Unusual reaction of α-diketones of the indole series with hydrazine

Article abstract of DOI:10.1007/s11172-006-0348-2

Symmetrical and unsymmetrical α-diketones of the indole series were synthesized by the Friedel-Crafts reaction of 3-indolylglyoxyl chlorides with heterocycles. A nonconventional reaction of N-unsubstituted diketones with hydrazine producing 3H-pyrazolo[3,4-c]quinoline derivatives was found. Springer Science+Business Media, Inc. 2006.

Full text of DOI:10.1007/s11172-006-0348-2

892
Russian Chemical Bulletin, International Edition, Vol. 55, No. 5, pp. 892—897, May, 2006
Unusual reaction of αꢀdiketones of the indole series with hydrazine
a
aꢀ
b
a
A. V. Kolotaev, L. I. Belen´kii, A. S. Kononikhin, and M. M. Krayushkin
aN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
7 Leninsky prosp., 119991 Moscow, Russian Federation.
4
Fax: +7 (495) 135 5328. Eꢀmail: kolotaev@pisem.net, libel@ioc.ac.ru
N. M. Emanuel Institute of Biochemical Physics, Russian Academy of Sciences,
b
4
ul. Kosygina, 117997 Moscow, Russian Federation.
Fax: +7 (495) 137 4101
Symmetrical and unsymmetrical αꢀdiketones of the indole series were synthesized by the
Friedel—Crafts reaction of 3ꢀindolylglyoxyl chlorides with heterocycles. A nonconventional
reaction of Nꢀunsubstituted diketones with hydrazine producing 3Hꢀpyrazolo[3,4ꢀc]quinoline
derivatives was found.
Key words: indolꢀ3ꢀylglyoxyl chlorides, αꢀdiketones, hydrazine hydrate, 3Hꢀpyrazoꢀ
lo[3,4ꢀc]quinolines, heterocyclization.
Recently, we have synthesized1 4ꢀhetarylꢀ2ꢀpheꢀ
nylꢀ5,6ꢀdithienylꢀ4Hꢀ1,3ꢀthiazines by cycloaddition of
indolyl)glyoxyloyl chloride 2, which were prepared by the
reaction of equimolar amounts of the substrate and oxalyl
chloride in diethyl ether (Scheme 2).
bis(2,5ꢀdimethylꢀ3ꢀthienyl)acetylene with heteroaromatic
2
aldehydes and thiobenzamide. Earlier, we have prepared
the aboveꢀmentioned acetylene by oxidation of bis(2,5ꢀdiꢀ
methylꢀ3ꢀthienyl)ethanedione bisꢀhydrazone. The aim of
the present study was to apply this approach to the synꢀ
Scheme 2
2
thesis of new acetylene derivatives from symmetrical and
unsymmetrical 1,2ꢀdiketones bearing the indolyl, benzoꢀ
thiophenyl, or thienyl substituents (Scheme 1).
Scheme 1
R = H (1), Me (2)
Reagents and conditions: (ClCO) , diethyl ether.
2
Acid chlorides 1 and 2 were used to acylate 2,5ꢀdiꢀ
methylthiophene and 2ꢀmethylbenzo[b]thiophene, reꢀ
spectively. To decrease the polarity of the medium (which
leads to a decrease in the solvation energy of the transiꢀ
tion state resulting in an increase in the selectivity of the
process), we used a mixture of 1,2ꢀdichloroethane (DCE)
2,4—6
and hexane (cf. lit. data
). The optimal AlCl : subꢀ
3
strate : acid chloride ratio was 4.5 : 1.5 : 1. The reactions
with the use of smaller amounts of the Lewis acid or an
equimolar amount of the substrate produced the target
compounds in lower yields.
The reaction of acid chloride 1 with 2,5ꢀdimethylꢀ
thiophene affords 1ꢀ(2,5ꢀdimethylꢀ3ꢀthienyl)ꢀ2ꢀ(2ꢀmeꢀ
thylꢀ3ꢀindolyl)ethanedione (3), and the reaction with
2ꢀmethylbenzo[b]thiophene gives 1ꢀ(2ꢀmethylꢀ3ꢀbenꢀ
zo[b]thienyl)ꢀ2ꢀ(2ꢀmethylꢀ3ꢀindolyl)ethanedione (4).
We synthesized αꢀdiketones starting from (2ꢀmethylꢀ
ꢀindolyl)glyoxyloyl chloride 1 and (1,2ꢀdimethylꢀ3ꢀ
3
3
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 862—866, May, 2006.
066ꢀ5285/06/5505ꢀ0892 © 2006 Springer Science+Business Media, Inc.
