A convenient iodination of indoles and derivatives

Article abstract of DOI:10.1016/j.tet.2012.05.053

We report a direct iodination of indole and derivative compounds with iodine monochloride (ICl) in the presence of Celite. This procedure has now been extended to the iodination of substituted indoles, azaindoles and pyrroles. The scope of this procedure

Full text of DOI:10.1016/j.tet.2012.05.053

Tetrahedron 68 (2012) 6269e6275
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A convenient iodination of indoles and derivatives
a
a
a
b
a,
*
ꢀ
Salha Hamri , Jose Rodríguez , Joan Basset , Gerald Guillaumet , M. Dolors Pujol
a
ꢁ
ꢁ
Laboratori de Química Farmaceutica (Unitat Associada al CSIC), Facultat de Farmacia, Universitat de Barcelona, Av. Diagonal 643, E-08028 Barcelona, Spain
Institut de Chimie Organique et Analytique, Universite d’Orleans, UMR CNRS 7311, BP-6759, rue de Chartres, 45067 Orleans, France
b
ꢀ
ꢀ
ꢀ
a r t i c l e i n f o
a b s t r a c t
Article history:
We report a direct iodination of indole and derivative compounds with iodine monochloride (ICl) in the
presence of CeliteÒ. This procedure has now been extended to the iodination of substituted indoles,
azaindoles and pyrroles. The scope of this procedure is exemplified by the iodination of melatonin in 98%
yield.
Received 9 March 2012
Received in revised form 13 May 2012
Accepted 15 May 2012
Available online 24 May 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Iodoindoles
Iodoazaindoles
Electrophilic substitution
Iodine reagents and iodination
1. Introduction
focused on the development of a more suitable method for the
iodination of indoles and azaindoles.
Halogenation of indoles and azaindoles is of prime importance
because of the versatility of halogenated compounds as starting
material for the synthesis of various bioactive molecules of phar-
maceutical interest.1a also the use of iododerivatives as radioac-
tively labelled diagnostic markers provides an incentive for the
study of new iodination methods.1b
Indoles and azaindoles bearing iodide at the 2- or 3-position are
of interest to synthetic chemists due to their reactivity and ease of
derivatization.1a,2
The preparation of iodoindoles is laborious and, in general, the
yields are low.3 Direct halogenation of the indole takes place
preferentially at the 3-position.4 It is more nucleophilic and could
give mixture of secondary compounds, such as polyhalogenated,
oxidized and indole-coupled compounds.4cef The direct synthesis
of iodinated benzene and derivatives is well known but the io-
dination of substituted indoles has received less attention.5 Acti-
vation by metallation at the 2-position of N-protected indoles has
been developed and constitutes an efficient strategy for the sub-
stitution with several electrophilic halogens.6,7
The Katritzky method is efficient for halogenation at the C-2 of
indole, but requires N-protection, previously or in situ, using CO2
gas, and metallation followed by addition of a halogenating
agent.4a,8 Two N-protected-3-iodoindoles were preparared by
Benhida and col. using bis-(trifluroacetoxy)iodobenzene/iodine/
pyridine reagent system in a moderate yield.9 Consequently we
2. Results and discussion
We found that the low electrophilicity of iodine hindered the
procedure for the iodination of indoles and derivatives. We re-
quired several iodoindoles for the synthesis of arylated compounds
and we were interested in developing a procedure for the prepa-
ration of monoiodated compounds, considered intermediates in
the synthetic routes to various biologically active compounds.
In the reaction conditions described below substituted and
unsubstituted indoles gave moderate to high yields of the corre-
sponding iodinated indoles as shown in Tables 1e4. When indole
was treated with I2 and Al2O3 in dichloromethane at room tem-
perature for 2 h, 2,3-diiodoindole was formed in 61% yield (Table 1,
entry 1). At first, essays using only molecular iodine (I2) in different
solvents were performed but the desired monoiodated product was
not observed under the conditions tested.
The choice of iodination reagent was important; I2 and catalyst
in different conditions gave reduced reactivity (Table 1, entry 3) or
complex mono- and diiodoindole reaction mixtures (Table 2, entry
1). Moreover, the options of classical stirring or ultrasound were
also tested; ultrasound simplifies the reaction, reduces the time of
reaction and facilitates the work-up procedure increasing the yield
in some cases (Table 1, entry 6 and Table 2, entries 2, 3, 7 and 11).
