Preparation of isoindolo[2,1-a]quinoxalines based on n-(2-aminophenyl) isoindole derivatives

Article abstract of DOI:10.1007/s10593-012-1096-x

A new method is proposed for the preparation of N-(2-aminophenyl)isoindoles by the reaction of o-(bromomethyl)benzophenones with 1,2-phenylenediamines. The reaction of N-(2-aminophenyl)isoindoles with Ac₂O leads to 1,N-diacetyl- or 1,N,N-triacetyl derivatives, whereas heating with formic acid or diethyl oxalate leads to cyclization with the formation of 11-arylisoindolo[2,1-a]quinoxaline derivatives. Salt formation in the 11-arylisoindolo[2,1-a]quin-oxaline series was studied.

Full text of DOI:10.1007/s10593-012-1096-x

Chemistry of Heterocyclic Compounds, Vol. 48, No. 7, October, 2012 (Russian Original Vol. 48, No. 7, July, 2012)
PREPARATION OF ISOINDOLO[2,1-a]QUINOXALINES BASED
ON N-(2-AMINOPHENYL)ISOINDOLE DERIVATIVES
V. V. Sypchenko1, L. M. Potikha1*, V. A. Kovtunenko1, V. N. Baumer2, and O. V. Shishkin1,2
A new method is proposed for the preparation of N-(2-aminophenyl)isoindoles by the reaction of
o-(bromomethyl)benzophenones with 1,2-phenylenediamines. The reaction of N-(2-aminophenyl)isoindoles
with Ac2O leads to 1,N-diacetyl- or 1,N,N-triacetyl derivatives, whereas heating with formic acid or diethyl
oxalate leads to cyclization with the formation of 11-arylisoindolo[2,1-a]quinoxaline derivatives. Salt
formation in the 11-arylisoindolo[2,1-a]quin-oxaline series was studied.
Keywords: N-(2-aminophenyl)isoindole, o-(bromomethyl)benzophenone, isoindolo[2,1-a]quinoxaline,
1,2-phenylenediamine, acylation.
Polycyclic nitrogen-containing heterocyclic compounds with a flat structure are quite promising in the
search for new chemotherapeutic medications [1]. Well-known antineoplastic chemotherapeutic medications
characterized by flat polycyclic systems, such as anthracyclines, camptothecin, and amsacrine, are capable of
inhibiting topoisomerases – enzymes that catalyze the transformation of one topological isomer of DNA to
another. Here a triple complex, containing the drug, DNA, and the enzyme, is formed. Recent research into the
biological activity of isoindolo[2,1-a]quinoxalines showed that these compounds have high cytotoxic activity
against a wide range of human cancer cells and at the molecular level are inhibitors of tubulin polymerase and
topoisomerase I. This confirms the prospects of using them as anticancer drugs [2, 3].
In all about 15 of isoindolo[2,1-a]quinoxaline derivatives have been described. Two methods have been
used for construction of the heterosystem, i.e., building the isoindole onto the quinoxaline fragment [4, 5] or the
quinoxaline onto the isoindole fragment [2, 3, 6]. In our opinion the second method [2, 3], which is based on the
cyclization of N-(2-aminophenyl)isoindole derivatives, presents greater possibilities for functionalization of the
system. However, the key compounds, 1-R-2-(2-aminophenyl)isoindoles of type 1, are not readily obtainable,
and methods for their synthesis are restricted to only two methods: reduction of isoindolo[2,1-a]benzimidazole
derivatives [7, 8] and the Strecker reaction of 1,2-phenylenediamines with phthalaldehyde [2, 3, 9]. Convincing
evidence for the structure of N-(2-aminophenyl)isoindole has only been presented in [2, 3, 9]. We are proposing
another method for the preparation of N-(2-aminophenyl)isoindoles, involving the reaction of
o-(bromomethyl)benzophenone derivatives 2 with 1,2-phenylenediamines.
_______
*To whom correspondence should be addressed, e-mail: potikha_l@mail.ru.
1Kyiv Taras Shevchenko National University, 64 Volodymirska St., Kyiv 01033, Ukraine.
2Scientific-Technological Complex "Institute of Monocrystals", National Academy of Sciences of Ukraine, 60
Lenina Ave., Kharkiv 61001, Ukraine; e-mail: shishkin@xray.isc.kharkov.com.
3V. N. Karazin Kharkiv National University, 4 Svobody Sq., Kharkiv 61077, Ukraine; e-mail:
shishkin@xray.isc.kharkov.com.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1113-1123, July, 2012. Original
article submitted November 28, 2011.
0009-3122/12/4807-1033©2012 Springer Science+Business Media New York
1033

{2-[1-(4-Chlorophenyl)-2H-isoindol-2-yl]aryl}amines 1a,b were obtained from [2-(bromomethyl)-
phenyl](4-chlorophenyl)methanone (2) by reaction in ethanol at 50°C with a twofold excess of the amine under
an inert atmosphere. The structure of the products was established on the basis of their spectral characteristics
(1H NMR, IR, UV), which agree with those of the 1,2-diarylisoindoles that we obtained earlier [10].
