Iron-catalyzed [3 + 2]-cycloaddition of: In situ generated N -ylides with alkynes or olefins: Access to multi-substituted/polycyclic pyrrole derivatives

Article abstract of DOI:10.1039/c9ob02571e

An iron-catalyzed one-pot three-component reaction of 1-substituted benzimidazoles with diazoacetates and electron-deficient alkynes or alkenes has been reported. Mechanistically, the reaction goes through a 1,3-dipolar cycloaddition of catalytically generated benzimidazolium N-ylides with various activated alkynes or alkenes, leading to multi-substituted and polycyclic fused pyrrole derivatives, respectively.

Full text of DOI:10.1039/c9ob02571e

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Iron-catalyzed [3 + 2]-cycloaddition of in situ
generated N-ylides with alkynes or olefins:
access to multi-substituted/polycyclic pyrrole
derivatives†
Cite this: DOI: 10.1039/c9ob02571e
Received 2nd December 2019,
Accepted 18th December 2019
a,b
Kai Zhou, a Ming Bao,a Jingjing Huang,a Zhenghui Kang, a Xinfang Xu,
DOI: 10.1039/c9ob02571e
a
rsc.li/obc
Wenhao Hu*a and Yu Qian
*
An iron-catalyzed one-pot three-component reaction of 1-substi- a very narrow range of aromatic heterocycles, such as pyridine,
tuted benzimidazoles with diazoacetates and electron-deficient quinoline, and isoquinoline derivatives. Thus, the develop-
alkynes or alkenes has been reported. Mechanistically, the reaction ment of effective catalytic approaches for the practical syn-
goes through a 1,3-dipolar cycloaddition of catalytically generated thesis of pyrrole derivatives with structural diversity, especially
benzimidazolium N-ylides with various activated alkynes or for the polycyclic frameworks, from readily available and
alkenes, leading to multi-substituted and polycyclic fused pyrrole stable materials with non-noble metal catalysts is highly
derivatives, respectively.
desirable.
The pyrrole derivatives are ubiquitous structural units in aro-
matic heterocycles, which are present in a variety of advanced
materials,1 natural products,2 and pharmaceutical com-
pounds.3 In particular, polycyclic pyrrole frameworks are of
particular interest because of their unique structural architec-
tures that have been found in many biologically active mole-
cules exhibiting a variety of activities, including anticancer,4
antimalarial,5 anti-inflammatory,6 antiviral,7 and antinocicep-
tive8 activities. Thus, the development of efficient and practical
synthetic methods towards this library of compounds with
structural diversity has attracted great attention in recent
decades and continues to be an appealing and active research
area.9–11 Generally, the 1,3-dipolar cycloaddition reactions of
pyridinium ylides,12 which are catalytically generated from
pyridines and diazo compounds, with activated alkynes
(Scheme 1a, path a) or alkenes (Scheme 1a, path b) provide a
straightforward way of generating a large number of con-
densed indolizine derivatives.13 The analogous [3 + 2]-cyclo-
addition of pyridines with vinyl diazoacetates also forms indo-
lizine derivatives (Scheme 1a, path c).14 Among these pub-
lished procedures, the substrate scope was seriously limited to
aGuangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery,
School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006,
China. E-mail: huwh9@mail.sysu.edu.cn, qianyu5@mail.sysu.edu.cn
bShanghai Engineering Research Center of Molecular Therapeutics and New Drug
Development, School of Chemistry and Molecular Engineering, East China Normal
University, 3663 North Zhongshan Rd., Shanghai 200062, China
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c9ob02571e
Scheme 1 Formation of N-ylides and their synthetic applications.
