Silica Gel-mediated Synthesis of β-Enamino Esters and its Application for the Synthesis of Indeno 4-Hydroxypyridin-2(1H)-Ones

Article abstract of DOI:10.1002/bkcs.11676

The full scope of SiO₂-based condensation of aliphatic or aromatic amines and β-keto esters to give β-enamino esters was examined. Functionalized linear β-enamino esters were easily obtained from SiO₂-based condensation of β-keto esters and amines only after simple filtration. It was also demonstrated that cyclic β-enamino esters with 99% purity can be prepared in a practically large scale (60 g) without using silica gel column chromatography. The utility of the present method was fortified by the preparation of pharmaceutically useful indeno-4-hydroxypyridin-2(1H)-one analogue 11.

Full text of DOI:10.1002/bkcs.11676

Article
DOI: 10.1002/bkcs.11676
BULLETIN OF THE
S.-H. Kim et al.
KOREAN CHEMICAL SOCIETY
Silica Gel-mediated Synthesis of β-Enamino Esters and its Application
for the Synthesis of Indeno 4-Hydroxypyridin-2(1H)-Ones
Soong-Hyun Kim,† Seri Bae,† Eun Bi Ko, Ga Young Park, Eunhye Lee, Hee Jong Hwang,
*
Chun Young Im, and Minsoo Song
Department of Medicinal Chemistry, New Drug Development Center (NDDC), Daegu-Gyeongbuk
Medical Innovation Foundation (DGMIF), Daegu 41061, South Korea. *E-mail: msong@dgmif.re.kr
†These authors contributed equally.
Received December 13, 2018, Accepted January 7, 2019
The full scope of SiO2-based condensation of aliphatic or aromatic amines and β-keto esters to give
β-enamino esters was examined. Functionalized linear β-enamino esters were easily obtained from SiO2-
based condensation of β-keto esters and amines only after simple filtration. It was also demonstrated that
cyclic β-enamino esters with 99% purity can be prepared in a practically large scale (60 g) without using
silica gel column chromatography. The utility of the present method was fortified by the preparation of
pharmaceutically useful indeno-4-hydroxypyridin-2(1H)-one analogue 11.
Keywords: SiO2-based condensation, β-keto ester, β-enamino ester, 4-hydroxypyridine-2(1H)-one
Introduction
carbonyl compounds. Additionally, its practical application
for the synthesis of pharmaceutically useful compounds
such as indeno-pyridine carboxylates (e.g., 11) is demon-
strated herein.
4-Hydroxypyridin-2(1H)-one comprises the core structure
of several biologically active natural products and pharma-
ceutical compounds such as illicicolin H,1 TAK-441,2 and
GSK360A3 (Figure 1). The synthesis of core
4-hydroxypyridin-2(1H)-ones typically involves alkylation
of corresponding cyclic anhydride with a malonate or ami-
dation by heating of N-alkylated aniline and triesters such
as triethyl methanetricarboxylate.3 Similarly, Rigby et al.
have utilized α,β-unsaturated isocyanates to produce
4-hydroxypyridin-2(1H)-one by the addition of ester eno-
lates to the electrophilic carbonyl carbon of the isocyanate
followed by cylization.4 Alternatively, the pyridone core
can be prepared from β-ketoesters by traditional amination
to give β-enamino esters, followed by cyclization with
diethyl malonate.2 Among these methods, the formation of
pyridinone core using β-ketoesters and amines as starting
materials has been widely used in the area of medicinal
chemistry research due to their experimental convenience
and versatility. As Sasaki et al. described, this process typi-
cally involves the condensation of amines in protic solvents
or in aprotic solvents with azeotropic removal of water.2
However, it also possesses some significant limitations in
practical use such as the long reaction time, harsh reaction
conditions, low chemical yields, and a narrow substrate tol-
erability. To overcome these limitations, Xu et al. nicely
described the formation of β-enamino carbonyl compounds
through silica gel-based solvent-free reactions of β-keto car-
bonyl compounds, with amines as a starting material.5
Intrigued by this synthetic methodology, we have decided
to investigate the full scope of this type of SiO2-based reac-
tion for the formation of linear and cyclic β-enamino
Results and Discussion
We initially screened the addition of various amines to
2-(methoxycarbonyl)cyclopentanone 1 (Table 1). In the
presence of SiO2 (1000 wt % was used for experimental
convenience), the condensation of most primary alkyl
amines with cyclic β-keto ester 1 (ratio 1:1) gave the
desired cyclic β-enamino esters with good yields (Table 1,
entry 1–8), while sterically bulkier aliphatic amines such as
dimethylamine and t-butyl amine gave no or only trace
amounts of desired products (entry 9 and 10). Functiona-
lized amines such as allylic amine, propargylic amine, and
ethanol amine were well tolerated to give cyclic β-enamino
esters with various functionalities in 66–73% yield (entry
11–13). When enantiomerically pure amine 2n was reacted
with β-keto ester 1, the condensation reaction was com-
pleted within an hour based on LCMS analysis. More
importantly, in this case, the enantiomeric ratio of (S)-
1-phenylethane-1-amine (2n) (>99.5:0.5, >99% ee) was
fully maintained throughout the reaction to give cyclic
β-enamino ester 3n with >99% ee in a ratio of 99.6:0.4
based on chiral HPLC analysis (entry 14). Amines posses-
sing pri- and sec-amines within the molecule, such as
4-amino piperidine 2o, gave the desired cyclic β-amino
ester in 85% yield without any competition with sec-amine
on the piperidine ring as expected (entry 15). Aromatic
amines with various substitutions (except electron with-
drawing groups) on the phenyl ring were generally well
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To understand the limitation of this SiO2-based conden-
sation reaction for β-enamino esters, we subjected 300 mg
of methyl 2-oxocyclopentane 1-carboxylate (1, 2.11 mmol)
to an amount of SiO2 varying up to 1 wt % (Table 3). We
found that 1 wt % SiO2 still gave the desired product 7 in
high yield (90%) (Table 3, entry 1–4). Encouraged by this
result, we ran the reaction in multigram scale in order to
demonstrate the practicality of our reaction. When 60 g of
1 was reacted with amine 6 in the presence of SiO2
(500 wt %) under mechanical stirring, we obtained the
desired product, after simple filtration using a glass filter, in
quantitative yield with 99% purity based on HPLC analysis
(Table 3, entry 5). No further purification such as silica gel
column chromatography was necessary. We believe that
this example strongly demonstrates the synthetic utility of
SiO2-based condensation of amines with β-keto esters for
the preparation of cyclic β-enamino esters in a large scale
setting.
