An efficient method for the synthesis of imidazo[1,5-a]quinoxalines from 3-acylquinoxalinones and benzylamines via a novel imidazoannulation

Article abstract of DOI:10.1016/j.tet.2009.08.081

The reaction of 3-aroylquinoxalin-2(1H)-ones and their N-alkyl analogues with benzylamines in DMSO proceeds through an intermediate formation of N-(α-quinoxalinylbenzylydene)benzylamine, which when subjected to oxidative cyclocondensation gives imidazo[1,

Full text of DOI:10.1016/j.tet.2009.08.081

Tetrahedron 65 (2009) 9412–9420
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An efficient method for the synthesis of imidazo[1,5-a]quinoxalines from
3-acylquinoxalinones and benzylamines via a novel imidazoannulation
*
Vakhid A. Mamedov , Aleksey A. Kalinin, Alsu A. Balandina, Il’dar Kh. Rizvanov, Shamil K. Latypov
A.E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Research Center of the Russian Academy of Sciences, Arbuzov Str. 8, Kazan 420088, Russian Federation
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 June 2009
Received in revised form 14 August 2009
Accepted 28 August 2009
Available online 3 September 2009
The reaction of 3-aroylquinoxalin-2(1H)-ones and their N-alkyl analogues with benzylamines in DMSO
proceeds through an intermediate formation of N-(a-quinoxalinylbenzylydene)benzylamine, which
when subjected to oxidative cyclocondensation gives imidazo[1,5-a]quinoxalines. Applying this new
approach of imidazoannullation to the bis-3-aroylquinoxalines makes it possible to develop funda-
mentally new methods of the synthesis of bis-imidazo[1,5-a]quinoxalines with the use of different
benzylamines and heteromacrocycles with the 1,3-bis(3-arylimidazo[1,5-a]quinoxalin-1-yl)benzene
structural fragment when m-xylylenediamine is used.
Keywords:
Quinoxalin-2(1H)-ones
Benzylamines
Imidazoannellation
Imidazo[1,5-a]quinoxalines
Macrocyclization
Mass spectrometry
IR
Ó 2009 Elsevier Ltd. All rights reserved.
NMR
N
1. Introduction
N
C
C
C
C
N
N
Imidazoquinoxalines are one of the important classes of hetero-
cycles that are often found in biologically active and pharmacolog-
ically useful agents such as Dazoquinast (antiallergic), LU 73068
(anticonvulsant (glycine/NMDA) but not the NMDA receptor an-
tagonist), FG 10571 NNC 14-0571, Panadiplon, U-78875 anxiolytic
(benzodiazepine receptor partial agonist), U-8044 (antidepressant,
anxiolytic), U-97775 (anxiolytic (GABAA receptor ligand)).1,2 Syn-
thetic sequences have attracted considerable attention in recent
years.3,4
Four methods have been previously developed for the prep-
aration of imidazo[1,5-a]quinoxalines based quinoxaline de-
rivatives. The first method involved intramolecular cyclization of
functionalized quinoxaline derivatives.2–8 Of the four sub-vari-
ants for the construction of the tricyclic system three a2–6, b7 and
c8 have been implemented (Chart 1). The second approach in-
volved the reaction of quinoxaline derivatives with the sources of
monoatomic synthons. Of the three possible sub-variants for the
construction of the tricyclic system only one d7,9,10 has been
developed. The third approach involves the cyclization of qui-
noxaline and quinoxalin-2(1H)-one derivatives proceeding with
N
N
a
b
N
N
C
C
N
C
C
N
N
N
N
f
c
N
N
d
e
N
C
C
N
C
N
N
C
N
N
Chart 1. Implemented methods for the construction of imidazo[1,5-a]quinoxalines
based on quinoxaline derivatives.
the formation of N(10)–C(1) and C(3)–C(3a) bonds on exposure to
a source of the C–N–C fragment (sub-variant f11–22) (Chart 1).
Recently, we have developed a fourth variant for the construc-
tion of imidazo[1,5-a]quinoxalin-2(1H)-ones, proceeding with the
* Corresponding author. Tel.: þ7 843 2727304; fax: þ7 843 2732253.
E-mail address: mamedov@iopc.knc.ru (V.A. Mamedov).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.08.081

V.A. Mamedov et al. / Tetrahedron 65 (2009) 9412–9420
9413
formation of N(10)–C(1) and N(2)–C(3) bonds (sub-variant e), i.e.,
the closure of the imidazole ring with the parting of compounds,
which provide the C–N fragment into the newly formed imid-
3-phenylimidazo[1,5-a]quinoxalin-4(5H)-ones 3b,c, 1-phenyl-3-
methylimidazo[1,5-a]quinoxalin-4(5H)-one 3d, 1-pyridyl-3-methyl-
imidazo[1,5-a]quinoxalin-4(5H)-one 3e and their N-alkylated
derivatives 3f–i (Table 1).
azo[1,5-a]quinoxalin-2(1H)-one system. The reactions of 3-a-
chlorobenzyl quinoxalin-2(1H)-ones with potassium thiocyanate
and potassium isocyanate, as synthetic equivalents of C–N synthons
led to the formation of 1-mercaptane and 1-hydroxy-derivatives of
imidazo[1,5-a]quinoxalin-4(5H)-ones6,10 correspondingly. In addi-
tion to inorganic reagents, benzylamine and m-xylylenediamine
provide a useful source of the C–N fragment. Previously, we found
that 3-benzoylquinoxalin-2(1H)-one (1a) when heated in DMSO at
the temperature of 150 ꢀC for 2 h undergoes condensation with the
formation of 1,3-diphenylimidazo[1,5-a]quinoxalin-4(5H)-one (3a)
(Scheme 1).23
Table 1
The synthesis of 1-phenyl- and hetarylimidazo[1,5-a]quinoxalin-4(5H)-ones 3b–i
R1
R1
R2
N
N
R1CH2NH2
DMSO, 4 h
R1CH2NH2
DMSO, 8 h
R2
R2
N
N
N
N
N
O
O
NH
3b-e
O
O
R3
R3
1a-d
3f-i
Entry
Substrates
Product (yield, %)
Ketone (R2, R3)
Amine (R1)
Ph
N
Ph
O
1
2
3
4
5
6
7
8
1a (Ph, H)
1a (Ph, H)
1b (Me, H)
1b (Me, H)
1c (Ph, Me)
1d (Ph, Et)
1d (Ph, Et)
1e (Ph, Pr)
2b (
2c (
a
-Py)
3b (66)
3c (63)
3d (40)
3e (51)
3f (65)
3g (76)
3h (66)
3i (75)
PhCH2NH2
2a
N
N
Ph
b-Py)
O
2a (Ph)
DMSO
2c (
2c (
b
b
-Py)
-Py)
NH
3a
O
NH
1a
2a (Ph)
2c ( -Py)
2a (Ph)
b
Scheme 1. Oxidative imidazoannulation of 3-benzoylquinoxalin-2-one (1a) with
benzylamine.
2. Results and discussion
In the IR spectra of imidazo[1,5-a]quinoxalin-4-ones 3 there are
no absorption bands of nCOket in the area of 1675–1714 cmꢁ1 char-
acteristic of the initial 3-acylquinoxalin-2(1H)-one 1. The mass
spectra of these compounds display molecular ion peaks at ap-
propriate m/z values. Variety of NMR correlation methods31,32 were
used to establish structures of these compounds. For example,
combination of 2D COSY and 1D TOCSY spectra allowed straight-
forward separation of three aromatic systems. 1H–13C HSQC and
particularly 1H–15N/13C HMBC correlations enable to assign these
aromatic spin systems to corresponding moieties (quinoxaline, Py/Ph
and Ph) and to prove the overall structure (e.g., on Fig. 1 some
experimental NMR connectivities are schematically shown for
3c). A number of NOEs strongly support these structural hy-
potheses (see Supplementary data).
The paper is devoted to the development of a new approach to
the design of imidazo[1,5-a]quinoxalines through the introduction
of the C–N fragment into quinoxaline derivatives, based on the
above-mentioned reaction (Scheme 1). In this case, both various
types of 3-aroyl(alkanoyl)quinoxalin-2-ones and benzyl-,
a(b)-
picolylamines were used and bis-analogues of the reagent were
used as well. The approach towards the construction of the imid-
azo[1,5-a]quinoxaline system could be represented in the following
retrosynthetic scheme (Scheme 2), which implies that the
interaction of 3-aroyl(alkanoyl)quinoxalin-2-ones of type C with
the compound D containing aminomethyl fragment at the first
stage of the reaction proceeds with the formation of Schiff bases B.
Under the reaction conditions in DMSO the latter are subjected to
intramolecular cyclization with the imidazoannulation to the qui-
noxaline system and the desired tricycle A is directly formed
(Scheme 2).
Good correlation (R2¼0.97) of calculated (GIAO DFT)33–36 versus
experimental 13C chemical shifts additionally proves the above
conclusions on the structures of 3c.
R1
R2
O
R2
N
R2
DMSO
DMSO
N
N
N
N
N
R1
N
O
R1
H2N
+
D
O
O
N
annulation
imination
R3
R3
R3
C
B
A
Scheme 2. Retrosynthetic representation of the implementation of the variant e.
