Electrochemical Oxidative Cyclization: Synthesis of Polysubstituted Pyrrole from Enamines

Article abstract of DOI:10.1002/ejoc.202001484

A conceptually novel method for the preparation of pyrrole is described by electrochemical-oxidation-induced intermolecular annulation via enamines. In a simple undivided cell, based on a sodium acetate-facilitated, polysubstituted pyrrole derivations has been facilely synthesized under external oxidant-free condition. This electrosynthetic approach providing an environmentally benign protocol for C?C bond cross-coupling and oxidative annulation, which features unparalleled broad scope of substrates and practicality.

Full text of DOI:10.1002/ejoc.202001484

Communications
doi.org/10.1002/ejoc.202001484
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Electrochemical Oxidative Cyclization: Synthesis of
Polysubstituted Pyrrole from Enamines
Zhiwei Chen,*[a] Guang Shi,[a] Wei Tang,[a] Jie Sun,[a] and Wenxing Wang[a]
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A conceptually novel method for the preparation of pyrrole is
described by electrochemical-oxidation-induced intermolecular
annulation via enamines. In a simple undivided cell, based on a
sodium acetate-facilitated, polysubstituted pyrrole derivations
has been facilely synthesized under external oxidant-free
condition. This electrosynthetic approach providing an environ-
mentally benign protocol for CÀ C bond cross-coupling and
oxidative annulation, which features unparalleled broad scope
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Figure 1. Natural products and bioactive molecules containing pyrrole.
of substrates and practicality.
Introduction
So far, studies have found that multisubstituted pyrroles exist
widely in a considerable amount of materials,[1] natural products
and bioactive molecules (Figure 1),[2] and exhibit versatile
pharmacological and biological properties, such as
antibacterial,[3] antifungal[4] and antitumor[5] properties. For
example, sunitinib is an anti-angiogenic tyrosine kinase receptor
(TKR) inhibitor of vascular endothelial growth factor receptor
(VEGFRs) and platelet-derived growth factor receptor
(PDGFRs).[2a] Methoxatin acts as
a
bacterial coenzyme.[2b]
Atorvastatin is used for the treatment of dyslipidemia.[2c] There-
fore, more and more attention has been paid to the synthesis
and application of polysubstituted pyrroles.
Several methods have been successfully established in the
construction of pyrrole derivatives over the past few years.[6] For
instance, Guan and co-workers used K2S2O8 as the oxidant to
synthesize multisubstituted pyrroles through enamines
(Scheme 1a).[6a] Over the past decades, enamines have been
shown to play an important role in organic reaction, with wide
applications in the synthesis of β-amino acids[7] and
heterocycles.[8] With our constant interest in the study of the
cyclization of enamines, we have disclosed the synthetic route
for construction multisubstituted unsymmetric pyrroles from
enamino esters via the copper-catalyzed tandem reaction
(Scheme 1b).[6b] However, such reactions inevitably use metals
and oxidants, all of them are unfavorable due to its environ-
mental and health hazards. Therefore, there is highly desired for
the advance of economic and green approaches for the
construction of these pyrrole-like motifs.
Scheme 1. Synthesis of multisubstituted pyrrole derivatives from enamines.
Recently, a series of electrochemical reactions have been
reported for the synthesis of CÀ C and CÀ X bonds.[9] Electro-
chemical-oxidation-induced intermolecular dehydrogenative
annulation reactions provided an effective and versatile strategy
to construct various heterocyclic compounds.[10] Herein, we
demonstrate an alternative electrochemical oxidation cycliza-
tion of enamines for the synthesis of symmetrical multisubsti-
tuted pyrroles (Scheme 1c).
