Multifunctionalization of Unactivated Cyclic Ketones via an Electrochemical Process: Access to Cyclic α-Enaminones

Article abstract of DOI:10.1021/acs.joc.8b02930

The multifunctionalization of unactivated cyclic ketones was developed via an electrochemically intermolecular α-amination under metal-free conditions. The reaction can be carried out smoothly with a broad scope of the aromatic amines substrates under mil

Full text of DOI:10.1021/acs.joc.8b02930

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Multifunctionalization of Unactivated Cyclic Ketones via an
Electrochemical Process: Access to Cyclic #-Enaminones
Kangfei Hu, Peng Qian, Ji-Hu Su, Zhibin Li, Jiawei Wang, Zhenggen Zha, and Zhiyong Wang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02930 • Publication Date (Web): 04 Jan 2019
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Multifunctionalization of Unactivated Cyclic Ketones via an
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Electrochemical Process: Access to Cyclic α-Enaminones
†
†
Kangfei Hu†, Peng Qian , Ji-Hu Su‡, Zhibin Li†, Jiawei Wang , Zhenggen Zha*† and
Zhiyong Wang*†
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†Hefei National Laboratory for Physical Science at Microscale, CAS Key Laboratory of Soft
Matter Chemistry & Center for Excellence in Molecular Synthesis of Chinese Academy of
Science, Collaborative Innovation Center of Suzhou Nano Science and Technology & School of
Chemistry and Material Science, University of Science and Technology of China, Hefei, Anhui
230026, P. R. China.
‡CAS Key Laboratory of Microscale Magnetic Resonance, Department of Modern Physics,
University of Science and Technology of China, Hefei, Anhui 230026, P. R. China
E-mail:zwang3@ustc.edu.cn
zgzha@ustc.edu.cn
O
O
R
Pt
CCE, I-
MeOH, RT
Pt
H
N
N
Ar
R
Ar
transition metal free
mild reaction conditions
atom economy
ABSTRACT: The multifunctionalization of unactivated cyclic ketones was developed via an
electrochemically intermolecular α-amination under metal free conditions. The reaction can be
carried out smoothly with a broad scope of the aromatic amines substrates under mild conditions,
affording a variety of α-enaminones with good to excellent yields in one step.
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α-Amino ketones are prevalent substructures, widely exist in biologically active natural
products, biomolecules and therapeutic agents.1 Since the extensive utility of the synthon,
development of efficient and atom-economical method is a longstanding goal in organic
synthesis.2 Various methods have been developed for α-amination, mainly divided into two types:
1) transition metal catalyzed α-amination reaction,3 2) chemical oxidants under metal-free
conditions.4 Recently, significant progress was made in β-functionalization of unactivated cyclic
ketones by MacMillan’s group using cooperative organocatalysis and photoredox catalysis.5
Despite the great achievement of monofunctionalization of unactivated cyclic ketones, direct
multifunctionalization of cyclic ketones in one step are rarely studied. Fu’s group reported
multifunctionalization of unactivated ketones by employing O-benzoylhydroxylamines as both
amination and oxidation reagents via a cooperative Cu and an organocatalyst to generate
α-enaminone (Scheme 1a).6 Zhao’s group reported the acid/base co-catalyzed α-amination of
cyclic ketones, in which dioxygen as an oxidant (Scheme 1b).7 Although considerable progress
has been made in α-amination reaction,8 development of direct oxidative α-amination of ketones
with different amines in the absence of metals and chemical oxidants remains challenging.
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Scheme 1. Methods for the mono- and multi-functionalization of (cyclic) ketones.
Our group has been focusing on elegant electrochemical catalysis for a long time.9 For instance,
we synthesized benzoylhydrazines,10 α-ketoamides,11 α-enaminone12 by virtue of electrochemistry.
Herein, we report a directly intermolecular oxidative α-amination of cyclic ketone by virtue of
electrochemistry under metal free conditions (Scheme 1c).
First of all, the reaction of aniline with cyclopentaone was employed as the model reaction.
Initially, the reaction was conducted in an undivided cell with KI as electrolyte and EtOH as
solvent at a constant current of 20 mA. To our delight, the desired product was obtained in 60%
isolated yield (entry 1, Table 1), which encouraged us to optimize the reaction conditions further.
First, different kinds of solvents were examined in this reaction (entries 1-6, Table 1). The
experimental results indicated that the alcohol solvents favored the reaction and MeOH was the
best choice, while other solvents could not promote the reaction, which can be ascribed to the
conductivity of the solvent, the polarity of the solvent and the solubility of the reaction mixtures in
the solvent (see page S3 of supporting information). Then various electrolytes were investigated.
