An efficient synthesis of indoles via a CuMgAl-LDH-catalyzed cyclization of 2-alkynylsulfonanilides

Article abstract of DOI:10.1016/j.tetlet.2018.09.009

A highly efficient method for the synthesis of indoles has been successfully developed via a CuMgAl-LDH-catalyzed intramolecular annulation reaction of 2-alkynylsulfonanilides. This CuMgAl-LDH catalyst features facile preparation, recovery, and reuse at l

Full text of DOI:10.1016/j.tetlet.2018.09.009

Accepted Manuscript
An efficient synthesis of indoles via a CuMgAl-LDH-catalyzed cyclization of
2-alkynylsulfonanilides
Sheng-Yan Zhang, Shan-Gang Sun, Yu-Shuang Guo, Xiao-Fan Lu, Dian-Shun
Guo
PII:
S0040-4039(18)31081-5
https://doi.org/10.1016/j.tetlet.2018.09.009
TETL 50248
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
28 July 2018
31 August 2018
3 September 2018
Please cite this article as: Zhang, S-Y., Sun, S-G., Guo, Y-S., Lu, X-F., Guo, D-S., An efficient synthesis of indoles
via a CuMgAl-LDH-catalyzed cyclization of 2-alkynylsulfonanilides, Tetrahedron Letters (2018), doi: https://
doi.org/10.1016/j.tetlet.2018.09.009
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Graphical Abstract
An efficient synthesis of indoles via a
CuMgAl-LDH-catalyzed cyclization of 2-
alkynylsulfonanilides
Leave this area blank for abstract info.
Sheng-Yan Zhang, Shan-Gang Sun, Yu-Shuang Guo, Xiao-Fan Lu and Dian-Shun Guo 

Tetrahedron
1
Tetrahedron Letters
An efficient synthesis of indoles via a CuMgAl-LDH-catalyzed cyclization of 2-
alkynylsulfonanilides
Sheng-Yan Zhang, Shan-Gang Sun, Yu-Shuang Guo, Xiao-Fan Lu and Dian-Shun Guo 
College of Chemistry, Chemical Engineering and Materials Science, Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in
Universities of Shandong, Shandong Normal University, Jinan 250014, P. R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A highly efficient method for the synthesis of indoles has been successfully developed via a
CuMgAl-LDH-catalyzed intramolecular annulation reaction of 2-alkynylsulfonanilides. This
CuMgAl-LDH catalyst features facile preparation, recovery, and reuse at least seven times
without a marked loss in the catalytic activity, as well as the unique dual activation. Moreover,
the crystal structures and Hirshfeld surface analysis of typical indole compounds were also
presented.
Available online
Keywords:
Indole
2009 Elsevier Ltd. All rights reserved.
2-Alkynylsulfonanilide
Cyclization reaction
CuMgAl-LDH catalyst
Hirshfeld surface analysis
Indoles, one of the most prevalent nitrogen-containing fused
heterocycles, are extensively found in natural products, bioactive
molecules and new functional materials.1 Especially, many indole
derivatives are important pharmaceuticals,2 involving arbidol,2c
bazedoxifene,2d pindolol,2e etc. (Fig. 1). Thus the development of
facile and practical strategies to construct indole scaffolds has
been attracting great interest over a century. A large number of
synthetic methods have been documented since the first practical
preparation of indole compounds by Fischer et al. in 1883,3 such
as the classical strategies,4 cyclization reactions,5-10 and multi-
component reactions.11 Thereinto the most popular method is the
intramolecular cyclization of 2-alkynylanilides under different
metal-,6 alkoxide-,7 fluoride-,8 TMG (tetramethylguanidine)-9, or
other reagents-10 catalyzed conditions (Scheme 1); while several
limitations involving harsh reaction conditions, recycle and
residual of catalyst still restrict its wide applicability. Therefore,
it is very significant to develop green, recyclable and efficient
catalysts for the indole synthesis.
Presently, layered double hydroxides (LDHs)12 have attracted
much attention largely because of their potential applications as
ion exchangers, adsorbents, catalysts or supports owing to their
high thermal stability, high dispersion and excellent catalytic
performance.13 To date, LDH-based heterogeneous catalysts have
been applied to various kinds of reactions for their recyclability,14
while there are no reports on the annulation of 2-alkynylanilides
to indoles using such catalysts, for which to activate either the
alkynyl function by some metals or the amino group by typical
bases could efficiently accelerate the reaction. In fact, only single
activation rather than dual activation was utilized to speed up the
cyclization reaction in most cases.6,7 Positively, the latter would
give rise to a better result.
Figure 1. Typical bioactive indole derivatives.
 Corresponding author.
E-mail: chdsguo@sdnu.edu.cn (D.-S. Guo)