As mentioned earlier, the synthetic utility of
4-hydroxypyridin-2(1H)-one analogues for the preparation
of pharmaceutically active compounds has been widely
demonstrated in the literature. For example, Smithkline
Beecham Co. (Philadelphia, PA, USA) has developed pro-
lyl hydroxylase inhibitors for anemia,3 and Martinez et al.
have reported the synthesis of allosteric inhibitor of GSK-
3β for chronic diseases such as congenital myotonic dys-
trophy type 1 (CDM1) and spinal muscular atrophy
(SMA)8 using 4-hydroxypyridin-2(1H)-one derivatives as
a core intermediate. Therefore, we decided to provide
Figure 1. Representative synthetic methods for 4-hydroxypyridin-
2(1H)-one core in natural products and pharmaceutically active
compounds.
tolerated. Most electron donating groups and halogens were
well suited to the condensation reactions and formed the
desired products in over 70% yields (entry 16–22). How-
ever, strong electron withdrawing groups, such as CF3,
esters, and nitro groups, were poorly tolerated and gave the
desired products in low yield or led to no reaction (entry
23–25). Finally, we were interested in finding out whether
a bare amine, such as AcONH4, can be tolerated in the
SiO2-based condensation reaction. It is clear from the litera-
ture that the desired product 3z can be used as a key inter-
mediate for the preparation of pharmaceutically important
compounds. For example, LG Life Sciences and Novartis
reported the synthesis of GPR120 agonists6 and PDE4
inhibitors,7 respectively, using 2-amino-1-cyclopentene car-
boxylate (3z) as a core intermediate. When 1.0 equiv of
AcONH4 was subjected to 1 in SiO2 following a typical
experimental procedure, the desired product cyclic pri-
amine 3z was obtained in 68% yield (entry 26).
Upon examining the scope of amine substrates, we paid
our attention to the structurally more complex β-keto esters,
such as 4a-d, which possess previously unknown complex-
ity (Table 2). Functionalized β-keto esters, such as
4-methoxy-3-oxobutanoate 4a and 3-oxo-3-phenyl pro-
panoate 4b, gave the product in 74 and 52% yield, respec-
tively (Table 2, entry 1 and 2). The E/Z ratio for
4-methoxy butenoate 5a was moderate, by giving an insep-
arable mixture of E and Z isomers in a ratio of 1:1. How-
ever, phenylacrylate 5b was obtained exclusively in the Z
configuration. Cyclic β-keto esters larger than five-
membered ring system presented some limitations in the
reaction outcome. β-Keto ester on a six-membered ring
gave an unidentifiable complex mixture probably due to
inherent 1,3-diaxial steric interactions in the ring (entry 3).
Seven-membered ring also gave the desired product in low
yield (Table 2, entry 4). It is not surprising that the corre-
sponding cyclic enamine was not obtained from cyclopeta-
none 4e, which does not have β-esters on the ring;
however, the imine obtained from the condensation reaction
was stable enough to give 5e after silica gel column in
moderate yield (41%).
another
important
example
of
synthesizing
4-hydroxypyridin-2(1H)-one analogues with more com-
plexity such as 11 using SiO2-based condensation of
amines and β-keto esters as a key step, as shown in
Scheme 1. 2,3-Dihydro-1H-indeno-1-one (8) (2g) was con-
verted to indene carboxylate 9 in 83% yield by carboxyla-
tion with dimethyl carbonate. Upon reaction with
phenethyl amine in the presence of SiO2 (1000 wt %) at
80 ꢀC, the desired β-enamino ester 10 was obtained in
66% yield within 4 h. Addition of ethyl malonyl chloride
followed by in situ cyclization using NaOEt at room tem-
perature directly gave the desired product 11 in over 80%
yield.
Experimental
General. All commercially available reagents were pur-
chased from Sigma Aldrich (St. Louis, MO, USA), Tokyo
Chemical Industry Co., Ltd. (TCI), Alfa Aesar (Ward Hill,
MA, USA), Fisher Scientific (Pittsburgh, PA, USA) and
used as received. All reaction mixtures were stirred magnet-
ically and monitored by thin-layer chromatography using
silica gel precoated glass plates, which were visualized with
UV light. Mass spectra were measured in positive electro-
spray ionization (ESI) mode on LCMS-2020 system
(Shimadzu, Tokyo, Japan). Flash column chromatography
was carried out using a CombiFlash® Rf system with
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Synthesis of β-Enamino Esters
KOREAN CHEMICAL SOCIETY
Table 1. Solvent-free synthesis of β-enamino esters with various amines.a
Entry
Amine
Yield (%)b
82
Entry
Amine
Yield (%)b
75
1
MeNH2 (2a)
14
(2n)
(2o)
2
i-PrNH2 (2b)
66
15
85
3
4
c-HexylNH2 (2c)
70
85
16
17
PhNH2 (2p)
p-Me-C6H4-NH2 (2q)
70
76
(2d)
5
76
18
p-MeO-C6H4-NH2 (2r)
79
(2e)
(2f)
(2g)
6
7
8
86
81
86
19
20
21
p-Me2N-C6H4-NH2 (2 s)
p-F-C6H4-NH2 (2 t)
p-Cl-C6H4-NH2 (2u)
77
71
58
(2h)
9
10
11
Me2NH (2i)
t-BuNH2 (2j)
N/R
3
71
22
23
24
p-Br-C6H4-NH2 (2v)
p-CF3-C6H4-NH2 (2w)
p-MeO2C-C6H4-NH2 (2x)
53
19
12
(2k)
(2l)
12
13
a
73
66
25
26
p-NO2-C6H4-NH2 (2y)
AcONH4 (2z)
N/R
68
(2m)
Reaction conditions: 1 (0.711 g, 5 mmol), SiO2 (7.11 g, 10 g per 1 g of 1), 2a-z (1.0 equiv), rt.
