Synthesis of 2-aminoindole-3-carboxylic acid derivatives by the copper(I) iodide catalyzed reaction of N -(2-iodophenyl)formamides with malononitrile or cyanoacetates

Article abstract of DOI:10.1055/s-0030-1258422

An efficient method for the synthesis of 2-aminoindole-3-carbonitriles and 2-aminoindole-3-carboxylates by the reaction of N-(2-iodophenyl)formamides with malononitrile and cyanoacetates, respectively, in the presence of a catalytic amount of copper(I) io

Full text of DOI:10.1055/s-0030-1258422

764
PAPER
Synthesis of 2-Aminoindole-3-carboxylic Acid Derivatives by the Copper(I)
Iodide Catalyzed Reaction of N-(2-Iodophenyl)formamides with Malononitrile
or Cyanoacetates
S
ynthesis of 2-A
m
a
inoindole-3
z
-carboxylic
u
Acid Deriva
h
tives iro Kobayashi,* Toshihide Komatsu, Yuki Yokoi, Hisatoshi Konishi
Division of Applied Chemistry, Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University,
4-101 Koyama-minami, Tottori 680-8552, Japan
Fax +81(857)315263; E-mail: kkoba@chem.tottori-u.ac.jp
Received 9 November 2010; revised 11 January 2011
used for the coupling reaction of iodobenzenes with 2a by
Abstract: An efficient method for the synthesis of 2-aminoindole-
Miura et al.4 However, the reaction resulted in the forma-
tion of an intractable mixture of products. This result may
be ascribed to the reaction of the amino group with malo-
nonitrile before its substitution with the iodo moiety.
3-carbonitriles and 2-aminoindole-3-carboxylates by the reaction of
N-(2-iodophenyl)formamides with malononitrile and cyanoace-
tates, respectively, in the presence of a catalytic amount of copper(I)
iodide using potassium carbonate as a base is reported.
Key words: 2-aminoindole-3-carboxylates, 2-aminoindole-3-car-
bonitriles, N-(2-iodophenyl)formamides, copper(I) iodide, coupling
Next, the use of N-(2-iodophenyl)formamide (1a), easily
prepared by N-formylation of 2-iodoaniline, as a substrate
in order to avoid the above mentioned undesired reactions
was examined. It was found that the synthesis of 3a and
ethyl 2-aminoindole-3-carboxylate (3b) by the reaction of
1a with 2a and ethyl cyanoacetate (2b), respectively,
could be achieved as depicted in Scheme 1. Thus, N-(2-io-
dophenyl)formamide (1a) was allowed to react with
malononitrile (2a) under the above-mentioned conditions
for one hour. Aqueous workup and purification of the
crude product using column chromatography on silica
gel5 afforded the desired product 3a in a satisfactory yield
(Table 1, entry 1). The reaction of 1a with 2b under the
same conditions also proceeded relative cleanly to afford
the desired product 3b in a comparable yield (entry 2).
The use of 20 mol% of the catalyst did not improve the
yields of 3a. Copper(I) bromide also proved to work well
in this reaction, but the yield of 3a was somewhat lower
(46%) than that with copper(I) iodide.
Elaborations of 2-aminoindole-3-carbonitrile1a and 3-
aminoindole-3-carboxylates1b,c to the corresponding high-
ly fused and biologically important heterocyclic com-
pounds have been reported in the literature. These indole
derivatives were prepared by the treatment of 1-chloro(or
bromo)-2-nitrobenzenes with malononitrile or ethyl cy-
anoacetate in the presence of an appropriate base followed
by reduction of the nitro group of the resulting substitu-
tion products.1–3 We became interested in pursuing a new
and general procedure for the preparation of 3-aminoin-
dole-3-carboxylic acid derivatives. On the other hand,
Miura et al. have already reported that the copper(I) iodide
catalyzed reaction of iodobenzenes with malononitrile
and cyanoacetates in the presence of a base gives arylma-
lononitriles and arylcyanoacetates, respectively.4 We
therefore envisaged that a similar copper(I) iodide cata-
lyzed reaction of 2-iodoanilines with malononitrile and
cyanoacetates would yield 2-aminoindole-3-carbonitriles
and 2-aminoindole-3-carboxylates, respectively. In the
course of our investigations, it was found that the reaction
of N-(2-iodophenyl)formamides with malononitrile and
cyanoacetates could be catalyzed by copper(I) iodide in
the presence of potassium carbonate to give 2-aminoin-
dole-3-carbonitriles and 2-aminoindole-3-carboxylates,
respectively. Herein, we report the results of our study,
which provides a new and efficient method for the synthe-
sis of these 2-aminoindole-3-carboxylic acid derivatives.