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On the other hand, the deprotonation of benzimidazolium initial exploration of a variety of commercially available metal
salts, which are generated from benzimidazoles and their catalysts in dichloromethane (DCM) at room temperature
corresponding haloalkanes, is an alternative approach for the showed that both [Fe(TPP)Cl] (TPP = tetraphenylporphyrin)
generation of benzimidazolium N-ylides (Scheme 1b).15,16 and [(MeCN)4Cu]PF6 could yield tetrasubstituted pyrrole 4a as
Inspired by these advances, and as a continuation of our inter- the major product instead of the fused product 5a in 82% and
est in catalytic carbene transformations,17,18 we are 63% yields, respectively (entries 3 and 4).19 In the cases with
intrigued by the possibility of using the catalytically generated Rh2(OAc)4 or CuBr as the catalysts, no desired adduct with 3a
benzimidazolium N-ylide species for the [3 + 2]-cycloaddition was observed, although the decomposition of 1a occurred
with activated alkynes or alkenes. Thus, it could enable syn- under these conditions (entries 1 and 2). Notably, when the
thetically appealing access to polycyclic pyrrole derivatives reaction was conducted under an open air atmosphere, 5a was
in terms of step- and atom-economy. Herein, we report an obtained in 56% yield combined with 4a in 28% yield (entry 5),
iron-catalyzed one-pot three-component of 1-substituted which implied that the oxygen in air prompted the oxidative
benzimidazoles with diazoacetates and electron-deficient aromatization process after the cycloaddition step, instead of
alkynes or alkenes, which provides general access to multi- ring-opening aromatization to form 4a. Next, a thorough screen-
substituted pyrroles and pyrrolo[1,2-a]benzimidazole deriva- ing of the solvents in the presence of [Fe(TPP)Cl] at room temp-
tives through the 1,3-dipolar cycloaddition of catalytically gen- erature showed the superiority of 1,4-dioxane over all the other
erated benzimidazolium N-ylides with activated alkynes or tested solvents in terms of yield and selectivity (entries 6–10),
alkenes, respectively (Scheme 1c). Notably, this is a rare and the corresponding reaction produced 4a in 90% yield
example of using catalytically generated benzimidazolium (entry 7). It is noteworthy that in these iron-catalyzed reactions,
N-ylides for the [3 + 2]-cycloaddition.16f In addition, these 4 Å molecular sieves were added to ensure the high catalytic
polycyclic pyrrole frameworks, including pyrrolo[1,2-a]quinoxa- efficiency of this catalyst in different solvents, and the reaction
linone derivatives that are easily accessible from these gener- was totally shut down in the absence of 4 Å molecular sieves in
ated substituted pyrroles under thermal conditions, are 1,4-dioxane (entry 11), whilst comparable reactivity was
present in many biologically and pharmaceutically active observed in DCM with or without the 4 Å molecular sieves.
compounds.4–8
Furthermore, 86% isolated yields were obtained when the reac-
To conduct the optimization of the designed reaction, ethyl tion was conducted on a 0.2 mmol scale in 1,4-dioxane cata-
diazoacetate 1a, N-benzyl benzimidazole 2a, and dimethyl lyzed by [Fe(TPP)Cl] (entry 12).
succinate 3a were chosen as model substrates (Table 1). The
With the optimal reaction conditions being established, we
set out to explore the substrate generality of this cycloaddition
reaction (Scheme 2). This iron-catalyzed cycloaddition proved
to be a general method for the facile construction of multi-sub-
stituted pyrroles. Diazo compounds 1 with a variety of ester
groups afforded the corresponding products in >83% yields
(4a–4e), although the α-alkyl or α-aryl substituted diazoacetates
gave a complex mixture. Substituted N-benzyl benzimidazoles
worked well under current conditions, leading to products 4f
and 4g in 70% and 76% yields, respectively. Then, different
propiolate derivatives were investigated, including diethyl but-
2-ynedioate, ethyl propiolate, methyl propiolate, and ethyl but-
2-ynoate, and all of them underwent the desired transform-
ation to give the cycloaddition products in 73%–83% yields
(4h–4k).
Encouraged by the above results, we further investigated
the reaction for the synthesis of pyrrolo[1,2-a]benzimidazoles
5. Due to the favourable ring-opening aromatization process
after the cycloaddition of in situ generated benzimidazolium
N-ylides with alkynes, the multi-substituted pyrroles 4 were
formed as the major products in this case. We envisioned that
by using alkenes as the dipolarophiles, instead of alkynes, the
formed corresponding [3 + 2]-cycloaddition adduct 7 would
not automatically lead to the analogous ring-opening aromati-
zation process, thus the oxidative aromatization pathway could
be selectively enabled in the presence of an appropriate
oxidant to form the fused polycyclic pyrrole derivatives 5.