1

Unusual reaction of indole αꢀdiketones
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 5, May, 2006
893
8
Analogously, acid chloride 2 is transformed into 1ꢀ(1,2ꢀdiꢀ
methylꢀ3ꢀindolyl)ꢀ2ꢀ(2,5ꢀdimethylꢀ3ꢀthienyl)ethaneꢀ
dione (5) and 1ꢀ(1,2ꢀdimethylꢀ3ꢀindolyl)ꢀ2ꢀ(2ꢀmethylꢀ
1,2ꢀbis(3ꢀindolyl)ethanedione and 1,2ꢀbis(2ꢀmethylꢀ3ꢀ
indolyl)ethanedione9 by the reaction of oxalyl chloride
with the corresponding indolylmagnesium bromides is inꢀ
convenient because of low yields.
3
ꢀbenzo[b]thienyl)ethanedione (6) (Scheme 3). The yields
of the diketones are 40—65%.
Our next aim was to synthesize bisꢀhydrazones
(
osazones) from αꢀdiketones 3—8 according to Scheme 1
and transform the resulting compounds into acetylenes.
Data on osazones of αꢀdiketones of the indole series are
lacking in the literature. Let us only mention the synthesis
of 1,2ꢀbis(2ꢀmethylꢀ3ꢀindolyl)ethanedione bisꢀphenylꢀ
hydrazone by refluxing a solution of 1,2ꢀbis(2ꢀmethylꢀ3ꢀ
indolyl)ethanedione in the presence of phenylhydrazine
Scheme 3
8
in acetic acid.
We found that diketone 7 remained intact after refluxꢀ
ing with a 16ꢀfold excess of hydrazine hydrate in ethanol
in the presence of a catalytic amount of pꢀTsOH for 1 day.
Refluxing in glacial acetic acid for 21 h unexpectedly
afforded 4ꢀ(2ꢀmethylꢀ3ꢀindolyl)ꢀ1ꢀmethylꢀ3Hꢀpyrazoꢀ
lo[3,4ꢀc]quinoline (9a) in 34% yield (Scheme 5) rather
than hydrazone. Raising the temperature to 170—175 °C
and the use of higherꢀboiling ethylene glycol in the
presence of an equivalent amount of hydrazine hydroꢀ
chloride led to a decrease in the reaction time to 2 h
and an increase in the yield of the reaction product
to 63%.W
R = H (1, 3, 4), Me (2, 5, 6)
Scheme 5
Reaction conditions and yields of products: DCE : hexane =
1
0 : 3, 1.2 h, the yield of 3 was 64%; DCE : hexane = 27 : 7, 6 h,
the yield of 4 was 59% (86%); DCE : hexane = 24 : 7, 3 h, the
yield of 5 was 45%; DCE : hexane = 10 : 3, 7 h, the yield
of 6 was 40% (71%). The yield with respect to unconsumed
2
ꢀmethylbenzo[b]thiophene is given in parentheses.
We synthesized symmetrical diketones, viz., 1,2ꢀbis(2ꢀ
methylꢀ3ꢀindolyl)ethanedione (7) and 1,2ꢀbis(1,2ꢀdiꢀ
methylꢀ3ꢀindolyl)ethanedione (8), in high yields
(
Scheme 4) according to a modified procedure developed
for the synthesis of 1,2ꢀbis(1ꢀmethylꢀ3ꢀindolyl)ethaneꢀ
dione7 (heating of an ethereal solution of a mixture of
the substrate and oxalyl chloride in the absence of a
catalyst). The known procedure for the synthesis of
Refluxing of αꢀdiketone 3 in glacial acetic acid in
the presence of a catalytic amount of pꢀTsOH for 22 h
afforded traces of 3Hꢀpyrazolo[3,4ꢀc]quinoline 9b
Scheme 4
(
TLC data), and 53% of the starting compound was reꢀ
covered. The use of ethylene glycol instead of acetic acid
led to an increase in the yield of compound 9b to 60%.
The reaction of 1ꢀ(2ꢀmethylꢀ3ꢀbenzo[b]thienyl)ꢀ2ꢀ
(
2ꢀmethylꢀ3ꢀindolyl)ethanedione (4) with hydrazine
hydrate in nꢀbutanol in the presence of pꢀTsOH for 8.5 h
produces 1ꢀmethylꢀ4ꢀ(2ꢀmethylꢀ3ꢀbenzo[b]thienyl)ꢀ3Hꢀ
pyrazolo[3,4ꢀc]quinoline 9c in 27% yield (see Scheme 5).
In acetic acid, the yield of the latter product is lower.
R = H (7, 81%), Me (8, 88%)
Reagents and conditions: (ClCO) , diethyl ether.
2

894
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 5, May, 2006
Kolotaev et al.
The reaction in ethylene glycol affords 3Hꢀpyrazoꢀ
lo[3,4ꢀc]quinoline 9c in 14% yield.
Scheme 7
Heating of Nꢀmethylindolylꢀsubstituted αꢀdiketones
5
and 8 with an excess of hydrazine hydrate in the presꢀ
ence of an equimolar amount of hydrazine hydrochloride
in ethylene glycol gave rise to a complex mixture of prodꢀ
ucts, which is apparently attributed to the fact that the
3
Hꢀpyrazolo[3,4ꢀc]quinoline system cannot be formed.