The experimental results showed that the iodide ion was necessary for the reaction, the reaction
did not work without iodide ion (entries 7-12, Table 1). Among the different iodide salts, KI
n
proved to be the optimal electrolyte for the reaction while the other iodide salts, such as Bu4NI,
Et4NI, Me4NI, NH4I and NaI gave low electrolytic efficiency (entries 8-11, Table 1), which can be
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ascribed to the good solubility and the high ion activity of KI in methanol (see page S3 of
supporting information).
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Table 1. Optimization of reaction conditions
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Entrya
1
Electrode
Pt|Pt
Pt|Pt
Pt|Pt
Pt|Pt
Pt|Pt
Pt|Pt
Pt|Pt
Pt|Pt
Pt|Pt
Pt|Pt
Pt|Pt
Pt|Pt
C|Pt
Electrolyte
KI
Solvent
EtOH
Yieldb
60 %
76 %
n.d.
2
KI
MeOH
DMF
3
KI
4
KI
DMSO
CH3CN
CH2Cl2
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
n.d.
5
KI
n.d.
6
KI
n.d.
7
NaI
Bu4NI
Et4NI
Me4NI
NH4I
LiClO4
KI
63 %
64 %
57 %
11 %
trace
n.d.
8
9
10
11
12
13
14
15
16c)
17d)
18e)
19f)
20g)
21h)
22i)
23j)
24k)
25l)
55 %
31 %
17 %
< 40 %
43 %
50 %
76 %
73 %
69 %
86 %
58 %
87 %
65 %
Pt|C
KI
C|C
KI
Pt|M
Pt|Pt
Pt|Pt
Pt|Pt
Pt|Pt
Pt|Pt
Pt|Pt
Pt|Pt
Pt|Pt
Pt|Pt
KI
KI
KI
KI
KI
KI
KI
KI
KI
KI
a
Reaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), electrolyte (1.0 mmol), solvent (5 mL), two platinum
b
electrodes, electrolyze at a constant current in an undivided cell at room temperature, CCE = constant current.
Isolated yield. c Metal electrode: Al , Ni, Cu. d I = 10 mA. e I = 30 mA. f I = 40 mA. g I = 50 mA. h I = 60 mA. i 0.1
M. j 0.2 M. k N2 atmosphere. l O2 atmosphere.
Subsequently, the different electrodes were studied in the reaction, including graphite, platinum,
and other metal electrodes. Of them, the platinums gave the best result (entries 13-16, Table 1),
which may due to its proper cell voltage. The current intensity was also optimized, 40 mA was
turned out to be the best constant current (entries 17-21, Table 1). We also modulated the substrate
concentration and ratio (entries 22-24, Table 1). It was found that 0.1 M of substrate concentration
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gave the desired product with a higher yield. When the reaction was conducted under nitrogen
atmosphere, the yield was slightly improved in comparison with the reaction under air (entries 24
and 22, Table 1). In contrast, the yield was decreased under oxygen atmosphere (entries 25, Table
1). Therefore, the optimal reaction conditions were established as follows: KI as electrolyte,
MeOH as solvent, and the reaction being carried out at a constant current of 40 mA for 3 h with
two platinum electrodes in an undivided cell at room temperature under air atmosphere.
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Having established the optimal reaction conditions, the substrate scope of the reaction was
investigated by evaluating a variety of aromatic amines and cyclic ketones under standard
conditions. As shown in Table 2, the reaction proceeded smoothly with different aromatic amines
to afford α-enaminones in moderate to good yields. The electronic effect of aromatic amines had a
great influence on the reaction. Generally, the strong electron-withdrawing groups disfavoured the
reaction. For example, the substrate 4-nitro-substituted aniline didn’t work in the reaction. The
moderate electron-withdrawing groups (CF3, di-halide substitution) led to the decrease of the yield
Table 2. Scope of aromatic amines.a, b
O
H
N
O
Pt
Pt
NH2
CCE, KI
R
R
MeOH (5 mL), RT
1
2a
3
O
O
O
O
O
O
O
H
N
H
H
H
N
N
N
F
Cl
Br
3a, 86%
3b, 87%
3c, 78%
3d, 86%
O
O
H
N
H
N
H
N
H
N
Me
I
F3C
Et
p-Me, 3g, 82%
o-Me, 3h, 70%
m-Me, 3i, 82%
3e, 71%
3f, 45%
3j, 82%
O
O
O
O
O
H
N
H
N
H
N
H
N
MeO
tBu
Ph
p-OMe, 3l, 80%
o-OMe, 3m, 78%
m-OMe, 3n, 80%
3k, 80%
3o, 70%
3p, 70%
Me
N
Et
N
Br
O
H
O
H
N
N
Cl
Me
Cl
3q, 72%
3r, 56%
3s, 80%
3t, 70%
a
Reaction conditions: 1 (0.5 mmol), 2a (1.0 mmol), KI (1.0 mmol), MeOH (5 mL), two platinum electrodes,
electrolyze at a constant current of 40 mA in an undivided cell at room temperature. b Isolated yield.