ICl, as a source of electrophilic iodine, is a suitable iodination
reagent.10a,b Several authors generated ICl in situ by adding NaI or
another salt to MCln.11 Our method is based on the mixture of
ICleCelite (both commercially available as separate ingredients) in
* Corresponding author. E-mail address: mdpujol@ub.edu (M. Dolors Pujol).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.05.053

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S. Hamri et al. / Tetrahedron 68 (2012) 6269e6275
Table 1
1 equiv was used (Table 2 compares entries 5 and 6). This procedure
Iodination of 2,3-unsubstituted indoles
led to the formation of 3-iodoindole from unsubstituted indole,
while the 5-bromoindole selectively gave the iodination at the
position 3 (Table 2, entries 10 and 11).
3
I
conditions
2
N
H
N
H
Indoles with alkyl substituents at C-3 gave lower yields, except
for the iodination of melatonin (Table 3, entries 8 and 9). The io-
dination of indoleacetal (Table 3, entry 1) gave two products;
a compound that was monoiodinated at the methyl group and the
triiodoindole, in low yields. The 3-indoleacetonitrile was iodinated
regioselectively at the 2-position of indole (Table 3, entries 2 and 4)
but when ICl was present in excess the diiodo-compound was
obtained (Table 3, entry 3). The acetamidoethylindole was also
converted to the corresponding monoiodoindole (Table 3, entry 6).
In contrast, when the starting indole had a bromoalkyl substituent
(Table 3, entry 5) the 2-iodination was moderate.
1
Entry
1
Conditions
Producta
Yield (%)b
61
I
Al2O3/CH2Cl2 I2/2 h
I
N
H
1
2
I
2
3
I2/KI/CuI Cyclodextrine CH2Cl2/2 h
I2/KI/CuCl2 CeliteÒ/CH2Cl2/2 h
36
43
N
H
The order of addition of the reagents affected the yield. Thus,
adding the indole to a suspension of ICl and Celite in dichloro-
methane gave higher yield than the addition of ICl to the suspen-
sion of indole and Celite in dichloromethane.
I
N
H
3
3
3
3
The iodination protocol was also applied to other substrates
substituted with different groups in the aromatic ring, and the
desired products were isolated in good yields (50%e98%) as show in
Table 3.
It should be mentioned that when the iodination was performed
using ICleCelite at room temperature for 1 h the reaction was found
to be incomplete (Table 3, entries 1 and 8). An 1:1 (w/w) ICleCelite
ratio gave maximum yield of the desired product. The Celite was
recycled from reaction mixture and the effectiveness of this recy-
cling was studied and found effective up to three times. The Celite
was recovered by filtration, washed in methanol and activated at
150 ꢀC for 24 h.
I
4
5
6
ICl (1.2 equiv)/CH2Cl2 CeliteÒ/rt/2 h
ICl (1 equiv)/CH2Cl2 CeliteÒ/rt/2 h
ICl (1 equiv)/CH2Cl2 CeliteÒ/2 h
58
78
82
N
H
I
N
H
I
Interestingly, 1 equiv of ICl gave better selectivity and the best
yield (Table 3, entry 4). Similar results were obtained with acet-
amidoethylindole (Table 3, entry 6).
N
H
We used the iodination conditions for the synthesis of iodoa-
zaindole and iodopyrrole (Table 4). Similarly, we also found that an
excess of ICl gave a mixture of mono- and diiodoindoles (Table 4,
entries 2 and 4).
I
7
ICl (1 equiv)/CH2Cl2/2 h
37
N
H
3
Evaluation of various iodination reactions showed that the ICl/
Celite strategy is effective for a range of indole or derivative com-
pounds (Table 4, entries 1, 5 and 6). Interestingly, when we used
2.2 equiv of ICl the 2,3-diiodoazaindole was obtained in 89% yield,
but the reaction was slower (24 h) (Table 4, entry 4).
ICl is an environmentally benign reagent for the oxidation
process. The scope, limitation, and further application of ICl/Celite
in iodination of heterocycles remain to be examined. Further
studies into the optimization of this method are currently
underway.
a
Structures were confirmed from their spectral data (NMR and IR).
