Copper(II)-Promoted Oxidation/[3+2]Cycloaddition/Aromatization Cascade: Efficient Synthesis of Tetrasubstituted NH -Pyrrole from Chalcones and Iminodiacetates

Article abstract of DOI:10.1055/s-0039-1689972

A simple and highly efficient method for the preparation of tetrasubstituted NH -pyrrole from a wide range of chalcones and diethyl iminodiacetates via a Cu(OAc) ₂ -promoted oxidation/[3+2]cycloaddition/aromatization cascade reaction has been developed. This reaction proceeds through dehydrogenations, deamination, and oxidative cyclization, affording the corresponding products in good to excellent yields. This convenient methodology for constructing tetrasubstituted NH -pyrroles has several advantages over existing methods, such as the use of easily accessible chalcones and readily available diethyl iminodiacetates, and mild reaction conditions. A wide range of substrates are tolerated.

Full text of DOI:10.1055/s-0039-1689972

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© Georg Thieme Verlag Stuttgart · New York
2019, 30, A–E
letter
A
en
Z.-q. Lin et al.
Letter
Synlett
Copper(II)-Promoted Oxidation/[3+2]Cycloaddition/Aromatiza-
tion Cascade: Efficient Synthesis of Tetrasubstituted NH-Pyrrole
from Chalcones and Iminodiacetates
O
Zhang-qi Lin
H
N
R3
Cu(OAc)2 (1.0 equiv)
Et3N (1.0 equiv)
O
O
OR4
Chao-dong Li
Zi-chun Zhou
Shuai Xue
H
R3
N
R1
R2
+
OR4
R1
DMF, 100 °C
O
R2
R3 = Ph, CO2R4
R4 = Et, Me, Pr, i-Pr, Bu, i-Bu
R1, R2 = Ar or Me
Jian-rong Gao
Qing Ye
atom- or step-economic
mild reaction conditions
24 examples, 45–94% yields
cheap catalyst
easy available starting materials
cascade reaction
Yu-jin Li*
College of Chemical Engineering, Zhejiang University of Technology,
Hangzhou 310014, P. R. of China
lyjzjut@zjut.edu.cn
Received: 11.04.2019
Accepted after revision: 16.06.2019
Published online: 12.06.2019
Given their important bioactive and therapeutic proper-
ties, pyrrole derivatives have attracted much attention from
the organic chemistry community, and a variety of efficient
methods have been reported for their synthesis, such as the
classic Hantzsch,6 Trofimov,7 Knorr or Paal–Knorr,8 [3+2]
cycloadditions,9 and Clauson–Kaas reactions.10 In addition,
pyrroles have also been synthesized through transition-
metal-catalyzed cyclization,11 and by many other approach-
es.12 Although many useful strategies for the construction
of polysubstituted pyrroles have been developed, some of
these methods suffer from serious limitations with respect
to atom- or step-economic considerations.13 Therefore, it is
highly desirable to establish a simple and efficient method
for synthesis of polysubstituted pyrroles from inexpensive,
readily available starting materials.
DOI: 10.1055/s-0039-1689972; Art ID: st-2019-k0206-l
Abstract A simple and highly efficient method for the preparation of
tetrasubstituted NH-pyrrole from a wide range of chalcones and diethyl
iminodiacetates via a Cu(OAc)2-promoted oxidation/[3+2]cycloaddi-
tion/aromatization cascade reaction has been developed. This reaction
proceeds through dehydrogenations, deamination, and oxidative cy-
clization, affording the corresponding products in good to excellent
yields. This convenient methodology for constructing tetrasubstituted
NH-pyrroles has several advantages over existing methods, such as the
use of easily accessible chalcones and readily available diethyl iminodia-
cetates, and mild reaction conditions. A wide range of substrates are
tolerated.