Isolated yield by flash column chromatography.
b
RediSep® Rf (Teledyne Isco, Lincoln, NE, USA). All
(A.KRÜSS Optronic). All known compounds, cyclic
β-enamino esters 3a,9 3m,10 3n,11 3p,12 3r,13 3z,14 5a,15
5b,16 5e,17 and 9,18 were identical with known value.
Typical Experimental Procedure. To a mixture of
1 (621 μL, 0.711 g, 5 mmol) and SiO2 (7.11 g, 10 g per
1 g of 1), was added corresponding amines 2a-z (1.0 equiv)
dropwise while stirring at rt. The resulting solid mixture
was typically stirred for 1 h to overnight at rt. Upon com-
plete consumption of starting material based on LCMS
NMR spectra were recorded on Bruker 400 (400 MHz for
1H NMR and 100 MHz for 13C NMR) spectrometer and
calibrated to the residual solvent peak or tetramethylsilane
(δ = 0 ppm). CDCl3 or CD3OD was used as the solvent.
High-resolution mass spectra (HRMS) were acquired on a
high-resolution Q-TOF mass spectrometer (ionization
mode: ESI). Melting points were determined in open capil-
lary tube using fully automatic melting point meter M5000
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Synthesis of β-Enamino Esters
KOREAN CHEMICAL SOCIETY
Table 2. Synthesis of β-enamino esters and imines with various β-keto esters and cyclic ketones.a
Entry
Ketone
Product
Yield (%)b
1
74 (E:Z = 1.0:1.1)
(4a)
(4b)
(5a)
(5b)
2
3
52 (Z only)
N/A (complex mixture)
(4c)
(5c)
4
17
41
(4d)
(4e)
(5d)
(5e)
5
a
Reaction conditions: All reactions were performed following typical experimental procedure. 4 (1.0 equiv), SiO2 (10 g per 1 g of 4), 2d (1.0
equiv), rt.
b
Isolated yield by flash column chromatography.
analysis, the solid mixture was purified by silica gel column
chromatography to give the desired products 3a-z upon
drying under vacuum (Table 1).
1.83 (p, J = 7.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
168.8, 165.9, 91.9, 50.0, 31.8, 31.0, 29.1, 20.8.
Methyl 2-(isopropylamino)cyclopent-1-ene-1-carboxylate
(3b). 0.181 mL (2.11 mmol, 1.0 equiv) of 2b was used to
give 254 mg of 3b (1.39 mmol, 66%) as pale yellow oil.
1H NMR (400 MHz, CDCl3) δ 7.35 (brs, NH), 3.60 (s, 3H),
3.58–3.51 (m, 1H), 2.57 (t, J = 7.6 Hz, 2H), 2.49 (t,
J = 7.2 Hz, 2H), 1.83 (p, J = 7.4 Hz, 2H), 1.19 (d, J = 6.4 Hz,
6H); 13C NMR (100 MHz, CDCl3) δ 168.8, 164.1, 91.6, 49.9,
46.2, 31.8, 28.7, 24.3, 21.1; HRMS (ESI): m/z [M + H]+ calcd
for C10H17NO2 184.1338, found 184.1329.
Methyl 2-(methylamino)cyclopent-1-ene-1-carboxylate
(3a).9 1.06 mL (2.11 mmol, 2 M solution in THF) of 2a
was used to give 267 mg of 3a (1.72 mmol, 82%) as a
1
beige solid. H NMR (400 MHz, CDCl3) δ 7.27 (brs, NH),
3.66 (s, 3H), 2.91 (d, J = 5.2 Hz, 3H), 2.57–2.50 (m, 4H),
Table 3. Multigram scale synthesis of cyclic β-enamino ester 7.a
Methyl 2-(cyclohexylamino)cyclopent-1-ene-1-carboxylate
(3c). 0.241 mL (2.11 mmol, 1.0 equiv) of 2c was used to give
1
331 mg of 3c (1.48 mmol, 70%) as colorless oil. H NMR
(400 MHz, CDCl3) δ 7.48 (brs, NH), 3.67 (s, 3H), 3.21–3.13
(m, 1H), 2.56 (t, J = 7.6 Hz, 2H), 2.49 (t, J = 7.18 Hz, 2H),
1.88–1.77 (m, 6H), 1.36–1.18 (m, 6H); 13C NMR (100 MHz,
CDCl3) δ 168.8, 164.3, 91.5, 53.3, 50.0, 34.6, 31.8, 28.7, 25.3,
24.7, 21.1; HRMS (ESI): m/z [M + H]+ calcd for C13H21NO2
224.1651, found 224.1639.
Entry
Amount of 1
SiO2 (wt %/1)
Yielda (%)
1
2
3
4
5
a
2.11 mmol (0.300 g)
2.11 mmol (0.300 g)
2.11 mmol (0.300 g)
2.11 mmol (0.300 g)
422 mmol (60.0 g)
1000
100
10
1
500
87
88
87
90
93
Methyl 2-(benzylamino)cyclopent-1-ene-1-carboxylate
(3d). 0.262 mL (2.11 mmol, 1.0 equiv) of 2d was used to
give 414 mg of 3d (1.79 mmol, 85%) as brown solid. mp
1
ꢀ
64.2 C, H NMR (400 MHz, CDCl3) δ 7.78 (brs, NH),
7.33 (m, 2H), 7.24 (m, 3H), 4.40 (d, J = 6.5 Hz, 2H), 3.69
(s, 3H), 2.54 (m, 4H), 1.82 (p, J = 7.6 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 168.8, 164.8, 139.2, 128.7, 127.3,
No further purification was performed after filtration using a glass
filter.
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Synthesis of β-Enamino Esters
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to give 447 mg of 3h (1.822 mmol, 86%) as brown oil. H
NMR (400 MHz, CDCl3) δ 7.45 (brs, NH), 7.31 (m, 2H),
7.24 (m, 1H), 7.19 (m, 2H), 3.67 (s, 3H), 3.41 (q,
J = 7.2 Hz, 2H), 2.82 (t, J = 7.2 Hz, 2H), 2.48 (t,
J = 7.0 Hz, 2H), 2.42 (t, J = 7.6 Hz, 2H), 1.77 (p,
J = 7.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 168.7,
164.7, 138.7, 128.8, 128.6, 126.5, 92.4, 50.1, 46.4, 37.8,
31.9, 29.0, 21.0; HRMS (ESI): m/z [M + H]+ calcd for
C15H19NO2 246.1494, found 246.1482.
