Copper-Catalyzed Chemodivergent Cyclization of N-(ortho-alkynyl)aryl-Pyrrole and Indoles

Article abstract of DOI:10.1021/acs.orglett.0c01519

Herein, we described an efficient copper-catalyzed chemo-divergent tandem reaction of N-(ortho-alkynyl)aryl-pyrrole and (iso)indoles, delivering ring-fused N-heterocycles in good yields in an atom-economical manner. N-(ortho-alkynyl)aryl-pyrrole and indol

Full text of DOI:10.1021/acs.orglett.0c01519

pubs.acs.org/OrgLett
Letter
Copper-Catalyzed Chemodivergent Cyclization of N‑(ortho-
alkynyl)aryl-Pyrrole and Indoles
Tengfei Yao, Tong Xia, Wei Yan, Haofeng Xu, Fang Zhang, Yuanjing Xiao, Junliang Zhang,*
and Lu Liu*
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ABSTRACT: Herein, we described an efficient copper-catalyzed
chemo-divergent tandem reaction of N-(ortho-alkynyl)aryl-pyrrole
and (iso)indoles, delivering ring-fused N-heterocycles in good
yields in an atom-economical manner. N-(ortho-alkynyl)aryl-
pyrrole and indoles undergo the tandem cyclization/migration
reaction, in which the group at 2-position was migrated to 3-
position. In contrast, the dearomative cyclization of N-(ortho-alkynyl)aryl-isoindoles would occur to deliver the N-fused tetracyclic
products efficiently.
itrogen-containing polycycles are widely present in
natural products, bioactive molecules, and materials.1
2,5-dione with 2-(phenylethynyl)aniline, under the catalysis of
p-TsOH, was selected as a model substrate. When the reaction
was catalyzed by Sc(OTf)3 in DCE at 90 °C for 12 h, the 1,3-
dimethyl-4-phenylpyrrolo[1,2-a]quinoline 2a via 6-endo-dig
cyclization and the sequential 1,2-migration of methyl group,
was observed in 16% NMR yield (Table 1, entry 1). The
possible 5-exo-dig reaction was not detected in the above-
mentioned condition. Encouraged by this result, we screened
several different triflate metal salts, including Bi(OTf)3,
In(OTf)3, and AgOTf, as well as Cu(OTf)2, in which
Cu(OTf)2 displayed the best catalytic efficiency, affording
the corresponding product 2a in the highest yield (see Table 1,
entries 2−6). The commonly used catalyst InCl3 for alkyne
cyclization reaction also worked in this transformation, but
giving the product 2a in only 48% NMR yield (Table 1, entry
7). Then, various copper salts with different counterion were
further tested, and all could not increase the yield, even under
higher temperature (Table 1, entries 8−11). Further solvent
screening, such as toluene, tetrahydrofuran (THF), and
dichloromethane (DCM), could not bring better results either
(Table 1, entries 12−16). In this transformation, Cu(OTf)2
should work as a π-acid to activate the carbon−carbon triple
bond, which could undergo the following nucleophilic addition
of the pyrrole ring.
N
Fused pyrrole derivatives, such as Valmerins, Hippadine,
alstorisine A, and Isoschizagaline, are often present many
useful bioacitivities.2 In addition, it is found that ring-fused
pyrroles have potential application in electronic devices, such
as OLEDs (organic light-emitting diodes) and OPVs (organic
photovoltaics), as well as energy conversion applications.3
With regard to the privileged existing and usefulness of fused
N-heterocycles, many efforts have been devoted to this
skeleton synthesis.4 Recently, the cycloisomerization of
(hetero)arenes with alkynes to construct cyclic scaffolds has
received much attention, because of its atom-economical
manner.5 In this context, the Friedel−Crafts6 cyclization of N-
(ortho-alkynyl)aryl-pyrrole and indoles represents one of the
most straightforward strategies to construct ring-fused pyrroles
and indoles (Scheme 1a), in which the group of 2-position was
limited to hydrogen and transferred to the β-position of alkyne
via protonation of the forming C-metal bond. The pioneering
work disclosed by Fu
including PtCl2, AuCl, GaCl3, InCl3, etc. were efficient for
̈
rstner showed that various metal salts
7
̈
achieving this type of transformation. Later, Gratzel, Bolm,
Shi, and others disclosed that several different Lewis acids and
Bronsted acids were efficient to catalyze this reaction.8 In
continuing with our interest in heterocycle synthesis and
alkyne chemistry,9 we wondered whether the R1 (R1 ≠ H)
group at the 2-position of pyrrole or indole would migrate to
the β-position of alkyne after the cyclization. We disclose
herein a copper-catalyzed regioselective and chemodivergent
tandem cyclization/migration10 or dearomative11 cyclization of
N-(ortho-alkynyl)aryl-pyrrole and (iso)indoles (Scheme 1b),
delivering various ring-fused N-heterocycles in good yields in
an atom-economical12 manner.
