Pd/C-Mediated synthesis of indoles in water

Article abstract of DOI:10.3762/bjoc.5.46

We describe the utility of a Pd/C-Cu mediated method in the synthesis of 2,s 5-disubstituted indoles in water via a coupling-cyclization strategy. Further application of this methodology has been demonstrated in the preparation of a target indole derivative via a 7-step process the key step being the Pd/C-mediated coupling reaction.

Full text of DOI:10.3762/bjoc.5.46

Pd/C-Mediated synthesis of indoles in water
Mohosin Layek1,2, Udaya Lakshmi1, Dipak Kalita1, Deepak K. Barange1,
Aminul Islam1, K. Mukkanti2 and Manojit Pal*,3,4
Full Research Paper
Open Access
Address:
Beilstein Journal of Organic Chemistry 2009, 5, No. 46.
1Dr. Reddy’s Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad
500049, India, 2Chemistry Division, Institute of Science and
Technology, JNT University, Kukatpally, Hyderabad 500072, India,
3New Drug Discovery, R&D Center, Matrix Laboratories Ltd., Anrich
Industrial Estate, Bollaram, Jinnaram Mandal, Medak District, Andra
Pradesh 502 325, India and 4(present address:) Institute of Life
Science, University of Hyderabad Campus, Gachibowli, Hyderabad
500 046, Andhra Pradesh, India
doi:10.3762/bjoc.5.46
Received: 12 July 2009
Accepted: 09 September 2009
Published: 23 September 2009
Associate Editor: I. Marek
© 2009 Layek et al; licensee Beilstein-Institut.
License and terms: see end of document.
Email:
Manojit Pal* - manojitpal@rediffmail.com
* Corresponding author
Keywords:
C–C bond; charcoal; copper; indoles; palladium
Abstract
We describe the utility of a Pd/C-Cu mediated method in the synthesis of 2,5-disubstituted indoles in water via a coupling-cycliza-
tion strategy. Further application of this methodology has been demonstrated in the preparation of a target indole derivative via a
7-step process the key step being the Pd/C-mediated coupling reaction.
Introduction
2-Substituted indoles (A, Figure 1) display a wide range of indole based compound libraries we decided to synthesize
pharmacological activities and therefore have been explored as compound C and its analogues.
a number of potential therapeutic agents [1] e.g. inhibitors of
proteases involved in coagulation [2,3], antagonists of A large number of methods [9-12] have been reported for the
G-protein-coupled receptors [4,5], anti-angiogenic compounds construction of indole ring many of which are mediated by
[6] and inhibitors of endothelinconverting-enzyme [7]. 5-Alkyl transition metal catalysts. Among these methods palladium
substituted indoles e.g. naratriptan (B, Figure 1) on the other mediated protocols have gain considerable interest [13]. In our
hand have been reported as a 5-HT1B/1D receptor agonists for effort towards the development of palladium-catalyzed reac-
the potential treatment of migraine headache [8]. Thus a tions in aqueous media, we have reported an efficient synthesis
combination of both in a single molecule was expected to of 2-substituted indoles via a Pd/C-catalyzed coupling-cycliza-
provide novel agent (C, Figure 1) of potential biological signi- tion process in water [14]. Herein, we report a further continu-
ficance. Due to our continued interest in the development of ation of our previous work towards the synthesis of a variety of
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Beilstein Journal of Organic Chemistry 2009, 5, No. 46.
