Synthesis and functionalization of 3-azolylquinoxalin-2(1 H)-ones

Article abstract of DOI:10.1055/s-0033-1340983

Ethyl 2-azolylglyoxylates react smoothly with o-phenylenediamines and 1,2-diaminocyclohexane in acetonitrile at room temperature to give the corresponding 3-azolylquinoxalin-2(1H)-ones and their saturated analogues in good to excellent yields. Georg Thiem

Full text of DOI:10.1055/s-0033-1340983

PAPER
▌A
paper
Synthesis and Functionalization of 3-Azolylquinoxalin-2(1H)-ones
Synthesis of Heterocycles
Oleksandr V. Geraschenko,*a,b Pavel V. Khodakovskiy,a,b Oleg V. Shishkin,c Andrey A. Tolmachev,a,b
Pavel K. Mykhailiuk*a,b
a
Enamine Ltd., Aleksandra Matrosova Street, 23, Kyiv 01103, Ukraine
b
Department of Chemistry, Kyiv National Taras Shevchenko University, Volodymyrska Street, 64, Kyiv 01033, Ukraine
Fax +380(44)2351273; E-mail: Geraschenko.Aleksandr@gmail.com; E-mail: Pavel.Mykhailiuk@gmail.com
c
STC, Institute for Single Crystals, National Academy of Science of Ukraine, 60 Lenina Ave., Kharkiv 61001, Ukraine
Accepted after revision: 21.02.2014; Received: 23.12.2013
Among many synthetic approaches to quinoxalin-2(1H)-
ones,12–16 direct condensation of 1,2-diaminobenzenes
with 2-ketocarboxylic acid is probably the most popular.
As a part of our research project aimed at the preparation17
and subsequent functionalization18 of ethyl azolylglyoxyl-
ates, herein we report on their use to obtain the corre-
spondingly substituted quinoxalin-2(1H)-ones.
Abstract: Ethyl 2-azolylglyoxylates react smoothly with o-phenyl-
enediamines and 1,2-diaminocyclohexane in acetonitrile at room
temperature to give the corresponding 3-azolylquinoxalin-2(1H)-
ones and their saturated analogues in good to excellent yields.
Key words: quinoxalin-2(1H)-ones, 2-azolylglyoxylates, conden-
sation, o-phenylenediamine, 1,2-diaminocyclohexane
First we examined the condensation of various ethyl 2-
azolylglyoxylates 1a–k with o-phenylenediamine (2a)
(Scheme 1, Table 1).
In recent decades derivatives of quinoxaline have gained
widespread application in organic chemistry, medicinal
chemistry, and drug discovery.1 Substituted quinoxalines
exhibit a broad spectrum of biological activity, e.g. antag-
onists of NMDA glutamate receptor,2 agents to treat insu-
lin-independent diabetes,3 and matrix metalloproteinase
inhibitors4 There are also compounds possessing
antibacterial5 and antiviral6 properties.
O
N
O
NH2
N
NH
Y
H2N
MeCN
OEt
Y
X
+
X
N
r.t.
92–99%
O
1
2a
3
X = N-Alk, S
Scientists have synthesized derivatives of quinoxalin-
2(1H)-ones that are potent thrombin inhibitors,7 antican-
cer,8 anxiolytic,9 antiallergic,10 and analgesic and
antispastic11 agents. FDA-approved antiasthmatic drug
bamaquimast and spasmolytic drug caroverine are worth
special mention (Figure 1).
Y = C, N
Scheme 1 Reaction of compounds 1a–k with o-phenylenediamine
(2a)
Table 1 Reaction Compounds 1a–k with o-Phenylenediamine (2a)
Starting material
Product
Yield (%)
O
N
O
O
N
N
O
N
O
N
NH
N
OEt
N
O
N
HN
Me
N
95
N
Me
O
O
Me
Me
caroverine
bamaquimast
1a
3a
Figure 1 Two marketed drugs bearing the quinoxalin-2(1H)-one
fragment: bamaquimast (antiasthmatic agent), caroverine (spasmolyt-
ic agent)
O
N
N
O
N
NH
Cl
OEt
N
Cl
N
98
95
Me
O
Indeed, the mode of biological activity of various quinox-
alin-2(1H)-ones depends strongly on the nature and posi-
tion of the substituents. Therefore, the elaboration of
novel strategies aimed at the synthesis of diversely substi-
tuted quinoxalin-2(1H)-ones is of true practical impor-
tance for drug discovery.
