Synthesis of fluorine-containing analogs of ellipticine and other heterocycles from 2-Nitro-and 2-amino-4,5-difluoroanilines

Article abstract of DOI:10.1134/S1070428007090217

2-Nitro- and 2-amino-4,5-difluoroanilines were used as starting materials to synthesize fluorine-containing imidazole, oxazole, and indoloquinoxaline derivatives. The latter may be regarded as ellipticine analogs.

Full text of DOI:10.1134/S1070428007090217

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2007, Vol. 43, No. 9, pp. 1387–1392. © Pleiades Publishing, Ltd., 2007.
Original Russian Text © V.N. Yarovenko, A.V. Polushina, K.S. Levchenko, I.V. Zavarzin, M.M. Krayushkin, S.K. Kotovskaya, V.N. Charushin, 2007,
published in Zhurnal Organicheskoi Khimii, 2007, Vol. 43, No. 9, pp. 1391–1396.
Dedicated to Full Member of the Russian Academy of Sciences
V.A. Tartakovskii on the 75th anniversary of his birth
Synthesis of Fluorine-Containing Analogs
of Ellipticine and Other Heterocycles from 2-Nitro-
and 2-Amino-4,5-difluoroanilines
V. N. Yarovenkoa, A. V. Polushinaa, K. S. Levchenkoa, I. V. Zavarzina, M. M. Krayushkina,
S. K. Kotovskayab, and V. N. Charushinc
a Zelinskii Institute of Organic Chemistry, Russian Academy of Sciences, Leninskii pr. 47, Moscow, 119991 Russia
e-mail: yarovladimir@tochka.ru
b Ural State Technical University, Yekaterinburg, Russia
c Postovskii Institute of Organic Synthesis, Ural Division, Russian Academy of Sciences,
ul. S. Kovalevskoi 20, Yekaterinburg, 620219 Russia
Received May 28, 2007
Abstract—2-Nitro- and 2-amino-4,5-difluoroanilines were used as starting materials to synthesize fluorine-
containing imidazole, oxazole, and indoloquinoxaline derivatives. The latter may be regarded as ellipticine
analogs.
DOI: 10.1134/S1070428007090217
Numerous fluorine-containing heterocycles, e.g.,
fluoropyrimidines, fluoroindoles, fluorobenzimid-
azoles, fluoroquinolines, fluoroquinazolines, fluoro-
naphthyridines, etc., exhibit strong biological activity
due to their ability to inhibit specific enzymes, good
solubility in lipids, and easy penetration through cell
membranes [1–3]. In particular, a broad series of com-
pounds was synthesized on the basis of 4,5-difluoro-
benzene-1,2-diamine. The latter is an important syn-
thon; the presence of four substituents in its benzene
ring provides the possibility for its versatile modifica-
tion, including preparation of fused heterocyclic struc-
tures [4–6].
moreover, it can be directly involved in heterocycliza-
tions.
In the synthesis of fluorine-containing compounds
we used monothiooxamide derivatives of 2-amino- and
2-nitro-4,5-difluoroanilines I and II. We previously
developed a convenient procedure for the preparation
of monothiooxamides by reaction of α-chloroacet-
amides with a preliminarily prepared solution of sulfur
in the corresponding amine and showed that these
compounds can be converted into various heterocyclic
systems [11].
Chloroacetanilide III was obtained by acylation of
4,5-difluoro-2-nitroaniline (I) with chloroacetyl chlo-
ride in dimethylformamide. The reaction of chloro-
acetyl chloride with 4,5-difluorobenzene-1,2-diamine
(II) in DMF gave N,N′-bis(chloroacetyl) derivative IV
which reacted with a solution of elemental sulfur in
morpholine to form the corresponding bis(monothio-
oxamide) V (Scheme 1). Under analogous conditions,
the transformation of N-(4,5-difluoro-2-nitrophenyl)-2-
chloroacetamide (III) was accompanied by expected
nucleophilic replacement of the fluorine atom in the
para position relative to the nitro group, yielding
compound VI. These data demonstrate different behav-
The goal of the present work was to extend the
above studies and synthesize fluorine-containing deriv-
atives of fused imidazoles, oxazoles, and indoloquin-
oxalines; the latter may be regarded as analogs of
natural alkaloids of the pyrido[4,3-b]carbazole series
which are known to possess antitumor activity [7–10].