Figure 1: Design of novel indole derivative C of pharmacological interest.
indole derivatives along with the preparation of target In our previous [14] as well as the present study we have used
compound C.
three equivalents of terminal alkynes to obtain the optimum
yields of products. It is possible that the excess equivalents of
terminal alkynes might undergo dimerization via oxidative
Results and Discussion
In our previous study after examining a number of N-substi- coupling though no significant amount of 1,3-butadiyne deriv-
tuted o-iodoanilides we have observed that the N-methanesulf- ative was isolated as a side product from any of the reactions
onyl derivative provided the best result in terms of product presented in Table 1. However, to assess the effect of using
nature and yields [14]. However, the presence of only one fewer equivalents of terminal alkynes we conducted an experi-
substituent, i.e. a methyl group on the o-iodoaniline ring was ment using 1a and 2a in a ratio of 1.0:1.2 without changing the
examined. Moreover, the presence of other sulfonyl groups e.g. other reaction conditions. The desired indole 3a was isolated in
the benzenesulfonyl moiety on the aniline nitrogen was not 60% yield (vs 79% of entry 1, Table 1) confirming the require-
studied. In the present study we aimed to conduct further ment for an excess amount of terminal alkyne to achieve the
research taking into account of above-mentioned aspects. Thus, best yield of the desired product.
when o-iodoanilide 1 was treated with terminal alkyne 2 (3.0
equiv) in water in the presence of 10% Pd/C (0.03 equiv), PPh3 We have also examined the use of a basic iodoaniline such as
(0.12 equiv), CuI (0.06 equiv) and 2-aminoethanol (3.0 equiv) N-methyl substituted 2-iodoaniline in the present coupling reac-
under nitrogen, 2-substituted indoles 3 were obtained in good tion with terminal alkynes. Isolation of 2-alkynyl substituted
yields (Scheme 1). The details of this study are summarized in N-methylaniline as a sole product rather than expected indole
Table 1.
indicated that the presence of an electron donating group on the
nitrogen was unfavourable for the cyclization step though the
C–C coupling reaction proceeded well under the conditions
employed.
Having prepared a variety of N-substituted indole derivatives
successfully we then undertook the synthesis of the target
indole C. Compound C was prepared from bromo compound 4
following a 7-step process using the Pd/C-mediated indole
synthesis as a key step as shown in Scheme 2. Thus treatment of
bromide 4 with Na2SO3 provided corresponding sulfonic acid 5
which on treating with PCl5 provided the sulfonyl chloride
derivative 6. On reaction with aqueous methylamine compound
6 provided the methanesulfonamide derivative 7, the nitro
group of which was reduced in the presence of Raney nickel to
yield the corresponding aniline derivative 8. Iodination of 8
using elemental iodine provided the o-iodoaniline derivative 9
which was converted to the corresponding methanesulfonamide
10. Compound 10 when reacted with phenylacetylene in the
presence of 10% Pd/C-CuI-PPh3 and 2-aminoethanol in water
provided the desired indole derivative C.
Scheme 1: Preparation of 2,5-disubstituted indole.
We have examined four anilides 1a–d each of which particip-
ated well in the present Pd/C-mediated coupling-cyclization
process. Substituents such as halogen atoms (1a, 1c and 1d) and
alkyl groups (1b) on the aryl ring were well tolerated. A range
of terminal alkynes 2 were employed in the present reaction to
obtain the corresponding indole 3 in 65–90% yield via a single
step method. Thus, we have extended the generality and scope
of our previously reported method considerably demonstrating
its potential in the synthesis of a diversity based indole library.
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Beilstein Journal of Organic Chemistry 2009, 5, No. 46.
Table 1: Pd/C-Catalyzed synthesis of 2,5-disubstituted N-sulfonyl-indoles in aqueous media.a
Entry
o-Iodoanilide 1
Alkyne 2; Y =
Time (h)
Product 3b
Yield (%)c
-CH2CH(OH)CH3
1.
10
79
2a
1a
1a
3a
3b
3c
-C6H4CH3-p
2.
3.
4
6
86
90
2b
2b
1b
1b
4.
10
75
2c
2b
3d
3e
5.
6.
12
14
78
90
1c
1c
2d
2c
3f
7.
10
76
1d
3g
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Beilstein Journal of Organic Chemistry 2009, 5, No. 46.
Table 1: Pd/C-Catalyzed synthesis of 2,5-disubstituted N-sulfonyl-indoles in aqueous media.a (continued)
-(CH2)3OH
8.