remarkably (3f, 3r, Table 2), while the weak electron-withdrawing groups gave moderate to good
yields under standard conditions (3b-3e, 3i, 3n, 3q, Table 2). On the other hand, the steric effect
had little effect on the reaction. For instance, the ortho-substituted methoxyl gave the cyclic
α-enaminone 3l with a similar yield in comparison with 3m, 3n. Both electronic effect and steric
effect influenced the yield of the corresponding substrate. Moreover, the aromatic secondary
amines were also employed in the reaction to give 3s and 3t with moderate yields as long as there
was no electron-withdrawing group on the amino substitution. Subsequently, the scope of cyclic
ketones were also investigated, and the results were listed in Table 3. The cyclopentanone,
substituted cyclopentanone and cyclohexane could be employed as the substrates to afford the
corresponding α-enaminones with moderate yields. Nevertheless, indanone and other linear
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ketones didn’t work in this reaction, perhaps due to the lower oxidation potential and poor
nucleophility of iodo-ketones to amines (see the transformation of 4 to 6 in the Scheme 3).
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Table 3. Scope of cyclic ketones.a, b
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a
Reaction conditions: 1a (0.5 mmol), 2 (1.0 mmol), KI (1.0 mmol), MeOH (5 mL), two platinum electrodes,
electrolyze at a constant current of 40 mA in an undivided cell at room temperature. b Isolated yield.
To understand the reaction mechanism, a series of control experiments were performed
(Scheme 2). When the radical scavengers 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) and
2,6-di-tert-butyl-4-methylphenol (BHT) were added to the reaction system respectively under
standard conditions, the reaction was completely suppressed (Scheme 2a, 2b). This suggested that
the reaction might go through a radical pathway. When 2.0 equivalent of molecular iodine was
added instead of KI, we detected a trace amount of target product (Scheme 2c), which excluded
that molecular iodine promoted the reaction. When 2-iodocyclopentanone 4 was employed as the
coupling partner with aniline under standard conditions, the corresponding α-enaminone was
obtained in 68% yield (Scheme 2d), which indicated that 2-iodocyclopentanone was likely to be
the intermediate of the reaction.
Scheme 2. Control experiments.
To further study the reaction process, electron paramagnetic resonance (EPR) experiments were
conducted to capture the possible free radicals involved in the reaction. As shown in Figure 1, a
complicated spectra
a
was obtained in the presence of the radical trapper
5,5-dimethyl-1-proline-N-oxide (DMPO). Two signals were identified by the characteristic
hyperfine constants for nitrogen and β-proton. One was assigned to be DMPO-5 with the A14N =
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15.6 G and A1H = 22.6 G, g = 2.0046. Another signal can be ascribed to DMPO-OH and the
hyperfine constants for nitrogen and proton were A14N = A1H = 14.8 G, g = 2.0047. Spectra c and
d were their corresponding simulations (DMPO-5 and DMPO-OH), respectively (see page S2-S3
of supporting information). When we overlapped the spectra c and d with an intensity ratio of 5:1,
the complicated spectra b were obtained, which was consistent with the experimental result a.
Therefore, these results further provided evidence for a radical process in the reaction.
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Figure 1. EPR spectra (X band, 9.7 GHz, room temperature) for reaction mixtures in the presence of the radical
trapper DMPO and their simulations (b-d). (a) Spectrum a was the experimental spectrum. (b) Simulation of
DMPO-5 and DMPO-OH. (c) DMPO-5. (d) Simulation of DMPO-OH. (e) Overlapping of spectra c and d with an
intensity ratio of 5:1 led to the complicated b, which was consistent with the experimental result a.
Based on the above experimental results and related reports, we proposed a possible mechanism
(Scheme 3). Initially, the iodide anion is oxidized to be iodine free radical in the anode, and then
reacts with cyclopentanone 2 to generate the radical 5, which was captured by DMPO and the
generated DMPO-5 radical was detected by EPR, with the liberation of one molecule of HI. The
radical coupling between radical 5 and iodine free radical yields 2-iodocyclopentanone 4. At the
same time, the radical 5 might be captured by oxygen molecular to give molecule 8, which is
unstable and easily transformed into 9, accompanying the loss of hydroxyl radical. Subsequent
nucleophilic attack of the intermediate 4 with aniline provides 2-(phenylamino)-cyclopentanone 6,
which undergoes anodic oxidation to form the intermediate 2-(phenylimino)-cyclopentanone 7.