5'
6'
7'
4'
H2N
R
Ar
Br
1'
3'
O
H2N
(from 1а)
2'
N
2
Ar
R
Ac
N
Ar
N
Ac2O
AcONa
, 5 h
EtOH, 50°C
Ac
Ac
H2N
1
3
2
1a,b
3
(from 1а)
Ac2O
Ac
Ar
N
AcOH
room temp.
1 h
H
N
Ac
4
1–4 Ar = 4-ClC6H4; a R = H, b R = NO2
The formation of the N-(2-aminophenyl)isoindoles 1a,b in the reaction is not an unambiguously
predictable result. This reaction is unusual in that one of the amino groups is retained during the reaction of the
dielectrophile with the dinucleophile (1,2-phenylenediamine). Usually all the reaction centers would react in
such cases. For example, isoindolo[2,1-a]benzimidazole derivatives are formed in the reaction of 1,2-phenyle-
nediamine with derivatives of phthalic acid, phthalaldehyde, o-acylbenzaldehyde, o-acylbenzoic acids, and
o-halomethylbenzoic acid [11]. The same direction of reaction could also be expected in the case of the halide 2,
as occurs in the reactions of 1,2-phenylenediamine with α,β-unsaturated γ-halo ketones of the aliphatic series
[12]. In practice, however, we observe similarity with the reaction of 1,2-phenylenediamine with
γ-bromodypnone, when 2-(2,4-diphenyl-1H-pyrrol-1-yl)aniline is formed [13].
During a further study of the properties of compounds 1a,b we started from known methods of building
the pyrazine ring onto pyrrole, developed by Chessman and Tuck [14, 15] and used by us earlier in the synthesis
of pyrrolo[1,2-a]quinoxaline derivatives [13]. Thus, with the aim of producing 6-methyl-
isoindolo[2,1-a]quinoxaline, an attempt was made to synthesize the corresponding N-[(isoindolyl)-
phenyl]acetamide by refluxing a solution of compound 1a in Ac2O in the presence of AcONa. In this case,
however, acylation takes place not only at the amino group but also at the α-position of the isoindole fragment
and leads to the triacyl derivative 3, while in the absence of AcONa in reaction with Ac2O in acetic acid at room
temperature it leads to the diacyl derivative 4. The position of the acetyl substituents in compound 4 is
confirmed not only by the absence of a signal for the H-3' proton in the 1H NMR spectrum (DMSO-d6), but also
by the presence of a broad signal for the protons of the NH group at 9.15 ppm, which exchange with D2O. In the
IR spectrum there are two narrow bands of medium intensity in the region of 3307 and 3287 cm-1, the
appearance of which results from amide-imide isomerism. This effect is also manifested by the broadening of
1
the νC=O stretching vibration band of the acetamide group at 1623 cm-1, while in the H NMR spectrum it leads
to a slight broadening of the signal for the methyl group protons of the NHAc substituent (singlet, 1.82 ppm in
DMSO-d6, 2.00 ppm in CDCl3). In CDCl3 solution the 2-phenyl and acetyl signal positions for the compound 4
are fixed in such conformation, where the effects of magnetically anisotropic groups are more pronounced. This
leads to a shift of certain proton signals (H-3,6, CH3 groups, the assignment of these signals was based on the
1034

1
data from a H–1H COSY experiment) that do not agree fully with the change in the polarity of the solvent,
compared to their position in the spectrum recorded in DMSO-d6 solution. In the 1H NMR spectrum (DMSO-d6) of
compound 3, the greater steric hindrances to free rotation about the C–N single bonds lead to the appearance of
two methyl proton signals of the NAc2 group. The presence of an acetyl substituent at the α-position of the
isoindole fragment of compounds 3 and 4 has yet another consequence – the appearance of atropisomers, which
is typical for compounds of N-arylpyrrole type with bulky substituents in the ortho positions [16]. The 1-acetyl
derivatives of 2-arylisoindole 3 and 4 also exist as mixtures of enantiomers. This is demonstrated by the data
1
from the H NMR spectrum of the sterically less crowded compound 3, recorded in CDCl3 solution in the
presence of the optically active Eu(III) heptafluorobutyryloxymethylenecamphorate (Eu(HFBC)3): splitting of
the series of signals in a ratio of 1:1 is observed (the signals were not assigned).
In [3], the cyclization of the 1-cyano derivatives of N-(2-aminophenyl)isoindole was carried out by
refluxing their solutions in acetic acid. It can be expected that the 1-acetyl derivatives will also be capable of
cyclization under these conditions. In the case of compounds 3 and 4, such a transformation must include a
stage of hydrolysis of the acetamides. However, no appreciable changes in structure were observed when their
solutions in acetic acid were refluxed (for more than 2 h), or heated in a solution of NaOH (10%). The desired
result, i.e., intramolecular cyclization to derivatives of isoindolo[2,1-a]quinoxaline, was achieved under
different conditions.
Thus, when solutions of compounds 1a,b were refluxed in formic acid for 12 h, 11-(4-chloro-
phenyl)isoindolo[2,1-a]quinoxalines 5a,b were obtained with yields of 81 and 61%. Heating of the compound
1a mixture with an excess of diethyl oxalate leads to the 6-ethoxycarbonyl derivative 6, which is readily
transformed into the corresponding 6-carboxylic acid 7 upon hydrolysis in an aqueous-alcoholic solution of
NaOH. The acid 7 proved unstable when heated above 180°C; it decomposed during an attempt to determine its
melting point. The decarboxylation of the acid 7 with the formation of compound 5a was achieved by heating
for 5 min on an oil bath at 180-200°C. It was not possible to transform compound 1b into an ester of type 6,
since its reaction with diethyl oxalate proceeded slower and was accompanied by the formation of a large
amount of side products.
