Copper-Catalyzed Oxidative Cyclization of Maleimides with Amines and Alkyne Esters: Direct Access to Fully Substituted Dihydropyrroles and Pyrrole Derivatives

Article abstract of DOI:10.1021/acs.orglett.7b02670

An efficient and practical Cu(I)-catalyzed oxidative cyclization cascade reaction of diverse amines, alkyne esters and maleimides has been developed. The reactions can afford 4,6-dioxopyrrolo[3,4-b]pyrrole-2,3-dicarboxylates and related derivatives with satisfactory yields by altering the reaction conditions slightly. The substrate scope highlights the flexibility of the catalyst, and a reaction mechanism is also proposed.

Full text of DOI:10.1021/acs.orglett.7b02670

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
Copper-Catalyzed Oxidative Cyclization of Maleimides with Amines
and Alkyne Esters: Direct Access to Fully Substituted
Dihydropyrroles and Pyrrole Derivatives
Jia-Nan Zhu,† Lei-Lei Chen,† Run-Xiang Zhou,† Bo Li,† Zhi-Yu Shao,† and Sheng-Yin Zhao*,†,‡
†Department of Chemistry, Donghua University, No. 2999 North Renmin Road, Shanghai 201620, P. R. China
‡State Key Laboratory of Bioorganic & Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, Shanghai 200032, P. R. China
S
* Supporting Information
ABSTRACT: An efficient and practical Cu(I)-catalyzed oxidative cyclization cascade reaction of diverse amines, alkyne esters
and maleimides has been developed. The reactions can afford 4,6-dioxopyrrolo[3,4-b]pyrrole-2,3-dicarboxylates and related
derivatives with satisfactory yields by altering the reaction conditions slightly. The substrate scope highlights the flexibility of the
catalyst, and a reaction mechanism is also proposed.
pyrroles via transition-metal catalysis.14 It is a pity that the major
he five-membered nitrogen-containing aromatic hetero-
Tcycle moieties are universal skeletons in biologically and
substrates are limited to alkynes. In contrast, to the best of our
knowledge, related C−H oxidative cyclization of β-enamino
pharmaceutically active compounds.1 Among them, dihydro-
esters with electron-deficient alkenes toward dihydropyrroles or
pyrroles is still unreported so far, and to date, only two examples
for the synthesis of fulleropyrroline15 and 2,3,4-trisubstituted
pyrroles16 were explored using amines and alkyne esters as the β-
enamino esters precursor. Most of the reaction substrates are
limited to electron-rich olefins. Besides, related C−H function-
alization of maleimides with various directed group substrates17
have been investigated to a great extent. However, the formation
of this similar skeletons containing maleimide is extremely rare18
up to now. Accordingly, it is considerable challenging but highly
desirable to discover a transition-metal-catalyzed direct oxidative
cyclization of electron-deficient alkenes with amines and alkyne
esters.
pyrroles or pyrroles are a vital class of aromatic heterocycle
compounds as they are not only in a large number of natural
products2 but also a useful building block for the synthesis of
complex natural products.3 For example, 4-aryl-2,3-dihydropyr-
role derivatives are the key intermediates in the synthesis of
( )-mesembrine,4 elwesine,5 and other bioactive molecules.6
Furthermore, spiropyrroline compounds7 display good antiviral
and antimicrobial activities. As for the pyrroles, they are
ubiquitous in functional materials,8 pharmaceutical substances,9
and organic synthesis.2d,10 For instance, A11 is the most stable
isomer and possesses a high performance pigment, and B12 is the
key substance for the synthesis of kinase inhibitors (Figure 1). As
a result, extensive attention has been paid to developing
approaches for the construction of these privileged molecules.
Over the past few years, transition-metal-catalyzed oxidative
functionalization of C−H bond with a N−H group has been the
most convenient and efficient procedure for the construction of
N-heterocycles.13 Enamines, a class of important N-heterocycle
precursors, have been widely used for the synthesis of valuable
It is well-known that β-enamino esters can be generated in situ
from the readily available amines and alkene esters.19 Herein, we
disclose the first direct oxidative copper-catalyzed annulation of
maleimides with amines and alkyne esters toward dihydropyrrole
synthesis. Subsequently, with the addition of K2S2O8 to the above
reaction system, our copper-catalyzed process also offers fully
substituted pyrrole derivatives.
The annulation reaction of aniline (1a), dimethyl acetylene-
dicarboxylate (2a), and N-phenylmaleimide (3a) was chosen as a
model reaction for optimization of the reaction conditions
Received: August 28, 2017
Figure 1. Selected examples of functional pyrroles.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02670
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(Table 1). First, several copper salt catalysts were investigated by
using DMSO as the solvent at 90 °C (entries 1−11).
