMR (400 MHz, CDCl3):  (1p) = 1.23 (d, J = 6.2 Hz, 6 H), 2.00 (d, J =
0.4 Hz, 3 H), 2.28 (t, J = 2.5 Hz, 1 H), 3.96 (dd, J = 2.5, 6.3 Hz, 2 H), 4.54
(s, 1 H), 4.99 (sept, J = 6.3 Hz, 1 H), 8.64 (br, 1 H);  (1p′) = 1.23 (d, J =
6.2 Hz, 6 H), 2.31 (s, 3 H), 2.31 (t, J = 2.5 Hz, 1 H), 3.81 (dd, J = 2.5,
5.0 Hz, 2 H), 4.20 (br, 1 H), 4.61 (s, 1 H), 5.01 (sept, J = 6.3 Hz, 1 H).
1H NMR (400 MHz, CDCl3):  = 1.39 (t, J = 7.1 Hz, 3 H), 1.43 (t, J =
7.2 Hz, 3 H), 4.40 (q, J = 7.2 Hz, 2 H), 4.47 (q, J = 7.2 Hz, 2 H), 7.49 (dd, J
= 4.8, 8.0 Hz, 1 H), 8.20 (dd, J = 1.7, 8.0 Hz, 1 H), 8.77 (dd, J = 1.7,
4.8 Hz, 1 H).
The mixture of 1p and 1p′ was reacted as described in the general
procedure (9 h) and the product was purified by silica gel chromatog-
raphy (n-hexane/EtOAc = 2:1) to afford 2p.
2-Phenylnicotinonitrile (2s)20
3-Oxo-3-phenylpropanenitrile (58.1 mg, 0.40 mmol) in EtOH (0.8 mL)
was added to propargylamine (51 L, 0.80 mmol) and AcOH (47 L,
0.80 mmol) at r.t. This mixture was heated to 50 °C and stirred for 12
h. The reaction mixture was evaporated to afford 1s, which was taken
forward without further purification.
1H NMR (400 MHz, CDCl3):  = 2.36 (t, J = 2.5 Hz, 1 H), 3.93 (dd, J = 2.5,
5.3 Hz, 2 H), 4.20 (s, 1 H), 4.56 (br, 1 H), 7.41−7.51 (m, 3 H), 7.55−7.60
(m, 2 H).
Yield: 34.3 mg (0.19 mmol, 48%); black oil.
IR (film): 1591, 1722, 2981 cm–1
.
1H NMR (400 MHz, CDCl3):  = 1.38 (d, J = 6.2 Hz, 6 H), 2.84 (s, 3 H),
5.26 (sept, J = 6.2 Hz, 1 H), 7.20 (dd, J = 4.8, 7.8 Hz, 1 H), 8.16 (dd, J =
1.8, 7.8 Hz, 1 H), 8.60 (dd, J = 1.8, 4.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3):  = 22.0, 24.7, 69.2, 121.2, 126.4, 138.7,
151.4, 159.6, 166.2.
Compound 1s was reacted as described in the general procedure
(used 20 mL of nitrobenzene, 5 h) and the product was purified by sil-
ica gel chromatography (n-hexane/EtOAc = 3:1) to afford 2s.
HRMS (ESI+): m/z [M + H]+ calcd for C10H14NO2: 180.1025; found:
180.1018.
Yield: 45.9 mg (0.26 mmol, 64%); yellow solid.
1H NMR (400 MHz, CDCl3):  = 7.36 (dd, J = 4.8, 7.9 Hz, 1 H), 7.48–7.57
(m, 3 H), 7.90–7.95 (m, 2 H), 8.07 (dd, J = 1.7, 7.9 Hz, 1 H), 8.87 (dd, J =
1.7, 4.8 Hz, 1 H).
tert-Butyl 2-Methylnicotinate (2q)
tert-Butyl 3-oxobutanoate (63.3 mg, 0.40 mmol) was added to prop-
argylamine (0.13 mL, 2.0 mmol) at r.t. and the mixture was stirred for
19 h. The reaction mixture was evaporated to afford cis/trans isomers
(1q/1q′ = 10:3), which was taken forward without further purifica-
tion.