Ar
R
1
HCO2H
N
1a,b
(CO2Et)2
, 12 h
4
6
N
5a,b
(from 1а)
110–120°C
4 h
180–200°C
5 min
Ar
Ar
N
N
NaOH
EtOH, H2O
60°С, 1 h
N
N
EtO2C
HO2C
6
7
5–7 Ar = 4-ClC6H4; 5 a R = H, b R = NO2
The structure of the isoindolo[2,1-a]quinoxalines 5-7 was established on the basis of data from
1
chromato-mass spectroscopy and NMR spectroscopy. In the H NMR spectra (DMSO-d6) of compounds 5-7
there are doublets for the H-4,7 protons and singlets for the H-6 proton at δ > 8.0 ppm (for compounds 5a,b),
the assignment of which was made according to the results of a NOE experiment. In the spectrum of the ester 6,
the signal of the H-7 proton is shifted upfield (at 8.06 ppm) in comparison with the corresponding signals for the
unsubstituted derivatives 5a,b and the acid 7 (8.41-8.55 ppm). We associate this effect with screening of the
1035

H-7 proton by ethoxy group in the favoured conformation of the compound 6 in DMSO solution containing
traces of water. This suggestion is supported by the NOE experiment data: during irradiation at the resonance
frequency of the methylene group of the ethoxy fragment at 4.65 ppm the intensity of the aromatic proton
doublet in the region of 8.07 ppm is increased, while from analysis of the compound 6 molecular model it
follows that the H-7 proton is situated closest to the 6-CO2Et substituent.
Final evidence for the structure of the reaction products 5-7 as derivatives of isoindolo[2,1-a]quin-
oxaline is provided by X-ray crystallographic analysis data for compound 5a (Fig. 1). According to the obtained
data, the tetracyclic fragment is planar within 0.009 Å. The aryl substituent in the molecule 5a is twisted almost
perpendicularly to the plane of the isoindoloquinoxaline fragment. (The dihedral angle N(12)–C(11)–C(13)–
C(18) amounts to -86.1(1)°). Here a greatly shortened H(1A)···C(13) molecular contact of 2.47 Å is formed
(sum of van der Waals radii 2.87 Å [17]). Since the hydrogen atom is directed towards the phenyl π-system of
the aryl substituent, it can be assumed that this interaction is an intramolecular C–H···π hydrogen bond (the
angle С(1)–Н(1А)···С(13) is 128°). The hydrogen atom of the C(10)–H(10A) bond is similarly placed.
However, the H(10A)···C(13) distance is much greater (3.00 Å), and the C(10)–H(10A)···C(13) angle is
practically straight (94°), which precludes the interpretation of this interaction as a C–H···π hydrogen bond.
Quantum-chemical calculations [18] of the compound 5a molecule by the М06-2Х/6-311G(d,p) method
indicated that the tetracyclic fragment in the crystal is planar due to intermolecular interactions. An isolated
molecule is slightly twisted, and the angle between the terminal benzene rings is 12°. The rotation angle of the
aryl substituent (54°) is slightly smaller than in a crystal. Here, however, the shortened intramolecular contact
С(1)–Н(1А)···С(13) of 2.43 Å is still retained. Analysis of the electron density distribution in terms of the Bader
"atoms in molecules" theory [19] showed the presence of a critical point for the bond between the H(1A) and
C(13) atoms, indicating the formation of a C–H···π hydrogen bond. At the same time, there is no critical point
between the H(10A) atom and the carbon atoms of the aromatic ring, which confirms the idea about the absence
of a second C–H···π hydrogen bond involving the given hydrogen atom.
Fig. 1. The molecular structure of compound 5a with the atoms represented by thermal vibration ellipsoids with
50% probability.
Compounds 5-7 are moderately soluble in polar solvents. Their solubility is higher in the presence of
strong acids (HBr, HCl, trifluoroacetic acid (TFA)) due to the formation of protonated salts [6]. In the UV
spectra of compounds 5a, 6, recorded in MeOH in the presence of hydrochloric acid, a bathochromic shift of the
long-wave absorption maximum is observed (406 and 404 in MeOH, 437 and 472 nm in MeOH/HCl,
respectively).
1036

We isolated isoindoloquinoxaline bromide 8a in the individual state, and by heating compound 5a with
benzyl bromide in acetonitrile we isolated a quaternary salt, the 5-benzyl derivative bromide 9. By analysis of
the 1H and 13C NMR spectra of compounds 5a, 6, and 9, recorded in CF3CO2D solution, it was possible to reach
certain conclusions concerning the structure of the isoindolo[2,1-a]quinoxalinium cation. An accurate
assignment of the proton and carbon signals for the protonated salts, formed during dissolution of compounds
5a, 6 in TFA (salts 8b,c), and of compound 9 was made on the basis of COSY, NOESY, HMQC, and HMBC
homo- and heteronuclear experiments.
