Synthesis of multisubstituted dihydroquinoxaline derivatives by tandem N-alkylation and addition reactions of 3-oxoquinoxaline-2-carboxylates

Article abstract of DOI:10.1002/ejoc.201500225

This report describes a one-pot synthesis of multisubstituted dihydroquinoxalin-2-ones using an umpolung N-alkylation followed by oxidation and C-alkylation reactions. Moreover, the synthesis of tricyclic compounds containing a dihydroquinoxaline skeleton was carried out by ring closing metathesis (RCM) of the resulting N,C-bis-addition products containing olefins.

Full text of DOI:10.1002/ejoc.201500225

FULL PAPER
DOI: 10.1002/ejoc.201500225
Synthesis of Multisubstituted Dihydroquinoxaline Derivatives by Tandem
N-Alkylation and Addition Reactions of 3-Oxoquinoxaline-2-carboxylates
[a]
[b]
[b]
[a]
Satoru Miyamaru, Kazuto Umezu, Akinori Ito, and Makoto Shimizu*
Keywords: Tandem reactions / Umpolung / Metathesis / Alkylation / Nucleophilic addition / Nitrogen heterocycles
This report describes a one-pot synthesis of multisubstituted quinoxaline skeleton was carried out by ring closing metath-
dihydroquinoxalin-2-ones using an umpolung N-alkylation
followed by oxidation and C-alkylation reactions. Moreover,
the synthesis of tricyclic compounds containing a dihydro-
esis (RCM) of the resulting N,C-bis-addition products con-
taining olefins.
Introduction
to the electron-withdrawing effect of the imino group. We
have developed umpolung reactions of α-imino esters using
organometallic reagents to give N-alkylated products, and
the subsequent C–C bond formation was carried out using
the iminium salt formed by oxidation of the intermediate
Compounds containing a nitrogen atom often have a
wide variety of important biological activities. Those with
a dihydroquinoxaline skeleton are used in many biologically
[
1]
active compounds. Examples are used as pharmaceuticals,
[9]
metal enolate producted in the N-alkylation. In this paper,
including antiviral compound 1, used for the treatment of
we report a one-pot synthesis of multisubstituted di
hydroquinoxalin-2-ones by N-alkylation/C-alkylation reac-
tions of 3-oxo-quinoxalin-2-carboxylate derivatives.
[
2]
[3]
[4]
HIV, anticancer compound 2, antitumor agent 3, and
[5]
they are also used as agrochemicals (Scheme 1).
Results and Discussion
For the initial N-alkylation step, the optimum reaction
conditions were examined using quinoxaline derivatives 4.
As shown in Table 1, the reaction of quinoxaline derivative
4
a (0.15 mmol) with ethylmagnesium bromide (3 equiv.) in
Scheme 1. Valuable compounds containing a dihydroquinoxaline
skeleton.
EtCN at –78 °C for 15 min led to the formation of N-ethyl-
ated product 5a in 48% yield (Table 1, entry 1). The protect-
ing group of the amide nitrogen was next examined
Various approaches to the synthesis of dihydroquinox-
alin-2-ones have been reported. For example copper-cata-
(Table 1, entries 2 and 3). The use of a methyl group as a
[
3,6]
lysed couplings,
palladium-catalysed intramolecular N-
protecting group did not give the desired product (Table 1,
entry 2), whereas the tert-butoxycarbonyl (Boc) derivative
gave N-ethylated product 5a in good yield, presumably due
to the ability of the electron-withdrawing Boc group to en-
hance the reactivity of the imine nitrogen (Table 1, entry 3).
Next, we examined various solvents using the N-Boc-pro-
tected substrate (i.e., 4c). The use of polar solvents such
as EtCN, THF, DME (1,2-dimethoxyethane), and MeCN
[
7]
arylation, Ugi four-component reactions followed by
[8]
palladium-assisted intramolecular N-arylation, and bi-
functional inverse-electron-demand hetero-Diels–Alder re-
actions using Lewis acids.[ However, the synthesis of
simple multisubstituted dihydroquinoxalin-2-ones has ra-
rely been reported.
2]
An umpolung reaction of an α-imino ester involving
nucleophilic addition to the nitrogen atom is difficult due
(
Table 1, entries 3–6) gave the product (i.e., 5a) in good
yields, whereas the use of nonpolar (Table 1, entries 7 and
) solvents such as CH Cl and toluene gave 5a in moderate
[
[
a] Department of Chemistry for Materials, Graduate School of
Engineering, Mie University,
8
2
2
Tsu, Mie 514-8507, Japan
yields. When the reaction was carried out for a longer reac-
tion time, the desired product was obtained in 90% yield
E-mail: mshimizu@chem.mie-u.ac.jp
www.fine.chem.mie-u.ac.jp
b] Kazuto Umezu, Akinori Ito, Ihara Chemical Industry Co., (Table 1, entry 9). The amount of the nucleophile is very
Ltd.,
important: when the amount of EtMgBr was decreased
4
-26, Ikenohata 1-chome, Taito-ku, Tokyo 110-0008, Japan
(Table 1, entries 10 and 11), the yield of N-alkylated prod-
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500225.
uct 5a decreased, and the yield of N-Et-NЈ-Boc product 6c
Eur. J. Org. Chem. 2015, 3327–3337
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3327

S. Miyamaru, K. Umezu, A. Ito, M. Shimizu
FULL PAPER
Table 1. Optimization of reaction conditions.
Entry
4
R
Solvent
Temp. °[C]
Time [min]
Yield [%]
5a
6
1
2
3
4
5
6
7
8
9
4a
4b
4c
4c
4c
4c
4c
4c
4c
4c
4c
H
EtCN
EtCN
EtCN
THF
DME
MeCN
–78
–78
–78
–78
–78
–40
–78
–78
–78
–78
–78
15
15
15
15
15
15
15
15
30
30
30
48
0
–
0
0
[a]
Me
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
Boc
6b
6c
6c
6c
6c
6c
6c
6c
6c
6c
73
69
60
58
27
48
90
71
10
7
11
13
20
9
4
8
2 2
CH Cl
Toluene
EtCN
EtCN
EtCN
[
[
b]
c]
10
1
1
49
[a] A complex mixture was obtained. [b] EtMgBr (2.5 equiv.) was used. [c] EtMgBr (1.5 equiv.) was used.
increased. However, the combined yield of N-ethylated groups containing a carbonyl moiety gave the desired N-
products 5a and 6c was not satisfactory (Table 1, entries 10 ethylated product (i.e., 5a) in moderate to good yields
and 11).
(Table 2, entries 1–5). An N-tosyl derivative gave the desired
Under the optimized conditions (Table 1, entry 9), N-ethylated product (i.e., 5a) in low yield with concomitant
several electron-withdrawing N-protecting groups were formation of many by-products, which suggests that an
II
examined. Quinoxaline derivatives 4c–4g with N-protecting Mg -chelated intermediate between the lactam and the
Table 2. Examination of various electron-withdrawing N-protecting
groups.
Table 3. Scope of Grignard reagents for N-alkylation.
[
a] tBuMgCl was used. [b] Yield of N-tBu-NЈ-Boc product 6d is
given in parentheses.
3328
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Synthesis of Multisubstituted Dihydroquinoxaline Derivatives
Table 4. Optimization of the tandem N,C-dialkylation.
Entry
4
R
nPrMgBr [equiv.]
NBS [equiv.]
EtMgBr [equiv.]
Yield [%]
7a
8
5c
[
[
a]
a]
22 (17)[b]
1
2
3
4
5
6
7
8
9
4c
4c
4c
4e
4e
4e
4e
4e
4e
Boc
Boc
Boc
Ac
Ac
Ac
Ac
Ac
Ac
3.0
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
2.5
2.5
2.5
2.0
2.0
2.4
2.4
2.4
2.4
3.0
2.0
2.0
2.0
3.0
3.0
3.0
1.5
3.0
8c
8c
8c
8e
8e
8e
8e
8e
8e
0
0
24
6
0
0
0
0
0
3
44
0
11
7
8
9
28
22
40
56
65
71
29
75
[
[
[
c]
c]
25
0
c,d]
[a] TMSCl was not used. [b] N,C-Dipropylation product 7j was obtained. [c] TMSCl was added first. [d] NCS was used instead of NBS.
carbonyl oxygens of the protecting group plays an impor- effect of the amounts of reagents was examined using quin-
tant role (Table 2, entry 6).
oxaline derivative 4e as a starting material. When the
The scope of the reaction in terms of the Grignard rea-
gents was examined next (Table 3). Linear primary alkyl
Grignard reagents gave the desired N-alkylation products
Table 5. Scope of Grignard reagents for N,C-dialkylation.[a]
(i.e., 5a–5e) in good yields (Table 3, entries 1–5). In con-
trast, bulky nucleophiles such as secondary, tertiary alkyl,
and phenyl Grignard reagents gave the desired products
(i.e., 5f–5h) in low yields (Table 3, entries 6–8). When pri-
mary Grignard reagents with functional groups such as a
terminal alkene or a cyclic acetal were used, the desired
products (i.e., 5i and 5j) were also obtained in good yields
(Table 3, entries 9 and 10).
Further studies were carried out on the oxidation of the
intermediate enolate into an iminium salt, and the subse-
quent addition of another Grignard reagent. As expected,
the N,C-dialkylated products were obtained (Table 4).
The initial N-alkylation reaction was carried out under
the optimized conditions, and this was followed by the
addition of N-bromosuccinimide (NBS) as an oxidant
(2.5 equiv.) and EtMgBr (3.0 equiv.) (Table 4, entry 1).
However, the reaction gave the N-propyl C-ethylated prod-
uct (i.e., 7a) in low yield, and the N,C-dipropylated product
was obtained as a by-product in 17% yield. When the
amount of nPrMgBr (1.5 equiv.) was decreased, none of the
N,C-dipropylated product was obtained (Table 4, entry 2).
When trimethylsilyl chloride (TMSCl) was used as an addi-
tive, the N-propyl C-ethylated products (i.e., 7a and 8c)
were obtained in moderate yields, which suggests that a
TMS enol derivative generated by silylation of the magne-
sium enolate intermediate would be suitable for oxidation
into an iminium salt (Table 4, entry 3). When quinoxaline
derivative 4e bearing an acetyl group was subjected to the
reaction conditions, the N-propyl C-ethylated product (i.e.,
1
[
a] TMSCl was added after the addition of R MgBr. [b] Using
7a) was obtained in 40% yield (Table 4, entry 4). Next, the tetraallyltin instead of allylmagnesium bromide.
Eur. J. Org. Chem. 2015, 3327–3337
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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3329

S. Miyamaru, K. Umezu, A. Ito, M. Shimizu
FULL PAPER
amounts of the nucleophile and the oxidant were increased, (i.e., 7g–7i) were obtained in good yields (Table 5, entries 7–
the desired product (i.e., 7a) was obtained in good yields 9).