Results and Discussion
In preliminary experiments, (Z)-ethyl 3-(methylamino)-3-phenyl-
acrylate 1a was used as model substrate to optimize reaction
conditions in order to develop a practical protocol for the
synthesis of multisubstituted pyrrole (Table 1). When the
electrochemical reaction was carried out in a three-necked
round-bottomed flask, platinum plate and graphite felt were
[a] Dr. Z. Chen, G. Shi, W. Tang, J. Sun, W. Wang
College of Pharmaceutical Sciences, Zhejiang University of Technology,
Hangzhou 310014, P.R. China
E-mail: chenzhiwei@zjut.edu.cn
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202001484
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Table 1. Optimization of reaction conditions.[a]
organic (Table 1, entry 14) and inorganic base (Table 1, en-
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try 15), all of them didn’t provide a significant increase in yields.
In addition, running the reactions without additive or under air
led to inferior results (Table 1, entries 16 and 17). Finally, the
control experiment verified that electricity was crucial for this
reaction, no product could be found when there was no
electricity (Table 1, entry 18).
Under the optimal reaction conditions, we tried to explore
the scope and limitation of the electrochemical transformation
(Table 2). The enamino esters bearing electron-donating group
such as methyl, methoxyl, tert-butyl and piperonyl groups on
the aryl ring at the para- or meta-position, afforded the desired
pyrroles in 53–80% yields (2c–2g, 2n). The product 2g was
further proved by X-ray analysis (CCDC No. 2036408,Figure 2).
Entry
Variation from standard conditions
Yield [%]
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None
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trace
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GF (+)jPt (À )
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GF (+)jGF (À )
Pt (+)jPt (À )
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6.0 mA, 6 h
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nBu4NBr instead of nBu4NPF6
nBu4NOAc instead of nBu4NPF6
THF instead of NMP
MeCN instead of NMP
DMSO instead of NMP
MeOH instead of NMP
CH2Cl2 instead of NMP
KOAc instead of NaOAc
DMAP instead of NaOAc
NaHCO3 instead of NaOAc
No additive
Table 2. Substrate Scope of Enamines.[a]
Under air
No electricity
[a] Reaction conditions: 1a (0.5 mmol, 102 mg), NaOAc (0.5 mmol, 41 mg),
nBu4NPF6 (0.03 M), N-Methyl pyrrolidone (NMP, 5.0 mL) in an undivided cell
with a platinum plate anode (20 mm×15 mm) and a graphite felt (GF)
cathode (20 mm×15 mm), constant current=3.0 mA (janode =1.0 mAcmÀ 2),
argon, rt, 10 h. Isolated yields.
employed as the anode and the cathode material, respectively.
The best condition was defined as treating the electrolysis with
NaOAc (1 eq.) as the additive and an electrolyte solution of
nBu4NPF6 (0.03 M) in N-Methyl pyrrolidone (NMP) at room
temperature under argon for 10 h (Table 1, entry 1). Under this
condition, an 85% yield of the desired pyrrole 2a was observed.
At first, some experiments with graphite felt was used as the
anode revealed no improvement over platinum plate (Table 1,
entries 2 and 3), platinum anode facilitated purification by
generating less by-products. Other cathode material such as
platinum was found to be less efficient than best procedure
(Table 1, entry 4). Then, increasing the current density gave the
final product in lower yield (Table 1, entry 5), even if a reduction
of the reaction time, thus manifested that a relatively low
constant current is potentially important. As for the choice of
electrolyte, no desired product was obtained when nBu4NPF6
[a] Reaction conditions: 1 (0.5 mmol, 102 mg), NaOAc (0.5 mmol, 41 mg),
nBu4NPF6 (0.03 M), NMP (5.0 mL) in an undivided cell with a platinum plate
anode (20 mm×15 mm) and a graphite felt (GF) cathode (20 mm×15 mm),
constant current=3.0 mA (janode =1.0 mAcmÀ 2), argon, rt, 10 h. Isolated
yields. [b] MeCN was used as solvent.
n
was replaced by Bu4NBr (Table 1, entry 6). When we employed
n
nBu4NOAc instead of Bu4NPF6 could give an acceptable yield of
56% (Table 1, entry 7). Aprotic solvents have shown excellent
performance to ensure medium yields (Table 1, entries 8–10).
