A new methodology of annelation of five- and seven-membered heterocycles to quinoxalines

Article abstract of DOI:10.1023/B:RUCB.0000011876.37291.0e

Pyrazolo[3,4-b]-, isoxazolo[4,5-b]-, benzo[2,3]-1,4-diazepino-, and benzo[2,3]-1-4-oxazepinoquinoxalines were prepared by reactions of 2-quinoxalinecarboxaldehyde with 1,2-N,N-, 1,2-N,O and 1,4-N,N- and 1,4-N,O-dinucleophiles.

Full text of DOI:10.1023/B:RUCB.0000011876.37291.0e

Russian Chemical Bulletin, International Edition, Vol. 52, No. 10, pp. 2175—2184, October, 2003
2175
A new methodology of annelation
of fiveꢀ and sevenꢀmembered heterocycles to quinoxalines
A. M. Boguslavskiy,a M. G. Ponizovskiy,a M. I. Kodess,b and V.N. Charushina
ꢀ
aUrals State Technical University, Russian Federation,
19 ul. Mira, 620002 Ekaterinburg, Russian Federation.
Fax: +7 (343 2) 74 0458. Eꢀmail: charushin@prm.uran.ru
bInstitute of Organic Synthesis of the Ural Division of the Russian Academy of Sciences,
20 ul. S. Kovalevskoi, 620219 Ekaterinburg, Russian Federation
Pyrazolo[3,4ꢀb]ꢀ, isoxazolo[4,5ꢀb]ꢀ, benzo[2,3]ꢀ1,4ꢀdiazepinoꢀ, and benzo[2,3]ꢀ1,4ꢀ
oxazepinoquinoxalines were prepared by reactions of 2ꢀquinoxalinecarboxaldehyde with
1,2ꢀN,Nꢀ, 1,2ꢀN,O and 1,4ꢀN,Nꢀ and 1,4ꢀN,Oꢀdinucleophiles.
Key words: 2ꢀquinoxalinecarboxaldehyde, dinucleophiles, pyrazolo[3,4ꢀb]quinoxalines,
isoxazolo[4,5ꢀb]quinoxalines, benzo[2,3]ꢀ1,4ꢀdiazepinoquinoxalines, benzo[2,3]ꢀ1,4ꢀ
oxazepinoquinoxalines.
ipso
New methods for the construction of heterocycles have
always attracted attention of organic chemists. In recent
years, the research of cyclization processes of azines with
1,2ꢀ, 1,3ꢀ, or 1,4ꢀbifunctional nucleophilic reagents has
been developed successfully to allow oneꢀstep preparaꢀ
tion of complex polycyclic heterocycles.1—6 Quite a lot of
examples of orthoꢀcyclization of 1,4ꢀazines with dinucleoꢀ
philes have been reported where cyclization products are
formed through the tandem SNipso—SNipso replacement of
halogen atoms or other nucleofugal groups in positions 2
and 3 of the pyrazine ring.7 The new strategies for the
synthesis of fused azines developed to date are based on
AN—AN diaddition (Scheme 1), AN—SNipso addition—subꢀ
SNHꢀSN
disubstitution, and other tandem reacꢀ
tions.1—6,8—10 Since the AN—AN nucleophilic diaddition
can be performed only for fairly πꢀdeficient systems, the
transformation of azines into cations through alkylation,
protonation, or acylation (in some cases, in situ) is a
common way of substrate activation (see Scheme 1). In
addition, owing to the action of alkylating8 or acylating9,10
reagents, the reactions of azines with dinucleophiles furꢀ
nish relatively stable cyclic adducts, which can be oxiꢀ
dized in some cases to give aromatic structures.10,11
The scope of annelation is markedly extended by usꢀ
ing azines whose molecules contain an exocyclic electroꢀ
philic group. Cyclization can be carried out along two
routes. In the first one (A), a dinucleophile first reacts
with the exocyclic electrophilic group, and the subseꢀ
quent activation of the azine induces the intramolecular
reaction. In the other case (B), activation of the azine
precedes the dinucleophile addition and the subsequent
intramolecular cyclization (Scheme 2). In both cases,
the process is a tandem reaction involving cyclization
and intramolecular nucleophilic replacement of hydroꢀ
gen, SNH. Examples of such transformation have been
reported.11—24
H
H
stitution, AN—SN addition—substitution, SNHꢀSN or
Scheme 1
This paper presents the results of the study of reacꢀ
tions of 2ꢀquinoxalinecarboxaldehyde (1) with 1,2ꢀN,Nꢀ,
1,2ꢀN,Oꢀ, 1,4ꢀN,Nꢀ and 1,4ꢀN,Oꢀdinucleophiles.
Since we failed to prepare the quaternary salt of
quinoxalinecarboxaldehyde 1 due to the extremely low
basicity of compound 1, the subsequent study was arranged
according to route A (see Scheme 2). As 1,2ꢀN,Nꢀdiꢀ
nucleophiles, we used monosubstituted hydrazines, which
R = H, Alkyl, Acyl
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 10, pp. 2060—2068, October, 2003.
1066ꢀ5285/03/5210ꢀ2175 $25.00 © 2003 Plenum Publishing Corporation

2176
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 10, October, 2003
Boguslavskiy et al.
Scheme 2
Scheme 3
R = H (a), Me (b), Bn (c), Ph (d), 4ꢀMeC6H4 (e), 4ꢀNO2C6H4 (f),
4ꢀHOOCC6H4 (g)
were condensed with aldehyde 1 to give hydrazones 2a—h
(Scheme 3).
1
The H NMR spectra of compounds 2 exhibit lowꢀ
field singlets for the H(3) proton of the heterocyclic
ring at 9.2—9.5 ppm and for the azomethine proton at
7.3—8.7 ppm (Table 1). With regard to the 13C NMR
chemical shifts and the spinꢀspin coupling constants of
1
3
the C(3) atom (142.9 ppm, JC,H = 186.3 Hz, JC,H
=
4.0 Hz) and the azomethine carbon atom (134.3 ppm,
Table 1. 1H NMR data (DMSOꢀd6) for compounds 2а—g, 8
Comꢀ
pound
δ (J/Hz)
R
H(6), H(7)
m, 2 H
H(5), H(8)
m, 2 H
NH
s, 1 H
H(3) CH=N
s, 1 H
s, 1 H
2a
2b
2c
7.35 (s, 2 H, NH2)
7.64—7.13
7.58—7.75
7.65—7.79
7.76—7.96
7.81—8.99
7.87—8.02
—
9.24
9.20
9.20
7.41
7.40
7.60
3.00 (d, 3 H, Me, J = 5.0)
4.50 (d, 2 H, CH2Ph, J = 5.0);
7.20—7.40 (m, 5 H, Ph)
8.40 (q, JH,Me = 5.0)
8.90 (t, JH,CH2 = 5.0)
2d
2e
6.85—7.35 (m, 5 H, Ph)
2.37 (s, 3 H, Me);
7.70—7.90
7.60—7.81
7.90—8.10
7.88—8.01
11.91
11.09
9.51
9.45
8.01
7.92
7.04—7.22 (m, 4 H, H(2´), H(3´),
H(5´), H(6´))
2f
7.35 (d, 2 H, H(2´), H(6´), J = 9.1);
8.17 (d, 2 H, H(3´), H(5´), J = 9.1)
3.30—4.60 (br.s, 1 H, COOH);
7.30 (d, 2 H, H(2´), H(6´), J = 8.5);
7.92 (d, 2 H, H(3´), H(5´), J = 8.5)
12.03 (s, 1 H, OH)
7.76—7.89
7.72—7.87
8.00—8.12
7.98—8.11
11.80
11.50
9.50
9.50
8.20
8.10
2g
8
7.80—8.00
8.05—8.25
—
9.35
8.33

Annelation of heterocycles to quinoxalines
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 10, October, 2003
2177
1JC,H = 166.4 Hz, 3JC,H = 3.7 Hz), the lowerꢀfield signal
can be attributed to the carbon atoms of the pyrazine ring.