The aboveꢀdescribed transformations of αꢀdiketones
, 4, and 7 are analogous to the reaction of 3ꢀacetylindole
3
with hydrazine hydrate (heating in a sealed tube at
50—160 °C for 5 h) giving rise to 4ꢀ(2ꢀaminophenyl)ꢀ3ꢀ
1
1
0
methylpyrazole (Scheme 6) as a result of the nucleoꢀ
philic attack on position 2 of the indole system. Refluxing
in ethanol in an open flask for 2 h afforded only hydrꢀ
azone. Heating of the latter with an eightfold excess of
hydrazine hydrate in a sealed tube at 150—160 °C for 3 h
gave the corresponding (aminophenyl)pyrazole. Hydrꢀ
azones of 2ꢀmethylꢀ and 2ꢀphenylꢀsubstituted 3ꢀacetylꢀ
indoles were not isolated; instead, the corresponding
(
aminophenyl)pyrazoles were obtained.
Scheme 6
1
ꢀphenylꢀsubstituted 4ꢀmethylꢀ2ꢀphenylꢀ2Hꢀpyrazoꢀ
1
2
lo[3,4ꢀc]quinolines were synthesized by the rearrangeꢀ
ment of phenylhydrazones of 2ꢀmethylꢀ and 2ꢀphenylꢀ
substituted 1ꢀ(3ꢀindolyl)propaneꢀ1,2ꢀdiones occurring
under reflux of their ethanolic solutions in the presence of
catalytic amounts of hydrochloric acid. The aboveꢀmenꢀ
tioned phenylhydrazones were prepared by the addition
of 2ꢀmethylꢀ and 2ꢀphenylindole to the corresponding
1
3
nitrile imine.
The structures of 3Hꢀpyrazolo[3,4ꢀc]quinolines 9a—c
1
were confirmed by H NMR spectra, which show the
R = H, Me, Ph
characteristic signals for the quinoline protons at posiꢀ
tions 6 and 9 at δ 8.2—8.5 and the pyrazole methyl at δ 2.9.
The mass spectra contain the molecular ion peaks [M]+
and the fragment ions formed as a result of the loss of the
methyl group from the molecular ion, as well as peaks of
the H C=N—CH species characteristic of alkylpyrazoles.
Heating of 3ꢀbenzoylindole and 3ꢀbenzoylꢀ2ꢀmethylꢀ
indole with an eightfold excess of hydrazine hydrate in
the presence of an equimolar amount of hydrazine hydroꢀ
chloride in ethanol in an autoclave at 150—160 °C
afforded 4ꢀ(2ꢀaminophenyl)ꢀ5ꢀphenylpyrazole and
2
2
4
ꢀ(2ꢀaminophenyl)ꢀ3(5)ꢀmethylꢀ5(3)ꢀphenylpyrazole,
Since the known 3ꢀmethylꢀ1Hꢀpyrazole exists in the
equilibrium with its tautomer, viz., 5ꢀmethylꢀ1Hꢀpyrazole,
there is, presumably, an equilibrium between 3Hꢀpyrazoꢀ
lo[3,4ꢀc]quinolines 9a—c and their 2Hꢀtautomers. Howꢀ
ever, it is necessary to perform additional investigations.
Thus, we demonstrated the possibility of preparing the
previously unknown 4ꢀhetarylꢀsubstituted 1ꢀmethylꢀ3Hꢀ
pyrazolo[3,4ꢀc]quinolines, which was exemplified by the
synthesis of NHꢀunsubstituted αꢀdiketones of the indole
series 3, 4, and 7. Apparently, the series of these comꢀ
pounds can be extended with the use of other heterocyclic
substituents.
1
1
respectively, in almost quantitative yields.
Presumably, 4ꢀ(2ꢀaminophenyl)ꢀ3(5)ꢀhetaroylꢀ5(3)ꢀ
methylpyrazoles formed from compounds 3, 4 and 7 unꢀ
dergo intramolecular cyclization giving rise to the quinoꢀ
line system. In further studies, we used the modified conꢀ
ditions of the reaction of 3ꢀbenzoylindole11 with hydrꢀ
azine hydrate.
The possible mechanism of the formation of comꢀ
pounds 9a—c is presented in Scheme 7.
3
HꢀPyrazolo[3,4ꢀc]quinolines, unlike their 2H isoꢀ
mers, were not described in the literature. 1ꢀMethylꢀ and

Unusual reaction of indole αꢀdiketones
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 5, May, 2006
895
Experimental
15.96 (2ꢀMeindole); 110.41 (C(3)); 111.19 (C(7)), 120.96, 122.98,
23.38 (C(4), C(5), C(6)), 126.99, 127.06 (C(4´), C(3a)), 132.29
(C(5´)), 135.12 (C(7a)), 136.46 (C(3´)), 147.11 (C(2)), 151.55
1
The 1H and 13C NMR spectra were recorded on Bruker
AMꢀ200 and Bruker AMꢀ250 spectrometers in CDCl3,
(C(2´)), 190.60, 190.83 (2 CO). MS (EI, 70 eV), m/z (I (%)):
rel
+
+
+
DMSOꢀd , and acetoneꢀd . The mass spectra (EI) were meaꢀ
297 [M] (6), 158 [(C H N)CO] (100), 139 [(C H S)CO]
9 8 6 7
6
6
+
+
sured on a Kratos instrument (70 eV) using a direct inlet system.