The ready availability of the starting reagentsd3-aroyl(alka-
noyl)quinoxalin-2-ones24–30 and appropriate amines and the sim-
plicity of the experimental procedure make this method widely
applicably.
5'
4'
6'
N
1'
1
2'
2"
N
3"
4"
3
9
1"
6"
N
9a
5a
8
7
3a
4
5"
2.1. Synthesis of imidazo[1,5-a]quinoxalin-4(5H)-ones 3b–i
N
H
O
6
The use of 3-acetylquinoxalin-2(1H)-one 1b and N-alkyl de-
rivatives 1c,d,e instead of 3-benzoylquinoxalin-2(1H)-one 1a as
well as aminomethylpyridines instead of benzylamine do not
preclude the reaction of imidazoannulation and lead to 1-pyridyl-
3c
Figure 1. The principal HMBC 1H–15N (grey arrows, from protons to nitrogens) and
NOE correlations (black arrows) for 3c.

9414
V.A. Mamedov et al. / Tetrahedron 65 (2009) 9412–9420
It is noteworthy that when compared with nonsubstituted 3-
spectra of 5 there are several lines at 2.5–5 ppm corresponding to
spacer protons. In general, the aromatic fragments of 1H NMR
spectra are similar to those for tricycles 3 although signals due to
different aromatic systems are partly superimposed (e.g., for 5f
Fig. 2a). However, each spin system can be easily discerned and
assigned to corresponding moieties in 1D TOCSY experiments (e.g.,
Fig. 2b–d). These fragments can be linked into a whole molecule by
1H–15N/13C HMBC correlations (Fig. 2e). Finally the combination of
inter moiety NOEs additionally supports the above derived
structures.
phenylimidazo[1,5-a]quinoxalin-4-one6,10 the introduction of aryl
substituent in the first position significantly shifts the signal H(9) to
high field (by ca. 1.3 ppm) due to the selective and strong aniso-
tropic effect of the aryl system.37–39
2.2. Synthesis of a,u-bis(1,3-diphenylimidazo[1,5-
a]quinoxalin-4-on-5-yl)alkanes 5a–g
This reaction has also been advantageously employed with com-
pounds containing two benzoylquinoxalin-2-one fragments, which
makes it possible to obtain podands with the terminal imidazo[1,5-
a]quinoxalin-4-one systems connected by a spacer with the atoms
N(5) of the imidazo[1,5-a]quinoxalin-4-one system. The interaction
2.3. Synthesis of 1,3-bis(imidazo[1,5-a]quinoxalin-
4-on-1-yl)benzenes 7a–d
of
due to the reaction of 3-benzoylquinoxalin-2(1H)-ones with various
dibromoalakanes with the benzyl-, )-picolylamines in the solu-
tion of DMSO at 150 ꢀC results in the formation of
-bis(1,3-
a,u-bis(3-benzoylquinoxalin-2-on-1-yl)alkanes 4, easily available
Another approach to the synthesis of bis-1,3-diphenyl-
imidazo[1,5-a]quinoxalin-4-ones includes m-xylylenediamine,
containing two aminomethyl-groups with the reaction of 3-ben-
zoylquinoxalin-2-ones instead of that of benzylamine with the
latter. The presence of heterocyclic fragments rigidly oriented
relative to each other at the meta-positions in the benzene ring
makes 1,3-dihetarylbenzenes very interesting both as bidentate
chelating agents and precursors of macrocycles. Lately bis-hetar-
ylbenzenes,40–43 their heteroanalogues44,45 and macrocycles,46–50
with the above fragments attracted considerable attention both
due to their ability to act as new receptors for different sub-
strates48,49 and as blocks in optical materials,42–44 and due to their
biological activity40,41 as well. Bis(imidazo[1,5-a]quinoxalin-4-
onyl)benzenes, as well as macrocycles, containing two imid-
azo[1,5-a]quinoxaline systems have not as yet been obtained.
The interaction of m-xylylenediamine (6) with various 3-
benzoylquinoxalin-2-ones 1 results in bisheteroarylbenzenes 7
(Table 3).
a(b
a,u
diphenylimidazo[1,5-a]quinoxalin-4-on-5-yl)alkanes 5 (Table 2).
Table 2
The synthesis of
a
,
u
-bis(1,3-diphenylimidazo[1,5-a]quinoxalin-4-on-5-yl)alkanes
5a–g
R
N
Ph
O
N
N
N
N
Ph
O
O
O
O
RCH2NH2
X
X
DMSO, 8 h
N
N
O
N
N
Ph
Ph
N
Table 3
R
4
The synthesis of 1,3-bis-imidazo[1,5-a]quinoxalin-4-on-1-ylbenzenes 7a–da
5
Ph
Ph
Entry
Substrates
Diketone (X)
Product (yield, %)
Ph
O
H2N
NH2
N
N
O
O
Amine (R)
N
6
O
N
N
1
2
3
4
5
6
4a (CH2OCH2)
4b ((CH2)4)
4b ((CH2)4)
4c ((CH2OCH2)2)
4e ((CH2OCH2)3)
4e ((CH2OCH2)3)
2a (Ph)
2a (Ph)
2c (b-Py)
2a (Ph)
2a (Ph)
2c (b-Py)
5a (48)
5b (77)
5c (65)
5d (60)
5e (79)
5f (65)
N
N
R
R
N
R
1
DMSO, 24 h
7
Entry
Ketone (R)
Product (yield, %)
1
2
3
4
1c (Me)
1d (Et)
1e (Pr)
1f (Bn)
7a (31)
7b (43)
7c (39)
7d (32)
There are no absorption bands of ketone carbonyl groups in the
IR spectra of compounds 5. There are molecular ion peaks of
compound 5 in the mass spectra of electron ionization. In 1H NMR
a
After solvent evaporation, the residue was purified by a short gel plug using
CH2Cl2.
Figure 2. Low field fragments of 1H NMR spectra of 5f in DMSO-d6 (600.1 MHz) at 303 K: (a) 1H spectrum; (b–d) 1D TOCSY spectra (excited protons are marked by an arrow); (e) the
principal HMBC 1H–15N (grey arrows, from protons to nitrogens) and the NOE correlations (black arrows) for 5f.

V.A. Mamedov et al. / Tetrahedron 65 (2009) 9412–9420
9415
In the mass spectra of electron ionization of compounds 7 there
appear peaks of corresponding molecular ions. Similar to the above
cases the structures of compounds 7 are directly established by
NMR correlation methods (see Supplementary data). In Figure 3 the
low field fragments of 1H NMR spectra of 7b are shown and for
comparison the data for 5d are also given. In general, in 7 the
phenyl group protons in position 3 (Ph00) undergo only small
changes as compared with compounds without such a xylylene-
linkage. At the same time there are significant low field shifts of
quinoxaline protons in 7b versus 5b that are probably due to the
mutual deshielding effect37–39 of ‘edge-to-edge’ orientated qui-
noxaline fragments in this strained system.
deshielding effects and therefore there are no straightforward re-
lationships between 3D structure and low/high field shifts in 1H
spectra. Therefore accurate high level non empirical calculations
and extensive NMR investigations must be performed to establish
finally the conformational structures.51 In the case of 8b 1H NMR
spectra most likely correspond to the equilibrium of conformations
with the population of ca. 1.0:2.0 in DMSO. In the case of macro-
cycle 8c there is no atropizomerism in 1H NMR spectra probably
because the size of the spacer is longer and the equilibrium is fast in
the NMR time scale. Conformational rigidity/flexibility is also
manifested in 1H NMR spectra of spacer protons. The geminal
protons of spacers are nonequivalent (Dd) in 8a and b while in 8c
Figure 3. Low field fragments of 1H NMR spectra of 5d, 7b and 8a–c in DMSO-d6 (600.1 MHz) at 303 K.
2.4. Synthesis of diimidazoquinoxalinabenzene-
cyclophanes 8a–c
they are essentially broadened. Large values of Dd are in particularly
vicinal to quinoxaline moiety in 8a/b (0.7 ppm) for the spacer
protons (N–CH2–CH2–O). In 8c these protons are almost not ob-
served in 1H NMR spectra at room temperature due to the strong
collapse of signals.
The combination of the above approaches to the synthesis of bis-
imidazo[1,5-a]quinoxalin-4-onylbenzenes with the interaction of
compounds 4 and m-xylylenediamine 6 makes it possible to syn-
thesize macrocyclic compoundsddiimidazoquinoxalinabenzene-
cyclophanes 8 in an 8–10% yields (Table 4). The use of LiClO4, NaCl, KI
as templates affects the yield of macrocycles in the interactions of
diketones 4e with diamino 6 in a different way. If the presence of Liþ
has virtually no effect on the yields of the formation of macro-
cycle 8b, which in this case is 8%, in the presence of Naþ the
yields increase by two times and become 14%. Further increase of
the cation size leads to the reduction of the yields by 11%. The
reaction under high dilution does not increase the yields of the
macrocycles 8. The use of AcOH instead of DMSO leads to
the formation of compound 8b with a 7% yield. The purification
of compounds 8 was performed by column chromatography with
subsequent recrystallization. When pre-processed the reaction
mixture was treated with the hydrochloride of semicarbazone for
3 h in boiling AcOH, which greatly facilitated the separation of
the desired products.