This assignment is confirmed by full analysis of the
placement giving rise to pyrazolo[3,4ꢀb]quinoxalinium
salts 6b—e via the intermediate σꢀadducts 5b—e (see
Scheme 4).
1
1
1H and 13C NMR spectra in terms of H—1H COSY,
In the H NMR spectra of salts 6b—e, the signal for
13C—1H HETCOR, and 1H—13C HMBC 2D experiments
for compounds 2d,h and by published data.25
the quaternary Nꢀmethyl group occurs at 4.1—4.8 ppm,
while the signal for the pyrazine ring proton is missing.
The signal for H(3) is shifted downfield by 1.6—2.0 ppm
due to the pyrazole ring formation. In conformity with
known regularities of azine quaternization,25 the 13C NMR
spectrum of compound 6d displays upfield shifts of the
signals for C(8a) and C(9а) (by 10.9 and 5.3 ppm with
respect to the C(4a) and C(3) signals of hydrazone 2d); in
addition, the signals of these carbon atoms are broadened
due to coupling with the Nꢀmethyl group protons. The
signal of the C(3а) atom shows itself as a doublet with
2JC,CH = 11.0 Hz at 145.8 ppm, whereas the signal of the
corresponding C(2) atom in the starting compound 2d is a
doublet of doublets with 2JC,CH = 9.4 and 2JC,CH = 6.6 Hz
recorded at 149.7 ppm. For unambiguous proof of the
structure of pyrazoloquinoxalinium salts 6, we performed
an Xꢀray diffraction study of iodide 6d (Fig. 1). The triꢀ
cyclic system in cation 6d was shown to be planar. The
phenyl substituent linked to the pyrazole N(3) atom and
the plane of the tricyclic system are arranged at a diꢀ
hedral angle of 43.8°. The N(4)—C(8), N(2)—C(7), and
N(1)—C(9) bond lengths in cation 6d are 1.29, 1.30, and
1.28 Å, which is close to the usual length of the C=N
multiple bonds in conjugated heterocycles;26 this implies
that the positive charge is mainly localized on the N(1)
atom of the pyrazine nucleus.
The intramolecular cyclization of hydrazones 2 reꢀ
quires activation of the N(4) atom of the azine ring. It was
found that alkylation of N,Nꢀdimethylhydrazone 2h
(model compound unable to undergo intramolecular
cyclization) with methyl iodide results in a mixture of
salts 3a and 3b in 1 : 9 ratio. These isomers cannot be
1
isolated; however, by analyzing the H and 13C NMR,
1H—1H NOESY, 13C—1H HETCOR, and 1H—13C
HMBC spectra, we determined their ratio and spectral
characteristics. Thus in the 1H NMR spectrum of salt 3b,
the signal of the Nꢀmethyl group at 4.66 ppm shows itself
as a doublet (4JMe,H(2) = 0.9 Hz) due to coupling with
the H(2) proton, whereas in the case of the isomeric salt
3а, the Nꢀmethyl group is responsible for a singlet at
4.25 ppm.
On treatment with methyl iodide in DMSO, hydrꢀ
azones 2b—g are transformed into two types of quaterꢀ
nary salts. Quaternization of hydrazones 2f,g with elecꢀ
tronꢀwithdrawing Nꢀaryl substituents affords quaternary
Nꢀmethyl hydrazone salts 4f,g (Scheme 4), but the reacꢀ
1
tion does not develop further. The H NMR spectra of
salts 4f,g exhibit a resonance signal due to the Nꢀmethyl
group in the region of 4.7—4.8 ppm, but the singlets for
the protons of the azomethine fragment (8.1—8.2 ppm)
and the pyrazine ring (10.1 ppm) are still retained. The
nucleophilicity of the NH fragment in compounds 2f,g is
much lower than in hydrazones 2b—e; in the latter case,
quaternization triggers intramolecular hydrogen disꢀ
NꢀAlkylhydrazones 2a—c, containing a more reactive
nucleophilic center, can undergo intramolecular cyclizaꢀ
tion not only under Nꢀalkylation but also under protonaꢀ
tion of nitrogen. Thus refluxing of hydrazones 2a—c in an
acidic water—alcohol affords pyrazolo[3,4ꢀb]quinoxalines
7a—c in good yields (Scheme 5).
Scheme 4
Scheme 5
R = Me (b), Bn (c), Ph (d), 4ꢀMeC6H4 (e), 4ꢀNO2C6H4 (f),
4ꢀHOOCC6H4 (g)
R = H (a), Me (b), CH2Ph (c)

2178
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 10, October, 2003
Boguslavskiy et al.
C(5)
N(2)
C(6)
C(7)
C(8)
C(4)
C(3)
N(4)
C(1)
N(3)
C(9)
C(2)
N(1)
C(16)
C(10)
C(15)
C(14)
C(13)
C(11)
C(12)
Fig. 1. Structure of cation 6d.
Scheme 6
As in the case of compounds 6b—e, intramolecular
cyclization is accompanied by nucleophilic displacement
of hydrogen in which atmospheric oxygen serves as the
oxidant, as indicated by the decrease in the reaction time
observed with air bubbling. This reaction does not proꢀ
ceed in a neutral medium, which implies the necessity of
acid catalysis. The 1H NMR spectra of compounds
7a—c clearly show characteristic multiplets due to four
protons of the benzene ring and the signal for the
H(3) atom of the pyrazole ring, which shifts upfield by
1.2—1.3 ppm relative to that for the starting hydrazones
(Table 2).
The annelation of an isoxazole ring to quinoxalines
(Scheme 6) was accomplished by using the simplest
1,2ꢀN,Oꢀdinucleophile, hydroxylamine, which was transꢀ
i. KMnO4, acetone.
Table 2. 1H NMR data (DMSOꢀd6, δ (J/Hz)) for 9ꢀmethylpyrazolo[3,4ꢀb]ꢀ9ꢀquinoxalinium iodides (4b—e), pyrazolo[3,4ꢀb]quinoxaꢀ
lines (5a—c), and isoxazolo[4,5ꢀb]quinoxaline (10)
Comꢀ
pound
R
N+Me
s, 3 H
H(6), H(7)
m, 2 H
H(5), H(8)
m, 2 H
H(3)
s
4b
4c
4.59 (s, 3 H, Me)
4.83
4.65
8.09—8.50
8.11—8.50
8.55—8.78
8.62—8.76
9.28
9.52
6.21 (s, 2 H, CH2Ph);
7.32—7.48 (m, 5 H, Ph)
7.70—7.88 (m, 5 H, Ph)
1.83—1.92 (m, 3 H, Me);
7.74 (d, 2 H, H(3´), H(5´), J = 7.5);
8.55 (d, 2 H, H(2´), H(6´), J = 7.5)
14.07 (s, 1 H, NH)
4d
4e
4.19
4.18
8.20—8.78
8.17—8.78
9.61
9.60
5a
5b
5c
—
—
—
7.82—7.95
7.80—7.91
7.80—8.00
8.13—8.26
8.11—8.20
8.15—8.31
8.74
8.66
8.82
4.18 (s, 3 H, Me)
5.88 (s, 2 H, CH2Ph);
7.25—7.35 (m, 5 H, Ph)
—
10
—
7.92—8.11
8.15—8.23
9.31

Annelation of heterocycles to quinoxalines
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 10, October, 2003
2179
Scheme 7
R = H, X = CH (a), R = Me, X = CH (b), R = H, X = N (c)
1
formed into oxime 8 via condensation with 2ꢀquinoxalineꢀ
carboxaldehyde.
