Three-component synthesis of poly-substituted tetrahydroindoles through p-TsOH promoted alkoxylation

Article abstract of DOI:10.1016/j.tetlet.2013.04.029

Concise and efficient three-component domino reactions to highly substituted tetrahydroindole derivatives promoted by p-TsOH have been developed under microwave irradiation condition. The direct C3-alkoxylation of indole framework was achieved in a one-pot operation. The reaction proceeds at fast rates and can be finished within 30 min, which makes workup convenient to give good chemical yields.

Full text of DOI:10.1016/j.tetlet.2013.04.029

Tetrahedron Letters 54 (2013) 3176–3179
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Three-component synthesis of poly-substituted tetrahydroindoles through
p-TsOH promoted alkoxylation
⇑
⇑
Qing-Qing Shi , Li-Ping Fu , Yu Shi , Hua-Qin Ding , Jing-Hua Luo , Bo Jiang , Shu-Jiang Tu
School of Chemistry and Chemical Engineering, and Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials, Jiangsu Normal University, Xuzhou 221116,
PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Concise and efficient three-component domino reactions to highly substituted tetrahydroindole deriva-
tives promoted by p-TsOH have been developed under microwave irradiation condition. The direct C3-
alkoxylation of indole framework was achieved in a one-pot operation. The reaction proceeds at fast rates
and can be finished within 30 min, which makes workup convenient to give good chemical yields.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 11 February 2013
Revised 31 March 2013
Accepted 8 April 2013
Available online 15 April 2013
Keywords:
Tetrahydroindole synthesis
Alkoxylation
Multicomponent domino reactions
The functional indoles oxygenated in the 3-position skeletons
serve as ‘privileged structures’ in many biologically active molecules
and pharmaceutical substances;1 they have also been found in nat-
ural alkaloids, such as Indican2 and koniamborine3 (Fig. 1). In addi-
synthesis of natural and natural-like products,17 becoming one of
the key tools that allows the creation of several bonds in a one-
pot manner and offer remarkable advantages like convergence,
operational simplicity, and facile automation.18 These reactions not
only can enable constructing complex structures in a single opera-
tion but also avoid tedious isolation and purification work-up.
Among these methodologies, MDRs toward the formation of various
heterocycles have been extensively studied.19 However, more effi-
cient methodologies for the synthesis of azaheterocyclic products
from readily available reactants remain to be extremely challenging
in the fields of organic and medicinal chemistry.
Recently, we have developed a series of unique MDRs for the
construction of multiple functional ring structures of chemical
and pharmaceutical importance.20 As a result of our continuous ef-
fort on these domino processes, herein, we would like to disclose
another new p-TsOH promoted MDRs of enaminones 2 with aryl-
glyoxal monohydrate 1 in the presence of alcohols 3 yielding
poly-substituted tetrahydroindoles (Scheme 1). The unique charac-
teristic of the present domino reaction demonstrates that the
tion,
a variety of synthetic 3-alkoxyindoles exhibited various
biological activities, including reversible inhibitors of aminopepti-
dase N/CD13,4 tubulin polymerization inhibitors,5 selective seroto-
nin 5-HT2 receptor ligands,6 and 5-HT6 receptor ligand mimics.7
Moreover, they have been used in the development of COX-2 inhib-
itors8 as well as applied as Mcl-1 inhibitors in the design of novel
antitumor agents.9 Because of their unique chemical and biological
characteristics, many methodologies for the synthesis of 3-alkoxyin-
doles have been developed. Most of them involved Pd-catalyzed alk-
oxylation of 3-bromoindoles,9 Baeyer–Villiger oxidation sequence of
3-formylindoles,10 Ti- and Zn-mediated hydroamination of silyl-pro-
tected propargylic alcohol with arylhydrazine,11 palladium-cata-
lyzed domino cyclizations,12 rhodium-catalyzed insertion of 3-
diazoindole,13 and benzoylperoxide oxidation of N-alkylindoles,14
and so on.15 Despite these limited 3-oxyindole syntheses, an explo-
ration of a facile protocol for the direct construction of indole skele-
ton and its C3-alkoxylation would be highly favorable.
OH
HO
In organic synthesis, the high-efficient synthetic strategies reflect
the sum of enormous efforts aimed at atom-economic and environ-
mental aspects, and remarkable selective control of constructing
natural products or natural-like structures.16 Multi-component
domino reactions (MDRs) have been successfully applied to total
HO
OH
O
O
OR1
Ar'
O
O
MeO
R
N
N
R
O
N
Ar
H
⇑
Indican
Corresponding authors. Tel./fax: +86 516 83500065.
E-mail addresses: jiangchem@jsnu.edu.cn (B. Jiang), laotu@jsnu.edu.cn (S.-J. Tu).
Koniamborine
This work
These authors contributed equally to this work.
Figure 1. several representative natural products.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.04.029