Finally, the imine interconverts mainly to the target product α-enaminone 3a. Simultaneously,
methanol is reduced in the cathode to give methoxide and hydrogen gas.
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Scheme 3. Plausible mechanism.
In summary, we developed an electrochemically oxidative α-amination of ketones to afford the
α-enaminones from facile starting materials via cross-coupling between (sp3) C-H/N-H under
metal-free conditions. The reaction features atom economic efficiency and good functional
tolerance. Additionally, the reaction intermediate was identified by EPR. Further studies will focus
on other types of substrates and applications in organic synthesis.
Experimental Section
General Information: All products were characterized by H NMR and 13C{1H} NMR, using
1
TMS as an internal reference (1H NMR: 400 MHz, 13C{1H} NMR: 100 MHz). The chemical shifts
(δ) and coupling constants (J) were expressed in ppm and Hz, respectively. HRMS (ESI) were
recorded on a Q-TOF Premier. Commercially available compounds were used without further
purification. Solvents were purified according to the standard procedures unless otherwise noted.
Representative Experimental Procedures: A mixture of electrolyte (1.0 mmol), amine (0.5
mmol), cyclic ketone (1.0 mmol) and MeOH (5 mL) were added to an undivided cell (15 mL).
The cell was equipped with platinum electrodes (1.5 cm × 1.5 cm × 0.3 cm) as both the anode and
cathode. The reaction mixture was stirred and electrolyzed at a constant current of 40 mA at room
temperature for corresponding time. The reaction was monitored by TLC. When the reaction was
finished, the solvent was removed with a rotary evaporator. The residue was purified by column
chromatography on silica gel to afford the desired product.
EPR measurements and simulations for the capture of radicals:
An undivided cell was equipped with a magnet stirrer, two platinum electrodes (1.5 cm × 1.5 cm ×
0.3 cm) as both the working electrode and the counter electrode, respectively. A mixture of
electrolyte (1.0 mmol), amine (0.5 mmol), cyclic ketone (1.0 mmol) and MeOH (5 mL) were
added to an undivided cell (15 mL). The cell was equipped with platinum electrodes (1.5 cm × 1.5
cm × 0.3 cm) as both the anode and cathode. The reaction mixture was stirred and electrolyzed at
a constant current of 40 mA at room temperature for 30 min. A 0.05 mL reaction solution was
taken out into a small tube and mixed well with 0.03 mL of DMPO aqueous solution. Then the
mixture was quick-frozen with liquid nitrogen and measured by EPR at room temperature. EPR
simulation was performed with EasySpin software package in Mathlab. The simulation parameters
were microwave frequency 9.097 GHz, g-2.0047 (without calibration). The hyperfine constants
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were shown in the main text.
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2-(phenylamino)cyclopent-2-enone (3a). The compound was prepared according to the general
procedure (3 h) and purified by column chromatography (PE/EA = 30/1) to give the product as a
yellow solid: 74.5 mg, 86% yield; mp = 110-112 °C. 1H NMR (400 MHz, CDCl3, ppm): 7.31-7.27
(m, 2H), 7.04-7.02 (m, 2H), 6.94-6.91 (m, 1H), 6.75 (s, 1H), 6.24 (br, 1H), 2.65 (t, J = 3.8 Hz, 2H),
2.47 (t, J = 4.0 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3, ppm): 204.8, 142.1, 140.2, 129.6,
124.8, 120.7, 116.6, 32.6, 24.2. HRMS (ESI) calcd for C11H12NO [M + H]+ 174.0919, found
174.0915.
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2-((4-fluorophenyl)amino)cyclopent-2-enone (3b). The compound was prepared according to the
general procedure (3 h) and purified by column chromatography (PE/EA = 30/1) to give the
1
product as a yellow solid: 83.2 mg, 87% yield; mp = 123-125 °C. H NMR (400 MHz, CDCl3,
ppm): 7.00-6.99 (m, 4H), 6.65 (t, J = 3.2 Hz, 1H), 6.13 (br, 1H), 2.65-2.62 (m, 2H), 2.49-2.46 (m,
3
2H). 13C{1H} NMR (100 MHz, CDCl3, ppm): 204.7, 158.6, 140.6, 138.0 (d, JC-F = 10.4 Hz),
123.9, 118.3 (d, 2JC-F = 30.0 Hz), 116.1 (d, 1JC-F = 89.2 Hz), 32.6, 23.9. Decoupling 19F NMR (377
MHz, CDCl3, ppm): -122.5. 19F NMR (377 MHz, CDCl3, ppm): -122.5 (m, J = 6.6 Hz). HRMS
(ESI) calcd for C11H11FNO [M + H]+ 192.0825, found 192.0821.
