Synthesis of new indolyl crown ethers catalyzed with ferric hydrogensulfate

Article abstract of DOI:10.1016/j.cclet.2012.04.006

Efficient reaction of bis-indolyl podand with different aldehydes using Fe(HSO₄)₃ as catalyst to afford the corresponding new indolyl crown ethers is described. The structures of three distinct isomers have been optimized using Hyper

Full text of DOI:10.1016/j.cclet.2012.04.006

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 673–676
www.elsevier.com/locate/cclet
Synthesis of new indolyl crown ethers catalyzed with
ferric hydrogensulfate
a
a
b
Hossein Eshghi a, , Mohammad Rahimizadeh , Zahra Bakhtiarpoor , Mehdi Pordel
*
a Department of Chemistry, School of Sciences, Ferdowsi University of Mashhad, P.O. Box 91775-1436, Mashhad, Iran
b Department of Chemistry, Faculty of Sciences, Islamic Azad University, Mashhad Branch, Mashhad, Iran
Received 16 February 2012
Available online 11 May 2012
Abstract
Efficient reaction of bis-indolyl podand with different aldehydes using Fe(HSO4)3 as catalyst to afford the corresponding new
indolyl crown ethers is described. The structures of three distinct isomers have been optimized using HyperChem geometry
1
optimizations. Also percentage of each isomer was obtained with H NMR spectroscopy.
# 2012 Hossein Eshghi. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Ferric hydrogensulfate; Bis-indolyl podand; Indolyl crown ether; Fe(HSO4)3
Crown ethers are heteromacrocycles in which the framework is typically comprised of repeating ethylene oxy units.
Nitrogen and sulfur commonly replace oxygen in this framework leading to a great variety of compounds that have
been used in molecular recognition studies and supramolecular chemistry [1–4]. Alkali metal cation–p interactions
have recently received considerable attention due to their biological importance [5–9]. There has been much progress
in the computational approaches in supramolecular chemistry, which may lead to the microscopic insight into the
structural and thermodynamical features involved in the processes of molecular recognition and supramolecular
organization [10–15]. Great progress for computational facilities provides us an opportunity to study the relatively
large and complicated supramolecular system. In this work, we have synthesized some new indolyl crown ethers and
have studied the structures and energies of their conformers.
1. Results and discussion
Bis-indolyl podand 2 was obtained in high yield by alkylation of 2-methyl indole 1 with triethylene glycol
ditosylate in the presence of KOH in DMF at room temperature. New bis-indolyl crown ethers have been synthesized
via Fe(HSO4)3 (10 mol%) catalyzed condensation of bis-indolyl podand 2 (1 equiv.) and aldehyde (1 equiv.) under
mild conditions (Scheme 1). The reaction is facile and complete within 60 min at room temperature. The structural
assignments of compounds 3a–e were determined based on the analytical and spectral data. In the 1H NMR spectrum
of 3e the three signals at 5.98, 6.08 and 6.17 ppm assignable to benzyl protons were attributed to three isomers of 3e.
* Corresponding author.
E-mail address: heshghi@um.ac.ir (H. Eshghi).
1001-8417/$ – see front matter # 2012 Hossein Eshghi. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2012.04.006