Ar
Ar
N
(from 5а)
N
HX
5a, 6
+
+
PhCH2Br
MeCN
, 1 h
N
X–
Br–
N
R1
H
Ph
8a–c
9
8a–c, 9 Ar = 4-ClC6H4; 8 a R1 = H, X = Br; b R1 = H, X = CF3CO2; c R1 = CO2Et, X = CF3CO2
It is difficult to reach a conclusion about the nature of the electron density distribution for the salts 8a-c
and 9 on the basis of existing data. To describe their structure in this case it is advantageous to consider their
limiting resonance structures A and B, corresponding to the two tautomeric forms of isoindole – the ortho-
quinoid structure and the isoindoline [20, 21]. In the studies [6, 22] such salts were assigned structures
corresponding to the resonance structure A. However, in the 13C NMR spectra (CF3CO2D) of the salts 8b,c, 9
the signal of the carbon C-11 is observed in the downfield region (146.4-150.7 ppm) in comparison to that
predicted for the structure A. The position of signals for C-6,6a,6b (upfield at 127-137 ppm) in relation to C-11
(in the most downfield region) also agrees with theoretical predictions for the spectrum of the corresponding
structure B.
Ar
Ar
N
+
N
+
N
N
R
R
A
B
We obtained further evidence for the larger contribution from structure B for salts of the 8a-c, 9 type
during analysis of X-ray crystallographic analysis data (Fig. 2) for the previously obtained protonated
isoindolo[2,1-a]quinoxalinium salt 10 [6], the uncondensed isoindole derivatives having ortho-quinoid
structures (compound 11) [10] or an isoindoline structure (compound 12) [23], and the compound 5a that we
synthesized.
The bond length values in the pyrrole rings of the molecules of compounds 5a, 10-12 indicate a
substantial contribution from the resonance structure B to the electron density distribution in the cations of the
isoindolo[2,1-a]quinoxalinium salts. Thus, whereas the lengths of the pyrrole ring C–N bonds in the molecules
of compounds 5a and 11 are close to the values typical of a C=N multiple bond in the aromatic system of
pyrrole (1.38 Å [24]), in the molecules of compounds 10 and 12 one of the bonds corresponds in length to a C–N
single bond (1.43-1.48 Å [24]), while the other corresponds to a C=N double bond (≤1.33 Å [24]). The increase
in the C(4a)–N(5) and N(5)–C(6) bond lengths in the pyrazine ring in transition from the base 5a to the salt 10
1037

also confirms our suggestion about the nature of electron density distribution changes in the isoindolo-
quinoxalinium cations.
Ar
1.416
1.447
1.417
1.442
1.342
1.320
1.407
1.400
N
1.380
N
1.443
+
1.361
1.385
–
BF4
N
N
1.320
1.345 H
R
5a
10
NH2
Ar
1.378
1.374
1.527
1.307
1.394
1.397
N
1.374
Ar1
1.432
N
1.488
1.479
R2
R1
R2
11
12
Fig. 2. The bond lengths in the molecules of 11-(4-chlorophenyl)isoindolo[2,1-a]quinoxaline (5a), 6-(5-methyl-
2-furyl)isoindolo[2,1-a]quinoxalin-5-ium tetrafluoroborate (10), 3-[3-(4-chlorophenyl)-2-(4-fluorophenyl)-2H-iso-
indol-1-yl]-1-phenylpyrrolidine-2,5-dione (11), and 3,3'-(3-amino-1H-isoindol-1,1-diyl)bis(1-methylpyrro-
lidine-2,5-dione) (12). The data from X-ray crystallographic analysis were obtained from the Cambridge
Structural Database (except for the synthesized compound 5a). Deposit numbers: CCDC 138680 (compound
10), CCDC 821341 (compound 11), CCDC 736675 (compound 12).
Thus, the reaction of o-(bromomethyl)benzophenones with 1,2-phenylenediamines leads to the
formation of N-(2-aminophenyl)isoindole derivatives – key compounds for further construction of condensed
systems with an isoindole ring. When heated with formic acid or diethyl oxalate, the 1-aryl-2-(2-amino-
phenyl)isoindoles gave 11-arylisoindolo[2,1-a]quinoxaline derivatives, which are easily protonated and
alkylated at the N(5) nitrogen atom with the formation of quaternary salts. The spectral and X-ray structural data
of the isoindolo[2,1-a]quinoxalinium salts indicate that the greater contribution to the electron density
distribution in them comes from the resonance structure corresponding to the isoindoline tautomer.
EXPERIMENTAL
1
The IR spectra were recorded in pellets with KBr on a Perkin Elmer Spectrum BX instrument. The H
and 13C NMR spectra were recorded on a Bruker Avance RX 500 instrument (500 and 125 MHz, respectively).
The two-dimensional correlation spectroscopy experiments were carried out on a Varian Mercury 400
1
instrument (400 MHz for H nuclei, 100 MHz for 13C nuclei) with TMS as internal standard. The UV spectra
were obtained in methanol on a Lambda 20 UV/VIS spectrometer. The elemental analyses were performed on a
Vario MICRO Cube CHNS analyzer. The melting points were determined in a Thiele tube. The purity of the
obtained compounds was monitored by HPLC mass spectroscopy on an Agilent 1100 Series instrument with an
Agilent LC/MSDSL selective detector (gradient elution: phase A – H2O + 0.1% HCO2H, phase B – MeCN +
0.1% HCO2H; ionization method – APCI, 400 V). [2-(Bromomethyl)phenyl](4-chlorophenyl)methanone (2)
was obtained according to the procedure in [25].