2
Tetrahedron
Scheme 1. Strategies for synthesis of indoles via cyclization of 2-
alkynylanilides.
Entry
1
Cat
Cu/mol%
Solvent
DCE
T/°C
80
t/h
8
Yield/%b
Free
0
2
Cat-1
--c
20
DCE
80
8
11
50
We envisioned that some metal species implanted in the layers
of the LDHs could activate the alkynyl function to increase its
electrophilicity, while the abundant alkalinity of LDHs could
activate the amino group to improve its nucleophilicity, which
might make the cyclization reaction to indoles more effectively.
Herein, we smartly implanted Cu2+ species in the layers of the
MgAl-LDH to create CuMgAl-LDH heterogeneous catalysts that
can efficiently promote the cyclization of 2-alkynylanilides to
yield indoles (Scheme 1) with a broad substrate scope. Moreover,
the crystal structures and Hirshfeld surface analysis of the typical
indole compounds were also reported.
3
Cat-2A
Cat-2B
Cat-2A
Cat-2A
Cat-2A
Cat-2A
Cat-2A
Cat-2A
Cat-2A
Cat-2A
Cat-2A
Cat-1c
DCE
80
5
4
20
20
DCE
80
8
9
49
96
Dioxane
100
5
20
20
20
20
20
20
10
5
Toluene
100
100
100
45
12
1
90
98
98
98
99
99
99
99
6
NMP
H2Od
7
2
8
EtOH
EtOH
EtOH
EtOH
EtOH
7
9
65
1.5
0.3
0.4
0.8
10
11
12
13
14
80
To evaluate our hypothesis, three LDH-based catalysts MgAl-
LDH (Cat-1), CuMgAl-LDH (Cat-2A, 5.0% Cu, w/w; Cat-2B,
2.0% Cu, w/w) were facilely prepared by co-precipitation with a
double drop technique,15 and fully confirmed by powder XRD,
TEM and FT-IR techniques (Figs. S1-S3, ESI). Moreover, the
SEM-mapping image of Cat-2A showed that the distribution of
Cu2+ is uniformity (Fig. S4, ESI). The content of Cu in Cat-2A
determined by ICP is 4.62%, similar to the theoretical content in
the designed Cat-2A (Table S1, ESI). Their catalytic performance
was assessed by a model reaction: the cyclization of 2-
phenylethynylsulfonanilide 1a in DCE. As shown in Table 1,
when the cyclization reaction was carried out under the catalyst-
free condition, no indole 2a was monitored after a long reaction
time (Table 1, entry 1). In a control experiment, indole 2a was
obtained in 11% yield in the presence of Cat-1 (Table 1, entry 2).
This preliminarily proved that the catalytic performance resulted
from the alkalinity of MgAl-LDH. Furthermore, Cat-2A showed
the highest activity, giving the product 2a in 50% yield within 5
h (Table 1, entry 3), which may be ascribed to a dual-activation
effect of Cu2+ ions and bases in the CuMgAl-LDH. Note that the
Cu2+ ions played a key catalytic effect. Differing loadings of Cu2+
ions in the CuMgAl-LDH were also tested. When Cat-2B was
used, the reaction time was prolonged to 8 h (Table 1, entry 4).
So Cat-2A was chosen to optimize the other reaction conditions.
To optimize the cyclization reaction conditions, a series of
experiments were carried out. First, through extensive screening,
we found that EtOH is the best solvent for the cyclization
reaction among the solvents screened (Table 1, entries 3, 5-8 and
11). For example, the cyclization reaction can completed within
0.3 h under reflux conditions (Table 1, entry 11), giving indole
2a in 99% yield. Interestingly, water is also an excellent solvent
for this reaction when an appropriate PTC (TBAB) was utilized,
although the reaction time is longer (Table 1, entry 8). Next, to
elevate the temperature can markedly shorten the reaction time
(Table 1, entries 9-11). Finally, the loading of catalyst on the
cyclization reaction was also examined. To decrease the loading
of Cat-2A catalyst to 10 mol% and 5 mol%, the reaction in EtOH
needs 0.4 h and 0.8 h, respectively (Table 1, entries 12 and 13),
still giving 99% yields. Moreover, when Cat-1 was used, the
cyclization reaction is faster in EtOH than in DCE (Table 1,
entries 1 and 13). In brief, the optimized cyclization parameters
include: 10 mol% Cat-2A, EtOH solvent, and reflux conditions.
Table 1
80
80
--c
EtOH
80
0.4
20
a Reaction conditions: 1a (0.50 mmol), solvent (5 mL).
b Isolated yields.
c Amount of Cat-1 (Mg2+/mmol) equals that of Cat-2A (Mg2+ and Cu2+/mmol).
d TBAB (0.03 mmol) was needed.
Table 2
Scope of cyclization of 2-alkynylsulfonanilidesa
a Reaction conditions: 1 (0.50 mmol), Cat-2A (0.05 mmol), EtOH (5 mL).
b Isolated yields.
With the optimized cyclization conditions in hand, the scope
and generality of this methodology was evaluated by a majority
of 2-alkynylsulfonanilides 1. As demonstrated in Table 2, this
cyclization reaction could tolerate a variety of functional groups,
yielding the desired indole products 2a-2s in near quantitative
yields. The introduction of electron-withdrawing groups (2b-2f,
2j-2l, 2p, 2q and 2s) or electron-donating groups (2g, 2h and 2r)
to the N-aryl ring hardly influences the cyclization reaction yields.
Various substituents connected to the alkynyl function were also
assessed. It was found that the cyclization of substrates with an
aliphatic alkynyl group (2i-2n and 2s) proceeds slightly faster
Optimization of cyclization of 2-phenylethynylsulfonanilide 1aa

