Unexpected Iodine-Promoted Aerobic Oxidation of α-Cyano-δ-keto Esters: A Facile Synthesis of α,δ-Dicarbonyl Esters

Article abstract of DOI:10.1055/s-0040-1707996

An efficient and green method for the synthesis of various α,δ-dicarbonyl esters has been developed via a conjugate addition of ethyl cyanoacetates to chalcones and subsequent iodine-promoted aerobic oxidation. The present protocol features mild reaction

Full text of DOI:10.1055/s-0040-1707996

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2020, 52, A–F
paper
A
en
H. Xu et al.
Paper
Synthesis
Unexpected Iodine-Promoted Aerobic Oxidation of -Cyano--keto
Esters: A Facile Synthesis of ,-Dicarbonyl Esters
Hui Xu
O
COOR3
R2
O
COOR3
R2
NC
Ming-Yue Weng
Hong Chen
Ze Zhang*
R2
O
O
R1
I2
+
R1
R1
EtOH, 50 °C
NC
COOR3
O from air
19 examples
up to 92% yield
School of Biological and Chemical Engineering,
Anhui Polytechnic University, Wuhu 241000,
P. R. of China
metal-free
air as the oxidant
good functional group tolerance
ethanol as the solvent
zhangze@ustc.edu.cn
good to excellent yields
Received: 04.01.2020
Accepted after revision: 25.02.2020
Published online: 16.03.2020
wards ,-dicarbonyl compounds is of great importance
and highly desirable.
On the other hand, molecular iodine (I2), as a versatile
and environmentally friendly reagent, has been widely ap-
plied in organic synthesis because of its low cost and its en-
vironmentally benign nature compared to the transition-
metal catalysts, high tolerance to air and moisture, and
abundant availability.11,12 Our group is interested in devel-
oping novel I2-promoted organic reactions, and has con-
structed several nitrogen-containing heterocycles including
pyrroles,13 dihydropyrroles,14,13c pyridines15 and imidazo-
lines.16 In our initial design, we envisioned that a -cyano-
-keto ester would react with a nucleophile such as p-tolue-
nesulfonamide in the presence of I2 to generate a dihydro-
pyrrole derivative. However, an unexpected product of ,-
dicarbonyl ester was obtained instead of the designed prod-
uct (Scheme 1), although the yield was somewhat low. To
our knowledge, this is a new organic transformation for the
construction of such a highly significant building block.
Thus, we decided to investigate this reaction in more detail.
DOI: 10.1055/s-0040-1707996; Art ID: ss-2020-g0005-op
Abstract An efficient and green method for the synthesis of various
,-dicarbonyl esters has been developed via a conjugate addition of
ethyl cyanoacetates to chalcones and subsequent iodine-promoted aer-
obic oxidation. The present protocol features mild reaction conditions,
high efficiency, easily available starting materials, and broad substrate
scope.
Key words cyanoacetates, ,-dicarbonyl esters, molecular iodine,
aerobic oxidation, two-step synthesis
,-Dicarbonyl compounds are versatile building blocks
for the construction of various carbocyclic and heterocyclic
compounds, such as cyclopentenones,1 pyrroles,2 furfu-
rans,3 dihydropyridazines,4 and thiophenes.5 As a conse-
quence, considerable efforts have been devoted to the syn-
thesis of this highly significant synthon. Among the current
synthetic strategies to access ,-dicarbonyl compounds,
the conjugate addition of acyl anion equivalents to ,-un-
saturated carbonyl compounds is the most commonly used
method.6 Other attractive methods include one-carbon ex-
pansion of ,-dicarbonyl compounds,7 nucleophilic substi-
tution of -halo ketones,8 oxidative coupling of enolates or
alkenes and so on.9 Recently, Kim and co-workers disclosed
a novel two-step synthesis of ,-dicarbonyl esters via con-
jugate addition of cyanoacetates to ,-unsaturated carbon-
yl compounds and subsequent CuI-catalyzed aerobic oxida-
tion.10 Although these methods are powerful, they often
suffer from some drawbacks, such as use of expensive met-
al catalysts, complex starting materials, toxic organic sol-
vents, harsh reaction conditions and so on. Therefore, the
development of greener and more efficient strategies to-
designed reaction pathway
Ph
COOEt
Ph
COOEt
NHTs
COOEt
Ph
NC
I
TsNH2
O
Ph
Ph
– I–
Ph
N
N
O
O
Ph
COOEt
NHTs
Ph
X
N
H
O
COOEt
Ph
NC
I2
EtOH, 50 °C
expected
O
TsNH2
+
Ph
O
COOEt
Ph
O
Ph
obtained
Scheme 1 Initial experiment
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–F
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
H. Xu et al.
Paper
Synthesis
Initially, a mixture of 1a (0.5 mmol), I2 (0.5 mmol) and
ethanol (5 mL) was stirred in an open tube at room tem-
perature (25 °C) for 8 h (Table 1, entry 1), and ethyl 2,5-di-
oxo-3,5-diphenylpentanoate (2a) was isolated in 34% yield.
