Synthesis of 6-aminopropyl-6H-indolo[2,3-b]quinoxaline derivatives

Article abstract of DOI:10.1002/jhet.805

A series of 6-(3-aminopropyl)-6H-indolo[2,3-b]quinoxalines were synthesized with high yields by the reaction of 6-(3-chloropropyl)-6H-indolo[2,3-b] quinoxaline and corresponding amines in presence of tetrabutylammonium iodide in boiling toluene or dimethylformamide at room temperature. It was found that boiling of 6-(3-chloropropyl)-6H-indolo[2,3-b]quinoxaline in acetone with sodium iodide or in acetic acid lead to intramolecular cyclization product.

Full text of DOI:10.1002/jhet.805

678
Synthesis of 6-Aminopropyl-6H-indolo[2,3-b]quinoxaline Derivatives
Vol 49
Marina O. Shibinskaya,a Nina A. Kutuzova,b Alexandr V. Mazepa,a,b
Sergey A. Lyakhov,a,b Sergey A. Andronati, Mykhayl Ju. Zubritsky,c
a,b
*
Valerij F. Galat,c Janusz Lipkowski,d and Victor Ch. Kravtsove
aA.V. Bogatsky Physico-Chemical Institute of NAS of Ukraine, Lyustdorfskaya doroga, 86, Odessa
65080, Ukraine
bOdessa National I.I. Mechnikov University, Dvoryanskaya str., 2, Odessa 65026, Ukraine
cL. M. Litvinenko Institute of Physical-Organic Chemistry and Coal Chemistry of the NAS of Ukraine,
70 R. Luxemburg St., Donetsk 83114, Ukraine
dInstitute of Physical Chemistry, Polish Academy of Sciences, Kasprzaka 44/52,
Warsaw 01-224, Poland
eInstitute of Applied Physics, Academy of Sciences of Moldova, Academiei str., 5 MD-2028,
Chişinău, R. Moldova
*
E-mail: Sergey_A_Lyakhov@ukr.net
Received August 18, 2010
DOI 10.1002/jhet.805
View this article online at wileyonlinelibrary.com.
A series of 6-(3-aminopropyl)-6H-indolo[2,3-b]quinoxalines were synthesized with high yields by the
reaction of 6-(3-chloropropyl)-6H-indolo[2,3-b]quinoxaline and corresponding amines in presence of
tetrabutylammonium iodide in boiling toluene or dimethylformamide at room temperature. It was found that
boiling of 6-(3-chloropropyl)-6H-indolo[2,3-b]quinoxaline in acetone with sodium iodide or in acetic acid
lead to intramolecular cyclization product.
J. Heterocyclic Chem., 49, 678 (2012).
INTRODUCTION
group play very important role in the ligands’ DNA affinity
and their sequence selectivity [9,10]. That is why the side
chain elongation retained our attention. For obtaining of
new potential DNA intercalators and interferon inductors
synthesis of 6-aminoalkyl-6H-indolo[2,3-b]quinoxalines
(Figure 1, n = 3ꢀ6) is seemed as rational. The aim of this
work was to synthesize 6-aminopropyl-6H-indolo[2,3-b]
quinoxalines (n = 3).
The indoloquinoxaline (Figure 1, n = 2) were synthe-
sized by Bergman and coworkers [1,2] and shown as
DNA intercalators [3,4] and antivirals against different
species of Herpesviridae family [1]. These compounds
have demonstrated antitumor [5] and antimicrobial activity
[6,7] also. Regarding intercalation ability of the above
compounds, we have synthesized some new 6-ami-
noethyl-6H-indolo[2,3-b]quinoxaline derivatives and
resynthesized known ones and have shown that they are
highly effective interferon inductors and demonstrate high
antiviral activity against vesicular stomatitis virus [8]. It is
known that interaction of the cationic side-chain amino
RESULTS AND DISCUSSION
Isatin (1) alkylation according [8] with 1-bromo-3-
chloropropane in DMF at room temperature in the presence
© 2012 HeteroCorporation

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Synthesis of 6-Aminopropyl-6H-indolo[2,3-b]quinoxaline Derivatives
679
Scheme 2. Synthesis of 6-(3-chloropropyl)-6H-indolo-[2,3-b]quinoxaline.
Figure 1. General structure of 6-aminoalkyl-6H-indolo[2,3-b]quinoxalines.
h 6-chloropropyl-6H-indolo-[2,3-b]quinoxaline (3) (Scheme
3). It is possible, this product formation is a main reason of
the compound 3 low yields while condensation of 2 with 1,2-
diaminobenzene in the acetic acid media.
of potassium carbonate gives the 1-chloropropylisatine (2) with
85% yield after recrystallization from heptane (Scheme 1).
Further condensation of 2 with 1,2-diaminobenzene under
the boiling in acetic acid leads to the 6-chloropropyl-6H-
indolo-[2,3-b]quinoxaline (3) with low yield (30%), whereas
the condensation of bromoethylisatine (4) with 1,2-diamino-
benzene under the same conditions leads to appropriate
tetracycle 5 with 80% yield [8].
On the other hand, 6-chloropropyl-6H-indolo-[2,3-b]
quinoxaline (3) may be synthesized via indoloquinoxaline
alkylation by 1-bromo-3-chloropropane. 6H-Indolo-[2,3-b]
quinoxaline (6) was prepared according to a published
method [11] with 85% yield (Scheme 2). Alkylation of 6
was carried out in dimethylformamide at room temperature in
the presence of equimolar quantity of sodium methylate in
methanol, and the product 3 was obtained in such manner with
80% yield (Scheme 2).
Aminodechlorination of 3 under treating with excess
of dipropylamine in boiling benzene or DMF under
room temperature during 70 h leads to 6-dipropylaminopropyl-
indoloquinoxaline (11) with yield less then 10%. Using
of ethanol as a solvent in this synthesis yielded 30% of
11, therewith insoluble in benzene compound was isolated
with nearly 40% yield. In consideration of low reactivity
of 3, chlorine replacement by iodine was attempted via boiling
of 3 in acetone in presence of sodium iodide (Scheme 3). But,
obtainment the iododerivative 7 was failed, because the
reaction led to another product highly soluble in polar solvents
(water, methanol, and ethanol) and insoluble in nonpolar ones
(heptane, benzene, and chloroform) and similar to the ana-
logues in the previous case. In addition it was found, that
compound 8 formed by boiling in acetic acid during 2
The molecular ions peak with m/z = 260, which may be
corresponded to the intramolecular cyclization product 8, is
present in FAB mass-spectra of both obtained side products.
The structure of product 8 was proved by single-crystal X-ray
diffraction analysis. View of 8 (X = I) is shown in Figure 2.
Molecules with the exception of hydrogen atoms of methylene
groups attached to nitrogen atoms and methylene group
associated with C10 is flat. The deviations of nonhydrogen
atoms (except C10) from the common plane are in the range
ꢀ0.073(3) to ꢀ0.126(3) Å with a root mean square deviation
of fitted atoms equals to 0.061 Å. Atom C10 deviates from this
plane on 0.628(4) Å, thus six-membered N1, C8, N2, C9, C10,
and C11 cycle has envelop conformation. Bond length of N1
and N2 atoms, Table 1, reveals the delocalization of double
N¼C bond, the distances N1ꢀC8 = 1.336(4) Å and N2ꢀC8
= 1.324(4) Å coincide within three standard deviations. The
bond length N3ꢀC7 = 1.292 (4) corresponds to double bond.
The average C—C bond length in benzene rings equals
1.400 Å. Bond angles [ꢁ] for compound 8 are listed in Table 2.
Avoiding compound 8 formation, we carried out obtaining
of amines 9ꢀ17 via two-step one-pot synthesis of compound
3 with corresponding amine excess in presence of 10 mol % of
tetrabutylammonium iodide in boiling toluene (compounds
10ꢀ17) or dimethylformamide (compound 9) at room temper-
ature (Scheme 4).
Purity of all synthesized compounds was controlled by thin-
layer chromatography on precoated silica gel F254 plates using
eluents of different composition.
The structure of the synthesized compounds was proved by
mass-spectrometry, NMR-spectroscopy, and elemental analyses.
Scheme 1. Synthesis of 6-(3-chloropropyl)- and 6-(2-bromoethyl)-6H-
Scheme 3. Synthesis of 6-iodopropyl-6H-indolo-[2,3-b]quinoxaline.
indolo-[2,3-b]quinoxalines.
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V. F. Galat, J. Lipkowski, and V. C. Kravtsov
structure reveals disorder, which may be treated as packing defect.