Isolated yields.
b
dichloromethane at room temperature. Celite is a porous inorganic
material (we used Celite-521Ò, a neutral form of SiO2 purchased
from SigmaeAldrich) with enormous surface area and several hy-
droxyl groups. These properties and the absence of chemical re-
activity turn Celite to an interesting inorganic carrier for supporting
different reagents.10c The reaction was tested in other solvents, such
as chloroform or acetonitrile but the yields were lower than in
dichloromethane. This method constitutes a mild, efficient and
relatively safe process for the iodination of indoles and derivatives.
Purification can be accomplished by filtration of the reaction mix-
ture through silica gel and provides the desired iodinated com-
pound in good yield (Table 2, entries 3 and 7). The results of this
study show that ICleCelite is the reagent of choice for the iodin-
ation of indoles. Thus, using dichloromethane as the solvent at
room temperature, the desired monoiodinated compounds were
obtained in 89% or 93% yields (Table 2, entries 6 and 7). The
iodoindole (5)12 was obtained in gram quantities in 85% yield under
the conditions of entry 6 (Table 2). The direct iodination of N-
phenylsulfonylindole in absence of Celite could also be achieved
but the yield was lower and the times of reaction are longer (Table
2, entry 8).
3. Conclusion
In summary, we have developed a method for the iodination of
a wide range of indoles and derivatives using ICl. This type of direct
conversion has proved to be attractive to chemists in general for
synthesizing new chemical compounds. We expect that these
substrates will become useful building blocks for the preparation of
more complex structures.
4. Experimental section
4.1. Materials
The stoichiometry of the reaction was studied and when more
than 1 equiv of ICl was used, the monoiodinated compound was
obtained, but in slightly lower isolated yield than when only
Commercial reagents and solvents were purchased from Sig-
maeAldrich and SDSeCarlo Erba.

S. Hamri et al. / Tetrahedron 68 (2012) 6269e6275
6271
Table 2
Iodination of substituted indoles
Entry Starting compound Conditions
Producta
Yield (%)b
I
I
1
2
I2/KI/CuCl2 cyclodextrine CH2Cl2/2 h
37þ18
I
N
N
N
R
R
R
4
5
R = phenylsulfonyl
R = phenylsulfonyl
I
N
I2/KI/CuCl2 CeliteÒ/CH2Cl2/2 h
67
R
R = phenylsulfonyl
5
I
N
3
4
5
6
ICl (1 equiv)/KI/CuCl2 CeliteÒ/CH2Cl2/1 h
ICl (1 equiv)/KI/CuCl2 CeliteÒ/CH2Cl2 8 h
ICl (1.4 equiv)/CH2Cl2 CeliteÒ/rt/8 h
ICl (1 equiv)/CH2Cl2 CeliteÒ/rt/4 h
92
R
R = phenylsulfonyl
5
I
N
87
R
R = phenylsulfonyl
5
I
I
16þ60
I
N
N
R
R
4
5
R = phenylsulfonyl
I
N
R
89 (85 in multigram scale,from 6 g of N-phenylsulfonylindole)
R = phenylsulfonyl
5
I
N
7
8
ICl (1 equiv)/CH2Cl2 CeliteÒ/1 h
93
38
R
R = phenylsulfonyl
5
I
N
ICl (1 equiv)/CH2Cl2/4 h
R
R = phenylsulfonyl
5
I
I
Br
Br
Br
9
ICl (1.2 equiv)/CH2Cl2 CeliteÒ/rt/4 h
ICl (1 equiv)/CH2Cl2 CeliteÒ/rt/4 h
I
25þ34
N
H
N
H
N
H
6
7
I
Br
10
68
N
H
7
I
Br
11
ICl (1 equiv)/CH2Cl2 CeliteÒ/1 h
76
N
H
7
a
Structures were confirmed from their spectral data (NMR and IR).