Table 4
The synthesis of diimidazoquinoxalinabenzenecyclophanes 8a–ca
O
O
Ph
Ph
N
Ph
N
Ph
N
N
N
N
O
O
O
O
N
N
6
N
N
DMSO,
24 h
O
O
O
O
O
O
n
n
4
8
Entry
Diketone (n)
Product (yield, %)
1
2
3
4c (0)
4e (1)
4f (2)
8a(I) (5,b 8c), 8a(II) (4,b 6c)
8b(I)þ8b(II) (8,b,c 14,d 11e)
8c (8b)
Compound 8a was obtained as a mixture of two diastereomers
(ca. 1:1), which were separated and characterized separately
(Fig. 3c and d). Presumably these diastereomers (conformers) are
due to the different (syn and anti) mutual orientation of tricyclic
systems. In fact, in these heteroaromatic systems there are a num-
ber of anisotropic fragments that can produce shielding/
a
After solvent evaporation, the residue was purified by a short gel plug using
CH2Cl2 as eluent and recrystallized from corresponding solvent.
b
Without template.
c
In the presence of Liþ as template.
d
In the presence of Naþ as template.
e
In the presence of Kþ as template.

9416
V.A. Mamedov et al. / Tetrahedron 65 (2009) 9412–9420
Mass spectra of these compounds displayed molecular ion peaks
at appropriate m/z values.
1405, 1338, 1248, 842, 748; 1H NMR (400.1 MHz, DMSO-d6):
d¼6.94
(2H, m, H8, H9), 7.28–7.42 (3H, m, H6, H7, H400), 7.45 (2H, dd, J 7.7,
7.4 Hz, H300/500), 7.67 (1H, dd, J 6.2, 5.3 Hz, H50), 7.98 (1H, d, J 7.5 Hz,
H60), 8.12 (1H, ddd, J 7.7, 7.7, 1.5 Hz, H50), 8.20 (2H, d, J 7.3 Hz, H200/
600), 8.76 (1H, d, J 4.7 Hz, H30), 11.48 (1H, s, NH). 13C NMR
3. Conclusions
In conclusion, we have shown that the reaction of 3-aroyl- and
alkanoylbenzoylquinoxalin-2-ones 1 with benzyl- and picolylamines
in DMSO at the temperature of 150 ꢀC provides a simple one-pot
procedure for the synthesis of imidazo[1,5-a]quinoxalin-4-one de-
rivatives 3b–i. Moreover, the combination of the above mentioned
reagents with their bis-analogues makes it possible to synthesize not
only bis-analogues 5a–g, 7b–e of imidazo[1,5-a]quinoxalin-4-
ones but also macrocyclic compounds with the diimidazoquin-
oxalinabenzene fragments 8a–c.
(150.9 MHz, DMSO-d6):
d
¼116.2, 117.6, 118.6, 120.8, 121.4, 124.9,
125.3, 126.8, 127.3, 127.8, 129.28, 129.33, 132.7, 137.5, 143.1, 143.3,
149.2, 150.2, 154.8. MS (EI, 70 eV): m/z (%)¼339 (Mþþ1, 34), 338
(Mþ, 84), 337 (100), 206 (22), 205 (60), 168 (42), 89 (11).
4.2.2. 3-Phenyl-1-(pyridin-3-yl)imidazo[1,5-a]quinoxalin-4(5H)-one
(3c). White powder, mp 339–341 ꢀC. Found: C, 74.63; H, 4.09; N,
16.48. C21H14N4O requires: C, 74.54; H, 4.17; N, 16.56%. IR (nmax
cmꢁ1, Nujol mull): 3220–2500 (br), 1662, 1612, 1595, 1566, 1331,
1302, 1273, 749, 722; 1H NMR (600.1 MHz, DMSO-d6):
ddd, J 8.4, 7.0, 1.5 Hz, H8), 7.04 (1H, d, J 8.4 Hz, H9), 7.31 (1H, dd, J 7.7,
7.6 Hz, H7), 7.34–7.41 (2H, m, H6, H400), 7.45 (2H, dd, J 7.7, 7.0 Hz,
H300/500), 7.66 (1H, dd, J 6.2, 4.8 Hz, H40), 8.16–8.22 (3H, m, H60, H200/
600), 8.83 (1H, dd, J 4.8, 1.5 Hz, H40), 8.93 (1H, d, J 1.8 Hz, H20). 13C
,
d¼6.94 (1H,
4. Experimental section
4.1. General
The melting points were determined on a Boetius hot-stage
apparatus and are uncorrected. Infrared (IR) spectra were recorded
on a Bruker Vector-22 spectrometer. NMR experiments were car-
ried out with Bruker spectrometers AVANCE-400 (400.1 MHz (1H),
100.6 MHz (13C)) and AVANCE-600 (600.1 MHz (1H), 150.9 MHz
NMR (150.9 MHz, DMSO-d6):
d
¼116.6 (C6), 116.7 (C9), 118.9 (C3a),
121.2 (C9a), 121.9 (C8), 123.7 (C50), 127.1 (C7), 127.6 (C300/500), 128.1
(C400), 128.2 (C10), 129.4 (C200/600), 129.7 (C5a), 132.7 (C100), 137.2
(C60), 141.6 (C1), 143.5 (C3), 149.7 (C20), 150.8 (C40), 155.1 (C4). 15N
NMR (60.8 MHz, CD3CN (external)):
d¼131.1 (N5), 172.4 (N10),
(
13C), 60.8 MHz (15N)) equipped with a pulsed gradient unit capable
312.7 (N30). MS (EI, 70 eV): m/z (%)¼339 (Mþþ1, 56), 338 (Mþ, 100),
of producing magnetic field pulse gradients in the z-direction of
337 (89), 236 (22), 235 (62), 205 (94), 179 (16).
53.5 G cmꢁ1. All spectra were acquired in a 5-mm gradient inverse
broad band probehead. Chemical shifts are reported on the
d
(ppm)
4.2.3. 3-Methyl-1-phenylimidazo[1,5-a]quinoxalin-4(5H)-one
scale and are relative to the residual 1H and 13C signal of DMSO-d6
and CDCl3. Chemical shifts of 3c were determined within the DFT
framework using a hybrid exchange-correlation functional, B3LYP,
at the 6-31G(d) level as implemented in Gaussian 98.52 Full ge-
ometry optimizations were performed at the ab initio RHF/6-31G
level. All data were referred to TMS (1H and 13C) chemical shifts that
were calculated in the same conditions. The MALDI mass spectra
were obtained on a Bruker UltraFlex III MALDI TOF/TOF instrument
with 2,5-dihydroxybenzoic acid (2,5-DHB) as a matrix. Mass spec-
tra electronic ionization (EI) was measured on a TRACE MS spec-
trometer. The elemental analyses were carried out at the
microanalysis laboratory of the Arbuzov Institute of Organic and
Physical Chemistry, Russian Academy of Sciences.
(3d). White powder, mp 290–292 ꢀC. Found: C, 74.25; H, 4.82; N,
15.15. C17H13N3O requires: C, 74.17; H, 4.76; N, 15.26%. IR (nmax
,
cmꢁ1, Nujol mull): 3220–2500 (br), 1673, 1618, 1573, 1504, 1409,
1332, 1253, 1122, 838, 697, 670, 584, 469; 1H NMR (400.1 MHz,
DMSO-d6):
d
¼2.63 (3H, c, Me), 6.87 (1H, ddd, J 8.5, 7.3, 1.6 Hz, H8),
7.01 (1H, d, J 8.5 Hz, H9), 7.26 (1H, ddd, J 8.1, 7.3, 1.2 Hz, H7), 7.29
(1H, dd, J 8.1, 1.6 Hz, H9), 7.58–7.67 (5H, m, Ph). 13C NMR
(150.9 MHz, DMSO-d6):
d
¼13.8, 116.2, 116.6, 118.4, 121.3, 121.4,
126.3, 128.6, 129.2, 129.68, 129.7, 131.9, 141.5, 143.1, 155.7. MS (EI,
70 eV): m/z (%)¼276 (Mþþ1, 26), 275 (Mþ, 100), 274 (28), 234 (26),
206 (6), 172 (36), 144 (42), 143 (39), 118.1 (22), 104 (8), 90 (14), 81
(32), 69 (40).
