Ga(DS)3-catalysed double hydroarylation of acetylenic esters with indoles for the synthesis of bisindolyl propanoates

Article abstract of DOI:10.1016/j.tetlet.2015.05.024

Abstract An efficient synthetic method for bisindolyl propanoates has been developed. Ga(DS)₃-catalysed double hydroarylation of acetylenic esters with indoles in water afforded regioselective products with up to 99% yield.

Full text of DOI:10.1016/j.tetlet.2015.05.024

Tetrahedron Letters 56 (2015) 3996–3998
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Tetrahedron Letters
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Ga(DS)3-catalysed double hydroarylation of acetylenic esters with
indoles for the synthesis of bisindolyl propanoates
c,
Li-Tao An a,b, Jing-Jing Cai b, Xiang-Qiang Pan b, Tang-Ming Chen b, Jian-Ping Zou b, , Wei Zhang
⇑
⇑
a College of Chemistry and Chemical Engineering, Huaiyin Normal University, Huaian, 111 West Changjiang Road, Huai’an, Jiangsu 223300, China
b College of Chemistry, Chemical Engineering and Material Science, Soochow University, Suzhou, 199 Ren’ai Road, Suzhou, Jiangsu 215123, China
c Department of Chemistry, University of Massachusetts Boston, 100 Morrissey Boulevard, Boston, MA 02125, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthetic method for bisindolyl propanoates has been developed. Ga(DS)3-catalysed double
Received 2 March 2015
Revised 5 May 2015
Accepted 7 May 2015
Available online 16 May 2015
hydroarylation of acetylenic esters with indoles in water afforded regioselective products with up to 99%
yield.
Ó 2015 Published by Elsevier Ltd.
Keywords:
Hydroarylation
Indole
Water
Bisindolyl propanoate
Water-tolerant Lewis acid
Indole is a privileged scaffold for N-containing heterocyclic
compounds.1 Among the indole derivatives, bisindolyl methanes
(BIMs) or diindolyl methanes (DIMs) have a wide range of biolog-
ical and pharmaceutical utilities (Fig. 1).2 For example, compound I
is for promoting beneficial estrogen metabolism in the human
body,2a compound II for the treatment of fibromyalgia2b and
compounds III–VI targeting multiple components of cancer cell
cycle regulation.2c–f Acid or base-promoted Friedel–Crafts
alkylation of indole with carbonyl compounds is a common
method for the synthesis of BIMs.3 Double hydroarylation of alky-
nes with indoles is another method.4 Metal catalysts of Pd,4a Pt,4b
Au,4c Cu(II)4d and Fe(III)4e have been used to promote the double
hydroarylation reactions. Even though, selective mono5 and dou-
ble4d–g hydroarylation is still a challenge.
The development of catalytic reactions in water is a topic of
green chemistry.6 The Hajela group reported the hydroarylation
of alkynone with indole in the presence of tetrabutylammonium
iodide (TBAI) in dimethyl sulfoxide with 10% aq NaOH to afford
mono hydroarylation product in moderate yield.5a To the best of
our knowledge, there are no reports on hydroarylation of alkynes
in aqueous media. As part of our continuous effort in the study
of gallium(III) salt catalysis7a–c and exploring environmentally
benign synthesis,7d we report here the hydroarylation of
acetylenic esters in aqueous phase using a water-tolerant Lewis
acid as a catalyst.
Indole 1a and ethyl propiolate 2a were used as the substrates for
the development of reaction conditions and catalyst screening
(Table 1). When the reactants were stirred with gallium triflate in
acetonitrile, the reaction gave a complicated mixture in 5 min
(Table 1, entry 1). Using other solvents, such as dichloromethane,
toluene, and 1,2-dichloroethane also did not give satisfactory
results (Table 1, entries 2–4). No product was detected from the
reaction in water (Table 1, entry 5). Because gallium triflate is a
strong Lewis acid,8 we then tried relatively weak Lewis acid gallium
iodide as a catalyst. The reaction in dichloromethane also gave a
complicated mixture (Table 1, entry 6). Until gallium dodecyl sul-
fate (Ga(DS)3) was used as a catalyst and water as a solvent, we
observed the formation of product. After screening the reaction time
(12–96 h), temperature (25–70 °C) and amount of the catalyst
(5–10 mol %) (Table 1, entries 7–10), we found that using 5 mol %
Ga(DS)3 catalyst in water at 70 °C for 18 h is an optimized reaction
condition which gave dihydroarylation product in a quantitative
yield (Table 1, entry 10). Using sodium dodecyl sulfate (SDS) as a
catalyst was also attempted (Table 1, entries 11 and 12), but product
yields were lower than that using Ga(DS)3 as a catalyst. The product
generated from the Ga(DS)3-catalysed reaction in H2O could be pre-
cipitated out from the reaction mixture at room temperature, but it
still contained some impurities. Since recrystallization of the crude
product from aqueous ethanol might cause a significant amount
⇑
Corresponding authors. Fax: +86 (512) 65880335 (J.-P.Z.), +1 (617) 2876030
(W.Z.).
E-mail addresses: jpzou@suda.edu.cn (J.-P. Zou), wei2.zhang@umb.edu
(W. Zhang).
http://dx.doi.org/10.1016/j.tetlet.2015.05.024
0040-4039/Ó 2015 Published by Elsevier Ltd.