Molecules related by mirror reflection occupy in the crystal the
same place with probability 66.6 and 33.3%. The positions of
peripheral atoms of overlapping molecules coincide within the
resolution of data, whereas two different positions of some internal
atoms (N1, N2, N3, C7, and C8) were well defined and
unambiguously identified. Two mirror-like overlapping molecules
(all atoms) were included in the model and restrains were applied
during refinement to make these molecules geometrically equal. All
nonhydrogen atoms were refined with anisotropic displacement
parameters. The hydrogen atoms were included in the models in
calculated positions and were refined as constrained to the bonding
atoms with isotropic temperature factors equal to 1.2 times the
value of the equivalent isotropic displacement parameter of the
parent carbon atom. Refinement converged at R1 = 0.0250,
wR2 = 0.0646 for all data and 263 parameters [R1 = 0.0234,
wR2 = 0.0636 for 3587 reflections with Io > 2s(Io)]. The
goodness-of-fit on F2 was equal 1.004. A weighting scheme
w = [s2(Fo2 + (0.0329P)2+ 2.30P]ꢀ1 where P = (max(Fo2, 0)
Figure 2. Molecular structure of 8 with numbering scheme.
+ 2Fc2)/3 was used in the final stage of refinement. The
residual electron density largest different peak and hole = 0.679
Molecular ions peaks (MH+) with intensity 100% are present in
mass-spectra with ionization method of fast atom bombardment
(FAB). Fragment ions set correspond to suggested structures.
The signals of aromatic and aliphatic protons are observed in
1H NMR-spectra of synthesized indoloquinoxaline derivatives.
The integral intensity and multiplicity of signals correspond to
assigned structures.
and ꢀ0.523 eÅꢀ3. Crystallographic data for the structures in
this article have been deposited with the Cambridge
Crystallographic Centre as supplementary publication numbers
CCDC 787810. Copies of data can be obtained, free of charge,
on application to CCDC, 12 Union Road, Cambridge CB2
1EZ, UK.
1-(3-Chloropropyl)-1H-indole-2,3-dione (2). Potassium
carbonate 33.5 g (0.17 mole) was added to a stirred solution of 10 g
(0.068 mole) 1H-indole-2,3-dione (1) in 100-mL dimethylformamide,
then 7 mL (10.7 g, 0.068 mole) 1-bromo-3-chloropropane was
added. After stirring at room temperature for 2 h, the inorganic
precipitate was filtered and washed with DMF 3 ꢂ 7 mL.
Filtrate was evaporated under reduced pressure, and the residue
was washed with water and filtered.
EXPERIMENTAL
All melting points are uncorrected. 1H NMR spectra were recorded
on a “Bruker Avance II” (400 MHz) spectrometer in CDCl3 solutions
with TMS as an internal standard. Mass-spectra with FAB ionization
were recorded on a VG 70-70 EQ spectrometer. Ionization was real-
ized using beam of argon-atoms with energy 10 kV (the compounds
were dissolved in 3-nitrobenzyl alcohol). Thin-layer chromatography
was performed on precoated silica gel F254 plates (Merck).
The product was dried and crystallized from heptane to yield
1
13.0 g (85%), mp 94ꢀ95ꢁC; H NMR (CDCl3): d 2.108ꢀ2.337
(m, 2H, CH2CH2Cl), 3.613 (t, J = 6.3 Hz, 2H, CH2Cl),
3.860ꢀ3.915 (m, 2H, CH2(CH2)2Cl), 6.983ꢀ7.023 (m, 1H,
ArH), 7.119 (t, J = 7.5 Hz, 1H, ArH), 7.559ꢀ7.637 (m, 2H,
ArH); MS: m/z = 225, 223 (M+). Anal. calcd. for C11H10ClNO2:
C, 59.07; H, 4.51; N, 6.26. Found: C, 59.13; H, 4.58; N, 6.19.
6-(3-Chloropropyl)-6H-indolo[2,3-b]quinoxaline (3). Method 1.
A mixture of 5.0 g (0.022 mole) 1-(3-chloropropyl)-1H-indole-2,3-
dione (2), 2.38 g (0.022 mole) o-phenylenediamine, and 60 mL of
acetic acid was boiled under reflux for 2 h. Then to a reaction
mixture was added 500 mL of water, and the product was extracted
with chloroform (4 ꢂ 20 mL). The organic layer was separated,
X-ray structure determination. Crystal data for 8, C17H14I1N3:
M = 387.21, crystal dimensions 0.15 ꢂ 0.10 ꢂ 0.10 mm3, monoclinic,
space group P21/n (no. 14), a = 7.0937(2) Å, b = 16.4411(5),
c = 12.8016(3), b = 94.4618(13), Å, V = 1488.50(7) Å3, Z = 4, F(000)
= 760, Dc = 1.728 g/m3, T = 100(2) K, m (Mo ꢀ Ka) = 2.148 mmꢀ1
,
Nonius Kappa-CCD diffractometer, θ max = 28.49, 3760
[R(int) = 0.0336] unique reflections, completeness = 99.9%. The
structure was solved by direct methods refined by full-matrix least
squares based on F2 using the program SHELXL97 [12]. The
Table 1
Bond lengths [Å] for the major occupancy position of disordered atoms for compound 8.