The 3-acylquinoxalin-2-ones were synthesized according to the
4.2.4. 3-Methyl-1-(pyridin-3-yl)imidazo[1,5-a]quinoxalin-4(5H)-one
(3e). White powder, mp >200 ꢀC (dec) (EtOH). Found: C, 69.48; H,
4.29; N, 20.32. C16H12N4O requires: C, 69.55; H, 4.38; N, 20.28%. IR
reported methods.27–30
4.2. General procedure for the synthesis of imidazo-
[1,5-a]quinoxalin-4(5H)-ones 3 and 1,3-bis(imidazo-
[1,5-a]quinoxalin-4-on-5-yl)alkanes 5
(
nmax, cmꢁ1, Nujol mull): 3200–2500 (br), 1671, 1618, 1573, 1507,
1492, 1412, 1331, 1253, 1193, 1124, 1024, 811, 764, 711; 1H NMR
(600.1 MHz, DMSO-d6):
d
¼2.64 (1H, s, CH3), 6.93 (1H, ddd, J 8.5, 7.2,
1.3 Hz, H8), 7.01 (1H, d, J 8.1 Hz, H9), 7.28 (1H, ddd, J 8.1, 7.2, 0.9 Hz,
H7), 7.32 (1H, dd, J 8.1, 1.3 Hz, H6), 7.63 (1H, dd, J 7.6, 5.0 Hz, H50),
8.11 (1H, ddd, J 7.7, 1.8, 1.8 Hz, H60), 8.81 (1H, dd, J 5.0, 1.8 Hz, H40),
8.85 (1H, d, J 1.4 Hz, H20), 11.31 (1H, s, NH). 13C NMR (150.9 MHz,
A
solution of benzylamine or appropriate picolylamine
(3.9 mmol) in DMSO (1 mL) was added to a solution of 3-acylqui-
noxalin-2-one 1a,b (2.0–3.3 mmol), 1c–e (2.8 mmol), 4a–e
(1.3 mmol) in DMSO (5 mL). The reaction mixture was stirred for
4–8 h at w150 ꢀC (Tables 1 and 2). When synthesizing 3b,c,f and 5b
the reaction mixture was left overnight at room temperature, while
the crystals of the product were precipitated, collected by suction
filtration, washed with EtOH (2ꢂ5 mL) and dried in air. When
synthesizing 3d,e,g,h,i and 5a,c–g after cooling to room tempera-
ture and standing overnight, the reaction mixture was poured into
water (20 mL). After collection by suction filtration the crude
product was washed with water (2ꢂ5 mL), dried in air and purified
by recrystallization from the appropriate solvent (Tables 1 and 2).
DMSO-d6):
d
¼13.8,116.1,116.8,119.0,121.3,121.6,123.4,126.5,128.1,
129.7, 136.8, 140.3, 141.8, 149.5, 150.5, 155.5. MS (MALDI TOF)¼277
(MþHþ), 299 (MþNaþ).
4.2.5. 5-Methyl-3-phenyl-1-(pyridin-3-yl)imidazo[1,5-a]quinoxalin-
4-one (3f). White powder, mp 234–236 ꢀC (DMSO). Found: C,
74.88; H, 4.49; N, 15.82. C22H16N4O requires: C, 74.98; H, 4.58; N,
15.90%. IR (nmax, cmꢁ1, Nujol mull): 1660, 1610, 1591, 1567, 1542,
1483, 1420, 1391, 1362, 1334, 1301, 1281, 1252, 1187, 1101, 970, 819,
754, 722, 695, 671; 1H NMR (600.1 MHz, CDCl3):
d
¼3.67 (3H, s, CH3),
6.97 (1H, ddd, J 8.1, 6.8, 1.4 Hz, H8), 7.29 (1H, d, J 8.5 Hz, H9), 7.33–
7.42 (3H, m, H6, H7, H400), 7.47 (2H, dd, J 7.7, 7.6 Hz, H300/500), 7.52
(1H, dd, J 7.7, 4.9 Hz, H50), 8.07 (1H, d, J 8.1 Hz, H60), 8.13 (2H, d,
J 7.4 Hz, H200/600), 8.82 (1H, d, J 4.9 Hz, H40), 8.98 (1H, s, H20). 13C NMR
4.2.1. 3-Phenyl-1-(pyridin-2-yl)imidazo[1,5-a]quinoxalin-4(5H)-one
(3b). White powder, mp 349–351 ꢀC. Found: C, 74.65; H, 4.21; N,
16.42. C21H14N4O requires: C, 74.54; H, 4.17; N, 16.56%. IR (nmax
,
cmꢁ1, Nujol mull): 3220–2500, 1671, 1615, 1586, 1558, 1487, 1428,
(150.9 MHz, DMSO-d6):
d¼28.5, 116.3, 116.9, 118.3, 121.8, 122.0,

V.A. Mamedov et al. / Tetrahedron 65 (2009) 9412–9420
9417
123.5,127.1,127.3,127.8,127.9,129.4,130.8,132.6, 136.8, 141.2,143.8,
(8), 407 (8), 381 (28), 363 (44), 337 (100), 260 (10), 234 (18), 219
(24), 205 (32), 102 (38).
149.5, 150.6, 154.6. MS (MALDI TOF)¼353 (MþHþ), 375 (MþNaþ).
4.2.6. 1,3-Diphenyl-5-ethylimidazo[1,5-a]quinoxalin-4-one
(3g). White powder, mp 175–177 ꢀC (EtOH). Found: C, 78.97; H,
5.29; N, 11.41. C24H19N3O requires: C, 78.88; H, 5.24, N, 11.50%. IR
4.2.10. 1,6-Bis(1,3-diphenylimidazo[1,5-a]quinoxalin-4-on-1-yl)hex-
ane (5b). White powder, mp 271–273 ꢀC (DMCO). Found: C, 79.46;
H, 5.28; N, 11.21. C50H40N6O2 requires: C, 79.34; H, 5.33; N, 11.10%. IR
(
nmax, cmꢁ1, Nujol mull): 1655, 1610, 1588, 1540, 1487, 1325, 1394,
(
nmax, cmꢁ1, Nujol mull): 1655, 1611, 1503, 1485, 1447, 1395, 1335,
1300, 1267, 1248, 1181, 1109, 858, 780, 744; 1H NMR (600.1 MHz,
DMSO-d6):
1300, 1250, 1121, 1050, 781, 747, 704, 694; 1H NMR (600.1 MHz,
DMSO-d6):
d
¼1.27 (3H, t, J 7.1 Hz, CH3), 4.27 (2H, q, J 7.1 Hz, CH2),
d
¼1.45–1.55 (4H, m, (CH2)2(CH2)2(CH2)2), 1.65–1.75 (4H,
6.97 (1H, dd, J 8.8, 7.8 Hz, H8), 7.18 (1H, d, J 8.8 Hz, H9), 7.36–7.41
(2H, m, H7, H400), 7.44 (2H, dd, J 8.1, 7.6 Hz, H300/500), 7.56–7.66 (4H,
m, H6, H30/50, H40), 7.71 (2H, d, J 8.0 Hz, H20/60), 8.14 (2H, d, J 7.6 Hz,
m, (CH2CH2(CH2)2CH2CH2)), 4.24 (4H, t, J 7.5 Hz, NCH2), 6.97 (2H, dd, J
8.3, 8.1 Hz, H8), 7.19 (2H, dd, J 8.4, 1.3 Hz, H9), 7.43–7.47 (4H, m, H7,
H400), 7.44 (4H, dd, J 7.6, 7.3 Hz, H300/500), 7.57 (2H, d, J 8.1 Hz, H6),
7.60–7.68 (6H, m, H30/50, H40), 7.72 (2H, dd, J 7.6, 1.6 Hz, H20/60), 8.14
(4H, dd, J 7.7, 1.3 Hz, H200/600). 13C NMR (150.9 MHz, DMSO-d6):
H200/600). 13C NMR (150.9 MHz, DMSO-d6):
d¼12.3 (CH3), 36.1 (CH2),
116.1 (C6), 117.4 (C9), 117.7 (C3a), 121.8 (C8), 122.2 (C9a), 127.1 (C7),
127.4 (C300/500), 127.9 (C400), 128.9 (C30/50), 129.4 (C20/60), 129.6 (C5a),
129.5 (C200/600), 130.1 (C40), 131.8 (C10), 132.9 (C100), 143.4 (C3), 144.0
(C1), 154.3 (C4). MS (MALDI TOF)¼366 (MþHþ), 388 (MþNaþ), 404
(MþKþ).
d
¼25.8, 26.5, 40.8, 116.1, 117.3, 117.6, 121.7, 122.1, 127.0, 127.4, 127.8,
128.8, 129.3, 129.5, 129.7, 130.0, 131.8, 132.9, 143.5, 144.0, 154.5. MS
(EI, 70 eV): m/z (%)¼757 (Mþþ1, 7), 756 (Mþ, 11), 420 (32), 406 (44),
378 (50), 364 (57), 337 (70), 322 (16), 205 (16).
4.2.7. 5-Ethyl-3-phenyl-1-(pyridin-3-yl)imidazo[1,5-a]quinoxalin-
4(5H)-one (3h). White powder, mp 208–210 ꢀC. Found: C, 75.28; H,
5.03; N, 15.32. C23H18N4O requires: C, 75.39; H, 4.95; N, 15.29%. IR
4.2.11. 1,6-Bis{3-phenyl-1-(pyridin-3-yl)imidazo[1,5-a]quinoxalin-4-
on-1-yl}hexane (5c). White powder, mp 278–280 ꢀC (DMCO).