Isolated yields.
b
4.2. General
uncorrected. IR spectra were obtained using a FTIR PerkineElmer
1600 Infrared Spectrophotometer. Only noteworthy IR absorptions
are listed (cmꢁ1). 1H and 13C NMR spectra were recorded on a Varian
Gemini-200 (200 and 50.3 MHz, respectively) or Varian Gemini-300
Melting points were obtained on an MFB-595010M Gallenkamp
apparatus with digital thermometer in open capillary tubes and are

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S. Hamri et al. / Tetrahedron 68 (2012) 6269e6275
Table 3
Iodination of 3-substituted indoles
Entry
Starting compound
Conditions
Producta
Yield (%)b
O
O
O
O
I
CH3
ICl (excess)/CH2Cl2 CeliteÒ/rt/1 h
16þ33
I
1
I
N
N
N
+
9
8
R
R
R
R = 4-methoxyphenylsulfonyl
R = 4-methoxyphenylsulfonyl
CN
CN
2
3
I2/KI/CuCl2 CeliteÒ CH2Cl2/4 h
58
I
N
H
N
H
10
I
CN
CN
ICl (1.4 equiv)/CH2Cl2 CeliteÒ/rt/4 h
24þ38
I
I
N
H
N
H
10
11
CN
4
5
ICl (1 equiv)/CH2Cl2 CeliteÒ/rt/4 h
ICl (1 equiv)/CH2Cl2 CeliteÒ/rt/7 h
60
50
I
N
H
10
Br
Br
I
N
H
N
H
12
HN
O
HN
O
6
7
ICl (1 equiv)/CH2Cl2 CeliteÒ/rt/5 h
57
I
N
H
N
H
13
I
HN
HN
O
O
ICl (1.2 equiv)/CH2Cl2 CeliteÒ/rt/8 h
8þ33
I
I
N
H
N
H
13
14
HN
HN
O
O
ICl (1.2 equiv)/KI/CuCl2/CeliteÒ/CH2Cl2/1 h
78
H3CO
8
H3CO
I
N
H
N
H
15
HN
O
ICl (1.2 equiv)/CH2Cl2 CeliteÒ/rt/8 h
98
H3CO
9
I
N
H
15
a
Structures were confirmed from their spectral data (NMR and IR).
Isolated yields.
b
(300 and 75.5 MHz) Instrument using CDCl3 as solvent with tetra-
methylsilane as internal standard, (CD3)2CO or (CD3)2SO. Other 1H,
13C NMR spectra and heterocorrelation 1He13C (HSQC and HMBC)
experiments were recorded on a Varian Gemini-400 (400 MHz and
(ppm) relative to the central peak of the solvent (
d
¼7.26 ppm for
CDCl3 in 1H NMR and
d
¼77.16 ppm for CDCl3 in 13C NMR). Mass
spectra were taken on a HewlettePackard 5988-A and high resolu-
tion mass spectra (HRMS) were recorded on. LC/MSD-TOF mass
spectrometer (Agilent Technologies). Column chromatography was
100.6 MHz). Chemical shifts (d scale) are reported in parts per million

S. Hamri et al. / Tetrahedron 68 (2012) 6269e6275
6273
Table 4
Iodination of 7-azaindole and pyrrole
Entry
1
Starting compound
Conditions
Producta
Yield (%)b
I
ICl (1 equiv)/CH2Cl2 CeliteÒ/rt/4 h
65
N
H
N
N
H
N
16
I
I
2
3
ICl (1.4 equiv)/CH2Cl2 CeliteÒ/rt/24 h
ICl (1 equiv)/CH2Cl2 CeliteÒ/rt/4 h
60þtraces
I
N
H
N
H
N
N
17
16
I
N
N
N
59
N
R
R
R = phenylsulfonyl
18
R = phenylsulfonyl
I
I
N
4
5
ICl (2.2 equiv)/CH2Cl2 CeliteÒ/rt/24 h
89
N
R
R = phenylsulfonyl
19
CH3
O
S
CH3
O
S
O
O
ICl (1 equiv)/CH2Cl2 CeliteÒ/rt/2 h
ICl (1 equiv)/CH2Cl2 CeliteÒ/rt/2 h
78
63
CH3
I
CH3
N
N
H3C
20
H3C
I
6
CHO
N
CHO
N
CH3
21
CH3
a
Structures were confirmed from their spectral data (NMR and IR).
Isolated yields.
b
performed with silica gel (E. Merck, 70e230 mesh). Reactions were
monitored by TLC using 0.25 mm silica gel F-254 (E. Merck). Ele-
mental analysis forC, H andN were determined on a Carlo Erbae1106
Analyser. All reagents were of commercially quality or were purified
before use. Organic solvents were of analytical grade or were purified
by standard procedures. Reactions were carried out under argon.