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H. Eshghi et al. / Chinese Chemical Letters 23 (2012) 673–676
R
3a: R=H
3b: R=Me
3c: R=Cl
3d: R=Br
3e: R=NO2
3f: R=OH
TsO
O
CH3 H3C
ArCHO, DCM
O
OTs
CH3
N
N
CH
O
3 H3C
O
DMF, KOH
rt, 12 h
Fe(HSO4)3, 60 min, rt
O
N
H
O
N
N
1
2
3a-e
Scheme 1. Synthesis of indolyl crown ethers.
This observation is clearly approved that all three isomers are converted to each other slowly and the chemical
moieties are different for their benzyl protons. One of the main reasons for slow conversion in three isomers of
compounds 3a–e, can be related to the methyl groups in 2-methyl indole rings. These isomeric relationships were not
reported in similar reaction with indole [16].
Fig. 1 shows three isomers of compound 3a. As it is cleared, there are two isomers in syn state and an isomer in anti
state. In isomers 3syn-H and 3syn-Ph two indole rings and also two methyl groups are syn oriented around the main cavity
of crown ethers. 3syn-H is a syn isomer of benzylic C–H bond to the indole rings whereas; 3syn-Ph is a syn isomer of
phenyl ring to the indole rings. Isomer 3anti is an anti oriented indole rings and also methyl groups which seems to be
more stable than syn-isomers. The HyperChem full optimizations without any constraint were carried out for each
isomer in compounds 3a–e. Table 1 reports the optimized energies of the three different isomers of 3a–e.
Fig. 1. Optimized structures of isomers 3syn-H, 3syn-Ph and 3anti
.
Table 1
Calculated energies (kcal/mol) of different isomers for compounds 3a–e.
a
b
Crown
Isomer 3syn-H
Isomer 3syn-Ph
Isomer 3anti
DE1
DE2
3a
3b
3c
3d
3e
À905,504.899
À929,863.384
À905,505.207
À929,864.881
À905,506.534
À929,865.723
À0.308
À1.497
À0.811
À1.181
À1.620
À1.635
À2.339
À16.056
À17.321
À2.349
À1,192,093.417
À2,511,597.467
À1,032,443.252
À1,192,094.229
À2,511,598.650
À1,032,444.872
À1,192,109.473
À2,511,614.788
À1,032,445.601
a
DE1 = E (3syn-Ph) À E (3syn-H).
b
DE2 = E (3anti) À E (3syn-H).