2-[1-(4-Chlorophenyl)-2H-isoindol-2-yl]aniline (1a). [2-(Bromomethyl)phenyl](4-chlorophenyl)-
methanone (2) (2.00 g, 6.46 mmol) was added to a solution of o-phenylenediamine (1.40 g, 12.92 mmol) in
EtOH (30 ml). The reaction mixture was stirred at 50°C for 30 min and cooled to room temperature. After
30 min the precipitate was filtered off. Yield 1.76 g (85%); mp 187-189°C (PhMe–hexane, 1:1). IR spectrum, ν,
1038

1
cm-1: 3466 (NH2), 3373 (NH2), 3034, 1616, 1505, 1496, 1466, 1343, 1311, 1087, 826, 747. H NMR spectrum
(DMSO-d6), δ, ppm (J, Hz): 7.62-7.61 (2H, m, H-4',7'); 7.38 (1H, s, H-3'); 7.32-7.31 (4H, m, H-2",3",5",6");
7.13 (1H, t, 3J = 8.0, Н-5); 6.97-6.96 (3H, m, H-3,5',6'); 6.80 (1H, d, 3J = 8.0, Н-6); 6.58 (1H, t, 3J = 8.0, Н-4);
4.85 (2Н, br. s, NH2). UV spectrum, λmax, nm (log ε): 246 (4.46), 286 (4.02), 304 (3.88), 354 (3.91). Found, %:
С 75.23; Н 4.79; N 8.83. C20H15ClN2. Calculated, %: С 75.35; Н 4.74; N 8.79.
2-[1-(4-Chlorophenyl)-2H-isoindol-2-yl]-4-nitroaniline (1b). A mixture of [2-(bromomethyl)phenyl]-
(4-chlorophenyl)methanone (2) (2.00 g, 6.46 mmol) and 4-nitro-1,2-phenylenediamine (1.98 g, 12.92 mmol) in
EtOH (20 ml) was stirred at 50°C for 3 h under an argon atmosphere. The precipitate was filtered off and
washed with hexane. Yield 1.23 g (52%); mp 202-205°C (PhMe–hexane, 1:1). IR spectrum, ν, cm-1: 3463
1
(NH2), 3354 (NH2), 1623, 1517 (NO2), 1491, 1308 (br.), 835, 747. H NMR spectrum (DMSO-d6 + CCl4), δ,
ppm (J, Hz): 8.03 (1H, dd, 3J = 9.2, 4J = 2.4, Н-5); 7.90 (1H, d, 4J = 2.4, Н-3); 7.59-7.58 (2H, m, H-4',7'); 7.46
3
(1H, s, H-3'); 7.33-7.32 (4H, m, H-2",3",5",6"); 6.98-6.99 (2H, m, H-5',6'); 6.81 (1H, d, J = 9.2, Н-6); 6.48
(2Н, br. s, NH2). UV spectrum, λmax, nm (log ε): 244 (4.34), 356 (3.98). Found, %: С 65.96; Н 3.82; N 11.49.
C20H14ClN3O2. Calculated, %: С 66.03; Н 3.88; N 11.55.
N-Acetyl-N-{2-[1-acetyl-3-(4-chlorophenyl)-2H-isoindol-2-yl]phenyl}acetamide (3). AcONa (0.20 g,
2.4 mmol) was added to a solution of compound 1a (0.32 g, 1.0 mmol) in Ac2O (5 ml). The mixture was
refluxed for 5 h. The excess of Ac2O was evaporated under vacuum, and water (10 ml) was added to the residue.
The precipitate was filtered off, washed with water and with 2-PrOH, and crystallized. Yield 0.18 g (40%); mp
220-221°C (DMF–EtOH, 1:1). IR spectrum, ν, cm-1: 3044, 1711 (C=O), 1700 (C=O), 1620, 1610, 1499, 1401,
1
3
1362, 1179, 1013, 763. H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 8.11 (1H, d, J = 9.2, H-7'); 7.87-7.86
3
(1H, m, Н-6); 7.70-7.30 (9H, m, Н Ar); 7.18 (1H, t, J = 7.6, H-4); 2.32 (3H, s, 1'-СОСН3); 1.86 (3H, s,
NСОСН3); 1.38 (3H, s, NСОСН3). Found, %: С 70.07; Н 4.81; N 6.37. C26H21ClN2O3. Calculated, %: С 70.19;
Н 4.76; N 6.30.