The highꢀresolution mass spectra were obtained on an LTQ
FT hybrid mass spectrometer (Thermo Finnigan, Germany) conꢀ
sisting of a linear quadrupole ion trap and a Fourier transform
ion cyclotron resonance mass spectrometer. A universal electroꢀ
spray ionization (ESI) source Finnigan Ion Max Source was
used as the ion source. Electrospraying of samples was carried
out at a voltage of the needle emitter of 4 kV; samples were
injected into the needle emitter at a rate of 1 µL min– . The
samples were dissolved in a 50 : 50 acetonitrile—water mixture
with the addition of 1% acetic acid.
(21), 130 [C H N] (25), 111 [C H S] (21).
9 8 6 7
1ꢀ(2ꢀMethylꢀ3ꢀbenzo[b]thienyl)ꢀ2ꢀ(2ꢀmethylꢀ3ꢀindolyl)ethaꢀ
nedione (4). Acid chloride 1 (1.00 g, 4.51 mmol) was added
portionwise to a stirred suspension of AlCl (2.70 g, 20.30 mmol)
3
in a mixture of 1,2ꢀdichloroethane (12 mL) and hexane (7 mL)
at 15—17 °C for 10 min. Then a solution of 2ꢀmethylbenꢀ
zo[b]thiophene (1.02 g, 6.77 mmol) in 1,2ꢀdichloroethane
(15 mL) was added for 40 min. The resulting dark solution with
a reddish tint was stirred at the same temperature for 5 h and
poured onto ice. Then dichloromethane (30 mL) was added.
The organic layer was separated and washed with water, an
aqueous solution of sodium hydrocarbonate, and water. The
solvent was evaporated. Column chromatography (AcOEt—peꢀ
troleum ether, 1 : 3, as the eluent) of the residue (1.72 g) afꢀ
forded the starting benzothiophene in a yield of 0.55 g and
diketone 4 in a yield of 0.89 g (59%), m.p. 178—179 °C (ethanol).
1
The melting points were measured on a Boetius hotꢀstage
apparatus and are uncorrected. The course of the reactions was
monitored by TLC on Merck plates (Silica gel 60 F254, visualꢀ
ization with UV light). Column chromatography was performed
on Merck SiO ꢀ60 silica gel (0.060—0.200 mm).
2
Aluminum chloride, 2ꢀmethylindole, oxalyl chloride, and
hydrazine hydrate were purchased from Merck.
Found (%): C, 71.69; H, 4.73; S, 9.92; N, 4.03. C20H NO S.
15 2
Calculated (%): C, 72.05; H, 4.53; S, 9.62; N, 4.20. 1H NMR
1
,2ꢀDimethylindole was synthesized from 2ꢀmethylindole
(CDCl ), δ: 2.47 (s, 3 H, 2ꢀMethioph); 2.70 (s, 3 H, 2ꢀMeindole);
7.14—7.24 (m, 3 H, 5,6ꢀHindole, 5ꢀHthioph); 7.33—7.44 (m, 2 H,
7ꢀHindole, 6ꢀHthioph); 7.76 (d, 1 H, 4ꢀHthioph, J4,5 = 7.9 Hz); 7.97
3
1
4
and iodomethane. 2ꢀMethylbenzo[b]thiophene was prepared
from benzothiophene and iodomethane.1 (2ꢀMethylꢀ3ꢀindoꢀ
lyl)glyoxyloyl chloride (1) was synthesized from oxalyl chloride
and 2ꢀmethylindole.3
5
(d, 1 H, 4ꢀHindole, J4,5 = 7.6 Hz); 8.51 (d, 1 H, 7ꢀHthioph, J6,7
=
7.9 Hz); 9.58 (br.s, 1 H, NH). MS (EI, 70 eV), m/z (I (%)):
rel
+
+
+
(
1,2ꢀDimethylꢀ3ꢀindolyl)glyoxyloyl chloride (2). Oxalyl chloꢀ
332 [M – 1] (3), 317 [M – Me – 1] (1), 175 [(C H S)CO]
9 7
+
+
ride (7.10 g, 4.8 mL, 55.92 mmol) was added dropwise to a
solution of 1,2ꢀdimethylindole (7.00 g, 48.21 mmol) in anhydrous
diethyl ether (100 mL) at 0—2 °C. The resulting suspension was
stirred at 0—5 °C for 2.5 h. The precipitate that formed was
filtered off and washed with anhydrous diethyl ether. The mother
liquor was concentrated to 10% of the initial volume and petroꢀ
leum ether was added. The precipitate that formed was comꢀ
bined with the first portion of the precipitate and dried in a
vacuum desiccator. Acid chloride 2 was obtained in a yield of
0.27 g (90%), m.p. 83 °C. Found (%): C, 61.47; H, 4.60;
Cl, 14.98; N, 5.30. C12H10ClNO . Calculated (%): C, 61.16;
H, 4.28; Cl, 15.04; N, 5.94. H NMR (CDCl ), δ: 2.73 (s, 3 H,
ꢀMe); 3.75 (s, 3 H, 1ꢀMe); 7.30—7.40 (m, 3 H, HHet(5,6,7));
.90 (d, 1 H, HHet(4), J4,5 = 7.2 Hz).