2-((4-chlorophenyl)amino)cyclopent-2-enone (3c). The compound was prepared according to the
general procedure (3.5 h) and purified by column chromatography (PE/EA = 30/1) to give the
1
product as a yellow solid: 80.9 mg, 78% yield; mp = 156-157 °C. H NMR (400 MHz, CDCl3,
ppm): 7.26-7.23 (m, 2H), 6.97-6.95 (m, 2H), 6.70 (t, J = 2.6 Hz, 1H), 6.23 (br, 1H), 2.66-2.64 (m,
2H), 2.48 (t, J = 3.8 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3, ppm): 204.5, 140.4, 139.5, 129.3,
125.7, 125.1, 117.9, 32.6, 24.1. HRMS (ESI) calcd for C11H11ClNO [M + H]+ 208.0529, found
208.0522.
2-((4-bromophenyl)amino)cyclopent-2-enone (3d). The compound was prepared according to the
general procedure (3.5 h) and purified by column chromatography (PE/EA = 30/1) to give the
1
product as a yellow solid: 108.1 mg, 86% yield; mp = 156-157 °C. H NMR (400 MHz, CDCl3,
ppm): 7.39-7.37 (m, 2H), 6.92-6.90 (m, 2H), 6.70 (t, J = 3.0 Hz, 1H), 6.23 (br, 1H), 2.66-2.65 (m,
2H), 2.47 (t, J = 4.2 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3, ppm): 204.6, 140.8, 139.9, 132.4,
125.3, 118.1, 113.0, 32.1, 24.2. HRMS (ESI) calcd for C11H11BrNO [M + H]+ 252.0024, found
252.0020.
2-((4-iodophenyl)amino)cyclopent-2-enone (3e). The compound was prepared according to the
general procedure (3 h) and purified by column chromatography (PE/EA = 30/1) to give the
1
product as a yellow solid: 106.2 mg, 71% yield; mp = 157-158 °C. H NMR (400 MHz, CDCl3,
ppm): 7.56-7.54 (m, 2H), 6.82-6.79 (m, 2H), 6.70 (t, J = 3.0 Hz, 1H), 6.24 (br, 1H), 2.66-2.65 (m,
2H), 2.48-2.46 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3, ppm): 204.5, 141.5, 139.7, 138.2,
125.5, 118.6, 82.6, 32.4, 24.1. HRMS (ESI) calcd for C11H11INO [M + H]+ 299.9885, found
299.9901.
2-((4-(trifluoromethyl)phenyl)amino)cyclopent-2-enone (3f). The compound was prepared
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according to the general procedure (3 h) and purified by column chromatography (PE/EA = 30/1)
to give the product as a yellow solid: 53.8 mg, 45% yield; mp = 144-145 °C. 1H NMR (400 MHz,
CDCl3, ppm): 7.54-7.52 (m, 2H), 7.08-7.06 (m, 2H), 6.83 (t, J = 3.2 Hz, 1H), 6.47 (br, 1H),
2.71-2.68 (m, 2H), 2.51-2.48 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3, ppm): 204.4, 144.6,
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139.3, 126.8 (q, JC-F = 14.9 Hz), 124.5, 122.7 (q, JC-F = 130.2 Hz), 115.8, 114.5, 32.3, 24.2.
Decoupling 19F NMR (377 MHz, CDCl3, ppm): -61.6. 19F NMR (377 MHz, CDCl3, ppm): -61.6.
HRMS (ESI) calcd for C12H11F3NO [M + H]+ 242.0793, found 242.0796.
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2-(p-tolylamino)cyclopent-2-enone (3g). The compound was prepared according to the general
procedure (3 h) and purified by column chromatography (PE/EA = 30/1) to give the product as a
yellow solid: 77.1 mg, 82% yield; mp = 115-117 °C. 1H NMR (400 MHz, CDCl3, ppm): 7.11-7.09
(m, 2H), 6.96-6.92 (m, 2H), 6.67 (t, J = 3.3 Hz, 1H), 2.65-2.62 (m, 2H), 2.48-2.45 (m, 2H), 2.29 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3, ppm): 204.9, 140.5, 139.3, 130.5, 129.9, 124.0, 116.9,
32.6, 24.0, 20.7. HRMS (ESI) calcd for C12H14NO [M + H]+ 188.1075, found 188.1075.
2-(o-tolylamino)cyclopent-2-enone (3h). The compound was prepared according to the general
procedure (4 h) and purified by column chromatography (PE/EA = 30/1) to give the product as
yellow oil: 65.5 mg, 70% yield. 1H NMR (400 MHz, CDCl3, ppm): 7.25-7.16 (m, 3H), 6.88 (t, J =
7.1 Hz, 1H), 6.67 (m, 1H), 6.05 (br, 1H), 2.65-2.64 (m, 2H), 2.50-2.48 (m, 2H), 2.27 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3, ppm): 204.8, 140.3, 139.8, 130.8, 126.8, 126.1, 124.5, 121.1,
115.8, 32.5, 23.9, 17.5. HRMS (ESI) calcd for C12H14NO [M + H]+ 188.1075, found 188.1074.