The synthetic schemes included mainly acylation of
the amino groups in 3,4-difluoroanilines with acid
chlorides. The nitro group in difluoroanilines gives rise
to additional potential for functionalization via activa-
tion of fluorine atom to nucleophilic substitution;
1387

1388
YAROVENKO et al.
Scheme 1.
S
O
O
N
F
F
NHCOCH2Cl
N
F
NH
O
Morpholine, S8
NO2
III
NO2
VI
F
F
NH2
X
ClCH2COCl
S
O
O
N
I, II
F
F
NHCOCH2Cl
NHCOCH2Cl
F
NH
O
Morpholine, S8
F
NH
O
N
S
IV
V
I, X = NO2; II, X = NH2.
Scheme 2.
X
S
Y
O
O
NH2
N
S8, Et3N
X
N
X
H
III
+
HN
F
NH
HN
NH
X
NO2
F
NO2
VIIa, VIIb
VIIIa, VIIIb
VII, X = NH2 (a), OH (b); VIII, X = NH2, Y = NH (a); X = OH, Y = O (b).
iors of fluoroanilines I and II and easy modification of
fluoroarenes activated due to the presence of a nitro
group.
Chloroacetanilide III was then used to synthesize
fused heterocyclic compounds. Benzimidazole and
1,3-benzoxazole derivatives VIIIa and VIIIb were
obtained by reactions of III with o-phenylenediamine
(VIIa) and o-aminophenol (VIIb), respectively, in the
presence of sulfur and triethylamine. The reactions
were accompanied by replacement of the fluorine atom
in the para position with respect to the nitro group by
the aromatic acid residue. Presumably, the process
involves intermediate formation of monothiooxamide
and its subsequent heterocyclization at the thioamide
carbonyl group (Scheme 2).
4,5-Difluorobenzene-1,2-diamine (II) reacted with
chloroacetamides IXa–IXc of the nitroaniline and
nitropyridine series in the presence of elemental sulfur
Scheme 3.
F
F
HN
H
SnCl2
EtOH
NHCOCH2Cl
NO2
N
F
F
N
N
S8, Et3N
N
II
+
O
N
H
N
H
R
Y
R
Y
NO2
R
Y
IXa–IXc
Xa–Xc
XIa–XIc
Y = CH, R = H (a), Cl (b); Y = N, R = H (c).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 9 2007

SYNTHESIS OF FLUORINE-CONTAINING ANALOGS OF ELLIPTICINE
1389
Scheme 4.
RR'NH (XIIIa–XIIIc)
S8, Et3N, DMF
F
F
F
F
S
N
N
ClCH2COOH, HCl
II
N
H
N
H
Cl
NRR'
XII
XIVa–XIVc
RR′N = morpholino (a); R = H, R′ = Ph (b), pyridin-2-yl (c).
and triethylamine to give benzimidazole derivatives
Xa–Xc (Scheme 3). The reduction of the nitro group in
compounds Xa–Xc was accompanied by intramolec-
ular cyclization which opens a way to fluorinated
2,2′-bibenzimidazoles XIa–XIc.
4,5-difluorobenzene-1,2-diamine (II) with isatins
XVIa–XVId in various solvents (dioxane, alcohol,
acetic acid). The best yields (60–75%) of 6-substituted
2,3-difluoro-6H-indolo[2,3-b]quinoxalines XVIIa–
XVIId were obtained when the reactions were carried
out in acetic acid (Scheme 6).
We also made an attempt to synthesize 2-chloro-
methyl-5,6-difluoro-1H-benzimidazole (XII) which at-
tracts considerable interest from the viewpoint of ob-
taining thioamides and heterocyclic compounds based
thereon. However, we failed to effect cyclization of
bis-chloroacetamide IV (see above) by thermolysis or
heating in polyphosphoric acid. We succeeded in
obtaining 2-chloromethyl-5,6-difluoro-1H-benzimid-
azole (XII) in good yield by reaction of difluorophen-
ylenediamine II with chloroacetic acid on heating in
boiling concentrated hydrochloric acid (Scheme 4).
Treatment of XII with elemental sulfur and amines
XIIIa–XIIIc in the presence of triethylamine in DMF
afforded thioamides XIVa–XIVc.
Scheme 6.