1
dione (3). Acid chloride 1 (0.44 g, 2 mmol) was added portionwise
to a stirred suspension of AlCl (1.20 g, 9 mmol) in a mixture of
hexane (3 mL) and 1,2ꢀdichloroethane (5 mL) for 10 min. Then
a solution of 2,5ꢀdimethylthiophene (0.34 g, 0.34 mL, 3 mmol)
in 1,2ꢀdichloroethane (5 mL) was added at room temperature.
The resulting crimson solution was stirred at the same temperaꢀ
ture for 70 min and poured onto ice. Then dichloromethane
(16), 158 [(C H N)CO] (100), 130 [C H N] (15).
9 8 9 8
1ꢀ(1,2ꢀDimethylꢀ3ꢀindolyl)ꢀ2ꢀ(2,5ꢀdimethylꢀ3ꢀthiꢀ
enyl)ethanedione (5). Acid chloride 2 (1.00 g, 4.24 mol) was
added with stirring to a suspension of AlCl (2.54 g, 19.09 mmol)
3
in a mixture of petroleum ether (7 mL) and 1,2ꢀdichloroethane
(12 mL) at 10 °C for 10 min. Then a solution of 2,5ꢀdimethylꢀ
thiophene (0.71 g, 0.73 mL, 6.37 mmol) in 1,2ꢀdichloroethane
(12 mL) was added for 15 min (the temperature of the mixture
raised to 18 °C). The reaction mixture was stirred at the same
temperature for 3 h and poured onto ice. Then dichloromethane
(30 mL) was added. The organic layer was separated, and the
aqueous layer was extracted with dichloromethane. The comꢀ
bined extracts were washed with water, an aqueous solution of
sodium hydrocarbonate, and water. After evaporation of the
solvent, a dark remainder (1.73 g) was obtained. Column chroꢀ
matography of the latter (ethyl acetate—light petroleum ether,
(1 : 3)—(1 : 2), as the eluent) afforded diketone 5 in a yield of
0.60 g (45%), m.p. 123—125 °C (ethanol). Found (%): C, 69.32;
1
2
1
3
2
7
ꢀ(2,5ꢀDimethylꢀ3ꢀthienyl)ꢀ2ꢀ(2ꢀmethylꢀ3ꢀindolyl)ethaneꢀ
3
H, 5.68; S, 10.32; N, 4.33. C18H17NO S. Calculated (%):
2
1
C, 69.43; H, 5.50; S, 10.30; N, 4.50. M = 311.41. H NMR
(CDCl ), δ: 2.34 (s, 3 H, 5ꢀMethioph); 2.62 (s, 3 H, 2ꢀMethioph);
3
2.76 (s, 3 H, 2ꢀMeindole); 3.65 (s, 3 H, 1ꢀMeindole); 6.97 (s, 1 H,
(
30 mL) was added. The organic layer was separated and washed
4ꢀHthioph); 7.19ꢀ7.30 (m, 3 H, 5,6,7ꢀHindole); 7.92 (d, 1 H, J4,5 =
+
with water, an aqueous solution of sodium hydrocarbonate, and
water. The solvent was evaporated. Diketone 3 was obtained in a
yield of 0.38 g (64%), m.p. 172—173 °C (ethanol). Found (%):
C, 68.86; H, 5.25; S 10.58. C17H15NO S. Calculated (%):
C, 68.66; H, 5.08; S, 10.78. H NMR (CDCl ), δ: 2.34 (s, 3 H,
7.98 Hz, 4ꢀH
(3), 172 [1/2 M] (100), 144 [1/2 M – CO] (9).
). MS (EI, 70 eV), m/z (I (%)): 311 [M]
indole rel
+
+
1ꢀ(1,2ꢀDimethylꢀ3ꢀindolyl)ꢀ2ꢀ(2ꢀmethylꢀ3ꢀbenzo[b]thiꢀ
enyl)ethanedione (6). Acid chloride 2 (1.00 g, 4.24 mmol) was
added portionwise to a stirred suspension of AlCl3 (2.54 g,
19.09 mmol) in a mixture of 1,2ꢀdichloroethane (12 mL)
and hexane (7 mL) at 10 °C for 10 min. Then a solution of
2ꢀmethylbenzo[b]thiophene (0.94 g, 6.37 mmol) in 1,2ꢀdichloroꢀ
ethane (12 mL) was added for 17 min (the temperature raised
2
1
3
5
6
ꢀMethioph); 2.52 (s, 3 H, 2ꢀMethioph); 2.75 (s, 3 H, 2ꢀMeindole);
.97 (s, 1 H, 4ꢀHthioph); 7.16—7.25 (m, 3 H, 5,6,7ꢀHindole); 7.98
d, 1 H, 4ꢀHindole, J4,5 = 7.70 Hz); 9.25 (br.s, 1 H, NH).