To further improve the yield, we focused on this model re-
action to optimize the reaction conditions. The influence of
reaction solvent was examined first.
reaction conditions were established as follows: 1a (0.5
mmol) and an equimolar amount of I2 was stirred in EtOH
(5 mL) under air atmosphere at 50 °C for 8 hours (entry 8).
Based on the above experimental results and on the
previous reports,17,10 a plausible reaction mechanism is
proposed in Scheme 2. The reaction begins with iodination
of 1a to give iodide A. Homolytic cleavage of the C–I bond of
A then gives carbon radical B, which reacts with oxygen
from air to generate peroxyl radical C.17 Subsequently, a
coupling reaction of radical C with iodine radical takes
place, affording intermediate D. Next, homolytic cleavage of
the O–O bond of D forms oxygen radical E. During this
transformation, a molar equivalent of IO• is formed and fur-
ther reacts with HI to give iodine radical, which is interme-
diately trapped by radical E to generate hypoiodite F. After-
wards, hypoiodite F reacts with 1a to give -hydroxynitrile
G and intermediate A. Finally, G eliminates a molar equiva-
lent of HCN to generate product 2a.10
Table 1 Optimization of the Reaction Conditionsa
O
COOEt
Ph
O
COOEt
Ph
NC
Ph
Ph
O
O
I2
+
solvent, temp
Ph
Ph
NC
COOEt
1a
2a
Entry
Solvent
Temp (°C)
Yield (%)
1
2
EtOH
MeCN
DMF
DCE
25
25
25
25
25
25
25
50
80
50
50
34
trace
trace
ND
ND
ND
32
3
I2
NC
CO2Et
Ph
NC
O
CO2Et
NC
O
CO2Et
Ph
O
4
I
Ph
Ph
Ph
Ph
Ph
Ph
5
THF
HI
B
1a
A
6
toluene
DMSO
EtOH
O2
I
7
8
91
NC
CO2Et
O
NC
O
CO2Et
NC
CO2Et
O
O
O
O
I
O
O
9
EtOH
17
Ph
Ph
Ph
Ph
Ph
10b
11c
EtOH
ND
trace
C
D
E
IO
EtOH
I
HI
a Reaction conditions: a mixture of 1a (0.5 mmol) and I2 (0.5 mmol) in or-
ganic solvent (5 mL) was stirred under air atmosphere at specified tem-
perature for 8 h. Isolated yields are given; ND = not detected.
b No iodine was used.
HIO
1a
NC
CO2Et
NC
CO2Et
OH
O
CO2Et
Ph
O
O
O
O
I
c Under N2 atmosphere.
Ph
Ph
Ph
Ph
HCN
F
A
G
2a
Scheme 2 Proposed reaction mechanism
It was found that the use of either acetonitrile (MeCN)
or N,N-dimethylformamide (DMF) as the solvents only gave
a trace amount of 2a (Table 1, entries 2 and 3), whereas 1,2-
dichloroethane (DCE), tetrahydrofuran (THF) and toluene as
the solvents were even worse and no product was detected
(entries 4–6). In addition, a similar yield was obtained
when dimethyl sulfoxide (DMSO) was employed (entry 7).
Subsequently, the effect of reaction temperature on the
product yield was investigated. As the reaction temperature
was increased to 50 °C, the yield of product 2a significantly
improved to 91% (entry 8). However, further increasing the
reaction temperature to 80 °C led to a dramatic decrease in
yield (entry 9). Further experiments indicated that I2 was
indispensable for this transformation, since no product
could be detected in the absence of I2 (entry 10). Moreover,
the reaction was also carried out under nitrogen atmo-
sphere and product 2a was delivered in only a trace amount
(entry 11), demonstrating that oxygen from the air played a
crucial role in this transformation. Therefore, the optimal
The substrate scope and generality of this reaction were
then explored (Scheme 3). First, a variety of chalcone deriv-
atives were investigated. Chalcones with the phenyl ring R1
bearing either electron-donating group (OMe) or electron-
withdraw group (NO2) at the para-position reacted well and
afforded the corresponding products 2b and 2d in 88% and
70% yields, respectively. Halogen-substituted chalcone also
worked well to give product 2c in 91% yield. To our delight,
when the phenyl ring of chalcone was replaced with a 2-fu-
ryl, 2-naphthyl or methyl group, the corresponding prod-
ucts 2e–g were obtained in 51–75% yields. Gratifyingly,
chalcones with either electron-donating groups (Me and
OMe) or electron-withdrawing group (NO2) on the phenyl
ring adjacent to the C–C double bond proceeded smoothly
in this reaction to provide products 2h–k in 73–87% yields.