H. Eshghi et al. / Chinese Chemical Letters 23 (2012) 673–676
675
Table 2
The detail results of each reaction including yields and percentage of isomers in compounds 3a–e.
Entry
p-R-C6H4-CHO
Yield %
Crown
Isomer 3syn-H (%)
Isomer 3syn-Ph (%)
Isomer 3anti (%)
1
2
3
4
5
6
H
70
82
65
67
80
62
3a
3b
3c
3d
3e
3f
25
25
50
Me
Cl
25
25
50
22
27.5
24
50.5
52
Br
24
NO2
OH
20.5
22.5
32
47.5
52.5
25
However, this calculation suggests that whereas syn isomers have a small differences in calculated energies
[À0.31 À (À1.62) kcal/mol] for all compounds 3a–e, anti isomers are more stable than syn isomers especially in the
cases of 3c (16.05 kcal/mol) and 3d (17.32 kcal/mol).
Also, these calculations are verifying that anti isomer in which two methyls are less hindered, is the most stable and
therefore, in the 1H NMR spectrum of 3e, the signal at 6.17 ppm is assignment to benzyl proton of 3anti. Percentage of
isomers can be easily obtained from relative integration of them. Similarly, percentage of each isomer in compound
3a–d can be determined with 1H NMR spectrum. Table 2 shows the detail results of each reaction including yields and
isomer ratios in compounds 3a–e. Molecular dynamic studies in low temperatures (À10 8C to À35 8C) showed that
these isomers do not convert together (not shown). Accordingly, we assigned these signals to the restricted isomers.
2. Experimental
Melting points were recorded on an Electrothermal type 9100 melting point apparatus. The IR spectra were
1
obtained on a 4300 Shimadzu spectrometer and only noteworthy absorptions are listed. The H NMR (500 MHz)
spectra were recorded on a Bruker DRX500 spectrometer. Chemical shifts are reported in ppm downfield from TMS as
internal standard; coupling constant J are given in Hz. The mass spectra were scanned on a Varian. Mat CH-7 at 70 ev.
Elemental analysis was performed on a Thermo Finnigan Flash EA microanalyzer. Fe(HSO4)3 was prepared according
to the published method [17]. Other reagents which were commercially available, obtained from Merck and Aldrich
companies.
2-Methyl-1-(2-2-[2-(2-methyl-1H-1-indolyl)ethoxy]ethoxyethyl)-1H-indole 2. Indole 1 (0.5 g, 4.27 mmol) was
added to a suspension of NaOH (0.256 g, 6.41 mmol) in dry DMF (30 mL), was stirred at 0 8C under nitrogen
atmosphere. A dry DMF (10 mL) solution of triethylene glycol ditosylate (1.1 g, 2.14 mmol) was added dropwise to
the suspension with stirring for 50 min at room temperature. After the reaction was complete, the organic solution was
filtered and evaporated in vacuum, extracted with EtOAc (3Â 20 mL) and washed with water and brine, then dried over
anhydrous Mg2SO4 and recrystallized in ethanol afforded 1.42 g (85%) 2 as a light yellow crystals. M.p.: 170–172 8C;
1H NMR (CDCl3, 500 MHz): d 2.40 (s, 6H), 3.39 (s, 4H), 3.63 (t, 4H, J = 5.9 Hz), 4.18 (t, 4H, J = 5.9 Hz), 6.21 (s, 2H),
6.93–7.38 (m, 6H), 7.38–7.58 (m, 2H). MS (70 eV): m/z 376 (M+). Anal. calcd. for C24H28N2O2 (376.49): C, 76.56; H,
7.50; N, 7.44. Found: C, 76.26; H, 7.41; N, 7.20.
General procedure for the synthesis of crowns 3a–f. Typical procedure: A mixture of bis-indole 2 (0.510 g,
1.30 mmol), benzaldehyde (1.30 mmol) and Fe(HSO4)3 (10 mol%) in dichloromethane (30 mL) was stirred at room
temperature for 60 min. After complete conversion, as indicated by TLC, the reaction mixture was concentrated in
vacuum, and purified by column chromatography on silica gel (Merck, 100–200 mesh, EtOAc–hexane, 3:7) to afford
the pure product 3a–f.
2-Methyl-3-[1-[2-(2-(2-(2-methyl-1H-1-indolyl)ethoxy)ethoxy)ethyl](phenyl)methyl]-1H-indole (3a). Yellow
1
crystals (EtOH), yield 70%, M.p.: 231–235 8C; H NMR (CDCl3, 500 MHz): d 1.70 (s, 50% of 6H), 1.95 (s,
50% of 6H), 3.1-3.7 (m, 8H), 4.20–4.42 (m, 4H), 5.98 (s, 25% of 1H), 6.07 (s, 25% of 1H), 6.17 (s, 50% of 1H), 6.71–
7.73 (m, 13H). MS (70 eV): m/z 464 (M+). Anal. calcd. for C31H32N2O2 (464.25): C, 80.14; H, 6.94; N, 6.03. Found:
C, 80.05; H, 6.91; N, 5.91.
2-Methyl-3-[1-[2-(2-(2-(2-methyl-1H-1-indolyl)ethoxy)ethoxy)ethyl](4-methylphenyl) methyl]-1H-indole (3b).
1
Yellow crystals (EtOH), yield 82%, M.p.: 300–302 8C; H NMR (CDCl3, 500 MHz): d 1.63 (s, 50% of 6H), 1.88
(s, 50% of 6H), 2.39 (s, 3H), 3.07–3.70 (m, 8H), 4.14–432 (m, 4H), 6.02 (s, 25% of 1H), 6.10 (s, 50% of 1H), 6.12