1H NMR (400 MHz, CDCl3):  (1q) = 1.46 (s, 9 H), 1.98 (d, J = 0.5 Hz,
3 H), 2.27 (t, J = 2.5 Hz, 1 H), 3.95 (dd, J = 2.5, 6.3 Hz, 2 H), 4.50 (q, J =
0.5 Hz, 1 H), 8.59 (br, 1 H);  (1q′) = 1.47 (s, 9 H), 2.28 (s, 3 H), 2.30 (t, J
= 2.5 Hz, 1 H), 3.79 (dd, J = 2.5, 5.0 Hz, 2 H), 4.05 (br, 1 H), 4.57 (s, 1 H).
2-(4-Chlorophenyl)nicotinonitrile (2t)21
3-(4-Chlorophenyl)-3-oxopropanenitrile (71.8 mg, 0.40 mmol) in
EtOH (4 mL) was added to propargylamine (0.13 mL, 2.0 mmol) and
AcOH (0.11 mL, 2.0 mmol) at r.t. This mixture was heated to 50 °C and
stirred for 20 h. The reaction mixture was evaporated to afford 1t,
which was taken forward without further purification.
1H NMR (400 MHz, CDCl3):  = 2.37 (t, J = 2.5 Hz, 1 H), 3.93 (dd, J = 2.5,
5.3 Hz, 2 H), 4.22 (s, 1 H), 4.51 (br, 1 H), 7.43 (d, J = 8.6 Hz, 2 H), 7.52
(d, J = 8.6 Hz, 2 H).
The mixture of 1q and 1q′ was reacted as described in the general
procedure (3 h) and the product was purified by silica gel chromatog-
raphy (n-hexane/EtOAc = 2:1) to afford 2q.
Compound 1t was reacted as described in the general procedure (20
mL of nitrobenzene, 3 h) and the compound was purified by silica gel
chromatography (n-hexane/EtOAc = 3:2) to afford 2t.
Yield: 13.6 mg (0.070 mmol, 18%); black oil.
IR (film): 1438, 1570, 1720, 2978 cm–1
.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

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Y. Chikayuki et al.
Paper
Synthesis
Yield: 79.5 mg (0.38 mmol, 95%); white solid.
Ahmad, R. U.; Hudyana, H.; Dubois, K.; Schmidt, M. E.; Bormans,
G.; Koole, M. J. Nucl. Med. 2013, 54, 1285. (c) Celen, S.; Koole, M.;
Ooms, M.; De Angelis, M.; Sannen, I.; Cornelis, J.; Alcazar, J.;
Schmidt, M.; Verbruggen, A.; Langlois, X.; van Laere, K.; Andres,
J.-I.; Bormans, G. NeuroImage 2013, 82, 13. (d) Ooms, M.; Attili,
B.; Celen, S.; Koole, M.; Verbruggen, A.; van Laere, K.; Bormans,
G. J. Neurochem. 2016, 139, 897.
1H NMR (400 MHz, CDCl3):  = 7.40 (dd, J = 4.8, 7.9 Hz, 1 H), 7.51 (dd, J
= 2.0, 6.7 Hz, 5 H), 7.89 (dd, J = 2.0, 6.7 Hz, 1 H), 8.08 (dd, J = 1.8,
7.9 Hz, 1 H), 8.88 (dd, J = 1.8, 7.9 Hz, 1 H).
3-(But-2-yn-1-ylamino)-1H-inden-1-one (5)
But-2-yn-1-ylamine (106 mg, 1.0 mmol) in EtOH (2 mL) was added to
10 M NaOH aq (0.1 mL, 0.1 mmol) and stirred at 50 °C for 30 min. Af-
ter filtering the precipitate, 1,3-indanedione (731 mg, 5.0 mmol) was
added to the filtrate, and the mixture was stirred at 50 °C for 17 h. The
reaction mixture was evaporated and purified by silica gel chroma-
tography (n-hexane/EtOAc = 1:1) to afford 5.