2,4-Dichloro-substituted chalcone also exhibited a high re-
activity, affording the ,-dicarbonyl ester 2l in an excellent
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–F

C
H. Xu et al.
Paper
Synthesis
yield of 92%. Furthermore, a series of products 2m–s were
also isolated in good yields of 75–89% when the ethyl group
was replaced with the methyl group.
(0.5 mmol) was first stirred in DMSO (5 mL) at 50 °C for 8 h
to generate 2a, and then aniline (1.0 mmol) was added and
the mixture was stirred at 100 °C for another 8 h. As ex-
pected, target pyrrole derivative 3a was obtained in a satis-
factory yield of 86%. It should be pointed out that when
EtOH was used as the solvent only a trace amount of prod-
uct 3a was obtained.
O
COOR3
R2
O
COOR3
R2
NC
R2
O
O
R1
I2 (1 equiv)
+
R1
EtOH, 50 °C
under air
R1
NC
COOR3
1a–s
2a–s
In summary, we have developed a novel method for the
efficient synthesis of a variety of ,-dicarbonyl esters via a
conjugate addition of ethyl cyanoacetates to chalcones and
a subsequent I2-promoted aerobic oxidation. Moreover, the
protocol can be extended to pyrrole synthesis. This protocol
features high efficiency, green reaction conditions (I2 as the
promoter, EtOH as the solvent and air as the oxidant) and
good functional-group tolerance. These merits make the
present method a practical alternative for the efficient syn-
thesis of highly significant ,-dicarbonyl esters.
O
CO2Et
O
O
CO2Et
O
CO2Et
O
O
MeO
Br
2a, 91%
2c, 91%
2b, 88%
O
O
CO2Et
O
O
CO2Et
O
O
CO2Et
O
O2N
2d, 70%
2e, 75%
2f, 51%
O
CO2Et
O
CO2Et
O
CO2Et
O
O
O
Me
All reagents were obtained from commercial sources and used with-
out further purification. NMR spectra were recorded with a 500 MHz
NMR spectrometer (500 MHz for 1H NMR; 126 MHz for 13C NMR). 1H
NMR chemical shifts were determined relative to internal TMS at  =
0.0 ppm. 13C NMR chemical shifts were determined relative to CDCl3
at  = 77.16 ppm. Data for 1H and 13C NMR are reported as: chemical
shift (, ppm), multiplicity (s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet). High-resolution mass spectra (HRMS) were
measured with ESI-TOF in a positive mode. Thin-layer chromatogra-
phy was performed on precoated glass-backed plates and visualized
with UV light at 254 nm. Flash column chromatography was per-
formed on silica gel. -Cyano--keto esters were prepared according
to the reported protocol.10
OMe
2g, 68%
2h, 79%
2i, 84%
O
O
CO2Et
O
CO2Et
O
CO2Et
O
O
Me
NO2
Cl
Cl
2j, 87%
2k, 73%
2l, 92%
O
O
CO2Me
O
O
CO2Me
O
O
CO2Me
MeO
Cl
2m, 89%
2n, 81%
2o, 86%
CO2Me
O
O
O
CO2Me
O
O
CO2Me
O
Typical Procedure
In an open tube, a mixture of ethyl 2-cyano-5-oxo-3,5-diphenyl-
pentanoate (1a; 160.7 mg, 0.5 mmol), molecular iodine (126.9 mg, 0.5
mmol), and chlorobenzene (5.0 mL) was stirred at 50 °C for 8 h. After
completion of the reaction (detected by TLC), the reaction mixture
was washed with aqueous sodium thiosulfate, dried over magnesium
sulfate, and concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel with EtOAc/
petroleum ether as the eluent, affording the desired product 2a (141.5
mg, 91%) as a colorless oil.
O2N
OMe
Br
2q, 75%
2r, 86%
2p, 88%
O
O
CO2Me
2s, 82%
Scheme 3 Two-step synthesis of ,-dicarbonyl esters 2a–s. Reagents
and conditions: 1 (0.5 mmol), I2 (0.5 mmol), EtOH (5 mL), stirred under
air atmosphere, 50 °C, 8 h. Isolated yields by silica gel column chroma-
tography.