However, protic solvents such as MeOH were not effective for
this transformation (Table 1, entry 11). Because alkoxy group
and the iminium ion may change into α-methoxylated
derivatives.[11] CH2Cl2 reduces the solubility of nBu4NPF6 and
decreases the conductivity of the reaction system, only a little
2a was detected (Table 1, entry 12). Subsequently, when NaOAc
was replaced by KOAc could give an acceptable yield of 68%
(Table 1, entry 13). The studies were elaborated with other
Figure 2. X-ray of structure of 2g.
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However, the reaction of an ortho-methyl substituted enami-
tolerated to yield the desired product 2q in 43% yield. In
addition to the À CO2Et group, the À CO2Me-substituted enamino
ester also shows similar reactivity to provide the pyrrole
compound 2r in 87% yield. To our delight, enaminone 1s was
successfully converted to the desired tetracarbonyl pyrrole 2s
in 30% yield. Treatment of ethyl 3-amino-3-phenylacrylate (1t)
afforded the desired pyrrole 2t in 54% yield. In the cases of N-
alkyl enamino esters such as propyl, cyclohexyl and benzyl,
expected products (2u–2w) were formed. N-Aryl enamino
esters with bromo and methyl on aryl rings, all gave the
corresponding pyrroles 2xa–2xc in 33–43% yields, the main
biproduct is olefin reduction product. When we trying group
that can be further derived, such as nitro group on the aryl ring
at the para-position, the desired oxidation product 2y was
obtained in 47% yield.
In order to investigate the utility of this electrochemical
annulation strategy, a gram-scale reaction of enamino ester 1a
was conducted in the 5 mmol scale (Scheme 2). When prolong-
ing the reaction time to 50 h, and the current is increasing to
15 mA, the pyrrole 2a was obtained in 61% isolated yield,
which showed the practicability of this strategy and great
potential for application.
As shown in Figure 3, the cyclic voltammogram (CV) of 1a,
and the reaction mixture to provide redox potential of the
substrate, we carried out experiments in MeCN, because the
oxidation potential is obscure in NMP. The oxidation peak of
enamino ester 1a was observed at 1.48 V vs Ag/AgCl. When we
added enamino ester 1a and 1.0 equiv. of NaOAc and stirred
for 5 minutes in MeCN, the oxidation peak decreased to 1.45 V
vs Ag/AgCl, indicated that sodium acetate accepted hydrogen
protons to slightly promote the electron transfer.
To further demonstrate the electrochemical annulating
ability of different substituted enamino esters, under the
standard conditions, an intermolecular competition experiment
with electron-donating (1d) and electron-withdrawing (1l) aryl
substituted enamino esters was performed (Scheme 3, eq 1).
The three annulation products were detected in this reaction,
2d, 2l, and crossover pyrrole 3 were isolated in 21%, 5% and
28% yields, respectively, suggesting that incorporation of EDGs
prefers this transformation. Finally, to obtain more insight into
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noester 1b resulted in complicated product mixtures, which
probably due to the steric effect. The 4-Br, 3-Cl, 4-Cl, 4-F, and 4-
CF3-substituted aryl enamino esters underwent the desired
reaction to give the products 2h–2l in moderate to good yields
ranging from 51% to 73%. These results indicated that
enamino esters containing an electron-donating substituent
were well compatible with this coupling/cyclization process.
Furthermore, the biaryl and naphthyl substrates gave the
products in 67% and 65% yield, respectively (2m and 2o). This
methodology is also successful with heterocyclic enamino ester
(2p, 51%). The α-methyl substituted enamino ester was well
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Scheme 2. Gram scale experiment.
Figure 3. Cyclic voltammetry (CV) studies (scan rate at 0.1 VsÀ 1). CV
characteristics of the reaction background (solvent MeCN and electrolyte
nBu4NPF6), enamino ester 1a, and a mixture of 1a and NaOAc.