Me
1b
3b
O
O
N
N
NH
OEt
N
N
N
O
Ph
Ph
SYNTHESIS 2014, 46, 000A–000F
Advanced online publication: 03.04.2014
1c
3c
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1340983; Art ID: SS-2012-Z0370-OP
© Georg Thieme Verlag Stuttgart · New York

B
O. V. Geraschenko et al.
PAPER
Table 1 Reaction Compounds 1a–k with o-Phenylenediamine (2a)
(continued)
The reaction proceeded smoothly in acetonitrile at room
temperature (Table 1). It was slightly exothermic, but no
external cooling was required when working on micromo-
lar quantities. Cooling, however, became necessary when
working on a molar scale. After mixing both reagents to-
gether in acetonitrile, the rapid formation of a precipitate
was observed. To complete the transformation, the reac-
tion mixture was stirred at room temperature for an addi-
tional 12 h. After recrystallization, all products 3a–k were
obtained as solids in excellent yields of 92–98%.
Starting material
Product
Yield (%)
O
O
N
N
N
NH
OEt
N
94
N
O
1d
3d
To expand the scope of the performed transformation, we
next challenged the reaction of the simplest glyoxylate 1a
with substituted o-phenylenediamines 2b–e. We used
symmetric diamines in order to avoid the formation of ste-
reoisomers. The target products 4a–d were obtained in
84–95% isolated yields (Table 2).
O
N
O
N
OEt
NH
N
N
O
N
94
92
1e
3e
O
O
N
Table 2 Reaction of Ketone 1a with o-Phenylenediamines 2b–e
N
NH
OEt
O
NH2
N
N
N
O
N
N
H2N
NH
O
MeCN
N
OEt
+
r.t.
84–95%
N
N
Me
R
O
Me
R
R
2b–e
1f
3f
1a
4a–d
R
O
N
O
N
Starting material
Product
Yield (%)
NH
OEt
N
N
N
99
92
O
Me
O
N
NH2
Me
NH
H2N
N
1g
3g
N
Me
93
O
N
O
N
NH
N
2b
OEt
N
N
4a
N
N
Me
O
O
Me
N
NH2
NH
1h
H2N
N
3h
N
Me
O
95
O
N
F
N
F
O
O
NH
N
Ph
3i
F
OEt
N
N
F
N
N
97
97
98
2c
O
4b
Ph
O
N
NH2
1i
NH
H2N
N
O
N
N
O
Me
N
91
NH
O
S
OEt
O
S
N
O
O
2d
4c
1j
3j
O
N
NH2
O
N
NH
N
H2N
O
O
N
N
NH
N
S
Me
OEt
O
84
S
O
O
1k
3k
2e
4d
Synthesis 2014, 46, A–F
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Heterocycles
C
We also studied the condensation of some glyoxylates
1a,c,e,g with 1,2-diaminocyclohexane (5) (Table 3);
products 6a–d were isolated in moderate yields of 40–
85%. It is interesting to note that though 1,2-diaminocy-
clohexane was used as a 1:1 mixture of cis and trans iso-
mers, the formed products precipitated from the reaction
mixture as a single stereoisomer. Presumably, epimeriza-
tion occurred during the formation of the intermediate
Schiff base.19,20 The trans stereoconfiguration of the ob-
tained compounds was determined by X-ray crystallo-
graphic analysis of product 6c (Figure 2).
Table 3 Reaction of Compounds 1a,c,e,g with 1,2-Diaminocyclo-
hexane (5)
Figure 2 X-ray diffraction structure of compound 6c21
O
O
N
N
NH2
NH
OEt
+
H2N
r.t.
O
N
O
N
N
N
N
MeCN
40–48%
O
column chromatography
silica gel, air
Alk
Alk
1a,c,e,g
NH
NH
N
N
N
5
N
6a–d
62%
cis/trans = 1:1
Starting material
Product
Yield (%)
6c
7
Scheme 2 Synthesis of compound 7
O
N
O
N
NH
OEt
N
Finally, to demonstrate the practical importance of the de-
veloped procedure, we performed the synthesis of com-
pound 8, an analogue of the launched drug caroverine
(Figure 1). In fact, alkylation of quinoxalinone 3a with 2-
chloro-N,N-diethylethylamine in dimethyl sulfoxide us-
ing sodium hydride as the base led to a mixture of N- and
O-alkylated products, from which the major N-alkylated
isomer 8 was isolated by column chromatography in 53%
yield (Scheme 3).
N
40
N
Me
O
Me
1a
6a
O
O
N
N
NH
OEt
N
N
N
N
48
85
45
O
Ph
Ph
1c
6b
O
O
O
O
N
N
N
N
OEt
NH
ClCH2CH2NEt2
53%
N
NH
N
N
N
N
O
N
N
N
Me
Me
3a
8 (analogue of caroverine)
1e
1g
6c
Scheme 3 Synthesis of compound 8, an analogue of the launched
drug caroverine (Figure 1)
O
N
O
N
N
OEt
N
N
N
In summary, we have developed a practical approach to
novel 3-azolylquinoxalin-2(1H)-ones and their saturated
derivatives from 2-azolylglyoxylates 1 and 1,2-diamino-
benzenes and -cyclohexanes. The reaction is practical, it
proceeds smoothly in acetonitrile at room temperature, it
gives products in excellent yields that requires no purifi-
cation by column chromatography. The conceptual im-
portance of the developed reaction was demonstrated by
the preparation of compound 8, an analogue of the
launched drug caroverine.
Me
O
Me
6d
Unexpectedly, attempts to purify product 6c by column
chromatography led to aromatization to form compound 7
(Scheme 2).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, A–F

D
O. V. Geraschenko et al.
PAPER
1H and 13C NMR spectra were recorded on a Bruker Avance 500
spectrometer at 499.9 MHz and 124.9 MHz, respectively. 19F NMR
spectra were recorded on a Varian 400 instrument at 376 MHz. In-
ternal standard from TMS (1H, 13C) and C6F6 (19F). Mass spectra
were recorded on an Agilent 1100 LCMSD SL instrument by chem-
ical ionization (CI).
1H NMR (500 MHz, DMSO-d6): δ = 4.84 (s, 2 H), 5.01 (d, J = 16.9
Hz, 1 H), 5.09(d, J = 10.1 Hz, 1 H), 5.97 (m, 1 H), 7.11 (s, 1 H), 7.36
(s, 3 H), 7.59 (t, J = 7.5 Hz, 1 H), 7.81 (d, J = 7.5 Hz, 1 H), 12.70 (s,
1 H).
13C NMR (125 MHz, DMSO-d6): δ = 49.85, 116.29, 117.91, 123.30,
124.17, 128.68, 129.35, 131.56, 132.32, 133.21, 134.86, 142.12,
149.04, 154.40.
3-Hetarylquinoxalin-2(1H)-ones 3, 4, 6; General Procedure
Glyoxylate 1 (10 mmol) was dissolved in MeCN (1 mL). The solu-
tion of 1,2-diamine 2 or 5 (10 mmol) in MeCN (20 mL) was added.
The mixture was stirred at r.t. overnight. The formed precipitate was
filtered off and was washed with MeCN (2 × 10 mL) on the filter.
The pure product was obtained by recrystallization (DMF).
MS (APCI): m/z = 253 [M + 1].
Anal. Calcd for C14H12N4O: C, 66.66; H, 4.79; N, 22.21. Found: C,
66.92; H, 4.85; N, 22.15.
3-(1-Butyl-1H-imidazol-2-yl)quinoxalin-2(1H)-one (3f)
Brown solid; yield: 3.5 g (92%); mp >200 °C (DMF).
3-(1-Methyl-1H-imidazol-2-yl)quinoxalin-2(1H)-one (3a)
White solid; yield: 4.3 g (95%); mp >200 °C (DMF).
1H NMR (500 MHz, DMSO-d6): δ = 3.78 (s, 3 H), 7.07 (s, 1 H), 7.36
(m, 3 H), 7.59 (t, J = 7.2 Hz, 1 H), 7.82 (d, J = 7.3 Hz, 1 H), 12.76
(s, 1 H).
13C NMR (125 MHz, DMSO-d6): δ = 34.87, 116.49, 124.13, 124.58,
128.43, 129.36, 131.47, 132.43, 133.29, 142.64, 148.55, 154.43.
1H NMR (500 MHz, DMSO-d6): δ = 0.82 (t, J = 7.4 Hz, 3 H), 1.23
(m, J = 7.1 Hz, 2 H), 1.70 (m, J = 6.7 Hz, 2 H), 4.15 (m, 2 H), 7.09
(s, 1 H), 7.38 (s, 2 H), 7.42 (s, 1 H), 7.60 (t, J = 7.5 Hz, 1 H), 7.80
(d, J = 7.5 Hz, 1 H), 12.63 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): δ = 13.88, 19.66, 33.20, 47.07,
115.62, 123.43, 124.25, 126.09, 128.47, 129.23, 131.46, 132.51,
133.51, 141.95, 154.50.
MS (APCI): m/z = 244 [M + 1].
MS (APCI): m/z = 269 [M + 1].
Anal. Calcd for C12H10N4O: C, 63.71; H, 4.4; N, 24.76. Found: C,
63.94; H, 4.75; N, 24.83.
Anal. Calcd for C15H16N4O: C, 67.15; H, 6.01; N, 20.88. Found: C,
67.31; H, 6.25; N, 21.05.
3-(5-Chloro-1-methyl-1H-imidazol-2-yl)quinoxalin-2(1H)-one
(3b)
3-(1-Methyl-1H-benzimidazol-2-yl)quinoxalin-2(1H)-one (3g)
Brown solid; yield: 4.7 g (99%); mp >200 °C (DMF).