11с, this process was not detected. The H NMR spectra
of tetracyclic compounds 12a—c do not exhibit signals
for the H(3) protons or the amino group of the starting
quinoxalines but instead, they contain a signal for the
NHꢀgroup proton of the diazepine ring in the region of
10—13 ppm.
The attempts to induce cyclization by quaternization
or protonation of oxime 8 in the presence of atmospheric
oxygen (by analogy with hydrazones) had not met with
success until we used potassium permanganate in acetone,
whereupon dihydroisoxazoloquinoxaline 9 was oxidized
to give isoxazoloquinoxaline 10.
The cyclizations of quinoxalinecarboxaldehyde 1 with
aromatic 1,2ꢀdiamines and 1,2ꢀaminophenols acting as
1,4ꢀN,Nꢀ and 1,4ꢀN,Oꢀdinucleophiles allow annelation of
benzodiazepine and benzoxazepine fragments to quinoxaꢀ
lines. A vital difference between our procedure and the
known condensation of 1,2ꢀdiamines with 1,3ꢀdicarbonyl
compounds27,28 is the fact that this method allows the
sevenꢀmembered ring to be closed inside the polycyclic
chain, which opens new opportunities for the synthesis of
biologically active compounds.
As in the case of oxime 8, cyclization of compound
14, resulting from condensation of aldehyde 1 with
orthoꢀaminophenol, was possible only when potassium
permanganate was used as the oxidant (Scheme 8). The
13C NMR spectra of compound 15 exhibit eight signals
for the benzene ring carbon atoms with spinꢀspin couꢀ
pling constants of 160—165 Hz, six signals for the quaterꢀ
Scheme 8
Azines 11a—с were prepared by a standard proceꢀ
dure.29 Intramolecular cyclization of compounds 11a—с
takes place on refluxing their alcohol solutions containing
a mineral acid additive and results in fused diazepines
12a—с (Scheme 7).
Cyclizations of derivatives 11a,b were found to give
side products, azomethines 13a,b, the route leading to
compounds 13a,b becoming the major one with an inꢀ
crease in the medium acidity. This seems to be due to
hydrolysis of azomethines 11a,b to 2ꢀquinoxalinecarbꢀ
oxaldehyde. This product enters into condensation with
imines 11a,b to give compounds 13a,b. For compound
i. KMnO4, acetone.

2180
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 10, October, 2003
Boguslavskiy et al.
2ꢀQuinoxalinecarboxaldehyde pꢀtolylhydrazone (2e). Yield
75%, m.p. 220—221 °C (from aqueous ethanol). Found (%):
C, 73.5; H, 5.1; N, 21.1. C16H14N4. Calculated (%): C, 73.3;
H, 5.4; N, 21.4.
2ꢀQuinoxalinecarboxaldehyde 4´ꢀnitrophenylhydrazone (2f).
Yield 63%, m.p. 255—256 °C (from glacial AcOH). Found (%):
C, 61.3; H, 3.7; N, 23.7. C15H11N5O2. Calculated (%): C, 61.4;
H, 3.8; N, 23.9.
2ꢀQuinoxalinecarboxaldehyde 4´ꢀcarboxyphenylhydrazone
(2g). Yield 87%, m.p. 338—340 °C (from glacial AcOH).
Found (%): C, 65.8, H, 4.1, N, 19.1. C16H12N4O2. Calcuꢀ
lated (%): C, 65.8; H, 4.1; N, 19.2.
2ꢀQuinoxalinecarboxaldehyde N,Nꢀdimethylhydrazone (2h).
Yield 66%, m.p. 78—79 °C (from water). Found (%): C, 65.8;
nary carbon atoms, and a signal for C(11a) as a doublet
with a coupling constant of 189.6 Hz. The spectral
data attest to the formation of benzo[2,3]ꢀ1,4ꢀoxazepiꢀ
no[6,7ꢀb]quinoxaline (15). The lack of reaction in an
acid medium or oxidation with air is due to the same
reasons as for oxime 8.
Thus, on the basis of tandem reactions of quinoxalineꢀ
carboxaldehyde 1 with 1,2ꢀ and 1,4ꢀdinucleophiles, we
developed facile methods for the preparation of pyrazoloꢀ
quinoxalines and their quaternary salts and fused
isoxazoloꢀ, benzodiazepinoꢀ, and oxazepinoquinoxaline
structures.
H, 6.3; N, 27.5. C11H12N4. Calculated (%): C, 66.0; H, 6.0;
1
N, 28.0. 13C NMR (DMSOꢀd6), δ: 42.18 (dq, Me, JC,H
=
=
Experimental
3
1
137.2 Hz, JC,CH3 = 3.0 Hz); 127.07 (d.sept, CH=N, JC,H
166.1 Hz, 4JC,CH = 1.3 Hz); 128.13 (dd, C(8), 1JC,H = 162.9 Hz,
3
1
3JC,C(6)H = 8.2 Hz); 128.28 (ddd, C(6), JC,H = 163.9 Hz,
1
H NMR spectra were recorded on a Bruker WMꢀ250 specꢀ
trometer operating at 250 MHz and a Bruker DRXꢀ400 instruꢀ
ment operating at 400 MHz; 13C NMR spectra were measured
and 2Dꢀexperiments were done using a Bruker DRXꢀ400 specꢀ
trometer with a frequency of 100 MHz. Tetramethylsilane was
used as the internal standard. Mass spectra were run on a Varian
MAT 311A spectrometer (accelerating voltage, 3 kV; cathode
emission current, 300 µA, ionizing energy, 70 eV; direct sample
injection to the source).
Synthesis of 2ꢀquinoxalinecarboxaldehyde hydrazones 2a—h
(general procedure). 2ꢀQuinoxalinecarboxaldehyde (1) (1 g,
6.3 mmol) in 15 mL of ethanol was gradually added at 60—70 °C
to a solution of the corresponding hydrazine or its hydrochloride
(6.3 mmol or, in the case of hydrazine hydrate, 25 mmol) in
10 mL of water. The reaction mixture was kept at the given
temperature for 3—5 min and cooled, and the precipitated
hydrazone was filtered off and recrystallized.
1H NMR spectra of compounds 2a—h are given in Table 1.
2ꢀQuinoxalinecarboxaldehyde hydrazone (2a). Yield 82%,
m.p. 145—146 °C (from water). Found (%): C, 62.9; H 4.7;
N, 32.4. C9H8N4. Calculated (%): C, 62.8; H, 4.7; N, 32.5.
MS (EI, 70 eV), m/z (Irel (%)): 172 [M]+ (100), 171 (38), 145
(42), 144 (11), 143 (28), 118 (44), 102 (46).
2ꢀQuinoxalinecarboxaldehyde methylhydrazone (2b). Yield
70%, m.p. 96—98 °C (from aqueous ethanol). Found (%):
C, 64.8; H, 5.2; N, 29.6. C10H10N4. Calculated (%): C, 64.5;
H, 5.4; N, 30.0.