Key words Cu(II)-promoted, tetrasubstituted NH-pyrrole, iminodiace-
tate, oxidation/[3+2] cycloaddition/aromatization, cascade reaction
Amino acid esters and their derivatives, which are com-
mercially available or easy accessible, are important precur-
sors of N-heterocycles for the construction of polysubstitut-
ed pyrroles.14 In 2015, Xie and co-workers reported an ef-
fective method to access tetrasubstituted NH-pyrroles from
amino acid esters by using a Cu/Pd system (Scheme 1A).14a
Moreover, our own team has developed novel approaches
for the synthesis of polysubstituted pyrroles via the 1,3-di-
polar cycloaddition reaction of quinones and amino acid es-
ters (Scheme 1B).15 Encouraged by these achievements and
by our ongoing study of N-substituted iminodiacetates as
N-heterocycle precursors,16 we speculated that commer-
cially available iminodiacetates could also be used to pre-
pare polysubstituted pyrroles. Herein, we report a straight-
forward and effective method for the synthesis of tetra sub-
stituted NH-pyrroles from chalcones and iminodiacetates
through an oxidation/[3+2] cycloaddition/aromatization
cascaded, promoted by Cu(OAc)2 (Scheme 1C).
Polysubstituted pyrroles are an important class of five-
membered heterocycles and they are found in numerous
natural products and pharmaceuticals, and have applica-
tions in material science.1 Ningalins A was isolated from a
Western Australian ascidian and was used as a precursor of
a cytotoxic antitumor agent,2 methoxatin acts as a bacterial
coenzyme,3 and Lycogarubins C plays an important role in
anti-HSV-I virus activity4 (Figure 1). Other compounds
bearing a polysubstituted pyrrole substructure exhibit im-
portant antimicrobial activities, and have also shown activ-
ity against ovarian cancer cell lines, and solid tumors.5
O
O
H
COOH
N
H
N
EtOOC
HN
COOMe
MeOOC
O
O
OH
HO
EtOOC
N
O
HO
N
N
OH
O
OH
H
H
HO
Lycogarubins C
Ningalins A
Methoxatin
Figure 1 Examples of functional polysubstituted pyrroles
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Z.-q. Lin et al.
Letter
Synlett
to be 1a (0.25 mmol) and 2a (0.5 mmol) promoted by
Cu(OAc)2 (1.0 equiv) with 1.0 equiv of Et3N at 100 °C in DMF
(1 mL) under an atmosphere of air for 8 h.
A. amino acid esters syntheses
Xie 2015
Cu(OAc)2 (1.2 equiv)
PdCl2 (5 mol%)
CO2R1 t-AmOH, 120 °C
H
N
R1O2C
CO2R2
CO2R2
CO2R1
With the optimal conditions in hand, we next examined
the scope of this useful reaction for the construction of a
range of tetrasubstituted NH-pyrroles (Table 2). Initially,
various substituted chalcones were reacted with diethyl
iminodiacetate (2a) under the optimal conditions. Gratify-
ingly, the results indicated that a range of chalcones with
different substituents on the aryl ring reacted smoothly
with diethyl iminodiacetate (2a) to generate the desired
products 3 in good to excellent yields (entries 1–10). Chal-
cones bearing different electron-donating and electron-
withdrawing substituents (R1) on the aromatic ring of ben-
zoyl group all reacted smoothly with 2a to produce the cor-
responding pyrroles 3 (entries 2–4). Similarly, a variety of
electron-donating or electron-withdrawing substituents
Cu(OAc)2 (1.0 equiv)
R
R
R2O2C
CO2R2
R
NH2
B. our previous work
N-substituted iminodiacetates syntheses 2014:
NH2
MeCN reflux
O
O
O
O
CO2Et
I2 (3.0 equiv)
O
R1
N
O
DBU (3.0 equiv)
N
R1
R2
R2
+
O
O
Xylene reflux
CO2Et
C. this work
O
H
N
R3
OR4
Cu(OAc)2 (1.0 equiv)
Et3N (1.0 equiv)
O
O
H
R3
N
R1
R2
R1
+
OR4
O
DMF, 100 °C
R2
1
3
2
Scheme 1 Synthesis of polysubstituted pyrroles
Our initial investigations focused on examining the fea-
sibility of the reaction of chalcone (1a) with diethyl imino-
diacetate (2a) and optimizing the reaction conditions for
application to the construction of a variety of tetrasubsti-
tuted NH-pyrroles. Pleasingly, the proposed reaction be-
tween 1a (0.25 mmol) and 2a (0.5 mmol) in the presence of
Cu(OAc)2 (1.0 equiv) afforded tetrasubstituted NH-pyrrole
3a in 56% yield by using NaHCO3 (2.0 equiv) as a base at
120 °C in toluene (1 mL). To improve the yield of 3a, various
reaction parameters were screened, including Cu source, re-
action temperature, base, and the ratio of staring materials.