The new products (2c–f,i,k,l,n–s), 2a, 2i and 2k were characterized by
1H NMR, 13C NMR and HRMS spectra. Other known compounds were
characterized by 1H NMR spectra.
Considering that the synthetic ,-dicarbonyl esters can
be further transformed into highly significant pyrroles, we
thus attempted a three-step pyrrole synthesis (Scheme 4).
In a representative experiment, adduct 1a (0.5 mmol) and I2
Ethyl 2,5-Dioxo-3,5-diphenylpentanoate (2a)
[CAS Reg. No. 1354642-76-4]
Yield: 141.5 mg (91%); colorless oil.
O
Ph
COOEt
Ph
O
COOEt
Ph
NC
Ph
Ph
O
O
I2
Ph NH2
+
Ph
CO2Et
DMSO, 50 °C
8 h, under air
100 °C, 8 h
N
Ph
Ph
Ph
NC
COOEt
1a
2a
3a, 86%
Scheme 4 Three-step synthesis of pyrrole 3a
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–F

D
H. Xu et al.
Paper
Synthesis
1H NMR (500 MHz, CDCl3):  = 7.97–7.93 (m, 2 H), 7.57 (t, J = 7.4 Hz,
1 H), 7.45 (t, J = 7.8 Hz, 2 H), 7.37–7.33 (m, 4 H), 7.32–7.27 (m, 1 H),
5.15 (dd, J = 10.6, 3.8 Hz, 1 H), 4.34–4.22 (m, 2 H), 4.03 (dd, J = 18.2,
10.6 Hz, 1 H), 3.43 (dd, J = 18.2, 3.8 Hz, 1 H), 1.30 (t, J = 7.1 Hz, 3 H).
13C NMR (126 MHz, CDCl3):  = 197.5, 192.3, 160.6, 136.2, 135.6,
133.6, 129.3 (2C), 129.0 (2C), 128.8 (2C), 128.3 (2C), 128.1, 62.6, 48.7,
43.2, 14.0.
1H NMR (500 MHz, CDCl3):  = 8.48 (s, 1 H), 8.00 (dd, J = 8.7, 1.7 Hz,
1 H), 7.93 (d, J = 8.0 Hz, 1 H), 7.90–7.85 (m, 2 H), 7.60 (ddd, J = 7.5, 6.9,
1.2 Hz, 1 H), 7.54 (ddd, J = 7.5, 6.9, 1.2 Hz, 1 H), 7.41–7.35 (m, 4 H),
7.33–7.29 (m, 1 H), 5.21 (dd, J = 10.7, 3.8 Hz, 1 H), 4.36–4.24 (m, 2 H),
4.17 (dd, J = 18.1, 10.7 Hz, 1 H), 3.59 (dd, J = 18.1, 3.8 Hz, 1 H), 1.32 (t,
J = 7.2 Hz, 3 H).
13C NMR (126 MHz, CDCl3):  = 197.4, 192.4, 160.6, 135.9, 135.7,
133.5, 132.6, 130.2, 129.7, 129.3 (2C), 129.1 (2C), 128.8, 128.7, 128.1,
128.0, 127.0, 123.9, 62.6, 48.8, 43.4, 14.1.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C19H19O4: 311.1283; found:
311.1280.
HRMS (ESI-TOF) m/z calcd for C23H21O4 [M + H]+ 361.1440; found:
361.1443.
Ethyl 5-(4-Methoxyphenyl)-2,5-dioxo-3-phenylpentanoate (2b)
[CAS Reg. No. CAS: 1415391-58-0]
Ethyl 2,5-Dioxo-3-phenylhexanoate (2g)
[CAS Reg. No. 1415391-59-1]
Yield: 149.2 mg (88%); light-yellow solid; mp 116–118 °C.
1H NMR (500 MHz, CDCl3):  = 7.93 (d, J = 8.9 Hz, 2 H), 7.37–7.27 (m,
5 H), 6.91 (d, J = 8.9 Hz, 2 H), 5.13 (dd, J = 10.8, 3.8 Hz, 1 H), 4.34–4.22
(m, 2 H), 3.99 (dd, J = 18.0, 10.8 Hz, 1 H), 3.86 (s, 3 H), 3.40 (dd, J =
18.0, 3.8 Hz, 1 H), 1.31 (t, J = 7.1 Hz, 3 H).
Yield: 84.4 mg (68%); colorless oil.
