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Mendeleev
Communications
Mendeleev Commun., 2014, 24, 40–41
Nucleophilic dimerization of indoline under oxidative conditions
Igor S. Kovalev,a Dmitry S. Kopchuk,*a,b Grigory V. Zyryanov,a,b
Vladimir L. Rusinova,b and Oleg N. Chupakhina,b
a Department of Organic Chemistry, Ural Federal University, 620002 Ekaterinburg, Russian Federation
b I. Ya. Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences,
620990 Ekaterinburg, Russian Federation. Fax: +7 343 374 1189; e-mail: dkopchuk@mail.ru
DOI: 10.1016/j.mencom.2013.12.013
Oxidation of indoline with 30% hydrogen peroxide in methanol in the presence of sodium tungstate affords the dimeric 3-oxo-1'H,3H-
2,3'-biindole-1-oxide.
The synthetic potential of SNH reactions is based on the funda-
mental ability of C–H bonds of p-deficient (het)arenes to be
i.e., 3-oxo-1'H,3H-2,3'-biindole-1-oxide 2 that is composed by
two intermediates of indoline oxidation.† The formation of
product 2 can be caused by the indoline oxidation directed in
two parallel pathways. Pathway A leads to indole 3;10 while
pathway B affords 3-oxo-3H-indole 1-oxide 4.9 The subsequent
nucleophilic attack of indole 3 at the position C-2 of intermediate
4 gives dimer 5. Finally, oxidation of adduct 5 results in the
biindole 2.
The spectral data fully correspond to the proposed structure
of 2. 1H NMR spectra contain the characteristic resonance of NH
proton of indole as a broad singlet at 11.95 ppm, whereas signals of
aliphatic protons of starting indoline 1 are absent. In the 13C NMR
spectra the resonance of carbonyl carbon at 187.1 ppm, as well as
resonances of other aromatic carbons are observed. ESI-MS spectra
contain clear peak of molecular ion [M+H]+ with m/z 263.0793
(calc. for C16H11N2O2, 263.0815). The study of CID fragmenta-
tion in mass spectra of molecular ion of product 2 [M+H]+
revealed the appearance of the characteristic ions: 246.0772
[M+H–OH]+; 146.0202 [M+H–Indole]+; 235.0849 [M+H–CO]+.
IR spectra manifest the valence absorption band of carbonyl
group at 1716 cm–1. EPR-spectroscopic study did not reveal the
presence of uncoupled electrons in product 2, so compound 2
does not contain any oxylic fragments in its structure.
cleaved with the subsequent formation of C–X bond (X = Csp3
,
Csp2, Csp, O, N, S, P, etc.) in interaction with various nucleophiles.
For instance, azines readily form sH-adducts and SNH substi-
tution products. Meantime, only few cases are known for the
dimerization of 6-membered p-deficient heterocycles, in parti-
cular mono- or diazines, such as pyrimidine,1 pyridine, quinolone
and isoquinoline,2 on treating with non-nucleophilic lithiating
superbases. Nucleophilic addition of two molecules of 3-methyl-
1-phenylpyrazol-5-one to 3-phenyl-1,2,4-triazine through the
dimerization step gives finally a 1,1,2,2-tetrakispyrazolylethane
derivative.3
Among azoles, reactions of nucleophilic addition are scarce.
Isatogens react easily with various nucleophiles4 and act as traps
for hydroxyl and superoxide radicals.5 The practical usefulness
of isatogens is confirmed by their antimicotic activity,6 as well as
moderate antibacterial activity in vitro.7 Therefore, search for
new isatogens is of current interest.
Isatogens can be obtained in yields from good to excellent by
condensation of o-ethynylnitrobenzenes catalyzed by gold(iii)
bromide,8 however, benzooxazoles would sometimes form as
by-products. Oxidation of 2-R-2,3-dihydro-1H-indoles derived
from the corresponding indoles,9 is another access to isatogens.
Herein, we describe a simple one-pot synthesis of isatogen
starting from 2,3-dihydroindole (Scheme 1). Oxidation of indoline
1 with 30% hydrogen peroxide in methanol in the presence of
sodium tangstate unexpectedly afforded the dimeric compound,
In summary, we have developed the efficient one-pot synthesis
of isatogen 2 by nucleophilic oxidative dimerization of indoline.
This work was supported by the Russian Ministry of Education
and Science (state contract nos. 14.740.11.1020, 14.A18.21.0817
†
3-Oxo-1'H,3H-2,3'-biindole-1-oxide 2. To a magnetically stirred suspen-
A
sion of sodium tungstate dihydrate (5 mg, 0.015 mmol) in MeOH (5 ml)
compound 1 (1 g, 8.4 mmol) was added, then H2O2 (30%, 2.8 ml) was
added dropwise at 0°C. The resulting mixture was gradually warmed to
room temperature and stirred for 3 h. The precipitate formed was filtered
off, washed with ethanol and chromatographed on SiO2 using 10%AcOEt in
toluene as an eluent to afford the product (Rf = 0.5) as violet crystals in 39%
yield (0.430 g, 1.64 mmol); mp > 250°C (decomp.). 1H NMR (400 MHz,
DMSO-d6–CCl4) d: 7.13 (td, 1H, J 7.5 and 1.3 Hz), 7.19 (td, 1H, J 7.5 and
1.1 Hz), 7.47 (d, 1H, J 7.8 Hz), 7.52 (d, 1H, J 7.8 Hz), 7.56 (d, 1H, J 7.5 Hz),
7.61 (d, 1H, J 7.0 Hz), 7.73 (td, 1H, J 7.7 and 1.0 Hz), 8.56 (d, 1H, J 8.0 Hz),
8.93 (d, 1H, J 3.0 Hz), 11.95 (br.s, 1H, NH). 13C NMR (CDCl3) d: 100.2,
104.6, 111.5, 113.5, 121.8, 122.0, 123.2, 124.0, 124.5, 124.6, 130.1, 130.2,
135.1, 136.1, 148.6, 187.1 (CO). IR (n/cm–1): 573, 749, 862, 1037, 1167,
1434, 1455, 1593, 1621, 1716 (CO), 3063, 3218. ESI-MS (CID), m/z (%):
263.0793 (15.5), 246.0772 (100), 235.0849 (32.8), 218.0823 (26.3),
146.0228 (10.2), 144.0434 (38.6), 120.0434 (2.6). Found (%): C, 73.35;
H, 3.74; N, 10.56. Calc. for C16H10N2O2 (%): C, 73.27; H, 3.84; N, 10.68.
For additional details, see Online Supplementary Materials.
H2O2,
Na2WO4
N
H
SNH
3
MeOH,
0 °C
O
N
H
B
1
N
O
4
O
O
H
[O]
N
N
N
H
N
OH
O
H
5
2
Scheme 1
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– 40 –
Kovalev, Igor S.