With this conception in mind, we conducted the condition
optimization for this transformation (see Table S1 in the ESI†),
Table 1 Condition optimization for the synthesis of multi-substituted
pyrrolesa
Entry
Cat (x mol%)
Solvent
Yields 4a/5ab (%)
1c
2c
3
Rh2(OAc)4 (2.0)
CuBr (20)
DCM
DCM
DCM
DCM
DCM
THF
1,4-Dioxane
DCE
MeCN
ND/ND
ND/ND
63/9
[(MeCN)4Cu]PF6 (5.0)
[Fe(TPP)Cl] (2.0)
[Fe(TPP)Cl] (2.0)
[Fe(TPP)Cl] (2.0)
[Fe(TPP)Cl] (2.0)
[Fe(TPP)Cl] (2.0)
[Fe(TPP)Cl] (2.0)
[Fe(TPP)Cl] (2.0)
[Fe(TPP)Cl] (2.0)
[Fe(TPP)Cl] (2.0)
4
82/18
28/56
50/23
90/<10
61/33
29/43
81/19
NR
5d
6e
7e
8e
9e
10e
11
12e
Toluene
1,4-Dioxane
1,4-Dioxane
86f/<10
a Unless otherwise noted, all reactions were carried out on a 0.1 mmol
scale (1a : 2a : 3a = 1.5 : 1.2 : 1) under an argon atmosphere at room
temperature. b The yields were determined by proton NMR of the crude
reaction mixture with p-nitrobenzaldehyde as an internal standard.
c Only decomposition of 1a was observed, and most of the 2a was recov-
ered. d Under an open air atmosphere. e The reaction was carried out in
the presence of 100 mg 4 Å MS (50 mg). f The reaction was conducted
on a 0.2 mmol scale and the yield given is the isolated yield. ND = not
detected. NR = no reaction.
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Scheme 2 Substrate scope for the synthesis of multi-substituted pyr-
roles. Reaction conditions: 1 (0.3 mmol), 2 (0.24 mmol), 3 (0.2 mmol),
4 Å MS (100 mg), and [Fe(TPP)Cl] (2.0 mmol%) in 1,4-dioxane (4.0 mL)
for 12 h under an argon atmosphere at room temperature. The yields
given are the isolated yields. a 3.0 equiv. of the diazo compound 1a were
used instead of 1.5 equiv. Ad = adamantyl.
Scheme 3 Substrate scope for the synthesis of polycyclic pyrroles.
Reaction conditions: 1 (0.3 mmol), 2 (0.24 mmol), 6 (0.2 mmol), and [Fe
(TPP)Cl] (2.0 mol%) in DCM (4.0 mL) for 12 h, then DDQ (0.44 mmol)
was added and stirred for 1 h. The yields given are the isolated yields.
a 3.0 equiv. of the diazo compound 1a were used instead of 1.5 equiv.
b THF was used as the solvent instead of DCM due to the low solubility
of the materials (2g and 6q). c The result in the parenthesis is the yield
for the other regioisomer.
and above 95% isolated yield was obtained when the
reaction was conducted on a 0.2 mmol scale in DCM
catalyzed by [Fe(TPP)Cl] in the presence of 2.2 equiv. of DDQ
(eqn (1)).16
ð1Þ
however, no identifiable by-product has been isolated.21 In the
case of non-protected benzimidazole, 3.0 equiv. of diazoketone
Subsequently, the substrate generality of this catalytic and were used, which not only contributed to the formation of
oxidative [3 + 2] cycloaddition was evaluated under the above N-ylide with benzimidazole, but also reacted with free N–H
optimized conditions (Scheme 3). In all these tested sub- species to give the corresponding insertion product (5g, >95%
strates, including a variety of diazoacetates (5a–5e)16g or diazo- yield). N-Methylmaleimide also tolerated under current con-
ketones (5f–5i), substituted N-benzyl benzimidazoles (5j–5m), ditions, delivering the tetracyclic product 5p in 44% yield.
and different types of alkenes (5n20–5q), smoothly afforded the Notably, the non-symmetric alkene, methyl (E)-4-amino-4-
corresponding polycyclic products in good to excellent yields, oxobut-2-enoate, selectively produced the corresponding
and with most of them in nearly quantitative yields (5a–5o). adduct 5q in 62% yield combined with the minor regioisomer
The lower yield of 5q may be due to the potential side reaction; in 8% yield (Scheme 3, noted).