Found: C, 75.86; H, 5.08; N, 14.71. C48H38N8O2 requires: C, 75.97; H,
5.05; N, 14.77%. IR (nmax, cmꢁ1, Nujol mull): 1649, 1592, 1501, 1485,
1411, 1396, 1301, 1254, 1112, 1053, 1025, 752, 698, 421; 1H NMR
(
nmax, cmꢁ1, Nujol mull): 1651, 1594, 1500, 1484, 1396, 1325, 1300,
1252, 1181, 1111, 754, 695; 1H NMR (600.1 MHz, DMSO-d6):
d
¼1.28
(3H, t, J 7.2 Hz, CH3), 4.28 (2H, q, J 7.2 Hz, CH2), 7.04 (1H, ddd, J 8.5,
7.8, 1.1 Hz, H8), 7.19 (1H, dd, J 8.5, 1.2 Hz, H9), 7.37–7.47 (4H, m, H7,
H300/500, H400), 7.62 (1H, d, J 8.5 Hz, H6), 7.65 (1H, ddd, J 7.7, 4.8,
0.7 Hz, H50), 8.14 (2H, d, J 7.2 Hz, H200/600), 8.18 (1H, ddd, J 7.9, 1.8,
1.8 Hz, H60), 8.82 (1H, dd, J 4.9, 1.5 Hz, H40), 8.93 (1H, d, J 1.5 Hz,
(400.1 MHz, DMSO-d6):
d
¼3.30 (CH2), 4.24 (4H, m, CH2N), 7.01 (2H,
ddd, J 8.4, 7.7, 1.1 Hz, H8), 7.17 (2H, dd, J 8.4, 1.1 Hz, H9), 7.35–7.47
(8H, m, H7, H300/500, H400), 7.58 (2H, d, J 8.4 Hz, H6), 7.64 (2H, ddd, J
7.7, 4.8, 0.8 Hz, H50), 8.12 (4H, ddd, J 7.0, 2.4, 1.5 Hz, H200/600), 8.17
(2H, ddd, J 7.9, 2.3, 2.0 Hz, H60), 8.82 (2H, dd, J 4.9, 1.5 Hz, H40), 8.92
H20). 13C NMR (150.9 MHz, DMSO-d6):
d
¼12.3 (CH3), 36.1 (CH2),
(2H, d, J 2.3 Hz, H20). 13C NMR (150.9 MHz, DMSO-d6):
d¼25.8, 26.5,
116.3 (C6), 117.4 (C9), 118.2 (C3a), 122.0 (C8, C9a), 123.7 (C50), 127.3
(C7), 127.5 (C300/500), 128.1 (C400), 128.1 (C10), 129.5 (C5a, C200/600),
132.7 (C100),137.1 (C60),141.2 (C1),143.7 (C3),149.7 (C20),150.8 (C40),
154.2 (C4). 15N NMR (60.8 MHz, CD3CN-d3 (external)): dþ¼137.5
(N5), 170.5 (N10), 312.7 (N30). MS (MALDI TOF)¼367 (MþH ), 389
(MþNaþ), 405 (MþKþ).
40.9, 116.3, 117.3, 118.1, 121.9, 122.0, 123.6, 127.3, 127.4, 128.0, 128.1,
129.5, 129.7, 132.7, 137.0, 141.2, 143.8, 149.6, 150.7, 154.4. MS (EI,
70 eV): m/z (%)¼758 (Mþ, 6), 421 (20), 420 (34), 407 (40), 365 (46),
352 (46), 338 (100), 337 (36), 223 (24), 219 (20), 205 (30), 18 (58).
4.2.12. 1,8-Bis(1,3-diphenylimidazo[1,5-a]quinoxalin-4-on-1-yl)-3,5-
dioxaoctane (5d). White powder, mp 216–218 ꢀC (DMCO). Found:
C, 76.27; H, 5.23; N, 10.56. C50H40N6O4 requires: C, 76.12; H, 5.11;
N, 10.65%. IR (nmax, cmꢁ1, Nujol mull): 1645, 1609, 1591, 1504, 1485,
1445, 1393, 1352, 1326, 1300, 1257, 1246, 1178, 1124, 1101, 1033,
4.2.8. 1,3-Diphenyl-5-propylimidazo[1,5-a]quinoxalin-4-one
(3i). White powder, mp 198–200 ꢀC (EtOH). Found: C, 75.69; H,
5.21; N, 14.62. C24H20N4O requires: C, 75.77; H, 5.30; N, 14.73%. IR
(
nmax, cmꢁ1, Nujol mull): 1647, 1607, 1589, 1546, 1484, 1334, 1324,
1005, 777, 744, 695, 670; 1H NMR (600.1 MHz, DMSO-d6):
d
¼3.57
1297, 1247, 1182, 1116, 786, 746, 708, 693; 1H NMR (400.1 MHz,
CDCl3):
(4H, s, CH2-3), 3.71 (4H, dd, J 7.3, 6.2 Hz, CH2-2), 4.32 (4H, dd, J 7.9,
6.2 Hz, CH2-1(CH2N)), 6.88 (2H, dd, J 8.3, 7.7 Hz, H8), 7.11 (2H, d, J
8.3 Hz, H9), 7.26 (2H, dd, J 8.3, 7.7 Hz, H7), 7.35 (2H, dd, J 7.7,
7.4 Hz, H400), 7.40 (4H, dd, J 8.3, 7.4 Hz, H300/500), 7.54–7.6 (6H, m,
H6, H30/50), 7.61–7.67 (6H, m, H20/60, H40), 8.10 (4H, d, J 7.7 Hz, H200/
d¼1.07 (3H, t, J 7.4 Hz, CH3), 1.83 (2H, m, CH2), 4.20 (2H, dd, J
9.7, 8.0 Hz, CH2N), 6.89 (1H, m, H8), 7.27–7.40 (4H, m, H6, H7, H9,
H400), 7.46 (2H, dd, J 7.6, 7.1 Hz, H300/500), 7.51–7.60 (3H, m, H30/50,
H40), 7.70 (2H, m, H20/60), 8.16 (2H, d, J 7.0 Hz, H200/600). 13C NMR
(150.9 MHz, DMSO-d6):
d
¼10.7, 19.9, 42.3, 116.0, 117.2, 117.5, 121.6,
600). 13C NMR (150.9 MHz, DMSO-d6):
d
¼40.9 (CH2-1(CH2N)), 67.4
122.0, 126.9, 127.2, 127.7, 128.7, 129.2, 129.4, 129.7, 129.9, 131.7,
132.8, 143.4, 143.8, 154.5. MS (MALDI TOF)¼380 (MþHþ), 402
(MþNaþ).
(CH2-2), 70.0 (CH2-3), 116.7 (C6), 117.1 (C9), 117.6 (C3a), 121.8 (C8),
122.0 (C9a), 126.8 (C7), 127.4 (C300/500), 128.0 (C400), 128.9 (C30/50),
129.3 (C20/60), 129.5 (C200/600), 130.1 (C5a, C40), 131.7 (C10), 132.8
(C100), 143.6 (C3), 144.0 (C1), 154.7 (C4). MS (EI, 70 eV): m/z
(%)¼788 (Mþ, 5), 452 (5), 425 (7), 394 (7), 364 (37), 337 (100), 322
(5), 234 (11), 219 (25), 205 (15).
4.2.9. 1,5-Bis(1,3-diphenylimidazo[1,5-a]quinoxalin-4-on-1-yl)-3-oxa-
pentane (5a). White powder, mp 174–176 ꢀC (DMCO). Found: C,
77.32; H, 4.95; N, 11.36. C48H36N6O3 requires: C, 77.40; H, 4.87; N,
11.28%. IR (nmax, cmꢁ1, Nujol mull): 1655, 1610, 1503, 1485, 1447,
1337, 1324, 1300, 1255, 1180, 1108, 1053, 781, 750, 694; 1H NMR
4.2.13. 1,11-Bis(1,3-diphenylimidazo[1,5-a]quinoxalin-4-on-1-yl)-
3,5,8-trioxaundecane (5e). White powder, mp 168–170 ꢀC (CH3CN).
Found: C, 74.89; H, 5.36, N, 10.00. C52H44N6O5 requires: C, 74.98; H,
5.32, N, 10.09%. IR (nmax, cmꢁ1, Nujol mull): 1655, 1609, 1552, 1502,
1485, 1444, 1395, 1363, 1331, 1289, 1251, 1178, 1102, 991, 750, 727,
(600.1 MHz, DMSO-d6):
d
¼3.85 (4H, t, J 5.5 Hz, OCH2), 4.39 (4H, t,
J 5.5 Hz, NCH2), 6.87 (2H, dd, J 8.1, 7.6 Hz, H8), 7.10 (2H, d, J 8.3 Hz,
H9), 7.15 (2H, dd, J 7.9, 7.3 Hz, H7), 7.37 (2H, dd, J 7.3, 6.5 Hz, H400),
7.41 (4H, dd, J 7.3, 7.1 Hz, H300/500), 7.57 (2H, d, J 8.9 Hz, H6), 7.60
(4H, d, J 7.1 Hz, H20/60), 7.64 (2H, dd, J 7.6, 6.8 Hz, H40), 7.65 (4H, d,
689, 669; 1H NMR (400.1 MHz, CDCl3):
d
¼3.53–3.59 (4H, m, OCH2),
3.59–3.63 (4H, m, OCH2), 3.85 (4H, t, J 6.0 Hz, OCH2), 4.42 (4H, t, J
6.0 Hz, NCH2), 6.86 (2H, ddd, J 8.2, 7.3, 1.0 Hz, H8), 7.22–7.30 (4H, m,
Ar), 7.34–7.40 (2H, m, Ar), 7.44 (4H, dd, J 7.6, 7.3 Hz, H300/500), 7.50–
7.59 (8H, m, Ar), 7.66–7.72 (4H, m, H20/60), 8.14 (4H, dd, J 7.6, 1.3 Hz,
J
7.6 Hz, H30/50), 8.12 (4H, d,
(150.9 MHz, DMSO-d6):
J
7.6 Hz, H200/600). 13C NMR
d
¼41.0, 67.5, 116.5, 117.0, 117.5, 121.7,
121.9, 126.6, 127.3, 127.8, 128.8, 129.2, 129.4, 129.9, 130.0, 131.8,
132.8, 143.6, 143.9, 154.8. MS (EI, 70 eV): m/z (%)¼746 (Mþþ2, 2),
745 (Mþþ1, 6), 744 (Mþ, 11), 746 (2), 745 (6), 744 [M]þ (11), 757
H200/600). 13C NMR (150.9 MHz, DMSO-d6):
d
¼67.3, 69.7, 69.8, 116.6,
117.1, 117.6, 121.8, 122.0, 126.7, 127.3, 127.9, 128.8, 129.2, 129.4, 130.0,

9418
V.A. Mamedov et al. / Tetrahedron 65 (2009) 9412–9420
130.1, 131.7, 132.8, 143.6, 143.9, 154.7. MS (MALDI TOF)¼833
(MþHþ), 855 (MþNaþ), 871 (MþKþ).