The results are summarized in Table 1.
To our delight, the yield of 3a improved to 70% when the
reaction temperature was decreased to 100 °C (Table 1, en-
tries 1–3). Subsequently, examination of different bases
showed that this plays a key role in the transformation. The
use of K2CO3, KOtBu, Cs2CO3, and DBU all resulted in de-
creased yields of 3a, while Et3N showed the highest effi-
ciency (entries 4–8). Encouraged by this result, Et3N was
chosen as the base for this reaction. Several other copper
sources were also investigated in this reaction (CuCl, CuCl2,
Cu(NO3)2, and CuI), but none were effective for the forma-
tion of tetrasubstituted NH-pyrrole 3a (entries 9–12). Sol-
vent screening revealed that DMF was the best solvent for
this transformation in terms of reactivity and selectivity, af-
fording 89% yield of 3a compared with toluene (85%), DMSO
(71%), xylene (85%) and THF (60%) (entries 13–16). Interest-
ingly, the yield of 3a did not drop when the loading of Et3N
was decreased to 1.0 equiv (entry 18). However, the oppo-
site happened when the amount of Cu(OAc)2 or 2a were de-
creased (entries 18 and 19). While investigating the oxida-
tion process, it was observed that the yield of 3a dropped
significantly to 22% under an atmosphere of nitrogen. The
main product in this case was tetrahydropyrrole 4a, which
had not been oxidized to the pyrrole. This indicated that ox-
ygen was an important co-oxidant in the reaction (entry
20). The optimal reaction conditions were therefore found
Table 1 Optimization of Reaction Conditionsa
O
CO2Et
NH
O
O
O
H
[Cu]
N
+
O
O
base
CO2Et
1a
2a
3a
Entry [Cu] (equiv)
Base (equiv) Solvent
T (°C)
Yield (%)b
1
2
Cu(OAc)2 (1)
NaHCO3 (2)
NaHCO3 (2)
NaHCO3 (2)
K2CO3 (2)
KtOBu (2)
CS2CO3 (2)
Et3N (2)
toluene
120
100
80
56
70
65
65
40
51
85
20
63
71
trace
60
71
89
85
60
90
39
85
22
Cu(OAc)2 (1)
Cu(OAc)2 (1)
Cu(OAc)2 (1)
Cu(OAc)2 (1)
Cu(OAc)2 (1)
Cu(OAc)2 (1)
Cu(OAc)2 (1)
CuCl (1)
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DMSO
DMF
3
4
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
5
6
7
8
DBU (2)
9
Et3N (2)
10
11
12
13
14
15
16
17
18
19c
20d
CuCl2 (1)
Et3N (2)
CuI (1)
Et3N (2)
Cu(NO3)2 (1)
Cu(OAc)2 (1)
Cu(OAc)2 (1)
Cu(OAc)2 (1)
Cu(OAc)2 (1)
Cu(OAc)2 (1)
Cu(OAc)2 (0.5)
Cu(OAc)2 (1)
Cu(OAc)2 (1)
Et3N (2)
Et3N (2)
Et3N (2)
Et3N (2)
xylene
THF
Et3N (2)
Et3N (1)
Et3N (1)
DMF
DMF
Et3N (1)
DMF
Et3N (1)
DMF
a Reaction conditions: 1a (0.25 mmol), 2a (2.0 equiv), base (1.0–2.0 equiv),
[Cu] (0.5–1.0 equiv) in solvent (1.0 mL) stirred for 8 h at 100 °C under air
conditions.
b Isolated yield.
c 2a (1.5 equiv).
d Under N2 atmosphere.
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E

C
Z.-q. Lin et al.
Letter
Synlett
(R2) on the aromatic ring also gave the same result (entries
5–7). However, when the R2 group was situated at the or-
tho- or meta-position of the aryl ring, the yields of the cor-
responding pyrrole were reduced to 63–74% (entries 8–10).
This indicated that steric hindrance or electronic effect of
the substituent on the benzene ring affected the reaction
slightly. Further experiments involved the evaluation of he-
teroaryl chalcones under the optimal reaction conditions. It
was found that heteroaryl chalcones including 2-furyl, 2-
thienyl and 2-naphthyl could also be effectively trans-
formed into the desired pyrroles 3k–m in good yields (en-
tries 11–13).
the reaction to proceed smoothly to afford the tetrasubsti-
tuted NH-pyrroles 3 in good to high yields (entries 14–20).
Furthermore, some non-chalcone related enones, such as
pent-3-en-2-one (1u), 1-phenyl-2-buten-1-one (1v), and
cyclohex-2-en-1-one (1w) were chosen to expand the ap-
plication of these method. To our delight, the target prod-
ucts 3u and 3v were obtained in moderate to good yields
(entries 21–22). When 1w was employed under the stan-
dard conditions, trace amount of the desired product was
obtained along with a complex byproduct (Scheme 2).
O
O
CO2Et
NH
Cu(OAc)2, Et3N
DMF, 100 °C
H
N
+
CO2Et
EtO2C
Table 2 Substrate Scope of the Reaction to give 3a
CO2Et
1w
2a
3w yield<10%
O
O
H
N
Scheme 2 Reaction of cyclohex-2-en-1-one (1w) with iminodiacetate (2a)
O
O
O
R3O
OR3
H
Cu(OAc)2
Et3N
N
+
R3O
OR3
R1
R2
R2
O
R1
2
1
Finally, we also investigated whether ethyl 2-(benzyl-
amino)acetate (2x) would be tolerated to construct the cor-
responding tetrasubstituted NH-pyrrole. The desired prod-
uct 3x was successfully isolated but was obtained in a rela-
tively low yield of 31%, because of the formation of several
unidentified byproducts (Scheme 3).
Entry
R1
R2
Ph
R3
Product 3 Yield (%)b
1
2
Ph
Et
3a
3b
3c
3d
3e
3f
90
75
88
92
80
86
90
70
74
63
88
73
82
85
75
84
90
93
82
86
65
81
Ph
Ph
Ph
4-BrC6H4
Et
3
4-NO2C6H4
Et
4
4-MeOC6H4
Et
O
O
Cu(OAc)2, Et3N
5
4-BrC6H4
Ph
Et
N
CO2Et
+
NH
H
DMF, 100 °C
6
4-NO2C6H4
Ph
Et
CO2Et
1a
2x
7
4-MeC6H4
Ph
Et
3g
3h
3i
3x 31%
8
3-MeC6H4
Ph
Et
Scheme 3 Reaction of chalcone (1a) with ethyl 2-(benzylamino)acetate (2x)
9
2-MeC6H4
Ph
Et
10
11
12
13
14
15
16
17
18
19
20
21
22
2,4-Cl2C6H4
Ph
Et
3j
Control experiments were conducted to gain insight
into the mechanism of this Cu(II)-promoted cycloaddition
reaction: (1) The yield of 3a decreased to 22% under a N2 at-
mosphere as the tetrahydropyrrole 4a had formed (molecu-
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Ph
2-naphthyl
2-furyl
2-thienyl
Ph
Et
3k
3l
Et
Et
3m
3n
3o
3p
3q
3r
Me
Me
Me
n-Pr
i-Pr
n-Bu
i-Bu
Et
1
lar peak at m/z 396.5 [M+1]+ by GC-MS and H NMR of 4a;
4-BrC6H4
4-MeOC6H4
Ph
see the Supporting Information for details) but did not oxi-
dize to pyrrole 3a; (2) The conditions did not lead to trans-
formation into 3a when 4a was reacted under oxygen with-
out Cu(OAc)2; (3) Compound 3a was afforded when 4a was
treated with Cu(OAc)2 (1.0 equiv) in argon for 0.5 h. (4)
Compound 3a could also be obtained when 4a and
Cu(OAc)2 (0.5 equiv) were reacted under oxygen for 2.0 h;
(5) Compound 1a reacted with 2a in the presence of a cata-
lytic amount of Cu(II) and oxygen for 8 h, and the desired
product 3a was obtained in 68% yield. (6) The desired prod-
uct 3a was obtained in 39% yield when 1a reacted with 2a
in the presence of a catalytic amount of Cu(II) under air for
8 h. The results indicated that a stoichiometric amount of
Cu(II) is needed in this reaction and O2 was an important
co-oxidant for pyrrole formation in this reaction when it
promoted Cu(I) and Cu(II) circulation (Scheme 4).
Ph
Ph
3s
3t
Ph
Me
3u
3v
Me
Et
a Reaction conditions: 1a (0.25 mmol), 2a (2.0 equiv), Et3N (1.0 equiv),
Cu(OAc)2 (1.0 equiv) in DMF (1.0 mL) stirred for 8 h at 100 °C under air con-
ditions.
b Isolated yield.
The scope of the reaction with respect to iminodiace-
tates 2 was studied by reacting with chalcones 1, as shown
in Table 2 (entries 14–20). Ester groups on the iminodiace-
tates 2, including Me, n-Pr, i-Pr, n-Bu and i-Bu, all allowed
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E

D
Z.-q. Lin et al.
Letter
Synlett
O
O
O
O
O2
Cu(I)
Cu(OAc)2 (1.0 equiv)
Et3N (1.0 equiv)
CO2Et
NH
N
EtO
base
OEt
O
O
H
B
O
O
CO2Et
Cu(II)
N
H
(1)
+ EtO2C
DMF, 100 °C, N2
8 h
N
N
O
EtO
OEt
EtO
OEt
A
2a
CO2Et
1a
2a
3a 22%
1a
O
CO2Et
O2
´
DMF, 100 °C
(2)
No transformation
NH
O
O
O
O
O
OEt
O
OEt
CO2Et
N
3a
O
EtO
OEt
Cu(II)/O2
NH
O
NH
CO2Et
CO2Et
NH
Cu(OAc)2 (1.0 equiv)
O
O
Successful
transformation
(3)
(4)
O
NH
EtO
EtO
DMF, 100 °C
0.5 h
C
3a
4a
CO2Et
CO2Et
4a
3a
O
Scheme 5 Proposed mechanism for the formation of 3a
CO2Et
Successful
transformation
Cu(OAc)2 (0.5 equiv)
NH
O2, DMF, 100 °C
2.0 h
CO2Et
3a
Funding Information
O
O
Cu(OAc)2 (0.5 equiv)
Et3N (1.0 equiv)
CO2Et
H
We gratefully acknowledge the financial supported by the Natural
Science Foundation of China (21606201), the National Natural Sci-
ence Foundation of Zhejiang (LY13B020016) and Technological Inno-
vation Program in Zhejiang Province (Zhejiang Xinmiao Talents
CO2Et
N
+
EtO2C
NH
(5)
DMF, 100 °C, O2
8 h
CO2Et
1a
2a
3a 68%
O
Program) (2017R403066).