O
R
+
II
O
N
R'
XVIa–XVId
R
F
F
N
N
AcOH
N
R'
We also demonstrated the possibility for synthesiz-
ing fused heterocycles from thioamides based on
2-chloromethyl-5,6-difluoro-1H-benzimidazole (XII).
Compound XII reacted with o-phenylenediamine and
o-aminophenol in the presence of sulfur to give 2-(1H-
benzimidazol-2-yl)- and 2-(1,3-benzoxazol-2-yl)-sub-
stituted 5,6-difluorobenzimidazoles XIa and XV,
respectively (Scheme 5).
XVIIa–XVIId
R = H, R′ = H (a), Me (b), Bu (c); R = Br, R′ = Et (d).
To conclude, we have proposed new approaches to
the synthesis of fluorine-containing elliptitcne analogs
and other fused heterocycles on the basis of difluoro-
aniline derivatives.
Scheme 5.
EXPERIMENTAL
NH2
XII
+
The 1H NMR spectra were recorded on Bruker AC-
200 (200 MHz) and WM-250 (250 MHz) spectrom-
eters from solutions in DMSO-d6; the 13C NMR spec-
tra were measured on a Bruker AC-200 instrument at
50.3 MHz using DMSO-d6 as solvent. The mass spec-
tra (electron impact, 70 eV) were obtained on a Varian
MAT CH-6 mass spectrometer with direct sample
admission into the ion source (accelerating voltage
1.75 kV). The melting points were determined on
a Boetius hot stage and were not corrected. The reac-
tion mixtures and isolated products were analyzed by
TLC on Silica gel 60 F254 (Merck).
XH
VIIa, VIIb
F
F
N
N
X
S8, Et3N, DMF
N
H
XIa, XV
VIIa, XIa, X = NH; VIIb, XV, X = O.
With a view to synthesize fluorine-containing ana-
logs of ellipticine [7–10], we examined reactions of
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 9 2007

1390
Chloroacetamides III and IV were synthesized
YAROVENKO et al.
acetanilide III was added, and the mixture was stirred
for 4 h at room temperature. The mixture was poured
into water, the precipitate was filtered off, dried, and
dissolved in acetone, the acetone solution was separat-
ed from the undissolved material, the solvent was
evaporated under reduced pressure, and the residue
was purified by thin-layer chromatography using pe-
troleum ether–ethyl acetate (3:1) as eluent.
according to the procedure described in [12].
2-Chloro-N-(4,5-difluoro-2-nitrophenyl)acet-
1
amide (III). Yield 97%, mp 84–85°C. H NMR spec-
trum, δ, ppm: 4.41 s (2H), 8.0 m (1H, Harom), 8.35 m
(1H, Harom), 10.8 s (1H, NH). Mass spectrum: m/z 250
[M]+. Found, %: C 38.27; H 2.12; N 11.09.
C8H5ClF2N2O3. Calculated, %: C 38.34; H 2.01;
N 11.18.
N-{5-[(2-Aminophenyl)amino]-4-fluoro-2-nitro-
phenyl}-1H-benzimidazole-2-carboxamide (VIIIa).
Yield 38%, mp 197–199°C. H NMR spectrum, δ,
ppm: 4.6 s (2H, NH2), 6.9 m (2H, Harom), 7.02 m (1H,
Harom), 7.1 m (1H, Harom), 7.3 d (2H, Harom, J = 7.4 Hz),
7.4 d (2H, Harom, J = 7.3 Hz), 7.9 m (1H, Harom), 8.1 m
(1H, Harom), 9.6 s (1H, NH), 10.2 s (1H, NH), 10.95 s
(1H, NH). Mass spectrum: m/z 406 [M]+. Found, %:
C 59.23; H 3.76; N 20.54. C20H15FN6O3. Calculated,
%: C 59.11; H 3.72; N 20.68.
N,N′-(4,5-Difluorobenzene-1,2-diyl)bis(2-chloro-
acetamide) (IV) was synthesized from 1 mol of di-
amine III and 2.4 mmol of chloroacetyl chloride. Yield
1
1
96%, mp 142–143°C. H NMR spectrum, δ, ppm:
4.33 s (4H), 7.65 m (2H, Harom), 9.78 s (2H, 2NH).
Mass spectrum: m/z 297 [M]+. Found, %: C 40.32;
H 2.63; N 9.57. C10H8Cl2F2N2O2. Calculated, %:
C 40.43; H 2.71; N 9.43.
Monothiooxamides V and VI (general procedure).
