Synthesis of Substituted Pyrroles via Copper-Catalyzed Cyclization of Ethyl Allenoates with Activated Isocyanides

Article abstract of DOI:10.1002/asia.201600761

A new method for the synthesis of di- and trisubstituted pyrroles via copper-catalyzed cyclization of ethyl allenoates with activated isocyanides has been developed. In contrast to related annulation reactions previously reported, this new process features a skeletal rearrangement in which the aryl sulfonyl moiety, which functions as the electron-withdrawing group in the α-carbon of the isocyanide, was found to migrate to the γ-carbon of the starting allenoate in the final product for the first time.

Full text of DOI:10.1002/asia.201600761

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Accepted Article
Title: Synthesis of Substituted Pyrroles via Copper-catalyzed Cyclization of Ethyl Al-
lenoates with Activated Isocyanides
Authors: Kui Lu; Fang Ding; Long Qin; Xiaoliang Jia; Chuanming Xu; Xia Zhao;
Qingwei Yao; Peng Yu
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Chemistry - An Asian Journal
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COMMUNICATION
Synthesis of Substituted Pyrroles via Copper-catalyzed
Cyclization of Ethyl Allenoates with Activated Isocyanides
[
a]
[a]
[a]
[a]
[a]
[b]
[c]
Kui Lu, * Fang Ding , Long Qin, Xiaoliang Jia , Chuanming Xu , Xia Zhao , Qingwei Yao and
[
a]
Peng Yu*
Abstract: A new method for the synthesis of di- and trisubstituted
pyrroles via copper-catalyzed cyclization of ethyl allenoates with
activated isocyanides was developed. In contrast to related
annulation reactions previously reported, this new process features a
skeletal rearrangement in which the aryl sulfonyl moiety, which
functions as the electro-withdrawing group in the α-carbon of the
isocyanide, was found to migrate to the γ-carbon of the starting
allenoate in the final product for the first time.
electron-withdrawing group at the α-position in the presence of a
variety of copper catalyst was known to give substituted pyrroles
[
7b]
as exemplified by the examples in Scheme 2.
We were
interested in the outcome of a similar process when an allenoate
such as 1a was employed as the electrophile in its reaction with
an activated isocyanide such as Tosmic 2a in the presence of
copper(I) oxide. The anticipated product 3aa′ was not formed,
but instead the reaction gave pyrrole 3aa. The latter was
isolated in 21% yield, and the structure was confirmed by single
[
11]
crystal X-ray analysis (Scheme 3).
Substituted pyrroles are structure units of many natural
products, synthetic pharmaceuticals, and organic conducting
materials. Pyrroles are also widely used as key intermediates in
[
1]
organic synthesis. Therefore, great efforts have been put to the
development of new methods for the efficient synthesis of
[2, 3]
[4]
substituted pyrroles.
Several isocyanides -based pyrrole
syntheses involving nucleophilic addition with alkenes have
[
5]
been reported, including the well-known Van-Leusen reaction
[7b]
Scheme 2. Isocyanide-propargylate Cyclization.
[
6]
and Barton-Zard reaction as well as 1,3-dipolar cyclization with
[
7]
[8]
[7b,
alkynes under the catalysis of copper, silver or phosphine.
9
]
Recently, the synthesis of tri-substituted pyrroles by
a
phosphine catalyzed [3 + 2] cyclization of activated isocyanides
[
10]
with allenoates has been reported by Zhao et al. (Pathway A,
[
9]
Scheme 1). In this letter, we report a copper catalyzed reaction
of isocyanides with allenoates which produces a structurally
different type of substituted pyrroles by following an alternative
reaction pathway (Pathway B, Scheme 1).
Scheme 3. Reaction of Allenoate 1a with Isocyanide 2a in the presence of
Cu
2
O
The formation of 3aa is also in contrast to an outcome
predicted based on the scenario of Pathway A in Scheme 1 in
[
9]
a phosphine catalyst process. Mechanistically, this new
observation points to a translocation of the sulfonyl group of
the isocyanide substrate to the γ-position of the starting
allenoate.
Encouraged by this interesting finding, the reaction was
optimized by screening various solvents such as 1,2-
Scheme 1. Isocyanide-allenoate Cyclization.
Reaction of propargylates with isocyanates bearing an
dichloroethane
(DCE),
MeCN,
toluene,
N,N-
dimethylformamide (DMF), tetrahydrofuran (THF) and EtOAc.
None of them gave any better result compared to 1,4-dioxane
(entries 1-7, Table 1). Interestingly, when water was added to
[
a]
Prof. K. Lu, F. Ding, L. Qin, X. Jia, C. Xu, Prof. P. Yu
China International Science and Technology Cooperation Base of
Food Nutrition/Safety and Medicinal Chemistry, Sino-French Joint
Lab of Food Nutrition/Safety and Medicinal Chemistry, Key
Laboratory of Industrial Microbiology of Ministry of Education, Tianjin
Key Laboratory of Industry Microbiology, College of Biotechnology,
Tianjin University of Science & Technology
Tianjin, China, 300457
E-mail: lukui@tust.edu.cn; yupeng@tust.edu.cn
Prof. X. Zhao
College of Chemistry
Tianjin Normal University
Tianjin, China, 300387
2
the reaction system with a ratio of 1:10 (H O/1,4-dioxane), the
yield of 3aa was increased to 35% (entry 8, Table 1). While
adding more water or reducing the amount of water in the
reaction system did not affect much on the yields (entries 9
and 10, Table 1). To improve the yield, the effect of the
catalyst loading and the reaction temperature was
2
investigated by using 20 mol% and 5 mol% Cu O as well as
[
b]
c]
decreasing the reaction temperature to 40 C and increasing
the reaction temperature to 40 C (entries 11-14, Table 1).
However none of them gave superior yield compared to 10
[
Dr. Q. Yao
Sphinx Scientific Laboratory Corporation
mol% Cu O at 50 C.
2
2
402 Heights Ave., Cody, Wyoming 82414, USA
Table 1. Optimization of Copper(I) oxide-Catalyzed Reaction of 1a with
2a.
[
a]
Supporting information for this article is given via a link at the end of
the document.
For internal use, please do not delete. Submitted_Manuscript