2-(m-tolylamino)cyclopent-2-enone (3i). The compound was prepared according to the general
procedure (3 h) and purified by column chromatography (PE/EA = 30/1) to give the product as a
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yellow solid: 76.8 mg, 82% yield; mp = 89-90 °C. H NMR (400 MHz, CDCl3, ppm): 7.20-7.16
(m, 1H), 6.86-6.84 (m, 2H), 6.76-6.73 (m, 2H), 6.19 (br, 1H), 2.66-2.63 (m, 2H), 2.48-2.45 (m,
2H), 2.33 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3, ppm): 204.8, 141.8, 140.2, 139.3, 129.3,
124.6, 121.8, 117.5, 113.8, 32.5, 24.0, 21.7. HRMS (ESI) calcd for C12H14NO [M + H]+ 188.1075,
found 188.1072.
2-((4-ethylphenyl)amino)cyclopent-2-enone (3j). The compound was prepared according to the
general procedure (3 h) and purified by column chromatography (PE/EA = 30/1) to give the
product as a yellow solid: 82.7 mg, 82% yield; mp = 83-84 °C. 1H NMR (400 MHz, CDCl3, ppm):
7.14-7.11 (m, 2H), 6.98-6.95 (m, 2H), 6.69 (t, J = 3.3 Hz, 1H), 6.15 (br, 1H), 2.65-2.56 (m, 4H),
3.48-2.45 (m, 2H), 1.21 (t, J = 7.6 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3, ppm): 204.1, 140.4,
139.4, 136.9, 128.6, 123.9, 116.8, 32.4, 28.1, 23.9, 15.7. HRMS (ESI) calcd for C13H16NO [M +
H]+ 202.1232, found 202.1232.
2-((4-(tert-butyl)phenyl)amino)cyclopent-2-enone (3k). The compound was prepared according to
the general procedure (3 h) and purified by column chromatography (PE/EA = 30/1) to give the
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product as a yellow solid: 119.7 mg, 80% yield; mp = 103-104 °C. H NMR (400 MHz, CDCl3,
ppm): 7.33-7.30 (m, 2H), 7.00-6.97 (m, 2H), 6.70 (t, J = 3.3 Hz, 1H), 6.16 (br, 1H), 2.65-2.62 (m,
2H), 2.48-2.46 (m, 2H), 1.30 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3, ppm): 204.9, 143.8, 140.4,
139.3, 126.2, 124.0, 116.5, 34.2, 32.5, 31.5, 24.0. HRMS (ESI) calcd for C15H20NO [M + H]+
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2-((4-methoxyphenyl)amino)cyclopent-2-enone (3l). The compound was prepared according to the
general procedure (3 h) and purified by column chromatography (PE/EA = 30/1) to give the
product as a yellow solid: 81.3 mg, 80% yield; mp = 90-92 °C. 1H NMR (400 MHz, CDCl3, ppm):
7.01-6.97 (m, 2H), 6.88-6.84 (m, 2H), 6.59 (t, J = 3.3 Hz, 1H), 6.00 (br, 1H), 3.78 (s, 3H),
2.63-2.60 (m, 2H), 2.48-2.46 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3, ppm): 204.8, 154.4,
141.2, 135.4, 123.0, 118.8, 114.8, 55.7, 32.7, 23.9. HRMS (ESI) calcd for C12H14NO2 [M + H]+
204.1025, found 204.1021.
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2-((2-methoxyphenyl)amino)cyclopent-2-enone (3m). The compound was prepared according to
the general procedure (3 h) and purified by column chromatography (PE/EA = 30/1) to give the
product as a white solid: 79.3 mg, 78% yield; mp = 84-85 °C. 1H NMR (400 MHz, CDCl3, ppm):
7.21-7.19 (m, 1H), 6.95-6.91 (m, 1H), 6.88-6.85 (m, 2H), 6.76 (t, J = 3.3 Hz, 1H), 3.88 (s, 3H),
2.67-2.64 (m, 2H), 2.48-2.46 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3, ppm): 204.9, 148.1,
139.9, 131.6, 124.6, 120.8, 120.3, 114.2, 110.2, 55.6, 32.4, 24.1. HRMS (ESI) calcd for
C12H14NO2 [M + H]+ 204.1025, found 204.1020.