1d
14
80
2e
3h
-CH2CH(OH)CH3
9.
1d
12
65
2a
3i
-C(CH3)2OH
10.
11.
12.
1d
1c
1d
10
14
10
70
75
78
2f
3j
2c
3k
2b
3l
-C6H5
2g
13.
1d
8
68
3m
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Beilstein Journal of Organic Chemistry 2009, 5, No. 46.
Table 1: Pd/C-Catalyzed synthesis of 2,5-disubstituted N-sulfonyl-indoles in aqueous media.a (continued)
14.
1d
12
70
2h
3n
-(CH2)3CH3
15.
1d
12
74
2i
3o
3p
-C6H4NO2-o
16.
1c
24
78
2j
17.
1c
12
78
2k
3q
18.
19.
1c
1c
-(CH2)3Cl2l
5
3
74
85
3r
2m
3s
aAll reactions were carried out by using 1 (1.0 equiv), 2 (3.0 equiv), 1:4:2 ratio of Pd/C:PPh3:CuI, 2-aminoethanol (3.0 equiv) in H2O.
bIdentified by 1H NMR, 13C NMR, IR, MS.
cIsolated yields.
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Beilstein Journal of Organic Chemistry 2009, 5, No. 46.
Scheme 2: Preparation of compound C.
Conclusions
ation method and the condition specified in each case: column,
In conclusion, we have demonstrated the potential of our previ- mobile phase (range used), flow rate, detection wavelength, and
ously reported palladium on carbon mediated practical synthesis retention times. All the reagents used are commercially avail-
of 2-substituted indoles in water. Besides preparing a wide able.
variety of indole derivatives the methodology was utilized to
General method for the preparation of
prepare one of our target indole derivatives smoothly. We
believe that the present demonstration would encourage o-iodoanilides (1a–d)
organic/medicinal chemists to explore the utility of this method- Step A (a typical procedure): A suspension of 4-fluoro aniline
ology for easy access to indole based agents of pharmaceutical (5.0 g, 0.045 mol) in aqueous solution (50.0 mL) of sodium
interest.
bicarbonate (0.045 mol) was stirred for 0.5 h. Then iodine
(0.040 mol) was added at 5–10 °C and the mixture was stirred
for 12.0 h. After completion, the reaction mixture was diluted
Experimental
General methods: Unless stated otherwise, reactions were with ethyl acetate (250 mL) and extracted with ethyl acetate (3
monitored by thin layer chromatography (TLC) on silica gel × 250 mL). The organic layers were collected, combined,
plates (60 F254), visualizing with ultraviolet light or iodine washed with saturated aqueous sodium thiosulfate solution (2 ×
spray. Flash chromatography was performed on silica gel 125 mL), dried over anhydrous Na2SO4 and concentrated under
(60–120 mesh) using distilled petroleum ether and ethyl acetate. vacuum. The crude product was purified by column chromato-
1H and 13C NMR spectra were determined either in CDCl3 or graphy on silica gel using 3:1, hexane\ethyl acetate to afford the
DMSO-d6 solution using 400 and 50 MHz spectrometers, desired product (6.4 g, 60% yield). 4-chloro-2-iodoaniline [15]:
respectively. Proton chemical shifts (δ) are relative to tetra- white solid, mp 42–43 °C; lH NMR (CDCl3, 400 MHz) δ 7.59
methylsilane (TMS, δ = 0.0) as internal standard and expressed (d, J = 2.2 Hz, 1H), 7.08 (dd, J = 8.6, 2.2 Hz, 1H), 6.62 (d, J =
in parts per million. Spin multiplicities are given as s (singlet), d 8.6 Hz, 1H), 4.19 (br s, NH2); m/z (ES Mass) 253 (M+1,
(doublet), t (triplet), and m (multiplet) as well as b (broad). 100%); IR (cm−1, KBr) 3370, 1475, 1215, 1140. 4-ethyl-2-
Coupling constants (J) are given in hertz. Infrared spectra were iodoaniline [16]: white solid, mp 38–41 °C; lH NMR (CDCl3,
recorded on a FTIR spectrometer. Melting points were determ- 400 MHz) δ 7.45 (m, 1H), 6.95 (m, 1H), 6.66 (d, J = 8.0 Hz,
ined by using thermal analysis and differential scanning calori- 1H), 3.85 (br s, NH2), 2.58 (m, 2H), 1.25 (s, 3H); m/z (ES
metry (DSC) was generated with the help of DSC-60A dector. Mass) 247 (M+1, 100%); IR (cm−1, KBr) 3347, 1480, 1333,
MS spectra were obtained on a mass spectrometer. Chromato- 1130. 4-fluoro-2-iodoaniline [17]: Orange oil; lH NMR (CDCl3,
graphic (HPLC) purity was determined by using area normaliz- 400 MHz) δ 7.35 (dd, J = 7.9, 2.2 Hz, 1H), 6.90–6.85 (m, 1H),
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Beilstein Journal of Organic Chemistry 2009, 5, No. 46.
