2-Arylhydroxynitroindoles: A new procedure for the cleavage of aryl methyl ethers

Article abstract of DOI:10.1002/jhet.769

A new procedure for the cleavage of aryl methyl ethers was developed. On this basis representatives of new types of 2-arylhydroxynitroindoles were synthesized. Copyright

Full text of DOI:10.1002/jhet.769

November 2011 2-Arylhydroxynitroindoles: A New Procedure for the Cleavage of
Aryl Methyl Ethers
1445
G. V. Kokurkina, M. D. Dutov,* and S. A. Shevelev
Zelinsky Institute of Organic Chemistry, RAS, 47 Leninsky prosp., Moscow 119991, Russia
*E-mail: dutov@ioc.ac.ru
Received September 17, 2010
DOI 10.1002/jhet.769
Published online 19 August 2011 in Wiley Online Library (wileyonlinelibrary.com).
A new procedure for the cleavage of aryl methyl ethers was developed. On this basis representatives
of new types of 2-arylhydroxynitroindoles were synthesized.
J. Heterocyclic Chem., 48, 1445 (2011).
INTRODUCTION
acid-catalyzed rearrangement of phenylhydrazones
accompanied by ammonia emission. Methoxynitroin-
doles 1a–d (Table 1) were synthesized from commercial
methoxynitroanilines by this method (Scheme 1).
The synthesis of indoles and investigation of their
reactivity are essential scientific issues, because an
indole ring stands among the most common structural
moieties of many natural alkaloids and biologically
active substances. In particular, an indole ring incorpo-
rates an indispensable amino acid tryptofan that is
involved in protein building in all living organisms. 3-
Indolylacetic acid and some of its derivatives generated
in plants in the course of oxidative deamination of tryp-
tofan are growth hormones [1]. Among the indole deriv-
atives applied in medicine most popular are indometa-
cin, an antiinflammatory agent and analgesic [2], indo-
mecin, an antibiotic, and pindolol, a noncardioselective
b-adrenoreceptor blocking agent with antianginal, antiar-
rhythmic, and hypotensive action [3]. Vincristine, alka-
loid of pink periwinkle (Vinca rosea), is a natural antitu-
moral agent that also includes an indole moiety [4].
As a next step, we supposed to transform methoxyni-
troindoles to the end product, that is, hydroxynitroin-
doles. The ether bond cleavage techniques with the use
of AlCl3 [6], BBr3 [7], and PhSH in the presence of
K2CO3 [8], HBr [9], and (CH3)3SiI [10] described in lit-
erature failed. Either resinification occurred or the reac-
tion did not run at all. Two researches formally not
related to our case prompted us the solution of this
problem. The authors of the first article [11] emphasize
the impact of ionic liquids as high polar media on the
cleavage of ethers under the action of benzoyl chloride.
The second [12] examines transesterification of methyl
esters of carbonic acids as affected by tetraalkylammo-
nium halides to produce corresponding alkyl esters and
points out that the tertiary ammonium salt melt used
without any solvent is optimal for the reaction. Originat-
ing from these results, we decided to look at the behav-
ior of indoles 1 in the melt of tetrabutylammonium bro-
mide, being both a high polar medium and, moreover, a
source of less solvated, and hence more nucleophilic,
bromide ions. Furthermore, tetrabutylammonium bro-
mide is neither hygroscopic nor high-melting, and at the
same time is rather readily available. It appeared that in
its melt, once the temperature reached 150ꢀC, the reac-
tion ran via the below scheme 2 to yield products 2c
and 3c (reaction time—0.5h), which we managed to
separate.
RESULTS AND DISCUSSION
In our previous articles, we communicated a synthetic
procedure for the preparation of new 2-arylindole repre-
sentatives with hydroxyl and nitro groups in 4- and 6-
positions, accordingly [5]. Our interest in the representa-
tives of this indole type was caused by the results of bi-
ological tests that demonstrated high fungicidal activity
of 2-aryl-4-hydroxy-6-nitroindole and its intermediates
when compared with the conventional benchmark, tria-
dimethon. In this article, we propose a method for the
synthesis of 2-aryl-X-hydroxy-Y-nitroindoles.
Of note is that in the reaction of tetrabutylammonium
bromide with preisolated ether, 3c the latter is spent com-
pletely and dealkylation product 2c is generated. We
The most popular and well-known method for the
preparation of indoles is Fischer synthesis based on the
C
V
2011 HeteroCorporation