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To understand the mechanism of the reaction, some 5f under mild conditions in 77% and 63% yields, respectively
control experiments were carried out. In the absence of an (see the ESI† for details).
oxidant, the corresponding [3 + 2]-cycloaddition adduct 7a was
isolated in quantitative yields (see the ESI† for details).20
This adduct could be quantitatively converted to pyrrolo[1,2-a]
benzimidazole 5a in >95% isolated yields in the presence of an
ð2Þ
oxidant. Moreover, no reaction occurs between benzimidazole
2a and the electrophilic alkyne 3a or alkene 6a in the
absence of the diazo compound under the current conditions
(see Fig. S1 and S2 in the ESI† for details). The diazo-
cycloadducts, which are generated from 1a and 3a in the pres-
ence of iron-catalyst, could not yield the pyrrole product 4a by
In conclusion, we have disclosed an iron-catalyzed one-pot
three-component reaction of 1-substituted benzimidazoles
with diazoacetates and electron-deficient alkynes or alkenes. A
broad range of important multi-substituted pyrroles, pyrrolo
[1,2-a]benzimidazole and pyrrolo[1,2-a]quinoxalinone deriva-
tives were selectively generated in good to excellent yields
adding 2a to the above crude reaction mixture (see Fig. S3 in
the ESI† for details). Based on these observations and
related literature reports,13–16 a possible mechanistic pathway
is proposed (Scheme 4). Initially, benzimidazolium N-ylide I
under mild conditions. This method features an inexpensive
was catalytically generated as the key intermediate in the
iron catalyst, readily available starting materials, mild reaction
conditions and operational simplicity. Mechanistically, the
presence of iron catalyst from 1 and 2.13,14 In the subsequent
cycloaddition with alkynes, tricyclic 2,5-dihydropyrrole II
reaction goes through a 1,3-dipolar cycloaddition of catalyti-
was generated followed by a fast isomerization, which is a
cally generated benzimidazolium N-ylides with activated
alkynes or alkenes. Potential applications using this strategy
thermodynamically favourable ring-opening aromatization
process, giving the multi-substituted pyrroles 4. Although
for the construction of structural appealing molecules are
competitive oxidative aromatization might occur, it would
under exploration in the laboratory.
lead only to the corresponding polycyclic fused pyrrole
derivatives 5 in minor or trace amounts due to the slow
reaction rate. During cycloaddition with alkenes that follows
the rule of syn-addition,20 pyrrolidine species III was
formed, which is relatively stable in comparison with II, and
the ring-opening aromatization process could not take
place for this intermediate, thus, oxidative aromatization of
this intermediate in the presence of DDQ smoothly led to
the polycyclic fused pyrroles 5 in quantitative yields in most
cases.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
Support for this research from the National Natural Science
Foundation of China (21901262 and 81973176), the National
Postdoctoral Program for Innovative Talents (BX20190399), the
Guangdong Provincial Key Laboratory of Chiral Molecule and
Drug Discovery (2019B030301005) and The Program for the
Guangdong Introducing Innovative and Entrepreneurial
Teams (No. 2016ZT06Y337) is greatly acknowledged.
To demonstrate the synthetic utility of the current method,
further transformations with this product were conducted. The
intramolecular ester to amide interconversion occurred
smoothly under thermal conditions, delivering the tricyclic
pyrrolo[1,2-a]quinoxalinone products 9 in good to high yields
(eqn (2)).16h The reduction product and hydrolysis product
were generated from the tricyclic pyrrolo[1,2-a]benzimidazole
Notes and references
1 (a) Z.-B. Zeng, X.-L. Shi, C.-Y. Chi, J. T. L. Navarrete,
J. Casado and J.-S. Wu, Chem. Soc. Rev., 2015, 44, 6578;
(b) A. Berlin, B. Vercelli and G. Zotti, Polym. Rev., 2008, 48,
493; (c) M. Boota, B. Anasori, C. Voigt, M.-Q. Zhao,
M. W. Barsoum and Y. Gogotsi, Adv. Mater., 2016, 28, 1517;
(d) R. K. C. Balasubramanyam, A. E. Kandjani, L. A. Jones,
S. R. Periasamy, S. Wong, R. Narayan, S. K. Bhargava,
S. J. Ippolito and P. Basak, Adv. Electron. Mater., 2018, 4,
1700626; (e) M. Krzeszewski, D. Gryko and D. T. Gryko, Acc.