N-{2-[1-Acetyl-3-(4-chlorophenyl)-2H-isoindol-2-yl]phenyl}acetamide (4). Ac2O (0.50 ml, 5.3 mmol)
was added to a mixture of compound 1a (0.32 g, 1.0 mmol) in AcOH (5 ml). The mixture was stirred at room
temperature for 1 h. With cooling on an ice bath, H2O (25 ml) was added to the mixture. After 30 min, the
precipitate was filtered off and crystallized from EtOH. Yield 0.21 g (52%); mp 189-190°C (EtOH). IR
1
spectrum, ν, cm-1: 3287, 3307 (NH), 1703 (C=O), 1623 (C=O), 1527, 1450, 1408, 1331, 1297, 750. H NMR
spectrum (DMSO-d6), δ, ppm (J, Hz): 9.15 (1Н, br. s, NH); 8.20 (1H, d, 3J = 7.6, H-7'); 7.81-7.80 (1H, m, Н-6);
7.58 (1H, d, 3J = 7.6, H-4'); 7.45-7.05 (9H, m, Н Ar); 2.22 (3H, s, 1'-СОСН3); 1.82 (3H, s, NСОСН3). 1H NMR
spectrum (400 MHz, CDCl3), δ, ppm (J, Hz): 8.06 (1Н, d, 3J = 8.0, Н-7'); 8.00 (1Н, d, 3J = 7.0, Н-6); 7.71 (1Н,
d, 3J = 8.0, Н-4'); 7.47 (1Н, t, 3J = 8.0, Н-6'); 7.39 (1Н, t, 3J = 7.5, Н-5); 7.36 (1Н, br. s, NH); 7.29-7.22 (3Н, m,
Н-5',3",5"); 7.17 (2Н, d, 3J = 8.0, Н-2",6"); 7.00 (1Н, t, 3J = 7.0, Н-4); 6.76 (1Н, d, 3J = 7.0, Н-3); 2.65 (3Н, s,
1'-СОСН3); 2.00 (3Н, s, NСОСН3). Found, %: С 71.68; Н 4.84; N 7.04. C24H19ClN2O2. Calculated, %: С 71.55;
Н 4.75; N 6.95.
11-(4-Chlorophenyl)isoindolo[2,1-a]quinoxaline (5a). A. Compound 1a (0.5 g, 1.57 mmol) was
dissolved with heating in HCOOH (10 ml). The mixture was refluxed for 12 h, the excess of the acid was
evaporated, and the residue was crystallized from MeNO2. Yield 0.42 g (81%); mp 237-238°C. IR spectrum, ν,
cm-1: 3044, 1577, 1459, 1320, 1219, 1087, 1013, 763, 740. 1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 9.58
(1H, s, H-6); 8.46 (1H, d, 3J = 8.0, H-7); 8.02 (1H, d, 3J = 8.0, H-4); 7.73-7.71 (4Н, m, Н-2',3',5',6'); 7.60-7.36
(6Н, m, Н-1,2,3,8,9,10). When CF3CO2D was used as solvent for the NMR spectra, the spectra of the
1
protonated form (8b) of the quinoxaline 5a were obtained. Compound 8b. H NMR spectrum (400 MHz,
CF3CO2D), δ, ppm (J, Hz): 9.09 (1Н, d, 3J = 8.0, Н-7); 7.92-7.91 (2Н, m, Н-4,8); 7.85 (1Н, d, 3J = 8.0, Н-10);
3
3
3
7.81 (1Н, d, J = 8.8, Н-1); 7.79-7.71 (4Н, m, Н-3,9,3',5'); 7.67 (2Н, d, J = 7.0, Н-2',6'); 7.47 (1Н, t, J = 8.0,
Н-2). 13C NMR spectrum (CF3CO2D), δ, ppm: 146.7 (С-11); 145.8 (С-4'); 138.3 (С-10a); 138.2 (C-8); 137.6
(2C, C-2',6'); 137.4 (2C, C-3',5'); 137.0 (C-3); 136.6 (C-6); 136.0 (C-9); 135.8 (C-6b); 135.2 (C-2); 134.7
(C-4a); 134.2 (C-1'); 132.6 (C-12a); 128.7 (C-10); 127.6 (C-4); 127.3 (C-6a); 126.5 (C-1); 125.2 (C-7). UV
1039

spectrum (MeOH), λmax, nm (log ε): 258 (5.32), 292 (5.04), 306 (4.94), 406 (5.04). UV spectrum (MeOH/HCl),
max, nm (log ε): 262 (5.35), 300 (5.06), 368 (4.71), 437 (5.14). Mass spectrum, m/z (Irel, %): 329 [M+H]+ (100),
λ
331 [M+H]+ (30). Found, %: С 76.84; Н 4.06; N 8.41. C21H13ClN2. Calculated, %: С 76.71; Н 3.99; N 8.52.
B. Isoindolo[2,1-a]quinoxaline-6-carboxylic acid 7 (0.37 g, 1.0 mmol) was placed in a test tube of heat-
resistant glass. With vigorous stirring, the mixture was heated on an oil bath at 180-200°C for 5 min. After
cooling, the melt was dissolved in MeNO2 with heating. The precipitate that separated after the solution had
cooled was filtered off and washed with MeNO2. Yield 0.16 g (50%). The physicochemical and spectral
characteristics of the reaction product agreed with the data given for compound 5a that was produced by method
A.