3JC,C(8)H = 7.8 Hz, 2JC,C(5)H = 2.4 Hz); 128.73 (dd, C(5), 1JC,H
=
=
=
3
1
162.5 Hz, JC,C(7)H = 7.4 Hz); 130.04 (dd, C(7), JC,H
3
3
163.3 Hz, JC,C(6)H = 9.1 Hz); 140.19 (ddd, C(4a), JC,C(8)H
11.4 Hz, JC,C(3)H = 9.4 Hz, JC,C(6)H = 5.5 Hz); 141.51 (dd,
C(8a), JC,C(5)H = 9.4 Hz, JC,C(7)H = 5.6 Hz); 142.74 (dd,
C(3), JC,H = 185.4 Hz, JC,CHN = 3.5 Hz); 150.52 (dd, C(2),
3
3
3
3
1
3
2
2JC,CHN = 9.5 Hz, JC,C(3)H = 6.3 Hz).
Synthesis of Nꢀmethyl salts 3a,b, 4f,g, and 6b—e (general
procedure). A solution of the specified 2ꢀquinoxalinecarbꢀ
oxaldehyde hydrazone 2 (2.0—2.5 mmol) in 2 mL of DMSO
containing methyl iodide (2 mL) was heated on a water bath
(40—50 °C) for 3 h. After cooling, the precipitated quaternary
salt was filtered off, washed with ether, and recrystallized.
A mixture of Nꢀmethyl salts 3a,b. The major product
formed upon methylation of compound 2h was 3ꢀdimethylꢀ
hydrazonomethylꢀ1ꢀmethylquinoxalinium iodide (3b). 1H NMR
(DMSOꢀd6), δ: 3.31 (d, 6 H, Me, 4J = 0.7 Hz); 4.66 (d, 3 H,
N+Me, 4J = 0.9 Hz); 7.41 (s, 1 H, CH=N); 8.01 (ddd, 1 H,
3
3
4
H(7), JH,H(5) = 8.7 Hz, JH,H(6) = 7.0 Hz, JH,H(5) =1.6 Hz);
8.08 (ddd, 1 H, H(6), J = 8.3 Hz, J = 7.0 Hz, J = 1.2 Hz); 8.17
3
4
(dd, 1 H, H(5), JH,H(6) = 8.3, JH,H(5) = 1.6); 8.41 (dd, 1 H,
H(8), 3JH,H(7) = 8.7 Hz, 4JH,H(6) = 1.2 Hz); 9.72 (s, 1 H, H(2)).
13C NMR (DMSOꢀd6), δ: 42.66 (br.q, Me, JC,H = 137.6 Hz);
1
45.49 (qd, N+Me, JC,H = 145.8 Hz, JC,H(2) = 4.4 Hz); 119.29
1
3
1
3
(dd, C(8), JC,H = 169.0 Hz, JC,C(6)H = 7.5 Hz); 123.92 (dm,
CH=N, JC,H = 170.8 Hz); 128.67 (m, C(8a)); 129.21 (dd,
C(5), JC,H = 168.5 Hz, JC,C(7)H = 7.0 Hz); 131.72 (dd,
1
1
3
2ꢀQuinoxalinecarboxaldehyde benzylhydrazone (2c). Yield
70%, m.p. 91—92 °C (from aqueous ethanol). Found (%):
C, 73.1; H, 5.4; N, 20.9. C16H14N4. Calculated (%): C, 73.3;
H, 5.4; N, 21.4.
1
3
C(7), JC,H = 167.3 Hz, JC,C(5)H = 8.6 Hz); 133.29 (dd, C(6),
1JC,H = 166.7 Hz, JC,C(8)H = 8.6 Hz); 140.81 (dm, C(2)
3
1JC,H = 196.4 Hz); 144.27 (dd, C(4a), JC,C(8)H = 9.3 Hz,
3
2
2ꢀQuinoxalinecarboxaldehyde phenylhydrazone (2d). Yield
75%, m.p. 210—212 °C (from ethanol). Found (%): C, 72.5;
H, 4.7; N, 22.5. C15H12N4. Calculated (%): C, 72.6; H, 4.9;
N, 22.6. 13C NMR (DMSOꢀd6), δ: 112.77 (dd, C(2´), C(6´),
3JC,C(6)H = 5.7 Hz); 153.00 (dd, C(3), JC,CHN = 7.4 Hz,
2JC,C(2)H = 4.3 Hz).
The side product formed upon the methylation of comꢀ
pounds 2h was 2ꢀdimethylhydrazonomethylꢀ1ꢀmethylquinoxaliꢀ
1JC,H = 160.5 Hz, 3JC,H(4´) = 7.3 Hz); 120.31 (dd, C(4´), 1JC,H
=
nium iodide (3a). H NMR (DMSOꢀd6), δ: 3.33 (s, 6 H, Me);
1
160.7 Hz, 3JC,H(2´) = JC,H(6´) = 7.4 Hz); 128.35, 128.74, 128.94,
130.14 (all m, C(5), C(6), C(7), C(8)); 129.13 (dm, C(3´),
C(5´), 1JC,H = 158.8 Hz); 134.37 (dd, HC=N, 1JC,H = 166.4 Hz,
3JC,H(3) = 3.7 Hz); 140.63 and 141.38 (both m, C(4a), C(8a));
3.65 (s, 3 H, N+Me); 7.55 (s, 1 H, CH=N); 7.81—7.88 (m, 1 H,
H(6)); 7.97—8.01 (m, 1 H, H(7)), 8.15—8.18 (m, 1 H, H(8));
3
4
8.30 (dd, 1 H, H(5), JH,H(6) = 8.7 Hz, JH,H(7) = 1.4 Hz); 8.98
(s, 1 H, H(3)). 13C NMR (DMSOꢀd6), δ: 37.30 (m, Me); 117.24
(dm, CH=N, 1JC,H = 170.8 Hz); 117.76, 129.14, 130,25, 133.10
(all m, C(5), C(6), C(7), C(8)); 128.7, 134.13 (both m, C(8a),
C(4a)); 146.60 (dm, C(3), 1JC,H = 198.0 Hz); 155.77 (m, C(2)),
1
3
142.90 (dd, C(3), JC,H = 186.3 Hz, JC,CHN = 4.0 Hz);
143.95 (m, C(1´)); 149.68 (dd, C(2), JC,CHN = 9.4 Hz,
2
2JC,C(3)H = 6.6 Hz).

Annelation of heterocycles to quinoxalines
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 10, October, 2003
2181
the signal of the quaternary N+Me group is in the region of the
solvent signals.
1HꢀPyrazolo[3,4ꢀb]quinoxaline (7a), yield 70%, m.p.
>250 °C (from AcOH). Found (%): C, 63.1; H, 3.7; N, 32.5.
C9H6N4. Calculated (%): C, 63.5; H, 3.6; N, 32.9. MS (EI,
70 eV), m/z (Irel (%)): 170 [M]+ (100), 143 (35), 116 (14).
1ꢀMethylꢀ1Hꢀpyrazolo[3,4ꢀb]quinoxaline (7b), yield 75%,
m.p. 129—130 °C (from aqueous ethanol). Found (%): C, 65.3;
H, 4.5; N, 30.4. C10H8N4. Calculated (%): C, 65.2; H, 4.4;
N, 30.4. MS (EI, 70 eV) m/z (Irel (%)): 184 [M]+ (100), 183 (18),
130 (12), 129 (24), 103 (14), 102 (13). 13C NMR (DMSOꢀd6), δ:
1ꢀMethylꢀ3ꢀ(4ꢀnitrophenylhydrazonomethyl)quinoxalinium
iodide (4f). Yield 67%, m.p. 314—315 °C (from AcOH—DMSO).
Found (%): C, 44.1; H, 3.3; N, 16.4. C16H14N5O2I. Calcuꢀ
1
lated (%): C, 44.2; H, 3.2; N, 16.1. H NMR (DMSOꢀd6), δ:
4.79 (s, 3 H, Me); 7.56 (m, 2 H, H(2´), H(6´)); 8.16—8.28 (m,
2 H, H(3´), H(5´)); 8.16—8.59 (m, 4 H, H(5), H(6), H(7),
H(8)); 8.31 (s, 1 H, CH=N), 10.13 (s, 1 H, H(2)); 12.26 (s,
1
1
1 H, NH). 13C NMR (DMSOꢀd6), δ: 45.41 (qd, Me, JC,H
=
=
33.76 (q, Me, JC,H = 140.8 Hz); 127.55, 128.07, 129.65 and
146.1 Hz, 3JC,H(2) = 4.6 Hz); 113.06 (dm, C(2´), C(6´), 1JC,H
130.65 (all m, C(5), C(6), C(7), C(8)); 132.70 (d, C(3), 1JC,H
=
2
167.1 Hz); 119.34, 129.96, 133.60 and 133.84 (all m, C(5),
197.0 Hz); 136.34 (d, C(3a), JC,H(3) = 10.1 Hz); 140.32 (ddd,
1
3
3
2
C(6), C(7), C(8)); 125.64 (dd, C(3´), C(5´), JC,H = 167.3 Hz,
C(4a), JC,C(8)H = 9.9 Hz, JC,C(6)H = 5.4 Hz, JC,C(5)H
=
=
3JC,H(2´)
=
3JC,H(5´) = 4.9 Hz); 129.51 (m, C(4´)); 136.61 (dd,
1.3 Hz); 140.60 (dd, C(8a), JC,C(5)H = 10.4 Hz, JC,C(7)H
3
3
CH=N, 1JC,H = 172.2 Hz, 3JC,H(2) = 3.7 Hz); 140.54 (tt, C(4´),
5.8 Hz); 141.58 (dq, C(9a), 3JC,CHN = 4.1 Hz, 3JC,Me = 2.0 Hz).
1ꢀBenzylꢀ1Hꢀpyrazolo[3,4ꢀb]quinoxaline (7c), yield 80%,
m.p. 113—114 °C (from aqueous ethanol). Found (%): C, 73.7;
H, 4.3; N, 21.2. C16H12N4. Calculated (%): C, 73.8;
H, 4.7; N, 21.5.
2ꢀQuinoxalinecarboxaldehyde oxime (8). Sodium acetate
(0.27, 3.2 mmol) was added to a solution of hydroxylamine
hydrochloride (0.25 g, 3.2 mmol) in 100 mL of water; then a
solution of aldehyde 1 (0.5 g, 3.2 mmol) was added at a temperaꢀ
ture of 70—75 °C. After keeping at this temperature for 10 min,
the mixture was cooled and the precipitate formed was filtered
off and recrystallized from water. Yield 78%, m.p. 195 °C.
Found (%): C, 62.1; H, 4.5; N, 24.0. C9H7N3O. Calculated (%):
C, 62.4; H, 4.1; N, 24.3. The 1H NMR spectrum is presented in
Table 1.
2JC,H(2´)
=
3JC,H(6´) = 9.5 Hz, JC,H(3´)
=
3JC,H(5´) = 3.4 Hz);
2
1
140.99 (dm, C(2), JC,H = 201.2 Hz); 143.82 (dd, C(4a),
3JC,C(8)H = 8.6 Hz, JC,C(6)H = 5.5 Hz); 148.63 (m, C(8a));
3
2
2
151.27 (dd, C(3), JC,CHN = 7.7 Hz, JC,C(2)H = 4.6 Hz).
3ꢀ(4ꢀCarboxyphenylhydrazonomethyl)ꢀ1ꢀmethylꢀ2ꢀquinꢀ
oxalinium iodide (4g). Yield 62%, m.p. 360—362 °C (from
AcOH—DMSO). Found (%): C, 46.7; H, 3.4; N, 12.6.
C17H15N4O2I. Calculated (%): C, 47.0; H, 3.5; N, 12.9.
1H NMR (DMSOꢀd6), δ: 4.0 (br.s, 1 H, COOH); 4.70 (s, 3 H,
Me); 7.48 (d, 2 H, H(2´), H(6´), 3JH,H(3´) = 3JH,H(5´) = 8.6 Hz);
7.93 (d, 2 H, H(3´), H(5´), JH,H(2´)
3
=
3JH,H(6´) = 8.6 Hz);
8.11—8.59 (m, 4 H, H(5), H(6), H(7), H(8)); 8.23 (s, 1 H,
CH=N); 10.01 (s, 1 H, H(2)); 11.98 (s, 1 H, NH).
1
The data of the H NMR spectra of compounds 4b—e are
given in Table 2.
Isoxazolo[4,5ꢀb]quinoxaline (10). A solution of KMnO4
(0.67 g, 4.3 mmol) in acetone was gradually added with stirring
at 50 °C to a solution of oxime 8 (0.3 g, 1.7 mmol) in 50 mL of
acetone. The reaction mixture was cooled and MnO2 was filꢀ
tered off and washed with a large volume of acetone. The acꢀ
etone solutions were combined and concentrated in vacuo to
dryness. The product was purified by chromatography (silica
gel, hexane—ethyl acetate solvent system). Yield 40%, m.p.
>250 °C. Found (%): C, 63.3; H, 2.5; N, 24.1. C9H5N3O. Calꢀ
culated (%): C, 63.2; H, 2.9; N, 24.6. The 1H NMR spectrum is
presented in Table 2.
1,9ꢀDimethylpyrazolo[3,4ꢀb]ꢀ9ꢀquinoxalinium iodide (6b).
Yield 43%, m.p. 186—187 °C (from aqueous PriOH). Found (%):
C, 40.1; H, 3.4; N, 16.9. C11H11N4I. Calculated (%): C, 40.5;
H, 3.4; N, 17.2.
1ꢀBenzylꢀ9ꢀmethylpyrazolo[3,4ꢀb]ꢀ9ꢀquinoxalinium iodide
(6c). Yield 74%, m.p. 186—187 °C (from propanꢀ2ꢀol).
Found (%): C, 50.4; H, 3.5; N, 13.7. C17H15IN4. Calculated (%):
C, 50.8; H 3.8; N 13.9.
9ꢀMethylꢀ1ꢀphenylpyrazolo[3,4ꢀb]ꢀ9ꢀquinoxalinium iodide
(6d). Yield 62%, m.p. 206—208 °C (from water). Found (%):
C, 49.4; H, 3.4; N, 14.2. C16H13N4I. Calculated (%): C, 49.5;
H, 3.4; N, 14.4. 13C NMR (DMSOꢀd6), δ: 38.64 (q, Me, 1JC,H
Synthesis of imines 11a—d (general procedure). A solution of
2ꢀquinoxalinecarboxaldehyde (1) (1 g, 6.3 mmol) in 15 mL of
ethanol was added dropwise with stirring at 60 °C to a solution
of the required amino derivative (8.2 mmol) in 15 mL of ethaꢀ
nol. After cooling the reaction mixture, the product was filtered
off and recrystallized (in the case of compound 11b, the reaction
mixture was concentrated in vacuo to dryness and recrystallized).
=
146.3 Hz); 117.76, 130.35, 131.28 and 132.53 (all m, C(5),
C(6), C(7), C(8)); 127.86 (dm, C(2´), C(6´), 1JC,H = 166.1 Hz);
129.72 (m, C(8a)); 130.09 (dm, C(3´), C(5´), 1JC,H = 165.4 Hz);
132.98 (m, C(1´)); 137.60 (m, C(9a)); 137.86 (dm, C(4´), 1JC,H
=
=
3
3
166.6 Hz); 140.31 (dd, C(4a), JC,C(8)H = 9.7 Hz, JC,C(6)H
5.4 Hz); 140.37 (d, C(3), JC,H = 204.8 Hz); 145.80 (d, C(3a),
2JC,H(3) = 11.0 Hz).