(5) For recent reviews, see: (a) Al-Zaydi, K. M.; Nhari, L. M. Orient. J.
Chem. 2006, 22, 1. (b) Chattopadhyay, A. K.; Hanessian, S. Chem.
Commun. 2015, 51, 16437. (c) Chattopadhyay, A. K.; Hanessian,
S. Chem. Commun. 2015, 51, 16450.
(6) For recent articles, see: (a) Abbiati, G.; Arcadi, A.; Bianchi, G.;
Giuseppe, D. S.; Marinelli, F.; Rossi, E. J. Org. Chem. 2003, 68,
6959. (b) Fañanás, J. F.; Arto, T.; Mendoza, A.; Rodríguez, F. Org.
Lett. 2011, 13, 4184. (c) Yamamoto, S.; Okamoto, K.; Murakoso,
M.; Kuninobu, Y.; Takai, K. Org. Lett. 2012, 14, 3182. (d) Lee, H.;
Sim, Y.-K.; Park, J.-W.; Jun, C.-H. Chem. Eur. J. 2014, 20, 323.
(e) Luo, C.-Z.; Jayakumar, J.; Gandeepan, P.; Wu, Y.-C.; Cheng, C.-
H. Org. Lett. 2015, 17, 924. (f) Jiang, H.; Yang, J.; Tang, X.; Li, J.;
Wu, W. J. Org. Chem. 2015, 80, 8763. (g) Barday, M.; Ho, K. Y. T.;
Halsall, C. T.; Aïssa, C. Org. Lett. 2016, 18, 1756. (h) Galenko, A.
V.; Shakirova, F. M.; Galenko, E. E.; Novikov, M. S.; Khlebnikov, A.
F. J. Org. Chem. 2017, 82, 5367. (i) Nizami, T. A.; Hua, R. Tetrahe-
dron 2017, 73, 6080.
(7) (a) Cacchi, S.; Fabrizi, G.; Filisti, E. Org. Lett. 2008, 10, 2629.
(b) Kelgokmen, Y.; Cayan, Y.; Zora, M. Eur. J. Org. Chem. 2017,
7167.
(8) (a) Felpin, F. X.; Ayad, T.; Mitra, S. Eur. J. Org. Chem. 2006, 2679.
(b) Thomas, S. W.; Venkatesan, K.; Muller, P.; Swager, T. M.
J. Am. Chem. Soc. 2006, 128, 16641. (c) International Council for
Harmonization of Technical Requirements for Pharmaceuticals
for Human Use (ICH) Guideline for Elemental Impurities (Q3D),
2019; https://database.ich.org/sites/default/files/Q3D-R1EW-
G_Document_Step4_Guideline_2019_0322.pdf.
Yield: 120 mg (0.61 mmol, 61%); yellow solid. This compound was un-
stable that it was used immediately for the next reaction.
1H NMR (400 MHz, CDCl3):  = 1.86 (t, J = 2.4 Hz, 3 H), 4.08 (dq, J = 2.5,
7.6 Hz, 2 H), 4.96 (s, 1 H), 5.36 (br, 1 H), 7.07−7.12 (m, 1 H), 7.31−7.38
(m, 2 H), 7.44−7.49 (m, 1 H).
Onychine (6)14
Compound 5 (39.4 mg, 0.2 mmol) was reacted as described in the
general procedure (20 mL of nitrobenzene, 14 h) and the product was
purified by silica gel chromatography (n-hexane/EtOAc = 1:1) to af-
ford 6.
Yield: 32.6 mg (0.17 mmol, 84%); yellow solid.