L.-T. An et al. / Tetrahedron Letters 56 (2015) 3996–3998
3997
MeO
Me
NH
NH
NH
MeO
N
H
N
H
N
H
I
III
II
H
N
O
NH
NH
HN
NH
NH
N
H
N
H
N
H
IV
V
VI
Figure 1. Biologically interested BIM compounds.
Table 1
Table 2
Optimization of reaction conditions
Ga(DS)3-catalysed synthesis of bisindoly propanoates
R1
NH
5 mol%
NH
Ga(DS)3
CO2R2
catalyst
solvent
2
CO2R2
+
+
CO2Et
N
H
H2O
R1
N
H
HN
70 oC, 18h
CO2Et
1
2
3
R1
HN
1a
2a
3a
NH
NH
NH
Entry
1a:2aa
Catalystb
Solvent
T (°C)
T (h)
Yieldc (%)
NH
CO2Et
1
2
3
4
5
6
7
8
1:1
1:1
1:2
1:2
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
Ga(OTf)3
Ga(OTf)3
Ga(OTf)3
Ga(OTf)3
Ga(OTf)3
GaI3
CH3CN
CH2Cl2
C6H5CH3
Cl(CH2)2Cl
H2O
CH2Cl2
H2O
H2O
H2O
H2O
H2O
H2O
25
25
25
25
25
25
25
70
70
70
70
70
0.08
12
12
12
24
12
96
18
12
18
18
24
Messy
Messy
Messy
Messy
n.r.
Messy
90
99
87
99
63
88
CO2Et
CO2Et
CO2Et
H
N
HN
HN
HN
3a,99%
3b, 94%
3d, 35%
3c,98%
110oC, 92%
Ga(DS)3
Ga(DS)3
Ga(DS)3
NH
NH
NH
NH
Br
9
d
10
11
12
Ga(DS)3
CO2Et
CO2Et
CO2Et
CO2Et
SDS
SDS
HN
HN
HN
HN
a
b
c
Molar ratio, 1 mmol indole was used.
10 mol %.
Isolated yield.
5 mol %.
Br
3e,65%
3f, 35%
3g, 84%
3h
48h, 34%
105oC, 96%
Br
110oC, 95%
50oC, 95%
d
NH
N
NH
NH
Br
loss of the product, flash column chromatography was employed for
purification. The double hydroarylation product 3a was fully char-
acterized by 1H NMR, 13C NMR, D2O exchange, and HRMS analysis.
The scope of the double hydroarylation was examined using a
series of substituted indoles (Table 2). Under the optimized condi-
tion developed for the synthesis of 3a, reactions of 2-methylindole
and 5-methylindole gave corresponding bisindolyl propanoates 3b
and 3c in high yields. It is noteworthy that the reaction of
3-methylindole occurred at the 2-position to give 3d, which could
be formed by initial attack at C-3 followed by a 1,2-shift of the
intermediate cation.9 The reactions of 3-methylindole, 7-methylin-
dole and 5-bromoindole have to be performed at higher
temperatures (105–110 °C) to give better yields for products 3d,
3e and 3f. The reaction of 6-methylindole is an exception. Due to
the side-reaction at a higher temperature, product 3g was obtained
in a better yield at a lower temperature (50 °C). Another interesting
observation was that the reaction of 4-methylindole gave 3h only
in 34% yield at 70 °C even for 48 h. A significant amount of starting
material was recovered from this reaction mixture. The electronic
effect of the substitution groups on the indole ring was evaluated.
CO2Et
CO2Me
HN
CO2Me
CO2Me
HN
Br
N
HN
Br
3i, 35%
3j, 35%
36 h, 40%
3k,97%
3l, 99%
100oC, 72 h, 85%
Comparing product 3f which was derived from 5-bromoindole
with product 3i which was derived from 5,7-dibromoindole, the
reaction for the latter required a higher temperature and longer
reaction time, because it has two electron-withdrawing bromo
groups attached to the indole ring. The H-bond donor character
of the indole NH group may play an important role in the catalyst
system. The reaction of methyl propiolate 2b with 1-methylindole
gave 3j in a low yield (40%), but it has good reactivity and regios-
electivity with indoles 1 to afford double hydroarylation products
3k and 3l.

3998
L.-T. An et al. / Tetrahedron Letters 56 (2015) 3996–3998
5 mol%
Ga(DS)3
References and notes
O
+
+
Ph
n.r
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N
H
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Ph
1a
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2c
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MeO2C
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70 oC, 36 h, 35%
Scheme 1.
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Reactions of disubstituted alkynes were also attempted. The
reaction of alkynone 2c did not give expected hydroarylation pro-
duct (Scheme 1A). Interestedly, monohydroarylation product 4a
was produced in low yield from the reaction of dimethyl
acetylenedicarboxylate 2d (Scheme 1B). In a similar work reported
by the Sarioz group,4h a double hydroarylation product was
observed in the presence of Montmorifor K10. The steric
hindrance of the diester and mild catalytic activity of Ga(DS)3 may
be responsible for the formation of only monohydroarylation
product 4a.
In summary, we have developed a straightforward and efficient
method for the synthesis of bisindolyl propanoates via double
hydroarylation of indoles in water and using Ga(DS)3 as a catalyst.
This chemo- and regioselectivity reaction affords products with up
to 99% yield.
Acknowledgements
We thank financial support from the National Natural Science
Foundation of China (21172163, 21472133, 21375044), Natural
Science Foundation of the Jiangsu Higher Education Institution
(JHB2012-54, 12KJD150002), Science and Technology Department
of Jiangsu Province (No. BY2012144).
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.05.
024.