Chem. Res., 2017, 50, 2334; (f) B. M. Rambo and
J. L. Sessler, Chem. – Eur. J., 2011, 17, 4946.
2 (a) A. Al-Mourabit, M. A. Zancanella, S. Tilvi and D. Romo,
Nat. Prod. Rep., 2011, 28, 1229; (b) A. Domagala, T. Jarosz
Scheme 4 Proposed reaction sequence.
Org. Biomol. Chem.
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Communication
and M. Lapkowski, Eur. J. Med. Chem., 2015, 100, 176;
(c) I. S. Young, P. D. Thornton and A. Thompson, Nat. Prod.
Rep., 2010, 27, 1801; (d) H. Fan, J. Fan, M. T. Hamann and
J.-F. Hu, Chem. Rev., 2008, 108, 264.
3 (a) V. M. Dembitsky, T. A. Gloriozova and V. V. Poroikov,
Mini-Rev. Med. Chem., 2005, 5, 319; (b) M. Biava,
G. C. Porretta, G. Poce, C. Battilocchio, S. Alfonso, A. De
Logu, F. Manetti and M. Botta, ChemMedChem, 2011, 6,
593; (c) S. S. Gholap, Eur. J. Med. Chem., 2016, 110, 13;
A. Mangravita-Novo, M. Vicchiarelli, L. H. Smith,
J. M. Streicher, M. G. Caron, L. S. Barak, L. M. Bohn,
T. D. Y. Chung and J. Aubé, ACS Chem. Neurosci., 2012, 3, 221.
9 For reviews: (a) V. Estévez, M. Villacampa and
J. C. Menéndez, Chem. Soc. Rev., 2014, 43, 4633;
(b) W. J. Olivier, J. A. Smith and A. C. Bissember, Org.
Biomol. Chem., 2018, 16, 1216; (c) Z.-S. Yin, Y. He and
P. Chiu, Chem. Soc. Rev., 2018, 47, 8881; (d) M. A. Cavitt,
L. H. Phun and S. France, Chem. Soc. Rev., 2014, 43, 804.
(d) V. Bhardwaj, D. Gumber, V. Abbot, S. Dhiman and 10 (a) G. Qiu, Q. Wang and J. Zhu, Org. Lett., 2017, 19, 270;
P. Sharma, RSC Adv., 2015, 5, 15233.
(b) W.-W. Tan and N. Yoshikai, Chem. Sci., 2015, 6, 6448;
(c) Z. Ling, F. Xie, I. D. Gridnev, M. Terada and
W.-B. Zhang, Chem. Commun., 2018, 54, 9446;
(d) B. Emayavaramban, M. Sen and B. Sundararaju, Org.
Lett., 2017, 19, 6; (e) J. C. Borghs, Y. Lebedev and
M. Rueping, Org. Lett., 2019, 21, 70.
4 (a) B. Budke, W. Tueckmantel, K. Miles, A. P. Kozikowski
and P. P. Connell, ChemMedChem, 2019, 14, 1031;
(b) V. Desplat, M. Vincenzi, R. Lucas, S. Massip,
S. Savrimoutou, S. Rubio, N. Pinaud, D. Bigat, E. Enriquez,
M. Marchivie, S. Routier, P. Sonnet, F. Rossi, L. Ronga and
J. Guillon, ChemMedChem, 2017, 12, 940; (c) F. Colombo, 11 (a) S. K. Mondal, A. Mandal, S. K. Manna, S. A. Ali,
C. Tintori, A. Furlan, S. Borrelli, M. S. Christodoulou,
R. Dono, F. Maina, M. Botta, M. Amat, J. Bosch and
D. Passarella, Bioorg. Med. Chem. Lett., 2012, 22, 4693;
M. Hossain, V. Venugopal, A. Jana and S. Samanta, Org.
Biomol. Chem., 2017, 15, 2411; (b) K. N. Tripathi, D. Ray
and R. P. Singh, Org. Biomol. Chem., 2017, 15, 10082.