1H NMR (400 MHz, CDCl3):  = 2.64 (d, J = 0.4 Hz, 3 H), 6.98 (dd, J = 0.5,
5.3 Hz, 1 H), 7.43 (dt, J = 1.0, 7.5 Hz, 1 H), 7.59 (dt, J = 1.0, 7.5 Hz, 1 H),
7.70 (d, J = 7.4 Hz, 1 H), 7.84 (d, J = 7.4 Hz, 1 H), 8.42 (d, J = 5.3 Hz,
1 H).
Supporting Information
(9) Sun, C. L.; Shi, Z. J. Chem. Rev. 2014, 114, 9219.
Supporting information for this article is available online at
(10) Cheng, G.; Weng, Y.; Yang, X.; Cui, X. Org. Lett. 2015, 17, 3790.
(11) Jiang, Y.; Park, C. M.; Loh, T. P. Org. Lett. 2014, 16, 3432.
(12) For representative isolation of onychine, see: (a) Almeida, M. E.
L.; Braz, R.; Bulow, F. V.; Gottlieb, O. R.; Maia, J. G. S. Phytochem-
istry 1976, 15, 1186. (b) Waterman, P. G.; Muhammad, I. Phyto-
chemistry 1985, 24, 523. (c) Goulart, M. O. F.; Santana, A. E. G.;
Oliveira, A. B.; Oliveira, G. G.; Maia, J. G. S. Phytochemistry 1986,
25, 1691. (d) Hufford, C. D.; Liu, S.; Clark, A. M. J. Nat. Prod. 1987,
50, 961. (e) Wu, Y.-C. Heterocycles 1989, 29, 463. (f) Chaves, M.
H.; Santos, L. A.; Lago, J. H. G.; Roque, N. F. J. Nat. Prod. 2001, 64,
240. (g) Achenbach, H.; Schwinn, A. Phytochemistry 1995, 38,
1037. (h) Prachayasittikul, S.; Manam, P.; Chinworrungsee, M.;
Isarankura-Na-Ayudhya, C.; Ruchirawat, S.; Prachayasittikul, V.
Molecules 2009, 14, 4414.
(13) For representative activity of onychine, see: (a) Ref. 12d.
(b) Koyama, J.; Morita, I.; Kobayashi, N.; Osakai, T.; Usuki, Y.;
Taniguchi, M. Bioorg. Med. Chem. Lett. 2005, 15, 1079. (c) Lago, J.
H. G.; Chaves, M. H.; Ayres, M. C. C.; Agripino, D. G.; Young, M. C.
M. Planta Med. 2007, 73, 292. (d) Marquise, N.; Chevallier, F.;
Nassar, E.; Frederich, M.; Ledoux, A.; Halauko, Y. S.; Ivashkevich,
O. A.; Matulis, V. E.; Roisnel, T.; Dorcet, V.; Mongin, F. Tetrahe-
dron 2016, 72, 825.
https://doi.org/10.1055/s-0039-1691575.
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References
(1) For reviews, see: (a) Zeni, G.; Larock, R. C. Chem. Rev. 2004, 104,
2285. (b) Varela, J. A.; Saa, C. Chem. Rev. 2004, 104, 3787.
(2) Bach, P.; Boström, J.; Brickmann, K.; van Giezen, J. J. J.; Hovland,
R.; Petersson, A. U.; Ray, A.; Zetterberg, F. Bioorg. Med. Chem.
Lett. 2011, 21, 2877.
(3) (a) Ning, Z.-Q.; Li, Z.-B.; Newman, M. J.; Shan, S.; Wang, X.-H.;
Pan, D.-S.; Zhang, J.; Dong, M.; Du, X.; Lu, X.-P. Cancer Chemo-
ther. Pharmacol. 2012, 69, 901. (b) Dong, M.; Ning, Z.-Q.; Xing,
P.-Y.; Xu, J.-L.; Cao, H.-X.; Dou, G.-F.; Meng, Z.-Y.; Shi, Y.-K.; Lu,
X.-P.; Feng, F.-Y. Cancer Chemother. Pharmacol. 2012, 69, 1413.