Methyl 2-(tert-butylamino)cyclopent-1-ene-1-carboxy-
late (3j). 0.739 mL (7.03 mmol, 1.0 equiv) of 2j was used
1
to give 37 mg of 3j (0.188 mmol, 3%) as colorless oil. H
Scheme 1. Application of SiO2-based condensation of β-keto ester
for pharmaceutically useful 4-hydroxypyridin-2(1H)-one deriva-
tives. a8 (15.1 mmol), dimethyl carbonate (76.0 mmol), NaH
(31.8 mmol), THF (0.3 M), reflux, 2 h. bSiO2 (2.70 g, 10 g per
1 g of 9), 9 (1.43 mmol), phenethylamine (3.72 mmol), 80 ꢀC,
4 h.c 10 (5.90 mmol) in DCE (0.5 M), ethyl malonyl chloride
(11.8 mmol), reflux, 3 h; NaOEt (11.8 mmol), EtOH (0.5 M), rt.,
2 h. All reaction yields are isolated yields.
NMR (400 MHz, CDCl3) δ 8.01 (brs, NH), 3.67 (s, 3H),
2.69 (t, J = 7.5 Hz, 2H), 2.43 (t, J = 7.2 Hz, 2H), 1.81 (p,
J = 7.4 Hz, 2H), 1.33 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 168.9, 164.9, 93.3, 51.7, 50.0, 33.4, 30.9, 27.8,
21.9; HRMS (ESI): m/z [M + H]+ calcd for C11H19NO2
198.1494, found 198.1489.
Methyl 2-(allylamino)cyclopent-1-enecarboxylate (3k).
120 mg (2.11 mmol, 1.0 equiv) of 2k was used to give
271 mg of 3k (1.495 mmol, 71%) as colorless oil. 1H
NMR (400 MHz, CDCl3) δ 7.48 (brs, NH), 5.90–5.81 (m,
1H), 5.20 (dd, J = 17.1, 1.3 Hz, 1H), 5.13 (dd, J = 10.2,
1.4 Hz, 1H), 3.82–3.78 (m, 2H), 3.68 (s, 3H), 2.55–2.50
(m, 4H), 1.82 (p, J = 7.5 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 168.7, 164.9, 135.3, 115.6, 92.8, 50.1, 46.8,
31.7, 29.0, 20.9; HRMS (ESI): m/z [M + H]+ calcd for
C10H15NO2 182.1181, found 182.1172.
126.7, 93.1, 50.1, 48.4, 32.0, 29.1, 20.9; HRMS (ESI): m/z
[M + H]+ calcd for C14H17NO2 232.1338, found 232.1325.
Methyl 2-((thiophen-3-ylmethyl)amino)cyclopent-
1-enecarboxylate (3e). 239 mg (2.11 mmol, 1.0 equiv) of
2e was used to give 298 mg of 3e (1.256 mmol, 76%) as
colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.71 (brs,
NH), 7.31–7.29 (m, 1H), 7.11–7.10 (m, 1H), 6.98 (dd,
J = 5.0, 1.2 Hz, 1H), 4.39 (d, J = 6.36 Hz, 2H), 3.68 (s,
3H), 2.59–2.51 (m, 4H), 1.83 (p, J = 7.6 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 168.8, 164.6, 140.3, 126.5,
126.4, 121.2, 93.2, 50.1, 44.1, 31.9, 29.0, 20.9; HRMS
(ESI): m/z [M + H]+ calcd for C12H15NO2S 238.0902,
found 238.0890.
Methyl 2-(prop-2-yn-1-ylamino)cyclopent-1-enecar-
boxy-late (3l). 116 mg (2.11 mmol, 1.0 equiv) of 2l was
used to give 276 mg of 3l (1.540 mmol, 73%) as yellow
1
ꢀ
solid. mp 59.4 C; H NMR (400 MHz, CDCl3) δ 7.42
(brs, NH), 3.94 (dd, J = 6.4, 2.5 Hz, 2H), 3.68 (s, 3H),
2.64 (t, J = 7.6 Hz, 2H), 2.53 (t, J = 7.2 Hz, 2H), 2.26
(t, J = 2.4 Hz, 1H), 1.86 (p, J = 7.6 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 168.6, 163.5, 95.0, 80.3, 71.7,
50.2, 33.9, 31.7, 29.1, 20.7; HRMS (ESI): m/z [M + H]+
calcd for C10H13NO2 180.1025, found 180.1015.
Methyl 2-((thiophen-2-ylmethyl)amino)cyclopent-
1-enecarboxylate (3f). 239 mg (2.11 mmol, 1.0 equiv) of
2f was used to give 408 mg of 3f (1.719 mmol, 86%) as
1
yellow oil. H NMR (400 MHz, CDCl3) δ 7.73 (brs, NH),
7.21 (dd, J = 5.0, 1.3 Hz, 1H), 6.95–6.91 (m, 2H), 4.54 (d,
J = 6.4 Hz, 2H), 3.67 (s, 3H), 2.61 (t, J = 7.6 Hz, 2H),
2.53 (t, J = 7.12 Hz, 2H), 1.84 (p, J = 7.64 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 168.7, 163.9, 142.6, 126.9,
124.8, 124.7, 93.9, 50.2, 43.7, 31.9, 29.1, 20.9; HRMS
(ESI): m/z [M + H]+ calcd for C12H15NO2S 238.0902,
found 238.0890.
Methyl 2-((2-hydroxyethyl)amino)cyclopent-1-ene-1-
carboxylate (3m).10 129 mg (2.11 mmol, 1.0 equiv) of 2m
was used to give 257 mg of 3m (1.388 mmol, 66%) as
1
white solid. H NMR (400 MHz, CDCl3) δ 7.48 (brs, NH),
3.69 (s, 1H), 3.66 (m, 4H), 3.36 (m, 2H), 2.57 (t,
J = 6.8 Hz, 2H), 2.50 (t, J = 5.2 Hz, 2H), 1.83 (p,
J = 7.5 Hz, 2H); 13C NMR(100 MHz, CDCl3) δ 168.9,
165.3, 92.5, 77.1, 62.1, 50.2, 47.0, 32.1, 28.9, 20.8.