7.1 Hz, CH3), 4.25 (4H, q, J 7.1 Hz, CH2), 7.05 (2H, dd, J 8.6, 7.7 Hz, H8),
7.35–7.45 (10H, m, H7, H9, H300/500, H400), 7.58 (2H, d, J 8.5 Hz, H6),
7.85 (1H, dd, J 8.7, 7.7 Hz, H50), 8.00 (2H, dd, J 7.7, 1.2 Hz, H40/H60),
8.08 (1H, s, H20), 8.15 (4H, d, J 7.4 Hz, H200/600). 13C NMR (150.9 MHz,
4.2.14. 1,11-Bis(1-pyrydinyl-3-phenylimidazo[1,5-a]quinoxalin-4-on-
1-yl)-3,5,8-trioxaundecane (5f). White powder, mp 202–204 ꢀC
(CH3CN). Found: C, 71.87; H, 5.03, N, 13.36. C50H42N8O5 requires: C,
71.93; H, 5.07, N, 13.42%. IR (nmax, cmꢁ1, Nujol mull): 1649, 1611,
1595, 1539, 1483, 1445, 1395, 1335, 1299, 1254, 1120, 1054, 1024,
DMSO-d6):
d
¼12.3 (CH3), 36.1 (CH2), 116.2 (C6), 117.5 (C9), 117.9
(C3a), 122.0 (C8), 122.1 (C9a), 127.3 (C7), 127.5 (C300/500), 128.0 (C400),
129.5 (C200/600), 129.6 (C5a), 129.8 (C50), 130.5 (C20), 131.0 (C40), 132.6
(C10), 132.8 (C100), 143.0 (C1), 143.5 (C3), 154.3 (C4). MS (EI, 70 eV):
m/z (%)¼653 (Mþþ1, 28), 652 (Mþ, 76), 549 (18), 326 (59), 312 (40),
273 (18), 261 (30), 233 (76), 205 (100), 157 (18),105 (20), 89 (44), 44
(58), 18 (86).
750, 716, 693, 669; 1H NMR (600.1 MHz, DMSO-d6):
d
¼3.45 (4H, m,
CH2-4), 3.51 (4H, m, CH2-3), 3.72 (4H, dd, J 6.7, 6.0 Hz, CH2-2), 4.36
(4H, dd, J 6.7, 6.0 Hz, CH2-1(CH2N)), 6.98 (2H, dd, J 8.5, 7.5 Hz, H8),
7.14 (2H, d, J 8.5 Hz, H9), 7.33–7.38 (4H, m, H7, H400), 7.41 (4H, dd, J
7.7, 7.5 Hz, H300/500), 7.62 (4H, m, H6, H50), 8.10 (4H, d, J 7.7 Hz, H200/
600), 8.13 (2H, ddd, J 7.9, 1.9, 1.7 Hz, H60), 8.81 (2H, dd, J 5.0, 1.4 Hz,
H40), 8.89 (2H, d, J 1.4 Hz, H20). 13C NMR (150.9 MHz, DMSO-d6):
4.3.3. 1,3-Bis(5-propyl-3-phenylimidazo[1,5-a]quinoxali–4-on-1-yl)-
benzene (7c). White powder, mp 146–148 ꢀC. Rf¼0.79 (EtAc/
hexane¼3:7). Found: C, 77.48; H, 5.27; N, 12.46. C44H36N6O2 re-
quires: C, 77.63; H, 5.33, N,12.34%. IR (nmax, cmꢁ1, Nujol mull): 1662,
1611, 1591, 1485, 1298, 1252, 1228, 1181, 1144, 1114, 1075, 783, 750,
d
¼40.9 (CH2-1(CH2N)), 67.3 (CH2-2), 69.7 (CH2-4), 69.9 (CH2-3),
116.9 (C6), 117.1 (C9), 118.1 (C3a), 121.8 (C9a), 122.1 (C8), 123.7 (C50),
127.1 (C7), 127.5 (C300/500), 128.1 (C10, C400), 129.5 (C200/600), 130.1
(C5a), 132.6 (C100), 137.0 (C60), 141.3 (C1), 144.0 (C3), 149.6 (C20),
150.8 (C40), 154.7 (C4). 15N NMR (60.8 MHz, CD3CN (external)):
694; 1H NMR (600.1 MHz, DMSO-d6):
d
¼0.98 (6H, t, J 7.4 Hz, Me),
1.65–1.72 (4H, m, CH2CH3), 4.18 (4H, t, J 7.4 Hz, NCH2), 7.09 (2H, dd, J
8.2, 7.6 Hz, H8), 7.30–7.50 (10H, m, H7,9, H300/500, H400), 7.59 (2H, d, J
8.7 Hz, H6), 7.88 (1H, dd, J 7.6, 7.6 Hz, H50), 8.02 (2H, d, J 7.6 Hz,
H40,60), 8.11 (1H, s, H20), 8.14 (4H, d, J 7.6 Hz, H200/600). 13C NMR
d
¼131.1 (N5), 170.6 (N10), 312.5 (N30). MS (MALDI TOF)¼835
(MþHþ).
(150.9 MHz, DMSO-d6):
d
¼10.1, 19.9, 42.2, 116.1, 117.3, 117.8, 121.7,
4.3. General procedure for the synthesis of 1,3-
bis(imidazo[1,5-a]quinoxalin-4-on-1-yl)-
benzenes 7 and cyclophanes 8
121.9, 126.9, 127.2, 127.8, 129.4, 129.6, 129.7, 130.4, 130.8, 132.6,
132.7, 142.8, 143.5, 154.4. MS (EI, 70 eV): m/z (%)¼682 (Mþ2, 2), 681
(Mþþ1, 10), 680 (Mþ, 24), 638 (6), 596 (8), 375 (10), 304 (16), 298
(36), 246 (25), 233 (29), 219 (49), 205 (100), 190 (18).
A solution of m-xylylenediamine (70 mg, 0.51 mmol) in DMSO
(1 mL) was added to the solution of 3-acylquinoxalin-2(1H)-one 1
4.3.4. 1,3-Bis(5-benzyl-3-phenylimidazo[1,5-a]quinoxalin-4-on-1-
yl)benzene (7d). White powder, mp 143–145 ꢀC. Rf¼0.82 (EtAc/
hexane¼3:7). Found: C, 80.47; H, 4.71; N, 10.75. C52H36N6O2 re-
quires: C, 80.39; H, 4.67; N, 10.82%. IR (nmax, cmꢁ1, Nujol mull):
1656, 1612, 1592, 1495, 1485, 1401, 1300, 1257, 1128, 1076, 1028, 960,
(0.72 mmol) or
a,u-bis(1,3-diphenylimidazo[1,5-a]quinoxalin-4-
on-5-yl)alkane 4 (0.34 mmol) in DMSO (5 mL). The reaction mix-
ture was stirred for 24 h at w150 ꢀC. The solvents were removed in
vacuum and after allowing the reaction mixture to cool to room
temperature water (5 mL) was added and the crystals of the
product were precipitated, collected by suction filtration, washed
with water (2ꢂ5 mL) and dried in air. The solution of semicarbazide
hydrochloride (33 mg, 0.3 mmol) in AcOH (5 mL) was added to
a solution of this crude product in AcOH (5 mL), and the reaction
mixture was stirred for 2 h at w120 ꢀC. The solvent was removed in
vacuum, and the crystals of the product were precipitated by ad-
dition of water (3 mL), collected by suction filtration, washed with
water (2ꢂ5 mL) and dried in air. After the usual column chro-
matographic purification process (CH2Cl2/CH2Cl2/EtOH¼100:1)
pure 7 and 8 were obtained as white solids (Tables 3 and 4).
782, 670, 458; 1H NMR (600.1 MHz, DMSO-d6):
d
¼5.40 (4H, s, CH2),
7.09 (2H, dd, J 8.2, 7.6 Hz, H8), 7.20–7.50 (22H, m, H 6, 7, 9, H300/500,
H400, CH2Ph), 7.88 (1H, dd, J 7.9, 7.4 Hz, H50), 8.05 (2H, d, J 7.4 Hz, H40/
60), 8.15 (1H, s, H20), 8.16 (4H, d, J 7.4 Hz, H200/600). 13C NMR
(150.9 MHz, DMSO-d6):
d
¼44.1, 116.7, 117.3, 117.7, 122.1, 122.2, 126.4,
126.8, 126.9, 127.4, 127.9, 128.4, 129.5, 129.8, 129.9, 130.5, 131.0,
132.6, 132.7, 136.2, 143.0, 144.0, 154.9. MS (EI, 70 eV): m/z (%)¼776
(Mþ, 2), 685 (6), 233 (3), 205 (7).
4.3.5. 14,34,-Dioxa-13,33-diphenyl-1,3(1,5)-diimidazo[1,5-a]quinox-
alina-2(1,3)benzene-6,9-dioxacycloundecane (8a(I)). White powder,
mp >360 ꢀC. IR (nmax, cmꢁ1, KBr): 3053, 2956, 2924, 2856, 1658,
1609, 1484, 1443, 1395, 1353, 1297, 1253, 1126, 1090, 1049, 992, 744,
4.3.1. 1,3-Bis(5-methyl-3-phenylimidazo[1,5-a]quinoxalin-4-on-1-
yl)benzene (7a). White powder, mp 321–323 ꢀC. Rf¼0.36 (EtAc/
hexane¼3:7). Found: C, 76.85; H, 4.61; N, 13.32. C40H28N6O2 re-
quires: C, 76.91; H, 4.52; N,13.45%. IR (nmax, cmꢁ1, Nujol mull): 1656,
1591, 1502, 1396, 1348, 1333, 1303, 1259, 1104, 750, 695; 1H NMR
711, 693; 1H NMR (600.1 MHz, DMSO-d6):
d
¼2.78 and 3.06 (4H, m,
CH2-3), 3.32 and 3.71 (4H, m, CH2-2), 4.11 and 4.71 (4H, m, CH2-
1(CH2N)), 6.89 (2H, dd, J 8.6, 7.7 Hz, H8), 7.01 (2H, d, J 8.6 Hz, H9),
7.05 (1H, s, H20), 7.20 (2H, ddd, J 8.6, 7.8, 1.1 Hz, H7), 7.42 (2H, dd, J
8.3, 7.3 Hz, H400), 7.46 (4H, dd, J 8.0, 7.3 Hz, H300/500), 7.61 (2H, d, J
8.5 Hz, H6), 8.04 (1H, dd, J 8.5, 7.7 Hz, H50), 8.17 (4H, d, J 8.0 Hz, H200/
600), 8.23 (2H, dd, J 7.7, 1.5 Hz, H40). 13C NMR (150.9 MHz, DMSO-d6):
(600.1 MHz, DMSO-d6):
d
¼3.60 (6H, s, Me), 7.11 (2H, dd, J 8.2,
7.6 Hz, H8), 7.35–7.50 (10H, m, H7,9, H300/500, H400), 7.58 (2H, d, J
7.8 Hz, H6), 7.89 (1H, dd, J 7.8, 7.6 Hz, H50), 8.03 (2H, d, J 7.7 Hz, H40/
60), 8.12 (1H, s, H20), 8.16 (4H, d, J 7.1 Hz, H200/600). 13C NMR
d
¼40.1 (CH2-1(CH2N)), 68.6 (CH2-2), 69.1 (CH2-3), 117.7 (C6), 118.7
(150.9 MHz, DMSO-d6):
d
¼28.5, 116.2, 117.1, 117.9, 121.88, 121.9,
(C9), 118.9 (C3a), 121.2 (C9a), 121.9 (C8), 126.9 (C7), 127.6 (C300/500),
128.5 (C400), 129.5 (C20, C200/600), 129.9 (C40), 130.4 (C5a), 130.6 (C10),
131.4 (C50), 132.1 (C100), 143.3 (C1), 144.8 (C3), 154.9 (C4). MS (EI,
70 eV): m/z (%) 711 (Mþþ1, 42), 710 (Mþ, 81), 597 (18), 596 (38), 233
(26), 219 (100), 218 (56), 190 (32), 165 (30), 91 (48), 69 (52), 43 (94).
126.9, 127.3, 127.8, 129.3, 129.6, 130.3, 130.81, 130.82, 132.5, 132.7,
142.9, 143.5, 154.6. MS (EI, 70 eV): m/z (%)¼625 (Mþþ1, 40), 624
(Mþ, 86), 521 (30), 381 (32), 337 (62), 312 (12), 273 (18), 233 (30),
218 (100), 205 (34), 150 (24), 106 (32), 97 (42), 94 (50), 54 (56).
4.3.2. 1,3-Bis(5-ethyl-3-phenylimidazo[1,5-a]quinoxalin-4-on-1-yl)-
benzene (7b). White powder, mp 322–324 ꢀC. Rf¼0.63 (EtAc/
hexane¼3:7). Found: C, 77.35; H, 4.81; N, 12.75. C42H32N6O2 re-
quires: C, 77.28; H, 4.94; N,12.87%. IR (nmax, cmꢁ1, Nujol mull): 1653,
1609, 1588, 1500, 1446, 1400, 1301, 1253, 1184, 1111, 926, 859, 823,
4.3.6. 14,34,-Dioxa-13,33-diphenyl-1,3(1,5)-diimidazo[1,5-a]quinox-
alina-2(1,3)benzene-6,9-dioxacycloundecane (8a(II)). White powder.
IR (nmax, cmꢁ1, KBr): 2922, 2854, 1662, 1608, 1481, 1446, 1412, 1387,
1359, 1334, 1299, 1255, 1118, 1049, 997, 747, 694; 1H NMR
(600.1 MHz, DMSO-d6):
d¼2.56 and 2.97 (4H, m, CH2-3), 3.44 and
728, 715, 695; 1H NMR (600.1 MHz, DMSO-d6):
d¼1.25 (6H, t, J
3.62 (4H, m, CH2-2), 4.05 and 4.77 (4H, m, CH2-1(CH2N)), 6.97 (2H,

V.A. Mamedov et al. / Tetrahedron 65 (2009) 9412–9420
9419
dd, J 8.8, 7.7 Hz, H8), 7.11 (1H, s, H20), 7.21–7.26 (4H, m, H7, H9), 7.36
References and notes
(2H, dd, J 8.0, 7.1 Hz, H400), 7.40 (4H, dd, J 8.0, 7.5 Hz, H300/500), 7.57 (2H,
d, J 8.2 Hz, H6), 8.02–8.07 (5H, m, H50, H200/600), 8.22 (2H, d, J 7.6 Hz,
1. Negwer, M.; Scharnow, H. G. Organic Chemical Drugs and their Synonyms; Wiley-
VCH: Weinheim, Germany, 2001; Vol. 2, p 3.
2. Ager, I. A.; Barnes, A. C.; Danswan, G. W.; Hairsine, P. W.; Kay, D. P.; Kennewell,
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3. Danswan, G. W.; Hairsine, P. W.; Rowlands, D. A.; Taylor, J. B.; Westwood, R.
J. Chem. Soc., Perkin Trans. 1 1982, 1049–1058.
4. Kurasawa, Yo.; Ichikawa, M.; Takada, A. Heterocycles 1983, 20, 269–271.
5. Kollenz, G. Liebigs Ann. Chem. 1972, 762, 23–28.
H40, H60). 13C NMR (150.9 MHz, DMSO-d6):
d¼40.3 (CH2-1(CH2N)),
68.4 (CH2-2), 70.2 (CH2-3), 117.9 (C6), 118.3 (C9), 118.8 (C3a), 121.8
(C9a), 123.6 (C8), 125.8 (C7), 127.6 (C300/500), 128.3 (C400), 129.3 (C200/
600), 129.4 (C40), 129.7 (C5a), 131.2 (C50), 131.4 (C20), 132.1 (C10)þ, 132.3
(C100),143.4 (C1),144.6 (C3),155.2 (C4). MS (MALDI TOF) [MH] ¼712.
6. Mamedov, V. A.; Kalinin, A. A.; Rizvanov, I. Kh.; Azancheev, N. M.; Efremov, Yu. Ya.;
Levin, Ya. A. Chem. Heterocycl. Compd. 2002, 38, 1121–1129.
7. Benkovic, S. J.; Barrows, T. H.; Farina, P. R. J. Am. Chem. Soc. 1973, 95, 8414–
8420.
8. Varano, F.; Catarzi, D.; Colotta, V.; Cecchi, L.; Filacchioni, G.; Galli, A.; Costagli, C.
Eur. J. Med. Chem. 2001, 36, 203–209.
9. Benkovic, S. J.; Benkovic, P. A.; Comfort, D. R. J. Am. Chem. Soc. 1969, 91, 5270–
5279.
10. Mamedov, V. A.; Kalinin, A. A.; Azancheev, N. M.; Levin, Ya. A. Russ. J. Org. Chem.
2003, 39, 125–130.
11. Nispen, S. P. J. M.; Mensink, C.; Leusen, A. M. Tetrahedron Lett. 1980, 21, 3723–
3726.
12. Chen, P.; Barrish, J. C.; Iwanowicz, E.; Lin, J.; Bednarz, M. S.; Chen, B. C. Tetra-
hedron Lett. 2001, 42, 4293–4295.
13. Jacobsen, E. J.; Stelzer, L. S.; Belonga, K. L.; Carter, D. B.; Im, W. B.; Sethy, V. H.;
Tang, A. H.; VonVoigtlander, P. F.; Petke, J. D. J. Med. Chem. 1996, 39, 3820–3836.
14. Jacobsen, E. J.; TenBrink, R. E.; Stelzer, L. S.; Belonga, K. L.; Carter, D. B.; Im, H. K.;
Im, W. B.; Sethy, V. H.; Tang, A. H.; VonVoigtlander, P. F.; Petke, J. D. J. Med. Chem.
1996, 39, 158–175.
15. Jacobsen, E. J.; Stelzer, L. S.; TenBrink, R. E.; Belonga, K. L.; Carter, D. B.; Im, H. K.;
Im, W. B.; Sethy, V. H.; Tang, A. H.; VonVoigtlander, P. F.; Petke, J. D.; Zhong, W. Z.;
Mickelson, J. W. J. Med. Chem. 1999, 42, 1123–1144.
16. TenBrink, R. E.; Im, W. B.; Sethy, V. H.; Tang, A. H.; Carter, D. B. J. Med. Chem.
1994, 37, 758–768.
17. Mickelson, J. W.; Jacobsen, E. J.; Carter, D. B.; Im, H. K.; Im, W. B.; Schreur, P. J. K.
D.; Sethy, V. H.; Tang, A. H.; McGee, J. E.; Petke, J. D. J. Med. Chem. 1996, 39,
4654–4666.
18. Watjen, F.; Hansen, H. C. Eur. Pat. Appl. EP. 368,652, 1990; Chem. Abstr. 1990, 113,
172052.
19. Watjen, F.; Engelstoft M. S. African ZA. 87 01,534, 1987; Chem. Abstr. 1988, 109,
110456.
4.3.7. 14,34,-Dioxa-13,33-diphenyl-1,3(1,5)-diimidazo[1,5-a]quinox-
a l i n a - 2 ( 1, 3 ) b e n z e n e - 6 , 9 ,12 - t r i o x a c y c l o t e t r a d e c a n e
(8b(I)þ8b(II)). White powder, mp 322–324 ꢀC (MeOH). IR (nmax
,
cmꢁ1, KBr): 2917, 2859, 1660, 1610, 1484, 1444, 1391, 1359, 1334,
1299, 1258, 1110, 1094, 1053, 996, 753, 702; 1H NMR (600.1 MHz,
DMSO-d6):
m, CH2-3, CH2-3
and 4.77–4.86 (12H, m, CH2-1, CH2-1
H8), 6.94 (2H, dd, J 8.7, 7.8 Hz, H8 ), 7.15 (2H, d, J 8.3 Hz, H9
7.31 (6H, m, H7, H7 ), 7.42 (10H,
), 7.33–7.39 (10H, m, H9, H400, H20
m, H300/500, H400), 7.47 (4H, dd, J 8.4, 7.6 Hz, H300/500 ), 7.52 (2H, s, H20),
7.62 (2H, d, J 8.9 Hz, H6 ), 7.66 (4H, d, J 8.8 Hz, H6), 8.04 (3H, dd, J
8.4, 7.8 Hz, H50, H50 ), 8.07 (8H, d, J 7.8 Hz, H200/600), 8.16 (4H, d, J
7.6 Hz, H200/600 ), 8.19–8.23 (6H, m, H40, H40 ). 13C NMR (150.9 MHz,
DMSO-d6): ), 67.6 (CH2-2 ), 68.4 (CH2-
¼40.0 (CH2-1), 40.2 (CH2-1
2), 69.5 (CH2-4), 69.6 (CH2-4 ), 70.0 (CH2-3 ), 70.1 (CH2-3), 117.4
(C6 ), 117.5 (C9), 117.6 (C6), 117.8 (C9 ), 118.1 (C3a), 121.5 (C9a ),
), 127.5
), 129.5 (C200/600),
), 130.7 (C40,
), 132.6 (C100),
). MS (EI,
d
¼2.86–3.03 (12H, m, CH2-4, CH2-4
), 3.52–3.71 (12H, m, CH2-2, CH2-2
), 6.71 (4H, dd, J 8.5, 7.8 Hz,
), 7.24–
*
), 3.05–3.24 (12H,
*
*
), 4.04–4.13
*
*
*
*
*
*
*
*
*
*
d
*
*
*
*
*
*
*
(C300/500), 127.6 (C300/50*0
*
), 128.2 (C400), 128.3 (C20
*
121.8 (C9a), 121.9 (C8 ), 122.4 (C8), 126.4 (C7), 126.7 (C7
*
129.6 (C200/600
*
), 130.0 (C20), 130.1 (C5a), 130.3 (C5a
), 132.2 (C30, C30 ), 132.5 (C100
), 154.9 (C4, C4
*
C40
*
), 130.8 (C50, C50
*
*
*
143.0 (C1, C1
*
), 144.0 (C3), 144.3 (C3
*
*
70 eV): m/z (%) 755 (Mþþ1, 6), 754 (Mþ, 14), 596 (14), 318 (6), 202
(7), 142 (100), 100 (38), 51 (14), 44 (66).
20. Hansen, H. C.; Watjen, F. Eur. Pat. Appl. EP. 347,094, 1989; Chem. Abstr. 1990, 113,
115337.
4.3.8. 14,34,-Dioxa-13,33-diphenyl-1,3(1,5)-diimidazo[1,5-a]quinox-
alina-2(1,3)benzene-6,9,12,15-tetraoxacycloheptadecane (8c). White
powder, mp 293–295 ꢀC (DMSO). IR (nmax, cmꢁ1, KBr): 2921, 2888,
2856, 1656, 1614, 1483, 1442, 1397, 1332, 1301, 1257, 1125, 1096,
21. Hansen, H. C.; Watjen, F. S. African ZA. 89 04,430, 1990; Chem. Abstr. 1990, 113,
212016.
22. Tenbrink R. E.; Jacobsen, E.J. U.S. Patent 5,541,324, 1996; Chem. Abstr. 1996, 125,
195687.
23. Mamedov, V. A.; Kalinin, A. A.; Gorbunova, E. A.; Bauer, I.; Habicher, W. D. Russ.
J. Org. Chem. 2004, 40, 1041–1046.
24. Tennant, G. J. Chem. Soc. 1963, 2428–2433.
25. Romanenko, V. D.; Burmistrov, S. I. Chem. Heterocycl. Compd. 1973, 138–142.
26. Piras, S.; Loriga, M.; Carta, A.; Paglietti, G.; Costi, M. P.; Ferrari, S. J. Heterocycl.
Chem. 2006, 541–548.
27. Mamedov, V. A.; Kalinin, A. A.; Gubaidullin, A. T.; Litvinov, I. A.; Levin, Ya. A.
Chem. Heterocycl. Compd. 2002, 38, 1504–1510.
28. Mamedov, V. A.; Kalinin, A. A.; Gubaidullin, A. T.; Isaykina, O. G.; Litvinov, I. A.
Russ. J. Org. Chem. 2003, 41, 599–606.
29. Mamedov, V. A.; Kalinin, A. A.; Gubaidullin, A. T.; Gorbunova, E. A.; Litvinov, I. A.
Russ. J. Org. Chem. 2006, 42, 1532–1543.
1067, 751, 696; 1H NMR (600.1 MHz, DMSO-d6):
d¼2.88 (4H, br,
CH2-5), 3.14 (4H, br, CH2-4), 3.31 (CH2-3), 3.67 (4H, br, CH2-2), 3.9–
5.0 (br, CH2-1), 6.86 (2H, br, H8), 7.29–7.36 (4H, m, H7, H9), 7.38 (2H,
dd, J 8.5, 7.4 Hz, H400), 7.44 (4H, dd, J 8.5, 7.7 Hz, H300/500), 7.66 (2H, d,
J 8.4 Hz, H6), 7.74 (1H, br, H20), 8.02 (1H, dd, J 8.5, 7.7 Hz, H50), 8.10
(4H, d, J 7.7 Hz, H200/600), 8.16 (2H, dd, J 7.7, 1.3 Hz, H40, H60). MS
(MALDI TOF) [MH]þ¼799.
30. Mamedov, V. A.; Kalinin, A. A.; Gubaidullin, A. T.; Chernova, A. V.; Litvinov, I. A.;
Levin, Ya. A.; Shagidullin, R. R. Russ. Chem. Bull. 2004, 53, 164–175.
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32. Atta-ur-Rahman. One and Two Dimensional NMR Spectroscopy; Elsevier:
Amsterdam, 1989.
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3744–3779.
34. Balandina, A. A.; Kalinin, A. A.; Mamedov, V. A.; Figadere, B.; Latypov, Sh. K.
Magn. Reson. Chem. 2005, 43, 816–828.
Acknowledgements
This work was financially supported by the Russian Foundation
for Basic Research (Grants No. 07-03-00613-a and 09-03-00123-a)
and the State contract No. 02.512.11.2237 Federal target program
‘Research and design on priority directions of development of sci-
ence and technology complex in Russia 2007–2012 years’. Part of
this investigation was carried out in NMR department of the Fed-
eral collective spectral analysis center for physical and chemical
investigations of structure, properties and composition of matter
and materials (CKP SAC) and the Federal CKP for physical and
chemical investigations of matter and materials (FCKP PCI) (state
contracts of the Russian Federation Ministry of education and sci-
ence No. 02.451.11.7036 and 02.451.11.7019).
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