Tetrahedron
3
than those with a phenyl group (2a-2h and 2o-2r). For instance,
the annulation of 1k and 1l only needs 5 min, giving indoles 2k
and 2l with 99% yields. Moreover, to replace the protecting
group on nitrogen atom also altered the reaction speed. When the
tosyl (Ts) group was changed into the methanesulfonyl (Ms)
group, the reaction time was generally prolonged, but the yields
keep well (e.g. 2a and 2o). Meanwhile, the cyclization of acetyl
(Ac) protected substrate was tried under the standard reaction
conditions, unfortunately, no desired indole product (2t) was
formed after a long reaction time. All indoles prepared were fully
1
confirmed through H NMR, 13C NMR, 19F NMR and HR-MS
analyses (ESI).
To evaluate the reusability of Cat-2A, the cyclization reaction
of 2-alkynylsulfonanilide 1a was repeated under the optimized
conditions (ESI) and the results are shown in Fig. 2. It was found
that the catalytic performance of Cat-2A still keeps high after
seven cycles. All cyclization reactions proceeded smoothly and
gave the desired product 2a in almost the same yield as in the
first run, needless to reactivate the catalyst.
Figure 3. A plausible mechanism for CuMgAl-LDH-catalyzed
cyclization of 2-alkynylsulfonanilides.
To understand the precise morphology of indole derivatives 2,
the crystal structures of 2a, 2c, and 2f were assessed by single
crystal X-ray diffraction analysis (Table 1, Table S2 and Fig. S5,
ESI). In their crystal structures, the indolyl plane is not coplanar
with the phenyl ring at its 2 position, creating dihedral angles of
43.5 and 43.9° for 2a and 2f, respectively. The benzene ring of
the Ts leans toward the indolyl plane, yielding dihedral angles of
64.3 and 64.7° for 2a and 2f, respectively. However, for 2c, the
benzene ring of the Ts is almost perpendicular with the indolyl
plane, giving a dihedral angle of 76.9°. This may be contributed
to the influence of F atom at 6 position of the indole ring. In their
packing, the key interactions are intermolecular C–H···O
contacts (Table S6, ESI).
To wholly learn the crystal packing driving forces, the
Hirshfeld surfaces and fingerprint plots were further analyzed
with CrystalExplorer.16 The surfaces mapped with close contacts
between vicinal molecules for 2a, 2c and 2f are shown in Fig. 4
and Figs. S6-S8 (ESI). The main C–H···O interactions of three
indole compounds are all depicted as red spots, suggesting that
they play a key role in their crystal packing. And the deep red
spot in 2c can be assigned to the C–H···F hydrogen bond due to
the existence of the F group at 6 position of the indole ring.
Moreover, various pale red spots were observed in other
orientations, standing for the weaker C–H···π and π···π contacts
(ESI).
The 2D fingerprint plots and decomposition for the primary
intermolecular contacts (Figs. S9-S12, ESI) provide evidence of
the crystal packing driving forces for 2a, 2c and 2f. The relative
contributions of the intermolecular contacts to the Hirshfeld
surface areas are summarized in Fig. S13 (ESI). The main