(
1
3
C NMR (CDCl ), δ: 14.75 (5ꢀMethioph); 14.89 (2ꢀMethioph);
3

896
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 5, May, 2006
Kolotaev et al.
to 18 °C). The resulting solution was stirred at the same temꢀ
perature for 7 h and poured onto ice. Then dichloromethane
tallized from DMF. Compound 9a was obtained in a yield of
1
0.64 g (63%), m.p. 332—334 °C. H NMR (DMSOꢀd ), δ: 2.09
6
(
30 mL) was added. The organic layer was separated and washed
(s, 3 H, 2ꢀMeindole); 2.88 (s, 3 H, 1ꢀMe); 6.98—7.07 (m, 1 H,
with water, an aqueous solution of sodium hydrocarbonate, and
water. The solution was concentrated. Column chromatography
6ꢀHindole); 7.08—7.17 (m, 1 H, 5ꢀHindole); 7.42 (d, 1 H, 7ꢀHindole,
J6,7 = 7.4 Hz); 7.51—7.72 (m, 3 H, 4ꢀHindole, 7ꢀH, 8ꢀH); 8.10
(
ethyl acetate—light petroleum ether, (1 : 3)—(1 : 2), as the
(m, 1 H, 9ꢀH); 8.36 (m, 1 H, 6ꢀH); 11.46 (br.s, 1 H, NHindole);
+
eluent) of the residue (1.53 g) afforded the starting benzoꢀ
thiophene in a yield of 0.55 g and diketone 6 in a yield of 0.60 g
(
H, 5.13; S, 8.54. C21H17NO S. Calculated (%): C, 72.60;
H, 4.93; S, 9.23. H NMR (CDCl ), δ: 2.72 (s, 3 H, 2ꢀMethioph);
13.15 (br.s, 1 H, NH). MS (EI, 70 eV), m/z (I (%)): 312 [M]
rel
+
+
(100), 311 [M – 1] (58), 297 [M – Me] (15), 270
[M – H C=N – CH ] (15). Highꢀresolution mass spectrum:
found: m/z [M + H] 313.144, [MH + 1] 314.149; C20H16N4;
calculated: M + H = 313.145.
+
40%), m.p. 202—203 °C (ethanol). Found (%): C, 72.87;
2
2
+
+
2
1
3
2
(
.74 (s, 3 H, 2ꢀMeindole); 3.74 (s, 3 H, 1ꢀMeindole); 7.17—7.47
m, 5 H, 5,6,7ꢀHindole, 5,6ꢀHthioph); 7.78 (d, 1 H, 7ꢀHthioph
J6,7 = 7.2 Hz); 7.92 (d, 1 H, 4ꢀHindole, J4,5 = 7.6 Hz); 8.55 (d,
4ꢀ(2,5ꢀDimethylꢀ3ꢀthienyl)ꢀ1ꢀmethylꢀ3Hꢀpyrazoꢀ
lo[3,4ꢀc]quinoline (9b). A solution of αꢀdiketone 3 (0.32 g,
1.08 mmol) and hydrazine hydrate (0.75 mL, 15.06 mmol) in
ethylene glycol (7 mL) was heated with stirring in the presence
of pꢀTsOH (∼ 20 mg) at 185—190 °C for 3 h. After cooling, the
reaction mixture was poured into water and the white precipiꢀ
tate that formed was filtered off in a yield of 0.31 g. The precipiꢀ
tate was recrystallized from ethanol. Quinoline 9b was obtained
in a yield of 0.19 g (60%), m.p. 176—177 °C. Found (%):
,
1
3
[
H, 4ꢀHthioph, J4,5 = 7.9 Hz). MS (EI, 70 eV), m/z (I (%)):
rel
47 [M] (3), 332 [M – Me]+ (3), 175 [(C H S)CO] (6), 172
+
+
9
7
(C10H10N)CO] (100), 147 [C H S] (6), 144 [C10H10N]+ (10).