2); 123.4 (CH, C-4); 126.5 (CH, C-6); 129.4 (C-5); 132.0 (C-3a); 133.7
(C-7a). HMRS (C8H4BrI2N) Calcd 446.7616, Found 446.7598.
4.3.2. 5-Bromo-3-iodo-1H-indole (7). Following the general pro-
cedure, compound 7 was obtained as a yellow solid in 76% yield. 1H
RMN (CDCl3, 300 MHz)
d
(ppm), 7.14 (d, J¼8.5 Hz,1H, H-7); 7.29(s,1H,
H-3); 7.33 (d, J¼8.5 Hz,1H, H-6); 7.77 (s,1H, H-4); 8.18 (s,1H, NH).13C
NMR (CDCl3, 75.5 MHz) d (ppm), 56.6 (C, C-3); 112.7 (CH, C-7); 114.1
4.3. Representative procedure for iodination of indoles and
derivatives 1e20
(C-5); 120.9 (C-3a); 122.0 (C-7a); 123.7 (CH, C-2); 126.1 (CH, C-4);
129.5 (CH, C-6). HMRS (C8H5BrIN) Calcd 320.8650, Found 320.8639.
A solution of indole, azaindole or pyrrole (0.1 mmol) in
dichloromethane (5 mL) was added to a suspension of 1:1 (w/w) ICl
(concentration indicated in the Table; 0.1 mmol¼162 mg) and Cel-
iteÒ (162 mg) ratio in dichloromethane (10 mL). The mixture was
stirred at room temperature for the time indicated in Tables 1e4 The
reaction mixturewas thenpoured into saturated thiosulfatesolution
(20 mL) extracted with dichloromethane (2ꢂ15 mL). The organic
layer was washed in brine and, dried over sodium sulfate and the
solvent was removed at reduced pressure. The desired compound
was purified by chromatography column using hexane and ethyl
acetate mixtures as eluting solvent. Yields of iodinated compounds
are summarized in Tables 1e4. All the compounds were character-
ized by IR, NMR and were compared with authentic samples.
4.3.3. 2,2-Diiodo-1-(2-iodo-1-(4-methoxyphenylsulfonyl)-1H-indol-
3-yl)ethanone (8). Following the general procedure but using ex-
cess of ICl (4 equiv), compound 8 was obtained as a yellow solid in
16% yield. Mp: 122e124 ꢀC (CH2Cl2). 1H RMN (CDCl3, 300 MHz)
d
(ppm), 3.88 (s, 3H, OCH3); 6,89 (d, J¼8.9 Hz, 2H, H-30, H-50); 7.27
(s, 1H, CHI2); 7.34 (d, J¼8.3 Hz, 1H, H-7); 7.41 (t, J¼8.34 Hz, 1H, H-6);
7.45 (t, J¼8.3 Hz, 1H, H-5); 7.82 (d, J¼8.9 Hz, 2H, H-20, H-60); 8.06 (d,
J¼8.3 Hz, 1H, H-4). 13C NMR (CDCl3, 75,5 MHz)
d
(ppm), ꢁ22.0
(CHI2); 55.8 (CH3eO); 112.8 (C-2); 114.3 (CH, C-7); 114.6 (CH, C-30,
C-50); 125.2 (CH, C-4); 126.2 (CH, C-6); 128.3 (C-3); 123.4 (CH, C-5);
127.1 (C-3a); 130.6 (CH, C-20, C-60); 132.6 (CH, C-5); 134.0 (C, C-10);
136.5 (C-3a); 140.6 (C-7a); 164.9 (C-40); 166.4 (CO). HMRS
(C17H12I3NO4S) Calcd 706.7621, Found 706.7601.