11-(4-Chlorophenyl)-2-nitroisoindolo[2,1-a]quinoxaline (5b). The compound was obtained similarly
to compound 5a from compound 1b (0.5 g, 1.37 mmol) and HCOOH (10 ml). Yield 0.31 g (61%); mp >300°C
(DMF). IR spectrum, ν, cm-1: 3121, 3059, 1592, 1517 (NO2), 1468, 1339 (NO2), 1323, 1305, 1217, 1197, 1145,
1
3
843, 729. H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 9.73 (1H, s, H-6); 8.55 (1H, d, J = 8.4, H-7); 8.50
4
3
4
3
(1H, d, J = 2.4, H-1); 8.36 (1H, dd, J = 9.2, J = 2.4, Н-3); 8.14 (1H, d, J = 9.2, H-4); 7.81-7.79 (4Н, m,
Н-2',3',5',6'); 7.67 (1Н, d, 3J = 8.0, Н-10); 7.61 (1Н, t, 3J = 7.5, Н-8); 7.52 (1Н, t, 3J = 7.5, Н-9). UV spectrum,
λ
max, nm (log ε): 209 (5.12), 252 (5.55), 277 (5.31), 309 (5.00), 403 (5.02). Mass spectrum, m/z (Irel, %): 374
[M+H]+ (100), 376 [M+H]+ (30). Found, %: С 67.42; Н 3.19; N 11.41. C21H12ClN3O2. Calculated, %: С 67.48;
Н 3.24; N 11.24.
Ethyl 11-(4-Chlorophenyl)isoindolo[2,1-a]quinoxaline-6-carboxylate (6). A mixture of compound
1a (0.64 g, 2.0 mmol) and diethyl oxalate (1.20 g, 8.2 mmol) was heated on an oil bath at 110-120°C for 4 h.
The reaction mixture was left at room temperature for 24 h, the precipitate was filtered off and washed with
MeNO2. Yield 0.41 g (51%); mp 186-187°C. IR spectrum, ν, cm-1: 3070, 2982, 1726 (C=O), 1455, 1305, 1246,
1207 (С–О), 1088, 1016, 765, 739. 1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 8.07 (1Н, d, 3J = 8.0, Н-7);
3
8.01 (1H, d, J = 7.5, H-4); 7.71-7.89 (4Н, m, Н-2',3',5',6'); 7.56-7.34 (6Н, m, Н-1,2,3,8,9,10); 4.65 (2H, q,
3
3J = 7.2, CH2СН3); 1.45 (3H, t, J = 7.2, СН2CH3). When CF3CO2D was used as solvent for the NMR spectra
the spectra of the protonated form (8c) of the quinoxaline 6 were obtained. Compound (8c). 1H NMR spectrum
3
(400 MHz, CF3CO2D), δ, ppm (J, Hz): 9.14 (1Н, d, J = 8.0, Н-7); 8.15-8.14 (2Н, m, Н-4,8); 8.06 (1Н, d,
3J = 7.5, Н-10); 8.00 (1Н, t, 3J = 7.5, Н-9); 7.91-7.90 (3Н, m, Н-3,3',5'); 7.83 (1Н, d, 3J = 9.0, Н-1); 7.79 (2Н, d,
3J = 7.0, Н-2',6'); 7.59 (1Н, t, 3J = 7.5, Н-2); 5.05 (2Н, q, 3J = 7.0, СН2СН3); 1.80 (3Н, t, 3J = 7.0, СН2СН3). 13C
NMR spectrum (CF3CO2D), δ, ppm: 167.7 (С=О); 150.7 (С-11); 146.5 (С-4'); 139.7 (С-10a); 139.3 (C-8);
137.9 (C-6); 137.8 (C-3); 137.7 (2C, C-2',6'); 137.4 (2C, C-3',5'); 137.2 (C-9); 135.2 (C-2); 134.5 (C-6b); 134.1
(C-4a); 133.8 (C-1'); 131.7 (C-12a); 130.9 (C-7); 129.6 (C-10); 128.3 (C-6a); 127.8 (C-4); 126.9 (C-1); 73.6
(CH2); 19.7 (CH3). UV spectrum (MeOH), λmax, nm (log ε): 209 (5.12), 252 (5.55), 277 (5.31), 310 (5.00), 404
(5.02). UV spectrum (MeOH/HCl), λmax, nm (log ε): 280 (5.38), 320 (4.97), 472 (5.10). Mass spectrum, m/z (Irel,
%): 401 [M+H]+ (100), 403 [M+H]+ (30). Found, %: С 72.24; Н 4.31; N 7.09. C24H17ClN2O2. Calculated, %:
С 71.91; Н 4.27; N 6.99.
11-(4-Chlorophenyl)isoindolo[2,1-a]quinoxaline-6-carboxylic Acid (7). NaOH (0.16 g, 4.0 mmol)
was added to a solution of compound 6 (0.37 g, 1.0 mmol) in 50% EtOH (20 ml). The reaction mixture was
heated at 60°C for 1 h, and the EtOH was distilled under vacuum. The solution was cooled and acidified with
1 M HCl. The precipitate was filtered off and washed with water. Yield 0.27 g (82%); mp >180°C (decomp.,
H2O). IR spectrum, ν, cm-1: 3439 (O–H), 3050, 2849, 1652 (C=O), 1613, 1598, 1528, 1448, 1407, 1356, 1212,
1
3
3
1088, 754. H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 8.41 (1H, d, J = 8.8, H-7); 8.07 (1H, d, J = 8.0,
H-4); 7.77-7.75 (4Н, m, Н-2',3',5',6'); 7.64-7.45 (6Н, m, Н-1,2,3,8,9,10). Found, %: С 70.81; Н 3.56; N 7.58.