2-((3-methoxyphenyl)amino)cyclopent-2-enone (3n). The compound was prepared according to
the general procedure (3 h) and purified by column chromatography (PE/EA = 30/1) to give the
product as a white solid: 80.9 mg, 80% yield; mp = 91-93 °C. 1H NMR (400 MHz, CDCl3, ppm):
7.21-7.17 (m, 1H), 6.76-6.74 (m, 1H), 6.64-6.59 (m, 2H), 6.49-6.47 (m, 1H), 6.24 (br, 1H), 3.80 (s,
3H), 2.66-2.63 (m, 2H), 2.48-2.45 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3, ppm): 204.7, 160.7,
143.0, 140.0, 130.2, 125.2, 109.4, 106.1, 102.8, 55.3, 32.4, 24.1. HRMS (ESI) calcd for
C12H14NO2 [M + H]+ 204.1025, found 204.1022.
2-([1, 1'-biphenyl]-4-ylamino)cyclopent-2-enone (3o). The compound was prepared according to
the general procedure (3 h) and purified by column chromatography (PE/EA = 30/1) to give the
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product as a yellow solid: 87.8 mg, 70% yield; mp = 205-207 °C. H NMR (400 MHz, CDCl3,
ppm): 7.57-7.53 (m, 4H), 7.44-7.40 (m, 2H), 7.32-7.28 (m, 1H), 7.12-7.10 (m, 2H), 6.79 (m, 1H),
6.31 (br, 1H), 2.69-2.68 (m, 2H), 2.50-2.48 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3, ppm):
204.8, 141.1, 140.7, 140.1, 133.8, 128.9, 128.1, 126.8, 126.7, 125.0, 116.9, 32.5, 24.1. HRMS
(ESI) calcd for C17H16NO [M + H]+ 250.1232, found 250.1230.
2-(naphthalen-1-ylamino)cyclopent-2-enone (3p). The compound was prepared according to the
general procedure (3 h) and purified by column chromatography (PE/EA = 30/1) to give the
product as a yellow solid: 78.1 mg, 70% yield; mp = 89-91 °C. 1H NMR (400 MHz, CDCl3, ppm):
8.01-7.98 (m, 1H), 7.86-7.84 (m, 1H), 7.54-7.48 (m, 3H), 7.44-7.40 (m, 1H), 7.33-7.31 (m, 1H),
6.73 (br, 1H), 6.70 (t, J = 3.2 Hz, 1H), 2.68-2.66 (m, 2H), 2.55-2.53 (m, 2H). 13C{1H} NMR (100
MHz, CDCl3, ppm): 204.9, 141.0, 137.1, 134.5, 128.7, 126.3, 125.9, 125.9, 125.9, 125.5, 122.1,
120.9, 112.8, 32.8, 24.0. HRMS (ESI) calcd for C15H14NO [M + H]+ 224.1075, found 224.1073.
2-((2-bromo-4-methylphenyl)amino)cyclopent-2-enone (3q). The compound was prepared
according to the general procedure (3 h) and purified by column chromatography (PE/EA = 30/1)
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to give the product as a yellow solid: 95.8 mg, 72% yield; mp = 112-113 °C. 1H NMR (400 MHz,
CDCl3, ppm): 7.36 (s, 1H), 7.18-7.16 (m, 1H), 7.07-7.05 (m, 1H), 6.70 (m, 1H), 6.66 (br, 1H),
2.65-2.64 (m, 2H), 2.49-2.47 (m, 2H), 2.27 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3, ppm):
204.4, 140.1, 136.9, 133.5, 131.6, 128.9, 125.0, 116.2, 112.7, 32.5, 24.1, 20.4. HRMS (ESI) calcd
for C12H13BrNO [M + H]+ 266.0181, found 266.0184.
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2-((3, 4-dichlorophenyl)amino)cyclopent-2-enone (3r). The compound was prepared according to
the general procedure (3 h) and purified by column chromatography (PE/EA = 30/1) to give the
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product as a white solid: 67.8 mg, 56% yield; mp = 147-148 °C. H NMR (400 MHz, CDCl3,
ppm): 7.31 (d, J = 8.7 Hz, 1H), 7.14 (s, 1H), 6.84 (d, J = 8.7 Hz, 1H), 6.74-6.73 (m, 1 H), 6.26 (br,
1H), 2.68-2.67 (m, 2H), 2.48 (t, J = 4.0 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3, ppm): 204.3,
141.3, 139.5, 133.1, 130.9, 126.1, 123.7, 117.7, 116.2, 32.3, 24.1. HRMS (ESI) calcd for
C11H10Cl2NO [M + H]+ 242.0139, found 242.0158.