4.3.1. 5-Bromo-2,3-diiodo-1H-indole (6). Following the general
procedure, compound 6 was obtained as oil in 25% yield. 1H RMN
4.3.4. 2-Iodo-1-(1-(4-methoxyphenylsulfonyl)-1H-indol-3-yl) etha-
none (9). Following the general procedure but using excess of ICl
(4 equiv), compound 9 was obtained as a solid in 33% yield. Mp:
(CDCl3, 300 MHz)
d
(ppm), 7.14 (d, J¼8.60 Hz, 1H, H-7); 7.31 (d,
J¼8.60 Hz, 1H, H-6); 7.67 (s, 1H, H-4); 8.20 (s, 1H, NH). 13C NMR
147e149 ꢀC (CH2Cl2). 1H NMR (CDCl3, 300 MHz)
d (ppm), 3.82 (s,
(CDCl3, 75.5 MHz)
d
(ppm), 58.1 (C-3); 112.1 (CH, C-7); 114.7 (C, C-
3H, OCH3); 4.30 (s, 2H, CH2); 6.93 (d, J¼9.2 Hz, 2H, H-30, H-50); 7.37

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S. Hamri et al. / Tetrahedron 68 (2012) 6269e6275
(m, 2H, H-5, H-6); 7.90 (d, J¼9.2 Hz, 2H, H-20, H-60); 7.93 (m, 1H, H-
H-2); 7.80 (d, J¼7.9 Hz, 1H, H-4); 8.34 (d, J¼4.8 Hz, 1H, H-6). 13C
7); 8.28 (m, 1H, H-4); 8.33 (s, 1H, H-2). 13C NMR (CDCl3, 100 MHz)
RMN (CDCl3, 75.5 MHz) d (ppm), 55.3 (C-3); 116.9 (CH, C-5); 124.5
d
(ppm), 2.63 (CH2); 55.8 (CH3eO); 113.1 (CH, C-7); 114.1 (C-3);
(C-3a); 130.6 (CH, C-2); 131.1 (CH, C-4); 143.2 (CH, C-6); 146.7 (C-
7a). 2-Iodo-1H-pyrrolo[2,3-b]pyridine (17).16 The compound 17 was
obtained as a solid in <2% yield. Mp¼112e114 ꢀC (hexane/ethyl
114.9 (CH, C-30, C-50); 117.4 (CH, C-4); 123.2 (CH, C-6); 124.7 (CH,
C-5); 126.0 (CH, 127.6 (C-3a)); 128.7 (C-10); 129.6 (CH (ꢂ2), C-20, C-
60); 132.8 (C, C-2); 134.8 (C-7a); 164.8 (C-40); 188.5 (CO). HMRS
(C17H14INO4S) Calcd 454.9688, Found 454.9702.
acetate 1:1) (115e116 ꢀC).16 1H RMN (CDCl3, 300 MHz)
d (ppm), 6.54
(s, 1H, H-3); 7.28 (t, J¼8.0 Hz, 1H, H-5); 7.50 (m, 2H, H-30 and H-50);
7.72e7.81 (m, 2H, H-4, H-40); 7.89 (d, J¼7.5 Hz, 2H, H-20 and H-60);
4.3.5. 2-(2-Iodo-1H-indol-3-yl) acetonitrile (10).13 Following the
general procedure, compound 10 was obtained as a yellow solid in
60% yield. Mp:118e120 ꢀC (ethylacetate), (Lit.116e118 ꢀC)13 1HRMN
8.43 (d, J¼8.0 Hz,1H, H-6). 13C RMN (CDCl3, 75.5 MHz)
d (ppm), 76.2
(C); 119.3 (CH, C-3), 120.6 (CH, C-5); 123.9 (C, C-3a), 127.8 (CH, C-4);
128.1 (CH, C-20, C-60); 129.4 (CH, C-30, C-50); 134.8 (CH, C-40); 138.9
(C-10); 149.5 (C, C-7a). Anal.Calcd(%) for C7H4I2N2: C, 22.73; H, 1.09;
N, 7.57. Found: C, 23.02; H, 1.34; N, 7.34.
(CDCl3, 300 MHz) d (ppm), 3.88 (s, 2H, CH2CN); 7.59e7.17 (m, 4H, H-
Ar (ꢂ4)); 8.25 (s, 1H, NH). 13C RMN (CDCl3, 75.5 MHz)
d (ppm), 14.7
(CH2); 77.3 (C-2); 104.9 (C-3); 111.9 (CH, C-7); 118.4 (CH, C-4); 120.5
(CH, C-6); 123.2 (CN); 123.2 (CH, C-5); 126.5 (C-3a); 136.6 (C-7a).