Scheme 3. Control Experiment.
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Acknowledgements
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We gratefully acknowledge the provincial planning project of
Zhejiang provincial science and technology department
(LGF19B060005) for financial support.
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Conflict of Interest
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The authors declare no conflict of interest.
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Keywords: Electrochemical
Polysubstituted pyrrole · Cross-coupling · Oxidative annulation
reactions
·
Enamines
·
[1] a) Y. Kawamoto, T. Bando, H. Sugiyama, Bioorg. Med. Chem. 2018, 26,
1393–1411; b) Y. Lei, Q. Liu, L. Dong, Z. Cai, J. Shi, J. Zhi, B. Tong, Y.
Dong, Chem. Eur. J. 2018, 24, 14269–14274; c) L. Dong, G. Shang, J. Shi,
J. Zhi, B. Tong, Y. Dong, J. Phys. Chem. C 2017, 121, 11658–11664; d) X.
Feng, B. Tong, J. Shen, J. Shi, T. Han, L. Chen, J. Zhi, P. Lu, Y. Ma, Y.
Dong, J. Phys. Chem. B 2010, 114, 16731–16736; e) T. Han, X. Feng, B.
Tong, J. Shi, L. Chen, J. Zhi, Y. Dong, Chem. Commun. 2012, 48, 416–418;
f) H. Wang, D. Chen, Y. Zhang, P. Liu, J. Shi, X. Feng, B. Tong, Y. Dong, J.
Mater. Chem. C 2015, 3, 7621–7626.
[2] a) J. Sourdon, F. Lager, T. Viel, D. Balvay, R. Moorhouse, E. Bennana, G.
Renault, P. L. Tharaux, N. Dhaun, B. Tavitian, Theranostics 2017, 7, 2757–
2774; b) I. S. Young, P. D. Thornton, A. Thompson, Nat. Prod. Rep. 2010,
27, 1801–1839; c) H. Zhou, A. Aguilar, J. Chen, L. Bai, L. Liu, J. L. Meagher,
C. Y. Yang, D. McEachern, X. Cong, J. A. Stuckey, S. Wang, J. Med. Chem.
2012, 55, 6149–6161; d) P. D. Bass, D. A. Gubler, T. C. Judd, R. M.
Williams, Chem. Rev. 2013, 113, 6816–6863; e) R. Jansen, S. Sood, K. I.
Mohr, B. Kunze, H. Irschik, M. Stadler, R. Müller, R. J. Nat. Prod. 2014, 77,
2545–2552; f) S. Ahmad, O. Alam, M. J. Naim, M. Shaquiquzzaman, M. M.
Alam, M. Iqbal, Eur. J. Med. Chem. 2018, 157, 527–561.
[3] A. Al-Mourabit, M. A. Zancanella, S. Tilvi, D. Romo, Nat. Prod. Rep. 2011,
28, 1229–1260.
[4] M.-Z. Wang, H. Xu, T.-W. Liu, Q. Feng, S.-J. Yu, S.-H. Wang, Z.-M. Li, Eur. J.
Med. Chem. 2011, 46, 1463–1472.
[5] A. D. Yamaguchi, K. M. Chepiga, J. Yamaguchi, K. Itami, H. M. Davies, J.
Am. Chem. Soc. 2015, 137, 644–647.
[6] a) P. Gao, J. Wang, Z.-J. Bai, L. Shen, Y.-Y. Yan, D.-S. Yang, M.-J. Fan, Z.-H.
Guan, Org. Lett. 2016, 18, 6074–6077; b) Z.-W. Chen, L. Zheng, J. Liu, Eur.
J. Org. Chem. 2019, 2019, 3051–3060; c) M.-N. Zhao, Z.-J. Zhang, Z.-H.
Ren, D.-S. Yang, Z.-H. Guan, Org. Lett. 2018, 20, 3088–3091; d) X.-Y.