N1-C8
N1-C1
N1-C11
N2-C8
N2-C17
N2-C9
N3-C7
N3-C12
1.336 (4)
1.411 (5)
1.449 (5)
1.324 (4)
1.394 (5)
1.508 (5)
1.292 (4)
1.379 (4)
C1–C2
C1–C6
C2–C3
C3–C4
C4–C5
C5–C6
C6–C7
C7–C8
1.392 (4)
1.414 (5)
1.421 (5)
1.406 (6)
1.407 (6)
1.404 (5)
1.479 (5)
1.446 (4)
C9–C10
C10–C11
C12–C13
C12–C17
C13–C14
C14–C15
C15–C16
C16–C17
1.540 (6)
1.512 (6)
1.401 (5)
1.416 (5)
1.361 (6)
1.404 (6)
1.364 (6)
1.407 (4)
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Table 2
Bond angles [ꢁ] for the major occupancy position of disordered atoms for compound 8.
C8-N1-C1
C8-N1-C11
C1-N1-C11
C8-N2-C17
C8-N2-C9
C17-N2-C9
C7-N3-C12
C2-C1-N1
C2-C1-C6
N1-C1-C6
C1-C2-C3
C2-C3-C4
108.2 (3)
120.9 (3)
130.7 (3)
117.2 (3)
119.1 (3)
123.5 (3)
114.8 (3)
128.2 (3)
121.6 (3)
110.2 (3)
117.7 (4)
121.1 (3)
C5-C4-C3
C4-C5-C6
C5-C6-C1
C5-C6-C7
C1-C6-C7
N3-C7-C8
N3-C7-C6
C8-C7-C6
N2-C8-N1
N2-C8-C7
N1-C8-C7
C10-C9-N2
120.3 (4)
119.0 (4)
120.2 (4)
134.4 (3)
105.5 (3)
123.2 (3)
131.9 (3)
104.8 (3)
126.6 (3)
122.1 (3)
111.3 (3)
108.6 (3)
C11-C10-C9
N1-C11-C10
C13-C12-C17
C13-C12-N3
C17-C12-N3
C14-C13-C12
C13-C14-C15
C16-C15-C14
C15-C16-C17
N2-C17-C16
N2-C17-C12
C16-C17-C12
113.5 (3)
108.3 (4)
119.2 (3)
116.0 (3)
124.8 (3)
120.5 (4)
119.3 (4)
122.3 (4)
118.2 (4)
122.1 (3)
117.8 (3)
120.1 (3)
dried over anhydrous sodium sulphate, and the solvent evaporated
under reduced pressure to afford the crude product. The crude
product was purified by column chromatography over silica gel
using benzene as eluent.
and 200-mL acetone was boiled under reflux for 10 h. The
reaction mixture was cooled, and the orange precipitate was
collected, washed with acetone 3 ꢂ 5 mL and crystallized from
ethanole to yield 5.9 g (90%), mp > 250ꢁC; MS: m/z = 260 (M+).
Yield: 1.95 g (30%), mp 141ꢀ142ꢁC (decomp.); 1H NMR
(CDCl3): d 2.434ꢀ2.499 (m, 2H, CH2CH2Cl), 3.625 (t, J = 7.8 Hz,
2H, CH2Cl), 4.636 (t, J = 7.8 Hz, 2H, CH2(CH2)2Cl), 7.381
(t, J = 8.4 Hz, 1H, ArH), 7.568 (d, J = 8.0 Hz, 1H, ArH),
7.656ꢀ7.771 (m, 3H, ArH), 8.125 (dd, J1 = 0.8 Hz, J2= 8.4
Hz, 1H, ArH), 8.302 (dd, J1 = 1.2 Hz, J2 = 8.4 Hz, 1H,
ArH), 8.474 (d, J = 8.6 Hz, 1H, ArH); MS: m/z = 298, 296
(M+). Anal. calcd. for C17H14ClN3: C, 69.04; H, 4.77; N,
14.21. Found: C, 69.10; H, 4.75; N, 14.20.
6H-Indolo[2,3-b]quinoxaline (6). 6H-Indolo[2,3-b]quinoxaline (6)
was prepared by Schunck and Marchlewski’s method [11]. After
recrystallization from dimethylformamide, it formed yellow needles.