Chemistry - An Asian Journal
10.1002/asia.201600761
COMMUNICATION
[
b]
entry
catalyst
temp (C)
50
solvent
1,4-dioxane
DCE
MeCN
toluene
DMF
yield (%)
21
1
2
3
4
5
6
7
8
9
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
2
2
2
2
2
2
2
2
2
2
2
2
O
O
O
O
O
O
O
O
O
O
O
O
With the optimized reaction conditions in hand, the generality
and substrate scope of the reaction were examined with a series
of activated isocyanides and allenoates. The results are
summarized in Scheme 4. Different γ-substituted allenoates (1b-
50
50
50
50
50
50
50
50
50
40
60
50
8
8
trace
9
19
trace
35
34
33
31
32
33
THF
EtOAc
1h) could cyclize with 2a using this catalytic protocol to give the
[
c]
d]
e]
c]
corresponding 3, 4-disubstituted pyrroles (3ba-3ha) in good
yield. When α-substituted Tosmics were treated with 1a under
the optimized conditions, the 2,3,4-trisubstituted pyrroles (3ab-
1,4-dioxane/H
1,4-dioxane/H
1,4-dioxane/H
1,4-dioxane/H
1,4-dioxane/H
1,4-dioxane/H
1,4-dioxane/H
2
O
[
[
[
2
O
10
11
12
13
14
2
O
2
2
2
2
O
3af) were obtained in 19-62% yield. To evaluate the electronic
[
c]
[c]
[c]
O
O
O
[
f]
effect of the sulfonyl group of the isocyanides, 1-[(1-
isocyanopropyl)sulfonyl]-4-methylbenzene (2g), 1-chloro-4-[(1-
Cu
Cu
2
O
[
g]
2
O
50
30
[
a] The reactions were carried out with 1a (0.6 mmol) and 2a (0.5 mmol) in
the presence of Cu O (0.025 mmol) in the appropriate solvent system (1
mL) for 2 h at the temperature indicated. [b] Yield of isolated product after
silica gel chromatography. [c] 1,4-dioxane : H O = 10 : 1. [d] 1,4-dioxane :
O = 5 : 1. [e] 1,4-dioxane : H O = 20 : 1. [f] Cu O (0.05 mmol) was used.
g] Cu O (0.0125 mmol) was used.
isocyanopropyl)sulfonyl]benzene
isocyanopropyl)sulfonyl]benzene
isocyanopropyl)sulfonyl]-4-methoxybenzene
(2h),
(2i),
1-fluoro-4-[(1-
1-[(1-
2
(2j)
and
2
[
(isocyanomethyl)sulfonyl]benzene (2k) were prepared and used
H
[
2
2
2
2
as new isocyanide substrates. It was found that compared to a
methyl group, the halogen substituted as well as the
unsubstituted substrates gave better yields of the desired
products (3ah and 3ai versus 3ag; as well as 3aa versus 3ak).
The combination of substitution on the allenoate (such as 1c)
and the isocyanide (such as 2g and 2j) results in a drastic drop
in the yield of the desired product (3cg and 3cj). For the reaction
between 1c and 2j, the final product 3cj was obtained in only 21%
yield. Careful examination of this reaction revealed that a major
by-product 3cj′ was isolated in 20% yield (Scheme 5).
To further optimize this reaction, other copper sources,
including CuOAc, CuCl, CuCN, Cu and CuBr (entries 1-5, Table
) were tested in 1,4-dioxane/H O at 50 C. These catalysts
turned out to be either completely inactive (entries 2 and 5) or
much inferior to Cu O (entries 1, 3 and 4). Next, several nitrogen
or phosphine ligands such as Et N, DBU, 2,2'-bipyridine (Bipy)
and PPh and phen (1,10-phenanthroline) were screened.
Among them, the combination of phen and Cu O showed the
best catalytic activity, and the desired product was obtained in
7% yield. It is worthy to mention that, when PPh was
2
2
2
2
3
3
2
3
3
employed as a ligand, the desired product was not detected, and
ethyl 2-(5-tosyl-1H-pyrrol-3-yl)acetate was obtained, in a similar
way as it was used as a catalyst alone as described in Zhao’s
[
9]
report. Further screening on the loading of phen revealed that
a 2 : 1 ratio between the ligand and Cu O gave the best yield
entry 11, Table 2). Although adding phen as ligand could also
2
(
increase the reaction yields when CuOAc and Cu were used as
catalysts, none of them showed superior results (entries 12 and
1
3, Table 2). Thus the optimized reaction conditions were found
to be as follows: 1a (0.6 mmol), 2a (0.5 mmol), Cu O (0.025
mmol), 1,10-phenanthroline (0.05 mmol), 1,4-dioxane/H O (10 :
, 0.5 mL) and at 50 C.
2
2
1
Table 2. Effect of Copper Catalysts and Ligands in the Reaction of 1a with 2a.
[
a]
[
b]
entry
catalyst
ligand
None
None
None
None
None
solvent
yield (%)
[
c]
1
2
3
4
5
6
7
8
9
CuOAc
1,4-dioxane/H
1,4-dioxane/H
1,4-dioxane/H
1,4-dioxane/H
1,4-dioxane/H
1,4-dioxane/H
1,4-dioxane/H
1,4-dioxane/H
1,4-dioxane/H
1,4-dioxane/H
1,4-dioxane/H
1,4-dioxane/H
1,4-dioxane/H
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
17
0
9
22
0
[
c,d]
CuCl
[
c,d]
Scheme 4. Pyrrole Synthesis by Copper-catalyzed Isocyanide-allenoate
CuCN
[
c,d]
Cyclization
Cu
[
c,d]
CuBr
2
Cu
Cu
Cu
Cu
Cu
Cu
2
2
2
2
2
2
O
O
O
O
O
O
3
Et N
27
22
33
DBU
Bipy
[
e]
PPh
phen
3
25
10
11
12
13
37
43
15
39
[
f]
Phen
phen
phen
[
c]
[f]
CuOAc
Cu
[
c]
[f]
[
a] Unless otherwise indicated, all reactions were carried out with 1a (0.6
mmol) and 2a (0.5 mmol) in the presence of Cu O (0.025 mmol) and Ligand
0.1 mmol) in the appropriate solvent system (1 mL) for 2 h at the temperature
Scheme 5. Copper-catalyzed Cyclization of 1c with 2j.
2
(
indicated. [b] Yield of isolated product after silica gel chromatography. [c]
catalyst (0.05 mmol). [d] Reaction time: 5h. [e] Ethyl 2-(5-tosyl-1H-pyrrol-3-
yl)acetate was obtained. [f] Ligand (0.05 mmol).
A plausible mechanism for the copper-catalyzed cyclization
between allenoate 1a and isocyanide 2a was proposed (Scheme
For internal use, please do not delete. Submitted_Manuscript