(c) Shi, Y.; Dong, M.; Hong, X.; Zhang, W.; Feng, J.; Zhu, J.; Yu, L.;
Ke, X.; Huang, H.; Shen, Z.; Fan, Y.; Li, W.; Zhao, X.; Qi, J.; Huang,
H.; Zhou, D.; Ning, Z.; Lu, X. Ann. Oncol. 2015, 26, 1766. (d) Lu,
X.; Ning, Z.; Li, Z.; Vao, H.; Wang, X. Intractable Rare Dis. Res.
2016, 5, 185. (e) Zhao, S.; Guo, J.; Zhao, Y.; Fei, C.; Zheng, Q.; Li,
X.; Chang, C. Am. J. Transl. Res. 2016, 8, 3169. (f) Jiang, Z.; Li, W.;
Hu, X.; Zhang, Q.; Sun, T.; Cui, S.; Wang, S.; Ouyang, Q.; Yin, Y.;
Geng, C.; Tong, Z.; Cheng, Y.; Pan, Y.; Sun, Y.; Wang, H.; Ouyang,
T.; Gu, K.; Feng, J.; Wang, X.; Wang, S.; Liu, T.; Gao, J.;
Cristofanilli, M.; Ning, Z.; Lu, X. Lancet Oncol. 2019, 20, 806.
(4) (a) Andres, J.-I.; De Angelis, M.; Alcazar, J.; Iturrino, L.; Langlois,
X.; Dedeurwaerdere, S.; Lenaerts, I.; Vanhoof, G.; Celen, S.;
Bormans, G. J. Med. Chem. 2011, 54, 5820. (b) van Laere, K.;
(14) For representative synthesis of onychine, see: (a) Koyama, J.;
Sugita, T.; Suzuta, Y.; Irie, H. Heterocycles 1979, 12, 1017.
(b) Tong, T. H.; Wong, H. N. C. Synth. Commun. 1992, 22, 1773.
(c) Rebstock, A.-S.; Mongin, F.; Trecourt, F.; Queguiner, G. Tetra-
hedron 2004, 60, 2181. (d) Clary, K. N.; Back, T. G. Synlett 2010,
2802. (e) Kraus, G. A.; Kempema, A. J. Nat. Prod. 2010, 73, 1967.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

I
Y. Chikayuki et al.
Paper
Synthesis
(f) Zhang, S.; Liao, L.-Y.; Zhang, F.; Duan, X.-F. J. Org. Chem. 2013,
78, 2720. (g) Taneichi, Y.; Shimada, K.; Korenaga, T. Heterocycles
2018, 96, 440. (h) Nishiyama, T.; Fujiwaki, T.; Hatae, N.;
Uchiyama, E.; Takeuchi, N.; Minami, K.; Yokoyama, C.; Kinoshita,
T.; Ishikura, M.; Hibino, S.; Choshi, T. Heterocycles 2018, 97, 383.
(i) Arita, M.; Yokoyama, S.; Asahara, H.; Nishiwaki, N. Synthesis
2019, 51, 2007.
(16) Allais, C.; Lieby-Muller, F.; Rodriguez, J.; Constantieux, T. Eur. J.
Org. Chem. 2013, 4131.
(17) Bellur, E.; Yawer, M.; Hussain, I.; Riahi, A.; Fatunsin, O.; Fischer,
C.; Langer, P. Synthesis 2009, 227.
(18) Ren, L.; Wang, L.; Lv, Y.; Shang, S.; Chen, B.; Gao, S. Green Chem.
2015, 4, 2369.
(19) Song, Z.; Huang, X.; Yi, W.; Zhang, W. Org. Lett. 2016, 18, 5640.
(20) Bessard, Y.; Crettaz, R. Heterocycles 1999, 51, 2589.
(21) Liu, C.; Wang, Q. Org. Lett. 2016, 18, 5118.
(15) (a) Berg-Nielsen, K.; Scattebol, L. Acta Chem. Scand., Ser. B 1978,
553. (b) Majumdar, K. C.; Samanta, S. K. Tetrahedron 2001, 57,
4955. (c) Xin, X.; Wang, D.; Li, X.; Wan, B. Tetrahedron 2013, 69,
10245.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I