N
aturalS
c
i
e
n
c
e
F
o
u
n
d
ati
o
n
of
C
h
i
n
a
(2
1
6
0
6
2
0
1)Nati
o
n
a
lNaturalS
c
i
e
n
c
e
F
o
u
n
d
ati
o
n
of
Z
h
e
j
i
a
n
g
Pro
v
i
n
c
e
(L
Y
1
3
B
0
2
0
0
1
6)
O
Cu(OAc)2 (0.5 equiv)
Et3N (1.0 equiv)
CO2Et
NH
H
CO2Et
N
+
EtO2C
(6)
DMF, 100 °C, air
8 h
Acknowledgment
CO2Et
1a
2a
3a 39%
We thank Alison McGonagle, PhD, from Liwen Bianji, Edanz Editing
China (www.liwenbianji.cn/ac), for editing the English text of a draft
of this manuscript.
Scheme 4 Studies on the oxidation process
From the aforementioned experimental results, we have
proposed a possible mechanism to account for the products
observed in the current reaction (Scheme 5). First, azome-
thine ylide A (which can be detected by GC-MS; see the
Supporting Information for details) is formed by oxidative
dehydrogenation of the diethyl iminodiacetate (2a), pro-
moted by Cu(OAc)2. Subsequently, nucleophile B is afforded
in the presence of base, and reacts with chalcone (1a) to
give C. Next, the five-membered heterocyclic intermediate
4a is generated through an intermolecular cycloaddition
from C. Finally, the corresponding pyrrole 3a is afforded
through oxidative aromatization by the co-oxidation with
O2 and Cu(OAc)2.
In summary, we have developed a novel and efficient
method for the synthesis of tetrasubstituted NH-pyrroles
through a Cu(II)-promoted oxidation/[3+2]cycloaddition/
aromatization cascade reaction.17,18 This protocol employs
various easily accessible chalcones and iminodiacetates un-
der mild reaction conditions, and the corresponding tetra-
substituted NH-pyrroles were obtained in good to excellent
yields, offering potential for a wide range of applications.
We believe these results will be important for developing
new reactions for the synthesis of polysubstituted pyrroles,
which have potential applications in the construction of
building blocks for natural products.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1689972.
S
u
p
p
orit
n
gInformati
o
n
S
u
p
p
orit
n
gInformati
o
n
References and Notes
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Synlett
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(18) All chemicals were purchased from commercial vendors and
were used as received without further purification. The 1H and
13C NMR spectra were recorded at 500 and 125 MHz, respec-
tively, in CDCl3 using TMS as internal standard with a Bruker
AM 500 spectrometer. Chemical shifts () are reported as parts
per million (ppm) and the following abbreviations are used to
identify the multiplicities: s=singlet, d=doublet, t=triplet,
q=quartet, m=multiplet, b=broad and all combinations thereof
can be explained by their integral parts. HRMS data were
obtained with a Thermo Scientific LTQ Orbitrap XL mass spec-
trometer and the GC-MS were recorded with an Agilent
(GC431-MS210). Thin-layer chromatography was performed on
pre-coated glass-backed plates and visualized with UV light at
254 nm. Flash column chromatography was performed on silica
gel (see the Supporting Information).
Synthesis of 3a; Typical Procedure
A mixture of chalcone 1a (0.25 mmol, 0.0520 g), diethyl imino-
diacetate 2a (0.5 mmol, 0.0945 g), Et3N (0.25 mmol, 0.0253 g),
and Cu(OAc)2 (0.25 mmol, 0.0498 g) was dissolved in DMF (1.0
mL) in a thick-walled tube (10 mL). The mixture was stirred at
100 °C for 8 h under air atmosphere, and the progress of the
reaction was monitored by TLC (PE/EtOAc = 2:1 (v/v)). Upon
completion, the mixture was cooled to r.t. and poured into satu-
rated aqueous NaCl (10.0 mL) and extracted with EtOAc
(3 × 10.0 mL). The acquired organic phases were combined and
dried over anhydrous Na2SO4. After removing the volatile sol-
vent, the product 3a was obtained as a white solid in 90% yield
by isolation with silica column chromatography (eluting sol-
vent: petroleum ether/EtOAc = 2:1 (v/v)).
© 2019. Thieme. All rights reserved. — Synlett 2019, 30, A–E