20). Solvent screening indicates that DMSO was the most
efficient. Compared to the reaction in DMSO, the reactions in
DMF and DCM gave relatively low yields in 35% and 20%,
respectively (entries 22 and 23). Other solvents such as CH3CN,
DMA, dioxane, HOAc, toluene, DCE, and PhCl are undesirable
(entries 24−29).
a
Table 1. Optimization of the Reaction Conditions
With the optimized reaction conditions available (Table 1,
entry 8), the scope of this oxidative cyclization reaction was then
investigated. The reaction showed good functional group
tolerance and proved to be a practical procedure for the
synthesis of target products (Scheme 1). To start with, various N-
substituted maleimides can react successfully under the reaction
conditions to give an effective access to products in 75−88%
yield (4a−d). It is noteworthy that this reaction was not limited
to N-protected maleimide, but it could also be extended to a free
b
entry
catalyst
CuCl2
solvent
4a yield (%)
1
2
3
4
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
CH3CN
DMF
trace
trace
0
CuBr2
CuF2
Cu(OTf)2
Cu(OAc)2
CuI
0
c
5
0
6
63
69
75
15
63
60
trace
77
66
63
0
Scheme 1. Results of Cu-Catalyzed Fully Substituted
7
CuBr
a,e
Dihydropyrrole (4) Synthesis
8
CuCl
9
Cu2O
10
11
CuSCN
CuCN
CuCl
d
12
e
13
CuCl
f
14
CuCl
g
15
CuCl
16
17
18
19
20
21
22
23
24
25
26
27
28
29
Fe(NO3)3.9H2O
CoCl3.6H2O
Ag2CO3
AgOAc
Pd(OAc)2
CuCl
0
0
0
0
0
CuCl
35
20
0
CuCl
DCM
CuCl
DMA
CuCl
dioxane
HOAc
toluene
DCE
0
CuCl
0
CuCl
0
CuCl
0
CuCl
PhCl
0
a
Reactions were carried out with 1a (0.5 mmol), 2a (0.5 mmol), 3a
(0.7 mmol), and CuCl (10 mol %) in solvent (2.0 mL) under air
b
c
atmosphere at 90 °C for 5 h. Isolated yield. Cu(OAc)2 (1 equiv) was
d
e
added. The reaction was run under N2 atmosphere. CuCl (20 mol
%) was added. The reaction was run at 70 °C. The reaction time was
f
g
24 h.
Unfortunately, when Cu(II) was used as the catalyst, we could
not afford the expected products (entries 1−5). On the contrary,
Cu(I) has the better results (entries 6−11). Obviously, the
reaction with CuCl as the catalyst in DMSO gave the desired
product 4a in 75% yield. The structure of 4a was confirmed
unambiguously by X-ray single-crystal diffraction.20 When CuI,
CuBr, Cu2O, CuSCN, and CuCN were selected as the catalysts,
the yields decreased, especially, Cu2O as the catalyst. However,
when the quantity of the catalyst was added to 20 mol %, the yield
was increased to 77% (entry 13). The control experiment
revealed that oxygen was necessary in this transformation (entry
12). Additionally, the yield was decreased to 66%, while the
temperature was lowered to 70 °C (entry 14). Furthermore,
when the reaction time was extended to 24 h, the yield was
decreased to 63% (entry 15). In addition, in the presence of other
catalysts such as Fe(NO3)3·9H2O, CoCl3·6H2O, Ag2CO3,
AgOAc, or Pd(OAc)2, the reaction was inefficient (entries 16−
a
Reactions were carried out with 1 (0.5 mmol), 2 (0.5 mmol), 3 (0.7
mmol), and CuCl (10 mol %) in DMSO (2.0 mL) under air
b
atmosphere at 90 °C for 5 h. The reactions were carried out for 12 h.
c
d
Compound 3 was added to 2 equiv. 1.0 mmol 1 and 2 were used.
Isolated yield.
e
B
DOI: 10.1021/acs.orglett.7b02670
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Organic Letters
Letter
NH maleimide although the yield is 40% (4e). A variety of
amines containing an electron-donating substituent such as a
methoxyl, cyclopentyl, n-butyl, or allyl group furnished the
corresponding products in 66−78% yield (4f, 4k−m). It should
be noted that the lower yield of product 4f might be due to the
steric effect of the σ-methoxyl group. Diverse amines including
electron-withdrawing substituents were smoothly tolerated in
the reaction, and the desired products were obtained in moderate
to good yields (51−70%). Fortunately, we unexpectedly
delivered the dihydropyrrole compounds containing nitro
functional group, which definitely extended their further
derivatization in a certain extent (4g−4j). When diverse alkyne
esters were used as the substrates, the reaction was well
compatible with alkyl- as well as aryl-substituted alkyne esters,
thus providing the corresponding products in moderate to
excellent yield (4n−q).