Yield: 85%, mp 294ꢀ295ꢁC.
(3-Indolo[2,3-b]quinoxalin-6-ylpropyl)-dimethylamine (9).
A
mixture of 1.37 mL (0.010 mole) 33% water solution of
dimethylamine, 1.0 g (0.0034 mole) 6-(3-chloropropyl)-6H-indolo
[2,3-b]quinoxaline (3), 0.13 g (0.00034 mole) tetrabutylammonium
iodide, and 30-mL dimethylformamide was stirred at room
temperature for 12ꢀ14 h. The completion of reaction was followed
by TLC. After completion, a mixture was evaporated under
reduced pressure. The residue was dissolved in 30-mL benzene and
extracted with 10% acetic acid (4 ꢂ 20 mL). This acetous extract
was neutralized with saturated solution of sodium carbonate to
pH = 9 and extracted with chloroforme (4 ꢂ 20 mL). The
organic layer was separated, dried over anhydrous sodium
sulphate, and the solvent evaporated under reduced pressure to
afford the crude product. The crude product was purified by
column chromatography over silica gel using benzene:
triethylamine (20:1) as eluent.
Yield: 0.78 g (75%), mp 106ꢀ107ꢁC; 1H NMR (CDCl3):
d 2.074ꢀ2.168 (m, 2H, CH2CH2N(CH3)2), 2.247 (s, 6H, N(CH3)2),
2.389 (t, 2H, J = 7.5 Hz, CH2N(CH3)2), 4.515 (t, J = 6.9 Hz, 2H,
CH2(CH2)2N(CH3)2), 7.341 (t, J = 7.5 Hz, 1H, ArH), 7.523
(d, J = 8.1 Hz, 1H, ArH), 7.618ꢀ7.750 (m, 3H, ArH), 8.122
(dd, J1 = 1.5 Hz, J2 = 8.1 Hz, 1H, ArH), 8.288 (dd, J1 = 1.5
Hz, J2 = 8.4 Hz, 1H, ArH), 8.454 (d, J = 7.8 Hz, 1H, ArH);
MS: m/z = 305 (MH+). Anal. calcd. for C19H20N4: C, 74.97;
H, 6.62; N, 18.41. Found: C, 74.92; H, 6.58; N, 18.35.
6-(3-Chloropropyl)-6H-indolo[2,3-b]quinoxaline (3). Method 2.
To a suspension of 10 g (0.046 mole) 6H-indolo[2,3-b]quinoxaline (6)
in dimethylformamide (200 mL) was added 9.1-mL 5 M solution of
sodium methylate in methanol, and the mixture was stirred at room
temperature for 10 min. Then, 4.5-mL (7.2 g, 0.046 mole) 1-bromo-
3-chloropropane was added, and reaction mixture was stirred at
room temperature for 2 h. After reaction completion reaction
mixture was evaporated under reduced pressure to dryness, the
residue was washed with water (5 ꢂ 50 mL) and dried. The crude
product was purified by crystallization from heptane to yield 10.8 g
(80%), mp 140ꢀ141ꢁC (decomp.).
2,3-Dihydro-1H-3a,8-diaza-12b-azonia-benzo[e]acephenanthrylene
iodide (8). A mixture of 5g (0.017 mole) 6-(3-chloropropyl)-6H-
indolo[2,3-b]quinoxaline (3), 2.57 g (0.017 mole) sodium iodide
General procedure for the synthesis of compounds
10ꢀ17. A mixture of 1.0 g (0.0034 mole) 6-(3-chloropropyl)-6H-
indolo[2,3-b]quinoxaline
(3),
0.13
g
(0.00034
mole)
Scheme 4. Synthesis of 6-aminopropyl-6H-indolo-[2,3-b]quinoxalines.
tetrabutylammonium iodide, 30-mL toluene, and 0.010 mole
corresponding amine was boiled under reflux for 12ꢀ18 h. The
completion of reaction was followed by TLC. After completion, a
reaction mixture was extracted with water (6 ꢂ 30 mL) to pH = 7,
then with 10% acetic acid (4 ꢂ 20 mL). The acetous extract was
neutralized with saturated solution of sodium carbonate to pH = 9
and extracted with chloroforme (4 ꢂ 20 mL). The organic layer was
separated, dried over anhydrous sodium sulphate, and the solvent
evaporated under reduced pressure to afford the crude product. The
crude product was purified by column chromatography over silica
gel using benzene:triethylamine (20:1) as eluent.