A mixture of 0.045 g (1.4 mmol) of sulfur and
0.94 mmol of morpholine in 1 ml of DMF was kept
for 30 min, 0.47 mmol of chloroacetanilide III or
0.24 mmol of compound IV was added, and the mix-
ture was left to stand for 6 h at room temperature. The
mixture was then poured into water, the precipitate was
filtered off and dissolved in acetone, the solution was
separated from the undissolved material, the solvent
was removed under reduced pressure, and the solid
residue was recrystallized from ethanol.
N-{5-[(2-Hydroxyphenyl)amino]-4-fluoro-2-nitro-
phenyl}-1,3-benzoxazole-2-carboxamide (VIIIb).
1
Yield 41%, mp 162–164°C. H NMR spectrum, δ,
ppm: 7.0 m (2H, Harom), 7.15 m (2H, Harom), 7.2 m
(1H, Harom), 7.4 m (2H, Harom), 7.55 m (1H, Harom, J =
7.3 Hz), 7.9 m (2H, Harom), 9.4 s (1H, NH), 9.8 s (1H,
NH), 10.6 s (1H, OH). Mass spectrum: m/z: 408 [M]+.
Found, %: C 58.89; H 3.17; N 13.79. C20H13FN4O5.
Calculated, %: C 58.83; H 3.21; N 13.72.
5,6-Difluoro-1H-benzimidazole-2-carboxamides
Xa–Xc (general procedure). A suspension of 3 mmol
of sulfur, 1.8 mmol of 4,5-difluorobenezene-1,2-di-
amine (II), and 2.2 mmol of triethylamine in 3 ml of
DMF was kept for 25 min, 0.9 mmol of chloroacet-
anilide IXa–IXc was added, and the mixture was
stirred for 5 h at room temperature. The mixture was
poured into water, the precipitate was filtered off,
dried, and dissolved in acetone, the solution was sep-
arated from the undissolved material, the solvent was
evaporated under reduced pressure, and the solid
residue was recrystallized from ethanol.
N,N′-(4,5-Difluorobenzene-1,2-diyl)bis(2-mor-
pholino-2-thioxoacetamide) (V). Yield 52%, mp 280–
282°C. 1H NMR spectrum, δ, ppm: 3.7 d (4H, CH2, J =
4.8 Hz), 3.78 s (8H), 4.12 d (4H, J = 4.65 Hz), 7.75 m
(2H, Harom), 10.0 s (2H, 2NH). Mass spectrum: m/z 458
[M]+. Found, %: C 47.06; H 4.24; N 12.36.
C18H20F2N4O4S2. Calculated, %: C 47.15; H 4.40;
N 12.22.
N-(4-Fluoro-5-morpholino-2-nitrophenyl)-2-mor-
pholino-2-thioxoacetamide (VI). Yield 78%, mp 169–
1
170°C. H NMR spectrum, δ, ppm: 3.75 m (10H),
5,6-Difluoro-N-(2-nitrophenyl)-1H-benzimid-
azole-2-carboxamide (Xa). Yield 70%, mp 181–
4.15 m (2H), 4.3 m (2H), 4.55 s (2H), 7.50 d (1H,
1
H
arom, J = 8.21 Hz), 7.98 m (1H, Harom), 11.0 s (1H,
183°C. H NMR spectrum, δ, ppm: 7.2 m (1H, Harom),
NH). Mass spectrum: m/z 398 [M]+. Found, %:
C 48.06; H 4.95; N 14.24. C16H19FN4O5S. Calculated,
%: C 48.24; H 4.81; N 14.06.
7.5 m (1H, Harom), 7.85 m (2H, Harom), 8.15 m (1H,
H
arom), 8.45 m (1H, Harom), 11.7 s (1H, NH), 13.85 s
(1H, NH). Mass spectrum: m/z 318 [M]+. Found, %:
C 52.89; H 2.50; N 17.51. C14H8F2N4O3. Calculated,
%: C 52.84; H 2.53; N 17.61.
Substituted benzimidazole- and 1,3-benzoxazole-
2-carboxamides VIIIa and VIIIb (general proce-
dure). A mixture of 0.3 mmol of sulfur, 0.2 mmol of
amine VIIa or VIIb, and 0.2 mmol of triethylamine in
1 ml of DMF was kept for 30 min, 0.1 mmol of chloro-
N-(4-Chloro-2-nitrophenyl)-5,6-difluoro-1H-
benzimidazole-2-carboxamide (Xb). Yield 76%,
1
mp 167–169°C. H NMR spectrum, δ, ppm: 7.0 m
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 9 2007

SYNTHESIS OF FLUORINE-CONTAINING ANALOGS OF ELLIPTICINE
1391
(1H, Harom), 7.2 m (1H, Harom), 7.5 m (2H, Harom),
7.8 m (1H, Harom), 11.3 s (1H, NH), 12.8 s (1H, NH).
Mass spectrum: m/z 353 [M]+. Found, %: C 47.55;
H 2.08; N 15.94. C14H7ClF2N4O3. Calculated, %:
C 47.68; H 2.00; N 15.89.
0.7 ml of concentrated hydrochloric acid was heated
for 5 h under reflux. The mixture was cooled to 0°C
and carefully neutralized to pH 7 by adding aqueous
ammonia, and the precipitate was filtered off and
washed with a small amount of ice water (3×0.5 ml).
1
Yield 60%, mp 166–168°C. H NMR spectrum, δ,
5,6-Difluoro-N-(2-nitropyridin-3-yl)-1H-benz-
imidazole-2-carboxamide (Xc). Yield 67%, mp 135–
ppm: 4.9 s (2H, CH2), 7.62 t (2H, Harom, J = 9.12 Hz),
10.0 s (1H, NH). Mass spectrum: m/z 202 [M]+. Found,
%: C 47.34; H 2.58; N 13.71. C8H5ClF2N2. Calculated,
%: C 47.43; H 2.49; N 13.83.
1
137°C. H NMR spectrum, δ, ppm: 7.7 m (1H, pyri-
dine), 7.9 m (1H, Harom), 8.0 m (1H, pyridine), 8.65 m
(2H, Harom), 11.5 s (1H, NH), 12.9 s (1H, NH). Mass
spectrum: m/z 319 [M]+. Found, %: C 48.74; H 2.13;
N 21.99. C13H7F2N5O3. Calculated, %: C 48.91;
H 2.21; N 21.94.
5,6-Difluoro-1H-benzimidazole-2-carbothio-
amides XIVa–XIVc, XIa, and XV (general proce-
dure). A mixture of 1.4 mmol of sulfur and 0.94 mmol
of amine XIIIa–XIIIc, VIIa, or VIIb, in 1 ml of DMF
was kept for 30 min, 0.2 mmol of compound XII was
added, and the mixture was left to stand for 3 h at
room temperature and poured into water. The precip-
itate was filtered off, washed with water, and dissolved
in acetone, the solution was separated from the undis-
solved material, the solvent was removed under re-
duced pressure, and the solid residue was recrystallized
from ethyl acetate or ethanol.
5,6-Difluoro-1H,1′H-2,2′-bibenzimidazoles XIa–
XIc (general procedure). A mixture of 1 mmol of
benzimidazole-2-carboxamide Xa–Xc and 5 mmol of
SnCl2·2H2O in 5 ml of ethanol was heated for 90 min
under reflux. The mixture was cooled to room tem-
perature, the solvent was removed under reduced pres-
sure, 5 ml of water and an aqueous solution of sodium
hydroxide were added to the residue, and the mixture
was extracted with ethyl acetate. The extract was evap-
orated, and the residue was purified by recrystalliza-
tion from ethanol or by thin-layer chromatography on
silica gel using ethyl acetate–petroleum ether (1:3) as
eluent.
5,6-Difluoro-2-(morpholinocarbonothioyl)-1H-
benzimidazole (XIVa). Yield 63%, mp 243–245°C.
1H NMR spectrum, δ, ppm: 3.72 t (2H, J = 4.66 Hz),
3.83 t (2H, J = 4.84 Hz), 4.20 t (2H, J = 4.64 Hz), 4.35 t
(2H, J = 4.77 Hz), 7.55 m (1H, Harom), 7.75 m (1H,
Harom), 13.10 s (1H, NH). Mass spectrum: m/z 283 [M]+.
Found, %: C 50.96; H 3.78; N 14.72. C12H11F2N3OS.
Calculated, %: C 50.88; H 3.91; N 14.83.
5,6-Difluoro-1H,1′H-2,2′-bibenzimidazole (XIa).
1
Yield 60%, mp 198–200°C. H NMR spectrum, δ,
ppm: 7.25 m (2H, Harom), 7.40 m (2H, Harom), 7.5 m
(2H, Harom), 11.55 s (1H, NH), 12.3 s (1H, NH). Mass
spectrum: m/z 270 [M]+. Found, %: C 62.27; H 2.91;
N 20.79. C14H8F2N4. Calculated, %: C 62.22; H 2.98;
N 20.73.
5,6-Difluoro-N-phenyl-1H-benzimidazole-2-
carbothioamide (XIVb). Yield 60%, mp 103–105°C.
1H NMR spectrum, δ, ppm: 7.35–7.94 m (7H, Harom),
12.33 s (1H, NH), 13.2 s (1H, NH). Mass spectrum:
m/z 289 [M]+. Found, %: C 58.03; H 3.30; N 14.65.
C14H9F2N3S. Calculated, %: C 58.12; H 3.14; N 14.52.
6′-Chloro-5,6-difluoro-1H,1′H-2,2′-bibenzimid-
1
azole (XIb). Yield 63%, mp 234–236°C. H NMR
spectrum, δ, ppm: 7.25 m (1H, Harom), 7.45 m (1H,
H
arom), 7.5 m (1H, Harom), 7.75 m (2H, Harom), 11.9 s
5,6-Difluoro-N-(pyridin-2-yl)-1H-benzimidazole-
2-carbothioamide (XIVc). Yield 58%, mp 249–
251°C. H NMR spectrum, δ, ppm: 7.1 m, 7.75 m,
7.8 m, and 7.9 m (1H each, pyridine); 8.2 m (2H,
Harom); 9.4 s and 10.2 s (1H each, NH). Mass spectrum:
m/z 290 [M]+. Found, %: C 53.88; H 2.64; N 19.42.
C13H8F2N4S. Calculated, %: C 53.79; H 2.78; N 19.30.
(1H, NH), 12.4 s (1H, NH). Mass spectrum: m/z 305
[M]+. Found, %: C 55.11; H 2.16; N 18.32.
C14H7ClF2N4. Calculated, %: C 55.19; H 2.32; N 18.39.
1
2-(5,6-Difluoro-1H-benzimidazol-2-yl)-3H-imid-
azo[4,5-b]pyridine (XIc). Yield 60%, mp 246–248°C.
1H NMR spectrum, δ, ppm: 7.8 m, 8.0 m, and 8.15 m
(1H each, 4-H, 5-H, 6-H); 8.4 m (2H, Harom); 11.15 s
and 12.0 s (1H each, NH). Mass spectrum: m/z 271
[M]+. Found, %: C 57.51; H 2.71; N 25.88. C13H7F2N5.
Calculated, %: C 57.57; H 2.60; N 25.82.
5,6-Difluoro-1H,1′H-2,2′-bibenzimidazole (XIa).
1
Yield 65%, mp 197–199°C. H NMR spectrum, δ,
ppm: 7.25 m (2H, Harom), 7.4 m (2H, Harom), 7.5 m (2H,
Harom), 11.55 s (1H, NH), 12.3 s (1H, NH). Mass spec-
trum: m/z 270 [M]+. Found, %: C 62.27; H 2.82;
N 20.61. C14H8F2N4. Calculated, %: C 62.22; H 2.98;
N 20.73.
2-Chloromethyl-5,6-difluoro-1H-benzimidazole
(XII). A mixture of 0.5 mmol of 4,5-difluorobenzene-
1,2-diamine and 0.74 mmol of chloroacetic acid in
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 9 2007

1392
YAROVENKO et al.
7.82 d (1H, Harom, J = 8.68 Hz), 7.93 m (1H, Harom),
2-(5,6-Difluoro-1H-benzimidazol-2-yl)-1,3-benz-
oxazole (XV). Yield 60%, mp 265–267°C. H NMR
1
8.12 m (1H, Harom), 8.24 m (1H, Harom), 8.45 m (1H,
spectrum, δ, ppm: 6.9 m (1H, Harom), 7.05 m (1H,
Harom), 7.15 m (1H, Harom), 7.5 m (1H, Harom), 7.9 m
(1H, Harom), 8.8 m (1H, Harom), 10.7 s (1H, NH). Mass
spectrum: m/z 271 [M]+. Found, %: C 62.07; H 2.64;
N 15.43. C14H7F2N3O. Calculated, %: C 62.00; H 2.60;
N 15.49.
H
arom). Mass spectrum: m/z 362 [M]+. Found, %:
C 53.12; H 2.71; N 11.69. C16H10BrF2N3. Calculated,
%: C 53.06; H 2.78; N 11.60.
This study was performed under financial support
by the Russian Foundation for Basic Research (project
no. 07-03-12112) and by the Council for Grants at the
President of the Russian Federation (program for state
support of leading scientific schools, project no. NSh-
9178.2006.3).
Indoloquinoxalines XVIIa–XVIId (general pro-
cedure). Compound XVIa–XVId, 1 mmol, was mixed
with 1 mmol of diamine II, a small amount of acetic
acid was added, and the mixture was heated for 30–
60 min. The mixture was then poured into water, and
the precipitate was filtered off, washed with water,
dried, and purified by thin-layer chromatography using
petroleum ether–ethyl acetate (3:2) as eluent.
REFERENCES
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2,3-Difluoro-6H-indolo[2,3-b]quinoxaline
1
(XVIIa). Yield 60%, mp 198–200°C. H NMR spec-
trum, δ, ppm: 7.38 t (1H, Harom, J = 7.50 Hz), 7.61 d
(1H, Harom, J = 8.08 Hz), 7.74 t (1H, Harom, J =
7.70 Hz), 8.08 m (1H, Harom), 8.27 m (1H, Harom),
8.34 d (1H, Harom, J = 7.78 Hz), 12.15 s (1H, NH).
Mass spectrum: m/z 255 [M]+. Found, %: C 65.81;
H 2.82; N 16.39. C14H7F2N3. Calculated, %: C 65.88;
H 2.76; N 16.46.
2,3-Difluoro-6-methyl-6H-indolo[2,3-b]quinoxa-
1
line (XVIIb). Yield 75%, mp 202–203°C. H NMR
spectrum, δ, ppm: 3.89 s (3H), 7.41 t (1H, Harom, J =
7.35 Hz), 7.72 d (1H, Harom, J = 8.14 Hz), 7.78 t (1H,
H
H
arom, J = 7.61 Hz), 8.04 m (1H, Harom), 8.21 m (1H,
arom), 8.32 d (1H, Harom, J = 7.66 Hz). Mass spectrum:
m/z 269 [M]+. Found, %: C 66.97; H 3.27; N 15.70.
C15H9F2N3. Calculated, %: C 66.91; H 3.37; N 15.61.
7. Suffness, M. and Cordell, C.A., The Alkaloids, 1985,
vol. 25, p. 89.
6-Butyl-2,3-difluoro-6H-indolo[2,3-b]quinoxaline
1
8. Gribble, G.W., The Alkaloids, 1990, vol. 39, p. 239.
9. Ishikura, M., Hino, A., Yaginuma, T., Aata, I., and
Katagiri, N., Tetrahedron, 2000, vol. 56, p. 193.
10. Chabane, H., Lamazzi, C., Thiery, V., Guilaumet, G.,
and Besson, T., Tetrahedron Lett., 2002, vol. 43,
p. 2483.
(XVIIc). Yield 65%, mp 144–145°C. H NMR spec-
trum, δ, ppm: 0.95 s (3H), 1.35 s (2H), 1.85 s (2H),
4.50 s (2H), 7.43 m (1H, Harom), 7.81 t (2H, Harom, J =
6.54 Hz), 8.11 m (1H, Harom), 8.27 m (1H, Harom),
8.37 d (1H, Harom, J = 7.68 Hz). Mass spectrum:
m/z 311 [M]+. Found, %: C 69.38; H 4.79; N 13.54.
C18H15F2N3. Calculated, %: C 69.44; H 4.86; N 13.50.
11. Krayushkin, M.M., Yarovenko, V.N., and Zavarzin, I.V.,
Izv. Ross. Akad. Nauk, Ser. Khim., 2004, p. 491.
9-Bromo-6-ethyl-2,3-difluoro-6H-indolo[2,3-b]-
quinoxaline (XVIId). Yield 60%, mp 216–217°C.
1H NMR spectrum, δ, ppm: 1.43 s (3H), 4.55 s (2H),
12. Zavarzin, I.V., Yarovenko, V.N., Shirokov, A.V., Smir-
nova, N.G., Es’kov, A.A., and Krauyshkin, M.M.,
Arkivoc, 2003, part (xiii), p. 205.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 9 2007