(d) F. Pierre, C. F. Regan, M. C. Chevrel, A. Siddiqui-Jain, 12 For reviews: (a) N. De and E. J. Yoo, ACS Catal., 2018, 8, 48;
D. Macalino, N. Streiner, D. Drygin, M. Haddach,
S. E. O’Brien, W. G. Rice and D. M. Ryckman, Bioorg. Med.
Chem. Lett., 2012, 22, 3327; (e) J. Miyashiro, K. W. Woods,
C. H. Park, X.-S. Liu, Y. Shi, E. F. Johnson, J. J. Bouska,
A. M. Olson, Y. Luo, E. H. Fry, V. L. Giranda and
T. D. Penning, Bioorg. Med. Chem. Lett., 2009, 19, 4050.
(b) J. Jacobs, E. V. Hende, S. Claessens and N. D. Kimpe,
Curr. Org. Chem., 2011, 15, 1340; (c) A. Kakehi, Heterocycles,
2012, 85, 1529; (d) S. Sowmiah, J. M. S. S. Esperança,
L. P. N. Rebelo and C. A. M. Afonso, Org. Chem. Front.,
2018, 5, 453; (e) X.-C. Xu, P. Y. Zavalij and M. P. Doyle,
J. Am. Chem. Soc., 2013, 135, 12439.
5 J. Guillon, A. Cohen, N. M. Gueddouda, R. NathDas, 13 (a) A. Padwa, D. J. Austin, L. Precedo and L. Zhi, J. Org.
S. Moreau, L. Ronga, S. Savrimoutou, L. Basmaciyan,
A. Monnier, M. Monget, S. Rubio, T. Garneri, N. Azas,
J. L. Mergny, C. Mullié and P. Sonnet, J. Enzyme Inhib. Med.
Chem., 2017, 32, 547.
6 (a) R. A. Smits, H. D. Lim, A. Hanzer, O. P. Zuiderveld,
E. Guaita, M. Adami, G. Coruzzi, R. Leurs and I. J. P. de
Esch, J. Med. Chem., 2008, 51, 2457; (b) J. Guillon,
M. L. Borgne, C. Rimbault, S. Moreau, S. Savrimoutou,
Chem., 1993, 58, 1144; (b) T. Douglas, A. Pordea and
J. Dowden, Org. Lett., 2017, 19, 6396; (c) J. Day,
B. McKeever-Abbas and J. Dowden, Angew. Chem., Int. Ed.,
2016, 55, 5809; (d) R. Chen, Y. Zhao, H. Sun, Y. Shao, Y. Xu,
M. Ma, L. Ma and X. Wan, J. Org. Chem., 2017, 82, 9291;
(e) M. He, N. Chen, J. Wang and S. Peng, Org. Lett., 2019,
21, 5167; (f) D. Zhang, L.-L. Lin, J. Yang, X.-H. Liu and
X.-M. Feng, Angew. Chem., Int. Ed., 2018, 57, 12323.
N. Pinaud, S. Baratin, M. Marchivie, S. Roche, A. Bollacke, 14 (a) J. Barluenga, G. Lonzi, L. Riesgo, L. A. López and
A. Pecci, L. Alvarez, V. Desplat and J. Jose, Eur. J. Med.
Chem., 2013, 65, 205; (c) J. Guillon, R. C. Reynolds,
J. M. Leger, M. A. Guie, S. Massip, P. Dallemagne and
C. Jarry, J. Enzyme Inhib. Med. Chem., 2004, 19, 489.
M. Tomás, J. Am. Chem. Soc., 2010, 132, 13200; (b) J. Vaitla,
A. Bayer and K. H. Hopmann, Angew. Chem., Int. Ed., 2018,
57, 16180; (c) L. A. López and J. González, Org. Biomol.
Chem., 2019, 17, 646.
7 (a) A. Furlan, F. Colombo, A. Kover, N. Issaly, C. Tintori, 15 (a) N. Fernandez, L. Carrillo, J. L. Vicario, D. Badia and
L. Angeli, V. Leroux, S. Letard, M. Amat, Y. Asses,
B. Maigret, P. Dubreuil, M. Botta, R. Dono, J. Bosch,
O. Piccolo, D. Passarella and F. Maina, Eur. J. Med. Chem.,
2012, 47, 239; (b) R. Liu, Z.-H. Huang, M. G. Murray,
X.-Y. Guo and G. Liu, J. Med. Chem., 2011, 54, 5747.
E.
Reyes,
Chem.
Commun.,
2011,
47,
12313;
(b) M. Kucukdisli and T. Opatz, Eur. J. Org. Chem., 2012,
4555; (c) D. S. Allgäuer, P. Mayer and H. Mayr, J. Am. Chem.