(Table 4, entries 5 and 6). Furthermore, when TMSCl was
A proposed reaction mechanism for the N-alkylation and
added initially, the N-propyl-C-ethylated product (i.e., 7a) N,C-dialkylation reaction is shown in Scheme 2. The elec-
was obtained in 71% yield (Table 4, entry 7). Decreasing tron density of the nitrogen atom of the imino group of
the amount of EtMgBr (1.5 equiv.) led to the formation of intermediate A decreases as a result of chelation with the
the desired product (i.e., 7a) in low yield, while the yield of magnesium halide, and therefore, the electrophilicity of the
N-alkylated product 5c increased (Table 4, entry 8). When nitrogen atom increases. N-Alkylation of quinoxaline deriv-
NCS (N-chlorosuccinimide) was used as the oxidant instead ative 4 generates magnesium enolate B. The addition of an-
of NBS, the best yield of 75% was obtained (Table 4, other Grignard reagent to the carbonyl group of the pro-
entry 9).
tecting group proceeds to form bis-magnesium species D,
The scope of the reaction in terms of the Grignard and hydrolysis of salt D gives the N-alkylated product (i.e.,
reagents was next examined under the optimized conditions 5). Regarding the N,C-dialkylation, N-alkylation/silylation
(Table 5). Primary alkyl Grignard reagents gave N,C-di- of quinoxaline derivative 4 generates ketene silyl acetal E
alkylated products in good yields (Table 5, entries 1, 2, 4, via magnesium enolate B. Two reaction pathways are
and 5), while iPrMgBr and the Grignard reagent containing possible. Deacetylation of ketene silyl acetal E with the
a cyclic acetal gave the desired products in moderate yields Grignard reagent forms dianion F (Path A). Dianion F
(Table 5, entries 3 and 6). In order to synthesize dihydro- reacts with an excess of TMSCl to give bis-trimethylsilyl
quinoxaline derivatives containing tricyclic structures, derivative G. Bis-trimethylsilyl derivative G is oxidized to
homoallyl and vinyl Grignard reagents, and tetraallyltin give iminium salt H, which reacts with another Grignard
were used. As a result, the desired N,C-dialkylated products reagent to give N,C-dialkylated product 7 after hydrolysis
Scheme 2. Proposed reaction mechanism.
3330
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Eur. J. Org. Chem. 2015, 3327–3337

Synthesis of Multisubstituted Dihydroquinoxaline Derivatives
of silylated product I. Alternatively, ketene silyl acetal E is The reaction of tricyclic compound 9g under H (1 atm) in
2
oxidized before the deacetylation to form iminium salt J, the presence of Pd(OH) /C (Pearlman’s catalyst, 4 mol-%)
2
which reacts with another Grignard reagent to give N,C- in EtOH for 1 h gave the desired product (i.e., 10g) in 91%
dialkylated product K. Deacetylation of K with an extra yield.
Grignard reagent gives N,C-dialkylated product 7 (Path B).
Finally, we examined a synthesis of tricyclic compounds
through a ring closing metathesis (RCM) reaction of N- Conclusions
homoallyl-C-vinyl compound 7g with Grubbs catalysts
In summary, we have developed a one-pot synthesis of
[
10]
(
Table 6). First, the reaction of the N-homoallyl-C-vinyl
compound 7g with Grubbs first-generation catalyst (4 mol-
) in toluene at reflux for 12 h gave tricyclic product 9g
multisubstituted dihydroquinoxalin-2-ones using an
umpolung N-alkylation and N,C-dialkylation. This method
is useful because it enables the introduction of two substitu-
ents into a dihydroquinoxaline skeleton in a one-pot pro-
cedure. Tricyclic compounds containing a dihydroquinox-
aline skeleton are attractive, because many of them show a
wide variety of biological activities. These compounds are
also readily accessible by the method described here.
%
in 55% yield (Table 6, entry 1). By using Grubbs second-
generation catalyst or Hoveyda–Grubbs’ second-generation
catalyst, the desired tricyclic product (i.e., 9g) was obtained
in high yields (Table 6, entries 2 and 3).
Table 6. Synthesis of tricyclic compounds by RCM.
Experimental Section
General Information: Infrared spectra were determined with a
1
13
JASCO FTIR 460 plus spectrometer. H and C NMR spectra
were recorded with a JEOL ECX-400P or a JEOL A-500 spectrom-
eter using tetramethylsilane as an internal standard. Mass spectra
were recorded with a JEOL MS-700D spectrometer. Tetra-
hydrofuran (THF) was distilled from benzophenone ketyl immedi-
ately before use. Dimethoxyethane (DME) was distilled from cal-
cium hydride and then from copper(I) chloride, and stored over
sodium. Toluene was dried with calcium chloride, distilled, and
stored over molecular sieves (4 Å). Propionitrile (EtCN) and aceto-
nitrile (MeCN) were distilled from phosphorus pentaoxide and
then from calcium hydride, and stored over molecular sieves (4 Å).
Entry Catalyst
Time [h]
Yield [%]
55[a]
78
1
2
3
Grubbs 1st
Grubbs 2
Hoveyda–Grubbs 2
12
3
3
nd
nd
84
[a] Carried out at reflux for 12 h.
Furthermore, the RCM of N,C-dialkylated compounds Dichloromethane (CH Cl ) was distilled from calcium hydride, and
2
2
7
(
g–7i was examined under the optimized conditions stored over molecular sieves (4 Å). Products were purified by col-
Scheme 3). The reaction of N-homoallyl C-vinyl product umn chromatography on silica gel (Kanto silica Gel 60N) and/or
preparative TLC on silica gel (Merck Kieselgel GF254).
7g and N-homoallyl C-allyl derivative 7h gave the desired
tricyclic products (i.e., 9g and 9h) in good yields. Using the Ethyl 2-Hydroxy-3-quinoxalinecarboxylate (4a): A 100 mL two-
N,C-dihomoallyl compound as substrate, the desired prod- necked round-bottomed flask was equipped with a magnetic stirrer
uct (i.e., 9i) was obtained in good yield under the influence bar, a rubber septum, and an argon balloon. 1,2-Benzenediamine
(
7.0 g, 40 mmol) was dissolved in EtOH (50 mL), and diethyl 2-
of the Grubbs first-generation catalyst in CH Cl . Re-
duction of the newly formed olefin was readily carried out.
2
2
ozomalonete (36.1 mL, 20 mmol) was added. The reaction mixture
was heated at reflux for 1 h with azeotropic removal of water, and
then it was concentrated in vacuo to give ethyl 2-hydroxy-3-quinox-
alinecarboxylate 4a (8.8 g, 95%) as a yellow solid, m.p. 175.5–
1
1
76.5 °C. H NMR (400 MHz, CDCl
3
): δ = 1.48 (t, J = 7.1 Hz, 3
H), 4.55 (q, J = 7.1 Hz, 2 H), 7.37–7.43 (m, 2 H), 7.61–7.65 (m, 1
1
3
H), 7.96–7.98 (m, 1 H), 11.72 (br., 1 H) ppm. C NMR (100 MHz,
CDCl ): δ = 14.2, 62.5, 116.5, 125.0, 130.1, 132.0, 132.1, 132.7,
48.4, 154.7, 163.4 ppm. IR (neat): ν˜ = 2965, 1741, 1658, 1611,
3
1
1
–
1
300, 1254, 1133, 1092, 902, 767, 755 cm . HRMS (EI): calcd. for
+
C
11
H
10
N
2
O
3
[M] 218.0691; found 218.0686.
Ethyl 4-Methyl-3-oxo-3,4-dihydroquinoxaline-2-carboxylate (4b): A
00 mL two-necked round-bottomed flask was equipped with a
2
magnetic stirrer bar, a rubber septum, and an argon balloon. A
solution of ethyl 2-hydroxy-3-quinoxalinecarboxylate (4a; 2.1 g,
9
.2 mmol) in DME (50 mL) was stirred at –5 °C to 5 °C, and then
NaH (60% in oil; 0.41 g, 10.2 mmol) was added. The resulting mix-
ture was stirred at room temperature. After 1 h, CH I (0.86 mL,
3.8 mmol) was added, and the mixture was stirred for 16 h. The
3
1
Scheme 3. Scope of the approach to tricyclic compounds. [a] Reac-
tion conditions: Grubbs first-generation catalyst (4 mol-%),
2
reaction was quenched with H O (50 mL), and the mixture was
CH
2
Cl
2
(10 mL)
,
room temp., 16 h.
extracted with ethyl acetate (3ϫ 10 mL). The combined extracts
3331
Eur. J. Org. Chem. 2015, 3327–3337
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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S. Miyamaru, K. Umezu, A. Ito, M. Shimizu
FULL PAPER
were washed with brine, dried with anhydrous Na
2
SO
4
, and con-
(400 MHz, CDCl
3
): δ = 1.48 (t, J = 7.2 Hz, 3 H), 2.47 (s, 3 H),
centrated in vacuo. The crude product was purified by silica gel
4.54 (q, J = 7.2 Hz, 2 H), 7.82–7.91 (m, 2 H), 8.05–8.07 (m, 1 H),
8.28–8.30 (m, 1 H) ppm. C NMR (100 MHz, CDCl ): δ = 14.2,
3
1
3
column chromatography (n-hexane/ethyl acetate, 2:3) to give 4b
1
(
1.9 g, 88%) as a white solid, m.p. 124.5–125.5 °C. H NMR 21.0, 62.7, 128.3, 130.0, 130.5, 132.9, 138.2, 140.4, 141.7, 150.3,
(
3
400 MHz, CDCl ): δ = 1.45 (t, J = 7.3 Hz, 3 H), 3.74 (s, 3 H), 162.8, 169.1 ppm. IR (neat): ν˜ = 2985, 1941, 1767, 1722, 1569,
–
1
4
7
2
1
1
2
.51 (q, J = 7.3 Hz, 2 H), 7.35–7.42 (m, 2 H), 7.64–7.69 (m, 1 H), 1374, 1326, 1186, 1135, 1084, 1011, 896, 770 cm . HRMS (EI):
.94–7.97 (m, 1 H) ppm. 13C NMR (100 MHz, CDCl
): δ = 14.1, calcd. for C13
H
N
[M] 260.0797; found 260.0784.