R
I
NHCHO
Y
1
R
CuI (cat.), K2CO3
DMSO
+
NH2
N
Y
H
3
CN
2
Scheme 1 Preparation of 2-aminoindole-3-carboxylic acid deriva-
tives
In order to synthesize 2-aminoindole-3-carbonitrile (3a),
2-iodoaniline was first subjected to the reaction with ma-
lononitrile (2a) (2 equiv) in DMSO containing a catalytic In order to investigate the scope of the present synthetic
amount (10 mol%) of copper(I) iodide and potassium car- method, the reactions using N-(2-iodophenyl)formamides
bonate (4 equiv) at 120 °C. These conditions are those 1b–f carrying a substituent at the 4-position, which could
be easily prepared from commercially available or
known6,7 2-iodoanilines upon treatment with formic acid,
as substrates under the similar conditions as mentioned for
the synthesis of 2a and 2b, were carried out. They pro-
ceeded successfully to afford the desired products 3c–l in
SYNTHESIS 2011, No. 5, pp 0764–0768
Advanced online publication: 03.02.2011
DOI: 10.1055/s-0030-1258422; Art ID: F19810SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
1
1

PAPER
Synthesis of 2-Aminoindole-3-carboxylic Acid Derivatives
765
Table 1 Preparation of 2-Aminoindole-3-carboxylic Acid Derivatives 3
Entry
1
2
Temp (°C)
120
120
110
120
80
Time
1 h
3 (Yield, %)a
3a (64)
3b (59)
3c (60)
3d (56)
3e (54)
3f (60)
1
1a (R = H)
2a (Y = CN)
2
1a
2b (Y = CO2Et)
10 min
1 h
3
1a
2c [Y = CO2(CH2)2OEt]
4
1b (R = Me)
2a
2c
2a
2b
2a
2b
2c
2a
2b
2c
45 min
3 h
5
1b
6
1c (R = i-Pr)
120
80
1 h
7
1c
1 h
3g (58)
3h (60)
3i (58)
8
1d (R = Cl)
100
80
45 min
1.5 h
45 min
20 min
20 min
10 min
9
1d
10
1d
80
3j (52)
11
1e (R = OMe)
1f (R = CO2Et)
1f
90
3k (38)
3l (53)
12
80
13
80
3m (55)
a Isolated yields.
the yields summarized in Table 1, entries 3–12. Each of natively, decarbonylation from 4 may first occur to fur-
these reactions was conducted as follows. First, the reac- nish the amino nitrile intermediate 6, which cyclizes
tion mixture was heated at 60 °C, and the temperature was intramolecularly to give 3. Unfortunately, however, we
raised at a 10 °C interval until TLC analyses had revealed have no evidence to clarify which is the correct route to 3.
1
that the reaction proceeded at a reasonable rate. After con- IR and H NMR analyses of the reaction mixtures inter-
firmation of complete consumption of the starting 2 by rupted before completion of the reaction of 1a with ethyl
TLC analyses, the reaction was quenched by adding 10% cyanoacetate (with and without aqueous workup) provid-
hydrochloric acid after cooling. Preparation of 2-ethoxy- ed no informative results. After coupling of 1 with malo-
ethyl 2-aminoindole-3-carboxylates (3c, 3e, 3j, and 3m) nonitrile or cyanoacetates, the cyclization/decar-
was successfully performed using 2-ethoxyethyl cyano- bonylation or decarbonylation/cyclization sequence ap-
acetate (2c) (entries 3, 5, 10, and 13). An electron-donating pears to proceed very quickly.
methoxy group proved to decrease the yield of the corre-
sponding product 3k (entry 11), while methyl, isopropyl,
and electron-withdrawing chloro and ethoxycarbonyl
groups did not affect the yields of the products (entries 4–
10, 12 and 13). We speculate that the poor yield of 3k may
be attributed to its somewhat lower stability during the re-
action. Attempts to improve the yield of 3k by conducting
reactions at lower temperatures were all in vain; the reac-
tions did not proceed to any satisfactory extent after rather
extended reaction times. It is worth mentioning here that
neither cyano-N,N-dimethylacetamide nor benzoylaceto-
nitrile performed well in the present reaction to give no
more than trace amounts of the expected 2-aminoindole
derivatives; in each case complicated reaction mixture
was obtained.