Next, the substrate scope of this tandem cyclization/
migration reaction was investigated (see Scheme 2). The
reactions of N-(ortho-alkynyl)aryl-pyrrole pyrroles 1b−1n
Received: May 3, 2020
2,5-Dimethyl-1-(2-(phenylethynyl)phenyl)-1H-pyrrole 1a,
which was readily available by the condensation of hexane-
https://dx.doi.org/10.1021/acs.orglett.0c01519
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Letter
a
Scheme 1. Intramolecular Cyclization of Pyrroles with
Alkynes To Access N-Fused Pyrroles Derivatives
Table 1. Optimization of Reaction Conditions
b
entry
catalyst
solvent
temperature, T (°C)
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Sc(OTf)3
Bi(OTf)3
In(OTf)3
Cu(OAc)2
AgOTf
Cu(OTf)2
InCl3
CuCl2
CuCl
CuBr
CuI
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
toluene
THF
DCM
Et2O
CH3CN
90
90
90
90
90
90
90
90
90
16
37
26
c
NR
29
99 (95)
48
27
NR
NR
NR
90
82
6
c
c
90
90
c
110
reflux
reflux
reflux
reflux
4
12
a
Reaction conditions: 1a (0.1 mmol), cat. (5 mol %), solvent (1 mL),
b
T °C. NMR yield; the number shown in parentheses is the isolated
yield. NR = no reaction.
c
A tetrasubstituted pyrrole derivative N-(ortho-alkynyl)aryl-
H-isoindole then attracted our attention. 3-Methyl-2-(2-
(phenylethynyl)phenyl)-2H-isoindole-1-carboxylate 5, which
could be easily synthesized from the cascade N−H insertion/5-
exo-dig cyclization of 2-(phenylethynyl)aniline with methyl 2-
diazo-2-(2-ethynylphenyl)acetate,13 was selected to test the
intramolecular cycloisomerization. Isoindole 5a underwent the
6-endo-dig cyclization/dearomatization cascade reaction cata-
lyzed by Cu(OTf)2, delivering the N-fused tetracyclic product
6a in 84% yield. As shown in Scheme 3, various substituents
and the end of alkynyl, aryl of aniline, and isoindole moiety had
no effect on this transformation, and the corresponding
cyclization/dearomatization products 6b−6n were obtained
in good to excellent efficiency. The bulky ester groups would
decrease the yield slightly, because of the steric hindrance (6o
and 6p).
were performed smoothly, which delivered the desired
products 2b−2n in excellent yields. These results indicated
that the different electron-nature aryl group bearing various
electron-withdrawing groups (EWGs) or electron-donating
groups (EDGs) at different sites of alkynyl moiety were
compatible. The R group could be aliphatic one, i.e., 1o, in
which the product 2o was given in 81% yield. It is noteworthy
that the cycloisomerization of terminal alkyne 1p succeeded via
abnormal anti-Markovnikov addition pathway, because of the
aromatic stability of product 2p. The substituent on N-aryl
moiety was also applicable to this transformation (2q). We
then examined the substituent effect on the migration via the
variation of different groups at the 2-positon of pyrrole. To our
delight, both alkyl and aryl groups were suitable for this
transformation, furnishing the desired cyclization/migration
products 2r−2w in excellent yields. Unsymmetric 2-methyl-5-
phenyl-pyrrole derived 1x was amenable to the cyclization
smoothly, giving the phenyl migration product 2x and methyl
migration product 2x′ in good yield with 2.4:1 regioselectivity.
Furthermore, N-(ortho-alkynyl)aryl-indoles 3a−3c were sub-
jected to this catalytic condition, giving the similar cyclization/
migration products 4a−4c in good to excellent yields. The
exact structure of product 2e was proved by single-crystal X-ray
analysis.
The polycyclic dihydroisoindolo[2,1-a]quinolone scaffold
could be also obtained directly from the starting 2-
(phenylethynyl)aniline with methyl 2-diazo-2-(2-
ethynylphenyl)acetate via double copper-catalyzed cyclo-
isomerization (Scheme 4), which provided a highly efficient
tool for polyheterocycle synthesis.