1
1
The data of the H NMR spectra of compounds 11a—d are
presented in Table 3.
9ꢀMethylꢀ1ꢀ(paraꢀtolyl)pyrazolo[3,4ꢀb]ꢀ9ꢀquinoxalinium
iodide (6e). Yield 71%, m.p. 304—305 °C (from water).
Found (%): C, 50.8; H, 3.5; N, 14.0. C17H15N4I. Calculated (%):
C, 50.8; H, 3.8; N, 13.9.
2ꢀ[Nꢀ(2ꢀAminophenyl)formimidoyl]quinoxaline (11a). Yield
82%, m.p. 121—123 °C (from acetonitrile). Found (%):
C, 72.3; H, 4.9; N, 22.1. C15H12N4. Calculated (%): C, 72.6;
H, 4.9; N, 22.6.
Synthesis of pyrazolo[3,4ꢀb]quinoxalines 7a,b,c (general proꢀ
cedure). Dilute sulfuric acid (рH = 2) (10 mL) was added to a
solution of the required hydrazone 2a—c (2.5—3.0 mmol) in
10 mL of ethanol, and the mixture was refluxed with air bubꢀ
bling for 4 h (in the case of 2a, for 10 min). After cooling and
neutralization with NaOH, the precipitate was filtered off and
recrystallized.
2[Nꢀ(Aminoꢀ4,5ꢀdimethylphenyl)formimidoyl]quinoxaline
(11b). Yield 72%, m.p. 162—163 °C (from a hexane—acetone
mixture). Found (%): C, 73.6 H, 5.8 N, 20.3. C17H16N4. Calcuꢀ
lated (%): C, 73.9; H, 5.8; N, 20.3.
2[Nꢀ(2ꢀAminoꢀ3ꢀpyridyl)formimidoyl]quinoxaline (11c).
Yield 65%, m.p. 219—220 °C (from ethanol). Found (%):
C, 67.4; H, 4.6; N, 27.9. C14H11N5. Calculated (%): C, 67.5;
H, 4.5; N, 28.1.
The 1H NMR spectra of the products are given in Table 2.

2182
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 10, October, 2003
Boguslavskiy et al.
1
Table 3. H NMR data (DMSOꢀd6, δ (J/Hz)) of Schiff´s bases of 2ꢀquinoxalinecarboxaldehyde 11a—d
Comꢀ
pound
Aryl
H(6), H(7)
m, 2 H
H(5), H(8)
m, 2 H
NH2
s, 2 H
H(3)
s, 1 H
CH=N
s, 1 H
11a
6.56—6.59 (m, 1 Н, Н(5´)); 6.79 (dd, 1 Н,
Н(3´), JH,H(4´) = 7.6, JH,H(5´) = 0.7);
7.05—7.09 (m, 1 Н, Н(4´)); 7.39 (dd, 1 Н, Н(6´),
JH,H(5´) = 7.3, JH,H(4´) = 0.7)
7.90—7.92
8.15—8.19
5.69
9.92
8.88
11b
11c
2.19 (s, 6 Н, Me); 6.60 (s, 1 Н, Н(3´));
7.23 (s, 1 Н, Н(6´))
6.69 (dd, 1 Н, Н(5´), JH,H(4´) = 7.5,
JH,H(6´) = 5.0); 7.67 (dd, 1 Н, Н(4´),
JH,H(5´) = 7.5); 7.85—7.98 (m, 3 H, H(6´),
H(6), H(7))
7.92—7.98
7.85—7.98
8.17—8.19
8.09—8.21
5.44
6.36
9.88
9.93
8.84
8.91
11d
6.82—7.08 (m, 2 Н, Н(3´), Н(5´)); 7.19—7.22
(m, 1 Н, H(4´)); 7.50 (br.d, 1 Н, H(6´),
JH,H(5´) = 7.9); 9.43 (s, 1 H, OH)
7.85—8.00
8.11—8.25
—
9.55
9.00
2ꢀ[Nꢀ(2ꢀHydroxyphenyl)formimidoyl]quinoxaline (11e). Yield
82%, m.p. 219—220 °C (from AcOH). Found (%): C, 72.3;
8.13—8.38 (m, 4 H, H(8), H(9), H(10), H(11)); 9.33 (s, 1 H,
H(6)); 10.19 (s, 1 H, NH).
H, 4.3; N, 16.7. C15H11N3O. Calculated (%): C, 72.3; H, 4.5;
Preparation of compounds 13a,b (general procedure). The
required compound 12 (2 mmol) was dissolved in 15 mL of
methanol, 10 mL of dilute sulfuric acid (рH = 2) was added, and
the mixture was refluxed for 3 h. After cooling, the reaction
mixture was neutralized with a solution of NaOH (25%) and the
precipitate formed was filtered off and recrystallized.
1
N, 16.9. 13C NMR (DMSOꢀd6), δ: 116.64 (dd, C(3´), JC,H
=
=
=
3
1
158.1 Hz, JC,C(5´)H = 8.2 Hz); 119.51 (dd, C(6´), JC,H
157.6 Hz, 3JC,C(4´)H´ = 8.2 Hz); 119.64 (dd, C(4´), JC,H
1
3
161.6 Hz, JC,C(6´)H = 8.5 Hz); 129.05, 129.34 (both m, C(5)
1
3
and C(8)); 129.55 (dd, C(5´), JC,H = 158.6 Hz, JC,CH
=
9.6 Hz); 130.77, 131.21 (both m, C(6) and C(7)); 135.68 (ddd,
N,N´ꢀ(Diꢀ2ꢀquinoxalylmethylene)ꢀ1,2ꢀdiaminobenzene (13a).
Yield 74%, m.p. 215—216 °C (from ethanol). Found (%):
C, 74.3; H, 4.0; N, 21.1. C24H16N6. Calculated (%): C, 74.2;
3
3
3
C(1´), JC,C(3´)H = 10.5 Hz, JC,C(5´)H = 8.9 Hz, JC,C(6´)H
5.9 Hz); 141.24 (dd, C(8a), JC,C(5)H = 8.4 Hz, JC,C(7)H
=
=
=
3
3
3
3
1
5.1 Hz); 142.14 (ddd, C(4a), JC,C(8)H = 11.5 Hz, JC,C(3)H
H, 4.2; N, 21.6. H NMR (DMSOꢀd6), δ: 6.45—6.62 (m, 2 H,
8.6 Hz, 3JC,C(6)H = 4.9 Hz); 144.49 (dd, C(3) 1JC,H = 189.0 Hz,
H(4), H(5)); 7.32—7.50 (m, 2 H, H(3), H(6)); 7.61—8.19 (m,
10 H, quinoxaline protons); 9.15, 9.87 (both s, each 1 H, CH=N,
CH=N´). MS (EI, 70 eV), m/z (Irel (%)): 388 [M]+ (100), 259
(81), 194 (9).
3JC,CHN = 3.7 Hz); 149.15 (dd, C(2´) JC,C(4´)H = 9.3 Hz,
3
3JC,C(6´)H = 9.3 Hz); 152.36 (dd, C(2), JC,CHN = 9.8 Hz,
2
1
2JC,C(3)H = 7.5 Hz); 156.77 (d, CH=N, JC,H = 167.9 Hz).
Synthesis of compounds 12a—c (general procedure). Comꢀ
pounds 11a—c (2 mmol) were dissolved in 20 mL of methanol,
1 mL of glacial acetic acid was added, and the mixture was
refluxed with air bubbling. After cooling, 10 mL of water was
added, and the precipitate was filtered off and recrystallized.