Methyl (S)-2-((1-phenylethyl)amino)cyclopent-1-ene-
1-carboxylate (3n).11 256 mg (2.11 mmol, 1.0 equiv) of
2n was used to give 387 mg of 3n (1.578 mmol, 75%)
as colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.83
(brs, NH), 7.31 (t, J = 7.6 Hz, 2H), 7.22 (m, 3H), 4.54
(q, J = 6.9 Hz, 1H), 3.69 (s, 1H), 2.45 (m, 3H), 2.19
(m, 1H), 1.67 (m, 1H), 1.49 (d, J = 7.6 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 168.9, 164.5, 145.2, 128.4,
127.0, 125.5, 93.1, 77.1, 54.3, 50.1, 32.3, 28.8,
24.9, 20.9.
Methyl 2-((furan-2-ylmethyl)amino)cyclopent-1-ene-
carboxy-late (3g). 205 mg (2.11 mmol, 1.0 equiv) of 2g
was used to give 379 mg of 3g (1.713 mmol, 81%) as color-
less oil. 1H NMR (400 MHz, CDCl3) δ 7.63 (brs, NH),
7.35–7.34 (m, 1H), 6.31–6.29 (m, 1H), 6.17–6.16 (m, 1H),
4.33 (d, J = 6.4 Hz, 2H), 3.67 (s, 3H), 2.63 (t, J = 7.6 Hz,
2H), 2.52 (t, J = 7.1 Hz, 2H), 1.84 (p, J = 7.6 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 168.7, 164.2, 152.3, 142.2, 110.3,
106.7, 93.7, 50.2, 41.7, 31.8, 29.1, 20.8; HRMS (ESI): m/z
[M + H]+ calcd for C12H15NO3 222.1130, found 222.1120.
Methyl 2-(phenethylamino)cyclopent-1-ene-1-carboxy-
late (3h). 0.262 mL (2.11 mmol, 1.0 equiv) of 2h was used
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Synthesis of β-Enamino Esters
KOREAN CHEMICAL SOCIETY
Methyl 2-(piperidin-4-ylamino)cyclopent-1-ene-1-car-
boxylate (3o). 0.232 mL (2.11 mmol, 1.0 equiv) of 2o was
used to give 404 mg of 3o (1.80 mmol, 85%) as white
123.1, 115.9, 115.6, 97.1, 77.1, 50.4, 32.2, 28.7, 21.6;
HRMS (ESI): m/z [M + H]+ calcd for C13H14FNO2
236.1087, found 236.1075.
1
ꢀ
solid. mp 100.3 C; H NMR (400 MHz, CDCl3) δ 7.49
(brs, NH), 3.67 (s, 3H), 3.31–3.26 (m, 1H), 3.09 (dt,
J = 12.9, 3.8 Hz, 2H), 2.68–2.62 (m, 2H), 2.57 (t,
J = 7.6 Hz, 2H), 2.50 (t, J = 7.0 Hz, 2H), 1.91–1.80 (m,
5H), 1.46–1.36 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
168.8, 163.8, 92.2, 51.8, 50.1, 45.1, 35.1, 31.9, 28.7, 21.1;
HRMS (ESI): m/z [M + H]+ calcd for C12H20N2O2
225.1603, found 225.1591.
Methyl 2-((4-chlorophenyl)amino)cyclopent-1-ene-1-
carboxylate (3u). 269 mg (2.11 mmol, 1.0 equiv) of 2u
was used to give 310 mg of 3u (1.23 mmol, 58%) as color-
1
less oil. H NMR (400 MHz, CDCl3) δ 9.56 (brs, NH),
7.23 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 3.73 (s,
3H), 2.76 (t, J = 7.3 Hz, 2H), 2.55 (t, J = 7.3 Hz, 2H),
1.88 (p, J = 7.3 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
168.8, 160.1, 139.3, 129.2, 128.3, 121.9, 98.1, 50.6, 33.5,
28.7, 21.8; HRMS (ESI): m/z [M + H]+ calcd for
C13H14ClNO2 252.0791, found 252.0783.
Methyl 2-(phenylamino)cyclopent-1-ene-1-carboxylate
(3p).12 0.193 mL (2.11 mmol, 1.0 equiv) of 2p was used to
1
give 320 mg of 3p (1.47 mmol, 70%) as colorless oil. H
Methyl 2-((4-bromophenyl)amino)cyclopent-1-ene-1-
carboxylate (3v). 363 mg (2.11 mmol, 1.0 equiv) of 2v
was used to give 330 mg of 3v (1.11 mmol, 53%) as color-
NMR (400 MHz, CDCl3) δ 9.58 (brs, NH), 7.26 (m, 2H),
7.02 (m, 3H), 3.74 (s, 3H), 2.79 (t, J = 7.3 Hz, 2H), 2.56
(t, J = 7.3 Hz, 2H), 1.87 (p, J = 7.3 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 168.8, 160.8, 140.6, 129.2, 123.2,
120.9, 97.3, 50.5, 33.6, 28.7, 21.9.
1
less oil. H NMR (400 MHz, CDCl3) δ 9.58 (brs, NH),
7.37 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 3.73 (s,
3H), 2.77 (t, J = 7.2 Hz, 2H), 2.55 (t, J = 7.2 Hz, 2H),
1.88 (p, J = 7.3 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
168.8, 160.0, 139.8, 132.2, 122.1, 98.3, 50.6, 33.6, 28.6,
21.8; HRMS (ESI): m/z [M + H]+ calcd for C13H14BrNO2
296.0286, found 296.0278.