Zhang, Z.-W. Yang, Z. Chen, J. Wang, D.-L. Yang, Z. Shen, L.-L. Hu, J.-W.
Xie, J. Zhang, H.-L. Cui, J. Org. Chem. 2016, 81, 1778–1785; e) P. Liu, M.
Yang, Y. Gong, Y. Yu, Y.-L. Zhao, Org. Lett. 2020, 22, 36–40. f) M. A.
Sukari, J. M. Vernon, Tetrahedron 1983, 39, 793–796.
Scheme 4. Plausible reaction mechanism.
this reaction mechanism, when 2 equiv. of 2,2,6,6-tetrameth-
ylpiperidine-1-oxyl (TEMPO) was added to the reaction system
(Scheme 3, eq 2), only trace product was formed. Instead, the
generation of a TEMPO-adduct 4 was detected by HRMS
analysis. Indicating that the electrochemical oxidative annulat-
ing of enamino esters proceeded by a radical pathway.
Considering the experimental results above and previous
literature reports,[6a,12] a possible mechanism was proposed for
the synthesis of polysubstituted pyrroles (Scheme 4). Firstly,
enamino ester 1a could isomerize to afford the imine A, which
single-electron-transfer (SET) oxidation form a C-radical inter-
mediate B at the anode. Then, self-coupling of the C-radical to
give the adduct intermediate C. Finally, CÀ N bond was formed
by the intramolecular nucleophilic addition produces D,
followed by elimination of MeNH2 to obtain the desired product
2a.
Conclusion
We described herein the novel and efficient intermolecular
oxidative coupling/cyclization of enamines, a variety of poly-
substituted pyrrole derivations were easily generated in high
yields through electrosynthetic approach at room temperature,
avoiding the addition of transition metal catalysts and oxidants.
Under these mild and green electrooxidation system, a broad
substrate scope are compatible. Further exploration on the
electrochemical-oxidation of enamines are ongoing in our
laboratory.
Deposition Number 2036408 (for 2g) contains the supple-
mentary crystallographic data for this paper. These data are
provided free of charge by the joint Cambridge Crystallographic
Data Centre and Fachinformationszentrum Karlsruhe Access
Structures service www.ccdc.cam.ac.uk/structures.
[7] a) X. Li, C. You, S. Li, H. Lv, X. Zhang, Org. Lett. 2017, 19, 5130–5133;
b) G.-H. Hou, W. Li, M. F. Ma, X. W. Zhang, X. M. Zhang, J. Am. Chem. Soc.
2010, 132, 12844–12846.
[8] a) P. Gao, J. Wang, Z. Bai, M. J. Fan, D. S. Yang, Z. H. Guan, Org. Lett.
2018, 20, 3627–3630; b) S. Peng, S. Liu, S. Zhang, S. Cao, J. Sun, Org. Lett.
2015, 17, 5032–5035; c) Y. Li, Y. Zhao, Y. Yuan, L. Kong, F. Zhang,
Synthesis 2017, 49, 3609–3618; d) F. Zhang, Z. Qin, L. Kong, Y. Zhao, Y.
Liu, Y. Li, Org. Lett. 2016, 18, 5150–5153; e) Y. Zhao, Q. Duan, Y. Zhou, Q.
Yao, Y. Li, Org. Biomol. Chem. 2016, 14, 2177–2181; f) S. Yugandar, S.
Konda, G. Parameshwarappa, H. Ila, J. Org. Chem. 2016, 81, 5606–5622;
g) W.-B. Cao, B.-B. Liu, X.-P. Xu, S.-J. Ji, Org. Chem. Front. 2018, 5, 1194–
1201; h) S.-S. Jang, J.-Y. Chang, G.-Y. Kang, S.-W. Youn, Asian J. Org.
Chem. 2019, 8, 1–7.