5HꢀBenzo[2,3]ꢀ1,4ꢀdiazepino[5,6ꢀb]quinoxaline (12a), yield
65%, m.p. 241—242 °C (from aqueous methanol). Found (%):
C, 73.3; H, 4.0; N, 22.9. C15H10N4. Calculated (%): C, 73.2;
N,N´ꢀ(Diꢀ2ꢀquinoxalylmethylene)ꢀ1,2ꢀdiaminoꢀ4,5ꢀdiꢀ
methylbenzene (13b). Yield 68%, m.p. >250 °C. Found (%):
C, 75.1; H, 4.5; N, 20.4. C26H20N6. Calculated (%): C, 75.0;
1
H, 4.8; N, 20.2. H NMR (DMSOꢀd6), δ: 2.40 (s, 6 H, Me);
6.48—6.51 (m, 2 H, H(3), H(6)); 7.52—8.22 (m, 10 H, quinꢀ
oxaline protons); 9.02, 9.83 (both s, each 1 H, CH=N, CH=N´).
Benzo[2,3]ꢀ1,4ꢀoxazepino[6,7ꢀb]quinoxaline (15). Potasꢀ
sium permanganate (2 g, 12.6 mmol) in acetone was added
dropwise with stirring at 50 °C to compound 2c (1 g, 4.02 mmol)
in 100 mL of acetone. The reaction mixture was cooled and
MnO2 was filtered off and washed with a large amount of acꢀ
etone. The acetone solutions were combined and concentrated
to dryness in vacuo. The product was purified by chromatoꢀ
graphy (silica gel, hexane—acetone). Yield 0.42 g (42%), m.p.
173—175 °C. Found (%): C, 72.5; H, 3.9; N, 16.6. C15H9N3O.
Calculated (%): C, 72.9; H, 3.7; N, 17.0. 1H NMR (DMSOꢀd6),
δ: 7.42—7.64 (m, 2 H, H(9), H(8)); 7.85—8.08 (m, 4 H, H(1),
H(2), H(3), H(4)); 8.11—8.34 (m, 2 H, H(7), H(10)); 9.71 (s,
1 H, H(12)). 13C NMR (DMSOꢀd6), δ: 111.55, 120.71, 125.46,
127.10, 129.10, 129.60, 131.45, 131.95 (all m, C(1), C(2), C(3),
C(4), C(7), C(8), C(9), C(10)); 140.97, 141.06, 142.13 (all m,
C(6a), C(10a), C(13a)); 140.58 (d, C(11a), 2JC,H(12) = 3.6 Hz);
144.32 (d, C(12), 1JC,H = 189.0 Hz); 150.54 (m, C(4a)); 159.64
(s, C(5a)). MS (EI, 70 eV), m/z (Irel (%)): 247 [M]+ (100),
173 (9), 145 (48), 129 (13), 119 (13), 102 (21).
1
H, 4.1; N, 22.8. H NMR (DMSOꢀd6), δ: 7.21—7.35 (m, 2 H,
H(2), H(3)); 7.62 (d, 1 H, H(4), J = 7.5 Hz); 7.77 (d, 1 H, H(1),
J = 7.4 Hz); 7.85—7.98 (m, 2 H, H(8), H(9)); 8.10—8.25 (m,
2 H, H(7), H(10)); 9.80 (s, 1 H, H(12)); 13.40 (s, 1 H, NH). MS
(EI, 70 eV), m/z (Irel (%)): 246 [M]+ (100), 144 (89), 118 (23),
102 (8).
5Hꢀ2,3ꢀDimethylbenzo[2,3]ꢀ1,4ꢀdiazepino[5,6ꢀb]quinoxaꢀ
line (12b), yield 65%, from aqueous methanol, m.p. >250 °C.
Found (%): C, 74.6; H, 4.9; N, 20.7. C17H14N4. Calculated (%):
C, 74.4; H, 5.1; N, 20.4. 1H NMR (DMSOꢀd6), δ: 2.35 (s, 6 H,
Me); 7.79—7.86 (m, 1 H, H(4)); 7.89—7.98 (m, 2 H, H(8),
H(9)); 8.04—8.09 (m, 1 H, H(1)); 8.13—8.21 (m, 2 H, H(7),
H(10)); 9.77 (s, 1 H, H(12)); 13.42 (br.s, 1 H, NH).
13HꢀPyrido[3´,2´:2,3]ꢀ1,4ꢀdiazepino[5,6ꢀb]quinoxaline
(12с), yield 82%, m.p. 175—177 °C. Found (%): C, 68.2; H, 3.4;
N, 28.0. C14H9N5. Calculated (%): C, 68.0; H, 3.7; N, 28.3.
1H NMR (DMSOꢀd6), δ: 7.88—8.12 (m, 3 H, H(2), H(3), H(4));

Annelation of heterocycles to quinoxalines
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 10, October, 2003
2183
Table 4. Basic bond lengths (d) in molecule 6d
wR2 = 0.0869 (for 2476 reflections with F 2 ≥ 2σ), R1(I ≥ 2σ(I )) =
0.0499, wR2 = 0.0899 for all reflections. The positions of hydroꢀ
gen atoms were calculated geometrically and refined isotropically
according to the "rider" model. The bond lengths and angles are
listed in Tables 4 and 5.
Bond
d/Å
Bond
d/Å
N(1)—C(9)
N(1)—C(1)
N(1)—C(16)
N(2)—C(7)
N(2)—C(6)
N(3)—C(9)
N(3)—N(4)
N(3)—C(10)
N(4)—C(8)
C(1)—C(6)
C(1)—C(2)
C(2)—C(3)
1.281(16)
1.389(9)
1.488(9)
1.300(10)
1.370(10)
1.375(10)
1.423(7)
1.440(8)
1.292(9)
1.414(9)
1.415(9)
1.352(12)
C(3)—C(4)
C(4)—C(5)
C(5)—C(6)
C(7)—C(8)
1.392(11)
1.367(10)
1.426(10)
1.422(9)
1.473(12)
1.376(12)
1.396(13)
1.371(10)
1.372(11)
1.376(12)
1.384(12)
This work was financially supported by the American
Civil Research and Development Foundation (CRDF)
(grant RECꢀ005) and by the Russian Foundation for Baꢀ
sic Research (projects No. 01ꢀ03ꢀ96456а and No. 00ꢀ03ꢀ
40139).
C(7)—C(9)
C(10)—C(15)
C(10)—C(11)
C(11)—C(12)
C(12)—C(13)
C(13)—C(14)
C(14)—C(15)
References
1. O. N. Chupakhin and D. N. Beresnev, Usp. Khim., 2002, 71,
803 [Russ. Chem. Rev., 2002, 71 (Engl. Transl.)]; Vestnik
RFFI, 2002, 29, 31.
Table 5. Basic bond angles (ω) in molecule 6d
Angle ω/deg Angle
2. V. N. Charushin, Proc. XXth European Colloquium on Heteroꢀ
cyclic Chemistry, Sweden, Stockholm, 2002, 10.
3. V. N. Charushin and O. N. Chupakhin, I mezhdunarodnaya
konferentsiya "Khimiya i biologicheskaya aktivnost' azotistykh
geterotsiklov i alkaloidov" [I Intern. Conf. "Chemistry and Bioꢀ
logical Activity of Nitrogen Heterocycles and Alkaloids], Proc.,
Iridiumꢀpress, Moscow, 2001, 1, 162 (in Russian).