Q.-Q. Shi et al. / Tetrahedron Letters 54 (2013) 3176–3179
3177
Table 1
O
O
OR1
Optimization of reaction conditions
O
p-TsOH
(1.0 equiv.)
OH
O
Ar
O
OEt
Ar
R
+
+
R1OH
R
N
80 °C
MW
NH
Ar'
R
O
OH
MW
R
Ar'
Ph
+
NH
EtOH
+
OH
OH
1a
N
Ph
1
2
3
4
p-ClPh
p-ClPh
Scheme 1. The MDRs of enaminones 2 with 1 and 3.
2a
3a
4a
formation of indole skeleton and its C3-alkoxylation were readily
achieved via metal-free [3+2] heterocyclization in a one-pot oper-
ation. To the best of our knowledge, the utilization of alkoxylation
strategy combined with multi-component domino reactions for
the preparation of polysubstituted tetrahydroindoles has not been
documented so far.
Entry
Promoter (equiv)
T (°C)
Time (min)
Yield (%)
1
2
3
4
5
6
7
8
HOAc (1.0)
80
80
80
80
60
100
80
80
30
30
20
20
30
20
20
20
no
trace
70
78
52
73
49
76
CF3COOH (1.0)
H2SO4 (1.0)
p-TsOH (1.0)
p-TsOH (1.0)
p-TsOH (1.0)
p-TsOH (0.5)
p-TsOH (1.5)
Our investigation was initiated by evaluating the domino reac-
tion of 2,2-dihydroxy-1-phenylethanone 1a with 3-(4-chloro-
phenyl amino)-5,5-dimethylcyclohex-2-enone 2a, and ethanol 3a.
The reaction was tested under a variety of different conditions.
The representative data are summarized in Table 1. It was found
that the reaction could not proceed at 80 °C under microwave
(MW) heating using HOAc or CF3COOH as a Brønsted acid promoter
(Table 1, entries 1–2). 1.0 equiv of H2SO4 gave the expected prod-
uct 4a in 70% yield (Table 1, entry 3). The identical reaction pro-
moted by 1.0 equiv of p-TsOH generated slightly higher yield of
product 4a (78%) than that promoted by H2SO4. Subsequently,
the same reaction promoted by p-TsOH was performed and re-
peated many times at different temperatures in a sealed vessel un-
der microwave irradiation for 20–30 min. The yield of product 4a
was increased from 52% to 78% as the temperature varied from
60–80 °C. Further increase of reaction temperature failed to im-
prove the yield of desired product 4a (entry 6). Next, we investi-
gated the amount of p-TsOH required for this domino reaction.
The results indicated that increasing the amount of p-TsOH from
0.5 to 1.0 equiv led to an increase in the yield from 49% to 78%
(Table 1, entries 4 and 7). The addition of larger amounts of p-TsOH
did not improve the yield of 4a (Table 1, entry 8). It was anticipated
that ethanol serves as an etherification reagent and reaction media
for the MDRs simultaneously.
With the above optimized conditions, we then proceeded to
probe the substrate diversity of this p-TsOH promoted three-com-
ponent domino reaction by using readily available starting materi-
als. The reactions presented in Table 2 preceded efficiently and
afforded the desired products in moderate to good yields. The sub-
stituents on the aromatic ring of arylglyoxal monohydrate 1 did
not hamper the reaction process. Reactions of methyl-, chloro-,
bromo-, or fluoro-substituted phenylglyoxal monohydrate 1 with
2 all worked well to provide the desired products in moderate to
good yields. The variation of Ar’ groups of b-enaminones including
electron-withdrawing groups or with electron-donating groups all
furnished the desired alkoxy-substituted indoles 4a–4f in good
Table 2
Domino synthesis of tetrahydroindoles 4 under MW21
O
O
OR1
O
p-TsOH
(1.0 equiv.)
OH
Ar
Ar
R
+
R1OH
+
R
N
Ar'
80 °C
MW
NH
Ar'
R
OH
R
1
2
3
4
Entry
4
Ar
Ar’
R
R1
Time (min)
Yielda (%)
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
Ph (1a)
4-ClPh (2a)
4-ClPh (2a)
4-BrPh (2b)
4-BrPh (2b)
4-MePh (2c)
Ph (2d)
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
Et
Et
Et
Et
Et
Et
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
20
25
25
22
26
24
24
22
30
25
28
25
22
22
21
25
24
20
30
25
78
81
84
79
74
80
86
83
87
85
76
83
81
78
85
75
70
76
65
69
4-BrPh (1b)
4-ClPh (1c)
4-MePh (1d)
4-MeOPh (1e)
4-FPh (1f)
4-FPh (1f)
Ph (1a)
4-BrPh (1b)
4-ClPh (1c)
4-MePh (1d)
Ph (1a)
4-BrPh (1b)
4-MePh (1d)
4-FPh (1f)
Ph (1a)
Ph (2d)
4-ClPh (2a)
4-ClPh(2a)
4-ClPh(2a)
4-ClPh(2a)
4-BrPh (2b)
4-BrPh(2b)
4-BrPh(2b)
4-MePh(2c)
4-ClPh (2e)
4-ClPh (2e)
4-ClPh (2e)
4-ClPh(2e)
4-MePh (2f)
9
10
11
12
13
14
15
16
17
18
19
20
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
4t
4-BrPh (1b)
4-BrPh (1b)
4-MeOPh (1e)
4-MeOPh (1e)
H
H
H
H
Et
Me
Me
Et
a
Isolated yield.