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H. Eshghi et al. / Chinese Chemical Letters 23 (2012) 673–676
(s, 25% of 1H), 6.65–7.45 (m, 12H). MS (70 eV): m/z 478 (M+). Anal. calcd. for C31H32N2O2 (478.26): C, 80.30; H,
7.16; N, 5.85. Found: C, 80.05; H, 6.91; N, 6.00.
2-Methyl-3-[1-[2-(2-(2-(2-methyl-1H-1-indolyl)ethoxy)ethoxy)ethyl](4-cholorophenyl)methyl]-1H-indole (3c).
1
Yellow crystals (EtOH), yield 65%, M.p.: 220–223 8C; H NMR (CDCl3, 500 MHz): d 1.61 (s, 49.5% of 6H),
1.88 (s, 50.5% of 6H), 3.05–3.72 (m, 8H), 4.12–4.32 (m, 4H), 6.05 (s, 72% of 1H), 6.13 (s, 28% of 1H), 6.71–7.70 (m,
12H). MS (70 eV): m/z 498 (M+). Anal. calcd. for C31H31ClN2O2 (498.21): C, 74.61; H, 6.26; N, 5.61. Found: C,
74.30; H, 6.19; N, 5.43.
2-Methyl-3-[1-[2-(2-(2-(2-methyl-1H-1-indolyl)ethoxy)ethoxy)ethyl](4-boromophenyl)methyl]-1H-indole (3d).
1
Yellow crystals (EtOH), yield 67%, M.p.: 270–272 8C; H NMR (CDCl3, 500 MHz): d 1.60 (s, 48% of 6H), 1.88
(s, 52% of 6H), 3.0–3.75 (m, 8H), 4.13–4.33 (m, 4H), 6.10 (s, 76% of 1H), 6.24 (s, 24% of 1H), 6.71–7.65 (m, 12H).
MS (70 eV): m/z 542 (M+). Anal. calcd. for C31H31BrN2O2 (542.16): C, 68.51; H, 5.75; N, 5.15. Found: C, 68.33; H,
5.69; N, 4.90.
2-Methyl-3-[1-[2-(2-(2-(2-methyl-1H-1-indolyl)ethoxy(ethoxy(ethyl](4-nitrophenyl)methyl]-1H-indole (3e). Yel-
1
low crystals (EtOH), yield 80%, M.p.: 259–262 8C; H NMR (CDCl3, 500 MHz): d 1.62 (s, 52.5% of 6H), 1.91 (s,
47.5% of 6H), 3.12–3.75 (m, 8H), 4.11–4.31 (m, 4H), 5.90 (s, 20.5% of 1H), 6.00 (s, 32% of 1H), 6.20 (s, 47.5% of
1H), 6.70–7.72 (m, 10H), 8.26 (d, 2H). MS (70 eV): m/z 509 (M+). Anal. calcd. for C31H31N3O4 (509.23): C, 73.06; H,
6.13; N, 8.25. Found: C, 72.83; H, 6.01; N, 8.14.
2-Methyl-3-[1-[2-(2-(2-(2-methyl-1H-1-indolyl)ethoxy(ethoxy(ethyl](3-hidrocyphenyl)methyl]-1H-indole
(3f).
1
Yellow crystals (EtOH), yield 62%, M.p.: 258–260 8C; H NMR (CDCl3, 500 MHz): d 1.63 (s, 47.5% of 6H),
1.88 (s, 52.5% of 6H), 3.02–3.68 (m, 8H), 4.15–4.35 (m, 4H), 4.58 (br s, 1H), 6.02 (s, 52.6% of 1H), 6.10 (s, 22.5% of
1H), 6.22 (s, 258% of 1H), 7.11–7.25 (m, 11H), 7.50–7.68 (m, 1H). MS (70 eV): m/z 480 (M+). Anal. calcd. for
C31H32N2O3 (480.24): C, 77.47; H, 6.71; N, 5.83. Found: C, 77.23; H, 6.63; N, 5.62.
3. Conclusion
In conclusion, we report the synthesis of new indolyl crown ethers from reaction of bis-indolyl podand and
aldehydes in the presence of Fe(HSO4)3. The reactions were carried out in a mild condition, short reaction times and
1
high yields. Stabilities of their isomers evaluated by HyperChem calculations and H NMR spectroscopy.
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