This copper-catalyzed tandem cyclization reaction is easy to
scale up. The reaction of 4.4 mmol of 1a was performed,
yielding the cyclization product 2a in 1.08 g and 90% yield
(Scheme 5). In order to examine the synthetic value of this
protocol, some transformations of 2a and 6a were also
performed (Scheme 5). Regioselective bromination of 2a with
Br2 led to dibromosubstituted product 7 with substitutions on
the 4-position of pyrrole ring and para-position of aniline,
which could occur via the following addition reaction with
benzaldehyde to give the monoalcohol 8 (Scheme 5b).
Meanwhile, the N-fused tetracyclic lactam 9 was obtained in
good yield via cleavage oxidation reaction of the CC double
B
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Scheme 2. Intramolecular Cyclization/Migration of Pyrroles
and Indoles
Scheme 3. Intramolecular Cyclization/Dearomatization of
Isoindoles
a
a
a
Unless otherwise noted, all reactions were carried out with 5 (0.4
mmol), Cu(OTf)2 (5 mol %) in DCE (2 mL) at 90 °C for 12 h.
b
Isolated yields.
Scheme 4. One-Pot Reaction
a
Unless otherwise noted, all reactions were performed with 1 or 3
(0.4 mmol), and Cu(OTf)2 (5 mol %) in DCE (2 mL) at 90 °C for
b
c
12 h. Isolated yields. Toluene instead of DCE at 110 °C.
Scheme 5. Gram-Scale Reaction and the Transformations of
Products
bond when the 6a was treated with m-CPBA. Note that the
formal [4 + 2] cycloaddition of 6a with o-QM proceeded
smoothly, giving the aza-spiroacetal 10 in 89% yield as a single
diastereoisomer. The structures of 9 and 10 were also proved
by the single-crystal X-ray analysis.
Finally, to further investigate the promising application of
the products, preliminary studies of the photophysical
characteristics of selected pyrrole products 2 were performed.
The results are summarized in Scheme 6 and Table S3 in the
Supporting Information. The fluorescence wavelengths of
these compounds ranged from 460 nm to 485 nm, and the
quantum efficiencies (Φ) ranged from 0.198 to 0.271. Then,
the absorption spectra of 2g in different solvents were also
recorded, which was observed to vary between 370 nm and
372 nm (see the Supporting Information for details).
Therefore, the absorption maxima of 2g in different solvents
did not change much.
byproduct-free access to various N-containing [5,6,6] tricycle
benzopyrrole cores. This transformation posed a broad scope
of substrates, mild conditions, atom and step economy, easy
operation, inexpensive catalysts, and facile transformations of
the products. While the efficiency and scope of the divergent
reaction remains to be further improved, the reaction mode
In summary, a chemodivergent intramolecular cascade
cyclization/1,2-migration or dearomatization of pyrrole de-
rivatives with alkynes has been realized, which offers a
C
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Letter
Yuanjing Xiao − School of Chemistry and Molecular
Scheme 6. Fluorescence Spectra of Pyrrolo[1,2-a]quinoline
2 in CH3CN
Engineering, East China Normal University, Shanghai 200241,
People’s Republic of China; orcid.org/0000-0002-0185-
1961
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01519
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (Nos. 21971066, 21772042, 21871093) and the
STCSM (No. 18JC1412300) for financial support.
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ASSOCIATED CONTENT
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https://pubs.acs.org/doi/10.1021/acs.orglett.0c01519.
Experimental procedures and characterization data
(PDF)
Accession Codes
CCDC 1936280−1936282 contain the supplementary crys-
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AUTHOR INFORMATION
Corresponding Authors
■
Junliang Zhang − Department of Chemistry, Fudan University,
Shanghai 200438, People’s Republic of China; orcid.org/
0000-0002-4636-2846; Email: junliangzhang@fudan.edu.cn
Lu Liu − School of Chemistry and Molecular Engineering and
Shanghai Engineering Research Center of Molecular
Therapeutics and New Drug Development, East China Normal
University, Shanghai 200241, People’s Republic of China;
orcid.org/0000-0003-2151-891X; Email: lliu@
chem.ecnu.edu.cn
Authors
Tengfei Yao − School of Chemistry and Molecular Engineering,
East China Normal University, Shanghai 200241, People’s
Republic of China
Tong Xia − School of Chemistry and Molecular Engineering,
East China Normal University, Shanghai 200241, People’s
Republic of China
Wei Yan − School of Chemistry and Molecular Engineering, East
China Normal University, Shanghai 200241, People’s Republic
of China
Haofeng Xu − School of Chemistry and Molecular Engineering,
East China Normal University, Shanghai 200241, People’s
Republic of China
Fang Zhang − School of Chemistry and Molecular Engineering,
East China Normal University, Shanghai 200241, People’s
Republic of China
D
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