1446
G. V. Kokurkina, M. D. Dutov, and S. A. Shevelev
Vol 48
Scheme 1. Synthesis of methoxynitroindoles 1a–d.
8.21 (s, 1H, Ar), 11.98 (s, 1H, NH). Anal. Calc. for.
C16H14N2O3: C 68.07; H 5.00; N 9.92. Found: C 68.41; H
5.14; N 9.67.
3-Methyl-5-methoxy-7-nitro-2-phenylindole (1b) This com-
pound was obtained as yellow solid, 55%, m.p. ¼ 127–
128ꢀC.1H-NMR: 2.37 (s, 3H, CH3), 3.90 (s, 3H, OCH3), 7.40–
7.45 (m, 1H, Ar), 7.50–7.55 (m, 2H, Ar), 7.63–7.70 (m, 4H,
Ar), 11.27 (s, 1H, NH). Anal. Calc. for C16H14N2O3: C 68.07;
H 5.00; N 9.92. Found: C 68.38; H 4.89; N 9.69.
3-Methyl-7-methoxy-4-nitro-2-phenylindole (1c) This com-
pound was obtained as orange solid, 63%, m.p. ¼ 130–131ꢀC.
1H-NMR: 2.31 (s, 3H, CH3), 4,05 (s, 3H, OCH3), 6,83(d, 1H,
J ¼ 8,6), 7.41–7.46 (m, 1H, Ar), 7.49–7.54 (m, 2H, Ar), 7.60–
7.63 (m, 2H, Ar), 7.86 (d, 1H, J ¼ 8.7), 12.00 (s, 1H, NAH).
Anal. Calc. for C16H14N2O3: C 68.07; H 5.00; N 9.92. Found:
C 68.18; H 5.21; N 9.61.
3-Methyl-4-methoxy-7-nitro-2-phenylindole (1d) This com-
pound was obtained as yellow solid, 43%, m.p. ¼ 139–140ꢀC. 1H-
NMR: 4.03 (s, 3H, OCH3), 6.76 (d, 1H, J ¼ 9), 7.39–7.44 (m, 1H,
Ar), 7.48–7.53 (m, 2H, Ar), 7.60–7.62 (m, 2H, Ar), 8.10–8.13 (d,
1H, J ¼ 9), 11.36 (s, 1H, NAH). Anal. Calc. for C16H14N2O3: C
68.07; H 5.00; N 9.92. Found: C 68.23; H 5.11; N 9.81.
General procedure for the preparation of compounds
2(a–d). A mixture of methoxynitroindole (1g, 0.004 mol) and
tetrabutylammonium bromide (7 g) is heated up to 150ꢀC and
stirred for 90 min (as the preparation of the mixture of com-
pounds 2c and 3c and time of reaction is 30 min). The reaction
mass is poured into 5% HCl and extracted with chloroform.
The extract is dried over Na2SO4, and the solvent is distilled.
The dry residue is purified using column chromatography
(silica gel, eluent—the mixture CCl4/EtOAc ¼ 10/4).
7-Hydroxy-3-methyl-5-nitro-2-phenylindole (2a) This com-
pound was obtained as red solid, 64%, m.p. ¼ 196–197ꢀC.1H-
NMR: 2.41 (s, 3H, CH3), 7.37–7.42 (m, 2H, Ar), 7.48–7.53
(m, 2H, Ar), 7.68–7.71 (m, 2H, Ar), 8.05 (d, 1H, J ¼ 8,6),
10.57 (s, 1H, OAH), 11.80 (s, 1H, NAH). Anal. Calc. for
C15H12N2O3: C 67.16; H 4.51; N 10.44. Found: C 67.31; H
4.26; N 10.32.
found that the increasing of the reaction time led to prod-
uct 2c only. Products 2a, 2b, and 2d were obtained in the
same manner for 1.5 h (Table 2). As known from litera-
ture, the tetrabutylammonium bromide decomposition
occurs during the thermolysis to yield tributyl amine and
butyl bromide, which, in our instance, alkylates hydrox-
yindole-2 resulted from demethylation. HPLC fully proves
the fact of the initial generation of hydroxyindole-2 rather
than of ether 3 in the reaction mixture.
EXPERIMENTAL
All reagents and solvents were used without further purifica-
tion or drying. All reagents were purchased from Acros Organ-
ics. The 1H-NMR spectra were recorded by Bruker AM-300.
The chemical shifts were given relative to Me4Si in DMSO-d6,
d, p.p.m., J, Hz. Melting points of the synthesized compounds
were measured on a Boetius hot stage according to Koffler
(heating rate 4ꢀC minꢁ1).
Compounds a–c were prepared by the known procedures
[13]. Compound d was prepared according to procedure given
in Ref. 13c.
