Copper-catalyzed synthesis of 2,3-disubstituted indoles from ortho-haloanilines and β-keto esters/β-diketone

Article abstract of DOI:10.1016/j.tet.2015.12.006

Tetrazole-1-acetic acid was identified as an efficient ligand to promote copper-catalyzed domino reaction of ortho-iodo/bromo-anilines with β-keto esters/β-diketone for 2,3-disubstituted indoles' synthesis with high yields under mild conditions. The proto

Full text of DOI:10.1016/j.tet.2015.12.006

Accepted Manuscript
Copper-catalyzed synthesis of 2,3-disubstituted indoles from ortho-haloanilines and
β-keto esters/β-diketone
Xiao-Guang Liu, Zi-Hao Li, Jian-Wei Xie, Ping Liu, Jie Zhang, Bin Dai
PII:
S0040-4020(15)30259-3
10.1016/j.tet.2015.12.006
TET 27332
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 4 September 2015
Revised Date: 25 November 2015
Accepted Date: 2 December 2015
Please cite this article as: Liu X-G, Li Z-H, Xie J-W, Liu P, Zhang J, Dai B, Copper-catalyzed synthesis of
2,3-disubstituted indoles from ortho-haloanilines and β-keto esters/β-diketone, Tetrahedron (2016), doi:
10.1016/j.tet.2015.12.006.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Copper-catalyzed synthesis of 2,3-
Leave this area blank for abstract info.
disubstituted indoles from ortho-haloanilines
and β-keto esters/β-diketone
Xiao-Guang Liu, Zi-Hao Li, Jian-Wei Xie , Ping Liu, Jie Zhang and Bin Dai
School of Chemistry and Chemical Engineering/Key Laboratory for Green Processing of Chemical Engineering
of Xinjiang Bingtuan, Shihezi University, North 4th Road, Shihezi 832003, China

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Copper-catalyzed synthesis of 2,3-disubstituted indoles from ortho-haloanilines and
β-keto esters/β-diketone
Xiao-Guang Liu, Zi-Hao Li, Jian-Wei Xie , Ping Liu, Jie Zhang and Bin Dai
School of Chemistry and Chemical Engineering/Key Laboratory for Green Processing of Chemical Engineering of Xinjiang Bingtuan, Shihezi University, North
th Road, Shihezi 832003, China
4
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Tetrazole-1-acetic acid was identified as an efficient ligand to promote copper-catalyzed domino
reaction of ortho-iodo/bromo-anilines with β-keto esters/β-diketone for 2,3-disubstituted indoles
synthesis with high yields under mild conditions. The protocol, with easy-available catalytic
system, shows good substrate tolerance towards various functional groups.
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
2,3-Disubstituted indoles
Copper
Domino reaction
Tetrazole-1-acetic acid
ortho-Haloanilines
1. Introduction
example, Ma et al. reported L-proline-assisted CuI-catalyzed
cross-coupling of 2-halotrifluoroacetanilides with β-keto esters or
β-ketone amides for the preparation of 2,3-disubstituted indoles.5
Meanwhile, Tanimori et al. proved that CuI/BINOL was an
effective catalytic system for these transformation.6 However, the
reaction is only limited to 2-iodoaniline, and substituted 2-
iodoanilines or 2-bromoanilines were not explored. Ligand-free
copper-mediated assemble 2,3-disubstituted indoles have also
been demonstrated, but with relatively high temperature (100-
130 °C) and narrow substrates scopes (lower yields for 2-
bromoanilines).7 Although some progresses have been made, we
believe such an interesting area is worthy of further exploration.
Indole motifs are present in a wide variety of substances
commonly found in nature and are known to be important
building blocks of numerous pharmaceuticals and agrochemicals,
which possess biological and pharmacological activities.
Moreover, over 200 are currently marked as drugs or undergoing
clinical trials.1 Considering the high importance of indole
derivatives and their wide applications, their preparation has
always been a hot topic in organic synthesis. Over the past few
decades, remarkable efforts have been made to develop novel and
efficient approaches for the construction of functionalized
indoles.1,2 Compared with Fisher indole synthesis (a classical
synthetic method for indole synthesis, starting from hydrazine)
first reported in 18833, transition-metal-catalyzed (especial for
copper and palladium) reactions have been considered as an
powerful and practical alternative strategies, such as C-H
activation reactions, cross-dehydrogenative coupling (CDC)
reactions, Buchwald indole synthesis and others.4
In recent years, we have been interested for some time in the
improvement and exploration of methodologies for Ullmann-type
C-N coupling reactions8 and their applications on the synthesis of
nitrogen-containing heterocycles9. We previously found that
tetrazole-1-acetic acid (TZA) was an efficient ligand for CuI-
based C-N coupling reaction of imidazoles with aryl iodides.8b
The catalytic activity and stability of the catalytic system maybe
mainly attributed to the excellent coordination capability of this
ligand with Cu(I) in this processes. As an extension, we herein
report a simple, convenient copper-catalyzed direct synthesis of
2,3-disubstituted indoles via domino reaction of ortho-
haloanilines with1,3-dicarbonyl compounds using TZA as the
ligand.
With respect to the above-mentioned indole syntheses,
“copper-ligand”-catalyzed domino reaction of 2-haloaniline with
1,3-dicarbonyl compounds is one of the attractive processes for
2,3-disubstituted indoles synthesis due to the diversity of
commercial available starting materials. And the ligands that
coordinate to the metal center play an important role in
improving the reaction efficiency and generality of catalyst
systems employed in copper-based cross-coupling reactions. For
———
Corresponding author. Tel.: +86-993-205-7213; fax: +86-993-205-7270; e-mail: cesxjw@foxmail.com

2
Tetrahedron
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2. Results and discussion
16
CuI
L4 Cs2CO3 H2O
120
120
120
100
80
18
17
18
19
20
21
CuI
CuI
CuI
CuI
CuI
L4 Cs2CO3 DMSO
L4 Cs2CO3 DMSO
L4 Cs2CO3 DMSO
L4 Cs2CO3 DMSO
L4 Cs2CO3 DMSO
81c
91d
92d
92d
70d
Initially, 2-iodoaniline (1a) and ethyl acetylacetate (2a) were
selected as model substrates to optimize the reaction conditions,
including copper species, ligands, bases, solvents and reaction
temperatures. The results are summarized in Table 1.
Investigation into the ligands revealed that the highest yield was
obtained when L4 was employed as the ligand, whereas lower
yield observed in the absence of ligands (entries 1-5). Among the
different copper sources evaluated, CuI was found to be the best
choice, and no reaction occurred without copper sources (entries
6-10). With the favorable ligand and copper source in hand, we
next screened the bases and solvents, and the observations
indicated that Cs2CO3 was the best base and DMSO was the most
suitable solvent for the catalytic reactions (entries 11-16), but
only 45% yield was obtained. Fortunately, the reaction yield
significantly improved up to 81%, when the substrate 2a was
increased from 1.5 equivalents to 4 equivalents (entry 17). This
might be due to the fact that the enhancement of substrate
concentration hampered the dehalogenation of 1a, and it was
determined by GC-MS analysis. A further increasing the ratios of
2a/1a results in further higher yield (91%, entry 18). It is
noteworthy that the same result obtained when lowering the
reaction temperature from 120 °C to 100 °C even to 80 °C
(entries 18-20). However, lower yield was observed when the
reaction temperature was further decreased to 60 °C (entry 21).
In summary, the results of the preliminary exploratory
investigations described above revealed that the optimal
conditions for the model reaction consist of CuI (10 mol%), L4
(20 mol%), Cs2CO3 (2 equiv.), and ethyl acetylacetate (6 equiv.)
in DMSO (1 mL) at 80 °C for 12h under air.
60
a
Reaction conditions: [Cu] (0.05 mmol), ligand (0.1 mmol),
base (1.0 mmol), ortho-iodoaniline (0.5 mmol), ethyl
acetylacetate (0.75 mmol), 12 h.
b Isolated yields.
c Ethyl acetylacetate (2.0 mmol).
d Ethyl acetylacetate (3.0 mmol)
With this efficient CuI/L4 catalytic system in hand, we
initially extended the scope of the substrate to various ortho-
iodoanilines derivatives and 1,3-dicarbonyl compounds. The
results are shown in Table 2. For β-keto esters, we were found
that most of substrates 2, including linear and branched chain
(3a-e), and cyclopropyl substituent (3f), worked well to afford
the corresponding 2,3-disubstituted indoles in 61-92% yields. But,
the reactions seemed to be sensitive to the steric hindrance on the
β-keto esters. For example, no desired product was detected
when ethyl 4,4-dimethyl-3-oxopentanoate was reacted with 2-
iodoaniline under the optimal conditions (3g), and only 56% and
46% yields were obtained, respectively, when aromatic rings
bearing the ethyl β-keto esters (3h and 3i). On the contrary, C-
arylated products were isolated in 70%, 38% and 49% yields
(3g’-i’). However, the yields of desired indole products 3h and 3i
could be increased with increasing the reaction temperature to
100 °C or 120 °C, which indicated that higher temperature was
benefit to the cyclization reactions. We were pleased to find the
reaction occurred well with acetylacetone in 90% yield (3j). For
2-iodoanilines, both electron-donating and electron-withdrawing
groups, except for nitro group, on the aromatic motifs could
smoothly be converted to the desired products in good to
excellent yields (3k-q). Additionally, the reaction of 3-
iodopyridin-2-amine gave the heteroindole in 43% yield (3r).
Furthermore, the reaction with unsymmetrical diketone produced
a mixture of regioisomers of 2-methylindole ketone and 2-
ethylindole ketone (ratio=10:7) in 88% isolated yield (3s).
Table 1Optimization of reaction conditionsa
Entry [Cu]
L
Base
Solvent T/°C Yield (%)b
1
CuI
CuI
CuI
CuI
CuI
L1 Cs2CO3 DMF
L2 Cs2CO3 DMF
L3 Cs2CO3 DMF
L4 Cs2CO3 DMF
120
120
120
120
120
120
120
120
120
120
120
120
120
120
20
21
24
40
15
9
2
Table 2 CuI/L4-catalysed synthesis of 2,3-disubstituted
indoles from ortho-iodoanilines and β-keto esters/β-diketone
under mild conditions.a
3
4
5
-
Cs2CO3 DMF
6
CuSO4 L4 Cs2CO3 DMF
7
CuBr
Cu2O
CuO
-
L4 Cs2CO3 DMF
L4 Cs2CO3 DMF
L4 Cs2CO3 DMF
L4 Cs2CO3 DMF
25
15
10
0
8
9
10
11
12
13
14
15
3a, 92%
3d, 92%
3b, 75%
3e, 76%
3c, 87%
3f, 61%
CuI
CuI
CuI
CuI
CuI
L4 K3PO4
L4 Na2CO3 DMF
L4 KOH DMF
L4 Cs2CO3 DMSO
L4 Cs2CO3 Dioxane 120
DMF
18
8
23
45
16

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3g, 0% (3g’, 70%)b
3g, 0% (3g’, 71%)c
3g, 0% (3g’, 74%)d
3h, 56% (3h’,
3i, 46% (3i’, 49%)b
3d, 72%
3m, 78%
3j, 71%
38%)b
a
Reaction conditions: CuI (0.05 mmol), L4 (0.1 mmol),
Cs2CO3 (1.0 mmol), ortho-bromoaniline (0.5 mmol), β-keto
ester/β-diketone (3.0 mmol), 80 °C, 36 h. Isolated yields.
3h, 62% (3h’,
3i, 50% (3i’, 47%)c
3i, 68% (3i’, 21%)d
35%)c
b 100 °C, 12 h.
c 120 °C, 12 h.