6.68–6.65 (m, 1H), 3.92 (br s, NH2); m/z (ES Mass) 237 (M+1, 75 mL), dried over Na2SO4, filtered and concentrated under
100%); 3354, 1471, 1213, 1135.
vacuum. The residue thus obtained was purified by column
chromatography (hexane/EtOAc) to afford the desired product.
Step B (a typical procedure): A mixture of 4-fluoro-2-iodo
aniline (6.4 g, 0.027 mol), DMAP (0.49 g, 0.004 mol) was Preparation of 2-(4-nitro-phenyl)-ethanesulfonic acid (5): A
dissolved in pyridine (50.0 mL) and cooled to 0–5 °C. To this mixture of 2-(4-nitro-phenyl)ethylbromide (2.5 g, 11.0 mmol),
was added methanesulfonyl chloride (4.0 g, 0.035 mol) drop- sodium sulfite (2.05 g, 16.0 mmol) and TBAB (0.116 g, 0.36
wise and the mixture was refluxed for 12 h. After completion of mmol) in water was refluxed for 3 h. The reaction mass was
the reaction, the mixture was cooled to 5–10 °C, neutralized cooled to room temperature and washed with ethyl acetate (5
with dil HCl and extracted with ethyl acetate (3 × 300 mL). The mL). The aqueous layer was acidified (pH ~ 2) with dil HCl and
organic layers were collected, combined, washed with saturated concentrated. The gummy residue obtained was treated with
aq. NaCl (2 × 250 mL), dried over anhydrous Na2SO4 and methanol (10 mL) and stirred for 0.5 h. It was then filtered and
concentrated under vacuum. The crude compound was purified the filtrate concentrated to give the crude product (2.4 g, 95%
by column chromatography on silica gel using 4:1 hexane\ethyl yield); brown liquid, Rf (80% ethyl acetate/n-hexane) 0.3; 1H
acetate to afford the desired product (5.1 g, 60% yield) as a NMR (DMSO-d6, 400 MHz) δ 8.15 (d, J = 8.4 Hz, 2H), 7.30 (d,
brown solid,
J = 8.4 Hz, 2H), 3.21 (bs, OH, 1H), IR (cm−1, KBr): 3411,
1312, 1145; m/z (ESMS) 232 (M+1, 100%); 13C NMR
N-(4-chloro-2-iodophenyl)methanesulfonamide [18] (1a): (DMSO-d6, 50 MHz) δ 146.5, 145.2, 128.2 (2C), 123.5 (2C),
White solid, mp 111 °C; lH NMR (CDCl3, 400 MHz) δ 58.5, 29.5; HRMS (ESI): calcd for C8H10NO5S (M+H)+
7.76–7.85 (m, 2H), 7.06–7.11 (m, 1H), 6.51 (br s, 1H), 3.15 (s, 232.0278, found 232.0275.