Y
R
CN
1
+
2
NHCHO
4
decarbonylation
Y
Y
R
R
CN
NH2
NH2
N
CHO
5
6
decarbonylation
The reaction sequence leading to the formation of 3 from
2-iodophenylformamides 1 and malononitrile or cyano-
acetates is thought to proceed as depicted in Scheme 2.
Thus, coupling of 1 with one of the active methylene com-
pounds generates the intermediate 4. Intramolecular cy-
clization of this intermediate provides 1-formylindole
intermediate 5, which on decarbonylation gives 3. Alter-
3
Scheme 2 Proposed pathways to the products
In conclusion, we have developed a concise method for
the synthesis of 2-aminoindole-3-carboxylic acid deriva-
tives based on the reaction of N-(2-iodopheny)form-
Synthesis 2011, No. 5, 764–768 © Thieme Stuttgart · New York

766
K. Kobayashi et al.
PAPER
N-(2-Iodo-4-methoxyphenyl)formamide (1e)
Yield: 76%; beige solid; mp 129–132 °C (hexane–CH2Cl2).
and the ready availability of the starting materials make IR: 3187, 1658 cm–1.
amides with malononitrile or cyanoacetates catalyzed by
copper(I) iodide. The easiness of experimental operations
1H NMR (CDCl3): d = 3.79 and 3.80 (2 s, combined 3 H), 6.90–8.45
(m, 5 H).
the present indole synthesis attractive.
Anal. Calcd for C8H8INO2: C, 34.68; H, 2.91; N, 5.06. Found: C,
34.63; H, 2.92; N, 4.88.
All melting points were obtained on a Laboratory Devices MEL-
TEMP II melting apparatus and are uncorrected. IR spectra were de-
termined with a Shimadzu FTIR-8300 spectrophotometer as KBr
disks. The 1H NMR spectra were determined using TMS as an in-
ternal reference with a JEOL ECP500 FT NMR spectrometer oper-
ating at 500 MHz. The 13C NMR spectra were determined using
TMS as an internal reference with a JEOL ECP500 FT NMR spec-
trometer operating at 125 MHz. Low-resolution mass spectra (EI,
70 eV) were measured by a JEOL JMS AX505 HA spectrometer.
TLC was carried out on a Merck Kieselgel 60 PF254. Column chro-
matography was performed using Wako Gel C-200E. All of the or-
ganic solvents used in this study were dried over appropriate drying
agents and distilled prior to use. 2-Iodo-4-methylaniline and 2-iodo-
4-(1-methylethyl)aniline were prepared by the iodination of the re-
spective anilines under the conditions reported previously.6 2-Iodo-
4-methoxyaniline was prepared from 4-methoxyaniline according
to the procedure reported by Murphy et al.7 Ethyl 4-formylamino-3-
iodobenzoate (1f) was prepared by the method previously reported
by us.8 All other chemicals used in this study were commercially
available.
2-Aminoindole-3-carbonitrile (3a);11 Typical Procedure
A mixture of 1a (0.25 g, 1.0 mmol) and malononitrile (0.13 g, 2.0
mmol) in DMSO (2.5 mL) containing CuI (19 mg, 0.10 mmol) and
K2CO3 (0.55 g, 4.0 mmol) was heated at 120 °C for 1 h under stir-
ring. To the cooled (0 °C) resulting mixture was added 10% aq HCl
until evolution of CO2 gas had ceased. H2O (10 mL) was added and
the mixture was extracted with EtOAc (3 × 10 mL). The combined
extracts were washed with H2O (3 × 10 mL) and then brine (10 mL),
and dried (Na2SO4). After evaporation of the solvent, the residue
was filtered through a 2 cm pad of neutral alumina (Merck Alumina
60 Neutral F254) using EtOAc–hexane (1:1) as solvent. The filtrate
was concentrated and subjected to column chromatography on sili-
ca gel (EtOAc–hexane, 1:1) to give 3a as a beige solid; yield: 0.10
g (64%); mp 186–187 °C (hexane–THF) (Lit.1a mp 187–188 °C)
(Table 1).