4. V. N. Charushin, O. N. Chupakhin, and H. C. van der Plas,
Adv. Heterocycl. Chem., 1988, 43, 301.
ω/deg
C(9)—N(1)—C(1) 117.8(6) C(1)—C(6)—C(5)
C(9)—N(1)—C(16) 120.9(6) N(2)—C(7)—C(8)
C(1)—N(1)—C(16) 121.1(6) N(2)—C(7)—C(9)
C(7)—N(2)—C(6) 115.9(6) C(8)—C(7)—C(9)
C(9)—N(3)—N(4) 111.3(7) N(4)—C(8)—C(7)
119.2(7)
132.1(6)
122.2(7)
105.6(7)
111.8(6)
C(9)—N(3)—C(10) 131.6(7) N(1)—C(9)—N(3) 134.6(8)
5. V. N. Charushin, S. G. Alexeev, O. N. Chupakhin, and
H. C. van der Plas, Adv. Heterocycl. Chem., 1989, 46, 73.
6. O. N. Chupakhin, B. V. Rudakov, S. G. Alexeev, and V. N.
Charushin, Heterocycles, 1992, 33, 931.
7. O. N. Chupakhin, V. N. Charushin, and M. G. Ponizovskii,
Khimiya Geterotsikl. Soedinen., 1984, 706 [Chem. Heterocycl.
Comp., 1984 (Engl. Transl.)].
8. V. N. Charushin and O. N. Chupakhin, Usp. Khim., 1984,
53, 1648 [Russ. Chem. Rev., 1984, 53 (Engl. Transl.)].
9. V. N. Charushin, N. N. Mochulskaya, A. A. Andreiko, M. I.
Kodess, and O. N. Chupakhin, Mendeleev Commun.,
2002, 28.
N(4)—N(3)—C(10) 116.6(6) N(1)—C(9)—C(7)
C(8)—N(4)—N(3) 107.3(5) N(3)—C(9)—C(7)
121.4(6)
103.9(10)
N(1)—C(1)—C(6) 119.2(6) C(15)—C(10)—C(11)120.8(7)
N(1)—C(1)—C(2) 121.2(6) C(15)—C(10)—N(3) 119.0(9)
C(6)—C(1)—C(2) 119.5(7) C(11)—C(10)—N(3) 120.1(8)
C(3)—C(2)—C(1) 119.0(7) C(12)—C(11)—C(10)118.1(7)
C(2)—C(3)—C(4) 122.5(7) C(11)—C(12)—C(13)121.3(7)
C(5)—C(4)—C(3) 120.2(7) C(14)—C(13)—C(12)120.4(8)
C(4)—C(5)—C(6) 119.4(7) C(13)—C(14)—C(15)119.3(8)
N(2)—C(6)—C(1) 122.8(7) C(10)—C(15)—C(14)119.9(8)
N(2)—C(6)—C(5) 118.0(6)
10. V. N. Charushin, N. N. Mochulskaya, A. A. Andreiko, V. I.
Philyakova, M. I. Kodess, and O. N. Chupakhin, Tetraꢀ
hedron Lett., 2003, 44, 2421.
11. O. N. Chupakhin, V. N. Charushin, and H. C. van der Plas,
Nucleophilic Aromatic Substitution of Hydrogen, Acad. Press,
New York, 1994, 368 pp.
Xꢀray diffraction study of compound 6d. The Xꢀray diffracꢀ
tion experiment was carried out on a Bruker AXS SMART 1000
diffractometer equipped with a CCD detector (λ(MoꢀKα) =
0.71073 Å, graphite monochromator, 293 K, ωꢀscan mode, scan
step 0.3°, frame measurement time 10 s, 2θmax = 60°).
The crystals C16H13IN4 were isolated from water, crystal
dimensions 0.6×0.2×0.5, colored red, molecular mass 389.21,
monoclinic system, space group Cs, a = 6.689(3) Å, b =
33.689(15) Å, c = 7.224(3) Å, α = 90°, β = 112.416(10)°, γ = 90°,
V = 1504.9(12) Å3, Z = 4, dcalc = 1.713 g cm–3, F(000) = 760,
µ = 2.126 cm–1, the scanning range was 2.42—30.10°, the total
number of measured reflections was 3863, the number of indeꢀ
pendent reflections was 2476, and Rint = 0.026.
A semiempirical absorption correction was applied.27 The
structure was solved by the direct method using the SHELXS97
program package28 and refined by the SHELXL97 package29
using the leastꢀsquares method in the anisotropic (or isotropic
for H atoms) approximation, the number of refined paramꢀ
eters was 190 for 2476 reflections. R1(I ≥ 2σ(I )) = 0.0395,
12. A. Rykowski, M. Mojzych, and Z. Karczmarzyk, Heteroꢀ
cycles, 2000, 53, 2175.
13. E. Lippmann, D. Steiner, and W. Shilov, Z. Chem., 1990,
30, 251.
14. M. Mehdi Baradarani and J. A. Joule, J. Chem. Soc., Perkin
Trans. 1, 1980, 72.
15. M. Mehdi Baradarani, L. Dalton, F. Heatly, D. Cohylakis,
and J. A. Joule, J. Chem. Soc., Perkin Trans. 1, 1985, 1503.
16. A. Karim Karim, M. Armengol, and J. A. Joule, Heteroꢀ
cycles, 2001, 55, 2139.
17. M. Armengol and J. A. Joule, J. Chem. Soc., Perkin Trans. 1,
2001, 154.
18. M. Armengol and J. A. Joule, J. Chem. Soc., Perkin Trans. 1,
2001, 978.

2184
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 10, October, 2003
Boguslavskiy et al.
19. G. Sarodnick and T. Linker, J. Heterocycl. Chem., 2001,
38, 829.
20. P. Mandhavan Pillai and P. Ramabhadran, Ind. J. Chem.,
Sect B, 1986, 25B, 960.
21. P. Mandhavan Pillai and P. Ramabhadran, Ind. J. Chem.,
Sect B, 1986, 25B, 901.
22. G. Henseke and W. Lemke, Chem. Ber., 1958, 91, 113.
23. G. Henseke and W. Lemke, Chem. Ber., 1958, 91, 2273.
24. G. Henseke and W. Lemke, Chem. Ber., 1959, 92, 509.
25. O. N. Chupakhin, V. N. Charushin, and A. R. Chernyshev,
Progress in Nuclear Magnetic Resonance Spectroscopy,
Pergamon Press, New York, 1987, 20, 95.
26. F. H. Allen, O. Kennard, D. G. Watson, L. Brammer,
A. G. Orpin, and R. Taylor, J. Chem. Soc., Perkin Trans. 2,
1987, 1.
28. A. V. Bogatskii, S. A. Andronati, and N. Ya. Golovenko,
Trankvilizatory [Tranquilizers] Naukova dumka, Kiev, 1980,
279 pp. (in Russian).
29. C Weygand and G. Hilgetag, Organisch chemishe
Experimentierkunst, Johann Ambrosius Barth, Leipzig, 1964.
30. G. M. Sheldrick, SADABS, Program for Scaling And Correcꢀ
tion of Area Detector Data, University of Göttingen, Göttingen
(Germany), 1997.
31. G. M. Sheldrick, SHELXS97, Program for the Solution of
Crystal Structures, University of Göttingen, Göttingen (Gerꢀ
many), 1997.
32. G. M. Sheldrick, SHELXL97, Program for the Refinement of
Crystal Structure, University of Göttingen, Göttingen (Gerꢀ
many), 1997.
27. D. Lloyd and H. McNab, Adv. Heterocycl. Chem.,
1998, 71.aaa
Received April 7, 2003;
in revised form June 2003