4.3.11. 2,3-Diiodo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]
pyridine
(19). Following the general procedure from 7-azaindole but using
excess of ICl (2.2 equiv), compound 19 was obtained as a solid in
4.3.6. 2-Iodo-2-(2-iodo-1H-indol-3-yl)acetonitrile (11). Following
the general procedure from the 2-indolylacetonitril but using ex-
cess of ICl (1.4 equiv), compound 11 was obtained as a solid in 39%
89% yield. 1H RMN (CDCl3, 300 MHz)
d
(ppm), 6.95 (dd, J1¼4.86 Hz,
J2¼7.89 Hz, 1H, H-5); 7.50 (m, 3H, H-30, H-50, H-40); 7.84 (d,
yield. 1H RMN ((CD6)2CO, 300 MHz)
d (ppm), 4.15 (s, 1H, CHCN);
J¼7.89 Hz, 1H, H-4); 8.18 (m, 2H, H-20, H-60); 8.43 (d, J¼4.86 Hz, 1H,
7.22 (d, J¼8.2 Hz, 1H, H-7); 7.40e7.31 (m, 1H, H-5); 7.60e7.54 (m,
H-6). 13C RMN (CDCl3, 75.5 MHz)
d (ppm), 73.4 (C); 109 (C), 120.9
1H, H-6); 7.85 (t, J¼8.2 Hz, 1H, H-4). 13C NMR (CDCl3, 75,5 MHz)
(CH, C-5); 123.3 (C, C-3a), 126.1 (CH, C-4); 128.9 (CH, C-20, C-60);
129.1 (CH, C-30, C-50); 134.8 (CH, C-40); 138.3 (C-10); 141.1 (CH, C-6);
149.2 (C, C-7a). Anal.Calcd(%) for C13H8I2N2O2S: C, 30.61; H, 1.58; N,
5.49. Found: C, 31.10; H, 1.88; N, 5.87.
d
(ppm), 25.4 (CH-I); 78.1 (C-2); 109.5 (CH, C-7); 114.0 (C-3); 117.1
(CN); 118.7 (CH, C-4); 122.5 (CH, C-6); 124.2 (CH, C-5); 128.4 (C-3a);
138.2 (C, C-7a). HMRS (C10H6I2N2) Calcd 407.8620, Found 407.8647.
4.3.7. 3-(2-Bromoethyl)-2-iodo-1H-indole (12). Following the gen-
eral procedure from the 3-(2-bromoethyl)indole with ICl (1 equiv),
compound 12 was obtained as yellow oil in 50% yield. 1H RMN
4.3.12. 1-Ethyl-5-iodo-2-methyl-3-(methylsulfonyl)-1H-pyrrole
(20). Following the general procedure from the substituted pyrrole,
the compound 20 was obtained as yellow oil in 78% yield. 1H RMN
(CDCl3, 300 MHz)
d
(ppm), 3.32 (t, J¼7.7 Hz, 2H, CH2-Ar); 3.63 (t,
(CDCl3, 300 MHz)
CH3eAr); 3.01 (s, 3H, CH3S); 3.95 (q, J¼7.3 Hz, 2H, CH2N); 6.39 (s,
1H, H-3). 13C RMN (CDCl3, 75.5 MHz)
(ppm), 10.7 (CH3); 15.9
(CH3); 42.6 (CH2eN); 44.9 (CH3eS); 117.6 (CH, C-4); 121.3 (C-3);
122.8 (C-5); 134.1 (C-2). Anal.Calcd(%) for C8H12INO2S: C, 30.68; H,
3.86; N, 4.47. Found: C, 30.45; H, 3.97; N, 4.89.
d
(ppm), 1.28 (t, J¼7.3 Hz, 3H, CH3); 2.48 (s, 3H,
J¼7.7 Hz, 2H, CH2Br); 7.24 (m, 2H, H-5, H-6); 7.36 (d, J¼7.9 Hz, 1H,
H-7); 7.50 (d, J¼7.9 Hz, 1H, H-4); 8.03 (s, 1H, NH). 13C RMN (CDCl3,
d
75.5 MHz)
d
(ppm), 28.7 (CH2); 32.5 (CH2eBr); 69.8 (C-2); 109.4
(CH, C-7); 115.4 (C-3); 119.0 (CH, C-4); 121.2 (CH, C-6); 124.4 (CH, C-
5); 126.2 (C-3a); 139.7 (C-7a). Anal. Calcd(%) forC10H9BrIN: C, 34.32;
H, 2.59; N, 4.00. Found: 34.60; H, 2.21; N, 4.36.