3H); m/z (ES Mass) 331 (M+1, 100%); 3255, 1480, 1335, 1165.
Preparation of 2-(4-nitro-phenyl)ethanesulfonic acid methyl-
N-(4-ethyl-2-iodophenyl)methanesulfonamide (1b): White amide (7): Compound 5 (3.70 g, 16.0 mmol) was cooled and
solid, mp 103 °C; lH NMR (CDCl3, 400 MHz) δ 7.65 (d, J = PCl5 (8.30 g, 40.0 mmol) was added under anhydrous condi-
2.0 Hz, 1H), 7.53 (d, J = 8.2 Hz, 1H), 7.19 (dd, J = 8.0 and 2.0 tions. The mixture was slowly heated to reflux with stirring for
Hz, 1H), 6.50 (br s, 1H), 2.98 (s, 3H) 2.57 (q, J = 7.6, 2H), 1.20 30 min. The reaction mixture was cooled to room temperature,
(t, J = 7.6, 3H); m/z (ES Mass) 325 (M+1, 100%); IR (cm−1, diluted with CH2Cl2 (8 mL), stirred for 15 min and filtered. The
KBr) 3248, 1486, 1323, 1148.
filtrate containing the acid chloride 6 was collected and used in
the next step directly. A saturated solution of methylamine was
N-(4-fluoro-2-iodophenyl)methanesulfonamide (1c): Brown cooled to 0–5 °C and to this was added the CH2Cl2 solution of
solid, mp 91 °C; lH NMR (CDCl3, 400 MHz) δ 7.55–7.65 (m, acid chloride 6 with stirring maintaining the temperature below
2H), 7.10–7.15 (m, 1H), 6.47 (br s, 1H), 2.99 (s, 3H); m/z (ES 0 °C. The reaction mixture was stirred at the same temperature
Mass) 315 (M+1, 100%); 3254, 1481, 1330, 1155.
for 0.5 h and then at room temperature for 3 h. After comple-
tion of the reaction the mixture was filtered and the filtrate was
N-(4-fluoro-2-iodophenyl)benzenesulfonamide [17] (1d): collected and concentrated. The gummy residue obtained was
Brown solid, mp 99 °C; lH NMR (CDCl3, 400 MHz) δ stirred with cold water (100–150 mL) for 0.5 h and then
7.57–7.66 (m, 3H), 7.35–7.38 (m, 1H), 7.21–7.26 (m, 2H), filtered. The solid obtained was washed for several times with
7.04–7.09 (m, 1H), 6.60 (br s, 1H), 2.39 (s, 3H); m/z (ES Mass) water, 20% ethyl acetate/n-hexane and dried to give the title
377 (M+1, 100%); IR (cm−1, KBr) 3254, 1478, 1337, 1167.
compound crude product (1.5 g, 38% yield) as a brown solid;
mp 132–136 °C; Rf (60% ethyl acetate/n-hexane) 0.3; 1H NMR
(DMSO-d6, 400 MHz) 8.17 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.4
Hz, 2H), 4.12 (bs, NH, 1H), 3.27–3.22 (m, 2 H), 2.87–2.83 (m,
General method for the preparation of
2-substituted indoles 3
A mixture of 1c (300 mg, 0.95 mmol), 10% Pd/C (31.28 mg, 2H), 2.70 (d, J = 4.5 Hz, 3H); IR (cm−1, KBr) 3411, 1312,
0.029 mmol), PPh3 (29.9 mg, 0.11 mmol), CuI (10.87 mg, 1145; m/z (ES Mass) 245 (M+1, 100%); 13C NMR (DMSO-d6,
0.057 mmol) and 2-aminoethanol (2.85 mmol) in H2O (8 mL) 50 MHz) δ 148.5, 145.6, 128.7 (2C), 124.5 (2C), 58.5, 24.8,
was stirred at 25 °C for 1 h under nitrogen. The acetylenic 24.4; HRMS (ESI): calcd for C9H13N2O4S (M+H)+ 245.0595,
compound 2 (2.85 mmol) was added slowly to the mixture with found 245.0592.