C22H13ClN2O2. Calculated, %: С 70.88; Н 3.51; N 7.51.
11-(4-Chlorophenyl)-5H-isoindolo[2,1-a]quinoxalin-12-ium Bromide (8a). Conc. HBr (1 ml) was
added to a suspension of isoindolo[2,1-a]quinoxaline 5a (0.33 g, 1.0 mmol) in MeCN (15 ml), and the mixture
was heated until the isoindoloquinoxaline had completely dissolved. After cooling, the precipitate was filtered
off and washed with EtOH. Yield 0.37 g (90%); mp >300°C (decomp., MeCN). IR spectrum, ν, cm-1: 3426
1040

(NH), 3044, 2579, 1641 (C=N+), 1540, 1483, 1450, 1323, 763. 1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz):
10.27 (1H, s, H-6); 8.79 (1H, d, 3J = 8.0, H-7); 8.22 (1Н, d, 3J = 8.0, Н-4); 7.87-7.76 (7Н, m, Н Ar); 7.72-7.64
3
(2Н, m, Н Ar); 7.48 (1Н, t, J = 8.0, H-2). Mass spectrum, m/z (Irel, %): 419 [M-Br]+ (100), 421 [M-Br]+ (30).
Found, %: С 61.51; Н 3.46; N 6.83. C21H14BrClN2. Calculated, %: С 61.56; Н 3.44; N 6.84.
5-Benzyl-11-(4-chlorophenyl)-5H-isoindolo[2,1-a]quinoxalin-12-ium Bromide (9). A mixture of
isoindolo[2,1-a]quinoxaline 5a (0.33 g, 1.0 mmol) and benzyl bromide (0.34 g, 2.0 mmol) in MeCN (15 ml)
was refluxed for 1 h. After cooling, the precipitate was filtered off, washed with acetone, and crystallized from
MeNO2. Yield 0.38 g (85%); mp >300°C (decomp.). IR spectrum, ν, cm-1: 3044, 2915, 1651, 1607, 1411, 1328,
1228, 1088, 763, 755. 1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 10.65 (1H, s, H-6); 8.70 (1H, d, 3J = 8.0,
H-7); 8.16 (1Н, d, 3J = 8.0, Н-4); 7.96-7.70 (9Н, m, Н Ar); 7.56-7.54 (3Н, m, Н Ar); 7.43-7.30 (3Н, m, Н Ar);
1
3
6.09 (2Н, s, NCH2). H NMR spectrum (CF3CO2D), δ, ppm (J, Hz): 9.34 (1Н, s, Н-6); 8.43 (1Н, d, J = 6.0,
3
3
Н-7); 8.05 (1Н, d, J = 7.0, Н-4); 7.96-7.95 (2Н, m, Н-1,8); 7.89 (1Н, d, J = 7.0, Н-10); 7.80-7.79 (3Н, m,
Н-9,3',5'); 7.73-7.72 (3Н, m, Н-3,2',6'); 7.49-7.47 (6Н, m, Н-2, Н Ph); 5.92 (2Н, s, NCH2). 13C NMR spectrum
(CF3CO2D), δ, ppm: 146.4 (C-11); 145.7 (C-4'); 140.9 (C-4"); 139.3 (C-4a); 138.2 (C-10a); 138.0 (C-8); 137.5
(2C, C-2',6'); 137.3 (2C, C-3',5'); 136.7 (C-3); 136.5 (2C, C-3",5"); 136.4 (C-6); 136.0 (C-9); 135.9 (C-1");
135.6 (C-6b); 135.1 (C-2); 134.1 (C-1'); 133.9 (2C, C-2",6"); 133.4 (C-12a); 128.6 (C-10); 127.0 (2C, C-4,6a);
126.2 (C-1); 125.3 (C-7); 65.7 (CH2). UV spectrum, λmax, nm (log ε): 264 (5.23), 308 (4.98), 370 (4.73), 452
(5.34). Found, %: С 67.41; Н 3.99; N 5.58. C28H20BrClN2. Calculated, %: С 67.28; Н 4.03; N 5.60.
X-Ray Crystallographic Investigation of Compound 5a. The crystals of compound 5a are
monoclinic, C21H13ClN2, at 293 K: a 13.6687(9), b 12.7536(8), c 9.2145(6) Å; β 92.996(6)°; V 1604.12(18) Å3;
Z 4; space group Р2(1)/с; dcalc 1.361 mg/cm3; μ(MoKα) 0.241 mm-1; F(000) 680. The unit cell parameters and the
intensities of 12039 reflections (2985 independent, Rint 0.049) were measured on an Xcalibur 3 diffractometer
(MoKα radiation, CCD detector, graphite monochromator, ω scanning, 2θmax 52°). The structure was solved by
the direct method with SHELXTL software [26]. The positions of the hydrogen atoms were revealed from an
electron density difference synthesis and refined by the "rider" model with Uiso = 1.2Ueq for a non-hydrogen
atom attached to a given hydrogen. The structure was refined by an F2 full-matrix least-squares treatment for
2985 reflections in anisotropic approximation for the non-hydrogen atoms to wR2 0.2180 (R1 0.0775 in 2096
reflections with I > 2σ(I), GOOF 1.035). The full crystallographic information was deposited at the Cambridge
Crystallographic Data Center (deposit CCDC 851257).
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