Chemistry - An Asian Journal
10.1002/asia.201600761
COMMUNICATION
6
). The transformation starts with a C-H bond activation of 2a by
along with 3ak. Notably, the exchanged products were the major
product in both cross reactions.
Cu
2
O catalyst to give a copper-isocyanide complex A with
O. A [3 + 2] cycloaddition between 1a
concurrent formation of H
2
In summary, we have developed a new method for the
synthesis of di-substituted or tri-substituted pyrroles by copper-
catalyzed cyclization of allenoates with activated isocyanides.
This new process features a skeletal rearrangement in which the
aryl sulfonyl moiety of the isocyanide translocates to the γ-
and intermediate A takes place to give intermediate B. The latter
undergoes protonolysis leading to the formation of intermediate
C and the regeneration Cu O. A Cu O-assisted elimination of
2 2
the 4-methylbenzenesulfinate group (Ts ) produces an
-
-
electrophilic species D. Recombination of D with Ts affords the
carbon of the starting allenoate. A plausible mechanism
pyrrole copper complex E. Protonolysis of compound E leads to
the formation of product 3aa and the regeneration of the copper
catalyst.
involving an elimination and re-addition of a Ts group was
proposed. Application of this catalytic system to construct other
types of nitrogen-containing heterocycles is underway in our
laboratory.
Acknowledgements
The authors sincerely thank the financial support from
National Science Foundation of China (Grants 21202118,
21572158, 21202119), China International Science and
technology cooperation projects (2013DFA31160). We thank
Prof. Hongchao Guo (China Agricultural University) for providing
the allenoates (synthesized in the National Key Technologies
R&D Program of China, 2012BAK25B03, CAU) for substrate
screening. We are thankful to the Research Centre of Modern
Analytical Technology, Tianjin University of Science and
Technology for high resolution mass spectrum analysis.
Keywords: Pyrrole Synthesis • Allenoates • Isocyanides •
Copper-catalyzed • Cyclization
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Chemistry III; Elsevier: Amsterdam, NY, 2008; b) H. Fan, J. Peng, M. T.
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Scheme 6. Proposed Mechanism for Copper-catalyzed Cyclization between
Allenoate 1a and Isocyanide 2a.
2004, 104, 2481-2506.
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108, 3395-3442; b) I. Nakamura, Y. Yamamoto, Chem. Rev. 2004, 104, 2127-
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144; l) W. J. Humenny, P. Kyriacou, K. Sapeta, A. Karadeolian, M. A. Kerr,
Scheme 7. Copper-catalyzed Cyclization of 1a with 2a and 2k in the Presence
of Sulfinates 4a and 4b
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While the isolation of 3cj′ in the reaction of 1c and 2j (Scheme
) is consistent with the proposed mechanism and supports the
5
formation of a nucleophilic sulfinate intermediate, two cross
reaction experiments were carried out to establish the
elimination and re-recombination process of sulfinate group.
When 1.2 equiv. of allenoate 1a and 1.0 equiv. of isocyanide 2a
were used as substrates, in the presence of sodium
benzenesulfinate (4a) (1.0 equiv.), both the ‘desired product’ 3aa
and crossover product 3ak were obtained (Scheme 7). When a
similar reaction between 1a and isocyanide 2k was performed in
the presence of 1.0 equiv. of sodium 4-methylbenzenesulfinate
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[
7
(
4b) (1.0 equiv.), the exchanged product 3aa was obtained
[
For internal use, please do not delete. Submitted_Manuscript

