Synthesis of 2-aminoindole derivatives with Hantzsch ester catalyzed by Pd/C

Article abstract of DOI:10.1002/cjoc.201200834

Catalytic hydrogenation of 2-cyano-2-(2-nitrophenyl)acetates bearing an electron withdrawing substituent to the nitrile, using Hantzsch ester catalyzed by Pd/C, affords 2-aminoindoles in good to excellent yields. Copyright

Full text of DOI:10.1002/cjoc.201200834

FULL PAPER
DOI: 10.1002/cjoc.201200834
Synthesis of 2-Aminoindole Derivatives with Hantzsch
Ester Catalyzed by Pd/C
Ruiguang Xing,*,a Qiuping Tian,b Qiang Liu,b and Yanan Lia
a College of Rare Earth, Inner Mongolia University of Science & Technology, Baotou,
Inner Mongolia 014010, China
b State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering,
Lanzhou University, Lanzhou, Gansu 730000, China
Catalytic hydrogenation of 2-cyano-2-(2-nitrophenyl)acetates bearing an electron withdrawing substituent to the
nitrile, using Hantzsch ester catalyzed by Pd/C, affords 2-aminoindoles in good to excellent yields.
Keywords 2-aminoindole, reductive cyclization, Hantzsch ester, palladium on carbon
Introduction
tic acid at high temperature currently is a common ap-
proach for the synthesis of 2-aminoindoles 2.[3] How-
ever, both zinc powder and acidic condition unfit envi-
ronmental points of view. Therefore, it is much desir-
able to develop a novel method for this kind of trans-
formation. Hydrogen has been widely used for the re-
ductive cyclization of 1. For instance, catalytic hydro-
genation of 1 over Pd/C affords indole-3-carboxylates
3[3c,4] or 2,3-unsubstituted indoles 4,[5] and in the pres-
ence of (Ph3P)4Pd gives N-hydroxy-2-aminoindoeles 5.[6]
To our knowledge, the production of 2-aminoindole
derivatives can not be easily achieved by hydrogen
molecules in the previous researches
Hantzsch 1,4-dihydropyridine (HEH) has been
widely used as a model compound of coenzyme
NAD(P)H,[7] which plays a pivotal role in biochemical
redox processes. Recent studies in our laboratory have
shown that the reducibility of HEH is dramatically en-
hanced in the presence of Pd/C.[8] Moreover, high
chemoselectivities have been achieved by regulating
reaction conditions, such as the amount of HEH, reac-
tion temperatures and solvents. We have examined the
selective reduction of a nitro group with HEH and Pd/C
in the presence of epoxy, ester or amide substituents
could successfully accomplished the synthesis of
2H-1,4-benzoxazine,[8c] benzoxazole,[8e] benzimida-
zole[8e] and quinoline[8f] derivatives. Herein, we wish to
report a novel method that 2-aminoindoles can be effi-
ciently synthesized via Pd/C-catalyzed intra-molecular
reductive cyclization in the presence of HEH.
2-Aminoindoles can be precursors for many phar-
macologically active compounds such as 2-diazoindoles
and 2-triazenoindoles, the latter related to a triazeno-
imidazole derivative, dacarbazine, which is currently
utilized in therapy against malignant melanoma and
Hodgkin’s disease.[1] 2-Aminoindoles are also useful
building blocks for the preparation of new ring systems,
such as the indolo[2,1-d]-[1,2,3,5]tetrazine related to
temozolomide, the antitumour drug active against ma-
lignant melanoma, mycosis fungoide and brain tu-
mours.[2]
To date, many synthetic methods have been devel-
oped for the synthesis of 2-aminoindoles. 2-Cyano-2-
(2-nitrophenyl)acetates 1 have been extensively used as
key intermediates in the synthesis of indole derivatives
by reductive cyclization (Scheme 1).
Reductive cyclization of 1 with zinc powder in ace-
Scheme 1
CO2R
CN
NO2
CO2R
Zn, AcOH
NH2
N
H
Δ
1
2
H2, Pd/C
(Ph3P)4Pd
EtOH/AcOH
CO2R
CO2R
NH2
or
N
H
N
N
H
Experimental
4
3
OH
1H NMR and 13C NMR spectra were recorded with a
5
*
E-mail: xingrg06@imust.cn; Tel.: 0086-472-5951536; Fax: 0086-472-5951536
Received August 17, 2012; accepted November 13, 2012; published online XXXX, 2012.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201200834 or from the author.
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1