3178
Q.-Q. Shi et al. / Tetrahedron Letters 54 (2013) 3176–3179
On the basis of experimental results, a reaction mechanism for
this domino reaction is postulated in Scheme 2. Firstly, arylglyoxal
monohydrate protonated by p-TsOH undergoes etherification of 3
to convert into intermediate B, followed SN2 type reaction of
enaminones 2 to yield C. Then, intramolecular cyclization of C pro-
moted by p-TsOH occurs, affording final tetrahydroindoles 4.
In conclusion, we have described a new p-TsOH promoted
three-component domino reaction involving alkoxylation process
which provides a general and efficient strategy for the synthesis
of tetrahydroindole derivatives with good yields in a one-pot man-
ner. The reaction process employs readily available enaminones
and arylglyoxal monohydrate as starting materials and involves
tandem protonation of hydroxyl group/etherification/second SN2/
intramolecular cyclization sequences. Further investigations are
in progress in our laboratory to evaluate the process with a broader
range of substrates, and to synthesize closely related natural-like
products and test their biological activity.
Acknowledgments
We are grateful for financial support from the National Science
Foundation of China (21072163, 21232004, 21272095, and
21102124), PAPD of Jiangsu Higher Education Institutions, the
NSF of Jiangsu Education Committee (11KJB150016), Jiangsu Sci-
ence and Technology Support Program (No. BE2011045), the Qing
Lan Project (12QLG006), and Doctoral Research Foundation of
Jiangsu Normal Univ. (JSNU, No. 10XLR20). Thanks Professor. Gui-
gen Li and Dr. Suresh Pindi for their generous assistance.
Figure 2. X-ray structure of 4m.
yields within a short period of time (Table 2, entries 1–6). Next, we
replaced ethanol 3a with methanol 3b and subjected to reaction
with enaminones and arylglyoxal monohydrates to investigate
the possibility of this transformation. Substituents on the phenyl
ring of 1 regardless of its electronic property were all successfully
engaged in this reaction, which can be readily transformed into the
corresponding methoxyl-substituted tetrahydroindoles 4g–4o
with 76%–87% yields. 5,5-Unsubstituted 3-aminocyclohex-2-enon-
es bearing both electron-deficient and electron-rich aromatic
groups 2e and 2f were converted into the corresponding alkoxy-
substituted tetrahydroindoles 4p–4t in 65%–76% yields, respec-
tively. The tolerance of functionalities, such as chloro, bromo in
this protocol provides the opportunity of their various further
chemical manipulations in products. It is worth mentioning that
the protocol provides a straightforward pathway to synthesize alk-
oxy-substituted indoles, which are generally prepared via metal-
catalyzed alkoxylation.11–13
In general, the reaction occurred at a very fast speed; in fact, all
cases can be finished within 20–30 min. Water is nearly a sole by-
product, which makes the work-up convenient. In most cases, the
products can precipitate out after the reaction mixture was poured
into cold water and was neutralized by diluted basic solution. The
structural elucidation of the products was determined from its IR,
1H NMR, 13C NMR, and HRMS spectra. The structure of compound
4m was unequivocally confirmed by X-ray analysis (Fig. 2).22
Supplementary data
Supplementary data (experimental details and spectroscopic
characterization of all compounds along with 1H, IR and mass spec-
tra) associated with this article can be found, in the online version,
at http://dx.doi.org/10.1016/j.tetlet.2013.04.029.
References and notes
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O
O
Ar'
O
O
N
H
H+
OH
OH
2
HOR1
OH
OH2
OR1
Ar
R
Ar
Ar
OH2
A
B
1
O
OR1
O
OR1
Ar
OH
Cyclization
-H+
Ar
R
NH
Ar'
N
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C
4
Scheme 2. The possible mechanism for tetrahydroindoles 4.