2-(methyl(phenyl)amino)cyclopent-2-enone (3s). The compound was prepared according to the
general procedure (3 h) and purified by column chromatography (PE/EA = 30/1) to give the
product as yellow oil: 74.9 mg, 80% yield. 1H NMR (400 MHz, CDCl3, ppm): 7.27-7.23 (m, 2H),
6.97-6.92 (m, 3H), 6.83-6.82 (m, 1H), 3.19 (s, 3H), 2.61-2.60 (m, 2H), 2.50-2.48 (m, 2H). 13C{1H}
NMR (100 MHz, CDCl3, ppm): 204.7, 149.1, 147.7, 140.0, 128.9, 121.9, 120.0, 39.6, 34.8, 23.7.
HRMS (ESI) calcd for C12H14NO [M + H]+ 188.1075, found 188.1071.
2-(ethyl(phenyl)amino)cyclopent-2-enone (3t). The compound was prepared according to the
general procedure (4 h) and purified by column chromatography (PE/EA = 30/1) (PE:EtOAc, 30/1)
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to give the product as yellow oil: 70.4 mg, 70% yield. H NMR (400 MHz, CDCl3, ppm):
7.26-7.21 (m, 2H), 6.97-6.90 (m, 2H), 6.79-6.78 (m, 1H), 3.70-3.65 (m, 2H), 2.61-2.58 (m, 2H),
2.48-2.45 (m, 2H), 1.14 (t, J = 8.0 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3, ppm): 205.0, 147.8,
146.3, 139.1, 128.9, 122.0, 121.0, 46.2, 34.9, 23.8, 12.6. HRMS (ESI) calcd for C13H16NO [M +
H]+ 202.1232, found 202.1233.
5-methyl-2-(phenylamino)cyclopent-2-enone (3u). The compound was prepared according to the
general procedure (4 h) and purified by column chromatography (PE/EA = 30/1) to give the
product as yellow oil: 49.6 mg, 53% yield. 1H NMR (400 MHz, CDCl3, ppm): 7.32-7.26 (m, 2H),
7.05-7.02 (m, 2H), 6.94-6.90 (m, 1H), 6.21 (br, 1H), 2.94-2.87 (m, 1H), 2.50-2.43 (m, 1H),
2.26-2.20 (m, 1H), 1.24 (d, J = 7.5 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3, ppm): 207.4, 141.8,
139.0, 129.4, 123.2, 120.9, 116.7, 38.0, 33.4, 16.5. HRMS (ESI) calcd for C12H14NO [M + H]+
188.1075, found 188.1070.
4-methyl-2-(phenylamino)cyclopent-2-enone (3v). The compound was prepared according to the
general procedure (4 h) and purified by column chromatography (PE/EA = 30/1) to give the
product as yellow oil: 60.8 mg, 65% yield. 1H NMR (400 MHz, CDCl3, ppm): 7.31-7.27 (m, 2H),
7.04-7.01 (m, 2H), 6.94-6.90 (m, 1H), 6.52 (d, J = 3.0 Hz, 1H), 6.18 (br, 1H), 3.01-2.96 (m, 1H),
2.73-2.67 (m, 1H), 2.03-1.98 (m, 1H), 1.22 (d, J = 6.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3,
ppm): 204.6, 141.7, 139.3, 130.5, 129.4, 120.9, 116.7, 41.2, 31.3, 21.8. HRMS (ESI) calcd for
C12H14NO [M + H]+ 188.1075, found 188.1074.
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2-(phenylamino)cyclohex-2-enone (3w)7. The compound was prepared according to the general
procedure (4 h) and purified by column chromatography (PE/EA = 30/1) to give the product as
yellow oil: 20.1 mg, 22% yield. 1H NMR (400 MHz, CDCl3, ppm): 7.27-7.23 (m, 1H), 7.03-7.01
(m, 2H), 6.92-6.88 (m, 1H), 6.41 (t, J = 4.7 Hz, 1H), 2.55 (t, J = 6.6 Hz, 2H), 2.45 (q, J = 5.5 Hz,
2H), 2.05-1.98 (m, 2H). 13C{1H} NMR (100 MHz, CDCl3, ppm): 195.7, 142.0, 136.4, 129.3,
121.2, 118.7, 116.5, 37.8, 24.7, 23.0.
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ASSOCIATED CONTENT
1H NMR and 13C{1H} NMR spectra for all the products (PDF)
AUTHOR INFORMATION
Corresponding Author
Fax: 86-551-3631760. E-mail: zwang3@ustc.edu.cn
zgzha@ustc.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS:
We are grateful to the financial support from the National Natural Science Foundation of China
(21472177, 21672200, 21432009, 21772185), and the assistance of the product characterization
from the Chemistry Experiment Teaching Center of University of Science and Technology of
China. This work was supported by the Strategic Priority Research Program of Chinese Academy
of Sciences (XDB20000000).
References
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