Xing et al.
FULL PAPER
Varian instrument (300 and 75 MHz, respectively) and
internally referenced to the tetramethylsilane signal or
residual protio solvent signals. Mass spectra were re-
corded by EI methods. HRMS data were determined
with a Bruker Daltonics APEXII 47e FTICR spec-
trometer. All reactions under standard conditions were
monitored by thin-layer chromatography (TLC) on gel
F254 plates. Silica gel (200－300 mesh) was used for
column chromatography. The employed solvents were
dried by the standard procedures. Commercially ob-
tained reagents were used without further purification.
Table 1 Synthesis of 2-aminoindole derivatives with 2-cyano-
2-(2-nitrophenyl)acetates 1 by HEHa
Y
Y
CN
NH2
HEH, Pd/C
EtOH, reflux
N
X
X
NO2
1a - 1g
H
2a - 2g
Substrate
X
Y
Product
2a
Yieldb/%
70.9
1a
1b
1c
1d
1e
1f
H
CO2Et
CO2Me
CO2But
CO2Et
CO2Et
CO2Me
CO2But
H
2b
2cc
69.5
H
53.4
Typical procedure for synthesis of product
Me
2d
2ec
2fc
2gc
53.0
To the CH3CH2OH solution (25 mL) of substrate
(1.0 mmol) were added HEH (3.5 mmol) and 10% Pd/C
(20 wt% of substrates), the mixture was refluxed under
argon atmosphere by stirring for 10 h. After completion,
the reaction was monitored by TLC, the solution was
filtered and the filtrate was concentrated under reduced
pressure. The corresponding compounds were isolated
by a column chromatography (silica gel).
CO2Me
CO2Me
CO2Me
75.2
80.4
1g
80.0
a
Reaction conditions: a mixture of 2-cyano-2-(2-nitrophenyl)
acetates (1, 1 mmol) and HEH (3.5 mmol) in 25 mL of ethanol
containing 10% Pd/C (20 wt% of substrates) was refluxed under
stirring and argon atmosphere in 10 h. b Isolated yields. All prod-
ucts were characterized by EI-MS, 1H NMR and 13C NMR.
c Products are unknown compounds. All products were character-
ized by EI-MS, 1H NMR, 13C NMR and HRMS.
Results and Discussion
We found that refluxing ethyl 2-nitrophenylcyano-
acetate (1a) with HEH in the presence of 10 % Pd/C in
ethanol generated 2-amino-3-carbethoxyindole (2a),
besides 2, another product was also obtained, which was
characterized to be diethyl 2,6-dimethyl-3,5-pyridinedi-
carboxylate 6 (Scheme 2). The amount of Pd/C mainly
influences the reaction time. For instance, the reaction
of 2a and 3.5 equiv. of HEH completed within 7 h in the
presence of 25 wt% of substrates of Pd/C, while 15 h
were needed when the amount of Pd/C decreased to 10
wt%. No reaction took place in the absence of Pd/C un-
der the same conditions. 20 wt% of substrates of Pd/C
was finally selected in this work, since the reaction
could complete well in 10 h.
ent Y was the cyano or trifluoromethyl group, the prod-
ucts obtained were not only 2-aminoindoles 2 but also
N-hydroxy-2-aminoindoeles 5 (Table 2). It seems that
the yields of 5 increased with the enhancement of elec-
tron-withdrawing abilities of substituent X and Y. Re-
ductive cyclization of 1k only produced the corre-
sponding N-hydroxy-2-aminoindoeles 5 in 80.2% yield.
Table 2 Reductive cyclization of 2-cyano-2-(2-nitrophenyl)-
acetates 1 by HEHa
Y
HEH, Pd/C
CN
EtOH, reflux
X
NO2
1a - 2g
Scheme 2
Y
Y
CO2Et
NH2
EtO2C
CO2Et
Me
NH2
+
N
CN
NO2
Pd/C
N
H
X
X
+
OH
5h - 5l
EtOH, reflux
Me
N
H
2h - 2l
1a
HEH
Substrate X
Y
Product
2h, 5hc
2i, 5i
Yieldb/%
CO2Et
NH2
1h
1i
CN
CO2Et
CF3 CO2Et
CF3 CO2Me
CF3 SO2Ph
30.3 (2h), 48.4 (5h)
16.9 (2i), 60.0 (5i)
17.2 (2j), 68.5 (5j)
80.2
EtO2C
Me
CO2Et
Me
+
N
N
1j
2j, 5jc
H
6
2a
1k
5k
a
Reaction conditions: a mixture of 2-cyano-2-(2-nitrophenyl)-
acetates (1, 1 mmol) and HEH (3.5 mmol) in 25 mL of ethanol
containing 10 % Pd/C (20 wt% of substrates) was refluxed under
stirring and argon atmosphere in 10 h. b Isolated yields. All prod-
ucts are known compounds and were characterized by EI-MS, 1H
We can conclude from Table 1 that the method was
successfully extended to synthesize some 2-aminoin-
doles. Substrates with electron-donating groups in the
phenyl nucleus (1d) and bulky esters α to the nitrile (1c)
gave desired products in lower yields. The best yield
was got when the substituent α to the nitrile Y was the
methoxycarbonyl group (1f). However, when substitu-
c
NMR and 13C NMR. Products are unknown compounds. All
1
products were characterized by EI-MS, H NMR, 13C NMR and
HRMS.
2
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Chin. J. Chem. 2012, XX, 1—4

Synthesis of 2-Aminoindole Derivatives with Hantzsch Ester Catalyzed by Pd/C
It has been reported the N-hydroxy-2-aminoindoles
can be reduced to the 2-aminoindole by catalytic hy-
drogenation under pressure.[4] Similar result was found
by refluxing 5a with HEH in the presence of Pd/C.
However, when 2-amino-3-carbethoxy-indoles bear
trifluoromethyl group in the phenyl nucleus, the reac-
tions could not proceed at all. For example, N-hydroxy-
2-aminoindole 5i was left intact after refluxing with
HEH in the presence of Pd/C in ethanol in 10 h (Scheme
3). It may be caused by strong electron-withdrawing
ability of trifluoromethyl group which inhibited the
reduction.
results and literature reports,[8,10] a plausible mechanism
could be drawn for this reductive cyclization (Scheme
4). Firstly, 2-cyano-2-(2-nitrophenyl)acetates 1 were
reduced to hydroxylamine intermediates 7 by 2 equiv.
of HEH. The intermediates 7 could rapidly subject to
ring closure to generate N-hydroxy-2-aminoindoeles 5.
7 could also be reduced to aniline intermediates 8 by
HEH. Ring closure of 8 onto the cyano group formed
the products 2, and the latter can also be generated by
reduction of 5 by HEH. In the present experiments, the
reduction of N-hydroxy-2-aminoindoeles 5 to 2-amino-
indoles 2 was affected by the substituent effects of X
and Y as mentioned in Scheme 3. When X and Y are
strong electron-withdrawing groups, the transformation
did not occur. As a result, both 2-aminoindoles 2 and
N-hydroxy-2-aminoindoeles 5 formed (Table 2).
Scheme 3
CO2Et
NH2
CO2Et
NH2
N
OH
HEH, Pd/C
EtOH, reflux
N
H
Conclusions
2a yield: 87%
5a
In summary, a mild and environmentally benign
method for synthesizing 2-aminoindoles have been de-
veloped by employing Hantzsch 1,4-dihydropyridine
(HEH) as reducing agents. Although the yield was not
satisfactory when substrates bear strong electron-with-
drawing groups in the phenyl nucleus, it is still the first
application of model compounds of coenzyme
NAD(P)H in the synthesis of indole derivatives. Exten-
sion of this method to other potential substrates and a
study of the detailed reaction mechanism are now in
progress in our laboratory.
CO2Et
NH2
N
OH
HEH, Pd/C
EtOH, reflux
No reaction
F3C
5i
The mechanism of selective reduction of nitro group
with Hantzsch ester in the presence of Pd/C catalyst has
been intensively investigated.[8,9] As illustrated in
Scheme 4, the hydrogen atom at the 4-position of HEH
was easily transferred in the form of hydride anion in
the initial step, which was followed by losing of the hy-
drogen atom at 1-position. In the present case, HEH acts
as reducing agent in a similar way. Based on the above
Acknowledgement
We thank the National Natural Science Foundation
of China (No. 21172102).
Scheme 4
H
H
EtO2C
Me
CO2Et
Me
EtO2C
Me
CO2Et
Me
-H+
-H-
EtO2C
Me
CO2Et
Me
N
N
H
N
H
6
HEH
Hantzsch pyridine
HEH
pyridine
Y
Y
2pyridine
2HEH
Y
Pd/C
CN
CN
NHOH
Pd/C
CN
NO2
- H2O
X
NH2
X
X
- H2O
8
7
1
HEH
pyridine
Y
Y
Pd/C
NH2
NH2
- H2O
N
N
H
X
X
OH
5
2
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Xing et al.
FULL PAPER
Synth. Commun. 2003, 33, 2229.
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