intermolecular contacts involve weak H···H, C···H/H···C and
O···H/H···O interactions. They totally occupy 96.2, 79.3 and
85.2% in the packing of 2a, 2c and 2f, respectively, in which the
percentages of C···H/H···C contacts are 32.1, 19.7 and 23.1%,
and those of O···H/H···O contacts are 14.1, 14.4 and 22.6%. In
addition, the contribution of F···H/H···F contacts in 2c is 9.3%
for the existence of F atom, and results in the decrease of the
percentage of C···H/H···C contacts. The decreased percentage of
C···H/H···C contacts and the increased percentage of
O···H/H···O contacts in 2f can be ascribed to the existence of
nitro group.
Figure 2. Recyclability of Cat-2A for cyclization reaction of 1a.
Comprehensive analysis of the results shown in Table 1 and
Table 2 revealed that the CuMgAl-LDH owns the dual-activation
and high catalytic activity originated in its Cu2+ and alkalinity.
Thus, based on such observations together with some suggestions
documented in the literature,6e,7a a plausible mechanism for the
CuMgAl-LDH-catalyzed cyclization of 2-alkynylsulfonanilides
has been proposed (Fig. 3). First, the Cu(II) in the CuMgAl-LDH
coordinates with the CC triple bond of 1 to form Cu(II) complex
I, while the in-situ base in the CuMgAl-LDH abstracts an acidic
NH proton, yielding a sulfonanilide anion II. Next, the anion
attacks the activated CC triple bond in a nucleophilic reaction,
giving intermediate III. Finally, a proton transfer occurs between
the LDHH and III, creating the desired indole 2 and CuMgAl-
LDH catalyst. Obviously, the coordination of Cu2+ with the CC
triple bond can promote the electrophilicity of alkynyl function,
and the formation of anion may increase the nucleophilicity of
the sulfonamide. This dual-activation efficiently accelerates the
cyclization reaction of 2-alkynylsulfonanilides, forming indoles
with excellent yields.

4
Tetrahedron
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7.
Acknowledgments
We are grateful for the financial support from the National
Natural Science Foundation of China (No. 21372147).
Supplementary data
Supplementary data (ESI) available: Experimental procedures,
powder XRD, TEM, FT-IR, SEM, NMR spectra, HR-MS, X-ray
crystallography, and Hirshfeld surface analysis can be found in
ESI. Crystallographic data for the structures 2a, 2c and 2f have
been deposited with the Cambridge Crystallography Data Centre
(CCDC No. 1849708, 1849710 and 1849709, respectively).
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Tetrahedron
5
16. (a) Spackman, M. A.; Jayatilaka, D. Cryst. Eng. Comm., 2009, 11,
19–32; (b) Wolff, S. K.; Grimwood, D. J.; McKinnon, J. J.;
Jayatilaka, D.; Spackman, M. A. CrystalExplorer, 2007.

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Highlights:
1.
A green synthesis of indoles via CuMgAl-
LDH-catalyzed cyclization is reported
2.
preparation and unique dual activation
3. This method shows broad substrate
scope, mild conditions and high efficiency
CuMgAl-LDH catalyst features facile

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