Q.-Q. Shi et al. / Tetrahedron Letters 54 (2013) 3176–3179
3179
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reaction system. Subsequently, the reaction vial was capped and then pre-
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80 °C; Absorption level: high; fixed hold time) until TLC (petroleum ether/
acetone 3:1) revealed that conversion of the starting material 2a was complete.
The reaction mixture was cooled to room temperature and was then
neutralized by 10% NaOH solution. Next, the system was diluted with cold
water (10 mL). The solid was collected by Büchner filtration and was purified
by recrystallization from 50% EtOH to afford the desired pure
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tetrahydroindoles 4b as
bromophenyl)-1-(4-chlorophenyl)-3-ethoxy-6,7-dihydro-6,6-dimethyl-1H-
indol-4(5H)-one (4b) IR (KBr,
cmÀ1): 3465, 1657, 1497, 1422, 1366, 1133,
a pale white solid (Mp: 211–212 °C). 2-(4-
m
1075, 1009, 831, 735, 696, 655, 514; 1H NMR (400 MHz, CDCl3) d: 7.39 (d,
J = 6.4 Hz, 3H, Ar–H), 7.29 (s, H, Ar–H), 7.10 (d, J = 8.0 Hz, 2H, Ar–H), 6.99 (d,
J = 8.4 Hz, 2H, Ar–H), 4.10 (m, 2H, CH2), 2.49 (s, 2H, CH2), 2.39 (s, 2H, CH2), 1.23
(t, J = 6.8 Hz, 3H, CH3), 1.07 (s,6H, CH3). 13C NMR (100 MHz, CDCl3) d: 192.5,
142.9, 140.6, 138.3, 136.5, 133.7, 132.4, 129.3, 129.1, 128.7, 122.6, 121.1, 112.8,
70.1, 52.7, 37.2, 35.3, 28.5, 15.4. HRMS (ESI): m/z calcd for [M+H]+
C24H24BrClNO2, 472.0679; found: 472.0635.
22. The single-crystal growth was carried out in co-solvent of EtOH and DMF at
room temperature. Crystal data for 4m (CCDC-921884): C23H21Br2NO2, crystal
dimension 0.45 Â 0.40 Â 0.21 mm, Triclinic, space group P-1, a = 8.8419(9) Å,
21. General procedure for the synthesis of tetrahydroindoles 4b: 1-(4-
bromophenyl)-2,2-dihydroxyethanone
(1b,
1.0 mmol,
0.231 g.)
was
b = 9.6936(11) Å, c = 13.4897(13) Å,
c
a
= 97.4180(10) Å, b = 91.3370(10) Å,
(Mo
introduced in a 10 mL initiator reaction vial, and 3-((4-chlorophenyl)amino)-
5,5-dimethylcyclohex-2-enone (2a, 1.0 mmol, 0.25 g), p-TsOH (1.0 mmol,
= 110.504(2) Å, V = 1070.96(19) Å3, Mr = 503.23, Z = 2, k = 0.71073 Å,
K ) = 3.803 mmÀ1, F(000) = 504, R1 = 0.0584, wR2 = 0.1078.
l
a