+
3
12
2
O
4
9.1, 62.3, 113.8, 124.2, 131.3, 132.5, 134.0, 149.0, 152.6,
Ethyl
4-Benzyloxycarbonyl-3-oxo-3,4-dihydroquinoxaline-2-carb-
63.8 ppm. IR (neat): ν˜ = 2997, 1740, 1666, 1469, 1309, 1367, 1246,
–1
+
oxylate (4f): A 50 mL two-necked round-bottomed flask was
equipped with a magnetic stirrer bar, a rubber septum, and an
argon balloon. Ethyl 2-hydroxy-3-quinoxalinecarboxylate (4a;
0.93 g, 4.0 mmol) was dissolved in THF (35 mL), and NaH (60%
in oil; 0.41 g, 10.2 mmol) was added. The mixture was stirred for
1 h at room temperature, then benzyl chloroformate (0.86 mL,
6.0 mmol) was added. The mixture was stirred at room temperature
for 4 h, and the precipitate was removed by filtration with the aid
of ethyl acetate. The filtrate was concentrated in vacuo. The crude
167, 1082, 761 cm . HRMS (EI): calcd. for C12
12 2 3
H N O [M]
32.0848; found 232.08412.
Ethyl 4-tert-Butoxycarbonyl-3-oxo-3,4-dihydroquinoxaline-2-carb-
oxylate (4c): A 100 mL two-necked round-bottomed flask was
equipped with a magnetic stirrer bar, a rubber septum, and an
argon balloon Ethyl 2-hydroxy-3-quinoxalinecarboxylate (4a; 1.2 g,
5
0
.0 mmol) and DMAP (4-dimethylaminopyridine; 61.0 mg,
.5 mmol) were dissolved in THF (40 mL), and then Boc
N (0.7 mL, 5.0 mmol)
were added. The resulting mixture was stirred at room temperature
for 3 h, then the reaction was quenched with H O (20 mL). The
mixture was extracted with ethyl acetate (2ϫ 20 mL). The com-
bined extracts were dried with anhydrous Na SO , and concen-
2
O
(5.7 mL, 25 mmol), DMF (8.0 mL), and Et
3
product was purified by silica gel column chromatography (toluene/
1
ethyl acetate, 10:1) to give 4f (332 mg, 26%) as a yellow oil.
NMR (400 MHz, CDCl
H
2
3
): δ = 1.39 (t, J = 7.0 Hz, 3 H), 4.46 (q, J
= 7.3 Hz, 2 H), 5.36 (s, 2 H), 7.36–7.42 (m, 3 H), 7.46–7.48 (m, 2
H), 7.84–7.92 (m, 2 H), 8.06–8.07 (m, 1 H), 8.29–8.30 (m, 1 H)
2
4
1
3
trated in vacuo. The crude product was purified by silica gel col-
ppm. C NMR (100 MHz, CDCl
3
): δ = 14.0, 62.8, 71.1, 128.3,
umn chromatography (n-hexane/ethyl acetate, 7:2) to give 4c (1.3 g,
128.6, 128.8, 129.9, 130.7, 133.0, 134.1, 138.1, 140.6, 141.3, 149.6,
1
81%) as a yellow oil. H NMR (400 MHz, CDCl
3
): δ = 1.49 (t, J 152.3, 162.6 ppm. IR (neat): ν˜ = 2983, 1766, 1728, 1574, 1468,
–
1
=
7.3 Hz, 3 H), 1.60 (s, 9 H), 4.55 (q, J = 7.3 Hz, 2 H), 7.82–7.91
1330, 1211, 1142, 1093, 785 cm . HRMS (EI): calcd. for
13
+
(
(
1
2
7
m, 2 H), 8.06–8.08 (m, 1 H), 8.28–8.30 (m, 1 H) ppm. C NMR
100 MHz, CDCl ): δ = 14.2, 27.6, 62.7, 85.1, 128.4, 129.9, 130.5,
32.8, 138.6, 140.4, 141.5, 149.9, 150.4, 162.9 ppm. IR (neat): ν˜ =
983, 1761, 1728, 1574, 1469, 1372, 1345, 1244, 1138, 1084,
19 16 2 5
C H N O [M] 352.1059; found 352.1064.
3
Ethyl 4-(Dimethylcarbamoyl)-3-oxo-3,4-dihydroquinoxaline-2-carb-
oxylate (4g): A 50 mL two-necked round-bottomed flask was
equipped with a magnetic stirrer bar, a rubber septum, and an
argon balloon. Ethyl 2-hydroxy-3-quinoxalinecarboxylate (4a;
–1
+
18 2 5
68 cm . HRMS (EI): calcd. for C16H N O [M] 318.1216;
found 318.1230.
1.2 g, 5.0 mmol), DMAP (61.0 mg, 0.5 mmol), and Et
3
N (0.84 mL,
Ethyl 4-Benzoyl-3-oxo-3,4-dihydroquinoxaline-2-carboxylate (4d): A
6.0 mmol) were dissolved in CH Cl (30 mL), and dimethylcarbam-
2
2
2
00 mL two-necked round-bottomed flask was equipped with a
magnetic stirrer bar, a rubber septum, and an argon balloon. Ethyl
-hydroxy-3-quinoxalinecarboxylate (4a; 0.93 g, 4.0 mmol) was dis-
solved in Et O (25 mL), and NaH (60% in oil; 0.41 g, 10.2 mmol)
oyl chloride (0.7 mL, 7.5 mmol) was added at 0 °C. The mixture
was stirred at 0 °C for 19 h, then at room temperature for 14 h, and
then it was concentrated in vacuo. The crude product was purified
by silica gel column chromatography (toluene/ethyl acetate, 10:2)
2
2
1
was added. The mixture was stirred for 1 h at room temperature,
then benzoyl chloride (0.7 mL, 6.0 mmol) was added. The mixture
was stirred at room temperature for 14 h, and then it was concen-
trated in vacuo. The crude product was purified by silica gel col-
umn chromatography (n-hexane/ethyl acetate, 4:1) to give 4d (1.0 g,
to give 4g (151 mg, 10%) as a yellow solid, m.p. 97.1–97.8 °C. H
NMR (400 MHz, CDCl
3
): δ = 1.46 (t, J = 7.1 Hz, 3 H), 3.06 (s, 3
H), 3.24 (s, 3 H), 4.49 (q, J = 7.1 Hz, 2 H), 7.78–7.88 (m, 2 H),
1
3
8.04–8.28 (m, 1 H), 8.26–8.28 (m, 1 H) ppm. C NMR (100 MHz,
CDCl ): δ = 14.1, 36.8, 62.5, 128.2, 129.9, 130.0, 132.5, 139.2,
140.0, 141.6, 150.6, 153.4, 163.2 ppm. IR (neat): ν˜ = 2978, 1730,
3
7
9%) as a white solid, m.p. 134.5–135 °C. 1H NMR (400 MHz,
–
1
CDCl ): δ = 1.25 (t, J = 7.1 Hz, 3 H), 4.41 (q, J = 7.1 Hz, 2 H), 1574, 1486, 1384, 1329, 1261, 1216, 1161, 776 cm . HRMS (EI):
3
+
7
8
.54–7.58 (m, 2 H), 7.68–7.72 (m, 1 H), 7.85–7.94 (m, 2 H), 8.10–
.12 (m, 1 H), 8.28–8.35 (m, 3 H) ppm. 13C NMR (100 MHz,
): δ = 13.9, 62.7, 128.4, 128.7, 130.1, 130.6, 132.9, 134.3,
38.8, 140.6, 141.8, 150.6, 162.8, 164.9 ppm. IR (neat): ν˜ = 2989,
744, 1724, 1148, 1327, 1240, 1210, 1140, 1088, 10545, 765,
calcd. for C14
15 3 4
H N O [M] 289.1063; found 289.1057.
Ethyl 3-Oxo-4-tosyl-3,4-dihydroquinoxaline-2-carboxylate (4h): A
CDCl
3
200 mL two-necked round-bottomed flask was equipped with a
1
1
7
magnetic stirrer bar, a rubber septum, and an argon balloon. Ethyl
2-hydroxy-3-quinoxalinecarboxylate (4a; 0.93 g, 4.0 mmol) was dis-
solved in THF (30 mL), and NaH (60% in oil; 0.19 g, 4.8 mmol)
was added. The mixture was stirred for 30 min at room tempera-
ture, then p-toluenesulfonyl chloride (0.92 g, 4.8 mmol) was added.
The mixture was stirred at room temperature for 3 h, and then it
was concentrated in vacuo. The crude product was purified by silica
gel column chromatography (n-hexane/ethyl acetate, 5:2) to give 4h
–1
+
14 2 4
44 cm . HRMS (EI): calcd. for C18H N O [M] 322.0954;
found 322.0945.
Ethyl 4-Acetyl-3-oxo-3,4-dihydroquinoxaline-2-carboxylate (4e): A
5
0 mL two-necked round-bottomed flask was equipped with a
magnetic stirrer bar, a rubber septum, and an argon balloon. Ethyl
-hydroxy-3-quinoxalinecarboxylate (4a; 0.93 g, 4.0 mmol) was dis-
2
1
solved in THF (35 mL), and NaH (60% in oil; 0.41 g, 10.2 mmol)
was added. The mixture was stirred at room temperature for 1 h,
then acetyl chloride (0.43 mL, 6.0 mmol) was added. The mixture
was stirred at room temperature for 18 h, and then it was concen-
trated in vacuo. The crude product was purified by silica gel col-
(1.07 g, 71%) as yellow crystals, m.p. 110–111 °C. H NMR
3
(400 MHz, CDCl ): δ = 1.46 (t, J = 7.1 Hz, 3 H), 2.48 (s, 3 H),
4.54 (q, J = 7.1 Hz, 2 H), 7.39–7.41 (m, 2 H), 7.79–7.87 (m, 2 H),
7.92–7.95 (m, 1 H), 8.04–8.06 (m, 2 H), 8.20–8.23 (m, 1 H) ppm.
1
3
C NMR (100 MHz, CDCl
3
): δ = 14.0, 21.7, 62.9, 128.1, 129.1,
umn chromatography (n-hexane/ethyl acetate, 7:3) to give 4e
129.7, 129.8, 130.5, 132.7, 133.7, 138.7, 134.0, 140.5, 145.8, 148.7,
1
(466 mg, 44%) as a yellow solid, m.p. 86.7–87.5 °C. H NMR 162.7 ppm. IR (neat): ν˜ = 2989, 1733, 1466, 1571, 1368, 1326, 1266,
3332
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 3327–3337

Synthesis of Multisubstituted Dihydroquinoxaline Derivatives
–1
S [M]+ 7.1, 7.1 Hz, 3 H), 1.60–1.78 (m, 2 H), 3.12 (ddd, J = 14.0, 8.5,
6.4 Hz, 1 H), 3.52 (ddd, J = 14.0, 8.6, 5.6 Hz, 1 H), 4.14 (dq, J =
1
3
202, 1070, 779 cm . HRMS (EI): calcd. for C18
72.0780; found 372.0791.
16 2 5
H N O
7
1
1
1
1
.2, 1.9 Hz, 2 H), 4.60 (s, 1 H), 6.74–6.80 (m, 3 H), 7.00–7.04 (m,
H), 8.23 (br. s, 1 H) ppm. C NMR (100 MHz, CDCl ): δ =
3
1.4, 14.1, 20.0, 51.3, 61.9, 65.2, 112.6, 115.6, 119.0, 124.4, 125.3,
N-Ethylation of Ethyl 4-tert-Butoxycarbonyl-3-oxo-3,4-dihydroquin-
oxaline-2-carboxylate (4c): (Table 1, entry 9): Under an argon at-
mosphere, a suspension of ethyl 4-tert-butoxycarbonyl-3-oxo-3,4-
dihydroquinoxaline-2-carboxylate (4c; 47.7 mg, 0.15 mmol) in
EtCN (1.0 mL) was stirred at –78 °C for 5 min, and then EtMgBr
1
3
33.9, 162.4, 167.7 ppm. IR (neat): ν˜ = 3194, 2964, 2871, 1745,
–
1
697, 1650, 1506, 1468, 1432, 1387, 1205, 750 cm . HRMS (EI):
+
calcd. for C14
Ethyl 1-Butyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-2-carboxylate
(5d): White solid (30.3 mg, 73%), m.p. 105.0–105.8 °C. H NMR
(400 MHz, CDCl ): δ = 0.95 (t, J = 7.4 Hz, 3 H), 1.18 (dd, J = 7.2,
18 2 3
H N O [M] 262.1317; found 262.1329.
(1.03 n in THF; 0.44 mL, 0.45 mmol, 3.0 equiv.) was added slowly.
The mixture was stirred for 25 min at that temperature, and then
it was stirred further at room temperature for 5 min. The reaction
1
was quenched with satd. aq. NaHCO
3
(20 mL), and the mixture
3
was extracted with ethyl acetate (3ϫ 10 mL). The combined or-
ganic extracts were washed with brine, dried with anhydrous
7.1 Hz, 3 H), 1.39 (tq, J = 14.6, 7.4 Hz, 2 H), 1.55–1.73 (m, 2 H),
3.16 (ddd, J = 14.5, 8.3, 6.2 Hz, 1 H), 3.56 (ddd, J = 14.5, 8.3,
5.7 Hz, 1 H), 4.13 (dq, J = 7.2, 1.7 Hz, 2 H), 4.61 (s, 1 H), 6.75–
Na
fied on silica gel TLC (n-hexane/ethyl acetate, 7:3) to give 5a
33.6 mg, 90%) and 6c (2.1 mg, 4%).
2 4
SO , and concentrated in vacuo. The crude product was puri-
1
3
6.81 (m, 3 H), 6.99–7.03 (m, 1 H), 7.26 (br. s, 1 H) ppm. C NMR
(100 MHz, CDCl ): δ = 13.8, 14.1, 20.2, 28.9, 49.2, 61.9, 65.1,
12.6, 115.7, 119.0, 124.4, 125.4, 133.9, 162.7, 167.7 ppm. IR
(neat): ν˜ = 3203, 3127, 2962, 2930, 2869, 1745, 1697, 1505, 1430,
(
3
1
Ethyl 1-Ethyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-2-carboxylate
1
(
5a): White solid, m.p. 119.5–120.5 °C. H NMR (400 MHz,
–
1
1
[
20 2 3
385, 1207, 1178, 754 cm . HRMS (EI): calcd. for C15H N O
3
CDCl ): δ = 1.17 (dd, J = 7.1, 7.1 Hz, 3 H), 1.27 (dd, J = 7.3,
+
M] 276.1474; found 276.1477.
7
7
6
.3 Hz, 3 H), 3.29 (dq, J = 14.1, 7.1 Hz, 1 H), 3.58 (dq, J = 14.1,
.1 Hz, 1 H), 4.13 (dq, J = 7.3, 7.3 Hz, 2 H), 6.75–6.83 (m, 3 H), Ethyl
.99–7.03 (m, 1 H), 9.46 (s, 1 H) ppm. C NMR (100 MHz, (5e): Yellow oil (34.7 mg, 76%). H NMR (400 MHz, CDCl
1-Hexyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-2-carboxylate
13
1
3
): δ =
CDCl
3
): δ = 12.3, 14.0, 43.7, 61.8, 64.3, 112.4, 115.9, 119.1, 124.4,
0.89 (t, J = 6.9 Hz, 3 H), 1.17 (dd, J = 7.5, 7.5 Hz, 3 H), 1.26–1.39
1
2
25.5, 133.7, 163.2, 167.8 ppm. IR (neat): ν˜ = 3186, 3058, 2975, (m, 6 H), 1.56–1.73 (m, 2 H), 3.15 (ddd, J = 14.1, 8.5, 5.9 Hz, 1
–
1
918, 1748, 1692, 1593, 1506, 1472, 1435, 1343, 1252, 744 cm .
H), 3.54 (ddd, J = 14.1, 8.5, 5.9 Hz, 1 H), 4.14 (dq, J = 7.5, 1.6 Hz,
+
HRMS (EI): calcd. for
48.1153.
C
13
H
16
N
2
O
3
[M] 248.1611; found
2 H), 4.61 (s, 1 H), 6.78–6.79 (m, 3 H), 6.99–7.03 (m, 1 H), 8.71
1
3
2
(br. s, 1 H) ppm. C NMR (100 MHz, CDCl
3
): δ = 14.0, 14.1,
2.5, 26.7, 26.7, 31.5, 49.5, 61.9, 65.1, 112.5, 119.0, 124.4, 125.3,
33.8, 162.7, 167.7 ppm. IR (neat): ν˜ = 3208, 2955, 2868, 1742,
2
1
1
Ethyl 4-tert-Butoxycarbonyl-1-ethyl-3-oxo-3,4-dihydroquinoxaline-
1
2
-carboxylate (6c): Yellow oil. H NMR (400 MHz, CDCl
3
): δ =
–
1
695, 1505, 1469, 1429, 1385, 1207, 1031, 755 cm . HRMS (EI):
1.12 (dq, J = 7.2, 7.2 Hz, 3 H), 1.25 (t, J = 7.1 Hz, 3 H), 1.56 (s, 9
+
24 2 3
calcd. for C17H N O [M] 304.1787; found 304.1793.
H), 3.30 (dq, J = 14.4, 7.2 Hz, 1 H), 3.56 (dq, J = 14.4, 7.2 Hz, 1
H), 4.14 (q, J = 7.1 Hz, 2 H), 4.93 (s, 1 H), 6.74–6.81 (m, 2 H),
Ethyl 1-Isopropyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-2-carboxylate
(5f): White solid (7.6 mg, 20%), m.p. 108.5–109.5 °C. 1H NMR
.12–7.23 (m, 2 H) ppm. 1 C NMR (100 MHz, CDCl
4.0, 27.6, 43.8, 59.3, 61.8, 84.8, 111.2, 118.5, 127.5, 128.7, 130.2,
3
7
1
1
1
C
3
): δ = 12.1,
(
=
400 MHz, CDCl
1.4 Hz, 3 H), 1.27 (d, J = 0.9 Hz, 3 H), 4.01–4.15 (m, 3 H), 4.71
(s, 1 H), 6.73–6.80 (m, 2 H), 6.90–6.92 (m, 1 H), 7.00–7.04 (m, 1
3
): δ = 1.17 (dd, J = 7.1, 7.1 Hz, 3 H), 1.26 (d, J
36.1, 148.7, 148.8, 167.3 ppm. IR (neat): ν˜ = 2980, 1742, 1693,
–1
490, 1371, 1250, 1200, 1130, 748 cm . HRMS (EI): calcd. for
1
3
+
3
H), 8.01 (br. s, 1 H) ppm. C NMR (100 MHz, CDCl ): δ = 13.9,
18
H
24
N
2
O
5
[M] 348.1685; found 348.1686.
1
1
1
9.9, 20.8, 49.9, 59.3, 61.9, 114.1, 115.8, 119.1, 124.4, 125.9, 134.1,
N-Methylation of Ethyl 4-tert-Butoxycarbonyl-3-oxo-3,4-dihydro-
quinoxaline-2-carboxylate (4c): (Table 3, entry 2): Under an argon
atmosphere, a suspension of ethyl 4-tert-butoxycarbonyl-3-oxo-3,4-
dihydroquinoxaline-2-carboxylate (4c; 47.7 mg, 0.15 mmol) in
EtCN (1.0 mL) was stirred at –78 °C for 5 min, and then MeMgBr
0.97 n in THF; 0.46 mL, 0.45 mmol, 3.0 equiv.) was added slowly.
The mixture was stirred for 25 min at that temperature, and then
it was stirred further at room temperature for 5 min. The reaction
63.0, 168.9 ppm. IR (neat): ν˜ = 3186, 3050, 2979, 2914, 2871,
–
1
737, 1677, 1505, 1438, 1396, 1367, 1296, 1193, 748 cm . HRMS
+
(
EI): calcd. for C14
18 2 3
H N O [M] 262.1317; found 262.1328.
Ethyl 3-Oxo-1-phenyl-1,2,3,4-tetrahydroquinoxaline-2-carboxylate
(
(
5g): White solid (7.6 mg, 20%), m.p. 191.0–192.0 °C. 1H NMR
400 MHz, CDCl ): δ = 1.20 (dd, J = 7.1, 7.1 Hz, 3 H), 4.21 (dq,
(
3
J = 7.1, 3.0 Hz, 2 H), 5.10 (s, 1 H), 6.91–6.97 (m, 3 H), 7.10–7.14
m, 2 H), 7.22–7.25 (m, 2 H), 7.32–7.77 (m, 2 H), 9.00 (br. s, 1 H)
(
was quenched with satd. aq. NaHCO
was extracted with ethyl acetate (3ϫ 10 mL). The combined ex-
tracts were washed with brine, dried with anhydrous Na SO , and
3
(20 mL), and the mixture
1
3
ppm. C NMR (100 MHz, CDCl
3
): δ = 14.0, 62.3, 65.6, 116.6,
17.8, 121.5, 121.7, 123.9, 124.1, 126.9, 129.5, 131.3, 144.3, 163.1,
67.7 ppm. IR (neat): ν˜ = 179, 3073, 3045, 2983, 2916, 1740, 1684,
1
1
1
2
4
concentrated in vacuo. The crude product was purified on silica
gel TLC (n-hexane/ethyl acetate, 7:3) to give ethyl 1-methyl-3-oxo-
–
1
597, 1502, 1373, 1281, 1127, 756 cm . HRMS (EI): calcd. for
+
17 16 2 3
C H N O [M] 296.1161; found 296. 1164.
1
,2,3,4-tetrahydroquinoxaline-2-carboxylate (5b; 23.0 mg, 65%) as
1
a white solid, m.p. 146.5–147.0 °C. H NMR (400 MHz, CDCl
3
):
Ethyl 4-tert-Butoxycarbonyl-1-tert-butyl-3-oxo-3,4-dihydroquinox-
1
δ = 1.18 (t, J = 7.1 Hz, 3 H), 3.02 (s, 3 H), 4.14 (q, J = 7.1 Hz, 2
aline-2-carboxylate (6d): Yellow oil (4.9 mg, 9%). H NMR
H), 4.53 (s, 1 H), 6.73–6.82 (m, 3 H), 7.00–7.06 (m, 1 H), 9.02 (br. (400 MHz, CDCl ): δ = 1.12 (t, J = 7.1 Hz, 3 H), 1.29 (s, 9 H),
3
s, 1 H) ppm. 13C NMR (100 MHz, CDCl
7.0, 112.1, 115.5, 119.3, 124.5, 125.2, 134.4, 162.6, 167.0 ppm. IR
neat): ν˜ = 3073, 2976, 2872, 1729, 1685, 1441, 1406, 1305, 1227, 14.0, 26.0, 27.6, 37.8, 61.8, 70.9, 85.2, 115.5, 115.9, 120.4, 124.5,
): δ = 14.1, 36.8, 61.9, 1.62 (s, 9 H), 4.10 (q, J = 7.1 Hz, 2 H), 4.62 (s, 1 H), 6.80–6.85 (m,
3
1
3
6
3
3 H), 6.94–6.98 (m, 1 H) ppm. C NMR (100 MHz, CDCl ): δ =
(
7
–1
+
38 cm . HRMS (EI): calcd. for C12
H
14
N
2
O
3
[M] 234.1004;
124.7, 133.5, 151.0, 163.1, 170.1 ppm. IR (neat): ν˜ = 2980, 2873,
–
1
found 234.1002.
1764, 1739, 1705, 1493, 1456, 1396, 1369, 1242, 1150 cm . HRMS
+
(
EI): calcd. for C20
28 2 5
H N O [M] 376.1998; found 376.1991.
Ethyl 3-Oxo-1-propyl-1,2,3,4-tetrahydroquinoxaline-2-carboxylate
(
1
5c): White solid (26.7 mg, 69%), m.p. 126–128.5 °C. H NMR Ethyl 1-(But-3-en-1-yl)-3-oxo-1,2,3,4-tetrahydroquinoxaline-2-carb-
1
(400 MHz, CDCl
3
): δ = 0.97 (q, J = 7.6 Hz, 3 H), 1.18 (dd, J =
oxylate (5i): Yellow solid (32.5 mg, 79%), m.p. 102.5–103.5 °C H
Eur. J. Org. Chem. 2015, 3327–3337
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3333

S. Miyamaru, K. Umezu, A. Ito, M. Shimizu
FULL PAPER
–
1
24 2 3
H N O
[M]+ 304.1787;
NMR (400 MHz, CDCl
3
): δ = 1.16 (dd, J = 7.1, 7.1 Hz, 3 H), 2.34–
746 cm . HRMS (EI): calcd. for C17
found 304.1793.
2.49 (m, 2 H), 3.24 (ddd, J = 14.2, 8.2, 6.3 Hz, 1 H), 3.65 (ddd, J
=
14.2, 8.2, 6.3 Hz, 1 H), 4.14 (dq, J = 7.1, 2.1 Hz, 2 H), 4.62 (s, 1
N-n-Propylation C-Ethylation of Ethyl 4-tert-Butoxycarbonyl-3-oxo-
,4-dihydroquinoxaline-2-carboxylate (4c): (Table 4, entry 3): Under
an argon atmosphere, a suspension of ethyl 4-tert-butoxycarbonyl-
H), 5.08 (dd, J = 10.3, 1.4 Hz, 1 H), 5.13 (dd, J = 17.2, 1.4 Hz, 1
H), 5.81 (dddd, J = 17.2, 10.3, 6.8, 6.7 Hz, 1 H), 6.79–6.68 (m, 3
H), 6.99–7.06 (m, 1 H), 8.71 (br. s, 1 H) ppm. 13C NMR (100 MHz,
3
3
0
-oxo-3,4-dihydroquinoxaline-2-carboxylate
.15 mmol) in EtCN (1.0 mL) was stirred at –78 °C for 5 min, and
(4c;
47.7 mg,
CDCl
3
): δ = 14.1, 31.2, 49.0, 62.0, 65.2, 112.6, 115.7, 117.1, 119.2,
24.5, 125.4, 133.5, 134.8, 162.5, 167.7 ppm. IR (neat): ν˜ = 3143,
081, 2980, 2919, 2872, 1742, 1701, 1652, 1506, 1433, 1384, 1252,
208, 1021, 780 cm . HRMS (EI): calcd. for C15
74.1317; found 274.1311.
1
3
1
2
nPrMgBr (1.02 n in THF; 0.22 mL, 0.45 mmol, 1.5 equiv.) was
added slowly. The mixture was stirred for 30 min, then TMSCl
–1
+
18 2 3
H N O [M]
(
0.06 mL, 0.45 mmol) was added at –78 °C. The mixture was stirred
for 10 min at –78 °C, then EtCN (1.0 mL) and NBS (66.7 mg,
Ethyl 1-[2-(1,3-Dioxan-2-yl)ethyl]-3-oxo-1,2,3,4-tetrahydroquinox- 0.38 mmol) were added at –78 °C. The mixture was stirred for
aline-2-carboxylate (5j): White solid (34.8 mg, 69%), m.p. 109– 10 min at –78 °C, then EtMgBr (0.98 n in THF; 0.31 mL,
1
1
3
3
4
(
(
10 °C. H NMR (400 MHz, CDCl
3
): δ = 1.18 (dd, J = 7.1, 7.1 Hz, 0.3 mmol, 2.0 equiv.) was added. The mixture was stirred for
30 min at –78 °C, then the reaction was quenched with satd. aq.
.32 (ddd, J = 14.6, 7.5, 7.4 Hz, 1 H), 3.68–3.78 (m, 3 H), 4.06– NaHCO (20 mL), and the mixture was extracted with ethyl acetate
.17 (m, 4 H), 4.60–4.62 (m, 2 H), 6.73–6.79 (m, 2 H), 6.82–6.84 (3ϫ 10 mL). The combined organic extracts were washed with
SO , and concentrated in vacuo.
H), 1.31–1.35 (m, 1 H), 1.82–1.90 (m, 1 H), 1.93–1.21 (m, 2 H),
3
m, 1 H), 6.99–7.03 (m, 1 H), 8.12 (br. s, 1 H) ppm. 1 C NMR brine, dried with anhydrous Na
100 MHz, CDCl
00.1, 112.7, 115.6, 119.0, 124.5, 125.2, 133.3, 162.1, 167.8 ppm.
IR (neat): ν˜ = 3196, 3077, 2966, 2853, 1730, 1686, 1509, 1438, 1360,
3
2
4
3
): δ = 14.1, 25.7, 32.4, 44.7, 62.0, 66.2, 66.9,
The crude product was purified by preparative silica gel TLC (n-
hexane/ethyl acetate, 7:3) to give 7a (9.7 mg, 22%) and 8c (14.0 mg,
24%).
1
–1
1
C
308, 1223, 1142, 1076, 744 cm . HRMS (EI): calcd. for
Ethyl 4-tert-Butoxycarbonyl-2-ethyl-3-oxo-1-propyl-3,4-dihydroquin-
+
17
H
22
N
2
O
5
[M] 334.1529; found 334.1543.
N-n-Propylation C-Ethylation of Ethyl 4-tert-Butoxycarbonyl-3-oxo-
,4-dihydroquinoxaline-2-carboxylate (4c): (Table 4, entry 1): Under 7.4 Hz, 3 H), 1.25 (dd, J = 7.1, 7.1 Hz, 3 H), 1.54–1.66 (m, 11 H),
1
oxaline-2-carboxylate (8c): Yellow oil.
CDCl
H NMR (400 MHz,
3
): δ = 0.91 (dd, J = 7.3, 7.3 Hz, 3 H), 0.97 (dd, J = 7.4,
3
an argon atmosphere, a suspension of ethyl 4-tert-butoxycarbonyl-
2.06 (dq, J = 15.1, 7.4, Hz, 1 H), 2.15 (dq, J = 15.1, 7.4 Hz, 1 H),
3
0
-oxo-3,4-dihydroquinoxaline-2-carboxylate
.15 mmol) in EtCN (1.0 mL) was stirred at –78 °C for 5 min, and
(4c;
47.7 mg,
2.94–3.08 (m, 2 H), 4.14–4.31 (m, 2 H), 6.44–6.46 (m, 1 H), 6.64–
6.67 (m, 1 H) ppm. C NMR (100 MHz, CDCl ): δ = 0, 11.2, 14.0,
3
1
3
then nPrMgBr (0.88 n in THF; 0.51 mL, 0.45 mmol, 3.0 equiv.) was
20.1, 26.4, 27.5, 47.5, 62.1, 69.7, 84.6, 109.4, 117.2, 127.7, 128.0,
added slowly. The mixture was stirred for 30 min, and then EtCN
128.7, 136.3, 148.1, 151.4, 168.8 ppm. IR (neat): ν˜ = 2979, 2878,
–
1
(1.0 mL) and NBS (66.7 mg, 0.38 mmol) were added at –78 °C. The
2769, 1744, 1686, 1506, 1462, 1370, 1294, 742 cm . HRMS (EI):
+
mixture was stirred for 10 min at –78 °C, and then EtMgBr (0.99 n
in THF; 0.45 mL, 0.45 mmol, 3.0 equiv.) was added. The mixture
was stirred for 30 min at –78 °C, then the reaction was quenched
30 2 5
calcd. for C21H N O [M] 390.2155; found 390.2149.
N-n-Propylation C-Ethylation of Ethyl 4-Acetyl-3-oxo-3,4-di-
hydroquinoxaline-2-carboxylate (4e): (Table 4, entry 4): Under an
argon atmosphere, a suspension of ethyl 4-acetyl-3-oxo-3,4-di-
hydroquinoxaline-2-carboxylate (4e; 39.0 mg, 0.15 mmol) in EtCN
with satd. aq. NaHCO
with ethyl acetate (3ϫ 10 mL). The combined extracts were washed
with brine, dried with anhydrous Na SO , and concentrated in
3
(20 mL), and the mixture was extracted
2
4
(
1.0 mL) was stirred at –78 °C for 5 min, and then nPrMgBr (1.02 n
vacuo. The crude product was purified on silica gel TLC (n-hexane/
ethyl acetate, 7:3) to give 7a (9.8 mg, 22%), 7j (8.1 mg, 17%), and
in THF; 0.22 mL, 0.45 mmol, 1.5 equiv.) was added slowly. The
mixture was stirred for 30 min, then TMSCl (0.06 mL, 0.45 mmol)
was added at –78 °C. The mixture was stirred for 10 min at –78 °C,
then EtCN (1.0 mL) and NBS (53.4 mg, 0.3 mmol) were added at
5c (1.2 mg, 3%).
Ethyl 2-Ethyl-3-oxo-1-propyl-1,2,3,4-tetrahydroquinoxaline-2-carb-
1
oxylate (7a): White crystals, m.p. 152.5–153.5 °C. H NMR –78 °C. The mixture was stirred for 10 min at –78 °C, then EtMgBr
400 MHz, CDCl ): δ = 0.93 (dd, J = 7.3, 7.3 Hz, 3 H), 0.94 (dd, (0.98 n in THF; 0.31 mL, 0.3 mmol, 2.0 equiv.) was added. The
J = 7.3, 7.3 Hz, 3 H), 1.14 (t, J = 7.1 Hz, 3 H), 1.57 (m, 2 H), 2.12 mixture was stirred for 30 min at –78 °C, then the reaction was
dq, J = 14.6, 7.3 Hz, 1 H), 2.47 (dq, J = 14.6, 7.3 Hz, 1 H), 3.01– quenched with satd. aq. NaHCO (20 mL), and the mixture was
.18 (m, 2 H), 4.16 (q, J = 7.1 Hz, 2 H), 6.56–6.58 (m, 1 H), 6.67– extracted with ethyl acetate (3ϫ 10 mL). The combined organic
(
3
(
3
3
7
.73 (m, 2 H), 6.94–6.98 (m, 1 H), 9.30 (br. s, 1 H) ppm. 1 C NMR
): δ = 8.2, 11.2, 13.9, 20.1, 26.1, 48.0, 61.8, 73.0,
11.4, 115.3, 117.9, 124.0, 124.3, 133.5, 165.8, 169.8 ppm. IR
3
2 4
extracts were washed with brine, dried with anhydrous Na SO ,
and concentrated in vacuo. The crude product was purified by pre-
parative silica gel TLC (n-hexane/ethyl acetate, 7:3) to give 7a
(100 MHz, CDCl
3
1
(
1
2
neat): ν˜ = 3190, 3053, 2979, 1878, 1738, 1677, 1510, 1438, 1408, (17.5 mg, 40%), 8e (3.2 mg, 6%), and 5c (4.3 mg, 11%).
–1
+
347, 1209, 747 cm . HRMS (EI): calcd. for C16
90.1630; found 290.1616.
22 2 3
H N O [M]
Ethyl 4-Acetyl-3-oxo-1,2-dipropyl-1,2,3,4-tetrahydroquinoxaline-2-
carboxylate (8e): Colourless oil. H NMR (400 MHz, CDCl ): δ =
3
1
Ethyl 3-Oxo-1,2-dipropyl-1,2,3,4-tetrahydroquinoxaline-2-carboxyl-
0.94 (dd, J = 7.3, 7.3 Hz, 3 H), 0.98 (dd, J = 7.3, 7.3 Hz, 3 H), 1.00
(dd, J = 7.3, 7.3 Hz, 3 H), 2.18 (dq, J = 14.8, 7.3 Hz, 1 H), 2.39
(dq, J = 148.8, 7.3 Hz, 1 H), 2.66 (s, 3 H), 3.10–3.26 (m, 2 H),
ate (7j): White solid, m.p. 120–120.8 °C. 1H NMR (400 MHz,
3
CDCl ): δ = 0.93 (dd, J = 6.9, 6.9 Hz, 3 H), 0.93 (t, J = 6.9, 6.9 Hz,
3
H), 1.14 (t, J = 7.3 Hz, 3 H), 1.35 (ddq, J = 12.6, 12.6, 6.8 Hz, 2 3.96–4.05 (m, 2 H), 6.85–6.93 (m, 2 H), 7.11–7.15 (m, 1 H), 7.39–
1
3
H), 1.62 (m, 2 H), 1.99–2.07 (m, 1 H), 2.35–2.43 (m, 1 H), 3.00– 7.41 (m, 1 H) ppm. C NMR (100 MHz, CDCl
3
): δ = 8.4, 11.3,
3
6
.17 (m, 2 H), 4.16 (q, J = 7.3 Hz, 2 H), 6.54–6.56 (m, 1 H), 6.66– 13.8, 20.7, 25.5, 27.7, 46.9, 61.6, 75.0, 115.2, 119.9, 122.6, 125.1,
.74 (m, 2 H), 6.93–6.98 (m, 1 H), 9.58 (br. s, 1 H) ppm. 1 C NMR
): δ = 11.2, 13.9, 14.1, 17.0, 20.1, 35.3, 48.1, 61.8,
2.6 111.2, 115.4, 117.8, 123.9, 124.3, 133.3, 166.0, 169.9 ppm. IR
3
126.1, 137.5, 169.5, 169.9, 172.3 ppm. IR (neat): ν˜ = 2962, 2933,
–
1
(100 MHz, CDCl
3
1874, 1737, 1723, 1797, 1499, 1460, 1366, 1247, 1185, 746 cm .
+
7
18 24 2 4
HRMS (EI): calcd. for C H N O [M] 332.1736; found
(neat): ν˜ = 3065, 2960, 2872, 1744, 1679, 1592, 1505, 1437, 1232, 332.1732.
3334
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 3327–3337

Synthesis of Multisubstituted Dihydroquinoxaline Derivatives
N-n-Propylation C-Ethylation of Ethyl 4-Acetyl-3-oxo-3,4-dihydro-
quinoxaline-2-carboxylate (4e): (Table 4, entry 9): Under an argon
NMR (100 MHz, CDCl
49.0, 61.7, 75.7, 111.2, 115.2, 117.7, 124.3, 124.4, 133.2, 164.7,
3
): δ = 11.1, 13.9, 18.1, 19.0, 19.9, 34.3,
atmosphere, a suspension of ethyl 4-acetyl-3-oxo-3,4-dihydroquin- 168.9 ppm. IR (neat): ν˜ = 3184, 3060, 2980, 2979, 1744, 1674, 1613,
–
1
oxaline-2-carboxylate (4e; 39.0 mg, 0.15 mmol) in EtCN (1.0 mL) 1505, 1435, 1387, 1348, 1236, 753 cm . HRMS (EI): calcd. for
+
was stirred at –78 °C for 5 min, and TMSCl (0.06 mL, 0.45 mmol)
was added at –78 °C. The mixture was stirred for 10 min, then
nPrMgBr (0.97 n in THF; 0.23 mL, 0.23 mmol, 1.5 equiv.) was
added slowly. The mixture was stirred for 30 min, then EtCN
C
17
H
24
N
2
O
3
[M] 304.1787; found 304.17822.
Ethyl 1-Ethyl-2-methyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-2-carb-
1
oxylate (7d): Yellow solid (22.7 mg, 58%), m.p. 97.5–98.0 °C.
NMR (400 MHz, CDCl ): δ = 1.17 (dd, J = 7.2, 7.2 Hz, 3 H), 1.22
t, J = 7.0 Hz, 3 H), 1.72 (s, 3 H), 3.23 (dq, J = 14.4, 7.2 Hz, 1 H),
.39 (dq, J = 14.4, 7.2 Hz, 1 H), 4.18 (q, J = 7.1 Hz, 2 H), 6.71–
.73 (m, 1 H), 6.76–6.77 (m, 2 H), 6.97–7.01 (m, 1 H), 9.00 (br. s,
H) ppm. C NMR (100 MHz, CDCl ): δ = 13.4, 14.0, 18.5, 40.7,
3
1.9, 68.8, 112.6, 115.5, 118.7, 124.2, 125.0, 133.0, 166.3,
70.2 ppm. IR (neat): ν˜ = 3195, 3064, 2989, 2933, 1736, 1677, 1508,
H
3
(1.0 mL) and NCS (48.1 mg, 0.36 mmol) were added at –78 °C. The
(
mixture was stirred for 10 min at –78 °C, then EtMgBr (0.86 n in
THF; 0.52 mL, 0.45 mmol, 3.0 equiv.) was added. The mixture was
stirred for 30 min at –78 °C, then the reaction was quenched with
3
6
1
6
1
1
13
satd. aq. NaHCO
ethyl acetate (3ϫ 10 mL). The combined organic extracts were
washed with brine, dried with anhydrous Na SO , and concen-
3
(20 mL), and the mixture was extracted with
2
4
–1
412, 1313, 1235, 1114, 738 cm . HRMS (EI): calcd. for
trated in vacuo. The crude product was purified by preparative sil-
+
C
14
H
18
N
2
O
3
[M] 262.1317; found 262.1312.
ica gel TLC (n-hexane/ethyl acetate, 7:3) to give 7a (32.5 mg, 75%)
1
Ethyl 1-Ethyl-3-oxo-2-propyl-1,2,3,4-tetrahydroquinoxaline-2-carb-
as white crystals, m.p. 152.5–153.5 °C. H NMR (400 MHz,
1
oxylate (7e): White solid (27.9 mg, 64%), m.p. 119–120 °C.
NMR (400 MHz, CDCl ): δ = 0.92 (dd, J = 7.3, 7.3 Hz, 3 H), 1.15
dd, J = 7.1, 7.1 Hz, 3 H), 1.19 (dd, J = 6.9, 6.9 Hz, 3 H), 1.29–
.43 (m, 2 H), 2.40 (ddd, J = 14.4, 11.3, 5.6 Hz, 1 H), 2.4 (ddd, J
= 14.3, 11.2, 5.6 Hz, 1 H), 3.18–3.36 (m, 2 H), 4.16 (dq, J = 7.1,
.1 Hz, 2 H), 6.63–6.71 (m, 3 H), 6.94–7.00 (m, 1 H), 9.02 (br. s, 1
H) ppm. C NMR (100 MHz, CDCl
6.3, 40.3, 61.8, 72.6, 111.3, 115.3, 117.8, 124.0, 124.3, 133.0, 165.8,
169.8 ppm. IR (neat): ν˜ = 3194, 3069, 2931, 2872, 1735, 1678, 1503,
H
CDCl
3
): δ = 0.93 (dd, J = 7.3, 7.3 Hz, 3 H), 0.94 (dd, J = 7.3,
7.3 Hz, 3 H), 1.14 (t, J = 7.1 Hz, 3 H), 1.57 (m, 2 H), 2.12 (dq, J
3
(
1
=
14.6, 7.3 Hz, 1 H), 2.47 (dq, J = 14.6, 7.3 Hz, 1 H), 3.01–3.18
(
(
(
1
(
m, 2 H), 4.16 (q, J = 7.1 Hz, 2 H), 6.56–6.58 (m, 1 H), 6.67–7.73
m, 2 H), 6.94–6.98 (m, 1 H), 9.30 (br. s, 1 H) ppm. 1 C NMR
100 MHz, CDCl ): δ = 8.2, 11.2, 13.9, 20.1, 26.1, 48.0, 61.8, 73.0,
11.4, 115.3, 117.9, 124.0, 124.3, 133.5, 165.8, 169.8 ppm. IR
neat): ν˜ = 3190, 3053, 2979, 1878, 1738, 1677, 1510, 1438, 1408,
3
1
3
1
3
3
): δ = 12.5, 14.0, 14.2, 17.0,
3
–1
+
1
2
347, 1209, 747 cm . HRMS (EI): calcd. for C16
90.1630; found 290.1616.
22 2 3
H N O [M]
–
1
1
460, 1301, 1221, 1183, 1021, 744 cm . HRMS (EI): calcd. for
+
16 22 2 3
C H N O [M] 290.1630; found 290.1636.
N-n-Propyl C-Methylation of Ethyl 4-Acetyl-3-oxo-3,4-dihydroquin-
oxaline-2-carboxylate (4e): (Table 5, entry 2): Under an argon at-
mosphere, a suspension of ethyl 4-acetyl-3-oxo-3,4-dihydroquinox-
alin-2-carboxylate (4e; 39.0 mg, 0.15 mmol) in EtCN (1.0 mL) was
stirred at –78 °C for 5 min, and TMSCl (0.06 mL, 0.45 mmol) was
added at –78 °C. The mixture was stirred for 10 min, then nPrMgBr
Ethyl 2-[2-(1,3-Dioxan-2-yl)ethyl]-1-ethyl-1,2,3,4-tetrahydro-quinox-
aline-2-carboxylate (7f): White solid (21.5 mg, 40%), m.p. 127.5–
1
1
7
1
3
28.5 °C. H NMR (400 MHz, CDCl
3
): δ = 1.15 (dd, J = 7.1,
.1 Hz, 3 H), 1.20 (t, J = 7.0 Hz, 3 H), 1.29–1.32 (m, 1 H), 1.58–
.73 (m, 2 H), 1.98–2.10 (m, 1 H), 3.24 (dq, J = 15.2, 7.3 Hz, 1 H),
.35 (dq, J = 15.4, 7.3 Hz, 1 H), 3.73 (t, J = 12.4 Hz, 2 H), 4.06
(
1.08 n in THF; 0.21 mL, 0.23 mmol, 1.5 equiv.) was added slowly.
The mixture was stirred for 30 min, then EtCN (1.0 mL) and NCS
48.1 mg, 0.36 mmol) were added at –78 °C. The mixture was
stirred for 10 min at –78 °C, then MeMgBr (1.08 n in THF;
.49 mL, 0.45 mmol, 3.0 equiv.) was added. The mixture was stirred
for 30 min at –78 °C, then the reaction was quenched with satd.
aq. NaHCO (20 mL), and the mixture was extracted with ethyl
acetate (3ϫ 10 mL). The combined organic extracts were washed
with brine, dried with anhydrous Na SO , and concentrated in
vacuo. The crude product was purified by preparative silica gel
TLC (n-hexane/ethyl acetate, 7:3) to give ethyl 2-methyl-3-oxo-1- aline-2-carboxylate (7g): Yellow solid (30.0 mg, 67%), m.p. 96.5–
(
(
(
ddd, J = 11.3, 10.5, 4.9 Hz, 2 H), 4.15 (q, J = 7.0 Hz, 2 H), 4.54
dd, J = 6.0 Hz, 1 H), 6.64–6.71 (m, 3 H), 6.94–6.98 (m, 1 H), 8.36
(
1
3
br. s, 1 H) ppm. C NMR (100 MHz, CDCl
3
): δ = 12.4, 13.9,
2
1
2
1
5.7, 27.4, 29.4, 40.2, 61.8, 66.8, 66.8, 72.2, 101.8, 111.6, 115.3,
17.9, 124.0, 124.3, 132.9, 165.3, 169.7 ppm. IR (neat): ν˜ = 3204,
0
983, 2853, 1741, 1687, 1508, 1447, 1395, 1334, 1313, 1245, 1141,
3
–
1
+
26 2 5
110, 749 cm . HRMS (EI): calcd. for C19H N O [M] 362.1842;
found 362.1856.
2
4
Ethyl 1-(But-3-en-1-yl)-3-oxo-2-vinyl-1,2,3,4-tetrahydro-quinox-
1
propyl-1,2,3,4-tetrahydroquinoxaline-2-carboxylate (7b; 27.4 mg,
97.5 °C. H NMR (400 MHz, CDCl ): δ = 1.22 (dd, J = 7.2, 7.2 Hz,
3
6
6%) as a white solid, m.p. 143.5–146 °C. 1H NMR (400 MHz,
3 H), 2.28–2.46 (m, 2 H), 3.22 (ddd, J = 15.2, 9.9, 5.1 Hz, 1 H),
CDCl
3
): δ = 0.93 (t, J = 7.6 Hz, 3 H), 1.15 (t, J = 7.2 Hz, 3 H), 3.51 (ddd, J = 15.2, 9.9, 6.0 Hz, 1 H), 4.24 (dq, J = 7.2, 4.8 Hz, 2
1
7
1
=
.59–1.69 (m, 2 H), 1.73 (s, 3 H), 3.09–3.27 (m, 2 H), 4.16 (q, J =
H), 5.06–5.11 (m, 2 H), 5.24 (d, J = 17.8 Hz, 1 H), 5.48 (d, J =
.2 Hz, 2 H), 6.69–6.67 (m, 1 H), 6.76–6.77 (m, 2 H), 6.96–7.02 (m, 10.7 Hz, 1 H), 5.79 (dddd, J = 17.1, 10.5, 6.8, 6.8 Hz, 1 H), 6.22
13
H), 7.26 8.97 (br. s, 1 H) ppm. C NMR (100 MHz, CDCl
3
): δ
(dd, J = 17.8, 10.7 Hz, 1 H), 6.74–6.80 (m, 3 H), 7.00–7.05 (m, 1
1
3
11.2, 13.9, 18.6, 20.9, 47.9, 61.8, 68.7, 112.8, 115.6, 118.9, 124.1, H), 9.05 (br. s, 1 H) ppm. C NMR (100 MHz, CDCl ): δ = 14.0,
3
1
25.1, 133.4, 166.5, 170.2 ppm. IR (neat): ν˜ = 3191, 2984, 2877, 31.7, 46.9, 62.2, 74.4, 112.3, 115.8, 116.7, 119.1, 119.6, 124.5, 124.6,
–1
1740, 1675, 1617, 1444, 1353, 748 cm . HRMS (EI): calcd. for 132.9, 133.2, 134.9, 164.3, 168.8 ppm. IR (neat): ν˜ = 3204, 3079,
+
–1
C
15
H
20
N
2
O
3
[M] 276.1474; found 276.1469.
2981, 2871, 1730, 1694, 1643, 1503, 1450, 1385, 917, 749 cm .
+
HRMS (EI): calcd. for
00.1460.
C
17
H
20
N
2
O
3
[M] 300.1474; found
Ethyl 2-Isopropyl-3-oxo-1-propyl-1,2,3,4-tetrahydroquinoxaline-2-
3
carboxylate (7c): White crystals (18.3 mg, 40%), m.p. 148–149 °C.
1
H NMR (400 MHz, CDCl
3
): δ = 0.90 (dd, J = 7.6, 7.6 Hz, 3 H),
.96 (d, J = 6.9 Hz, 3 H), 1.10 (d, J = 6.9 Hz, 3 H), 1.24 (dd, J =
Ethyl 2-Allyl-1-(but-3-en-1-yl)-3-oxo-1,2,3,4-tetrahydro-quinoxaline-
2-carboxylate (7h): Yellow oil (32.3 mg, 68%). H NMR (400 MHz,
1
0
7
6
.1 Hz, 3 H), 1.45–1.58 (m, 2 H), 1.67–1.78 (m, 1 H), 2.63 (q, J = CDCl
.9 Hz, 1 H), 2.99 (ddd, J = 15.2, 11.4, 5.0 Hz, 1 H), 3.33 (ddd, J
15.2, 10.7, 5.0 Hz, 1 H), 4.20–4.29 (m, 2 H), 6.56–6.58 (m, 1 H),
3
): δ = 1.17 (t, J = 7.1 Hz, 3 H), 2.29–2.44 (m, 2 H), 2.87 (dd,
J = 15.1, 7.5 Hz, 1 H), 3.14–3.22 (m, 2 H), 3.36 (ddd, J = 15.2,
10.1, 5.5 Hz, 1 H), 4.12 (q, J = 7.1 Hz, 2 H), 5.04 (d, J = 10.0 Hz,
1 H), 5.09 (dd, J = 9.6, 1.4 Hz, 1 H), 5.12 (dd, J = 15.6, 1.4 Hz, 1
=
1
3
6.65–6.71 (m, 2 H), 6.93–6.98 (m, 1 H), 9.14 (br. s, 1 H) ppm.
C
Eur. J. Org. Chem. 2015, 3327–3337
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3335

S. Miyamaru, K. Umezu, A. Ito, M. Shimizu
FULL PAPER
H), 5.16 (dd, J = 16.8, 1.6 Hz, 1 H), 5.71–5.84 (m, 2 H), 6.61–6.64
71.4, 112.7, 115.2, 118.3, 124.3, 127.9, 132.2, 133.9, 166.4,
(
m, 1 H), 6.71–6.76 (m, 2 H), 6.96–7.00 (m, 1 H), 8.65 (br. s, 1 H) 168.3 ppm. IR (neat): ν˜ = 3185, 3072, 2973, 2951, 1750, 1679, 1506,
13
–1
ppm. C NMR (100 MHz, CDCl
3
): δ = 13.9, 31.2, 37.2, 45.8, 62.0,
2.4, 111.8, 115.5, 116.7, 118.5, 119.5, 124.3, 124.4, 131.8, 132.9,
34.7, 165.36, 169.3 ppm. IR (neat): ν˜ = 3208, 3078, 2980, 2913,
1436, 1376, 1181, 749 cm . HRMS (EI): calcd. for C17
[M] 300.1474; found 300.1468.
H
20
N
2
O
3
+
7
1
1
Hydrogenation of Ethyl 6-Oxo-5,6,9,10-tetrahydro-6aH-pyrido[1,2-
a]quinoxaline-6a-carboxylate (9g): (Table 6 structure): A suspension
of ethyl 6-oxo-5,6,9,10-tetrahydro-6aH-pyrido[1,2-a]quinoxaline-
–1
741, 1684, 1640, 1612, 1507, 1434, 1230, 917, 744 cm . HRMS
+
(
22 2 3
EI): calcd. for C18H N O [M] 314.1630; found 314.1624.