4.3.13. 4-Iodo-1-methyl-1H-pyrrole-2-carbaldehyde (21).17 Following
the general procedure from N-methylpyrrole-3-carbaldehyde, the
compound 21 was obtained as solid in 63% yield. Mp¼72e75 ꢀC. 1H
4.3.8. N-(2-(2-Iodo-1H-indol-3-yl)ethyl)acetamide (13). Following
the general procedure from the N-(2-(1H-indol-3-yl)ethyl)acetamide
compound 13 was obtained as a solid in 57% yield. Mp: 54e56 ꢀC
RMN (CDCl3, 300 MHz) d (ppm), 3.94 (s, 3H, CH3); 6.91 (s, 1H, H-3);
(ethyl acetate). 1H RMN (CDCl3, 300 MHz)
d
(ppm), 1.92 (s, 3H, CH3);
6.98 (s, 1H, H-5); 9.50 (s, 1H, CHO). 13C RMN (CDCl3, 75.5 MHz)
d (ppm), 36.9 (CH3); 77,0 (C, C-4); 130.3 (CH, C-3); 133.9 (C, C-2);
2.96 (t, J¼6.0 Hz, 2H, CH2eAr); 3.55 (t, J¼6.0 Hz, 2H, CH2NH); 5.50 (s,
1H, NH); 7.20e7.11 (m, 2H, H-5, H-6); 7.29 (d, J¼6.0 Hz,1H, H-7); 7.51
(d, J¼6.0 Hz, 1H, H-4); 8.28 (s, 1H, NH). 13C RMN (CDCl3, 75.5 MHz)
136.3 (CH, C-5); 179.1 (CHO). Anal.Calcd(%) for C6H6INO: C, 30.66;
H, 2.57; N, 5.96. Found: C, 30.96; H, 2.23; N, 5.55.
d
(ppm), 24.2 (CH3); 30.0 (CH2eAr); 39.7 (CH2eN); 81.8 (C-2); 109.6
(C-3); 110.9 (CH, C-7); 118.4 (CH, C-4); 120.7 (CH, C-6); 122.9 (CH, C-5);
134.8(C-3a);141.9(C-7a);170.5 (C]O). Anal. for C12H13IN2O. Calcd:C,
43.92; H, 3.99; N, 8.54. Found: 44.12; H, 4.32; N, 8.22.
Acknowledgements
We thank to the Ministerio de Economia y Competitividad
(Spain) (CTQ2011-29285-C02-01) for financial support.
4.3.9. N-(2-(2-Iodo-5-methoxy-1H-indol-3-yl) ethyl) acetamide
(15).14 Following the general procedure from the melatonin the
iodoemelatonin 15 was obtained as a solid in 98% yield. Mp:
Supplementary data
53e55 ꢀC (hexane/ethyl acetate).1H RMN (CDCl3, 300 MHz)
d (ppm),
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2012.05.053.
1.93 (s, 3H, CH3); 2.92 (t, J¼6.5 Hz, 2H, CH2eAr); 3.53 (t, J¼6.5 Hz, 2H,
CH2N); 3.84 (s, 3H, OCH3); 5.55 (s, 1H, NH); 6.84 (d, J¼8.8 Hz, 1H, H-
6); 6.96 (s, 1H, H-4); 7.18 (d, J¼8.8 Hz, 1H, H-7); 8.21 (s, 1H, NH). 13C
References and notes
RMN (CDCl3, 75.5 MHz) d (ppm), 22.6 (CH3); 24.5 (CH2); 40.3 (CH2);
55.5 (CH3eO); 59.8 (C-2); 100.6 (CH, C-4); 109.3 (C-3); 111.9 (CH, C-
7); 112.2 (CH, C-6); 122.2 (C, C-3a); 132.8 (CH, C-7a); 154.2 (C-5);
169.6 (C, CO). MS (EI) m/z 359 (MþH); 232 (MHþꢁI).
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