stirring. The reaction mixture was then stirred at 80 °C for the
time indicated in Table 1. The mixture was cooled to room Preparation of 2-(4-amino-phenyl)ethanesulfonic acid methyl-
temperature, diluted with EtOAc (120 mL) and filtered through amide (8): A solution of compound 7 (1.55 g, 6.3 mmol) was
celite. The filtrate was collected, washed with cold water (2 × dissolved in 1:1 methanol/ethyl acetate (30 mL) and hydrogen-
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Beilstein Journal of Organic Chemistry 2009, 5, No. 46.
ated in the presence of Raney nickel (1.5 g) at 65 to 70 psi for 2H), 2.81 (s, 3H), 2.71 (d, J = 4.5 Hz, 3H); IR (cm−1, KBr)
4–5 h. The reaction mixture was filtered through celite bed. The 3276, 1476, 1364, 1156; m/z (ES Mass): 418 (M+1, 100%); 13C
filtrate was collected, concentrated and dried to give the title NMR (DMSO-d6, 200 MHz): 142.8, 140.1, 135.0, 131.7, 129.6,
compound (1.0 g, 74% yield) as a brown solid; mp 126–128 °C; 104.0, 49.5, 43.8, 28.5, 28.1; HRMS (ESI): calcd for
Rf (75% ethyl acetate/n-hexane) 0.3; 1H NMR (DMSO-d6 400 C10H16N2O4S2I (M+H)+ 418.9596, found 418.9607.
MHz) δ 6.90 (d, J = 8.5 Hz, 2H), 6.88 (bs, NH, 1H), 6.50 (d, J =
8.2 Hz, 2H), 4.91 (bs, NH, 2H), 3.17–3.12 (m, 2 H), 2.77–2.73 Preparation of 2-(1-methanesulfonyl-2-phenyl-1H-indol-5-
(m, 2H), 2.56 (d, J = 4.5 Hz, 3H); IR (KBr, cm−1) 3411, 1312, yl)ethanesulfonic acid methylamide (C): A mixture of 10 (1.0 g,
1145; m/z (ES Mass): 215 (M+1, 100%); 13C NMR (DMSO-d6, 2.39 mmol), 10% Pd/C (76.0 mg, 0.071 mmol), PPh3 (75.22
50 MHz): 146.9, 128.7 (2C), 125.2, 114.0 (2C), 51.0, 28.5, mg, 0.28 mmol), CuI (27.4 mg, 0.14 mmol) and 2-aminoeth-
28.3; HRMS (ESI): calcd for C9H15N2O2S (M+H)+ 215.0854, anol (0.44 g, 7.17 mmol) in H2O (25 mL) was stirred at 25 °C
found 215.0856.