Chemistry - An Asian Journal
10.1002/asia.201600761
COMMUNICATION
2009, 15, 227-236; b) S. Kamijo, C. Kanazawa, Y. Yamamoto, J. Am. Chem.
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[
4
11] Crystal Data for C15 H17 N O S (M =307.36 g/mol): monoclinic, space
group P2
1
/n (no. 14), a = 9.20292(11) Å, b = 16.86838(17) Å, c =
3
9
1
.97837(11) Å, β = 96.5549(11)°, V = 1538.90(3) Å , Z = 22, T =
-
1
3
00.01(10) K, μ(CuKα) = 10.126 mm , Dcalc = 2.608 g/cm , 16551
reflections measured (10.35° ≤ 2Θ ≤ 148.918°), 3098 unique (Rint
=
0
.0283, Rsigma = 0.0162) which were used in all calculations. The final R
1
2
was 0.0347 (I > 2σ(I)) and wR was 0.0925 (all data). CCDC 1479897
For internal use, please do not delete. Submitted_Manuscript

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COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Kui Lu,* Fang Ding, Long Qin, Xiaoliang
Jia, Chuanming Xu, Xia Zhao, Qingwei
Yao, Peng Yu*
Page No. – Page No.
Synthesis of Substituted Pyrroles via
Copper-catalyzed Cyclization of Ethyl
Allenoates with Activated
Text for Table of Contents
Isocyanides
A copper-catalyzed cyclization of ethyl allenoates with activated isocyanides to synthesis of di- and trisubstituted pyrroles was
developed
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