Scheme 2. Results of Cu-Catalyzed Fully Substituted Pyrrole
(5) Synthesis
a,c
Intriguingly, the combination of dihydropyrrole formation and
subsequent dehydrogenation aromatization in one process was
realized in our copper-catalyzed process. When the above-
mentioned reaction conditions were altered slightly, with 2.5
equiv of oxidant in DMSO at 90 °C for another 12 h, the
synthetically more attractive fully substituted pyrroles 5 were
isolated as single products in high yield (Table 2). Different
a
Reactions were carried out with 1 (0.5 mmol), 2 (0.5 mmol), 3 (0.7
mmol), CuCl (10 mol %), and K2S2O8 (1.25 mmol) in a solvent
DMSO (4.0 mL) under air atmosphere at 90 °C for 12 h. Compound
3 was added to 2 equiv. Isolated yield.
b
c
Scheme 3. Control Experiments
a
Table 2. Optimization of the Reaction Conditions
b
entry
1
oxidants
solvent
none
5a yield (%)
DDQ
0
12
72
55
trace
0
c
2
DDQ
none
3
K2S2O8
TBHP
H2O2
none
4
none
5
none
6
MnO2
none
7
DTBP
CH3CO3H
K2S2O8
K2S2O8
K2S2O8
K2S2O8
none
0
8
none
0
9
toluene
DMF
DCM
CH3CO2H
55
45
68
57
10
11
12
a
Reactions were carried out with 1a (0.5 mmol), 2a (0.5 mmol), 3a
(0.7 mmol), CuCl (10 mol %), and oxidant (1.25 mmol) in a mixed
solvent (DMSO/solvent = 1:1, totally, 4 mL) under air atmosphere at
90 °C for 12 h. Isolated yield. DDQ (1.5 mmol) was added, and the
reaction time was extended to 40 h.
4ao1 and 4ao2 was 2:1, confirmed by NMR (Scheme 3A).
Notably, when TEMPO was added to the reaction of p-anisidine,
dimethyl acetylenedicarboxylate and N-phenylmaleimide under
the standard conditions, the desired product 4o was not
detected. Instead, the tautomers 4ao1 as well as 4ao2 was
observed in the ratio of 2:1 (Scheme 3B). The control
experiments showed that the reaction proceeded through a
radical process.
b
c
oxidants were examined, and the result indicated that none of the
other oxidants was superior to K2S2O8 (entries 1−8). Moreover,
additional solvent could not facilitate better reaction progress
(entries 9−12).
As shown in (Scheme 2), the results showed that both
electron-donating (5a,c,e,f) and electron-withdrawing
(5b,d,g,h) substituents were tolerated well and provided the
corresponding products in moderate to excellent yield (42−
72%).
We then conducted a series of experiments to unveil the nature
of the reaction mechanism (Scheme 3). The reaction using p-
anisidine, dimethyl acetylenedicarboxylate, and TEMPO
(2,2,6,6-tetramethyl-1-piperidinyloxy) was tested under the
standard conditions. Interestingly, the proportion of tautomers
On the basis of our experimental results and previous
reports,14g a possible radical mechanism for oxidative coupling
of maleimides with amines and alkyne esters is proposed in
Scheme 4. Initially, β-enamino esters were generated in situ from
amines and alkene esters. Subsequently, single-electron oxidation
of the β-imine ester derived from the tautomer of β-enamino
esters generates a radical intermediate. The succedent single-
electron inserts into CC of maleimide to form C−C
propagation, which is further oxidized by copper(I) to obtain a
carbocation. Subsequent intramolecular cyclization leads to the
C
DOI: 10.1021/acs.orglett.7b02670
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Organic Letters
Letter
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annulation of maleimides with amines and alkyne esters to
synthesize fully substituted dihydropyrroles via the cleavage of
C(sp2)−H/N−H bonds. The reaction features mild conditions,
a relatively broad scope, and high efficiency. With the addition of
K2S2O8, our copper-catalyzed process can afford fully substituted
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b02670.
Experimental details, characterization data of all com-
pounds, and 1H and 13C NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: syzhao8@dhu.edu.cn.
ORCID
Sheng-Yin Zhao: 0000-0002-5778-8068
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge financial support from Shanghai Municipal
Natural Science Foundation (No. 15ZR1401400) and the Open
Funds from the State Key Laboratory of Bioorganic & Natural
products Chemistry (2013).
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̈
D
DOI: 10.1021/acs.orglett.7b02670
Org. Lett. XXXX, XXX, XXX−XXX