Diethyl-(3-indolo[2,3-b]quinoxalin-6-ylpropyl)-amine (10). Yield:
0.89 g (79%), mp 85ꢀ86ꢁC; 1H NMR (CDCl3): d 0.999 (t, J = 7.2 Hz,
6H, N(CH2CH3)2), 2.070ꢀ2.166 (m, 2H, CH2CH2N(C2H5)2),
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2.506ꢀ2.603 (m, 6H, CH2N(CH2CH3)2), 4.506 (t, J = 7.2 Hz, 2H, CH2
(CH2)2N(C2H5)2), 7.346 (t, J = 7.5 Hz, 1H, ArH), 7.509 (d, J = 7.2 Hz,
1H, ArH), 7.621ꢀ7.755 (m, 3H, ArH), 8.123 (dd, J1 = 1.2 Hz,
J2 = 8.4 Hz, 1H, ArH), 8.290 (dd, J1 = 1.5 Hz, J2 = 7.8 Hz, 1H,
ArH), 8.460 (d, J = 7.8 Hz, 1H, ArH); MS: m/z = 333 (MH+).
Anal. calcd. for C21H24N4: C, 75.87; H, 7.28; N, 16.85. Found:
C, 75.89; H, 7.24; N, 16.90.
d 2.085ꢀ2.176 (m, 2H, CH2CH2N(CH2CH2)2N), 2.313 (s, 3H,
NCH3), 2.412ꢀ2.456 (m, 10H, CH2N(CH2CH2)2N),
4.540 (t, 2H, J = 6.9 Hz, NCH2(CH2)2N(CH2CH2)2N),
7.327 (t, J = 7.2 Hz, 1H, ArH), 7.542 (d, J = 8.7 Hz,
1H, ArH), 7.610ꢀ7.777 (m, 3H, ArH), 8.108 (dd, J1 = 1.2 Hz,
J2 = 8.4 Hz, 1H, ArH), 8.295 (dd, J1 = 1.8 Hz, J2 = 8.1 Hz,
1H, ArH), 8.465 (d, J = 8.1 Hz, 1H, ArH); MS: m/z = 360
(MH+). Anal. calcd. for C22H25N5: C, 73.51; H, 7.01; N, 19.48.
Found: C, 73.48; H, 6.95; N, 19.39.
(3-Indolo[2,3-b]quinoxalin-6-ylpropyl)-dipropylamine (11). Yield:
0.94 g (77%), mp 66ꢀ67ꢁC; 1H NMR (CDCl3): d 0.873 (t, J = 7.5 Hz,
6H, N(CH2CH2CH3)2), 1.417ꢀ1.543 (m, 4H, N(CH2CH2CH3)2),
2.103ꢀ2.198 (m, 2H, CH2CH2N(C3H7)2), d 2.440 (t, J = 7.8 Hz, 4H,
N(CH2CH2CH3)2), 2.633 (m, J = 6.6 Hz, 2H, CH2N(C3H7)2),
4.533 (t, J = 6.9 Hz, 2H, CH2(CH2)2N(C3H7)2), 7.366 (t, J = 6.9 Hz,
1H, ArH), 7.531 (d, J = 8.7 Hz, 1H, ArH), 7.614ꢀ7.795
(m, 3H, ArH), 8.129 (dd, J1 = 0.9 Hz, J2 = 8.1 Hz, 1H, ArH),
8.301 (dd, J1 = 1.2 Hz, J2 = 8.1 Hz, 1H, ArH), 8.476 (d, J = 8.1 Hz,
1H, ArH); MS: m/z = 361 (MH+). Anal. calcd. for C23H28N4: C,
76.63; H, 7.83; N, 15.54. Found: C, 76.55; H, 7.78; N, 15.55.