for 1 h under nitrogen. The acetylenic compound 2g (0.73 g,
7.17 mmol) was added slowly to the mixture with stirring. The
Preparation of 2-(4-amino-3-iodo-phenyl)ethanesulfonic acid reaction mixture was then stirred at 80 °C for 12 h. The mixture
methylamide (9): A suspension of compound 8 (1.0 g, 4.67 was cooled to room temperature, diluted with EtOAc (250 mL)
mmol) in aqueous solution (10.0 mL) of sodium bicarbonate and filtered through celite. The filtrate was collected, washed
(4.67 mmol) was stirred for 0.5 h. Then iodine (4.20 mmol) was with cold water (2 × 125 mL), dried over Na2SO4, filtered and
added at 5–10 °C and the mixture was stirred for 6.0 h. After concentrated under vacuum. The residue thus obtained was
completion, the reaction mixture was diluted with ethyl acetate purified by column chromatography (hexane/EtOAc) to afford
(50 mL) and extracted with ethyl acetate (3 × 50 mL). The the desired product (0.75 g, 80% yield) as a brown solid, mp
organic layers were collected, combined, washed with saturated 150–152 °C; Rf (60% ethyl acetate/n-hexane) 0.3; 1H NMR
aqueous sodium thiosulfate solution (2 × 25 mL), dried over (DMSO-d6, 400 MHz) δ 7.89 (d, J = 8.2 Hz, 2H), 7.58–7.51 (m,
anhydrous Na2SO4 and concentrated under vacuum. The crude 3H), 7.43–7.31 (m, 3H), 6.99 (bs, NH, 1H), 6.81 (s, 1H),
product was purified by column chromatography on silica gel 3.35–3.29 (m, 2H), 3.08–3.04 (m, 5H), 2.60 (d, J = 4.8 Hz, 3H);
using 7:3 hexane/ethyl acetate to afford the desired product IR (cm−1, KBr) 3275, 1363, 1320, 1173.6; m/z (ES Mass) 393
(1.24 g, 78% yield); brown solid; mp 98–100 °C; Rf (60% ethyl (M+1, 100%); 13C NMR (DMSO-d6, 200 MHz) δ 141.5, 135.9,
acetate/n-hexane) 0.3; 1H NMR (CDCl3, 400 MHz) δ 7.41 (s, 134.4, 131.9, 129.9, 129.8 (2C), 127.5 (2C), 125.3, 120.5,
1H), 6.98 (d, J = 8.0 Hz, 1H), 6.89 (bs, NH, 1H), 6.69 (d, J = 115.0, 112.0, 59.7, 50.7, 38.6, 30.6, 20.7; HRMS (ESI): calcd
8.0 Hz, 1H), 5.06 (bs, NH, 2H), 3.19–3.15 (m, 2 H), 2.74–2.73 for C18H21N2O4S2 (M+H)+ 393.0943, found 393.0942.
(m, 2H), 2.58 (d, J = 4.5 Hz, 3H); IR (cm−1, KBr) 3387, 1499,
1307, 1147; m/z (ES Mass) 341 (M+1, 100%); 13C NMR
Supporting Information
(DMSO-d6, 200 MHz): 146.8, 137.8, 129.1, 128.0, 114.2, 83.1,
50.6, 28.5, 27.6; HRMS (ESI): calcd for C9H14N2O2SI (M+H)+
Supporting Information File 1
340.9821, found 340.9824.
Spectral data of 2-substituted indoles 3a–s.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-5-46-S1.doc]
Preparation of 2-(3-iodo-4-methanesulfonylamino-
phenyl)ethanesulfonic acid methylamide (10): A mixture of
compound 9 (1.0 g, 2.94 mmol), DMAP (53.21 mg, 0.43 mmol)
was dissolved in pyridine (5.0 mL) and cooled to 0–5 °C. To
this was added methanesulfonyl chloride (3.82 mmol) dropwise
and the mixture was refluxed for 12 h. After completion of the
reaction, the mixture was cooled to 5–10 °C, neutralized with
dil HCl and extracted with ethyl acetate (3 × 50 mL). The
organic layers were collected, combined, washed with saturated
aq. NaCl (2 × 25 mL), dried over anhydrous Na2SO4 and
concentrated under vacuum. The crude compound was purified
by column chromatography on silica gel using 9:1 hexane/ethyl
acetate to afford the desired product (1.0 g, 82% yield) as a
brown solid, mp 156–158 °C; Rf (20% ethyl acetate/n-hexane)
0.3; 1H NMR (DMSO-d6, 400 MHz) δ 7.88 (s, 1H), 7.40–7.34
(m, 3H), 6.57 (bs, NH, 1H ), 3.26–3.23 (m, 2H), 3.21–3.02 (m,
Acknowledgments
The authors thank Dr. V. Dahanukar and Mr. A. Mukherjee for
their encouragement and the analytical group of DRL for spec-
tral data. Mr. M. L. thanks CPS-DRL, Hyderabad, India for
allowing him to pursue this work as a part of his Ph.D. program.
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