3h, 70% (3h’,
28%)d
Although 2-bromoanilines are less reactive than 2-
iodoanilines, the domino reactions of bromo derivatives were
also efficiently carried out using the CuI/L4 catalytic system, and
various ortho-bromoanilines and β-keto esters/β-diketone were
tolerated to give indoles in 66-78% yields with only prolonging
the reaction time to 36 h (Table 3). Meanwhile, the same yields
were also obtained in 12 h, when the reaction temperature was
increased to 100 °C or 120 °C. Unfortunately, the reaction for
ortho-chloroaniline under these conditions is still a challenge.
Based on previous literature reports7a,10 and our experimental
results, a possible mechanism composed of two catalytic paths of
the CuI/L4-calalyzed reaction of ortho-haloanilines with β-keto
esters/β-diketone is proposed and shown in Scheme 1. In path A,
the chelating CuI with TZA formed reactive species I, and the
subsequent oxidative addition of I with imine 4, which generated
from the condensation of 1 and 2, provided Cu(III)-complex II.
In the presence of Cs2CO3, the intramolecular nucleophilic
substitution of intermediate II gives III, followed by reductive
elimination led to desired indoles derivatives 3a-s and regenerate
the active Cu(I) species I. In path B, because of steric hindrance
on the β-keto esters, the oxidative addition was occurred between
the chelating I and 1 to provide IV, and exchanged of X with 2
gave V. Reduction-elimination of V led to 3g’-i’ and I.
3j, 90%
3m, 80%
3p, 87%
3k, 90%
3n, 74%
3q, 88%
3l, 83%
3o, 32%
3r, 43%
(3s), 88%e
Reaction conditions: CuI (0.05 mmol), L4 (0.1 mmol),
Cs2CO3 (1.0 mmol), ortho-iodoaniline (0.5 mmol), β-keto
ester/β-diketone (3.0 mmol), 80 °C, 12 h. Isolated yields.
a
3. Conclusion
In conclusion, we have established for the first time tetrazole-
1-acetic acid as an ideal ligand for promoting CuI-catalyzed
domino reaction of ortho-haloanilines with β-keto esters/β-
diketone for 2,3-disubstituted indoles synthesis without the
protection by an inert gas. A variety of ortho-iodo/bromo-
anilines and β-keto esters/β-diketone could be reacted well to
produce the target products with high yields. The good substrate
tolerances, simple and cheap catalytic system in combination
with experimental ease, render this method viable for use in
industrial and academic research.
b C-arylated products.
c 100 °C.
d 120 °C.
e
A mixture of 2-methylindole isomer and 2-ethylindole
isomer (3s) (ratio=10:7), determined by 1H NMR spectroscopy.
Table 3 CuI/L4-catalyzed synthesis of 2,3-disubstituted
indoles from ortho-bromoanilines and β-keto esters/β-
diketone under mild conditions.a
4. Experimental
4.1. General
Unless otherwise stated, all reagents were purchased from
commercial suppliers and used without further purification.
Column chromatography was performed with silica gel (200-300
mesh) purchased from Qingdao Haiyang Chemical Co. Ltd.
Thin-layer chromatography was carried out with Merck silica gel
GF254 plates. All 2,3-disubstituted indoles are characterized by 1H
NMR, 13C NMR and MS, which were compared with the
previously reported dates. H NMR and 13C NMR spectra were
1
3a, 72%, 77%b,
3b, 66%
3c, 71%
recorded at room temperature on a Varian Inova-400 instrument
74%c
1
at 400 MHz for H NMR and 100 MHz for 13C NMR. Mass
spectra were recorded on GC-MS (Agilent 7890A/5975C)
instrument under EI model or LC-MS (Shimadzu LCMS-2010A)

4
Tetrahedron
X
ACCEPTED MANUSCRIPXT
COR3
R2
COR3
+
condensation
NH2
N
4
O
R2
R1
R1
1
2
3a-s
3g'-i'
COR3
R2
III
CuL COR3
III
CuL
N
III
R2 reductive
elimination
reductive
elimination
O
R1
NH2
R1
V
[ICuL]
I
CsX
Path B
Path A
CsX
2
oxidative
addition
oxidative
addition
X
III
X
IIICuL
CuL COR3
Cs2CO3
4
1
Cs2CO3
N
II
R2
R1
NH2
R1
IV
O
L-=
L-
-I-
N
N
[LICuI]-
[ICuL]
I
ICuI
N
N
O
Scheme 1. Plausible reaction mechanism.