6-(3-Piperidin-1-ylpropyl)-6H-indolo[2,3-b]quinoxaline
(12). Yield: 0.89 g (76%), mp 116ꢀ117ꢁC; 1H NMR (CDCl3):
d 1.337ꢀ1.486 (m, 2H, N(CH2CH2)2CH2), 1.523ꢀ1.683 (m, 4H, N
(CH2CH2)2CH2), 2.161ꢀ2.255 (m, 2H, CH2CH2N(CH2CH2)2CH2),
2.303ꢀ2.538 (m, 6H, CH2N(CH2CH2)2CH2), 4.540 (t, J = 6.9 Hz,
2H, CH2(CH2)2N(CH2CH2)2CH2), 7.355 (t, J = 7.2 Hz, 1H, ArH),
7.572 (d, J = 8.1 Hz, 1H, ArH), 7.614ꢀ7.783 (m, 3H, ArH), 8.121
(dd, J1 = 1.2 Hz, J2 = 8.4 Hz, 1H, ArH), 8.296 (dd, J1 = 1.5 Hz, J2
= 7.8 Hz, 1H, ArH), 8.463 (d, J = 7.8 Hz, 1H, ArH); MS: m/z = 345
(MH+). Anal. calcd. for C22H24N4: C, 76.71; H, 7.02; N, 16.26.
Found: C, 76.69; H, 7.11; N, 16.27.
6-(3-Morpholin-4-ylpropyl)-6H-indolo[2,3-b]quinoxaline
1
(16). Yield: 0.94 g (80%), mp 90ꢀ91ꢁC; H NMR (CDCl3):
d 2.101ꢀ2.168 (m, 2H, CH2CH2N(CH2CH2)2O), 2.356ꢀ2.415
(m, 6H, CH2N(CH2CH2)2O), 3.641 (t, J = 4.8 Hz, 4H, N(CH2CH2)2O),
4.558 (t, 2H, J = 6.8 Hz, CH2(CH2)2N(CH2CH2)2O), 7.358
(t, J = 7.6 Hz, 1H, ArH), 7.549 (d, J = 8.4 Hz, 1H, ArH),
7.643ꢀ7.682 (m, 3H, ArH), 8.111 (dd, J1 = 1.2 Hz, J2 = 8.4 Hz,
1H, ArH), 8.299 (dd, J1 = 0.8 Hz, J2 = 8.4 Hz, 1H, ArH), 8.473
(d, J = 7.6 Hz, 1H, ArH); MS: m/z = 360 (MH+). MS: m/z = 347
(MH+). Anal. calcd. for C21H22N4O: C, 72.81; H, 6.40; N, 16.17.
Found: C, 72.75; H, 6.37; N, 16.17.
2-(3-Indolo[2,3-b]quinoxalin-6-ylpropylamino)-ethanol
1
(17). Yield: 0.58 g (73%), mp 125ꢀ126ꢁC; H NMR (CDCl3):
d 2.017ꢀ2.172 (m, 2H, CH2CH2NHCH2CH2MH), 2.397ꢀ2.629
(m, 3H, NCH2CH2MH), 2.702 (t, J = 5.1 Hz, 2H, NHCH2CH2OH),
3.651 (t, J = 7.8 Hz, 2H, CH2NCH2CH2OH), 4.557 (t, 2H,
J = 6.3 Hz, CH2(CH2)2NHCH2CH2OH), 7.362 (t, J = 7.5
Hz, 1H, ArH), 7.474 (d,
J = 8.4 Hz, 1H, ArH),
7.601ꢀ7.784 (m, 3H, ArH), 8.125 (d, J = 8.4 Hz, 1H, ArH),
8.282 (d, J = 8.1 Hz, 1H, ArH), 8.468 (d, J = 7.8 Hz, 1H,
ArH); MS: m/z = 321 (MH+). Anal. calcd. for C19H20N4O:
C, 71.23; H, 6.29; N, 17.49. Found: C, 71.30; H, 6.20; N,
17.41.
6-[3-(2-Methylpiperidin-1-yl)propyl]-6H-indolo[2,3-b]quinoxaline
(13). Yield: 0.90 g (74%), mp 95ꢀ96ꢁC; 1H NMR (CDCl3): d 1.110
(d, J = 6.3 Hz, 3H, CHCH3), 1.144ꢀ1.302 (m, 6H, NCH(CH3)CH2
(CH2)3), 1.590ꢀ1.908 (m, 4H, NCH2(CH2)2NCH(CH3)CH2(CH2)3),
2.444ꢀ2.619 (m, 2H, NCH(CH3)CH2(CH2)3), 2.729ꢀ2.829
(m, 1H, CHCH3), 4.601 (t, J = 7.8 Hz, 2H, CH2(CH2)2NCH
(CH3)CH2(CH2)3), 7.402 (t, J = 7.5 Hz, 1H, ArH), 7.580
(d, J = 8.1 Hz, 1H, ArH), 7.650ꢀ7.804 (m, 3H, ArH),
8.107 (dd, J1 = 1.5 Hz, J2 = 8.4 Hz, 1H, ArH), 8.317
(dd, J1 = 1.8 Hz, J2 = 8.1 Hz, 1H, ArH), 8.486 (d, J = 7.8 Hz,
1H, ArH); MS: m/z = 359 (MH+). Anal. calcd. for C23H26N4: C,
77.06; H, 7.31; N, 15.53. Found: C, 77.11; H, 7.33; N, 15.69.