IR: 3397, 3269, 3239, 2189, 1643, 1624 cm–1.
1H NMR (CDCl3): d = 4.69 (br s, 2 H), 7.08 (dd, J = 7.8, 1.4 Hz, 1
H), 7.14–7.17 (m, 2 H), 7.43 (dd, J = 7.8, 1.4 Hz, 1 H), 7.98 (br s, 1
N-(2-Iodophenyl)formamides 1
H).
These compounds were prepared by N-formylation of the respec-
tive 2-iodoanilines with formic acid in toluene under azeotropic
conditions.8
Ethyl 2-Aminoindole-3-carboxylate (3b)12,13
Beige solid; mp 179–181 °C (hexane–THF) (Lit.12 mp 178–180 °C).
N-(2-Iodophenyl)formamide (1a)9,10
Yield: 96%; beige solid; mp 112–113 °C (toluene) (Lit.9 mp 113–
113.5 °C).
IR: 3460, 3352, 3258, 1648, 1614, 1602 cm–1.
1H NMR (CDCl3): d = 1.44 (t, J = 7.3 Hz, 3 H), 4.37 (q, J = 7.3 Hz,
2 H), 5.69 (br s, 2 H), 7.04 (dd, J = 7.8, 7.3 Hz, 1 H), 7.10 (d, J = 7.8
Hz, 1 H), 7.14 (dd, J = 7.8, 7.3 Hz, 1 H), 7.81 (br s, 2 H).
IR: 3323, 1660 cm–1.
1H NMR (DMSO-d6): d = 6.94 and 7.00 (2 dd, J = 7.8, 7.3 Hz each,
combined 1 H), 7.31–7.42 (m, 1 H), 7.76 (dd, J = 7.8, 1.4 Hz, 1 H),
7.87 and 7.89 (2 d, J = 7.8 Hz, 1 H), 8.32 (s, 1 H), 9.54 (br s, 1 H).
13C NMR (DMSO-d6): d = 14.74, 57.99, 83.59, 109.66, 117.99,
119.28, 120.35, 126.34, 132.62, 153.54, 165.84.
2-Ethoxyethyl 2-Aminoindole-3-carboxylate (3c)
Beige solid; mp 90–92 °C (hexane–CH2Cl2).
IR: 3456, 3345, 1651, 1625, 1616 cm–1.
1H NMR (CDCl3): d = 1.24 (t, J = 6.9 Hz, 3 H), 3.62 (q, J = 6.9 Hz,
2 H), 3.81 (t, J = 5.0 Hz, 2 H), 4.47 (t, J = 5.0 Hz, 2 H), 5.66 (br s,
2 H), 6.99–7.04 (m, 2 H), 7.12 (td, J = 7.6, 1.5 Hz, 1 H), 7.81 (d,
J = 7.6 Hz, 1 H), 8.09 (br s, 1 H).
13C NMR (DMSO-d6): d = 15.14, 62.21, 66.69, 68.89, 85.69,
109.56, 119.11, 120.50, 121.61, 126.58, 132.07, 152.62, 166.77.
N-(2-Iodo-4-methylphenyl)formamide (1b)
Yield: 79%; beige solid; mp 100–102 °C (hexane–CH2Cl2).
IR: 3268, 1667 cm–1.
1H NMR (CDCl3): d = 2.29 and 2.31 (2 s, combined 3 H), 7.08–8.59
(m, 5 H).
Anal. Calcd for C8H8INO: C, 36.81; H, 3.09; N, 5.37. Found: C,
36.77; H, 3.18; N, 5.24.
N-[2-Iodo-4-(1-methylethyl)phenyl]formamide (1c)
Yield: 75%; pale-yellow solid; mp 80–82 °C (hexane–CH2Cl2).
IR: 3188, 1661 cm–1.
1H NMR (CDCl3): d = 1.22 and 1.44 (2 d, J = 6.9 Hz each, com-
bined 6 H), 2.80–2.90 (m, 1 H), 7.12–8.60 (m, 5 H).
MS: m/z = 248 (100%, [M+]).
Anal. Calcd for C13H16N2O3: C, 62.89; H, 6.50; N, 11.28. Found: C,
62.83; H, 6.78; N, 11.08.
2-Amino-5-methylindole-3-carbonitrile (3d)
Pale-yellow solid; mp 185–187 °C (hexane–THF).
IR: 3381, 3293, 3221, 2187, 1641, 1630 cm–1.
Anal. Calcd for C10H12INO: C, 41.54; H, 4.18; N, 4.84. Found: C,
41.49; H, 4.37; N, 4.70.
1H NMR (DMSO-d6): d = 2.49 (s, 3 H), 6.62 (br s, 2 H), 6.69 (d,
N-(4-Chloro-2-iodophenyl)formamide (1d)
Yield: 97%; beige solid; mp 139–140 °C (hexane–CH2Cl2).
IR: 3273, 1669 cm–1.
1H NMR (CDCl3): d = 7.13–8.62 (m, 5 H).
J = 8.2 Hz, 1 H), 6.91 (s, 1 H), 6.98 (d, J = 8.2 Hz, 1 H), 10.52 (s, 1
H).
13C NMR (DMSO-d6): d = 21.06, 61.39, 109.86, 115.37, 117.93,
120.61, 128.49, 129.19, 130.18, 153.78.
MS: m/z = 171 (100%, [M+]).
Anal. Calcd for C7H12ClINO: C, 29.87; H, 1.79; N, 4.98. Found: C,
29.75; H, 1.73; N, 4.90.
Synthesis 2011, No. 5, 764–768 © Thieme Stuttgart · New York

PAPER
Synthesis of 2-Aminoindole-3-carboxylic Acid Derivatives
767
Anal. Calcd for C10H9N3: C, 70.16; H, 5.30; N, 24.54. Found: C,
69.92; H, 5.35; N, 24.44.
13C NMR (DMSO-d6): d = 14.76, 58.28, 83.48, 110.97, 117.03,
118.82, 124.95, 128.31, 131.36, 154.24, 165.44.
MS: m/z = 238 (100%, [M+]).
2-Ethoxyethyl 2-Amino-5-methylindole-3-carboxylate (3e)
Beige solid; mp 125–127 °C (hexane–THF).
IR: 3458, 3354, 3271, 1661, 1643, 1620, 1603 cm–1.
Anal. Calcd for C11H11ClN2O2: C, 55.36; H, 4.65; N, 11.74. Found:
C, 55.17; H, 5.33; N, 9.87.
1H NMR (DMSO-d6): d = 1.26 (t, J = 7.3 Hz, 3 H), 2.41 (s, 3 H),
3.63 (q, J = 7.3 Hz, 2 H), 3.81 (t, J = 5.0 Hz, 2 H), 4.47 (t, J = 5.0
Hz, 2 H), 5.62 (br s, 2 H), 6.84 (d, J = 8.2 Hz, 1 H), 6.94 (d, J = 8.2
Hz, 1 H), 7.64 (br s, 1 H), 7.80 (br s, 1 H).
13C NMR (CDCl3): d = 15.15, 21.56, 62.16, 66.69, 68.91, 85.38,
109.22, 119.39, 121.50, 125.50, 130.24, 130.95, 154.83, 170.58.
2-Ethoxyethyl 2-Amino-5-chloroindole-3-carboxylate (3j)
Beige solid; mp 142–144 °C (hexane–THF).
IR: 3474, 3347, 1632, 1613 cm–1.
1H NMR (DMSO-d6): d = 1.28 (t, J = 7.3 Hz, 3 H), 3.65 (q, J = 7.3
Hz, 2 H), 3.83 (t, J = 5.0 Hz, 2 H), 4.47 (t, J = 5.0 Hz, 2 H), 5.70 (br
s, 2 H), 6.92–6.96 (m, 2 H), 7.74 (br s, 1 H), 8.04 (br s, 1 H).
13C NMR (DMSO-d6): d = 15.11, 61.48, 65.56, 68.23, 83.38,
110.89, 117.20, 118.80, 124.95, 128.16, 131.32, 154.21, 170.19.
MS: m/z = 262 (100%, [M+]).
Anal. Calcd for C14H18N2O3: C, 64.10; H, 6.92; N, 10.68. Found: C,
64.02; H, 6.95; N, 10.54.
MS: m/z = 282 (100%, [M+]).
Anal. Calcd for C13H15ClN2O3: C, 55.23; H, 5.35; N, 9.91. Found:
C, 55.09; H, 4.78; N, 11.54.
2-Amino-5-(1-methylethyl)indole-3-carbonitrile (3f)
Pale-yellow solid; mp 168–170 °C (hexane–THF).
IR (KBr): 3431, 3345, 3304, 2185, 1636, 1622 cm–1.
2-Amino-5-methoxyindole-3-carbonitrile (3k)
Beige solid; mp 170–172 °C (hexane–THF).
IR: 3399, 3285, 2187, 1645, 1628 cm–1.
1H NMR (DMSO-d6): d = 3.71 (s, 3 H), 6.48 (dd, J = 8.7, 2.3 Hz, 1
H), 6.638 (br s, 2 H), 6.641 (d, J = 2.3 Hz, 1 H), 6.99 (d, J = 8.7 Hz,
1 H), 10.47 (br s, 1 H).
13C NMR (DMSO-d6): d = 55.33, 62.15, 99.36, 107.40, 110.76,
117.94, 126.57, 129.21, 154.14, 154.66.
1H NMR (DMSO-d6): d = 1.19 (d, J = 6.9 Hz, 6 H), 2.83–2.91 (sept,
J = 6.9 Hz, 1 H), 6.62 (br s, 2 H), 6.77 (dd, J = 8.2, 1.4 Hz, 1 H),
6.95 (d, J = 1.4 Hz, 1 H), 7.01 (d, J = 8.2 Hz, 1 H), 10.53 (br s, 1 H).
13C NMR (DMSO-d6): d = 24.53, 33.49, 61.61, 109.93, 112.56,
118.05, 118.19, 128.34, 130.46, 140.81, 153.88.
MS: m/z = 199 (100%, [M+]).
Anal. Calcd for C12H13N3: C, 72.33; H, 6.58; N, 21.09. Found: C,
72.03; H, 6.55; N, 20.94.
MS: m/z = 187 (100%, [M+]).
Anal. Calcd for C10H9N3O: C, 64.16; H, 4.85; N, 22.45. Found: C,
63.96; H, 4.88; N, 22.56.
Ethyl 2-Amino-5-(1-methylethyl)indole-3-carboxylate (3g)
Beige solid; mp 122–124 °C (hexane–CH2Cl2).
IR: 3474, 3372, 3219, 1653, 1622, 1603 cm–1.
Diethyl 2-Aminoindole-3,5-dicarboxylate (3l)
Beige solid; mp 198–201 °C (hexane–THF).
IR: 3449, 3315, 1675, 1632 cm–1.
1H NMR (DMSO-d6): d = 1.38 and 1.40 (2 t, J = 7.3 Hz each, com-
bined 6 H), 4.31 and 4.33 (2 q, J = 7.3 Hz each, combined 4 H), 6.94
(br s, 2 H), 7.25 (d, J = 8.3 Hz, 1 H), 7.62 (d, J = 8.3 Hz, 1 H), 8.29
(s, 1 H), 11.09 (br s, 1 H).
13C NMR (DMSO-d6): d = 14.34, 14.71, 58.32, 60.67, 83.70,
109.45, 119.48, 121.22, 122.03, 126.63, 136.05, 154.35, 165.49,
166.86.
1H NMR (DMSO-d6): d = 1.29 (d, J = 6.9 Hz, 6 H), 1.45 (t, J = 7.3
Hz, 3 H), 2.98 (sept, J = 6.9 Hz, 1 H), 4.38 (q, J = 7.3 Hz, 2 H), 5.62
(br s, 2 H), 6.92 (dd, J = 8.2, 1.8 Hz, 1 H), 6.98 (d, J = 8.2 Hz, 1 H),
7.68 (br s, 1 H), 7.79 (br s, 1 H).
13C NMR (DMSO-d6): d = 14.79, 24.70, 34.42, 59.43, 85.79,
109.51, 116.85, 119.18, 126.68, 130.53, 142.69, 152.81, 167.67.
MS: m/z = 246 (100%, [M+]).
Anal. Calcd for C14H18N2O2: C, 68.27; H, 7.37; N, 11.37. Found: C,
68.26; H, 7.50; N, 11.08.
MS: m/z = 276 (100%, [M+]).
2-Amino-5-chloroindole-3-carbonitrile (3h)
Beige solid; mp 209–212 °C (hexane–THF).
IR: 3468, 3366, 2197, 1638, 1630 cm–1.
Anal. Calcd for C14H16N2O4: C, 60.86; H, 5.84; N, 10.14. Found: C,
60.83; H, 5.94; N, 10.16.
1H NMR (DMSO-d6): d = 6.82 (br s, 2 H), 6.89 (dd, J = 8.2, 2.3 Hz,
1 H), 7.06 (d, J = 2.3 Hz, 1 H), 7.08 (d, J = 8.2 Hz, 1 H), 10.88 (br
s, 1 H).
2-Ethoxyethyl 2-Amino-5-(ethoxycarbonyl)indole-3-carboxy-
late (3m)
Beige solid; mp 161–163 °C (hexane–THF).
13C NMR (DMSO-d6): d = 61.67, 111.42, 114.21, 117.04, 119.20,
IR: 3470, 3363, 1690, 1668, 1618 cm–1.
128.49, 129.89, 130.82, 154.62.
1H NMR (DMSO-d6): d = 1.14 (t, J = 7.3 Hz, 3 H), 1.30 (t, J = 7.3
Hz, 3 H), 3.54 (q, J = 7.3 Hz, 2 H), 3.70 (t, J = 5.0 Hz, 2 H), 4.24–
4.30 (m, 4 H), 6.85 (br s, 2 H), 7.18 (d, J = 8.2 Hz, 1 H), 7.56 (dd,
J = 8.2, 1.8 Hz, 1 H), 8.24 (d, J = 1.8 Hz, 1 H), 11.01 (br s, 1 H).
13C NMR (DMSO-d6): d = 14.30, 15.10, 59.93, 61.78, 65.69, 68.26,
83.59, 109.38, 119.47, 121.27, 122.08, 124.90, 128.02, 151.46,
166.77 (2 C).
MS: m/z = 191 (100%, [M+]).
Anal. Calcd for C9H6ClN3: C, 56.41; H, 3.16; N, 21.93. Found: C,
56.35; H, 3.15; N, 22.05.
2-Ethyl 2-Amino-5-chloroindole-3-carboxylate (3i)
Beige solid; mp 191–193 °C (hexane–THF).
IR: 3457, 3350, 1655, 1641, 1605 cm–1.
MS: m/z = 320 (100%, [M+]).
1H NMR (DMSO-d6): d = 1.30 (t, J = 6.9 Hz, 3 H), 4.22 (q, J = 6.9
Hz, 2 H), 6.80 (br s, 2 H), 6.86 (d, J = 8.4 Hz, 1 H), 7.09 (d, J = 8.4
Hz, 1 H), 7.46 (s, 1 H), 10.77 (br s, 1 H).
Anal. Calcd for C16H20N2O5: C, 59.99; H, 6.29; N, 8.74. Found: C,
59.89; H, 6.38; N, 8.77.
Synthesis 2011, No. 5, 764–768 © Thieme Stuttgart · New York

768
K. Kobayashi et al.
PAPER
(5) Before subjection to column chromatography on silica gel,
the mixture must be filtered through a small pad of neutral
alumina. Omission of this filtration procedure did not give
3a in a satisfactory purity. For details, see the experimental
section.
Acknowledgment
We acknowledge the assistance of Mrs. Miyuki Tanmatsu of this
university for recording mass spectra and performing combustion
analyses.
(6) Xiao, W.-J.; Alper, H. J. Org. Chem. 1999, 64, 9646.
(7) Lizos, D.; Tripoli, R.; Murphy, J. A. Chem. Commun. 2001,
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Synthesis 2011, No. 5, 764–768 © Thieme Stuttgart · New York