1H NMR (500 MHz, CDCl3):  = 7.32 (t, J = 7.2 Hz, 2 H), 7.29–7.23 (m,
3 H), 4.94 (dd, J = 10.5, 4.0 Hz, 1 H), 4.29–4.17 (m, 2 H), 3.48 (dd, J =
18.3, 10.5 Hz, 1 H), 2.83 (dd, J = 18.3, 4.0 Hz, 1 H), 2.18 (s, 3 H), 1.26 (t,
J = 7.1 Hz, 3 H).
Ethyl 5-(4-Bromophenyl)-2,5-dioxo-3-phenylpentanoate (2c)
Yield: 177.0 mg (91%); colorless oil.
Ethyl 3-(4-Methoxyphenyl)-2,5-dioxo-5-phenylpentanoate (2h)
[CAS Reg. No. 1253042-08-8]
1H NMR (500 MHz, CDCl3):  = 7.80 (d, J = 8.6 Hz, 2 H), 7.59 (d, J =
8.6 Hz, 2 H), 7.36–7.27 (m, 5 H), 5.13 (dd, J = 10.4, 3.9 Hz, 1 H), 4.32–
4.20 (m, 2 H), 3.97 (dd, J = 18.1, 10.4 Hz, 1 H), 3.35 (dd, J = 18.1, 3.7 Hz,
1 H), 1.28 (t, J = 7.1 Hz, 3 H).
13C NMR (126 MHz, CDCl3):  = 196.5, 192.2, 160.5, 135.4, 135.0, 132.1
(2C), 129.8 (2C), 129.3 (2C), 129.0 (2C), 128.9, 128.2, 62.6, 48.7, 43.0,
14.0.
Yield: 134.5 mg (79%); light-yellow oil.
1H NMR (500 MHz, CDCl3):  = 7.95 (d, J = 7.3 Hz, 3 H), 7.57 (t, J =
7.4 Hz, 1 H), 7.45 (t, J = 7.7 Hz, 3 H), 7.26 (d, J = 8.7 Hz, 2 H), 6.88 (d, J =
8.7 Hz, 2 H), 5.10 (dd, J = 10.5, 3.9 Hz, 1 H), 4.34–4.22 (m, 2 H), 3.99
(dd, J = 18.2, 10.5 Hz, 1 H), 3.79 (s, 3 H), 3.40 (dd, J = 18.2, 3.9 Hz, 1 H),
1.31 (t, J = 7.1 Hz, 3 H).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C19H18BrO4: 389.0388; found:
389.0375.
Ethyl 2,5-Dioxo-5-phenyl-3-(m-tolyl)pentanoate (2i)
[CAS Reg. No. 1415391-64-8]
Ethyl 5-(4-Nitrophenyl)-2,5-dioxo-3-phenylpentanoate (2d)
Yield: 124.5 mg (70%); yellow solid; mp 134–136 °C.
Yield: 136.0 mg (84%); colorless oil.
1H NMR (500 MHz, CDCl3):  = 8.30 (d, J = 8.9 Hz, 2 H), 8.12 (d, J =
8.9 Hz, 2 H), 7.39–7.29 (m, 5 H), 5.17 (dd, J = 10.4, 3.8 Hz, 1 H), 4.33–
4.23 (m, 2 H), 4.05 (dd, J = 18.3, 10.4 Hz, 1 H), 3.41 (dd, J = 18.3, 3.8 Hz,
1 H), 1.29 (t, J = 7.1 Hz, 3 H).
13C NMR (126 MHz, CDCl3):  = 196.1, 192.0, 160.4, 150.7, 140.6,
134.9, 129.4 (2C), 129.3 (2C), 129.0 (2C), 128.4, 124.0 (2C), 62.7, 48.8,
43.2, 14.0.
1H NMR (500 MHz, CDCl3):  = 7.97–7.93 (m, 2 H), 7.57 (t, J = 7.4 Hz,
1 H), 7.45 (t, J = 7.8 Hz, 2 H), 7.24 (t, J = 6.8 Hz, 1 H), 7.16–7.13 (m,
2 H), 7.10 (d, J = 7.6 Hz, 1 H), 5.12 (dd, J = 10.7, 3.7 Hz, 1 H), 4.34–4.22
(m, 2 H), 4.02 (dd, J = 18.2, 10.7 Hz, 1 H), 3.41 (dd, J = 18.2, 3.7 Hz,
1 H), 2.34 (s, 3 H), 1.31 (t, J = 7.1 Hz, 3 H).
13C NMR (125 MHz, CDCl3):  = 197.5, 192.3, 160.5, 139.0, 136.2,
135.4, 133.6, 129.6, 129.1, 128.9, 128.8 (2C), 128.3 (2C), 126.1, 62.6,
48.5, 43.3, 21.5, 14.0.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C19H18NO6: 356.1134; found:
356.1103.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C20H21O4: 325.1440; found:
325.1436.
Ethyl 5-(Furan-2-yl)-2,5-dioxo-3-phenylpentanoate (2e)
Ethyl 2,5-Dioxo-5-phenyl-3-(o-tolyl)pentanoate (2j)
[CAS Reg. No. 1415391-63-7]
Yield: 112.2 mg (75%); colorless oil.
1H NMR (500 MHz, CDCl3):  = 7.57 (d, J = 0.9 Hz, 1 H), 7.37–7.27 (m,
5 H), 7.20 (d, J = 3.6 Hz, 1 H), 6.53 (dd, J = 3.6, 1.6 Hz, 1 H), 5.11 (dd, J =
10.3, 4.3 Hz, 1 H), 4.31–4.19 (m, 2 H), 3.87 (dd, J = 18.1, 10.3 Hz, 1 H),
3.29 (dd, J = 18.1, 4.3 Hz, 1 H), 1.28 (t, J = 7.1 Hz, 3 H).
13C NMR (126 MHz, CDCl3):  = 192.2, 186.5, 160.5, 152.3, 146.7,
135.4, 129.3 (2C), 129.0 (2C), 128.1, 117.5, 112.5, 62.6, 48.3, 42.3,
14.0.
Yield: 140.8 mg (87%); colorless oil.
1H NMR (500 MHz, CDCl3):  = 7.97–7.93 (m, 2 H), 7.56 (t, J = 7.4 Hz,
1 H), 7.45 (t, J = 7.8 Hz, 2 H), 7.24 (d, J = 7.1 Hz, 1 H), 7.21–7.13 (m,
2 H), 7.06 (dd, J = 7.5, 1.4 Hz, 1 H), 5.37 (dd, J = 10.3, 3.6 Hz, 1 H),
4.29–4.17 (m, 2 H), 3.93 (dd, J = 18.2, 10.3 Hz, 1 H), 3.26 (dd, J = 18.2,
3.7 Hz, 1 H), 2.54 (s, 3 H), 1.26 (t, J = 7.1 Hz, 3 H).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C17H17O5: 301.1076; found:
301.1075.
Ethyl 3-(4-Nitrophenyl)-2,5-dioxo-5-phenylpentanoate (2k)
[CAS Reg. No. CAS: 147753-55-7]
Ethyl 5-(Naphthalen-2-yl)-2,5-dioxo-3-phenylpentanoate (2f)
Yield: 129.6 mg (73%); yellow solid; mp 77–79 °C.
Yield: 92.1 mg (51%); white solid; mp 126–128 °C.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–F

E
H. Xu et al.
Paper
Synthesis
1H NMR (500 MHz, CDCl3):  = 8.21 (d, J = 8.7 Hz, 2 H), 7.95 (d, J =
7.3 Hz, 2 H), 7.60 (t, J = 7.4 Hz, 1 H), 7.7 (d, J = 8.7 Hz, 3 H), 7.47 (t, J =
7.8 Hz, 2 H), 5.27 (dd, J = 10.4, 4.1 Hz, 1 H), 4.38–4.26 (m, 2 H), 4.05
(dd, J = 18.1, 10.4 Hz, 1 H), 3.52 (dd, J = 18.1, 4.1 Hz, 1 H), 1.35 (t, J =
7.1 Hz, 3 H).
13C NMR (126 MHz, CDCl3):  = 196.1, 191.6, 160.8, 150.8, 140.5,
134.8, 129.5 (2C), 129.3 (2C), 128.9 (2C), 128.4, 124.1 (2C), 53.2, 48.7,
43.4, 18.6.
Methyl 5-(4-Bromophenyl)-2,5-dioxo-3-phenylpentanoate (2p)
Yield: 164.4 mg (88%); colorless oil.
1H NMR (500 MHz, CDCl3):  = 7.81 (d, J = 8.6 Hz, 2 H), 7.60 (d, J =
8.6 Hz, 2 H), 7.38–7.28 (m, 5 H), 5.14 (dd, J = 10.8, 3.7 Hz, 1 H), 3.99
(dd, J = 18.2, 10.8 Hz, 1 H), 3.84 (s, 3 H), 3.39 (dd, J = 18.2, 3.7 Hz, 1 H).
13C NMR (126 MHz, CDCl3):  = 196.5, 191.9, 160.9, 135.2, 134.9, 132.2
(2C), 129.8 (2C), 129.4 (2C), 129.0 (2C), 128.9, 128.3, 53.2, 48.6, 43.2.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C18H16BrO4: 375.0232; found:
375.0244.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C19H18NO6: 356.1134; found:
356.1128.
Methyl 5-(4-Nitrophenyl)-2,5-dioxo-3-phenylpentanoate (2q)
Ethyl 3-(2,4-Dichlorophenyl)-2,5-dioxo-5-phenylpentanoate (2l)
Yield: 128.1 mg (75%); yellow solid; mp 141–143 °C.
Yield: 174.0 mg (92%); colorless oil.
1H NMR (500 MHz, CDCl3):  = 8.31 (d, J = 8.9 Hz, 2 H), 8.11 (d, J =
8.9 Hz, 2 H), 7.39–7.30 (m, 5 H), 5.18 (dd, J = 10.7, 3.6 Hz, 1 H), 4.06
(dd, J = 18.4, 10.7 Hz, 1 H), 3.84 (s, 3 H), 3.43 (dd, J = 18.4, 3.6 Hz, 1 H).
13C NMR (126 MHz, CDCl3):  = 196.1, 191.5, 160.7, 150.5, 140.3,
134.7, 129.23 (2C), 129.16 (2C), 128.8 (2C), 128.1, 123.8 (2C), 52.9,
48.6, 43.1.
1H NMR (500 MHz, CDCl3):  = 7.96–7.92 (m, 2 H), 7.58 (t, J = 7.4 Hz,
1 H), 7.48–7.43 (m, 3 H), 7.23 (dd, J = 8.4, 2.1 Hz, 1 H), 7.14 (d, J =
8.4 Hz, 1 H), 5.54 (dd, J = 10.3, 3.7 Hz, 1 H), 4.34–4.23 (m, 2 H), 3.88
(dd, J = 18.1, 10.3 Hz, 1 H), 3.37 (dd, J = 18.1, 3.7 Hz, 1 H), 1.31 (t, J =
7.1 Hz, 3 H).
13C NMR (126 MHz, CDCl3):  = 196.7, 191.9, 160.3, 136.0, 135.2,
134.7, 133.7, 132.7, 130.4, 130.3, 128.8 (2C), 128.3 (2C), 127.8, 62.8,
45.4, 41.8, 14.0.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C18H16NO6: 342.0978; found:
342.0979.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C19H17Cl2O4: 379.0504; found:
379.0506.
Methyl 3-(4-Methoxyphenyl)-2,5-dioxo-5-phenylpentanoate (2r)
Yield: 140.3 mg (86%); colorless oil.
Methyl 2,5-Dioxo-3,5-diphenylpentanoate (2m)
[CAS Reg. No. 1292310-23-6]
1H NMR (500 MHz, CDCl3):  = 7.96–7.92 (m, 2 H), 7.55 (t, J = 7.4 Hz,
1 H), 7.44 (t, J = 7.8 Hz, 2 H), 7.26 (d, J = 8.7 Hz, 2 H), 6.88 (d, J = 8.7 Hz,
2 H), 5.10 (dd, J = 10.7, 3.8 Hz, 1 H), 4.00 (dd, J = 18.2, 10.7 Hz, 1 H),
3.82 (s, 3 H), 3.77 (s, 3 H), 3.41 (dd, J = 18.2, 3.8 Hz, 1 H).
13C NMR (126 MHz, CDCl3):  = 197.5, 191.9, 161.1, 159.5, 136.1,
133.5, 130.1 (2C), 128.7 (2C), 128.2 (2C), 127.0, 114.7 (2C), 55.3, 52.9,
47.7, 43.1.
Yield: 132.2 mg (89%); colorless oil.
1H NMR (500 MHz, CDCl3):  = 7.97–7.93 (m, 2 H), 7.57 (t, J = 7.4 Hz,
1 H), 7.45 (t, J = 7.8 Hz, 2 H), 7.37–7.28 (m, 5 H), 5.15 (dd, J = 10.8,
3.7 Hz, 1 H), 4.04 (dd, J = 18.2, 10.8 Hz, 1 H), 3.84 (s, 3 H), 3.46 (dd, J =
18.2, 3.7 Hz, 1 H).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C19H19O5: 327.1232; found:
327.1230.
Methyl 5-(4-Methoxyphenyl)-2,5-dioxo-3-phenylpentanoate (2n)
Yield: 132.5 mg (81%); light-yellow solid; mp 60–62 °C.
Methyl 2,5-Dioxo-5-phenyl-3-(o-tolyl)pentanoate (2s)
1H NMR (500 MHz, CDCl3):  = 7.92 (d, J = 8.9 Hz, 2 H), 7.37–7.27 (m,
5 H), 6.91 (d, J = 8.9 Hz, 2 H), 5.13 (dd, J = 11.0, 3.7 Hz, 1 H), 4.00 (dd,
J = 18.0, 11.0 Hz, 1 H), 3.86 (s, 3 H), 3.84 (s, 3 H), 3.43 (dd, J = 18.0,
3.7 Hz, 1 H).
13C NMR (126 MHz, CDCl3):  = 196.0, 192.1, 164.0, 161.0, 135.6, 130.6
(2C), 129.3 (2C), 129.1, 129.0 (2C), 128.1, 114.0 (2C), 55.6, 53.1, 48.5,
43.4.
Yield: 126.9 mg (82%); colorless oil.
1H NMR (500 MHz, CDCl3):  = 7.95–7.91 (m, 2 H), 7.54 (t, J = 7.4 Hz,
1 H), 7.42 (t, J = 7.8 Hz, 2 H), 7.23 (d, J = 7.2 Hz, 1 H), 7.20–7.13 (m,
2 H),7.07 (dd, J = 7.5, 1.4 Hz, 1 H), 5.39 (dd, J = 10.5, 3.6 Hz, 1 H), 3.92
(dd, J = 18.3, 10.5 Hz, 1 H), 3.76 (s, 3 H), 3.28 (dd, J = 18.3, 3.6 Hz, 1 H),
2.54 (s, 3 H).
13C NMR (126 MHz, CDCl3):  = 197.3, 192.0, 161.1, 137.2, 136.1,
133.8, 133.4, 131.4, 128.6 (2C), 128.1 (2C), 127.9, 127.6, 126.6, 52.8,
44.6, 42.3, 19.7.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C19H19O5: 327.1232; found:
327.1234.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C19H19O4: 311.1283; found:
311.1281.
Methyl 5-(4-Chlorophenyl)-2,5-dioxo-3-phenylpentanoate (2o)
Yield: 142.2 mg (86%); colorless oil.
1H NMR (500 MHz, CDCl3):  = 7.89 (d, J = 8.6 Hz, 2 H), 7.42 (d, J =
8.6 Hz, 2 H), 7.38–7.28 (m, 5 H), 5.14 (dd, J = 10.8, 3.6 Hz, 1 H), 4.00
(dd, J = 18.2, 10.8 Hz, 1 H), 3.83 (s, 3 H), 3.40 (dd, J = 18.2, 3.6 Hz, 1 H).
13C NMR (126 MHz, CDCl3):  = 196.3, 191.9, 160.9, 140.2, 135.2,
134.4, 129.7 (2C), 129.4 (2C), 129.1 (2C), 129.0 (2C), 128.2, 53.1, 48.6,
43.2
Ethyl 1,3,5-Triphenyl-1H-pyrrole-2-carboxylate (3a)
[CAS Reg. No. 1373319-66-4]
Yield: 157.7 mg (86%); white solid.
1H NMR (500 MHz, CDCl3):  = 7.57–7.52 (m, 2 H), 7.39 (t, J = 7.5 Hz,
2 H), 7.35–7.29 (m, 4 H), 7.27–7.22 (m, 2 H), 7.19–7.15 (m, 3 H), 7.14–
7.09 (m, 2 H), 6.48 (s, 1 H), 3.96 (q, J = 7.1 Hz, 2 H), 0.87 (t, J = 7.1 Hz,
3 H).
HRMS (ESI-TOF): m/z [M + H]+ calcd for C18H16ClO4: 331.0737; found:
331.0735.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–F

F
H. Xu et al.
Paper
Synthesis
Funding Information
(7) (a) Xue, S.; Li, L.-Z.; Liu, Y.-K.; Guo, Q.-X. J. Org. Chem. 2006, 71,
215. (b) Voituriez, A.; Zimmer, L. E.; Charette, A. B. J. Org. Chem.
2010, 75, 1244.
(8) (a) Yasuda, M.; Tsuji, S.; Shigeyoshi, Y.; Baba, A. J. Am. Chem. Soc.
2002, 124, 7440. (b) Liu, C.; Deng, Y.; Wang, J.; Yang, Y.; Tang, S.;
Lei, A. Angew. Chem. Int. Ed. 2011, 50, 7337.
This work was supported by the Introduction of Talent Research Start-
up Fund of Anhui Polytechnic University (2018YQQ015) and Natural
Science Foundation for Universities of Anhui Province (KJ2019ZD14).
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(9) (a) Avetta, C. T. Jr.; Konkol, L. C.; Taylor, C. N.; Dugan, K. C.; Stern,
C. L.; Thomson, R. J. Org. Lett. 2008, 10, 5621. (b) Clift, M. D.;
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1707996.
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T. Chem. Soc. Rev. 2004, 33, 354. (b) Togo, H.; Iida, S. Synlett
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© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–F