Yellow solid; yield: 5.2 g (98%); mp >200 °C (DMF).
1H NMR (500 MHz, DMSO-d6): δ = 3.87 (s, 3 H), 7.30 (t, J = 7.0
Hz, 1 H), 7.36–7.43 (m, 3 H), 7.66 (d, J = 7.6 Hz, 2 H), 7.73 (d, J =
7.3 Hz, 1 H), 7.90 (d, J = 7.3 Hz, 1 H), 12.84 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): δ =31.68, 111.10, 116.31, 120.17,
122.72, 123.80, 124.27, 129.80, 132.35, 133.30, 136.22, 142.71,
148.54, 149.82, 154.45, 154.46.
1H NMR (500 MHz, DMSO-d6): δ = 3.67 (s, 3 H), 7.20 (s, 1 H), 7.36
(s, 2 H), 7.61 (t, J = 7.3 Hz, 1 H), 7.83 (d, J = 7.3 Hz, 1 H), 12.73 (s,
1 H).
13C NMR (125 MHz, DMSO-d6): δ = 32.52, 115.95, 119.76, 124.08,
125.76, 129.52, 131.86, 132.11, 133.0, 142.73, 148.78, 154.20.
MS (APCI): m/z = 261 [M + 1].
MS (APCI): m/z = 277 [M + 1].
Anal. Calcd for C12H9ClN4O: C, 55.29; H, 3.48; Cl, 13.60; N, 21.49.
Found: C, 55.47; H, 3.61; Cl, 13.52; N, 21.68.
Anal. Calcd for C16H12N4O: C, 69.55; H, 4.38; N, 20.28. Found: C,
69.72; H, 4.53; N, 20.22.
3-(1-Benzyl-1H-imidazol-2-yl)quinoxalin-2(1H)-one (3c)
3-(2-Methyl-2H-1,2,4-triazol-3-yl)quinoxalin-2(1H)-one (3h)
Yellow solid; yield: 3.8 g (95%); mp >200 °C (DMF).
Yellow solid; yield: 3.8 g (92%); mp >200 °C (DMF).
1H NMR (500 MHz, DMSO-d6): δ = 5.46 (s, 2 H), 7.10–7.17 (m, 3
H), 7.21 (m, 1 H), 7.23–7.29 (m, 2 H), 7.34 (s, 2 H), 7.43 (s, 1 H),
7.57 (t, J = 7.2 Hz, 1 H), 7.75 (d, J = 7.2 Hz, 1 H), 12.67 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): δ = 50.77, 116.34, 123.47, 123.88,
124.18, 127.79, 127.97, 128.86, 128.93, 129.25, 131.55, 132.27,
133.13, 138.15, 142.19, 154.36.
1H NMR (500 MHz, DMSO-d6): δ = 3.94 (s, 3 H), 7.37–7.41 (m, 2
H), 7.65 (t, J = 7.6 Hz, 1 H), 7.87 (d, J = 7.6 Hz, 1 H), 8.01 (s, 1 H),
12.87 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): δ = 37.36, 116.16, 124.24, 129.80,
132.10, 132.55, 133.25, 148.05, 149.99, 150.96, 153.95.
MS (APCI): m/z = 228 [M + 1].
MS (APCI): m/z = 303 [M + 1].
Anal. Calcd for C11H9N5O: C, 58.15; H, 3.99; N, 30.82. Found: C,
58.32; H, 4.11; N, 30.76.
Anal. Calcd for C18H14N4O: C, 71.51; H, 4.67; N, 18.53. Found: C,
71.75; H, 4.95; N, 18.71.
3-(2-Benzyl-2H-1,2,4-triazol-3-yl)quinoxalin-2(1H)-one (3i)
3-(1-Vinyl-1H-imidazol-2-yl)quinoxalin-2(1H)-one (3d)
Yellow solid; yield: 4.4 g (97%); mp >200 °C (DMF).
Brown solid; yield: 4.2 g (94%); mp >200 °C (DMF).
1H NMR (500 MHz, DMSO-d6): δ = 5.52 (s, 2 H), 7.25 (m, 3 H),
7.30 (m, 2 H), 7.38 (m, 2 H), 7.66 (t, J = 7.3 Hz, 1 H), 7.82 (d, J =
7.3 Hz, 1 H), 8.15 (s, 1 H), 12.86 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): δ = 53.16, 116.18, 124.26, 128.20,
128.45, 128.85, 129.74, 132.03, 132.63, 133.31, 136.70, 148.02,
150.02, 151.43, 154.0.
1H NMR (500 MHz, DMSO-d6): δ = 4.87 (d, J = 8.3 Hz, 1 H), 5.50
(d, J = 15.4 Hz, 1 H), 7.18 (s, 1 H), 7.24 (m, 1 H), 7.34–7.38 (m, 2
H), 7.61 (t, J = 7.5 Hz, 1 H), 7.82 (d, J = 7.5 Hz, 1 H), 7.89 (s, 1 H),
12.71 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): δ = 102.56, 116.09, 118.26,
124.05, 129.57, 129.99, 130.95, 131.91, 132.24, 133.19, 142.07,
149.16, 154.50.
MS (APCI): m/z = 304 [M + 1].
MS (APCI): m/z = 239 [M + 1].
Anal. Calcd for C17H13N5O: C, 67.32; H, 4.32; N, 23.09. Found: C,
67.40; H, 4.38; N, 23.17.
Anal. Calcd for C13H10N4O: C, 65.54; H, 4.23; N, 23.52. Found: C,
65.81; H, 4.38; N, 23.68.
3-(4-Methylthiazol-2-yl)quinoxalin-2(1H)-one (3j)
Black solid; yield: 5.7 g (97%); mp >200 °C (DMF).
1H NMR (500 MHz, DMSO-d6): δ = 2.51 (s, 3 H), 7.40 (m, 2 H),
7.60 (m, 2 H), 7.94 (d, J = 7.8 Hz, 1 H), 12.96 (s, 1 H).
3-(1-Allyl-1H-imidazol-2-yl)quinoxalin-2(1H)-one (3e)
Brown solid; yield: 3.1 g (94%); mp >200 °C (DMF).
Synthesis 2014, 46, A–F
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Heterocycles
E
13C NMR (125 MHz, DMSO-d6): δ = 17.42, 116.03, 120.87, 124.44,
129.75, 131.52, 132.16, 132.66, 147.28, 153.89, 154.14, 158.08.
1H NMR (500 MHz, DMSO-d6): δ = 2.18 (m, J = 5.1 Hz, 2 H), 3.80
(s, 3 H), 4.20 (t, J = 5.1 Hz, 2 H), 4.28 (t, J = 5.1 Hz, 2 H), 6.94 (s,
1 H), 7.08 (s, 1 H), 7.36 (s, 1 H), 7.41 (s, 1 H), 12.63 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): δ = 31.58, 34.98, 71.29, 71.38,
107.84, 120.44, 124.55, 127.97, 128.94, 130.57, 142.61, 145.87,
148.62, 154.41, 154.97.
MS (APCI): m/z = 244 [M + 1].
Anal. Calcd for C12H9N3OS: C, 59.24; H, 3.73; N, 17.27; S, 13.18.
Found: C, 59.43; H, 3.85; N, 17.23; S, 13.22.
3-Benzothiazol-2-ylquinoxalin-2(1H)-one (3k)
MS (APCI): m/z = 299 [M + 1].
Black solid; yield: 4.9 g (98%); mp >200 °C (DMF).
Anal. Calcd for C15H14N4O3: C, 60.40; H, 4.73; N, 18.78. Found: C,
60.53; H, 4.85; N, 18.67.
1H NMR (500 MHz, DMSO-d6): δ = 7.44 (m, 2 H), 7.55 (t, J = 7.5
Hz, 1 H), 7.62 (t, J = 7.6 Hz, 1 H), 7.67 (t, J = 7.6 Hz, 1 H), 8.01 (d,
J = 8.1 Hz, 1 H), 8.22 (m, 2 H), 13.08 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): δ = 116.14, 122.68, 124.36,
124.65, 126.80, 127.18, 130.16, 132.56, 132.68, 132.82, 137.16,
147.81, 152.89, 154.34, 160.48.
3-(1-Methyl-1H-imidazol-2-yl)-4a,5,6,7,8,8a-hexahydroquinox-
alin-2(1H)-one (6a)
White solid; yield: 2.4 g (40%); mp >200 °C (DMF).
1H NMR (500 MHz, DMSO-d6): δ = 1.25–1.46 (m, 4 H), 1.71 (m, 1
H), 1.78 (m, 1 H), 1.95 (m, 1 H), 2.23 (m, 1 H), 3.14 (m, 1 H), 3.25
(m, 1 H), 3.68 (s, 3 H), 6.94 (s, 1 H), 7.23 (s, 1 H), 8.60 (s, 1 H).
MS (APCI): m/z = 280 [M + 1].
Anal. Calcd for C15H9N3OS: C, 64.50; H, 3.25; N, 15.04; S, 11.48.
Found: C, 64.72; H, 3.48; N, 15.12; S, 11.64.
13C NMR (125 MHz, DMSO-d6): δ = 23.75, 25.23, 30.65, 31.87,
34.48, 53.83, 63.06, 123.96, 127.93, 142.36, 156.05, 156.61.
6,7-Dimethyl-3-(1-methyl-1H-imidazol-2-yl)quinoxalin-2(1H)-
one (4a)
MS (APCI): m/z = 233 [M + 1].
Anal. Calcd for C12H16N4O: C, 62.05; H, 6.94; N, 24.12. Found: C,
62.27; H, 7.11; N, 24.18.
Yellow solid; yield: 3.4 g (93%); mp >200 °C (DMF).
1H NMR (500 MHz, DMSO-d6): δ = 2.32 (s, 3 H), 2.35 (s, 3 H), 3.79
(s, 3 H), 7.07 (s, 1 H), 7.16 (s, 1 H), 7.35 (s, 1 H), 7.60 (s, 1 H), 12.66
(s, 1 H).
13C NMR (125 MHz, DMSO-d6): δ = 19.43, 20.38, 34.86, 116.80,
124.39, 128.15, 129.03, 131.21, 131.71, 133.14, 141.40, 142.81,
146.93, 154.57.
3-(1-Benzyl-1H-imidazol-2-yl)-4a,5,6,7,8,8a-hexahydroquinox-
alin-2(1H)-one (6b)
White solid; yield: 2.9 g (48%); mp >200 °C (DMF).
1H NMR (500 MHz, DMSO-d6): δ = 1.20–1.42 (m, 4 H), 1.68 (m, 1
H), 1.75 (m, 1 H), 1.91 (m, 1 H), 2.19 (m, 1 H), 2.97 (m, 1 H), 3.18
(m, 1 H), 5.30 (d, J = 15.2 Hz, 1 H), 5.30 (d, J = 15.2 Hz, 1 H), 7.00
(s, 1 H), 7.18 (m, 2 H), 7.25–7.36 (m, 4 H), 8.56 (s, 1 H).
MS (APCI): m/z = 255 [M + 1].
Anal. Calcd for C14H14N4O: C, 66.13; H, 5.55; N, 22.03. Found: C,
66.30; H, 5.68; N, 22.18.
13C NMR (125 MHz, DMSO-d6): δ = 23.71, 25.17, 30.58, 31.81,
50.22, 53.71, 62.93, 123.26, 127.98, 128.01, 128.32, 128.92,
138.08, 142.0, 156.02, 156.51.
6,7-Difluoro-3-(1-methyl-1H-imidazol-2-yl)quinoxalin-2(1H)-
one (4b)
Grey solid; yield: 3.6 g (95%); mp >200 °C (DMF).
1H NMR (500 MHz, DMSO-d6): δ = 3.91 (s, 3 H), 7.14 (s, 1 H), 7.43
(m, 2 H), 7.95 (s, 1 H), 13.24 (s, 1 H).
MS (APCI): m/z = 309 [M + 1].
Anal. Calcd for C18H20N4O: C, 70.11; H, 6.54; N, 18.17. Found: C,
70.29; H, 6.72; N, 18.09.
13C NMR (125 MHz, DMSO-d6): δ = 35.51, 105.84, 116.47, 116.61,
125.51, 128.09, 129.73, 132.17, 142.03, 147.12 (d, JCF = 260.3 Hz),
151.57 (dd, JCF = 252.1 Hz, 3JCF = 14.5 Hz), 154.62.
19F NMR (376 MHz, DMSO-d6): δ = –142.24 (br s, 1 F), –132.20
(m, 1 F).
3-(1-Allyl-1H-imidazol-2-yl)-4a,5,6,7,8,8a-hexahydroquinoxa-
lin-2(1H)-one (6c)
White solid; yield: 8.2 g (85%); 90% purity. The analytical sample
was obtained by crystallization (DMF); mp >200 °C (DMF).
1H NMR (500 MHz, DMSO-d6): δ = 1.22–1.45 (m, 4 H), 1.72 (m, 1
H), 1.77 (m, 1 H), 1.96 (m, 1 H), 2.25 (m, 1 H), 3.12 (m, 1 H), 3.23
(m, 1 H), 4.68 (dd, 2J = 15.6 Hz, 3J = 5.2 Hz, 1 H), 4.78 (dd, 2J =
15.6 Hz, 3J = 5.2 Hz, 1 H), 5.05 (d, J = 17.2 Hz, 1 H), 5.14 (d, J =
10.1 Hz, 1 H), 5.91 (m, 1 H), 6.98 (s, 1 H), 7.24 (s, 1 H), 8.58 (s, 1
H).
MS (APCI): m/z = 263 [M + 1].
Anal. Calcd for C12H8F2N4O: C, 54.97; H, 3.08; N, 21.37. Found:
C, 55.13; H, 3.27; N, 21.45.
13C NMR (125 MHz, DMSO-d6): δ = 23.54, 25.20, 30.64, 31.85,
53.77, 55.49, 63.02, 117.94, 122.75, 128.11, 134.68, 141.93,
156.54, 159.09.
8-(1-Methyl-1H-imidazol-2-yl)-2,3-dihydro[1,4]dioxino[2,3-
g]quinoxalin-7(6H)-one (4c)
Black solid; yield: 3.8 g (91%); mp >200 °C (DMF).
1H NMR (500 MHz, DMSO-d6): δ = 3.83 (s, 3 H), 4.32 (s, 2 H), 4.38
(s, 2 H), 6.85 (s, 1 H), 7.09 (s, 1 H), 7.30 (s, 1 H), 7.36 (s, 1 H), 12.53
(s, 1 H).
13C NMR (125 MHz, DMSO-d6): δ = 35.08, 64.30, 65.22, 103.37,
115.29, 124.52, 127.69, 128.23, 129.71, 141.60, 142.69, 144.26,
147.63, 154.42.
MS (APCI): m/z = 259 [M + 1].
Anal. Calcd for C14H18N4O: C, 65.09; H, 7.02; N, 21.69. Found: C,
65.27; H, 7.24; N, 21.50.
3-(1-Allyl-1H-imidazol-2-yl)-5,6,7,8-tetrahydroquinoxalin-
2(1H)-one (7)
Compound 6c (100 mg) was dissolved in MeOH (5mL) and silica
gel (5 g) was added. The solvent was evaporated in vacuo. The solid
was transferred into to the column charged with silica gel (t-
BuOMe). Evaporation of the solvent afforded the pure compound 7
as a brown solid; yield: 52 mg (62%); mp 85 °C.
1H NMR (500 MHz, CDCl3): δ = 1.88 (m, 4 H), 2.83 (m, 2 H), 2.86
(m, 2 H), 5.11 (d, J = 16.7 Hz, 1 H), 5.20 (d, J = 10 Hz, 1 H), 5.35
(d, J = 5.5 Hz, 2 H), 6.02 (m, 1 H), 7.0 (s, 1 H), 7.10 (s, 1 H), 13.90
(s, 1 H).
MS (APCI): m/z = 285 [M + 1].
Anal. Calcd for C14H12N4O3: C, 59.15; H, 4.25; N, 19.71. Found: C,
59.34; H, 4.36; N, 19.62.
3-(1-Methyl-1H-imidazol-2-yl)-8,9-dihydro-7H-[1,4]dioxepi-
no[2,3-g]quinoxalin-2(1H)-one (4d)
Black solid; yield: 2.9 g (84%); mp >200 °C (DMF).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, A–F

F
O. V. Geraschenko et al.
PAPER
13C NMR (125 MHz, CDCl3): δ = 22.21, 22.59, 30.52, 31.43, 50.54,
117.35, 122.26, 125.17, 126.99, 133.13, 141.40, 142.35, 149.38,
156.97.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
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MS (APCI): m/z = 257 [M + 1].
References
Anal. Calcd for C14H16N4O: C, 65.61; H, 6.29; N, 21.86. Found: C,
65.74; H, 6.38; N, 21.79.
(1) Carta, A.; Piras, S.; Loriga, G.; Paglietti, G. Mini-Rev. Med.
Chem. 2006, 6, 1179; and references therein.
(2) Nikam, S. S.; Bigge, C. F. Drugs Future 1999, 24, 1107.
(3) Hyae-Gyeong, C.; Chul-Min, L.; Beom-Tae, K.; Ki-jun, H.
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3-(1-Methyl-1H-benzimidazol-2-yl)-4a,5,6,7,8,8a-hexahydro-
quinoxalin-2(1H)-one (6d)
White solid; yield: 2.6 g (45%); mp >200 °C (DMF).
1H NMR (500 MHz, DMSO-d6): δ = 1.21–1.49 (m, 4 H), 1.72 (m, 1
H), 1.79 (m, 1 H), 1.99 (m, 1 H), 2.29 (m, 1 H), 3.27 (m, 1 H), 3.41
(m, 1 H), 3.82 (s, 3 H), 7.28 (t, J = 7.7 Hz, 1 H), 7.35 (t, J = 7.7 Hz,
1 H), 7.60 (d, J = 7.7 Hz, 1 H), 7.69 (d, J = 7.7 Hz, 1 H), 8.80 (s, 1
H).
13C NMR (125 MHz, DMSO-d6): δ = 23.17, 25.27, 30.67, 31.43,
31.71, 53.92, 63.50, 111.01, 120.06, 122.63, 123.65, 135.96,
142.36, 148.25, 156.52, 156.78.
(4) Xun, L.; Yonggang, L.; Wenfang, X.; Jian, Z.; Huawei, Z.
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McClanahan, T. B.; Mertz, T. E.; Potoczak, R. E.;
Narasimhan, L. S.; Holland, D. R.; Rapundalo, S. T.;
Edmunds, J. J. J. Med. Chem. 2004, 47, 4089.
(8) Carta, A.; Sanna, P.; Loriga, M.; Setzu, M. G.; La Colla, P.;
Loddo, R. Farmaco 2002, 57, 19.
(9) Tang, A. H.; Franklin, S. R.; Himes, C. S.; Ho, P. M.
J. Pharmacol. Exp. Ther. 1991, 259, 248.
(10) Ager, I. R.; Barnes, A. C.; Danswan, G. W.; Hairsine, P. W.;
Kay, D. P.; Kennewell, P. D.; Matharu, S. S.; Miller, P.;
Robson, P.; Rowlands, D. A.; Tully, W. R.; Westwood, R.
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(11) Manca, P.; Peana, A.; Savelli, F.; Mule, A.; Pirisino, G.
Farmaco 1992, 47, 519.
(12) Brown, D. J. In Quinoxalines: Supplement II; Taylor, E. C.;
Wipf, P.; Weissberger, A., Eds.; John Wiley & Sons: New
Jersey, 2004, 92; 1–189-239.
(13) Gris, J.; Glisoni, R.; Fabian, L.; Fernández, B.; Moglioni, A.
Tetrahedron Lett. 2008, 49, 1053.
(14) Andrioletti, B.; Rose, E.; Szydlo, F.; Duhayon, C.
Tetrahedron Lett. 2008, 49, 3749.
MS (APCI): m/z = 283 [M + 1].
Anal. Calcd for C16H18N4O: C, 68.06; H, 6.43; N, 19.84. Found: C,
68.21; H, 6.57; N, 19.72.
1-[2-(Diethylamino)ethyl]-3-(1-methyl-1H-imidazol-2-yl)qui-
noxalin-2(1H)-one (8)
NaH (80 mg, 60% in mineral oil, 2 mmol) was added to a solution
of 3a (226.2 mg, 1 mmol) in DMSO (5 mL). After stirring the mix-
ture for 1 h at r.t., 2-chloro-N,N-diethylethylamine hydrochloride
(172.1 mg, 1 mmol) was added. The mixture was stirred overnight
at r.t. for 12 h. It was then poured into H2O (100 mL) and extracted
with EtOAc (2 × 20 mL). The organic layer was washed with brine,
dried (Na2SO4), and evaporated under vacuum. The solvent was dis-
tilled off under reduced pressure. The residue was purified by col-
umn chromatography (hexane–EtOAc, 1:1) to give 8 (172 mg, 0.53
mol, 53%) as an yellow oil.
1H NMR (500 MHz, CDCl3): δ = 1.07 (t, J = 6.7 Hz, 6 H), 2.67 (q,
J = 6.7 Hz, 4 H), 2.80 (t, J = 7.5 Hz, 2 H), 3.91 (s, 3 H), 4.40 (t, J =
7.5 Hz, 2 H), 7.02 (s, 1 H), 7.23 (s, 1 H), 7.33 (t, J = 7.8 Hz, 1 H),
7.42 (d, J = 7.8 Hz, 1 H), 7.58 (t, J = 7.8 Hz, 1 H), 7.88 (d, J = 7.8
Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 11.95, 35.52, 41.16, 47.61, 49.29,
113.73, 123.72, 124.16, 129.51, 130.68, 131.18, 132.66, 132.86,
142.29, 146.55, 153.43.
(15) Mukherjee, C.; Watanabe, K.; Biehl, E. Tetrahedron Lett.
2012, 53, 6008.
(16) Shi, F.; Tan, W.; Zhang, H.; Li, M.; Ye, Q.; Ma, G.; Tu, S.;
Li, G. Adv. Synth. Catal. 2013, 355, 3715.
(17) Geraschenko, O. V.; Khodakovskiy, P.; Shishkin, O.;
Mykhailiuk, P.; Zaporozhets, O.; Tolmachev, A. Synthesis
2011, 1633.
(18) Geraschenko, O. V.; Khodakovskiy, P. V.; Shivanyuk, O.
N.; Shishkin, O. V.; Mykhailiuk, P. K.; Tolmachev, A. A.
Synthesis 2012, 44, 1263.
MS (APCI): m/z = 326 [M + 1].
Anal. Calcd for C18H23N5O: C, 66.44; H, 7.12; N, 21.52. Found: C,
66.58; H, 7.30; N, 21.63.
(19) Soloshonok, V. A.; Ono, T. J. Org. Chem. 1997, 62, 3030.
(20) Unfortunately, all attempts to isolate the cis isomers from the
mother liquor failed.
Acknowledgement
All authors are grateful to Dr. Oleg Lozinski for help with the ma-
nuscript preparation.
(21) CCDC number for compound 6c is 913386.
Synthesis 2014, 46, A–F
© Georg Thieme Verlag Stuttgart · New York