Soc., 2013, 135, 15216; (d) J. Brioche, C. Meyer and J. Cossy,
Org. Lett., 2015, 17, 2800; (e) B. Shen, B. Li and B. Wang,
Org. Lett., 2016, 18, 2816; (f) S. R. Pathipati, A. V. D. Werf
and N. Selander, Org. Lett., 2018, 20, 3691.
8 Antinociception/neuropathic pain: (a) M. Brindisi,
G. Borrelli, S. Brogi, A. Grillo, S. Maramai, M. Paolino,
M. Benedusi, A. Pecorelli, G. Valacchi, L. D. C. Mannelli, 16 (a) X. Fang, Y.-M. Wu, J. Deng and S.-W. Wong,
C. Ghelardini, M. Allarà, A. Ligresti, P. Minetti,
G. Campiani, V. D. Marzo, S. Butini and S. Gemma,
ChemMedChem, 2018, 13, 2090; (b) K. J. Frankowski,
M. P. Hedrick, P. Gosalia, K. Li, S. Shi, D. Whipple, P. Ghosh,
T. E. Prisinzano, F. J. Schoenen, Y. Su, S. Vasile, E. Sergienko,
W. Gray, S. Hariharan, L. Milan, S. Heynen-Genel,
Tetrahedron, 2004, 60, 5487; (b) Y. Matsuda, K. Yamashita,
K. Takahashi, S. Ide, K. Torisu and K. Furuno, Heterocycles,
1992, 33, 295; (c) E. Georgescu, A. Nicolescu, F. Georgescu,
S. Shova, F. Teodorescu, A.-M. Macsim and C. Deleanu,
Synthesis, 2015, 47, 1643; (d) E. Georgescu, A. Nicolescu,
F. Georgescu, F. Teodorescu, S. Shova, A. T. Marinoiu,
This journal is © The Royal Society of Chemistry 2019
Org. Biomol. Chem.

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Communication
Organic & Biomolecular Chemistry
F. Dumitrascu and C. Deleanu, Tetrahedron, 2016, 72, 2507;
(e) C. Moldoveanu, G. Zbancioc, D. Mantu, D. Maftei and
I. Mangalagiu, PLoS One, 2016, 11, e0156129;
(f) R. C. F. Jones, J. N. Iley, M. Sanchis-Amat, X. Zhang and
M. R. J. Elsegood, Tetrahedron Lett., 2009, 50, 3577;
(g) O. Meth-Cohn, Tetrahedron Lett., 1975, 16, 413;
L. Qiu, W. Hu, Y. Qian and X. Xu, Chem. Commun., 2019,
55, 6393; (c) K. Hong, H. Su, C. Pei, X. Lv, W. Hu, L. Qiu
and X. Xu, Org. Lett., 2019, 21, 3328; (d) Q. Zeng, K. Dong,
J. Huang, L. Qiu and X. Xu, Org. Biomol. Chem., 2019, 17,
2326; (e) K. Dong, C. Pei, Q. Zeng, H. Wei, M. P. Doyle and
X. Xu, ACS Catal., 2018, 8, 9543.
(h) E. Georgescu, A. Nicolescu, F. Georgescu, F. Teodorescu, 19 D. Dumitrescu, E. Georgescu, M. R. Caira, C. Draghici and
D. Marinescu, A. M. Macsim and C. Deleanu, Beilstein
J. Org. Chem., 2014, 10, 2377.
17 For a review: C. Pei, C. Zhang, Y. Qian and X. Xu, Org.
Biomol. Chem., 2018, 16, 8677.
18 (a) C. Zhang, H. Li, C. Pei, L. Qiu, W. Hu, X. Bao and X. Xu,
ACS Catal., 2019, 9, 2440; (b) K. Dong, C. Pei, Q. Zeng,
F. Dumitrascu, Synlett, 2017, 28, 2241.
20 B. Wang, J. Hu, X. Zhang, Y. Hu and H. Hu, J. Heterocycl.
Chem., 2000, 37, 1533.
21 R. C. F. Jones, J. N. Iley, M. Sanchis-Amat, X. Zhang,
V. McKee, S. J. Colesc and T. Gelbrichc, Chem. Commun.,
2011, 47, 7965.
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2019