+
+
9 7
1
,2ꢀBis(2ꢀmethylꢀ3ꢀindolyl)ethanedione (7). Oxalyl chloride
3.20 g, 2.10 mL, 25.16 mmol) was added to a solution of
ꢀmethylindole (6.00 g, 45.74 mmol) in anhydrous diethyl ether
38 mL) at 1—7 °C for 30 min, which led to the formation of a
red precipitate. The resulting suspension was stirred at 30 °C for
.3 h and kept for 16 h. The black precipitate that formed was
(
2
(
C, 69.57; H, 5.58; N, 13.85. C17H15N S. Calculated (%):
3
1
C, 69.60; H, 5.15; N, 14.32. H NMR (DMSOꢀd ), δ: 2.48 (s,
6
3
3 H, 5ꢀMethioph); 2.58 (s, 3 H, 2ꢀMethioph); 2.86 (s, 3 H,
1ꢀMe); 7.15 (s, 1 H, 4ꢀHthioph); 7.57—7.74 (m, 2 H, 7ꢀH,
8ꢀH); 8.03—8.15 (m, 1 H, 9ꢀH); 8.25—8.40 (m, 1 H, 6ꢀH);
filtered off, washed with diethyl ether, and dried. Filtration of
the crude diketone in a 1 : 2 mixture of ethyl acetate and petroꢀ
leum ether through a layer of silica gel afforded colorless diꢀ
ketone 7 in a yield of 5.82 g (81%), m.p. 272—274 °C (ethaꢀ
nol). Found (%): C, 75.81; H, 5.51; N, 8.59. C20H16N O .
13.38 (br.s, 1 H, NH). MS (EI, 70 eV), m/z (I (%)): 294
rel
+
+
+
[M + 1] (34), 293 [M] (98), 278 [M – Me] (65), 251 [M –
+
H C=N – CH ] (40).
2
2
2
2
1
Calculated (%): C, 75.93; H, 5.10; N, 8.85. H NMR
1ꢀMethylꢀ4ꢀ(2ꢀmethylꢀ3ꢀbenzo[b]thienyl)ꢀ3Hꢀpyrazoꢀ
(
5
4
(CD ) CO), δ: 2.63 (s, 3 H, 2ꢀMe); 7.13—7.23 (m, 2 H,
,6ꢀHHet); 7.44 (d, 1 H, 7ꢀHHet, J6,7 = 6.7 Hz); 8.10 (d, 1 H,
ꢀHHet, J4,5 = 7.9 Hz); 11.09 (br.s, 1 H, NH). 13C NMR
lo[3,4ꢀc]quinoline (9c). A mixture of 1,2ꢀethanedione 4 (0.24 g,
0.72 mmol) and hydrazine hydrate (0.52 mL, 10.80 mmol) in
nꢀbutanol (2 mL) in the presence of pꢀTsOH was refluxed for
8.5 h, poured into water, and extracted with dichloromethane.
The organic layer was separated, washed several times with waꢀ
ter, and concentrated. The residue (0.35 g) was recrystallized
from ethanol. 1ꢀMethylꢀ4ꢀ(2ꢀmethylꢀ3ꢀbenzo[b]thienyl)ꢀ3Hꢀ
pyrazolo[3,4ꢀc]quinoline 9c was obtained in a yield of 61 mg
(26.5%), m.p. 228—230 °C. After repeated recrystallization from
3
2
(
(CD ) CO), δ: 14.78 (2ꢀMe), 111.62 (C(3)), 112.45 (C(8)),
3 2
1
1
[
22.07, 123.29, 123.90 (C(5,6,7)), 128.75 (C(4)), 136.85 (C(2)),
92.93 (CO). MS (EI, 70 eV), m/z (I (%)): 316 [M]+ (3), 158
rel
1/2 M] (100), 130 [1/2 M – CO]+ (19).
+
1
,2ꢀBis(1,2ꢀdimethylꢀ3ꢀindolyl)ethanedione (8). A solution
of oxalyl chloride (0.57 g, 0.39 mL, 4.48 mmol) in diethyl ether
(
(
–
2
formed was filtered off, washed with diethyl ether, and dried.
The yield of the compound was 1.50 g (97%). Recrystallization
from DMF afforded colorless diketone 8, m.p. 274—276 °C.
Found (%): C, 76.59; H, 5.94 N, 8.12. C22H20N O . Calcuꢀ
1
10 mL) was added dropwise to a solution of 1,2ꢀdimethylindole
1.48 g, 9.85 mmol) in anhydrous diethyl ether (12 mL) at
1—2 °C for 20 min. The reaction mixture was stirred at
dioxane, m.p. 234—235 °C. H NMR (DMSOꢀd ), δ: 2.63 (s,
6
3 H, 2ꢀMethioph); 2.91 (s, 3 H, 1ꢀMe); 7.23 (1H, m, 5ꢀHthioph);
7.65 (m, 3 H, 7ꢀH, 8ꢀH, 6ꢀHthioph); 7.89 (d, 1 H, 4ꢀHthioph, J =
8.2 Hz); 8.15 (m, 1 H, 9ꢀH); 8.32 (m, 1 H, 7ꢀHthioph); 8.45
(m, 1 H, 6ꢀH); 8.99 (br.s, 1 H, NH), m.p. 234—235 °C (diꢀ
7—30 °C for 2 h and kept for 16 h. The red precipitate that
+
oxane). MS (EI, 70 eV), m/z (I (%)): 329 [M + 1] (100),
rel
+
+
314 [M – Me] (47), 300 [M – N2 – 1] (12), 287 [M –
H C=N – CH ] (28). Highꢀresolution mass spectrum: found
m/z [M + H] 330.097, [MH + 1] 331.100; C20H15N S; calcuꢀ
+
2
2
2
2
1
+
+
lated (%): C, 76.72; H, 5.85; N, 8.13. H NMR (CDCl ), δ: 2.70
3
3
(
5
s, 3 H, 2ꢀMe); 3.70 (s, 3 H, 1ꢀMe); 7.14—7.35 (m, 3 H,
,6,7ꢀHHet); 8.06 (d, 1 H, 4ꢀHHet, J4,5 = 7.2 Hz). 13C NMR
lated: M = 330.106.
