Simple procedure for preparation of quinoxalin-2(1H)-one 3-[oxo(cyclo)alkyl(idene)] derivatives

Article abstract of DOI:10.1134/S1070428006110194

A simple preparative procedure was developed for 3-(2-oxoalkylidene)-3,4- dihydroquinoxalin-2(1H)-ones, 4,5-dihydroxy-1-[3-oxo-3,4-dihydroquinoxalin-2(1H) -ylidene]-3,5-octadiene-2,7-dione, and 3-(2,3-dihydroxy-4-methyl-5-oxo-1,3- cyclopentadien-1-yl)quinoxalin-2(1H)-one by reaction of methyl ketones first with diethyl oxalate in the presence of sodium, and then with o-phenylenediamine.

Full text of DOI:10.1134/S1070428006110194

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2006, Vol. 42, No. 11, pp. 1715−1718.  Pleiades Publishing, Inc. 2006.
Original Russian Text  V.O. Koz’minykh, V.I. Goncharov, E.N. Koz’minykh, 2006, published in Zhurnal Organicheskoi Khimii, 2006, Vol. 42,
No. 11, pp. 1727−1730.
Simple Procedure for Preparation of Quinoxalin-2(1H)-one
3-[Oxo(cyclo)alkyl(idene)] Derivatives
a
b
a
V. O. Koz’minykh , V. I. Goncharov , and E. N. Koz’minykh
aPerm State Pedagogical University, Perm, 614990 Russia
e-mail: kvoncstu@yahoo.com
b
Stavropol State Medical Academy, Stavropol, Russia
Received December 19, 2005
Abstract—A simple preparative procedure was developed for 3-(2-oxoalkylidene)-3,4-dihydroquinoxalin-2(1H)-
ones, 4,5-dihydroxy-1-[3-oxo-3,4-dihydroquinoxalin-2(1H)-ylidene]-3,5-octadiene-2,7-dione, and 3-(2,3-dihydroxy-
4-methyl-5-oxo-1,3-cyclopentadien-1-yl)quinoxalin-2(1H)-one by reaction of methyl ketones first with diethyl oxalate
in the presence of sodium, and then with o-phenylenediamine.
DOI: 10.1134/S1070428006110194
3(2)-[Oxoalkyl(idene)] derivatives of quinoxalin-2(3)-
ene)-3,4-dihydroquinoxalin-2(1H)-ones Ia–Ic, and also for
ones are extensively used in organic synthesis and exhibit
a biological action [1–5]. We developed a very simple
and convenient preparative procedure for 3-(2-oxoalkylid-
4,5-dihydroxy-1-[3-oxo-3,4-dihydroquinoxalin-2(1H)-
ylidene]-3,5-octadiene-2,7-dione (II) and 3-(2,3-di-
hydroxy-4-methyl-5-oxo-1,3-cyclopentadien-1-yl)quin-
Scheme 1.
O
R
R = Me (a),
t-Bu (b),
Ph (c)
H
N
(
1:1:1:1)*
N
H
O
O
H
_
(
1) Na, C H
Ia Ic
O
O
6
6
NH
(
2)
2 ,
H
O
CH3
NH2
CH COOH
R
CH3
H C O
O
5
2
H
3
R = Me
_
_
_
(2:2:3:1)*
N
O
C H OH, H O,
O
OC H
2
5
2
2
5
CH COONa
3
N
H
O
II
OH
O
H
N
R = Et
CH3
(
1:2:2:1)*
O
N
H
O
III
*
Molar ratio ketone–diethyl oxalatet–Na–o-phenylenediamine.is given in parentheses.
1715

1716
KOZ’MINYKH et al.
oxalin-2(1H)-one (III) by reaction of acetone, pinacolone,
acetophenone or 2-butanone with diethyl oxalate in the
presence of sodium at boiling in benzene followed by
treating with acetic acid and o-phenylenediamine
enoliza-tion of the carbonyl groups in two β-dicarbonyl
units of the polyketide chain, and the downfield shift of
1
3
proton signals from methine groups C H, C H and from
1
'
N H confirms the presence of intramolecular hydrogen
1
'
bonds in the chelate N H-ring and conjugated OH-ring.
In solution of compound II we did not find possible tauto-
mers, in particular, forms IV–VI with nonenolized frag-
(
Scheme 1).
Compounds I–III obtained are crystalline substances
colored from yellow to dark red, insoluble in water,
sparingly soluble in the common organic solvents and
soluble at heating in acetic acid, DMF, and DMSO.
ment CH C=X (X = O, N–, Scheme 2) whose formation
2
could not be a priori excluded (cf., for instance, [6]).
1
In the H NMR spectrum of quinoxalinone III
The structure of compounds synthesized was con-
1
registered in DMSO-d proton signals of N H group of
6
1
1
firmed by IR, H NMR, and mass spectra. In the H NMR
spectrum of compound II registered in DMSO-d6
appeared singlets from protons of three methine groups
heterocyclic amide unit (δ 11.68 ppm) and of hydroxy
3'
2'
groups C OH (δ 7.95 ppm) and C OH (δ 14.10 ppm) of
the cyclopentadiene fragment were present. The
downfield shift of the latter signal indicated the hydrogen
6
1
3
C H, C H, and C H at δ 6.05, 7.06, and 7.08 ppm; there-
with two latter signals are located downfield and have
nearly identical chemical shift; signals from the protons
2'
bond formation between the hydrogen of the C OH
hydroxy group and N4 atom of the quinoxaline in a six-
4
'
1'
of N H and N H of the quinoxaline ring were observed
at 11.84 and 12.93 ppm. The lack in the spectrum of
membered chelate ring. The possible tautomeric form
VII did not appear in the spectrum of compound III for
4
possible signals of CH groups protons indicates the
no signal from the proton at N atom was observed
2
Scheme 2.
H
H
O
O
O
O
O
O
O
O
O
O
CH3
H
O
CH3
H
O
CH3
O
OH
O
H
N
H
H
N
N
N
CH3
O
N
H
O
N
H
O
N
H
N
H
O
IV
V
VI
VII
+
+
+
HO
CH3
O
CH3
H
O
N
CH C O
2
N
N
O
OH
N
O
N
N
H
O
N
H
O
N
H
O
O
N
VIII
A
B
C
C H N O
C H N O
C H N O
1
5
7
2
3
11 10
2
2
10 7 2 2
m/z 263
m/z 202
m/z 187
+
+
+
CH3
O
N
N
N
CH2
N
H
N
H
O
H
D
E
F
C H N O
C H N O
C H N
9
8
2
8
5
2
8 7 2
m/z 160
m/z 145
m/z 131
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 42 No. 11 2006

SIMPLE PROCEDURE FOR PREPARATION OF QUINOXALIN-2(1H)-ONE...
1717
(
Scheme 2). Nonetheless it is yet difficult to choose
added by small pieces 0.46 g (20 mmol) of sodium, and
the reaction mixture was boiled for 2–3 h. The solvent
was evaporated, the residue was thoroughly ground with
20–30 ml of ice water, then at stirring was added 10 ml
of acetic acid and 2.16 g (20 mmol) of o-phenylendiamine.
After 3–4 h the separated precipitate of compounds Ia–
Ic was filtered off, dried, and recrystallized from acetic
acid or DMF.
between two very close regioisomeric forms III and VIII
distinguished by the reciprocal position of a hydroxy group
and a methyl substituent at C and C atoms of the
alicyclic unit.
3
'
4'
In the mass spectrum of compound II the molecular
ion peak is lacking, but characteristic peaks of fragment
ions appear at m/z 263 A, 202 B, 187 C, 160 D, 145 E,
and 131 F corresponding to the major fragmentation
directions of this polyketide (Scheme 2) in full agreement
with published data on analogous substances [6].
(
3-(2-Oxopropylidene)-3,4-dihydroquinoxalin-
(1H)-one (Ia). Yield 3.0 g (74%), mp 267–268°C
decomp., DMF) (publ.: mp 256–257°C [13]).
-(3,3-Dimethyl-2-oxobutylidene)-3,4-dihydro-
quinoxalin-2(1H)-one (Ib). Yield 3.85 g (79%), mp
28–229°C (DMF) (publ.: mp 226–227 [13], 229–230°C
6]).
3-(2-Oxo-2-phenylethylidene)-3,4-dihydro-
2
(
3
Quinoxalinones Ia–Ic and II result from o-phenyl-
endiamine reaction with intermediate products of Claisen
condensation of equimolar amounts of methyl ketones
and diethyl oxalate: ethyl 2-hydroxy-4-oxo-2-alkenoates
2
[
(acylpyruvates) IX [7, 8] and ethyl 2,6,7-trihydroxy-4,9-
dioxo-2,5,7- decatrienoate (X) [9, 10] (Scheme 3). The
primary product of 2-butanone condensation with diethyl
oxalate (in a ratio 1:2), ethyl 2-hydroxy(3-hydroxy-4-
methyl-2,5-dioxo-3-cyclopenten-2-ylidene)acetate (XI)
quinoxalin-2(1H)-one (Ic). Yield 4.50 g (85%), mp
268–269°C (decomp., CH COOH) (publ.: mp 266–267
3
[3, 13], 264–265°C [6].
4
,5-Dihydroxy-1-[3-oxo-3,4-dihydroquinoxalin-
[10, 11] (Scheme 3) also reacted with o-phenylendiamine
2
(1H)-ylidene]-3,5-octadiene-2,7-dione (II). To
yielding the target compound III.
a mixture of 1.4 ml (20 mmol) of acetone, 2.8 ml
(20 mmol) of diethyl oxalate, and 30 ml of benzene at
stirring and cooling was added by small pieces 0.69 g
Thus a simple and convenient preparative method was
developed for 3-[oxo(cyclo)-alkyl(idene)]-substituted
quinoxalin-2(1H)-ones that according to our data [12]
was also suitable for the synthesis of other versatile
acylmethyl (oxoylidene) derivatives of quinoxaline and
(30 mmol) of sodium, and the reaction mixture was boiled
for 2.5 h. The solvent was evaporated, the residue was
thoroughly ground with 30 ml of ice water, then at stirring
was added 10 ml of acetic acid and 1.08 g (10 mmol) of
1,4-benzoxazine.
Scheme 2.
EXPERIMENTAL
IR spectra of quinoxalinones II and III were recorded
O
O
R
R
H
on a spectrophotometer Specord M-80 from mulls in
OC H
OC H
2 5
2
5
1
mineral oil. H NMR spectra of compounds II and III
O
O
O
O
O
were registered on a spectrometer Bruker DRX-500
H
IX
H
(
500.13 MHz) in DMSO-d , internal reference TMS.
6
O
O
Mass spectra of compounds II and III were measured
on Finnigan MAT INCOS-50 instrument in the mode of
direct sample admission into the ion source (electron
impact). The homogeneity of compounds I–III was
confirmed by TLC on Silufol UV-254® plates in a system
benzene–ethyl ether–acetone, 10:9:1, development in
iodine vapor. Physical constants and spectral character-
istics of the known 3-(2-oxoalkylidene)-3,4-dihydro-
quinoxalin-2(1H)-ones Ia–Ic are reported in [3, 6, 13].
H3C
OC H
2 5
O
O
O
H
X
H3C
HO
O
H
O
O
OC H
2
5
3
-(2-Oxoalkylidene)-3,4-dihydroquinoxalin-
O
2
(1H)-ones Ia–Ic. To a mixture of 20 mmol of acetone,
pinacolone, or acetophenone, 2.8 ml (20 mmol) of diethyl
oxalate, and 30 ml of benzene at stirring and cooling was
XI
R = Me, t-Bu, Ph.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 42 No. 11 2006

1718
KOZ’MINYKH et al.
–
1
o-phenylendiamine.After 3–4 h the separated precipitate
of compound II was filtered off, dried, and recrystallized
from DMF. Yield 1.70 g (54%), mp 227–228°C (decomp.).
From the residue after crystallization a small amount of
compound Ia was isolated. Yield 0.3 g (15%), mp 267–
DMF). IR spectrum, ν, cm : 3240–3195 (OH), 3185
1
2
5'
1
(N H
), 1678 (C =O
), 1665 (C =O). H NMR
amide
amide
6
spectrum, δ, ppm: 1.87 s (3H, CH ), 7.14 t (1H, C H,
3
7
8
J 8.0 Hz), 7.32 t (1H, C H, J 8.4 Hz), 7.40 d (1H, C H,
3
'
5
J 8.8 Hz), 7.95 s (1H, C OH), 8.05 d (1H, C H,
J 9.0 Hz), 11.68 br.s (1H, N1H), 14.10 br.s (1H, C2'OH).
2
68°C (decomp., DMF).
–
1
4'
Mass spectrum, m/z (I , %) (ions with I > 5% are
Compound II. IR spectrum, ν, cm : 3170 (N Hamide),
rel
rel
3
'
1
reported): 270 (22) [M]+, 226 (9), 225 (11), 224 (22) [M–
1
667 (C =O
), 1590–1620 (=COH
spectrum, δ, ppm: 2.17 s (3H, CH ), 6.05 s (1H, C H),
.06 s (1H, C H), 7.08s (1H, C H), 7.06–7.35 m (4H,
C H ), 7.70 br.s (2H, C OH, C OH), 11.84 s (1H, N H),
2.93 s (1H, N H). Mass spectrum, m/z (I , %) (ions
with Irel > 2% are reported): 263 (2) [M–CH –2H O]
). H NMR
amide
chelate
6
CO–H O]+ = [C H N O ]+, 223 (9), 198 (10), 197 (12),
3
2 13 8 2 2
1
3
+
7
169 (22), 168 (31) [M – C H N] , 167 (5), 153 (5), 140
7 4
4
5
4'
+
(5), 129 (5), 114 (5), 112 (7), 103 (5), 102 (8) [C H N] ,
6
4
7 4
1
'
+
1
84 (12), 77 (15) [C H ] , 76 (10), 75 (5), 73 (32), 70 (7),
6 5
rel
+
63 (8), 52 (7), 51 (11), 50 (11), 45 (8), 44 (100), 42 (22),
41 (13), 40 (10), 39 (18), 38 (5). Found, %: C 61.97;
H 3.50; N 10.56. C H N O . Calculated, %: C 62.22;
3
2
+
+
A, 224 (2) [C H N O ] , 202 (12) [M–2CH CO–CO]
13
8
2
2
2
+
B, 187 (11) [M–CH CO–2CH CO] C , 160 (12) [M–
3
2
14 10
2
4
+
3
CH CO–CO] D, 159 (7), 158 (4), 145 (2) [M–
CH CO–3CH CO] E, 132 (12) [M–3CH CO–2 CO] ,
31 (16) [M–3CH CO–2CO–H] F, 117 (3), 104 (4),
2
03 (3) [C H N] , 92 (3), 91 (3), 90 (6) [C H N] , 89
3), 78 (3), 77 (8) [C H ] , 76 (5), 75 (4), 65 (7), 64 (7),
3 (8), 52 (5), 51 (6), 50 (6), 45 (9), 44 (100), 43 (40), 42
8), 41 (5), 40 (8), 39 (12), 38 (6). Found, %: C 61.47;
H 4.30; N 9.23. C H N O . Calculated, %: C 61.14;
H 3.73; N 10.37. M 270.
2
+
+
3
2
2
+
REFERENCES
1
1
(
6
(
+
+
7
5
6
4
1. Heterocyclic Compounds, Elderfield, R.C., Ed., NewYork:
+
6 5
Wiley, 1957.
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1
6
14
2
5
H 4.49; N 8.91. M 314.
139 p.
4
. Koz’minykh, V.O., Igidov, N.M., Koz’minykh, E.N., and
3
-(2,3-Dihydroxy-4-methyl-5-oxo-1,3-cyclo-
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pentadien-1-yl)quinoxalin-2(1H)-one (III). To
a mixture of 0.9 ml (10 mmol) of 2-butanone, 2.8 ml
(
20 mmol) of diethyl oxalate, and 20 ml of benzene at
stirring and cooling was added by small pieces 0.46 g
20 mmol) of sodium, and the reaction mixture was boiled
for 3 h. The solvent was evaporated, the residue was
thoroughly ground with 20 ml of ice water, then at stirring
was added 10 ml of acetic acid and 1.08 g (10 mmol) of
o-phenylendiamine. After 3 h the separated precipitate
of compound III was filtered off, dried, and recrystallized
from DMF. Yield 1.95 g (72%), mp 298–300°C (decomp.,
5
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sinteza i modifikatsii geterotsiklov (Selected Methods of
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6
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 42 No. 11 2006