6
2
a-carboxylate (9g; 12.8 mg, 0.05 mmol) and Pd(OH) /C (20 wt.-
Ethyl 1,2-Di(but-3-en-1-yl)-3-oxo-1,2,3,4-tetrahydro-quinoxaline-2-
carboxylate (7i): Yellow solid (32.3 mg, 66%), m.p. 96–97 °C. H
1
%; 1.4 mg, 2.0 μmol) in EtOH (5 mL) was stirred at room tempera-
ture. The reaction mixture was stirred under a hydrogen atmo-
sphere at room temperature for 1 h. The mixture was then filtered
through a pad of Celite, and concentrated in vacuo to give ethyl 6-
oxo-5,6,7,8,9,10-hexahydro-6aH-pyrido[1,2-a]quinoxaline-6a-carb-
NMR (400 MHz, CDCl
H), 2.31 (m, 2 H), 2.49, 2.57 (m, 1 H), 3.15–3.32 (m, 2 H), 4.17
q, J = 7.1 Hz, 2 H), 4.95 (d, J = 10.1 Hz, 1 H), 4.99 (dd, J = 17.0,
3
): δ = 1.16 (t, J = 7.1 Hz, 3 H), 2.11 (m,
3
(
1
6
1
4
1
2
7
.4 Hz, 1 H), 5.11 (d, J = 17.0, 1.4 Hz, 1 H), 5.75 (m, 2 H), 6.62–
oxylate (10g; 12.5 mg, 91%) as a yellow solid, m.p. 160.5–161.5 °C.
.64 (m, 1 H), 6.69–6.76 (m, 2 H), 6.97–7.02 (m, 1 H), 8.65 (br. s,
1
H) ppm. 13C NMR (100 MHz, CDCl
H NMR (400 MHz, CDCl ): δ = 1.08 (dd, J = 7.1, 7.1 Hz, 3 H),
3
): δ = 14.0, 27.9, 31.2, 32.1,
3
1.46–1.71 (m, 2 H), 1.83–2.07 (m, 3 H), 2.64–2.68 (m, 1 H), 3.29–
5.6, 62.0, 72.3, 111.6, 115.6, 115.4, 117.0, 118.3, 124.0, 124.4,
32.9, 134.6, 137.1, 165.4, 169.5 ppm. IR (neat): ν˜ = 3202, 3078,
981, 2923, 2868, 1729, 1695, 1503, 1431, 1385, 1303, 1256, 917,
3.36 (m, 1 H), 3.50–3.53 (m, 1 H), 3.98–4.401 (m, 2 H), 6.76–6.86 (3
1
3
H), 7.00–7.04 (m, 1 H), 8.68 (br. s, 1 H) ppm. C NMR (100 MHz,
CDCl ): δ = 14.0, 19.8, 24.2, 44.3, 61.5, 65.9, 112.8, 115.2, 119.7,
–1
+
48 cm . HRMS (EI): calcd. for C19
H
24
N
2
O
3
[M] 328.1787;
3
1
3
7
24.2, 125.3, 136.5, 165.5, 165.5, 169.6 ppm. IR (neat): ν˜ = 3192,
074, 2981, 2860, 1737, 1687, 1591, 1507, 1383, 1209, 958,
48 cm . HRMS (EI): calcd. for C15H N O [M] 274.1317;
18 2 3
found 328.1800.
RCM Reaction of Ethyl 1-(But-3-en-1-yl)-3-oxo-2-vinyl-1,2,3,4-
tetrahydroquinoxaline-2-carboxylate (7g): (Table 6, entry 3 and
structure): Under an argon atmosphere, a suspension of ethyl 1-
–1
+
found 274.1316.
(but-3-en-1-yl)-3-oxo-2-vinyl-1,2,3,4-tetrahydroquinoxaline-2-carb-
oxylate (7g; 23.9 mg, 0.08 mmol) in toluene (4.5 mL) was stirred at Acknowledgments
room temperature. A solution of Hoveyda–Grubbs second-genera-
This work was supported by Grant-in-Aid for Scientific Research
B) and on Innovative Areas “Organic Synthesis Based on Reaction
Integration, Development of New Methods and Creation of New
Substances” from the Japan Society for the Promotion of Science
and the Ministry of Education, Culture, Sports, Science, and Tech-
nology (MEXT).
tion catalyst (2.0 mg, 3.2 μmmol) in toluene (2.0 mL) was added.
The mixture was stirred for 3 h at room temperature, then it was
filtered through a pad of Celite, and concentrated in vacuo. The
crude product was purified by preparative silica gel TLC (toluene/
ethyl acetate, 20:1) to give ethyl 6-oxo-5,6,9,10-tetrahydro-6aH-pyr-
(
ido[1,2-a]quinoxaline-6a-carboxylate (9g; 18.2 mg, 84%) as a white
1
solid, m.p. 186.5–187.2 °C. H NMR (400 MHz, CDCl
3
): δ = 1.07
(
2
dd, J = 7.1, 7.1 Hz, 3 H), 2.28 (ddd, J = 17.7, 5.1, 5.1 Hz, 1 H),
.40–2.50 (m, 1 H), 3.59 (ddd, J = 11.2, 11.2, 4.5 Hz, 1 H), 3.69
[1] a) S. X. Cai, S. M. Kher, Z.-L. Zhou, V. Ilyin, S. A. Espitia,
M. Tran, J. E. Hawkinson, R. M. Woodward, E. Weber, J. F. W.
Keana, J. Med. Chem. 1997, 40, 730–738; b) M. Patel, R. J.
McHugh, B. C. Cordova, R. M. Klabe, S. Erickson-Viitanen,
G. L. Trainor, J. D. Rodgers, Bioorg. Med. Chem. Lett. 2000,
(dd, J = 11.3, 4.5 Hz, 1 H), 3.96–4.11 (m, 2 H), 6.20 (ddd, J = 10.2,
5
.9, 2.1 Hz, 1 H), 6.32 (dd, J = 10.2, 5.9, 2.1 Hz, 1 H), 6.79–6.93
m, 3 H), 7.04–7.08 (m, 1 H), 8.24 (br. s, 1 H) ppm. 1 C NMR
3
(
(
1
0, 1729–1731; c) L. M. Cass, K. H. P. Moore, N. S. Dallow,
A. E. Jones, J. R. Sisson, W. T. Prince, J. Clin. Pharmacol. 2001,
0, 528–538; d) D.-S. Su, M. K. Markowitz, R. M. DiPardo,
100 MHz, CDCl
20.0, 121.8, 124.2, 125.8, 128.2, 136.0, 164.4, 168.8 ppm. IR
neat): ν˜ = 3192, 3061, 2989, 2924, 2859, 1738, 1683, 1612, 1503,
3
): δ = 14.0, 24.0, 40.0, 61.8, 65.5, 113.0, 115.7,
1
(
1
K. L. Murphy, C. M. Harrell, S. S. O’Malley, R. W. Ransom,
R. S. L. Chang, S. Ha, F. J. Hess, D. J. Pettibone, G. S. Masson,
S. Boyce, R. M. Freidinger, M. G. Bock, J. Am. Chem. Soc.
–1
1
463, 1366, 1503, 1463, 1366, 1214, 754 cm . HRMS (EI): calcd.
+
16 2 3
for C15H N O [M] 272.1161; found 272.1155.
2
003, 125, 7516–7517; e) L. A. Cruz, E. Estébanez-Perpiña, S.
Ethyl 6-Oxo-5,6,10,11-tetrahydroazepino[1,2-a]quinoxaline-6a(7H)-
carboxylate (9h): White solid (19.7 mg, 76%), m.p. 165–166 °C. H
Pfaff, S. Borngraeber, N. Bao, J. Blethrow, R. J. Fletterick,
P. M. England, J. Med. Chem. 2008, 51, 5856–5860; f) P. E.
Mahaney, M. B. Webb, F. Ye, J. P. Sabatucci, R. J. Steffan,
C. C. Chadwick, D. C. Harnish, E. J. Trybulski, Bioorg. Med.
Chem. 2006, 14, 3455–3466; g) D. V. Smil, S. Manku, Y. A.
Chantigny, S. Leit, A. Wahhab, T. P. Yan, M. Fournel, C. Mar-
oun, Z. Li, A.-M. Lemieuz, A. Nicolescu, J. Rahil, S. Lefebvre,
A. Panetta, J. M. Besterman, R. Déziel, Bioorg. Med. Chem.
Lett. 2009, 19, 688–692.
1
NMR (400 MHz, CDCl
3
): δ = 1.10 (dd, J = 7.1, 7.1 Hz, 3 H), 2.40–
.54 (m, 2 H), 3.06–3.22 (m, 2 H), 3.83 (ddd, J = 8.9, 3.6, 3.6 Hz,
H), 3.94–4.01 (m, 2 H), 4.02–4.14 (m, 2 H), 6.72–6.78 (m, 2 H),
2
1
6
1
3
.89–6.91 (m, 1 H), 6.99–7.03 (m, 1 H), 8.22 (br. s, 1 H) ppm.
): δ = 14.0, 29.8, 30.6, 43.4, 61.7, 72.5,
13.3, 115.7, 118.7, 123.4, 124.3, 125.1, 131.3, 134.6, 163.8,
70.1 ppm. IR (neat): ν˜ = 3185, 3072, 2973, 2951, 1750, 1679, 1506,
C
NMR (100 MHz, CDCl
3
1
1
1
[
[
[
[
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18 2 3
436, 1376, 1181, 749 cm . HRMS (EI): calcd. for C16H N O
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[M] 286.1317; found 286.1301.
Ethyl
6-Oxo-5,6,7,8,11,12-hexahydro-6aH-azocino[1,2-a]quinox-
aline-6a-carboxylate (9i): White solid (17.0 mg, 70%), m.p. 100–
1
1
2
2
3
01 °C. H NMR (400 MHz, CDCl ): δ = 1.27 (t, J = 7.1 Hz, 3 H),
.04 (ddd, J = 10.8, 10.9, 6.1 Hz, 1 H), 2.20–2.27 (m, 3 H), 2.46–
.57 (m, 1 H), 3.52 (ddd, J = 16.1, 6.9, 3.5 Hz, 1 H), 3.72 (ddd, J
=
2
15.9, 6.7, 3.5 Hz, 1 H), 4.28 (q, J = 7.1 Hz, 2 H), 5.65–5.75 (m,
H), 6.70–6.79 (m, 3 H), 6.97–7.01 (m, 1 H), 8.71 (br. s, 1 H) ppm.
1
3
C NMR (100 MHz, CDCl
3
): δ = 14.0, 22.9, 26.4, 34.0, 47.7, 62.0,
3336
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 3327–3337

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Published Online: April 7, 2015
Eur. J. Org. Chem. 2015, 3327–3337
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3337