(
(
CDCl ), δ: 12.68 (2ꢀMe); 29.83 (1ꢀMe), 109.41 (C(3)), 110.57
C(7)), 121.34 (C(4)), 122.85 (C(5,6)), 126.76 (C(3a)),
3
References
1
37.15 (C(7a)), 147.25 (C(2)), 191.49 (CO). MS (EI, 70 eV),
m/z (Irel (%)): 344 [M]+ (2), 172 [1/2 M] (100), 144
1/2 M – CO]+ (14), 129 [1/2 M – CO – Me]+ (5).
ꢀMethylꢀ4ꢀ(2ꢀmethylꢀ3ꢀindolyl)ꢀ3Hꢀpyrazolo[3,4ꢀc]quinoꢀ
+
1. L. I. Belen´kii, A. V. Kolotaev, V. Z. Shirinyan, M. M.
Krayushkin, Yu. P. Strokach, T. M. Valova, Z. O. Golotyuk,
and V. A. Barachevskii, Khim. Geterotsikl. Soedin., 2005, 100
[Chem. Heterocycl. Comp., 2005, 41 (Engl. Transl.)].
2. L. I. Belen´kii, V. Z. Shirinyan, G. P. Gromova, A. V.
Kolotaev, Yu. A. Strelenko, S. N. Tandura, A. N. Shumskii,
and M. M. Krayushkin, Khim. Geterotsikl. Soedin.,
2003, 1785 [Chem. Heterocycl. Comp., 2003, 39 (Engl.
Transl.)].
[
1
line (9a). A solution of ethanedione 7 (1.04 g, 3.28 mmol) and
hydrazine hydrate (2.30 mL, 45.99 mol) in ethylene glycol
(
3
15 mL) in the presence of hydrazine hydrochloride (0.23 g,
.28 mmol) was heated with stirring at 170—175 °C for 2 h.
Then the reaction mixture was cooled and poured into water.
The precipitate that formed (0.47 g) was filtered off and recrysꢀ

Unusual reaction of indole αꢀdiketones
Russ.Chem.Bull., Int.Ed., Vol. 55, No. 5, May, 2006
897
3
4
. M. Giua, Gazz. Chim. Ital., 1954, 54, 593; Chem. Abstr.,
925, 19, 280.
. M. M. Krayushkin, V. Z. Shirinyan, L. I. Belen´kii, A. Yu.
Shadronov, L. G. Vorontsova, and Z. A. Starikova, Izv. Akad.
Nauk, Ser. Khim., 2002, 1392 [Russ. Chem. Bull., Int. Ed.,
9. B. Oddo and G. Sanna, Gazz. Chim. Ital., 1921, 51 II, 337.
10. C. Alberti, Gazz. Chim. Ital., 1947, 77, 398.
11. C. Alberti, Gazz. Chim. Ital., 1959, 89, 1033.
12. G. Gusmano, G. Macaluso, N. Vivona, and M. Ruccia,
Heterocycles, 1986, 24, 3181.
1
2
002, 51, 1510].
13. M. Ruccia, N. Vivona, G. Gusmano, M. L. Marino, and
F. Piozzi, Tetrahedron, 1973, 29, 3159.
5
6
. M. M. Krayushkin, V. Z. Shirinyan, L. I. Belen´kii, and
A. Yu. Shadronov, Izv. Akad. Nauk, Ser. Khim., 2002, 1396
14. H. Heaney and S. V. Ley, Org. Synth. Vol. 54, 58.
15. E. N. Karaulova, Sintez sul´fidov, tiofenov i tiolov, tipa
soedinenii, vstrechayushchikhsya v neftyakh [Synthesis of Sulꢀ
fides, Thiophenes, and Thiols of Compound Types Present in
Petroleums], Nauka, Moscow, 1988, 180 pp. (in Russian).
[Russ. Chem. Bull., Int. Ed., 2002, 51, 1515].
. M. M. Krayushkin, V. N. Yarovenko, I. P. Sedishev, I. V.
Zavarzin, L. G. Vorontsova, and Z. A. Starikova, Zh. Org.
Khim., 2005, 41, 875 [Russ. J. Org. Chem., 2005, 41 (Engl.
Transl.)].
7
8
. F. Millich and E. I. Becker, J. Org. Chem., 1958, 23, 1096.
. G. Sanna, Gazz. Chim. Ital., 1922, 52 II, 165; Chem. Abstr.,
1
923, 17, 1639.
Received February 20, 2006