Methyl 2-(p-tolylamino)cyclopent-1-ene-1-carboxylate
(3q). 226 mg (2.11 mmol, 1.0 equiv) of 2q was used to
1
give 371 mg of 3q (1.604 mmol, 76%) as colorless oil. H
NMR (400 MHz, CDCl3) δ 9.48 (brs, NH), 7.06 (d,
J = 7.9 Hz, 2H), 6.92 (d, J = 8.1 Hz, 2H), 3.72 (s, 3H),
2.72 (t, J = 7.6 Hz, 2H), 2.55 (t, J = 7.6 Hz, 2H), 2.28 (s,
3H), 1.84 (p, J = 7.6 Hz, 2H); 13C NMR (100 MHz,
CDCl3) δ 168.8, 161.3, 138.0, 133.1, 129.3, 121.3, 96.5,
77.1, 50.4, 33.5, 28.8, 21.8, 20.7; HRMS (ESI): m/z
[M + H]+ calcd for C14H17NO2 232.1338, found 232.1329.
Methyl 2-((4-methoxyphenyl)amino)cyclopent-1-ene-
1-carboxylate (3r).13 260 mg (2.11 mmol, 1.0 equiv) of 2r
was used to give 412 mg of 3r (1.667 mmol, 79%) as ivory
Methyl 2-((4-(trifluoromethyl)phenyl)amino)cyclope-
nt-1-enecarboxylate (3w). 0.262 mL (2.11 mmol, 1.0
equiv) of 2w was used to give 110 mg of 3w (0.386 mmol,
1
19%) as yellow oil. H NMR (400 MHz, CDCl3) δ 9.87
(brs, NH), 7.50 (d, J = 8.5 Hz, 2H), 7.08 (d, J = 8.5 Hz,
2H), 3.75 (s, 3H), 2.89 (t, J = 7.3 Hz, 2H), 2.57 (t,
J = 7.3 Hz, 2H), 1.93 (p, J = 7.3 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 168.8, 159.1, 148.3, 126.5 (q, JC-
= 3.7 Hz, CH), 124.2 (q, JC-F = 272 Hz, CF3), 124.1 (q,
F
1
oil. H NMR (400 MHz, CDCl3) δ 9.29 (brs, NH), 6.98 (d,
JC-F = 33 Hz, C), 119.0, 100.1, 50.7, 33.9, 28.5, 21.8;
HRMS (ESI): m/z [M + H]+ calcd for C14H14F3NO2
286.1055, found 286.1044.
J = 8.9 Hz, 2H), 6.82 (d, J = 9.1 Hz, 2H), 3.77 (s, 3H),
3.72 (s, 3H), 2.64 (t, J = 7.2 Hz, 2H), 2.55 (t, J = 7.1 Hz,
2H), 1.82 (p, J = 7.3 Hz, 2H); 13C NMR(100 MHz,
CDCl3) δ 168.8, 161.9, 156.4, 133.6, 123.6, 114.3, 95.7,
77.1, 55.4, 50.3, 33.2, 28.8, 21.6.
Methyl 4-((2-(methoxycarbonyl)cyclopent-1-en-1-yl)
amino)benzoate (3x). 319 mg (2.11 mmol, 1.0 equiv) of
2x was used to give 69 mg of 3x (0.251 mmol, 12%) as
1
Methyl 2-((4-(dimethylamino)phenyl)amino)cyclope-
nt-1-ene-1-carboxylate (3s). 287 mg (2.11 mmol, 1.0
yellow oil. H NMR (400 MHz, CDCl3) δ 9.94 (brs, NH),
7.93 (d, J = 8.7 Hz, 2H), 7.03 (d, J = 8.7 Hz, 2H), 3.88 (s,
3H), 3.75 (s, 3H), 2.94 (t, J = 7.3 Hz, 2H), 2.57 (t,
J = 7.3 Hz, 2H), 1.94 (p, J = 7.3 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 168.7, 166.7, 158.7, 144.9, 131.1,
123.5, 118.2, 100.4, 51.9, 50.7, 34.1, 28.5, 21.9; HRMS
(ESI): m/z [M + H]+ calcd for C15H17NO4 276.1236, found
276.1226.
equiv) of 2s was used to give 423 mg of 3s (1.625 mmol,
1
ꢀ
77%) as orange solid. mp 89.5 C; H NMR (400 MHz,
CDCl3) δ 9.20 (brs, NH), 6.95 (d, J = 8.8 Hz, 2H), 6.60 (d,
J = 9.1 Hz, 2H), 3.72 (s, 3H), 2.90 (s, 6H), 2.61 (t,
J = 7.7 Hz, 2H), 2.55 (t, J = 6.9 Hz, 2H) 1.82 (p,
J = 7.5 Hz, 2H); 13C NMR(100 MHz, CDCl3) δ 168.8,
162.8, 147.9, 130.2, 124.0, 113.0, 94.6, 77.1, 50.3, 40.9,
38.0, 33.2, 28.9, 21.4; HRMS (ESI): m/z [M + H]+ calcd
for C15H20N2O2 261.1603, found 261.1590.
Methyl 2-aminocyclopent-1-ene-1-carboxylate (3z).14
27.1 mg (0.352 mmol, 1.0 equiv) of 2z was used to give
1
33.8 mg of 3z (0.239 mmol, 68%) as white solid. H NMR
Methyl 2-((4-fluorophenyl)amino)cyclopent-1-ene-1-
carboxylate (3t). 235 mg (2.11 mmol, 1.0 equiv) of 2t was
used to give 353 mg of 3t (1.498 mmol, 71%) as white
(400 MHz, CDCl3) δ 3.69 (s, 3H), 2.55–2.45 (m, 4H),
1.87–1.78 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 168.5,
162.0, 95.1, 50.2, 35.1, 29.5, 20.8.
1
solid. mp 51.7 ꢀC; H NMR (400 MHz, CDCl3) δ 9.43
Methyl 3-(benzylamino)-4-methoxybut-2-enoate (5a).15
106 mg (0.725 mmol, 1.0 equiv) of 4a was used to give
127 mg of 5a (0.540 mmol, 74%; E:Z = 1.0:1.1) as a yellow
oil. 1H NMR (400 MHz, CDCl3) E isomer: δ 7.40–7.27 (m,
(brs, NH), 6.99 (m, 4H), 3.73 (s, 3H), 2.68 (t, J = 7.7 Hz,
2H), 2.56 (t, J = 7.7 Hz, 2H), 1.85 (p, J = 7.8 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 168.7, 160.4, 158.0, 136.6,
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Synthesis of β-Enamino Esters
KOREAN CHEMICAL SOCIETY
5H), 5.90 (s, NH), 4.71 (s, 1H), 4.49 (d, J = 6.4 Hz, 2H),
3.98 (s, 2H), 3.60 (s, 3H), 3.42 (s, 3H); Z isomer: H NMR
Synthesis of Ethyl 4-Hydroxy-2-Oxo-1-Phenethyl-2,-
5-Dihydro-1H-Indeno[1,2-b]Pyridine-3-Carboxylate (11).
Methyl 1-oxo-2,3-dihydro-1H-indene-2-carboxylate (9).18
A solution of 1-indanone 8 (2.00 g, 15.1 mmol) in THF
(16.0 mL) was added dropwise to a stirred suspension of
dimethyl carbonate (6.37 mL, 76.0 mmol) in THF (32.0 mL)
containing sodium hydride 60% in oil (1.27 g, 31.8 mmol)
under nitrogen atmosphere. The reaction mixture was heated
to reflux for 2 h. Once completion, the reaction mixture was
acidified with 1 M HCl (15 mL), and then extracted with
Et2O (20 mL × 2). The combined organic layers were
washed with brine (20 mL), dried over sodium sulfate and
filtered. The filtrate was concentrated, and purified by MPLC
(0% to 30% EtOAc/hexanes) to give 9 as a yellow oil
(2.38 g, 83% yield). The product was isolated as a mixture
1
(400 MHz, CDCl3) δ 8.64 (s, NH), 7.40–7.27 (m, 5H), 4.74
(d, J = 0.9 Hz, 2H), 4.62 (s, 1H), 4.20 (d, J = 5.2 Hz, 2H),
3.65 (s, 3H), 3.35 (s, 3H).
(Z)-Methyl 3-(benzylamino)-3-phenylacrylate (5b).16
113 mg (0.634 mmol, 1.0 equiv) of 4b was used to give
1
88 mg of 5b (0.319 mmol, 52%) as colorless oil. H NMR
(400 MHz, CDCl3) δ 8.90 (s, 1H), 7.42–7.31 (m, 4H),
7.31–7.23 (m, 4H), 7.17 (d, J = 6.9 Hz, 2H), 4.68 (s, 1H),
4.27 (d, J = 6.5 Hz, 2H), 3.69 (s, 3H).
Methyl 2-(benzylamino)cyclohept-1-ene-1-carboxylate
(5d). 275 mL (1.763 mmol, 1.0 equiv) of 4d was used to
give 78 mg of 5d (0.301 mmol, 17%) as white solid. mp
1
ꢀ
100.5 C; H NMR (400 MHz, CDCl3) δ 9.67 (brs, NH),
7.33 (m, 2H), 7.25 (m, 3H), 4.45 (d, J = 6.2 Hz, 2H), 3.67
(s, 3H), 2.47 (m, 4H), 1.66 (m, 2H), 1.42 (m, 4H); 13C
NMR (100 MHz, CDCl3) δ 171.0, 167.6, 139.7, 128.6,
127.1, 126.7, 95.0, 50.4, 46.9, 31.8, 28.7, 28.4, 25.9, 25.0;
HRMS (ESI): m/z [M + H]+ calcd for C16H21NO2
260.1651, found 260.1637.
1
1
of keto and enol tautomer (ratio 6:1 by H NMR). H NMR
(400 MHz, CDCl3), keto tautomer: δ 7.78 (d, J = 7.7 Hz,
1H), 7.63 (td, J = 7.5 Hz, 1.0 Hz, 1H), 7.50 (d, J = 7.7 Hz,
1H), 7.40 (t, J = 7.1 Hz, 1H), 3.79 (s, 3H), 3.74 (dd, J = 8.3,
4.1 Hz, 1H), 3.57 (dd, J = 17.3, 4.0 Hz, 1H), 3.38 (dd,
J = 17.3, 8.3 Hz, 1H); enol tautomer: δ 10.37 (brs, 1H),
7.63–7.67 (m, 1H), 7.45–7.49 (m, 1H), 7.42 (td, J = 7.3,
1.5 Hz, 1H), 7.35–7.37 (m, 1H), 3.86 (s, 3H), 3.52 (s, 2H).
Methyl 3-(phenethylamino)-1H-indene-2-carboxylate
(10). Flask was filled with SiO2 (2.70 g, 10 g per 1 g of 9).
While stirring, 9 (0.27 g, 1.43 mmol) was added dropwise
to the silica gel, followed by the addition of phenethyla-
N-Cyclopentylidene-1-phenylmethanamine (5e).17 300 mg
(3.57 mmol, 1.0 equiv) of 4e was used to give 254 mg of 5e
(1.47 mmol, 41%) as brown oil. 1H NMR (400 MHz,
CDCl3) δ 7.34 (dd, J = 9.6, 3.4 Hz, 4H), 7.26–7.19 (m,
1H), 4.43 (s, 2H), 2.41 (t, J = 7.3 Hz, 2H), 2.30 (t,
J = 7.0 Hz, 2H), 1.86 (dd, J = 14.0, 7.0 Hz, 2H), 1.78 (dd,
J = 14.0, 7.2 Hz, 2H).
ꢀ
mine (0.47 mL, 3.72 mmol) dropwise at 0 C giving off
Methyl 2-((4-chlorobenzyl)amino)cyclopent-1-enecar
boxylate (7). 300 mg (2.11 mmol, 1.0 equiv) of 1 was used
to give 488 mg of 7 (1.836 mmol, 87%) as white solid. mp
96.3 C; H NMR (400 MHz, CDCl3) δ 7.76 (s, 1H), 7.30
(d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.5 Hz, 2H), 4.36 (d,
J = 6.5 Hz, 2H), 3.69 (s, 3H), 2.52 (dd, J = 15.3, 7.9 Hz,
4H), 1.87–1.77 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
164.54, 137.80, 133.06, 128.86, 128.05, 93.69, 50.23,
47.73, 31.99, 29.07, 20.89; HRMS (ESI): m/z [M + H]+
calcd for C14H16ClNO2 266.0948, found 266.0938.
Multigram scale synthesis of methyl 2-((4-chloro-ben-
zyl)amino)cyclopent-1-enecarboxylate (7). To a 2 L three
neck round bottom flask was placed 300 g (500 wt %)
of SiO2 and equipped with a mechanical stirrer in the
center and two dropping funnels on each side necks of
the flask. 52.4 mL (60 g, 422 mmol) of 1 and 54.1 mL
(62.8 g, 443 mmol) of 2 were added dropwise using
each dropping funnels while stirring at rt. (Caution. Mild
heat is being generated while stirring). The reaction mix-
ture was stirred for 2 h until complete consumption of
starting materials based on LCMS analysis. After comple-
tion of the condensation reaction, the solid reaction mix-
ture was filtered through glass filter while rinsing it with
CH2Cl2 (~1 L). Removal of the solvent and drying under
vacuum gave 104.3 g of 7 as a pale yellow solid in 93%
yield with >99% purity based on HPLC analysis. All the
other spectral data were matched with those as described
above.
some heat and solid ꢀchunk. The resulting solid mixture was
stirred for 4 h at 80 C. Upon the complete consumption of
starting material based on LCMS analysis, the solid mixture
was loaded on silica gel and purified by MPLC (0% to
30% EtOAc/Hexanes) to give 10 as a white gummy foam
1
ꢀ
1
(0.28 g, 66% yield). H NMR (400 MHz, CDCl3) δ 7.88
(brs, 1H), 7.82 (d, J = 7.7 Hz, 1H), 7.48 (d, J = 7.4 Hz,
1H), 7.41–7.36 (m, 1H), 7.35–7.33 (d, J = 7.0 Hz, 2H),
7.31–7.26 (m, 4H), 4.00 (dd, J = 13.9, 6.8 Hz, 2H), 3.76
(s, 3H), 3.54 (s, 2H), 3.04 (t, J = 7.5 Hz, 2H); 13C NMR
(100 MHz, CDCl3) δ 168.8, 159.3, 145.8, 138.7, 138.1,
128.9, 128.8, 128.6, 126.8, 126.5, 125.3, 123.4, 96.6, 50.5,
46.6, 37.7, 34.6; HRMS (ESI): m/z [M + H]+ calcd for
C19H19NO2 294.1494, found 294.1484.
Ethyl 4-hydroxy-2-oxo-1-phenethyl-2,5-dihydro-1H-
indeno[1,2-b]pyridine-3-carboxylate (11). To a solution
of 10 (1.73 g, 5.90 mmol) in DCE (11.8 mL) was added
ethyl malonyl chloride (1.51 mL, 11.8 mmol) at room tem-
perature. The reaction mixture was heated to reflux for 3 h.
Upon completion of starting material based on LCMS anal-
ysis, the mixture was quenched with water (10 mL) and
extracted with DCM (50 mL × 3). The organic layer was
separated and washed with water (20 mL × 3). The com-
bined organic layers were washed again with aq. sat.
NaHCO3 (20 mL) and brine (10 mL), dried over sodium
sulfate and filtered. The filtrate was concentrated in vacuo
to give brown oil, which was subjected to the next step
without further purification. To a solution of the crude
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BULLETIN OF THE
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Synthesis of β-Enamino Esters
KOREAN CHEMICAL SOCIETY
intermediate in EtOH (11.8 mL) was added slowly sodium
ethoxide (4.62 mL, 11.8 mmol) and the resulting mixture
was allowed to stir at room temperature for 2 h. Upon com-
plete consumption of starting material based on LCMS
analysis, the mixture was filtered through a glass filter with
EtOAc rinsing. The filtered solid was dried under vacuum
to give the desired product 11 as pale green solid (1.79 g)
in 81% yield over 2 steps. mp >200 C (burnt); H NMR
(400 MHz, CD3OD) δ 7.94 (d, J = 7.3 Hz, 1H), 7.63 (d,
J = 6.4 Hz, 1H), 7.47–7.38 (m, 4H), 7.36 (dd, J = 10.3,
4.9 Hz, 2H), 7.25 (t, J = 7.3 Hz, 1H), 4.72–4.62 (m, 2H),
4.34 (q, J = 7.2 Hz, 2H), 3.68 (s, 2H), 3.16–3.07 (m, 2H),
1.39 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CD3OD) δ
173.9, 170.1, 164.5, 145.1, 144.7, 138.4, 136.7, 128.4,
128.3, 127.0, 126.5, 126.2, 125.2, 121.9, 121.6, 104.7,
59.8, 44.1, 35.1, 32.7, 13.3; HRMS (ESI): m/z [M + H]+
calcd for C23H21NO4 376.1549, found 376.1538.
References
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Conclusion
In conclusion, we have examined the full scope of SiO2-
based condensation of amines and β-keto esters to give
β-enamino esters. Aliphatic and aromatic amines were
mostly well tolerated, and limitations were found in sterically
bulkier amines and aromatic amines with electron withdraw-
ing substitutions. Among cyclic β-keto esters, five-membered
ring system showed optimum results. It was demonstrated
that linear β-keto esters can be used in SiO2-based condensa-
tion to form synthetically useful functionalized linear
β-enamino esters, although stereoselective formation of ole-
fin geometry still requires further investigation. It was also
demonstrated that cyclic β-enamino esters were prepared in a
large scale. The utility of the present method was fortified by
the preparation of pharmaceutically useful 4-hydroxypyridin-
2(1H)-one analogues with higher complexity than the related
compounds known in the literature.
16. W. Xinjun, L. Yang, W. Chao, Z. Li, L. Xiaoxia, S. Jian,
Chem. Eur. J. 2011, 17, 2846.
Acknowledgments. This research was provided by the
Bio & Medical Technology Development Program of the
National Research Foundation (NRF) & funded by the
Korean government (MSIT) (NRF-2017M3A9G2077568).
17. A. A. El-Barbary, S. Carlsson, S.-O. Lawesson, Tetrahedron
1982, 38, 405.
18. I. Geibel, J. Christoffers, Eur. J. Org. Chem. 2016,
2016, 918.
Supporting Information. Additional supporting informa-
tion is available in the online version of this article.
Bull. Korean Chem. Soc. 2019
© 2019 Korean Chemical Society, Seoul & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.bkcs.wiley-vch.de
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