Compd. 2015, 51, 4-16; (g) Guo, T.; Huang, F.; Yu, L.; Yu, Z.
Tetrahedron Lett. 2015, 56, 296-302; (h) Zi, W.; Zuo, Z.; Ma, D.
Acc. Chem. Res. 2015, 48, 702-711; (i) Feng, Y.; Zhang, H.;
Cheng, G.; Cui, X. Chin. J. Org. Chem. 2014, 34, 1499-1508; (j)
Bartoli, G.; Dalpozzo, R.; Nardi, M. Chem. Soc. Rev. 2014, 43,
4728-4750.
instrument under ESI model. MALDI-TOF-MS data were
obtained on a Bruker BIFLEX III TOF mass spectrometer.
4.2. Typical procedure for the synthesis of 2,3-disubstituted
indoles 3a-3t
3. Fischer, E.; Jourdan, F. Ber. Dtsch.Chem. Ges. 1883, 16, 2241-
2245.
To a 10 mL of sealed tube was added CuI (0.05 mmol), L4
(0.1 mmol), ortho-iodo/bromoaniline (0.5 mmol), β-keto ester/β-
diketone (3.0 mmol), Cs2CO3 (1.0 mmol) and DMSO (1 mL).
The reaction mixture was reacted at 80 °C in a preheated oil bath
4. Yan, H.; Wang, H.; Li, X.; Xin, X.; Wang, C.; Wan, B. Angew.
Chem. Int. Ed. 2015, 54, 10613-10617 and references cited therein.
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(b) Chen, Y.; Wang, Y.; Sun, Z.; Ma, D. Org. Lett. 2008, 10, 625-
628.
6. Tanimori, S.; Ura, H.; Kirihata, M. Eur. J. Org. Chem. 2007,
3977-3980.
7. (a) Ali, M. A.; Punniyamurthy, T. Synlett 2011, 623-626; (b)
Okuro, K.; Furuune, M.; Miura, M.; Nomura, M. J. Org. Chem.
1993, 58, 7606-7607; (c) Suzuki, H.; Thiruvikraman, S. V.; Osuka,
A. Synthesis 1984, 616-617.
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for 12
h (for ortho-iodoanilines) or 36 h (for ortho-
bromoanilines). The reaction mixture was cooled to room
temperature, extracted with ethyl acetate (3×20 mL). The
combined organic phases was washed with water and brine, dried
over anhydrous Na2SO4, and concentrated in vacuo. The residue
was purified by flash column chromatograph on silica gel (ethyl
acetate/petroleum ether as the eluent) to afford the target
products 3a-3t.
Acknowledgments
We gratefully thank the National Basic Research Program of
China (973 Program, no. 2012CB722603), the NSFC
(no.21463022) and Training Program for Distinguished Youth
Scholars of Shihezi University (no. 2014ZRKXJQ05) for their
financial support.
References and notes
1. S. M. Bronner, S. M.; Im, G. Y. J.; Garg, N. K. Heterocycles in
Natural Product Synthesis, Wiley-VCH Verlag GmbH & Co.
KGaA, 2011.
2. For some selected recent reviews, see: (a) Yoshikai, N.; Wei, Y.
Asian J. Org. Chem. 2013, 2, 466-478; (b) Praveen, P. J.;
Parameswaran, P. S.; Majik, M. S. Synthesis 2015, 47, 1827-1837;
(c) Bartoli, G.; Dalpozzo, R.; Nardi, M. Chem. Soc. Rev. 2014, 43,
4728-4750; (d) Zhang, B.; Studer, A. Chem. Soc. Rev. 2015, 44,
3505-3521; (e) Xu, W.; Gavia, D. J.; Tang, Y. Nat. Prod. Rep.
2014, 31, 1474-1487; (f) Gupta, N.; Goyal, D. Chem. Heterocycl.
Supplementary Material
Supplementary materials (1H, 13C NMR and HRMS data plus
their copies) associated with this article can be found in the
online version, at http://