6-[3-(4-Methylpiperidin-1-yl)propyl]-6H-indolo[2,3-b]
REFERENCES AND NOTES
[1] Harmenberg, J.; Wahren, B.; Bergman, J.; Åkerfeldt, S.;
Lundblad, L. Antimicrob Agents Chemother 1988, 32, 1720.
[2] Harmenberg, J.; Åkesson-Johansson, A.; Gräslund, A.;
Malmfors, T.; Bergman, J.; Wahren, B.; Åkerfeldt, S.; Lundblad, L.;
Cox, S. Antiviral Res 1991, 15, 193.
[3] Behravan, G.; Leijon, M.; Sehlstedt, U.; Norden, B.; Vallberg,
H; Bergman, J.; Gräslund, A. Biopolymers 1994, 34, 599.
[4] Arimondo, P. B.; Baldeyrou, B.; Laine, W.; Bal, C.; Alphonse,
F.-A.; Routier, S.; Coudert, G.; Me’rour, J.-Y.; Colson, P.; Houssier, C.;
Bailly, C. Chem-Biol Interact 2001, 138, 59.
[5] Hirata, K.; Araya, J.; Nakaike, S.; Kitamura, K.; Ishida, T.
Chem Pharm Bull 2001, 49, 44.
[6] Varma, R. S.; Pandey, R. K. Arch Pharm 1981, 314, 307.
[7] Manna, K.; Agrawal, Y. K. Bioorg Med Chem Lett 2009, 19,
2688.
1
quinoxaline (14). Yield: 0.96 g (79%), mp 97ꢀ98ꢁC; H NMR
(CDCl3): d 0.909 (d, J = 6.0 Hz, 3H, CHCH3), 1.234ꢀ1.346 (m, 3H,
N(CH2CH2)2CHCH3), 1.619ꢀ1.662 (m, 2H, N(CH2CH2)2CHCH3),
0
2.156ꢀ2.227 (m, 2H, N(CH2 CH2)2CHCH3), 2.910 (t, J = 7.2 Hz,
0
2H, CH2N(CH2CH2)2CHCH3), 3.094ꢀ3.131 (m, 2H, N(CH2CH2 )2
CHCH3), 4.651 (t, J = 7.2 Hz, 2H, CH2CH2N(CH2CH2)2CHCH3),
7.353 (t, J = 6.9 Hz, 1H, ArH), 7.585 (d, J = 8.1 Hz, 1H, ArH),
7.624ꢀ7.757 (m, 3H, ArH), 8.116 (dd, J1 = 1.2 Hz, J2 = 8.4 Hz,
1H, ArH), 8.289 (dd, J1 = 1.2 Hz, J2 = 8.4 Hz, 1H, ArH), 8.454
(d, J = 7.5 Hz, 1H, ArH); MS: m/z = 359 (MH+). Anal. calcd. for
C23H26N4: C, 77.06; H, 7.31; N, 15.63. Found: C, 77.06; H, 7.41;
N, 15.65.
[8] Shibinskaya, M. O.; Lyakhov, S. A.; Mazepa, A. V.;
Andronati, S. A.; Turov, A. V.; Zholobak, N. M.; Spivak, N. Ya. Eur J
Med Chem 2010, 45, 1237.
[9] Chaires, J. B.; Mergny, J. L. Biochimie 2008, 90, 973.
[10] Chaires, J.B. Curr Opin Struct Biol 1998, 8, 314.
[11] Schunck, E.; Marchlewski, L. Chem Berichte 1895, 28, 2525.
[12] Sheldrick, G. M. Acta Crystallogr 2008, A64, 112.
6-[3-(4-Methylpiperazin-1-yl)-propyl]-6H-indolo[2,3-b]quinoxaline
(15). Yield: 0.95 g (78%), mp 129ꢀ130ꢁC; 1H NMR (CDCl3):
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet