Fused Nitrogen-Containing Heterocycles: III. 4-Oxo-1-phenyl-4,5- dihydroimidazo[1,5-a]quinoxalines. A Retrosynthetic Approach

Article abstract of DOI:10.1023/A:1023463117204

Retrosynthetic analysis of the structure of imidazo[1,5-a]quinoxalines made it possible to develop new convenient procedures for preparation of these compounds by reaction of 3-(α-chlorobenzyl)-1,2-dihydroquinoxalin-2-one with potassium thiocyanate or isocyanate as synthetic equivalent of the two-membered N^-=C⁺ building blocks and by reaction of 3-(α-aminobenzyl)-1,2-dihydroquinoxalin-2-one with carbon disulfide, triethoxymethane, aromatic aldehydes, or acetic anhydride as synthetic equivalent of the one-membered RC³⁺ synthon.

Full text of DOI:10.1023/A:1023463117204

Russian Journal of Organic Chemistry, Vol. 39, No. 1, 2003, pp. 125 130. Translated from Zhurnal Organicheskoi Khimii, Vol. 39, No. 1, 2003,
pp. 135 140.
Original Russian Text Copyright
2003 by Mamedov, Kalinin, Azancheev, Levin.
Fused Nitrogen-Containing Heterocycles:
III.* 4-Oxo-1-phenyl-4,5-dihydroimidazo[1,5-a]quinoxalines.
A Retrosynthetic Approach
V. A. Mamedov, A. A. Kalinin, N. M. Azancheev, and Ya. A. Levin
Arbuzov Institute of Organic and Physical Chemistry, Kazan Research Center, Russian Academy of Sciences,
ul. Arbuzova 8, Kazan, 420088 Tatarstan, Russia
e-mail: mamedov@iopc.kcn.ru
Received June 27, 2001
Abstract Retrosynthetic analysis of the structure of imidazo[1,5-a]quinoxalines made it possible to develop
new convenient procedures for preparation of these compounds by reaction of 3-( -chlorobenzyl)-1,2-dihydro-
quinoxalin-2-one with potassium thiocyanate or isocyanate as synthetic equivalent of the two-membered
N
C+ building blocks and by reaction of 3-( -aminobenzyl)-1,2-dihydroquinoxalin-2-one with carbon
disulfide, triethoxymethane, aromatic aldehydes, or acetic anhydride as synthetic equivalent of the one-
membered RC3+ synthon.
A wide spectrum of biological activity recently
revealed in the series of imidazo[1,5-a]quinoxaline
derivatives [2 4] and related azoloquinoxalines [5]
makes it promising to develop convenient methods for
preparation of these fused heterocylic compounds. We
previously showed that a relatively short route to
3-phenyl derivatives IV is based on the use of readily
accessible 3-( -thiocyanatobenzyl)-1,2-dihydroquino-
xalin-2-one (II), which is capable of undergoing intra-
molecular ring closure with formation of not only
thiazolo[3,4-a]quinoxalin-4-one I [6] but also (due to
thiocyanate isothiocyanate rearrangement) compound
III. The latter is then converted into the target imid-
azo[1,5-a]quinoxaline system IV (Scheme 1). This
process corresponds to path 1 (through synthon A,
R = SH) in the retrosynthetic scheme shown below
(Scheme 2). As follows from Scheme 2, another syn-
thetic equivalent of A may be oxygen-containing
analog of III, 3-( -isocyanatobenzyl)-1,2-dihydro-
quinoxalin-2-one (V). Its formation can be represented
as a result of nucleophilic substitution of the chlorine
atom in 3-( -chlorobenzyl)-1,2-dihydroquinoxalin-2-
one (VI) by cyanate ion through its nitrogen atom
which is more nucleophilic than oxygen. However, we
failed to obtain isocyanate V or isomeric cyanate VII
from VI and KOCN in DMSO at room temperature,
i.e., under conditions ensuring almost quantitative
formation of thiocyanate II by analogous reaction
with KSCN [6]. A probable reason is too high and
versatile reactivity of the expected isocyanate V
and/or cyanate VII. On the other hand, there is no
need of isolating compound V or VII as intermediate
products, for the reaction of chloride VI with KOCN
in boiling dimethylformamide directly gives imidazo-
quinoxaline IVa in a good yield (Scheme 3). The
above route to imidazo[1,5-a]quinoxalines starting
Scheme 1.
____________
*
For communication II, see [1].
1070-4280/03/3901-0125$25.00 2003 MAIK Nauka/Interperiodica

126
MAMEDOV et al.
Scheme 2.
IV, R = OH (a), SH (b), H (c), Ph (d), 4-MeOC6H4 (e), Me (f).
from accessible chloride VI is shorter than the known
procedure for building up isocyanate intermediates (as
synthetic equivalents of A) through the corresponding
carboxylic acid hydrazide and azide (according to
Curtius) [7].
From the retrosynthetic viewpoint, the formation of
imidazo[1,5-a]quinoxalines IVa and IVb can also be
latter are numerous compounds, e.g., carbon disulfide,
ortho esters, acylating agents, etc. However, this
approach requires development of procedures for
preparation of amine VIII as synthetic equivalent
of C. Our attempt to obtain amine VIII from chloride
VI and ammonia resulted in formation of a mixture of
products. The reduction of azide IX with LiAlH4 was
also unsuccessful [8]. We succeeded in converting
the azide moiety into amine by the Staudinger reac-
tion [9]. Azide IX smoothly reacted with triethyl
phosphite to give unstable phosphorane X which
underwent hydrolysis by the action of atmospheric
moisture during isolation. As a result, 3-( -diethoxy-
phosphinoylaminobenzyl)-1,2-dihydroquinoxalin-2-
one (XI) was obtained (Scheme 4).
represented by division of the target structure into
+
synthons B and RC N ; synthetic equivalents of the
latter may be potassium cyanate and thiocyanate
(path 2 in Scheme 2). Paths 1 and 2 are similar in the
preparative respect.
The most attractive is to build up the imidazo-
[1,5-a]quinoxaline system from synthons C and RC3+
(path 3 in Scheme 2). Synthetic equivalents of the
Scheme 3.
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FUSED NITROGEN-CONTAINING HETEROCYCLES: III.
127
Scheme 4.
All 3-( -X-benzyl)-1,2-dihydroquinoxalin-2-ones
reported previously [6, 8, 10] (X = Cl, SCN, N3,
NHPh) exist exclusively or almost exclusively in the
imino form (the nitrogen atom in position 4 of the
quinoxaline ring is pyridine-like). This follows from
trum. Signals from the methyl protons of the ethoxy
groups appear as two doublets of doublets (rather than
triplets) with coupling constants 3J of 7.32 and
6.72 Hz, while the corresponding methylene protons
( 3.75 4.00 ppm) give rise to two groups of unre-
solved multiplets (rather than doublets of quartets); the
signal intensity ratio is 3:1. These data indicate the
presence of two spin systems ABM3X and A B M3X,
which is possible if the molecule contains an asym-
metric carbon atom. In order to determine the coupling
1
the presence in the H NMR spectra of one signal
from proton at sp3-hybridized carbon atom,
6.5 ppm. According to the H NMR data, amidophos-
6.0
1
phate XI also has structure XIa. Its IR spectrum con-
1
tains an absorption band at 1610 cm ( C N) in
2
3
1
constants JAB and JPOCH, the H NMR spectra were
recorded with successive irradiation of samples at
the resonance frequences corresponding to all nuclei
constituting the ABM3X system. The resulting values,
addition to strong bands corresponding to stretching
vibrations of the carbonyl group and N H bond of
1
the amidophosphate moiety (1665 and 3190 cm ,
respectively). The aminobenzyl (XIa) rather than
aminobenzylidene (XIb) structure is also confirmed
3
2JAB = 14.5 Hz and JPOCH = 10.5 Hz were refined
1
by signals in the upfield region of the H NMR spec-
by simulation of the spectrum with the use of WIN
Table 1. Yields, melting points, and elemental analyses of imidazo[1,5-a]quinoxalin-4-ones IVa and IVd IVf and
quinoxalin-2-ones VIII, XI, and XIIa
Found, %
H
Calculated, %
H
Comp.
no.
Yield,
%
mp, C (solvent)
Formula
C
N
C
N
IVa
IVd
IVe
IVf
60
58
93
53
81
>360 (DMSO)
313 315 (DMF i-PrOH, 1: 2) 78.70
330 332 (DMF i-PrOH, 1: 2) 75.11
266 268 (AcOH H2O, 1: 1)
224 226 (H2O)
68.93
4.10
4.27
5.11
4.37
5.15
17.57
12.46
11.21
15.05
14.34
C16H11N3O2
C22H15N3O
C23H17N3O2
C17H13N3O
C15H13N3O
1.25HClb
69.31
78.32
75.19
74.17
60.69
4.00
4.48
4.66
4.76
4.84
17.31
12.46
11.44
15.26
14.15
73.92
61.05
VIII
c
XI
XII
75
56
170 173 (i-PrOH)
259 261 (AcOH H2O, 1: 1)
59.32
69.56
5.72
4.58
11.08
14.45
C21H26N3PO4
C17H15N3O2
58.91
69.61
5.97
5.15
10.84
14.33
a
b
c
The data for compounds IVb and IVc and methods of their purification were identical to those reported in [1].
Found Cl, %: 14.39. Calculated Cl, %: 14.93.
Found P, %: 7.95. Calculated P, %: 7.99.
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128
MAMEDOV et al.
1
Table 2. IR and H NMR spectra of imidazo[1,5-a]quinoxalin-4-ones IVa and IVd IVf and quinoxalin-2-ones VIII,
XI, and XII
Comp.
no.
1
IR spectrum, , cm
1H NMR spectrum (DMSO-d6), , ppm
IVa
IVd
IVe
1670 (C O), 1700 (C O), 7.09 7.48 m (6H, 6-H, 7-H, 8-H, m-H, p-H), 7.90 d (2H, o-H, J = 6.9 Hz),
2400 3220 (NH) 8.75 d (1H, 9-H, J = 7.9 Hz), 10.87 br.s (1H, NH), 11.87 br.s (1H, NH)
1615 (C N), 1660 (C O), 6.84 7.02 m (2H, quinoxaline), 7.23 7.67 m (10H, quinoxaline; m-H, p-H),
2570 3220 (NH) 8.17 d (2H, o-H, J = 7.34 Hz), 11.44 br.s (1H, NH)
1610 (C N), 1660 (C O), 3.90 s (3H, CH3), 6.82 7.02 m (1H, p-H), 7.15 d (1H, 9-H, J = 8.9 Hz), 7.18 d
2570 3220 (NH)
(2H, m-H in MeOC6H4, J = 8.5 Hz), 7.26 7.56 m (5H, 6-H, 7-H, 8-H; m-H
in Ph), 7.65 d (2H, o-H in MeOC6H4, J = 8.5 Hz), 8.12 8.28 m (2H, o-H in
Ph), 11.50 br.s (1H, NH)
IVf
1605 (C N), 1660 (C O), 2.95 s (3H, CH3), 7.18 7.22 m (1H, p-H), 7.24 7.42 m (5H, 6-H, 7-H, 8-H,
2480 3220 (NH)
m-H, p-H), 8.05 d (1H, 9-H, J = 8.3 Hz), 8.14 d (2H, o-H, J = 8.3 Hz),
11.30 br.s (1H, NH)
VIII
XI
1662 (C O), 2370 3520 5.80 s (1H, PhCH, 7.36 7.62 m (8H, C6H5, 6-H, 7-H, 8-H), 7.88 d (1H, 5-H,
(NH) J = 6.83 Hz), 9.12 br.s (2H, NH2); 11.80 br.s (1H, NH)
1610 (C N), 1662 (C O), 1.12 d.d (3H, CH3CH2, J = 7.32, 6.72 Hz), 1.17 d.d (3H, CH3CH2, J = 7.32,
2490 3330 (NH)
6.72 Hz), 3.29 3.96 m (4H, 2CH3CH2), 5.81 d (1H, PhCH, J = 8.64 Hz),
7.23 7.53 m (8H, C6H5, 6-H, 7-H, 8-H), 7.91 d (1H, 5-H, J = 6.91 Hz)
XII
1610 (C N), 1660 (C O), 1.94 s (3H, CH3), 6.43 d (1H, PhCH, J = 8.2 Hz), 7.19 7.46 m (8H, C6H5,
2580 3220 (NH), 3395
(NH)
quinoxaline), 7.79 d (1H, 5-H, J = 7.3 Hz), 8.42 br.s (1H, NHAc), 12.43 br.s
(1H, N1H)
DAISY program (correlation coefficient R = 0.995).
A fairly large difference in the chemical shifts of
Here, aldehydes were only arbitrarily (for the sake
of brevity) assigned to synthetic equivalents of RC3+.
In fact, they are equivalents of RCH2+ whose reaction
with VIII leads to dihydro derivatives of IVd and
IVe. Products IVd and IVe are likely to be formed by
oxidation of the initially obtained dihydro derivatives
with atmospheric oxygen. As a result, aldehydes give
rise to the same compounds as those obtained from
the corresponding carboxylic acid derivatives, so that
the above assumption may be regarded as justified.
By carrying out the reaction of amine VIII hydro-
chloride with acetic anhydride in a stepwise mode,
we succeeded in isolating and characterizing inter-
mediate 3-( -acetylaminobenzyl)quinoxalin-2-one
(XII) which is a synthetic equivalent of A. Intramole-
cular condensation of XII in acetic acid gives
imidazo[1,5-a]quinoxaline IVf (Scheme 6). This reac-
tion may be regarded as one more version of path 1.
the methyl protons (
0.12 ppm) should be noted,
as well as an upfield shift (by 0.15 ppm) of a part
of the methylene proton multiplet, whose intensity
corresponds to one proton. Presumably, this is the
result of not only restricted rotation about the partially
double N P bond but also anisochronous effect of
the benzene and/or quinoxaline system on three
methyl protons and one methylene proton of the
ethoxy group.
The desired amine VIII was obtain in high yield
(as hydrochloride) by treatment of amidophosphate XI
with dry hydrogen chloride. Reactions of VIII HCl
with one-carbon synthons smoothly yields imidazo-
[1,5-a]quinoxalines IVb IVf (Scheme 5). We thus
accomplished the synthesis of compounds IV accord-
ing to path 3 (through synthon C).
Scheme 5.
Scheme 6.
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FUSED NITROGEN-CONTAINING HETEROCYCLES: III.
129
Table 3. 13C NMR spectra of imidazo[1,5-a]quinoxalines IVd IVf in DMSO acetone-d6 (10: 1), C, ppm (J, Hz)
Atom
IVd
IVe
IVf
CH3
55.01 q (J = 144.58)
116.16 d.br.d (J = 165.5, 9.5)
116.41 d.d.d (J = 162.6, 7.4, 2.6)
118.02 br.s
15.58 q (J = 129.95)
118.16 d.m (J = 162.8)
123.79 d.m (J = 163.5)
119.42 br.s
C7, C8
116.21 d.m (J = 165.7),
116.42 d.m (J = 160.6)
118.19 br.s
C3a
C3
121.07 m
121.20 m
123.39 m
C6, C9
121.10 d.d (J = 162.74, 7.8),
126.30 d.d (J = 63.8, 7.8)
143.06 d.d.d (J = 5.7, 4.9, 1.7),
144.07 d.d.d (J = 4.2, 4.2, 4.6)
154.72 s
160.07 br.s
127.41 d.t (J = 161.8, 7.3),
129.56 d.t (J = 161.8, 7.5)
121.11 d.d.d (J = 161.8, 8.0, 1.3),
126.20 d.d (J = 162.9, 8.6)
142.90 d.d (J = 4.3, 4.2),
144.95 d.d (J = 4.2, 4.0)
154.75 s
160.39 br.s
127.35 d.t (J = 161.4, 7.8),
129.41 t (J = 4.6 Hz)a
127.89 d.d (J = 163.9, 8.2),
117.58 d.d.d (J = 163.0, 7.9, 1.4)
134.55 d.d (J = 8.2, 7.5),
143.69 m
156.22 s
144.73 q (J = 7.3)
C5a, C9a
C O
C N
Cp
129.07 d.d.d (J = 161.1, 7.8, 7.7)
Co
Cm
Ci
129.03 d.d.d (J = 167.3, 7.2, 7.1), 129.99 d.m (J = 162.1),
129.02 d.d.d (J = 166.3, 7.3, 7.1) 130.48 d.d (J = 162.1, 7.1)a
128.38 d.d.d (J = 162.6, 6.4, 1.9), 126.93 d.d.d (J = 159.6, 7.5, 0.8), 128.79 d.d (J = 159.5, 7.7)
126.98 d.d.d (J = 159.7, 8.1, 1.0) 114.11 d.d (J = 161.5, 4.5)a
130.75 d.d.d (J = 161.1, 7.7, 7.6)
132.71 t (J = 7.4),
131.69 t (J = 7.5)
132.70 t (J = 8.2),
123.67 t (J = 8.2)a
130.83 d.d.d (J = 1.1, 6.9, 6.8)
a
Signals of the 4-methoxyphenyl group.
The structure of imidazo[1,5-a]quinoxalin-2-ones
1-Mercapto-3-phenylimidazo[1,5-a]quinoxalin-
4(5H)-one (IVb). To a mixture of 0.70 g (2.4 mmol)
of aminoquinoxaline VIII hydrochloride (see below)
and 50 ml of methanol we added 0.6 g (10.7 mmol) of
potassium hydroxide. The mixture was refluxed for
a few minutes and cooled, 1 ml of carbon disulfide
was added, and the mixture was refluxed for 3 h. The
mixture was cooled, an additional 1 ml of CS2 was
added, and the mixture was refluxed for 3 h again.
After cooling, the crystals were filtered off and
washed with water and a mixture of acetic acid with
isopropyl alcohol. Yield 0.63 g (90%). The properties
of compound IVb were identical to those of the prod-
uct described in [1].
3-Phenylimidazo[1,5-a]quinoxalin-4(5H)-one
(IVc). A mixture of 0.30 g (1 mmol) of aminoquino-
xaline VIII hydrochloride and 10 ml of triethyl ortho-
formate was refluxed for 6 h. It was then cooled,
and the crystals were filtered off and washed with
an aqueous solution of sodium carbonate, water, and
IVa IVf was proved by elemental analyses (Table 1)
1
and IR and H and 13C NMR data (Tables 2, 3).
EXPERIMENTAL
The melting points were determined on a Boetius
device. The IR spectra were taken on a UR-20 spec-
trometer from samples dispersed in mineral oil. The
1H NMR spectra were recorded on a Bruker MCL-250
instrument at 250.13 MHz. The 13C and 31P NMR
spectra were obtained on a Bruker WV-400 spectrom-
eter at 100.60 and 161.98 MHz, respectively.
3-Phenylimidazo[1,5-a]quinoxaline-1,4(2H,5H)-
dione (IVa). To a mixture of 0.50 g (1.9 mmol) of
3-( -chlorobenzyl)-1,2-dihydroquinoxalin-2-one [10]
and 6 ml of dry DMF we added a twofold amount of
KNCO. The mixture was refluxed for 6 h, cooled, and
poured into water. The crystals were filtered off and
washed with water and isopropyl alcohol.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 1 2003

130
MAMEDOV et al.
isopropyl alcohol. Yield 0.22 g (84%). The properties
of compound IVc coincided with those of the product
described in [1].
off and washed with dioxane. 31P NMR spectrum:
6.89 (DMSO), 7.10 ppm (AcOH).
P
N- -(3-Oxo-3,4-dihydroquinoxalin-2-yl)benzyl-
acetamide (XII). A solution of 0.20 g (0.67 mmol)
of aminoquinoxaline VIII hydrochloride in 3 ml of
acetic anhydride was refluxed for 5 min. The mixture
was left overnight, and the crystals were filtered off
and washed with a solution of sodium carbonate,
water, and isopropyl alcohol.
1,3-Diphenylimidazo[1,5-a]quinoxalin-4(5H)-one
(IVd). A mixture of 0.38 g (1.3 mmol) of amino-
quinoxaline VIII hydrochloride, 10 ml of dioxane,
and excess (0.7 ml) benzaldehyde was refluxed for
9 h. The resulting solution was cooled and poured
into water, and an aqueous solution of sodium carbo-
nate was added. The crystals were filtered off and
washed with water and isopropyl alcohol.
REFERENCES
1-(4-Methoxyphenyl)-3-phenylimidazo[1,5-a]-
quinoxalin-4(5H)-one (IVe). A mixture of 0.50 g
(1.7 mmol) of aminoquinoxaline VIII hydrochloride,
10 ml of dioxane, and excess (0.7 ml) p-methoxy-
benzaldehyde was refluxed for 15 h. The product was
isolated as described above for compound IVd.
1-Methyl-3-phenylimidazo[1,5-a]quinoxalin-
4(5H)-one (IVf). A solution of 0.20 g (0.67 mmol)
of aminoquinoxaline VIII hydrochloride in 3 ml of
acetic anhydride was refluxed for 4 h. The mixture
was left overnight, and the crystals were filtered off
and washed with an aqueous solution of sodium car-
bonate, water, and isopropyl alcohol.
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chloride (VIII). Dry hydrogen chloride was bubbled
over a period of 2 h under stirring through a suspen-
sion of 3.0 g (7.2 mmol) of quinoxaline XI (see
below) in 20 ml of dioxane. Initial quinoxaline XI
dissolved, and crystals of the product separated from
the solution. The mixture was left overnight, and the
crystals were filtered off and washed with dioxane.
The filtrate was partially evaporated to isolate an addi-
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Diethyl -[3-oxo-3,4-dihydroquinoxalin-2(1H)-
ylidene]benzylamidophosphate (XI). Azidoquinoxa-
line VI [8], 8 g (2.88 mmol), and triethyl phosphite,
5 ml, were dissolved in 50 ml of anhydrous dioxane
on stirring at 40 C. The solution was stirred for 48 h
at room temperature; evolution of nitrogen was ob-
served during the process, and crystals began to
separate on the second day. The crystals were filtered
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Soedin., 2002, p. 1704.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 39 No. 1 2003