[9] a) H. Wang, X. Gao, Z. Lv, T. Abdelilah, A.-W. Lei, Chem. Rev. 2019, 119,
6769–6787; b) S. Tang, L. Zeng, A.-W. Lei, J. Am. Chem. Soc. 2018, 140,
13128–13135; c) M. Yan, Y. Kawamata, P. S. Baran, Chem. Rev. 2017, 117,
13230–13319; d) S. Liang, K. Xu, C.-C. Zeng, H.-Y. Tian, B.-G. Sun, Adv.
Synth. Catal. 2018, 360, 4266–4292; e) H.-T. Tang, J.-S. Jia, Y.-M. Pan, Org.
Biomol. Chem., 2020, 18, 5315–5333; f) M. D. Kärkäs, Chem. Soc. Rev.,
2018, 47, 5786–5865; g) R. Francke, R. D. Little, Chem. Soc. Rev. 2014, 43,
2492–2521; h) Y. Jiang, K. Xu, C.-C. Zeng, Chem. Rev. 2018, 118, 4485–
4540; i) A. Wiebe, T. Gieshoff, S. Mçhle, E. Rodrigo, M. Zirbes, S. R.
Eur. J. Org. Chem. 2021, 951–955
www.eurjoc.org
954
© 2021 Wiley-VCH GmbH

Communications
doi.org/10.1002/ejoc.202001484
Waldvogel, Angew. Chem. Int. Ed. 2018, 57, 5594–5619; Angew. Chem.
[11] a) T.-S. Kam, T.-M. Lim, G.-H. Tan, J. Chem. Soc. Perkin Trans. 1 2001,
1594–1604; b) E. Sierecki, G. Errasti, T. Martens, J. Royer, Tetrahedron
2010, 66, 10002–10007; c) D.-S. Lee, Tetrahedron: Asymmetry 2009, 20,
2014–2020; d) S. S. Libendi, Y. Demizu, Y. Matsumura, O. Onomura,
Tetrahedron 2008, 64, 3935–3942.
1
2
3
4
5
6
7
8
9
2018, 130, 5694–5721; j) C. Kingston, M. D. Palkowitz, Y. Takahira, J. C.
Vantourout, B. K. Peters, Y. Kawamata, P. S. Baran, Acc. Chem. Res. 2020,
53, 72–83; k) K.-J. Jiao, Y.-K. Xing, Q.-L. Yang, H. Qiu, T.-S. Mei, Acc. Chem.
Res. 2020, 53, 300–310; l) P. Xiong, H.-C. Xu, Acc. Chem. Res. 2019, 52,
3339–3350; m) L. Ackermann, Acc. Chem. Res. 2020, 53, 84–104; n) R. C.
Samanta, T. H. Meyer, I. Siewert, L. Ackermann, Chem. Sci. 2020, 11,
8657–8670.
[12] X. Gao, P. Wang, Q. Wang, J. Chen, A.-W. Lei, Green Chem. 2019, 21,
4941–4945.
[10] a) X. Hu, G. Zhang, F. Bu, L. Nie, A.-W. Lei, ACS Catal. 2018, 8, 9370–
9375; b) J. Hua, Z. Fang, J. Xu, M. Bian, C. Liu, W. He, N. Zhu, Z. Yang, K.
Guo, Green Chem. 2019, 21, 4706–4711; c) P. Huang, P. Wang, S. Wang,
S. Tang, A.-W. Lei, Green Chem. 2018, 20, 4870–4874; d) Z. Ye, M. Ding,
Y. Wu, Y. Li, W. Hua, F. Zhang, Green Chem. 2018, 20, 1732–1737; e) S.
Zhang, L. Li, M. Xue, R. Zhang, K. Xu, C. Zeng, Org. Lett. 2018, 20, 3443–
3446; f) Y. Jiang, K. Xu, C. Zeng, Chem. Rev. 2018, 118, 4485–4540.
Manuscript received: November 11, 2020
Revised manuscript received: December 27, 2020
Accepted manuscript online: January 16, 2021
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