3-Methoxy-6-nitrophenylhydrazine (d). This compound
1
was obtained as red solid, 68%, m.p. ¼ 160–161ꢀC. H-NMR:
3.91 (s, 3H, OCH3), 6.59–6.63 (m, 1H, Ar), 6.98 (d, 1H, J ¼
8.7), 8.12 (d, 1H, J ¼ 8.8), 9.35 (s, 1H, NAH), 10.51(s, 2H,
NAH). Anal. Calc. for C7H9N3O3: C, 45.90; H, 4.95; N,
22.94. Found: C, 45.76; H, 4.67; N, 22.74.
General procedure for the preparation of compounds
1(a–d). Propiophenone (1.34 g, 0.01 mol) and trifluoroacetic
acid (0.5 g, 0.004 mol) are added to methoxynitrophenylhydra-
zine solution (1.83 g, 0.01 mol) in formic acid (15 mL) and
refluxed for 2 h. The reaction mass is cooled, and the precipi-
tate is filtered off, dried, and purified using column chromatog-
raphy (silica gel, eluent—chloroform).
3-Methyl-7-methoxy-5-nitro-2-phenylindole (1a) This com-
pound was obtained as yellow solid, 36%, m.p. ¼ 175–176ꢀC.
1H-NMR: 2.42 (s, 3H, CH3), 4.05 (s, 3H, OCH3), 7.38–7.43
(m, 1H, Ar), 7.48–7.53 (m, 3H, Ar), 7.68–7.71 (m, 2H, Ar),
5-Hydroxy-3-methyl-7-nitro-2-phenylindole (2b) This com-
pound was obtained as red solid, 53%, m.p. ¼ 172–173ꢀC.1H-
Table 1
Table 2
Methoxynitroindoles.
Hydroxynitroindoles.
Product
R1
R2
Yield (%)
Entry
R1
R2
R3
R4
Yield (%)
1a
1b
1c
1d
7-OCH3
5-OCH3
7-OCH3
4-OCH3
5-NO2
7-NO2
4-NO2
7-NO2
36
55
63
43
a
b
c
7-OCH3
5-OCH3
7-OCH3
4-OCH3
5-NO2
7-NO2
4-NO2
7-NO2
7-OH
5-OH
7-OH
4-OH
–
64
53
61
86
–
7-OC4H9
–
d
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2011
2-Arylhydroxynitroindoles: A New Procedure for the Cleavage of Aryl Methyl Ethers
1447
Scheme 2. Cleavage of aryl methyl ethers.
REFERENCES AND NOTES
NMR: 2.33 (s, 3H, CH3), 7.40–7.44 (m, 2H, Ar), 7.49–7.56
(m, 2H, Ar), 7.66–7.68 (m, 2H, Ar), 9.62 (s, 1H, OAH), 11.14
(s, 1H, NAH). Anal. Calc. for C15H12N2O3: C 67.16; H 4.51;
N 10.44. Found: C 67.42; H 4.17; N 10.53.
7-Hydroxy-3-methyl-4-nitro-2-phenylindole (2c) This com-
pound was obtained as red solid, 61%, m.p. ¼ 219–220ꢀC.1H-
NMR: 2.33 (s, 3H, CH3), 6.63 (d, 1H, J ¼ 8,5), 7.42–7.46 (m,
1H, Ar), 7.50–7.55 (m, 2H, Ar), 7.61–7.64 (m, 2H, Ar), 7.77–
7.80 (d, 1H, J ¼ 8,5), 11.10 (s, 1H, OAH), 11.83 (s, 1H,
NAH). Anal. Found %: C 67.21; H 4.30; N 10.57. Calcd. for.
C15H12N2O3 %: C 67.16; H 4.51; N 10.44.
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4-Hydroxy-3-methyl-7-nitro-2-phenylindole (2d) This com-
pound was obtained as red solid, 86%, m.p. ¼ 201–202ꢀC.1H-
NMR: 6.57 (d, 1H, J ¼ 8,9), 7.38–7.43 (m, 1H, Ar), 7.48–7.53
(m, 2H, Ar), 7.61–7.64 (m, 2H, Ar), 7.98–8.01 (d, 1H, J ¼
8.9), 11.19 (s, 1H, OAH), 11.32 (s, 1H, NAH). Anal. Calc. for
C15H12N2O3: C 67.16; H 4.51; N 10.44. Found: C 67.03; H
4.68; N 10.37.
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pound was obtained as yellow solid, 56%, m.p. ¼ 139–
140ꢀC.1H-NMR: 0.93–0.98 (m, 3H), 1.49–1.61 (m, 2H), 1.77–
1.86 (m,2H), 2.31 (s,3H), 4.24–4.28 (m, 2H), 6.80 (d,1H, J ¼
8,7), 7.43–7.48 (m,1H), 7.51–7.56 (m, 2H), 7.59–7.62 (m, 2H),
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J
¼
8,7), 11.92 (s, 1H). Anal. Calc. for
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Acknowledgment. The authors thank the Russian Foundation
for Basic Research (Grant No 10-03-00623) for financial support.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet